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12592607

The distal arthrogryposes (DAs) are a group of disorders characterized by multiple congenital contractures of the limbs. We previously mapped a locus for DA type 2B (DA2B), the most common of the DAs, to chromosome 11. We now report that DA2B is caused by mutations in TNNI2 that are predicted to disrupt the carboxy-terminal domain of an isoform of troponin I (TnI) specific to the troponin-tropomyosin (Tc-Tm) complex of fast-twitch myofibers. Because the DAs are genetically heterogeneous, we sought additional candidate genes by examining modifiers of mutant Drosophila isoforms of TnI. One of these modifiers, Tm2, encodes tropomyosin, another component of the Tc-Tm complex. A human homologue of Tm2, TPM2, encodes beta-tropomyosin and maps to the critical interval of DA type 1 (DA1). We discovered that DA1 is caused by substitution of a highly conserved amino acid residue in beta-tropomyosin. These findings suggest that DAs, in general, may be caused by mutations in genes encoding proteins of the contractile apparatus specific to fast-twitch myofibers. This provides a new opportunity to directly study the etiology and pathogenesis of multiple-congenital-contracture syndromes.

4 25 distal arthrogryposes HP:0005684 74 106 multiple congenital contractures HP:0005188 94 119 contractures of the limbs HP:0003121 478 491 heterogeneous HP:0001425 1149 1180 multiple-congenital-contracture HP:0005188

4006277

Branchio-oto-renal (BOR) syndrome is a developmental complex presenting with various combinations of ear pits, branchial cleft cysts, deafness and renal anomalies, which is inherited as an autosomal dominant trait. This report describes a father and 2 children with BOR syndrome in which gustatory lacrimation (GL) was also present in 2 of them. GL is considered to be a rare, non-hereditary type of anomalous, cranial nerve-end organ innervation. Since lacrimal stenosis, which can clinically mimic GL, is also a feature of the BOR syndrome, future reports require lacrimal reflex testing and duct patency evaluation to define this variation in the BOR phenotype.

101 109 ear pits HP:0004467 111 132 branchial cleft cysts HP:0009796 134 142 deafness HP:0000404 147 162 renal anomalies HP:0000077 189 213 autosomal dominant trait HP:0000006 288 309 gustatory lacrimation HP:0100274 411 446 cranial nerve-end organ innervation HP:0001291 454 471 lacrimal stenosis HP:0007925

9321755

DNA mapping studies in two families provide further information on the Angelman syndrome critical region, which has recently been defined by the gene UBE3A. The first family has probable familial Angelman syndrome with a maternally imprinted inheritance pattern. A 5 year old girl with this disorder has a 14 year old brother and an 11 year old male cousin who have less typical clinical features. DNA microsatellite analysis has shown that the three share a common segment of the same grandpaternal chromosome 15q11-q13 that overlaps with UBE3A. The child with typical Angelman syndrome has an additional maternal recombination 5' to UBE3A. The second family is a mother and son both of whom have mental retardation but no other features of Angelman syndrome despite an extensive DNA deletion on the telomeric side of UBE3A. Together, the two families identify a region between loci D15S210 and D15S986 which forms part of the Angelman syndrome critical region. A new microsatellite (D15S1234) is described which can be used in place of the LS6-1 marker at locus D15S113.

698 716 mental retardation HP:0001249

8832722

A young male infant was noted at birth to have bilateral cleft lip and palate, bilateral microphthalmos and ocular colobomata, and a dysplastic left kidney. His mother had similar ophthalmological findings and milder facial anomalies which included abnormality of the philtrum and bilateral congenital nasolacrimal duct obstruction. His maternal grandmother had mild facial anomalies including a short philtrum and bilateral congenital nasolacrimal duct obstruction but had no evidence of any ocular abnormalities. The spectrum of abnormalities seen in this family are similar to those described in the branchio-oculo-facial syndrome, a rare dominantly inherited syndrome in which there are a number of developmental abnormalities of the eye, face, and kidney. Although the precise cause of this syndrome is unknown, it is likely to be caused by mutations in a gene responsible for the ordered closure of the foetal fissure and fusion of facial structures.

2 7 young HP:0003593 47 66 bilateral cleft lip HP:0100336 47 77 bilateral cleft lip and palate HP:0002744 57 77 cleft lip and palate HP:0000175 79 103 bilateral microphthalmos HP:0007633 108 125 ocular colobomata HP:0007995 133 155 dysplastic left kidney HP:0004741 180 205 ophthalmological findings HP:0000478 210 233 milder facial anomalies HP:0004675 249 276 abnormality of the philtrum HP:0000288 281 331 bilateral congenital nasolacrimal duct obstruction HP:0007669 362 383 mild facial anomalies HP:0004675 396 410 short philtrum HP:0000322 415 465 bilateral congenital nasolacrimal duct obstruction HP:0007669 493 513 ocular abnormalities HP:0000284 642 662 dominantly inherited HP:0000006 703 730 developmental abnormalities HP:0001263 717 741 abnormalities of the eye HP:0000478

1363801

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct mental retardation disorders associated with deletions of proximal 15q (q11-q13) of different parental origin. Yeast artificial chromosome (YAC) clones were isolated for 9 previously mapped DNA probes from this region, and for one newly derived marker, LS6-1 (D15S113). A YAC contig of 1-1.5 Mb encompassing four markers (ML34, IR4-3R, PW71, and TD189-1) was constructed. Multi-color fluorescence in situ hybridization (FISH) analysis of interphase nuclei was combined with YAC contig information to provide the following order of markers: cen-IR39-ML34-IR4-3R-PW71-TD189-1-LS6++ +-1-TD3-21-GABRB3-IR10-1-CMW1-tel. FISH analysis was performed on 8 cases of PWS and 3 cases of AS, including 5 patients with normal karyotypes. All eleven patients were deleted for YACs in the interval from IR4-3R to GABRB3. On the proximal side of the deletion interval, 10/10 breakpoints fell within a single ML34 YAC of 370 kb. On the distal side, 8/9 breakpoints fell within a single IR10-1 YAC of 200 kb. These results indicate a striking consistency in the location of the proximal and distal breakpoints in PWS and AS patients. FISH analysis on a previously reported case of familial AS confirmed a submicroscopic deletion including YACs corresponding to LS6-1, TD3-21 and GABRB3 and supports the separation of the PWS and AS critical regions. Since these three YACs do not overlap each other, the minimum size of the AS critical region is > or = 650 kb.

68 86 mental retardation HP:0001249 1231 1242 familial AS HP:0000005

10631923

Townes-Brocks syndrome (TBS) has been recognized as a dominant inherited syndrome. We report 2 cases of TBS. Case 1 was operated on for imperforate anus. Triphalangeal thumb and ear anomalies were remarkable. Deafness was diagnosed when the patient was 6 months old. Anomalies of the semicircular canals and the incus with inculomalleolar fusion were shown when the patient was 3.5 years old. During childhood, recurrent episodes of abdominal pain appeared. The diagnosis of hereditary angioneurotic edema (HANE) was made. HANE was familial as the father, the father's brother and the paternal grand mother were also affected. The parents of case 2, a female, are both mildly mentally retarded. This was the first pregnancy of the mother who had short stature. The child had an antepositioned anus, bifid right thumb, large toes, low set ears, microretrognathia and deafness. A (5, 16) translocation was observed in a child with TBS. At the breakpoint in 16q21.1, a gene coding for a transcription factor SALL1 has been identified and it was shown that mutations in the putative zinc finger of SALL1 cause TBS.

54 72 dominant inherited HP:0000006 136 152 imperforate anus HP:0002023 154 173 Triphalangeal thumb HP:0001199 178 191 ear anomalies HP:0000598 209 217 Deafness HP:0000404 267 303 Anomalies of the semicircular canals HP:0011380 267 317 Anomalies of the semicircular canals and the incus HP:0011453 323 345 inculomalleolar fusion HP:0005473 400 409 childhood HP:0011463 421 447 episodes of abdominal pain HP:0002574 500 505 edema HP:0000969 669 693 mildly mentally retarded HP:0001256 746 759 short stature HP:0004322 778 797 antepositioned anus HP:0001545 799 816 bifid right thumb HP:0009944 818 828 large toes HP:0010511 830 842 low set ears HP:0000369 844 861 microretrognathia HP:0000308 866 874 deafness HP:0000404

7977374

Club foot is one of the most common human congenital malformations. Distal arthrogryposis type I (DA-1) is a frequent cause of dominantly inherited club foot. Performing a genomewide search using short tandem repeat (STR) polymorphisms, we have mapped a DA-1 gene to the pericentromeric region of chromosome 9 in a large kindred. Linkage analysis has generated a positive lod score of 5.90 at theta = 0, with the marker GS-4. Multiple recombinants bracketing the region have been identified. Analysis of an additional family demonstrated no linkage to the same locus, indicating likely locus heterogeneity. Of the autosomal congenital contracture disorders causing positional foot deformities, this is the first to be mapped.

0 9 Club foot HP:0001762 68 89 Distal arthrogryposis HP:0005684 127 147 dominantly inherited HP:0000006 148 157 club foot HP:0001762 586 605 locus heterogeneity HP:0001425 624 646 congenital contracture HP:0002803 665 692 positional foot deformities HP:0005656

3321989

We report on two sibs with Angelman "happy puppet" syndrome. Out of 48 families reported in the literature, this is only the fourth family with affected sibs. A review of the literature shows a low but not negligible recurrence risk. Different explanations for this are discussed.

37 49 happy puppet HP:0100024

8669439

The Townes-Brocks syndrome (TBS) is comprised of a triad including characteristic anal, thumb, and ear anomalies. There are many other organ system abnormalities which may be present. However, the literature does not emphasize craniofacial findings except with reference to the typical ear configuration. A three-generation family is described in which craniofacial manifestations were prominent and a Goldenhar-like condition was considered as the most likely diagnosis. However, with the recent birth of an affected male who had an imperforate anus, the diagnosis of TBS was also considered. The family manifests a variety of Goldenhar-like findings, including epibulbar dermoids, hemifacial microsomia, preauricular tags, macrostomia, and micrognathia in addition to classical ear, radial, and anal findings of TBS. We report on this family to point out a possible biological relationship of these two conditions.

82 112 anal, thumb, and ear anomalies HP:0004378 88 112 thumb, and ear anomalies HP:0001172 99 112 ear anomalies HP:0000598 135 161 organ system abnormalities HP:0000118 227 248 craniofacial findings HP:0000271 278 303 typical ear configuration HP:0000598 353 380 craniofacial manifestations HP:0000271 534 550 imperforate anus HP:0002023 663 681 epibulbar dermoids HP:0001140 683 704 hemifacial microsomia HP:0000271 706 723 preauricular tags HP:0000384 725 736 macrostomia HP:0000181 742 754 micrognathia HP:0000347 780 810 ear, radial, and anal findings HP:0000598 785 810 radial, and anal findings HP:0002818 797 810 anal findings HP:0004378

10771486

Schwannomas in the skin are frequently observed in neurofibromatosis 2 patients. In about one-quarter of the cases, skin tumors are the first clinical symptoms of this disease. Recognizing neurofibromatosis-2-related skin tumors is therefore important for early diagnosis of neurofibromatosis 2, especially in pediatric patients. In this study, we examined 40 skin tumors (36 schwannomas and four neurofibromas) from 20 neurofibromatosis 2 patients for NF2 mutations and allelic loss. NF2 mutations have been identified in blood from 15 (75%) of the 20 patients. We found NF2 mutations in five (13%) and NF2 allelic loss in 18 (45%) of the 40 analyzed tumors. Genetic alterations (allelic loss or mutation) were thus found in 50 (63%) out of the total of 80 examined alleles. In 17 (43%) tumors, alterations were found on both NF2 alleles. These results suggest that, as in the case of vestibular schwannomas and meningiomas, loss of functional NF2 gene product is also the critical event in the development of skin schwannomas. Identification of genetic alterations of the NF2 gene in skin tumors may help to identify neurofibromatosis-2-associated skin tumors, thus assisting in the diagnosis of neurofibromatosis 2 in ambiguous cases, and excluding neurofibromatosis 1 in unclear cases. We also report that the detection rate of constitutional mutations was higher in patients with skin tumors (65%) than in patients without skin tumors (40%).

0 23 Schwannomas in the skin HP:0009593 51 68 neurofibromatosis HP:0006746 116 127 skin tumors HP:0008069 189 206 neurofibromatosis HP:0006746 217 228 skin tumors HP:0008069 275 292 neurofibromatosis HP:0006746 360 371 skin tumors HP:0008069 376 387 schwannomas HP:0100008 397 410 neurofibromas HP:0001067 420 437 neurofibromatosis HP:0006746 652 658 tumors HP:0002664 788 794 tumors HP:0002664 886 908 vestibular schwannomas HP:0009588 913 924 meningiomas HP:0002858 1011 1027 skin schwannomas HP:0009593 1086 1097 skin tumors HP:0008069 1119 1136 neurofibromatosis HP:0006746 1150 1161 skin tumors HP:0008069 1198 1215 neurofibromatosis HP:0006746 1252 1269 neurofibromatosis HP:0006746 1385 1396 skin tumors HP:0008069 1428 1439 skin tumors HP:0008069

8352281

Nevoid basal cell carcinoma syndrome (NBCCS; basal cell nevus syndrome or Gorlin syndrome) is a cancer-predisposition syndrome characterized by multiple basal cell carcinomas (BCCs) and diverse developmental defects. The gene for NBCCS has been mapped to 9q23.1-q31 in North American and European families. In addition, loss of heterozygosity (LOH) for genetic markers in this region has been detected in sporadic BCCs, indicating that the NBCCS gene is probably a tumor-suppressor gene. In this study we have determined that the NBCCS gene is also linked to this region in Australasian pedigrees and that there is no significant evidence of heterogeneity. We have defined the localization of the gene by multipoint and haplotype analysis of 15 families, using four microsatellite markers. LOH at these loci was detected in 50% of sporadic BCCs, a rate that is significantly higher than that in other skin lesions used as controls.

7 27 basal cell carcinoma HP:0002671 45 70 basal cell nevus syndrome HP:0002671 96 102 cancer HP:0002664 153 174 basal cell carcinomas HP:0002671 194 215 developmental defects HP:0001263 405 413 sporadic HP:0003745 465 470 tumor HP:0002664 642 655 heterogeneity HP:0001425 831 839 sporadic HP:0003745 901 913 skin lesions HP:0011355

2354548

A father and son are described with an autosomal dominant branchial cleft syndrome resembling both the branchio-oto-renal and the branchio-oculo-facial syndrome. Both syndromes may represent variant expressions of the same autosomal dominant gene.

39 57 autosomal dominant HP:0000006 58 73 branchial cleft HP:0009794 223 241 autosomal dominant HP:0000006

1931625

We have investigated the incidence of Gorlin syndrome (GS) in patients with the childhood brain tumour, medulloblastoma. One hundred and seventy-three consecutive cases of medulloblastoma in the North-West Regional Health Authority between 1954 and 1989 (Manchester Regional Health Board before 1974) were studied. After review of case notes, X-rays and health surveys only 2/173 cases had evidence supporting a diagnosis of GS. A further case at 50% risk of GS died of a brain tumour aged 4 years. The incidence of GS in medulloblastoma is, therefore, probably between 1-2%. A population based study of GS in the region started in 1983 was used to assess the incidence of medulloblastoma in GS, which was found to be between 3-5%. This figure is lower than previous estimates, but this is the first population based study undertaken. In view of the early age of onset in GS (mean 2 years) children presenting with medulloblastoma, especially under 5 years, should be examined for signs of the syndrome. Those at high risk of developing multiple invasive basal cell carcinomata will then be identified.

80 89 childhood HP:0011463 90 102 brain tumour HP:0100006 104 119 medulloblastoma HP:0002885 172 187 medulloblastoma HP:0002885 472 484 brain tumour HP:0100006 522 537 medulloblastoma HP:0002885 673 688 medulloblastoma HP:0002885 850 868 early age of onset HP:0003593 915 930 medulloblastoma HP:0002885 1055 1077 basal cell carcinomata HP:0002671

2729353

We report on a 4-year-old girl with Angelman syndrome who has an apparent de-novo del(15) (q11q13) originating from a maternally derived chromosome. Her mother had severe brachycephaly, sensorineural hearing loss, speech impediment, and mild ataxia. CT brain scans showed an enlarged foramen magnum in the mother and daughter but magnetic resonance imaging (MRI) showed no brainstem abnormality in either. This family demonstrates that some Angelman syndrome cases may be dominantly transmitted with variable expression and associated with abnormal or cytogenetically apparently normal chromosome 15.

171 184 brachycephaly HP:0000248 186 212 sensorineural hearing loss HP:0000407 214 231 speech impediment HP:0002167 237 248 mild ataxia HP:0001251 275 298 enlarged foramen magnum HP:0002700 373 394 brainstem abnormality HP:0002363 472 494 dominantly transmitted HP:0000006 500 519 variable expression HP:0003828

1110452

Older paternal age has previously been documented as a factor in sporadic fresh mutational cases of several autosomal dominant disorders. In this collaborative study, an older mean paternal age has been documented in sporadic cases of at least five additional dominantly inheritable disorders; the basal cell nevus syndrome, the Waardenburg syndrome, the Crouzon syndrome, the oculo-dental-digital sysdrome, and the Treacher-Collins syndrome. It was also found to be a factor in acrodysostosis and progeria, suggesting a fresh mutant gene etiology for these two conditions in which virtually all cases have been sporadic and the mode of genetic etiology has been unknown.

65 73 sporadic HP:0003745 108 126 autosomal dominant HP:0000006 217 231 sporadic cases HP:0003745 260 292 dominantly inheritable disorders HP:0000006 298 323 basal cell nevus syndrome HP:0002671 612 620 sporadic HP:0003745

2466440

Thirty six children with typical features of Angelman's syndrome, including global developmental delay, ataxia, episodes of paroxysmal laughter, seizures, and microcephaly were studied. The series included three sibships of three affected sisters, two affected brothers, and two affected sisters, respectively. The facial appearance is characterised by a prominent jaw, a wide mouth, and a pointed chin. Tongue thrusting is common. The movement disorder consists of a wide based, ataxic gait with frequent jerky limb movements and flapping of the hands. Tone is variable in the limbs with normal reflexes, and the plantar responses are usually flexor. The syndrome is being diagnosed more often, and attention is drawn to its diagnostic aspects.

76 102 global developmental delay HP:0001263 104 110 ataxia HP:0001251 112 143 episodes of paroxysmal laughter HP:0000749 145 153 seizures HP:0001250 159 171 microcephaly HP:0000252 315 332 facial appearance HP:0001999 355 368 prominent jaw HP:0002051 372 382 wide mouth HP:0000154 390 402 pointed chin HP:0000307 404 420 Tongue thrusting HP:0000182 436 453 movement disorder HP:0100022 468 491 wide based, ataxic gait HP:0002136 506 526 jerky limb movements HP:0002276 531 552 flapping of the hands HP:0100023 562 570 variable HP:0003813

8160736

We present 3 individuals, a mother, her son, and an unrelated child, with a number of manifestations reported in the branchio-oculo-facial syndrome (BOFS). The former 2 individuals lacked the ocular and branchial abnormalities normally encountered in this syndrome. However, unilateral renal agenesis was present in the first child, a defect infrequently found in the BOF syndrome. Both the mother and her son also had bilateral supra-auricular sinuses. These defects may represent persistence of the otic vesicle sinus tract. The second child has a mild expression of this condition, among the mildest reported in the literature. The BOFS appears to represent a spectrum involving the development of the optic vesicles, branchial arches, eyes, face, lips, and kidneys. The variations seen in this disorder and the overlap between this condition and the branchio-oto-renal syndrome may represent different mutations within a single gene or may be a contiguous gene deletion syndrome.

275 300 unilateral renal agenesis HP:0000122 419 452 bilateral supra-auricular sinuses HP:0008606 686 719 development of the optic vesicles HP:0000478 721 737 branchial arches HP:0009794 949 982 contiguous gene deletion syndrome HP:0001466

292745

This paper is based on our experience with the Gorlin-Goltz syndrome and on data from 14 patients of the Nordwestdeutsche Kieferklinik in whom this disorder was detected, treated and followed up. A clinical concept has been produced, with a diagnostic check list including a genetic and a dermatological routine work up as well as a radiological survey of the jaws and skeleton. Whenever multiple basal cell carcinomas plus the typical jaw lesions are found in a patient, the diagnosis is easy. A minimum diagnostic criterion is the combination of either the skin tumours or multiple odontogenic keratocysts plus a positive family history for this disorder, bifid ribs, lamellar calcification of the falx cerebri or any one of the skeletal abnormalities typical of this syndrome. All those in whom this disorder is diagnosed or suspected should be followed up for the rest of their lives. The family should be examined and genetic counselling should be offered.

397 418 basal cell carcinomas HP:0002671 436 447 jaw lesions HP:0000209 559 571 skin tumours HP:0008069 584 607 odontogenic keratocysts HP:0010603 658 668 bifid ribs HP:0000892 679 712 calcification of the falx cerebri HP:0005462 731 753 skeletal abnormalities HP:0000924

3409926

An EEG study has been carried out on 19 children (including siblings in 3 families) with clinical features of Angelman syndrome. The age at time of the first EEG ranged from 11 months to 11 years with the majority under 5 years. Six children had no history of seizures at the time of the first EEG. One or more of the following EEG abnormalities were seen in all patients: 1. Persistent rhythmic 4-6/s activities reaching more than 200 microV not associated with drowsiness. 2. Prolonged runs of rhythmic 2-3/s activity (200-500 microV) often more prominent anteriorly, sometimes associated with discharges (ill-defined spike/wave complexes). 3. Spikes mixed with 3-4/s components usually more than 200 microV mainly posteriorly and facilitated by, or only seen with, eye closure. Two and sometimes three of these EEG features could be present in the same record particularly at a young age. The appearance of discharges mixed with slow components on eye closure was the commonest finding seen at some stage in 17 patients (aged from 11 months to over 12 years). The EEG features of Angelman syndrome appear to be sufficiently characteristic to help identify patients at an early age before the clinical features become obvious and at a time when genetic counselling may be particularly important.

260 268 seizures HP:0001250 328 345 EEG abnormalities HP:0002353 376 412 Persistent rhythmic 4-6/s activities HP:0010846 463 473 drowsiness HP:0002329 881 890 young age HP:0003593 1174 1183 early age HP:0003593

15994874

Neurofibromatosis 2 (NF2) patients with constitutional splice site NF2 mutations have greater variability in disease severity than NF2 patients with other types of mutations; the cause of this variability is unknown. We evaluated genotype-phenotype correlations, with particular focus on the location of splice site mutations, using mutation and clinical information on 831 patients from 528 NF2 families with identified constitutional NF2 mutations. The clinical characteristics examined were age at onset of symptoms of NF2 and number of intracranial meningiomas, which are the primary indices of the severity of NF2. Two regression models were used to analyse genotype-phenotype correlations. People with splice site mutations in exons 1-5 had more severe disease than those with splice site mutations in exons 11-15. This result is compatible with studies showing that exons 2 and 3 are required for self-association of the amino terminal of the NF2 protein in vitro, and that deletions of exons 2 and 3 in transgenic and knockout mouse models of NF2 cause a high prevalence of Schwann cell derived tumours.

0 17 Neurofibromatosis HP:0006746 94 105 variability HP:0003812 193 204 variability HP:0003812 540 564 intracranial meningiomas HP:0100009 1082 1110 Schwann cell derived tumours HP:0100008

10051003

Townes-Brocks syndrome (TBS) is an autosomal dominant disorder with multiple malformations and variable expression. Major findings include external ear anomalies, hearing loss, preaxial polydactyly and triphalangeal thumbs, imperforate anus, and renal malformations. Most patients with Townes-Brocks syndrome have normal intelligence, although mental retardation has been noted in a few.

35 62 autosomal dominant disorder HP:0000006 95 114 variable expression HP:0003828 139 161 external ear anomalies HP:0000356 163 175 hearing loss HP:0000365 177 197 preaxial polydactyly HP:0001177 202 222 triphalangeal thumbs HP:0001199 224 240 imperforate anus HP:0002023 246 265 renal malformations HP:0000792 344 362 mental retardation HP:0001249

11455389

Brachydactyly type A-1 (BDA-1; MIM 112500) is characterized by shortening or missing of the middle phalanges (Fig. 1a). It was first identified by Farabee in 1903 (ref. 2), is the first recorded example of a human anomaly with Mendelian autosomal-dominant inheritance and, as such, is cited in most genetic and biological textbooks. Here we show that mutations in IHH, which encodes Indian hedgehog, cause BDA-1. We have identified three heterozygous missense mutations in the region encoding the amino-terminal signaling domain in all affected members of three large, unrelated families. The three mutant amino acids, which are conserved across all vertebrates and invertebrates studied so far, are predicted to be adjacent on the surface of IHH.

0 22 Brachydactyly type A-1 HP:0009371 24 29 BDA-1 HP:0009371 63 108 shortening or missing of the middle phalanges HP:0005819 77 108 missing of the middle phalanges HP:0009843 237 267 autosomal-dominant inheritance HP:0000006

2012134

The diagnosis of Angelman syndrome (AS) has seldom been made in infants because the previously described characteristic manifestations usually are not apparent until after age 2 years. We describe 4 AS patients, one of whom has oculocutaneous albinism, who were less than 2 years old when first evaluated. All 4 have deletions of the region q11.2-q13 of chromosome 15. In the 3 cases in which parents were available for study the deleted chromosome 15 was maternally derived, as determined by cytological markers. All of the patients presented with severe to profound global developmental delay and postnatal-onset microcephaly; they had seizures, hypotonia, hyperreflexia, and hyperkinesis. All were hypopigmented as compared to their relatives. Each had eye abnormalities; all had choroidal pigment hypoplasia. None were initially described as having an abnormal appearance. We believe that AS is far more common than previously thought and present these 4 children to emphasize the manifestations that may be helpful in making the diagnosis in the young patient. We also emphasize the hypopigmentation that patients with AS frequently have, including what we think is the first reported case of albinism and AS.

228 251 oculocutaneous albinism HP:0001107 549 594 severe to profound global developmental delay HP:0007106 599 627 postnatal-onset microcephaly HP:0005484 638 646 seizures HP:0001250 648 657 hypotonia HP:0001252 659 672 hyperreflexia HP:0001347 678 690 hyperkinesis HP:0002487 701 714 hypopigmented HP:0001010 756 773 eye abnormalities HP:0000478 783 811 choroidal pigment hypoplasia HP:0007757 1051 1056 young HP:0003593 1088 1104 hypopigmentation HP:0007513 1198 1206 albinism HP:0001022

8786067

Angelman syndrome (AS) is characterized by severe mental retardation, absent speech, puppet-like movements, inappropriate laughter, epilepsy, and abnormal electroencephalogram. The majority of AS patients (approximately 65%) have a maternal deficiency within chromosomal region 15q11-q13, caused by maternal deletion or paternal uniparental disomy (UPD). Approximately 35% of AS patients exhibit neither detectable deletion nor UPD, but a subset of these patients have abnormal methylation at several loci in the 15q11-q13 region. We describe here three patients with Angelman syndrome belonging to an extended inbred family. High resolution chromosome analysis combined with DNA analysis using 14 marker loci from the 15ql1-q13 region failed to detect a deletion in any of the three patients. Paternal UPD of chromosome 15 was detected in one case, while the other two patients have abnormal methylation at D15S9, D15S63, and SNRPN. Although the three patients are distantly related, the chromosome 15q11-q13 haplotypes are different, suggesting that independent mutations gave rise to AS in this family.

43 68 severe mental retardation HP:0002187 70 83 absent speech HP:0001344 85 106 puppet-like movements HP:0100022 108 130 inappropriate laughter HP:0000748 132 140 epilepsy HP:0001250 146 175 abnormal electroencephalogram HP:0002353

1496982

Neurofibromatosis type 2 (NF2) is an autosomal dominant syndrome characterized by the development of vestibular schwannomas and other tumors of the nervous system, including cranial and spinal meningiomas, schwannomas, and ependymomas. The presence of bilateral vestibular schwannomas is sufficient for the diagnosis. Skin manifestations are less common than in neurofibromatosis type 1 (NF1; von Recklinghausen disease). The apparent clinical distinction between NF1 and NF2 has been confirmed at the level of the gene locus by linkage studies; the gene for NF1 maps to chromosome 17, whereas the gene for NF2 has been assigned (in a single family) to chromosome 22. To increase the precision of the genetic mapping of NF2 and to determine whether additional susceptibility loci exist, we have performed linkage analysis on 12 families with NF2 by using four polymorphic markers from chromosome 22 and a marker at the NF1 locus on chromosome 17. Our results confirm the assignment of the gene for NF2 to chromosome 22 and do not support the hypothesis of genetic heterogeneity. We believe that chromosome 22 markers can now be used for presymptomatic diagnosis in selected families. The NF2 gene is tightly linked to the D22S32 locus (maximum lod score 4.12; recombination fraction 0). A CA-repeat polymorphism at the CRYB2 locus was the most informative marker in our families (lod score 5.99), but because the observed recombination fraction between NF2 and CRYB2 was 10 cM, predictions using this marker will need to be interpreted with caution.

0 17 Neurofibromatosis HP:0006746 37 55 autosomal dominant HP:0000006 101 123 vestibular schwannomas HP:0009588 128 140 other tumors HP:0003008 134 162 tumors of the nervous system HP:0004375 174 204 cranial and spinal meningiomas HP:0100009 186 204 spinal meningiomas HP:0100010 206 217 schwannomas HP:0100008 223 234 ependymomas HP:0002888 252 284 bilateral vestibular schwannomas HP:0009589 318 337 Skin manifestations HP:0000951 362 379 neurofibromatosis HP:0006746 1056 1077 genetic heterogeneity HP:0001425

7485365

To evaluate the ocular abnormalities in patients with clinically diagnosed neurofibromatosis 2 and asymptomatic gene carriers. Probands were ascertained through a surgical otolaryngology practice. In a cross-sectional study, we examined 49 patients with neurofibromatosis 2, 30 offspring of patients, and, as a comparison group, 18 parents and siblings of patients with sporadic neurofibromatosis 2. The examination included a complete neuro-ophthalmic assessment, physical examination, and, for patients and first-degree relatives at risk, cranial and spinal magnetic resonance imaging with gadolinium enhancement, if not previously performed. The most common ocular abnormalities were posterior subcapsular or capsular, cortical, or mixed lens opacities in 33 (67%) of 49 patients with neurofibromatosis 2 and retinal hamartomas in 11 (22%). We used segregation analysis to determine the mutation carrier status of six at-risk offspring who were 30 years old or younger in two multigeneration families. Three asymptomatic mutation carriers had cataracts, whereas those who were predicted not to carry the mutation did not have cataracts. Asymptomatic mutation carriers may have developmental abnormalities of the eye that are detectable in childhood or adolescence, a finding that may assist in early diagnosis of the disease. A variety of ocular abnormalities are present in neurofibromatosis 2, including cataracts, retinal hamartomas, and ocular motor deficits. Many of these are developmental or acquired early in life and may assist in presymptomatic diagnosis. For screening at-risk relatives of patients with neurofibromatosis 2, the types of cataract that are most suggestive of neurofibromatosis 2 are plaque-like posterior subcapsular or capsular cataract and cortical cataract with onset under the age of 30 years.

16 36 ocular abnormalities HP:0000284 75 92 neurofibromatosis HP:0006746 255 272 neurofibromatosis HP:0006746 371 379 sporadic HP:0003745 380 397 neurofibromatosis HP:0006746 663 683 ocular abnormalities HP:0000284 689 757 posterior subcapsular or capsular, cortical, or mixed lens opacities HP:0007787 714 757 capsular, cortical, or mixed lens opacities HP:0100020 724 757 cortical, or mixed lens opacities HP:0100019 743 757 lens opacities HP:0000518 790 807 neurofibromatosis HP:0006746 814 832 retinal hamartomas HP:0009594 1048 1057 cataracts HP:0000518 1131 1140 cataracts HP:0000518 1182 1209 developmental abnormalities HP:0001263 1196 1220 abnormalities of the eye HP:0000478 1244 1253 childhood HP:0011463 1257 1268 adolescence HP:0011462 1345 1365 ocular abnormalities HP:0000284 1381 1398 neurofibromatosis HP:0006746 1412 1421 cataracts HP:0000518 1423 1441 retinal hamartomas HP:0009594 1447 1468 ocular motor deficits HP:0006860 1621 1638 neurofibromatosis HP:0006746 1655 1663 cataract HP:0000518 1692 1709 neurofibromatosis HP:0006746 1728 1770 posterior subcapsular or capsular cataract HP:0007787 1753 1770 capsular cataract HP:0100017 1775 1792 cortical cataract HP:0100019

11425952

The authors report a patient with neurofibromatosis type 2 (NF2) presenting with an axonal mononeuropathy multiplex. Sural nerve biopsy showed small scattered groups of Schwann cells transformed into irregular branching cells with abnormal cell-cell contacts. The authors hypothesize that defective Schwann cell function, due to inactivation of the NF2 gene product merlin, leads to changes in morphology, cell-cell contact, and growth, and finally to degeneration of axons.

34 51 neurofibromatosis HP:0006746 84 115 axonal mononeuropathy multiplex HP:0009831 169 194 Schwann cells transformed HP:0100008 289 320 defective Schwann cell function HP:0100008 452 473 degeneration of axons HP:0000764

7417945

Four patients representing four generations of one family suffered from the multiple nevoid basal cell carcinoma syndrome. These cases are described and the importance of examination and careful supervision of the progeny of such patients is discussed. A unique finding in this series was a large congenital lung cyst occupying the left thoracic cavity of 1 patient.

76 91 multiple nevoid HP:0001054 92 112 basal cell carcinoma HP:0002671 297 317 congenital lung cyst HP:0006540

6964893

Several pedigrees with 19 new cases of the earpits-deafness syndrome (McK +12510) [28] are presented. Mention is made of clinical findings obtained in audiometric and vestibular studies, studies of renal function and configuration and polytomographic studies of the labyrinth, and results of exploratory tympanotomies are discussed. The literature is reviewed and the features found in 138 cases and in our 19 cases are presented. The earpits-deafness syndrome is an autosomal dominant disorder in which affected individuals may have sensorineural, conductive or mixed hearing loss, preauricular pits, structural defects of the outer, middle and inner ear, lacrimal duct stenosis, branchial fistulas or cysts of the second branchial arch, and renal anomalies ranging from mild hypoplasia to complete absence. Not all the features of the syndrome are expressed in all carriers of the gene. Pits, branchial clefts and hearing loss are frequently expressed. The incidence of renal malformation is higher, as mentioned earlier in the literature. The poor results of exploratory tympanotomies are discussed. On the basis of personal observations as well as in view of data from the literature it is maintained that the BOR (branchio-oto-renal dysplasia) syndrome [12,30-32] and the BO (branchio-oto dysplasia) syndrome are in fact the same affection. It is also maintained that no separate syndromes can be distinguished on the basis of the type of hearing loss. The present knowledge of the syndrome is summarized in terms of the information available for genetic counselling.

43 50 earpits HP:0004467 51 59 deafness HP:0000404 435 442 earpits HP:0004467 443 451 deafness HP:0000404 467 494 autosomal dominant disorder HP:0000006 534 581 sensorineural, conductive or mixed hearing loss HP:0000407 549 581 conductive or mixed hearing loss HP:0000405 563 581 mixed hearing loss HP:0000410 583 600 preauricular pits HP:0004467 613 655 defects of the outer, middle and inner ear HP:0000359 657 679 lacrimal duct stenosis HP:0007925 681 699 branchial fistulas HP:0009795 681 708 branchial fistulas or cysts HP:0009796 723 732 branchial HP:0009794 743 758 renal anomalies HP:0000077 889 893 Pits HP:0004467 895 911 branchial clefts HP:0009794 916 928 hearing loss HP:0000365 972 990 renal malformation HP:0000792 1232 1247 renal dysplasia HP:0000110 1444 1456 hearing loss HP:0000365

3674117

Deletions, duplications, and rearrangements of the long arm of chromosome 15 are frequently associated with the clinical diagnosis of the Prader-Willi syndrome. However, a number of other clinical entities have also been associated with similar, if not identical, cytogenetic defects, arguing for clinical heterogeneity associated with abnormalities in this region of chromosome 15. We present 3 patients who all appear to have deletions in 15q11-15q12, such as described for many patients with Prader-Willi syndrome; however, none of these patients has classical clinical features of the Prader-Willi syndrome. The first patient is a child with Williams syndrome, the second, Angelman (Happy Puppet) syndrome, and the third is a child with hypotonia of infancy, obesity, and developmental delay, but who does not meet specific diagnostic criteria for the Prader-Willi syndrome. It is proposed that different molecular abnormalities involving specific points or segments along the long arm of chromosome 15 might account for the clinical diversity seen among these and other patients.

297 319 clinical heterogeneity HP:0003812 741 761 hypotonia of infancy HP:0001319 763 770 obesity HP:0001513 776 795 developmental delay HP:0001263

3098672

Cell cultures grown from peripheral neurofibromas of three patients suffering from sporadic peripheral neurofibromatosis (NF) were analysed cytogenetically at early in vitro passages. The NF-cultures exhibited a 6.7-fold higher frequency of aneuploid mitoses, including pseudodiploids, than the control cultures derived from the skin of three healthy donors. The predominant numerical anomaly was monosomy 22. Several, as yet unidentified marker chromosomes occurred in the NF-cultures, which also showed a much higher level of unstable chromosomal anomalies. The role of monosomy 22 in tumorigenesis of meningiomas and neurofibromas is discussed.

36 49 neurofibromas HP:0001067 83 91 sporadic HP:0003745 103 120 neurofibromatosis HP:0006746 604 615 meningiomas HP:0002858 620 633 neurofibromas HP:0001067

1583664

A four generation autosomal dominant pedigree of brachydactyly type C is presented with its radiological features. The hands and feet were similarly affected. All the subjects showing these changes had shortening of the big toes and, in addition, had cupped ears.

18 36 autosomal dominant HP:0000006 49 69 brachydactyly type C HP:0009373 202 228 shortening of the big toes HP:0010109 251 262 cupped ears HP:0000378

10066029

Nevoid basal cell carcinoma syndrome (NBCCS) is a hereditary condition transmitted as an autosomal dominant trait with complete penetrance and variable expressivity. The syndrome is characterised by numerous basal cell carcinomas (BCCs), odontogenic keratocysts of the jaws, palmar and/or plantar pits, skeletal abnormalities and intracranial calcifications. In this paper, the clinical features of 37 Italian patients are reviewed. Jaw cysts and calcification of falx cerebri were the most frequently observed anomalies, followed by BCCs and palmar/plantar pits. Similar to the case of African Americans, the relatively low frequency of BCCs in the Italian population is probably due to protective skin pigmentation. A future search based on mutation screening might establish a possible genotype phenotype correlation in Italian patients.

7 27 basal cell carcinoma HP:0002671 89 113 autosomal dominant trait HP:0000006 143 164 variable expressivity HP:0003828 208 229 basal cell carcinomas HP:0002671 238 261 odontogenic keratocysts HP:0010603 250 273 keratocysts of the jaws HP:0010603 275 301 palmar and/or plantar pits HP:0010612 289 301 plantar pits HP:0010612 303 325 skeletal abnormalities HP:0000924 330 357 intracranial calcifications HP:0002514 433 442 Jaw cysts HP:0010603 447 476 calcification of falx cerebri HP:0005462 534 538 BCCs HP:0002671 543 562 palmar/plantar pits HP:0010610 550 562 plantar pits HP:0010612

7802001

We analyzed 61 Angelman syndrome (AS) patients by cytogenetic and molecular techniques. On the basis of molecular findings, the patients were classified into the following 4 groups: familial cases without deletion, familial cases with submicroscopic deletion, sporadic cases with deletion, and sporadic cases without deletion. Among 53 sporadic cases, 37 (70%) had molecular deletion, which commonly extended from D15S9 to D15S12, although not all deletions were identical. Of 8 familial cases, 3 sibs from one family had a molecular deletion involving only 2 loci, D15S10 and GABRB3, which define the critical region for AS phenotypes. The parental origin of deletion, both in sporadic and familial cases, was exclusively maternal and consistent with a genomic imprinting hypothesis. Among sporadic and familial cases without deletion, no uniparental disomy was found and most of them were shown to inherit chromosomes 15 from both parents (biparental inheritance). A discrepancy between cytogenetic and molecular deletion was observed in 14 (26%) of 53 patients in whom cytogenetic analysis could be performed. Ten (43%) of 23 patients with a normal karyotype showed a molecular deletion, and 4 (13%) of 30 patients with cytogenetic deletion, del(15) (q11q13), showed no molecular deletion. Most clinical manifestations, including neurological signs and facial characteristics, were not distinct in each group except for hypopigmentation of skin or hair. Familial cases with submicroscopic deletion were not associated with hypopigmentation. These findings suggested that a gene for hypopigmentation is located outside the critical region of AS and is not imprinted.

182 196 familial cases HP:0000005 260 274 sporadic cases HP:0003745 294 308 sporadic cases HP:0003745 336 350 sporadic cases HP:0003745 678 686 sporadic HP:0003745 791 799 sporadic HP:0003745 1333 1351 neurological signs HP:0000707 1356 1378 facial characteristics HP:0001999 1423 1447 hypopigmentation of skin HP:0001010 1423 1455 hypopigmentation of skin or hair HP:0005599 1526 1542 hypopigmentation HP:0007513 1585 1601 hypopigmentation HP:0007513

9486718

Nevoid basal cell carcinoma syndrome (NBCCS) is rare in black persons. We describe an 11-year-old black boy with NBCCS who presented with exotropia and a painful, expanding, cystic mass in the left posterior alveolar ridge. Further examination revealed odontogenic keratocysts with palmar and plantar pitting. Less than 5% of reported patients with NBCCS are black. To our knowledge, this is the first report of a black patient with NBCCS presenting with exotropia and an impacted molar displaced into the orbit by an odontogenic keratocyst.

7 27 basal cell carcinoma HP:0002671 138 147 exotropia HP:0000577 174 222 cystic mass in the left posterior alveolar ridge HP:0006477 253 276 odontogenic keratocysts HP:0010603 282 308 palmar and plantar pitting HP:0010612 455 464 exotropia HP:0000577 518 540 odontogenic keratocyst HP:0010603

8042672

The nevoid basal cell carcinoma syndrome (NBCC) is an autosomal dominant multisystem disorder with variable expressivity. We present the clinical findings on 11 African-American NBCC cases from 2 families and a review of the literature of NBCC in African-Americans. The 2 new families, as well as those previously reported, suggest minimal expression of the basal cell carcinomas and full expression of the other components of the syndrome. The 3 most common findings in the 11 cases were jaw cysts, palmar and/or plantar pits, and calcification of the falx cerebri. Only 44% (4/11) of these cases had one or more confirmed basal cell carcinomas. This frequency is substantially less than that observed in whites (90% with basal cell carcinomas). The relative lack of these skin tumors in African-Americans partly reflects ultraviolet radiation protection resulting from increased skin pigmentation. Future research should help identify the specific mutation(s) in blacks as well as other modifying genes and environmental exposures that may contribute to the varied manifestations of the syndrome.

11 31 basal cell carcinoma HP:0002671 54 72 autosomal dominant HP:0000006 99 120 variable expressivity HP:0003828 358 379 basal cell carcinomas HP:0002671 489 498 jaw cysts HP:0010603 500 526 palmar and/or plantar pits HP:0010612 514 526 plantar pits HP:0010612 532 565 calcification of the falx cerebri HP:0005462 624 645 basal cell carcinomas HP:0002671 723 744 basal cell carcinomas HP:0002671 774 785 skin tumors HP:0008069 871 898 increased skin pigmentation HP:0000953

7200726

A mother and son with bilateral branchial sinuses, intrauterine and postnatal growth retardation, unusual facial appearance, and premature aging in the mother are reported. No other members of the family are similarly affected. No hormonal or systemic cause of growth retardation was identified. Chromosomal studies with G-banding were normal. It is suggested that this syndrome is a dominant trait, the mother being the initial mutant.

22 49 bilateral branchial sinuses HP:0009794 51 96 intrauterine and postnatal growth retardation HP:0001511 68 96 postnatal growth retardation HP:0008897 98 123 unusual facial appearance HP:0002004 129 144 premature aging HP:0002216 261 279 growth retardation HP:0001510 384 398 dominant trait HP:0000006

7319144

Nine children with the "happy puppet" syndrome are presented here and 19 previously reported cases are reviewed. A characteristic psychological profile is suggested by the children's "unfocused" activities and inconsistent responsiveness to their surroundings. Behavioral characteristics are atypical for mental age and do not appear to represent unusual seizure equivalents. Recognition of such non-adaptive behavior may be of importance in selecting specific treatment and management techniques to modify the characteristics of this syndrome at an early age.

24 36 happy puppet HP:0100024 183 205 "unfocused" activities HP:0000708 261 287 Behavioral characteristics HP:0000708 355 362 seizure HP:0001250 396 417 non-adaptive behavior HP:0000708 550 559 early age HP:0003593

9096761

Nevoid basal cell carcinoma syndrome (NBCC; Gorlin syndrome), an autosomal dominant disorder linked to 9q22.3-q31, and caused by mutations in PTC, the human homologue of the Drosophila patched gene, comprises multiple basal cell carcinomas, keratocysts of the jaw, palmar/plantar pits, spine and rib anomalies and calcification of the falx cerebri. We reviewed the findings on 105 affected individuals examined at the NIH since 1985. The data included 48 males and 57 females ranging in age from 4 months to 87 years. Eighty percent of whites (71/90) and 38% (5/13) of African-Americans had at least one basal cell carcinoma (BCC), with the first tumor occurring at a mean age of 23 (median 20) years and 21 (median 20) years, respectively. Excluding individuals exposed to radiation therapy, the number of BCCs ranged from 1 to > 1,000 (median 8) and 1 to 3 (median 2), respectively, in the 2 groups. Jaw cysts occurred in 78/105 (74%) with the first tumor occurring in 80% by the age of 20 years. The number of total jaw cysts ranged from 1 to 28 (median 3). Palmar pits and plantar pits were seen in 87%. Ovarian fibromas were diagnosed by ultrasound in 9/52 (17%) at a mean age of 30 years. Medulloblastoma occurred in 4 patients at a mean age of 2.3 years. Three patients had cleft lip or palate. Physical findings include "coarse face" in 54%, relative macrocephaly in 50%, hypertelorism in 42%, frontal bossing in 27%, pectus deformity in 13%, and Sprengel deformity in 11%. Important radiological signs included calcification of the falx cerebri in 65%, of the tentorium cerebelli in 20%, bridged sella in 68%, bifid ribs in 26%, hemivertebrae in 15%, fusion of the vertebral bodies in 10%, and flame shaped lucencies of the phalanges, metacarpal, and carpal bones of the hands in 30%. Several traits previously considered components of the syndrome (including short fourth metacarpal, scoliosis, cervical ribs and spina bifida occulta) were not found to be significantly increased in the affected individuals. This study delineates the frequency of the clinical and radiological anomalies in NBCC in a large population of US patients and discusses guidelines for diagnosis and management.

7 27 basal cell carcinoma HP:0002671 65 92 autosomal dominant disorder HP:0000006 218 239 basal cell carcinomas HP:0002671 241 263 keratocysts of the jaw HP:0010603 265 284 palmar/plantar pits HP:0010610 272 284 plantar pits HP:0010612 286 309 spine and rib anomalies HP:0000925 296 309 rib anomalies HP:0000772 314 347 calcification of the falx cerebri HP:0005462 604 624 basal cell carcinoma HP:0002671 647 652 tumor HP:0002664 902 911 Jaw cysts HP:0010603 952 957 tumor HP:0002664 1019 1028 jaw cysts HP:0010603 1061 1072 Palmar pits HP:0010610 1077 1089 plantar pits HP:0010612 1108 1124 Ovarian fibromas HP:0010618 1195 1210 Medulloblastoma HP:0002885 1281 1300 cleft lip or palate HP:0000175 1281 1290 cleft lip HP:0100333 1329 1340 coarse face HP:0000280 1350 1371 relative macrocephaly HP:0004482 1380 1393 hypertelorism HP:0000316 1402 1417 frontal bossing HP:0002007 1426 1442 pectus deformity HP:0000766 1455 1473 Sprengel deformity HP:0000912 1520 1553 calcification of the falx cerebri HP:0005462 1597 1610 bridged sella HP:0005449 1619 1629 bifid ribs HP:0000892 1638 1651 hemivertebrae HP:0002937 1660 1690 fusion of the vertebral bodies HP:0002948 1869 1892 short fourth metacarpal HP:0010044 1894 1903 scoliosis HP:0002650 1905 1918 cervical ribs HP:0000891 1923 1943 spina bifida occulta HP:0003298

17431915

We report on wide phenotypic variations within a family with SALL1 mutations; the elder sister presented with a Townes-Brocks syndrome phenotype including external ear anomalies, preaxial polydactyly, and anteriorly placed anus, whereas the younger sister presented with a phenotype resembling Goldenhar syndrome, including atretic ear canals, mandibular hypoplasia, and right preaxial polydactyly as well as an epibulbar dermoid. The mother had abnormal external ears but was otherwise structurally normal, and the father was asymptomatic. Analysis of the SALL1 gene revealed that both daughters were heterozygous for nonsense mutation 1256T>A (L419X), that is present 5' to the region encoding the first double zinc finger. The mother was heterozygous for the L419X mutation. The younger daughter is the first patient with a SALL1 mutation to exhibit a classic Goldenhar syndrome-like phenotype with an epibulbar dermoid. The observation lends further support to the concept that Goldenhar syndrome is an etiologically heterogeneous disorder that may have a genetic basis in some cases.

13 55 wide phenotypic variations within a family HP:0003822 155 177 external ear anomalies HP:0000356 179 199 preaxial polydactyly HP:0001177 205 227 anteriorly placed anus HP:0001545 324 342 atretic ear canals HP:0000413 344 365 mandibular hypoplasia HP:0000347 377 397 preaxial polydactyly HP:0001177 412 429 epibulbar dermoid HP:0001140 905 922 epibulbar dermoid HP:0001140 1021 1034 heterogeneous HP:0001425

1484939

The clinical features, age at onset of symptoms and survival of 150 patients with type 2 neurofibromatosis were studied. The mean age at onset was 21.57 years (n = 110) and no patients presented after 55 years of age. Patients presented with symptoms attributable to vestibular schwannomas (acoustic neuroma), cranial meningiomas and spinal tumours. In 100 patients studied personally by the authors 44 per cent presented with deafness and this was unilateral in the majority (35/44). Deafness was accompanied by tinnitus in a further 10 per cent and muscle weakness or wasting was the first symptom in 12 per cent. Less common presenting symptoms were seizures (8 per cent), vertigo (8 per cent) numbness and tingling (2 per cent) and blindness (1 per cent). Eleven patients were diagnosed asymptomatically through screening. Café au lait spots occurred in 43 per cent (n = 43) but only one case had six. Skin tumours were detected in 68 per cent (68/100) and 38 per cent (34/90) had an identifiable lens opacity or cataract. The mean age at death in 40 cases was 36.25 years and all but one death was a result of a complication of neurofibromatosis. There are marked inter-family differences in disease severity and tumour susceptibility.

89 106 neurofibromatosis HP:0006746 267 289 vestibular schwannomas HP:0009588 291 307 acoustic neuroma HP:0009588 310 329 cranial meningiomas HP:0100009 334 348 spinal tumours HP:0010302 427 435 deafness HP:0000404 485 493 Deafness HP:0000404 513 521 tinnitus HP:0000360 551 566 muscle weakness HP:0001324 551 577 muscle weakness or wasting HP:0003202 653 661 seizures HP:0001250 676 683 vertigo HP:0002321 736 745 blindness HP:0000618 827 845 Café au lait spots HP:0000957 906 918 Skin tumours HP:0008069 1001 1013 lens opacity HP:0000518 1017 1025 cataract HP:0000518 1133 1150 neurofibromatosis HP:0006746 1169 1193 inter-family differences HP:0003813 1218 1224 tumour HP:0002664

998578

A woman with the autosomal dominant syndrome of preauricular pits, cervical fistulae, and partial deafness gave birth to two children with preauricular pits and severe renal dysgenesis. The facies had some features of the Potter facies of renal agenesis. One child died soon after birth because of pneumothorax and immature development of the lungs. We suggest that all infants with renal agenesis or dysgenesis be examined for preauricular pits because of the high recurrence risk of renal anomalies in families with this syndrome.

17 35 autosomal dominant HP:0000006 48 65 preauricular pits HP:0004467 67 84 cervical fistulae HP:0009795 90 106 partial deafness HP:0000365 139 156 preauricular pits HP:0004467 161 184 severe renal dysgenesis HP:0008680 222 235 Potter facies HP:0002009 239 253 renal agenesis HP:0000104 265 286 died soon after birth HP:0001432 298 310 pneumothorax HP:0002107 315 348 immature development of the lungs HP:0002088 383 397 renal agenesis HP:0000104 383 411 renal agenesis or dysgenesis HP:0008680 428 445 preauricular pits HP:0004467 485 500 renal anomalies HP:0000077

3740720

Branchio-oto-renal dysplasia, often called the BOR syndrome, in its full expression consists of hearing loss of conductive, sensorineural, or mixed type; preauricular pits; auricular deformities; lateral cervical sinuses, cysts, or fistulas; and renal malformations. The condition is inherited in an autosomal dominant mode. The findings in three affected families are described, and pertinent genetic and clinical aspects are discussed. The potential seriousness of the renal and aural malformations stresses the importance of early recognition of this syndrome.

13 28 renal dysplasia HP:0000110 96 152 hearing loss of conductive, sensorineural, or mixed type HP:0000410 96 137 hearing loss of conductive, sensorineural HP:0000407 154 171 preauricular pits HP:0004467 200 219 lateral cervical sinuses HP:0000077 232 240 fistulas HP:0009794 246 265 renal malformations HP:0000792 300 318 autosomal dominant HP:0000006 358 363 milie HP:0001056

8494033

Chromosome region 15q is thought to contain one or more genes that are important for melanin pigment synthesis in the hair, skin, and eyes. Hypopigmentation has been identified in the Prader-Willi (PWS) and Angelman (AS) syndromes. We have examined 6 individuals with AS to further characterize the pigment pattern in this condition. The age of the 5 girls and one boy ranged from 2.4 to 7.0 years. None had obvious albinism. Hair color ranged from light blond to brown. Skin was type I in 3 and type II in 3. Eye changes included nystagmus in 2, strabismus in 4, and reduced retinal pigment in 5. The mean hairbulb tyrosinase activity was 0.37 +/- 0.44 pmol/hb/120 min for the individuals with AS, with a range of 0.00 to 1.13 (normal brown control 1.49 +/- 0.79, normal blond control 1.50 +/- 0.85). Electron microscopic examination of hairbulb melanocytes showed normal melanosome and melanocyte architecture and number, but reduced melanin formation, with many stage II and III premelanosomes but few stage IV fully melanized melanosomes. Hypopigmentation characterized by light skin, reduced retinal pigment, low hairbulb tyrosinase activity, and incomplete melanization of melanosomes is part of the phenotype of AS, and is similar to that found in PWS.

85 138 melanin pigment synthesis in the hair, skin, and eyes HP:0007513 140 156 Hypopigmentation HP:0007513 416 424 albinism HP:0001022 531 540 nystagmus HP:0000639 547 557 strabismus HP:0000486 568 591 reduced retinal pigment HP:0007746 1043 1059 Hypopigmentation HP:0007513

3585943

We report a girl aged 11 and her brother aged five, both with the typical features of Angelman syndrome, and three isolated cases. This report, together with a review of published reports and contact with previous authors, has revealed a total of 41 sibs of probands, although only nine of these are known to have been later born. The possible effect of voluntary restriction of family size after the birth of an affected child is discussed in relation to the possibility of autosomal recessive inheritance, but a recurrence risk of 5% is appropriate for use in the genetic clinic.

115 129 isolated cases HP:0001420 475 506 autosomal recessive inheritance HP:0000007

6823972

No difference in survival was observed between cultured cells from basal cell naevus syndrome (BCNS) patients and normal controls following exposure of fibroblasts to ionizing radiation. Potential lethal damage repair in BCNS cells, measured by holding experiments, was also no different from normal. G0-irradiated lymphocytes from BCNS patients were found to have a significantly higher level of X-ray-induced chromosome aberrations compared with normals. This increase is, however, small, and, taken together with the survival data, suggests that increased cell killing as a measure of the unusual clinical radiosensitivity is not the major effect of the BCNS gene.

67 84 basal cell naevus HP:0002671

9557895

The causal heterogeneity of Angelman syndrome (AS) makes providing information regarding recurrence risk both important and challenging, and may have a dramatic impact on reproductive decision-making for the nuclear and extended family. Most cases of AS result from typical large de novo deletions of 15q11-q13, and are expected to have a low (<1%) risk of recurrence. AS due to paternal uniparental disomy (UPD), which occurs in the absence of a parental translocation, is likewise expected to have a <1% risk of recurrence. Parental transmission of a structurally or functionally unbalanced chromosome complement can lead to 15q11-q13 deletions or to UPD and will result in case-specific recurrence risks. In instances where there is no identifiable large deletion or UPD, the risk for recurrence may be as high as 50% as the result of either a maternally inherited imprinting center (IC) mutation or a ubiquitin-protein ligase (UBE3A) gene mutation. Individuals with AS who have none of the above abnormalities comprise a significant proportion of cases, and some may be at a 50% recurrence risk. Misdiagnoses, as well, can be represented in this group. In light of the many conditions which are clinically similar to AS, it is essential to address the possibility of diagnostic uncertainty and potential misdiagnosis prior to the provision of genetic counseling. Summaries of the different causal classes of AS as an algorithm for determination of recurrence risks are presented.

11 24 heterogeneity HP:0001425 280 287 de novo HP:0003745

11169564

Hereditary isolated brachydactyly type C (OMIM 113100) mostly follows an autosomal dominant pattern of inheritance with a marked variability in expression. This phenotype has been mapped to two different loci on chromosomes 12q24 and 20q11.2. The latter locus contains the cartilage-derived morphogenetic protein (CDMP)1 gene, in which a null mutation has been found in patients with malformations restricted to the upper limbs. A more complex brachydactyly type C phenotype has been mapped to chromosome 12q24. Differences in complexity of these phenotypes have been attributed to locus heterogeneity. Clinical subclassification based on the degree of complexity of the phenotype has therefore been suggested. We present patients with a complex brachydactyly type C phenotype in whom there is considerable intra- and interfamilial variability in expression. We show that clinical subclassification based on the complexity of the brachydactyly type C phenotype related to the genetic defect is not feasible. We present evidence that differences in complexity are not only due to locus heterogeneity, but that genetic modifiers and/or environmental factors must also play a role.

20 40 brachydactyly type C HP:0009373 73 91 autosomal dominant HP:0000006 122 154 marked variability in expression HP:0003828 384 427 malformations restricted to the upper limbs HP:0002817 444 464 brachydactyly type C HP:0009373 582 601 locus heterogeneity HP:0001425 746 766 brachydactyly type C HP:0009373 794 843 considerable intra- and interfamilial variability HP:0003822 818 843 interfamilial variability HP:0003812 832 857 variability in expression HP:0003828 930 950 brachydactyly type C HP:0009373 1079 1098 locus heterogeneity HP:0001425

1357962

Uniparental disomy has recently been recognized to cause human disorders, including Prader-Willi syndrome (PWS). We describe a particularly instructive case which raises important issues concerning the mechanisms producing uniparental disomy and whose evaluation provides evidence that trisomy may precede uniparental disomy in a fetus. Chorionic villus sampling performed for advanced maternal age revealed trisomy 15 in all direct and cultured cells, though the fetus appeared normal. Chromosome analysis of amniocytes obtained at 15 wk was normal in over 100 cells studied. The child was hypotonic at birth, and high-resolution banding failed to reveal the deletion of 15q11-13, a deletion which is found in 50%-70% of patients with PWS. Over time, typical features of PWS developed. Molecular genetic analysis using probes for chromosome 15 revealed maternal disomy. Maternal nondisjunction with fertilization of a disomic egg by a normal sperm, followed by loss of the paternal 15, is a likely cause of confined placental mosaicism and uniparental disomy in this case of PWS, and advanced maternal age may be a predisposing factor.

591 609 hypotonic at birth HP:0008935

11484202

Townes-Brocks syndrome (TBS) is a condition with imperforate anus, hand anomalies, and ear malformations with sensorineural hearing loss. Many cases are sporadic. Within and between families, the phenotype displays striking variability. Recently, the disease-causing gene for TBS was identified as SALL1, a zinc finger transcription factor. Here, we report a three-generation family with seven affected individuals who have a novel SALL1 mutation. Unique cardiac anomalies seen in this family include lethal truncus arteriosus in one patient and a lethal complicated defect, including pulmonary valve atresia, in a second patient. These severe cardiac anomalies have not previously been reported in a familial case of TBS. This family and a review of the literature indicate that cardiac evaluation is warranted in all individuals with this disorder. In addition, hypoplastic thumbs were seen in two individuals in this family and should, therefore, be considered a true feature of TBS.

49 65 imperforate anus HP:0002023 67 81 hand anomalies HP:0001155 87 104 ear malformations HP:0000598 110 136 sensorineural hearing loss HP:0000407 153 161 sporadic HP:0003745 163 235 Within and between families, the phenotype displays striking variability HP:0003822 224 235 variability HP:0003812 455 472 cardiac anomalies HP:0001627 508 526 truncus arteriosus HP:0001660 585 608 pulmonary valve atresia HP:0005134 644 661 cardiac anomalies HP:0001627 864 882 hypoplastic thumbs HP:0009778

8988171

Angelman syndrome (AS), characterized by mental retardation, seizures, frequent smiling and laughter, and abnormal gait, is one of the best examples of human disease in which genetic imprinting plays a role. In about 70% of cases, AS is caused by de novo maternal deletions at 15q11-q13 (ref. 2). Approximately 2% of AS cases are caused by paternal uniparental disomy (UPD) of chromosome 15 (ref. 3) and 2-3% are caused by "imprinting mutations'. In the remaining 25% of AS cases, no deletion, uniparental disomy (UPD), or methylation abnormality is detectable, and these cases, unlike deletions or UPD, can be familial. These cases are likely to result from mutations in a gene that is expressed either exclusively or preferentially from the maternal chromosome 15. We have found that a 15q inversion inherited by an AS child from her normal mother disrupts the 5' end of the UBE3A (E6-AP) gene, the product of which functions in protein ubiquitination. We have looked for novel UBE3A mutations in nondeletion/non-UPD/non-imprinting mutation (NDUI) AS patients and have found one patient who is heterozygous for a 5-bp de novo tandem duplication. We have also found in two brothers a heterozygous mutation, an A to G transition that creates a new 3' splice junction 7 bp upstream from the normal splice junction. Both mutations are predicted to cause a frameshift and premature termination of translation. Our results demonstrate that UBE3A mutations are one cause of AS and indicate a possible abnormality in ubiquitin-mediated protein degradation during brain development in this disease.

41 59 mental retardation HP:0001249 61 69 seizures HP:0001250 71 100 frequent smiling and laughter HP:0000749 92 100 laughter HP:0000748 106 119 abnormal gait HP:0001288 247 254 de novo HP:0003745 1120 1127 de novo HP:0003745

1362220

Angelman syndrome (AS) and Prader-Willi syndrome (PWS) have become the classical examples of genomic imprinting in man, as completely different phenotypes are generated by the absence of maternal (AS) or paternal (PWS) contributions to the q11-13 region of chromosome 15 as a result of deletion or uniparental disomy. Apparently, most patients are sporadic cases. The genetic mechanism underlying familial AS has remained enigmatic for a long time. Recently, evidence has been emerging suggesting autosomal dominant inheritance of a detectable or undetectable defect in a gene or genes at 15q11-13, subject to genomic imprinting. The present report describes an unusually large pedigree with segregation of AS through maternal inheritance and apparent asymptomatic transmission through several male ancestors. Deletion and paternal disomy at 15q11-13 were excluded. However, the genetic defect is still located in this region, as we obtained a maximum lod score of 5.40 for linkage to the GABA receptor locus GABRB3 and the anonymous DNA marker D15S10, which have been mapped within or adjacent to the AS critical region at 15q11-13. The size of the pedigree allowed calculation of an odds ratio in favour of genomic imprinting of 9.25 x 10(5). This family illustrates the necessity of extensive pedigree analysis when considering recurrence risks for relatives of AS patients, those without detectable deletion or disomy in particular.

348 362 sporadic cases HP:0003745 397 408 familial AS HP:0000005 497 527 autosomal dominant inheritance HP:0000006

14699618

The phenotype of Gorlin-Goltz syndrome or basal cell nevus syndrome (BCNS, #109400, OMIM), a Mendelian trait due to PTCH mutations has been reported in a few cases of interstitial deletion of chromosome 9q. We present an 11-year-old girl with clinical features consistent with BCNS including bridging of sella turcica, biparietal bossing, downward slanting palpebral fissures, mandible prognathism, pectus excavatum, thumb abnormalities, occult spina bifida at L5-S4, numerous basal cell nevi, and single basal cell carcinoma. Cytogenetic analysis using high-resolution banding techniques and fluorescence in situ hybridization (FISH) revealed interstitial chromosome deletion 9q22.32-q33.2 involving the PTCH gene as a secondary breakage event to a chromosome translocation t(9;17)(q34.1;p11.2)mat. Further FISH studies showed the translocation breakpoint on 9q34.11 maps proximal to ABL, between the BAC clone RP11-88G17 and the LMX1B gene. The latter gene encodes a transcription factor, in which loss of function mutations are responsible for the nail-patella syndrome (NPS, #161200 OMIM). Interestingly, some features of our proband (e.g., bilateral patellar dysplasia and abnormal clavicular shape), as well as her healthy sister who carries the same translocation, are also found in patients with NPS. The chromosome 17p11.2 breakpoint maps in the Smith-Magenis syndrome common deletion region, within two overlapping BAC clones, CTD-2354J3 and RP11-311F12.

42 67 basal cell nevus syndrome HP:0002671 292 317 bridging of sella turcica HP:0005449 319 337 biparietal bossing HP:0000242 339 375 downward slanting palpebral fissures HP:0000494 377 397 mandible prognathism HP:0000303 399 415 pectus excavatum HP:0000767 417 436 thumb abnormalities HP:0001172 438 457 occult spina bifida HP:0003298 468 492 numerous basal cell nevi HP:0001054 505 525 basal cell carcinoma HP:0002671 1155 1173 patellar dysplasia HP:0006446 1178 1203 abnormal clavicular shape HP:0000889

7905534

Angelman syndrome (AS) results from a lack of maternal contribution from chromosome 15q11-13, arising from de novo deletion in most cases or rarely from uniparental disomy. These families are associated with a low recurrence risk. However, in a minority of families, more than one child is affected. No deletion has been found in these families, except one. The mode of inheritance in these families is autosomal dominant modified by imprinting. Sporadic cases, with no observable deletion, therefore pose a counselling dilemma as there could be a recurrence risk as high as 50%. We present a series of 93 AS patients, showing the relative contribution of these different genetic mechanisms. Eighty-one AS patients were sporadic cases while 12 cases came from six families. Sixty cases had deletions in 15q11-13 detected by a set of highly polymorphic (CA)n repeats markers and conventional RFLPs. Ten sporadic cases plus all 12 familial cases had no detectable deletion. In addition, two cases of de novo deletions occurred in a chromosome 15 carrying a pericentric inversion. In one of these the AS child had a cousin with Prader-Willi syndrome (PWS) arising from a de novo deletion in an inv(15) inherited from his father. One case arose from a maternal balanced t(9;15)(p24;q15) translocation. There were three cases of uniparental disomy. Five patients were monoallelic for all loci across the minimal AS critical region, but the presence of a deletion cannot be confirmed. In familial cases, all affected sibs inherited the same maternal chromosome 15 markers for the region 15q11-13. Two cases were observed with a de novo deletion starting close to the locus D15S11 (IR4-2R), providing evidence for the development of classical AS with smaller deletions. Cytogenetic analysis proved limited in its ability to detect deletions, detecting only 42 out of 60 cases. However, cytogenetic analysis is still essential to detect chromosomal abnormalities other than deletions such as inversions and balanced translocations since both have an increased risk for deletions. A staged diagnostic strategy based on the use of highly informative (CA)n repeat markers is proposed.

107 114 de novo HP:0003745 362 381 mode of inheritance HP:0000005 403 421 autosomal dominant HP:0000006 446 460 Sporadic cases HP:0003745 720 734 sporadic cases HP:0003745 902 916 sporadic cases HP:0003745 929 943 familial cases HP:0000005 1482 1496 familial cases HP:0000005

2309778

Six patients, including two sibs, with Angelman syndrome (AS; three females and three males, aged 11 to 18 years) were studied cytogenetically. Molecular analysis was also performed. Using high-resolution banding technique, we detected a microdeletion in the proximal region of chromosome 15q in four cases. The deleted segment was heterogenous between these patients, and the common deleted region appeared to be 15q11.2. Four patients with deleted 15q were all sporadic cases, whereas in the sib cases we could not detect a visible deletion in the long arm of chromosome 15. However, there was no clinical difference between sporadic cases and sib cases. Densitometric analysis of autoradiographic bands of Southern hybridization using two DNA segments, pML34 and pTD3-21, as probes demonstrated that two patients had only one copy for each of the probes. In the remaining four patients, including the sibs, two copies of each sequence were retained. The probes used here detect a molecular deletion in most Prader-Willi syndrome patients. Thus the segment causing AS is localized adjacent to the critical segment of Prader-Willi syndrome. There seemed to be heterogeneity for the molecular deletion within AS individuals.

463 477 sporadic cases HP:0003745 627 641 sporadic cases HP:0003745 1161 1174 heterogeneity HP:0001425

2282716

Clinical and genetic data of 10 patients with neurofibromatosis 2 (NF-2) are presented. Interestingly, no family history of neurofibromatosis was detectable in any of them, which indicates that these are sporadic cases of NF-2, most likely due to a new mutational event. According to our own results and the data in the literature, sporadic cases of NF-2 are clinically characterized by a high incidence of multiple meningiomas and spinal tumors in addition to the bilateral occurrence of acoustic neurinomas. The clinical heterogeneity of NF-2 is pointed out and the possible existence of different forms of this disease is discussed.

46 63 neurofibromatosis HP:0006746 124 141 neurofibromatosis HP:0006746 204 218 sporadic cases HP:0003745 332 346 sporadic cases HP:0003745 416 427 meningiomas HP:0002858 432 445 spinal tumors HP:0010302 465 508 bilateral occurrence of acoustic neurinomas HP:0009589 514 536 clinical heterogeneity HP:0003812

7446562

We report on a 32-year-old Italian man, his 5-year-old daughter, and his 3 1/2-year-old son, all of whom had congenital joint contractures. Each has severe ulnar deviation of fingers and soft-tissue contractures of both hands; and each had bilateral clubfeet at birth. The father is short in stature, as are the children, who also have delayed carpal ossification. The findings in this family suggest autosomal-dominant inheritance of the condition. The clinical features are consistent with the condition currently referred to as "distal" arthrogryposis.

109 138 congenital joint contractures HP:0002803 156 182 ulnar deviation of fingers HP:0009465 199 225 contractures of both hands HP:0006096 240 258 bilateral clubfeet HP:0001776 283 299 short in stature HP:0001509 336 363 delayed carpal ossification HP:0001216 401 431 autosomal-dominant inheritance HP:0000006 531 554 "distal" arthrogryposis HP:0005684

1479599

The major defining features, age at onset of symptoms, and survival in 150 patients with type 2 neurofibromatosis (NF2) have been studied. The mean age at onset was 21.57 years (n = 110) and no cases presented after 55 years of age. Patients presented with symptoms attributable to vestibular schwannomas (acoustic neuroma), cranial meningiomas, and spinal tumours. In 97 cases studied personally by the authors, skin and eye examination were found to be useful to detect early signs of the condition. Examination of the skin is likely to assist in early diagnosis in at least 10% of cases and examination of the eye for a lens opacity or cataract in at least as many again. There are marked interfamilial differences in disease severity and tumour susceptibility. Vestibular schwannomas are not fully penetrant, but the condition is usually expressed in another way. Alteration to the current diagnostic criteria is advocated to cover the lack of provision for new mutations. A screening protocol is proposed and the effect of disease heterogeneity on management is discussed.

96 113 neurofibromatosis HP:0006746 282 304 vestibular schwannomas HP:0009588 306 322 acoustic neuroma HP:0009588 325 344 cranial meningiomas HP:0100009 350 364 spinal tumours HP:0010302 623 635 lens opacity HP:0000518 639 647 cataract HP:0000518 692 717 interfamilial differences HP:0003822 742 748 tumour HP:0002664 765 787 Vestibular schwannomas HP:0009588 1036 1049 heterogeneity HP:0001425

15734008

To report new ocular manifestations of branchio-oculo-facial (BOF) syndrome. Case report. A 10-year-old girl with known BOF syndrome was referred because of a fundus lesion in her left eye. She had undergone excision of a left orbital dermoid cyst at age 18 months and a branchial cleft fistula from the right side of neck at age 4 years. Examination disclosed openings of sinus tracts on each side of the nose connecting the lacrimal sac to skin. In the right eye, an iris pigment epithelial cyst was confirmed with ultrasound biomicroscopy. In the left eye, there was a combined hamartoma of the retina and retina pigment epithelium. BOF syndrome can display mild to severe craniofacial, auricular, oral, and ophthalmic anomalies. In this case, the ophthalmic manifestations included lacrimal sac fistula, orbital dermoid cyst, iris pigment epithelial cyst, and combined hamartoma of the retina and retinal pigment epithelium.

14 35 ocular manifestations HP:0000478 161 174 fundus lesion HP:0001144 225 250 left orbital dermoid cyst HP:0001144 274 297 branchial cleft fistula HP:0009795 472 500 iris pigment epithelial cyst HP:0000525 584 607 hamartoma of the retina HP:0009594 612 637 retina pigment epithelium HP:0008051 680 735 craniofacial, auricular, oral, and ophthalmic anomalies HP:0002260 694 735 auricular, oral, and ophthalmic anomalies HP:0000598 705 735 oral, and ophthalmic anomalies HP:0000153 715 735 ophthalmic anomalies HP:0000478 790 810 lacrimal sac fistula HP:0000521 812 832 orbital dermoid cyst HP:0001144 834 862 iris pigment epithelial cyst HP:0000525 877 900 hamartoma of the retina HP:0009594 905 931 retinal pigment epithelium HP:0008051

8318482

This prospective study of 96 individuals from 29 families with neurofibromatosis 2, 49 of whom were affected, confirms in an extended series the previously reported association between posterior subcapsular/capsular cataract and neurofibromatosis 2. Posterior subcapsular/capsular cataracts were found in 36 (80%) of the 45 affected individuals (four individuals were excluded from statistical analyses). In addition, the association of peripheral cortical lens opacities with neurofibromatosis 2 was found to be statistically significant. Seventeen of the patients with neurofibromatosis 2 (37.8%) had peripheral cortical cataracts in comparison with none of the unaffected family members (p < 0.0001). In three patients peripheral cortical opacities were present despite the absence of posterior subcapsular/capsular cataracts. These findings support the inclusion of cortical cataracts of early onset, in addition to posterior subcapsular/capsular cataracts, in the diagnostic criteria of neurofibromatosis 2.

63 80 neurofibromatosis HP:0006746 185 224 posterior subcapsular/capsular cataract HP:0007787 195 224 subcapsular/capsular cataract HP:0000523 207 224 capsular cataract HP:0100017 229 246 neurofibromatosis HP:0006746 250 290 Posterior subcapsular/capsular cataracts HP:0007787 260 290 subcapsular/capsular cataracts HP:0000523 272 290 capsular cataracts HP:0100017 437 471 peripheral cortical lens opacities HP:0100019 477 494 neurofibromatosis HP:0006746 571 588 neurofibromatosis HP:0006746 603 632 peripheral cortical cataracts HP:0008011 722 751 peripheral cortical opacities HP:0008011 788 828 posterior subcapsular/capsular cataracts HP:0007787 798 828 subcapsular/capsular cataracts HP:0000523 810 828 capsular cataracts HP:0100017 870 903 cortical cataracts of early onset HP:0007876 920 960 posterior subcapsular/capsular cataracts HP:0007787 930 960 subcapsular/capsular cataracts HP:0000523 942 960 capsular cataracts HP:0100017 992 1009 neurofibromatosis HP:0006746

8755919

The gene predisposing to neurofibromatosis type 2 (NF2) on human chromosome 22 has revealed a wide variety of different mutations in NF2 individuals. These patients display a marked variability in clinical presentation, ranging from very severe disease with numerous tumors at a young age to a relatively mild condition much later in life. To investigate whether this phenotypic heterogeneity is determined by the type of mutation in NF2, we have collected clinical information on 111 NF2 cases from 73 different families on whom we have performed mutation screening in this gene. Sixty-seven individuals (56.2%) from 41 of these kindreds revealed 36 different putative disease-causing mutations. These include 26 proposed protein-truncating alterations (frameshift deletions/insertions and nonsense mutations), 6 splice-site mutations, 2 missense mutations, 1 base substitution in the 3' UTR of the NF2 cDNA, and a single 3-bp in-frame insertion. Seventeen of these mutations are novel, whereas the remaining 19 have been described previously in other NF2 individuals or sporadic tumors. When individuals harboring protein-truncating mutations are compared with cases with single codon alterations, a significant correlation (P < .001) with clinical outcome is observed. Twenty-four of 28 patients with mutations that cause premature truncation of the NF2 protein, schwannomin, present with severe phenotypes. In contrast, all 16 cases from three families with mutations that affect only a single amino acid have mild NF2. These data provide conclusive evidence that a phenotype/genotype correlation exists for certain NF2 mutations.

25 42 neurofibromatosis HP:0006746 182 193 variability HP:0003812 258 273 numerous tumors HP:0003008 279 288 young age HP:0003593 305 338 mild condition much later in life HP:0003664 379 392 heterogeneity HP:0001425 1072 1080 sporadic HP:0003745 1081 1087 tumors HP:0002664

7246489

Five new cases are presented of a syndrome characterized mainly by severe mental retardation, epilepsy, puppet-like ataxic movements, microbrachycephaly, prognathism, tongue protrusion, and inappropriate paroxysms of laughter. The cases are analyzed with reference to personal and family histories, clinical findings, and results of special investigations (biochemical, chromosomal, dermatoglyphic, EEG, and radiologic). The findings are compared with those in the 22 patients described previously. Though clinically distinctive, there is as yet no clear-cut evidence as to cause.

67 92 severe mental retardation HP:0002187 94 102 epilepsy HP:0001250 104 132 puppet-like ataxic movements HP:0001251 134 152 microbrachycephaly HP:0002258 154 165 prognathism HP:0000303 167 184 tongue protrusion HP:0010808 190 225 inappropriate paroxysms of laughter HP:0000748

8681379

The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of other tumors, and developmental abnormalities. NBCCS maps to chromosome 9q22.3. Familial and sporadic BCCs display loss of heterozygosity in this region, consistent with the gene being a tumor suppressor. A human sequence (PTC) with strong homology to the Drosophila segment polarity gene, patched, was isolated from a YAC and cosmid contig of the NBCCS region. Mutation analysis revealed alterations of PTC in NBCCS patients and in related tumors. We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types.

11 31 basal cell carcinoma HP:0002671 55 82 autosomal dominant disorder HP:0000006 109 130 basal cell carcinomas HP:0002671 139 156 pits of the palms HP:0010610 139 166 pits of the palms and soles HP:0010612 168 183 jaw keratocysts HP:0010603 198 210 other tumors HP:0003008 216 243 developmental abnormalities HP:0001263 291 299 sporadic HP:0003745 385 390 tumor HP:0002664 639 645 tumors HP:0002664 725 752 developmental abnormalities HP:0001263

10440824

We describe a 14-month-old girl with unilateral congenital cholesteatoma and anomalies of the facial nerve in addition to the more common branchial arch, otic, and renal malformations comprising the branchio-oto-renal (BOR) syndrome. Her mother also has the BOR syndrome and unilateral duplication of the facial nerve. This is the first study of a BOR patient with congenital cholesteatoma and the second family in which cholesteatoma and anomalies of the facial nerve are described in patients with the BO/BOR syndrome. We review the congenital cholesteatoma literature and discuss hypotheses for the pathogenesis of this entity in light of this new report.

59 72 cholesteatoma HP:0009797 77 106 anomalies of the facial nerve HP:0010827 138 183 branchial arch, otic, and renal malformations HP:0009794 138 147 branchial HP:0009794 154 183 otic, and renal malformations HP:0000598 164 183 renal malformations HP:0000792 275 317 unilateral duplication of the facial nerve HP:0010827 376 389 cholesteatoma HP:0009797 421 434 cholesteatoma HP:0009797 439 468 anomalies of the facial nerve HP:0010827 546 559 cholesteatoma HP:0009797

12219090

Interferon regulatory factor 6 (IRF6) belongs to a family of nine transcription factors that share a highly conserved helix-turn-helix DNA-binding domain and a less conserved protein-binding domain. Most IRFs regulate the expression of interferon-alpha and -beta after viral infection, but the function of IRF6 is unknown. The gene encoding IRF6 is located in the critical region for the Van der Woude syndrome (VWS; OMIM 119300) locus at chromosome 1q32-q41 (refs 2,3). The disorder is an autosomal dominant form of cleft lip and palate with lip pits, and is the most common syndromic form of cleft lip or palate. Popliteal pterygium syndrome (PPS; OMIM 119500) is a disorder with a similar orofacial phenotype that also includes skin and genital anomalies. Phenotypic overlap and linkage data suggest that these two disorders are allelic. We found a nonsense mutation in IRF6 in the affected twin of a pair of monozygotic twins who were discordant for VWS. Subsequently, we identified mutations in IRF6 in 45 additional unrelated families affected with VWS and distinct mutations in 13 families affected with PPS. Expression analyses showed high levels of Irf6 mRNA along the medial edge of the fusing palate, tooth buds, hair follicles, genitalia and skin. Our observations demonstrate that haploinsufficiency of IRF6 disrupts orofacial development and are consistent with dominant-negative mutations disturbing development of the skin and genitalia.

490 513 autosomal dominant form HP:0000006 517 526 cleft lip HP:0100333 517 537 cleft lip and palate HP:0000175 543 551 lip pits HP:0000196 594 613 cleft lip or palate HP:0000175 594 603 cleft lip HP:0100333 615 634 Popliteal pterygium HP:0009756 731 757 skin and genital anomalies HP:0000951 740 757 genital anomalies HP:0000078 1376 1384 dominant HP:0000006

9931336

Mutations of the human Patched gene ( PTCH ) have been identified in individuals with the nevoid basal cell carcinoma syndrome (NBCCS) as well as in sporadic basal cell carcinomas and medulloblastomas. We have isolated a homologue of this tumour suppressor gene and localized it to the short arm of chromosome 1 (1p32.1-32.3). Patched 2 ( PTCH2 ) comprises 22 coding exons and spans approximately 15 kb of genomic DNA. The gene encodes a 1203 amino acid putative transmembrane protein which is highly homologous to the PTCH product. We have characterized the genomic structure of PTCH2 and have used single-stranded conformational polymorphism analysis to search for mutations in PTCH2 in NBCCS patients, basal cell carcinomas and in medulloblastomas. To date, we have identified one truncating mutation in a medulloblastoma and a change in a splice donor site in a basal cell carcinoma, suggesting that the gene plays a role in the development of some tumours.

97 117 basal cell carcinoma HP:0002671 149 157 sporadic HP:0003745 158 179 basal cell carcinomas HP:0002671 184 200 medulloblastomas HP:0002885 705 726 basal cell carcinomas HP:0002671 734 750 medulloblastomas HP:0002885 809 824 medulloblastoma HP:0002885 866 886 basal cell carcinoma HP:0002671 953 960 tumours HP:0002664

15470370

Angelman syndrome (AS) can result from either a 15q11-q13 deletion (del), paternal uniparental disomy (UPD), imprinting, or UBE3A mutations. Here, we describe the phenotypic and behavioral variability detected in 49 patients with different classes of deletions and nine patients with UPD. Diagnosis was made by methylation pattern analysis of exon 1 of the SNRPN-SNURF gene and by microsatellite profiling of loci within and outside the 15q11-q13 region. There were no major phenotypic differences between the two main classes (BP1-BP3; BP2-BP3) of AS deletion patients, except for the absence of vocalization, more prevalent in patients with BP1-BP3 deletions, and for the age of sitting without support, which was lower in patients with BP2-BP3 deletions. Our data suggest that gene deletions (NIPA1, NIPA2, CYF1P1, GCP5) mapped to the region between breakpoints BP1 and BP2 may be involved in the severity of speech impairment, since all BP1-BP3 deletion patients showed complete absence of vocalization, while 38.1% of the BP2-BP3 deletion patients were able to pronounce syllabic sounds, with doubtful meaning. Compared to UPD patients, deletion patients presented a higher incidence of swallowing disorders (73.9% del x 22.2% UPD) and hypotonia (73.3% del x 28.57% UPD). In addition, children with UPD showed better physical growth, fewer or no seizures, a lower incidence of microcephaly, less ataxia and higher cognitive skills. As a consequence of their milder or less typical phenotype, AS may remain undiagnosed, leading to an overall underdiagnosis of the disease.

189 200 variability HP:0003812 586 609 absence of vocalization HP:0001344 912 929 speech impairment HP:0002167 983 1006 absence of vocalization HP:0001344 1192 1212 swallowing disorders HP:0002015 1241 1250 hypotonia HP:0001252 1351 1359 seizures HP:0001250 1382 1394 microcephaly HP:0000252 1401 1407 ataxia HP:0001251

16401744

Angelman syndrome (AS) is a neurogenetic disorder characterized by severe mental retardation, speech disorder, stereotyped jerky movements, and a peculiar behavioral profile, with a happy disposition and outbursts of laughter. Most patients with AS present with epilepsy and suggestive electroencephalographic patterns, which may be used as diagnostic criteria. To study epilepsy and response to treatment in a series of patients with AS determined by deletion. Parent and caregiver interview and medical record review. Epilepsy Center at the University of São Paulo. Nineteen patients with AS determined by deletion of chromosome 15q11-13. Epilepsy severity, epilepsy evolution, and response to antiepileptic drug treatment. All patients with AS in this group had generalized epilepsy, and 10 (53%) also had partial epilepsy. Main seizure types were atypical absences and myoclonic and tonic-clonic seizures. Mean age at onset was 1 year 1 month. Epilepsy aggravated by fever occurred in 10 patients (53%) and status epilepticus in 16 (84%). Eighteen patients (95%) had previous or current history of daily seizures, of which 14 (64%) had disabling seizures. Multiple seizure types were observed in 13 patients (53%). History of refractory epilepsy was reported in 16 patients (84%). Parents reported improvement, characterized by decrease in seizure frequency or seizure control, at the mean age of 5.3 years. Therefore, most of these patients had a period of refractory epilepsy; however, improvement occurred during late childhood and puberty. The best therapeutic response was obtained with valproic acid alone or in association with phenobarbital or clonazepam. Epilepsy was aggravated by carbamazepine, oxcarbazepine, and vigabatrin. Patients with AS with deletion have epilepsy with early onset and stereotyped electroclinical profile regarding seizure type, severity, and response to antiepileptic drug treatment. Another feature of AS is the age-related improvement, even in refractory cases, during late childhood and puberty. These characteristics are not specific to this syndrome but, when inserted in the proper clinical context, may anticipate diagnosis. We believe that AS should be considered a differential diagnosis in developmentally delayed infants with severe, generalized, cryptogenic epilepsy; however, a proper electroclinical delineation of each genetic group is mandatory.

67 92 severe mental retardation HP:0002187 94 109 speech disorder HP:0007170 111 138 stereotyped jerky movements HP:0007087 155 173 behavioral profile HP:0000715 182 199 happy disposition HP:0100024 204 225 outbursts of laughter HP:0000749 262 270 epilepsy HP:0001250 286 318 electroencephalographic patterns HP:0002353 372 380 epilepsy HP:0001250 523 531 epilepsy HP:0001250 646 654 epilepsy HP:0001250 665 673 epilepsy HP:0001250 783 791 epilepsy HP:0001250 823 831 epilepsy HP:0001250 838 845 seizure HP:0001250 857 874 atypical absences HP:0007270 879 914 myoclonic and tonic-clonic seizures HP:0002123 879 888 myoclonic HP:0001336 893 914 tonic-clonic seizures HP:0002069 954 962 Epilepsy HP:0001250 977 982 fever HP:0001945 1017 1035 status epilepticus HP:0002133 1114 1122 seizures HP:0001250 1156 1164 seizures HP:0001250 1175 1182 seizure HP:0001250 1247 1255 epilepsy HP:0001250 1350 1357 seizure HP:0001250 1371 1378 seizure HP:0001250 1479 1487 epilepsy HP:0001250 1531 1540 childhood HP:0011463 1674 1682 Epilepsy HP:0001250 1784 1792 epilepsy HP:0001250 1798 1809 early onset HP:0003593 1826 1849 electroclinical profile HP:0002353 1860 1867 seizure HP:0001250 2022 2031 childhood HP:0011463 2246 2269 developmentally delayed HP:0001263 2316 2324 epilepsy HP:0001250

1951448

We report on 2 children with Townes-Brocks syndrome (TBS) and mental retardation. One child had mild hearing loss, but the other only had hearing loss at 8000 Hz. These cases suggest that there may be an increased incidence of mental retardation in individuals with TBS.

62 80 mental retardation HP:0001249 101 113 hearing loss HP:0000365 138 150 hearing loss HP:0000365 227 245 mental retardation HP:0001249

10417280

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct neurobehavioral disorders that most often arise from a 4-Mb deletion of chromosome 15q11-q13 during paternal or maternal gametogenesis, respectively. At a de novo frequency of approximately.67-1/10,000 births, these deletions represent a common structural chromosome change in the human genome. To elucidate the mechanism underlying these events, we characterized the regions that contain two proximal breakpoint clusters and a distal cluster. Novel DNA sequences potentially associated with the breakpoints were positionally cloned from YACs within or near these regions. Analyses of rodent-human somatic-cell hybrids, YAC contigs, and FISH of normal or rearranged chromosomes 15 identified duplicated sequences (the END repeats) at or near the breakpoints. The END-repeat units are derived from large genomic duplications of a novel gene (HERC2), many copies of which are transcriptionally active in germline tissues. One of five PWS/AS patients analyzed to date has an identifiable, rearranged HERC2 transcript derived from the deletion event. We postulate that the END repeats flanking 15q11-q13 mediate homologous recombination resulting in deletion. Furthermore, we propose that active transcription of these repeats in male and female germ cells may facilitate the homologous recombination process.

68 93 neurobehavioral disorders HP:0000708 223 230 de novo HP:0003745

3105060

Bilateral acoustic neurofibromatosis (BANF) is a genetic defect associated with multiple tumors of neural crest origin. Specific loss of alleles from chromosome 22 was detected with polymorphic DNA markers in two acoustic neuromas, two neurofibromas, and one meningioma from BANF patients. This indicates a common pathogenetic mechanism for all three tumor types. The two neurofibromas were among three taken from the same patient, and both showed loss of identical alleles demonstrating that the same chromosome suffered deletion in both tumors. The third neurofibroma from this patient showed no detectable loss of heterozygosity, which suggests the possibility of a more subtle mutational event that affects chromosome 22. In the two acoustic neuromas, only a portion of chromosome 22 was deleted, narrowing the possible chromosomal location of the gene that causes BANF to the region distal to the D22S9 locus in band 22q11. The identification of progressively smaller deletions on chromosome 22 in these tumor types may well provide a means to clone and characterize the defect.

0 36 Bilateral acoustic neurofibromatosis HP:0009589 38 42 BANF HP:0009589 80 111 multiple tumors of neural crest HP:0004375 213 230 acoustic neuromas HP:0009588 236 249 neurofibromas HP:0001067 259 269 meningioma HP:0002858 351 356 tumor HP:0002664 372 385 neurofibromas HP:0001067 539 545 tumors HP:0002664 557 569 neurofibroma HP:0001067 737 754 acoustic neuromas HP:0009588 1009 1014 tumor HP:0002664

18423521

Branchio-oculo-facial syndrome (BOFS) is a rare autosomal-dominant cleft palate-craniofacial disorder with variable expressivity. The major features include cutaneous anomalies (cervical, infra- and/or supra-auricular defects, often with dermal thymus), ocular anomalies, characteristic facial appearance (malformed pinnae, oral clefts), and, less commonly, renal and ectodermal (dental and hair) anomalies. The molecular basis for this disorder is heretofore unknown. We detected a 3.2 Mb deletion by 500K SNP microarray in an affected mother and son with BOFS at chromosome 6p24.3. Candidate genes in this region were selected for sequencing on the basis of their expression patterns and involvement in developmental pathways associated with the clinical findings of BOFS. Four additional BOFS patients were found to have de novo missense mutations in the highly conserved exons 4 and 5 (basic region of the DNA binding domain) of the TFAP2A gene in the candidate deleted region. We conclude BOFS is caused by mutations involving TFAP2A. More patients need to be studied to determine possible genetic heterogeneity and to establish whether there are genotype-phenotype correlations.

48 66 autosomal-dominant HP:0000006 67 79 cleft palate HP:0000175 80 101 craniofacial disorder HP:0002260 107 128 variable expressivity HP:0003828 157 176 cutaneous anomalies HP:0000951 188 225 infra- and/or supra-auricular defects HP:0000377 254 270 ocular anomalies HP:0000284 287 304 facial appearance HP:0001999 306 322 malformed pinnae HP:0000356 324 335 oral clefts HP:0000202 358 406 renal and ectodermal (dental and hair) anomalies HP:0000077 368 406 ectodermal (dental and hair) anomalies HP:0000164 824 831 de novo HP:0003745 1095 1116 genetic heterogeneity HP:0001425

8145850

The mutation brachypodism (bp) alters the length and number of bones in the limbs of mice but spares the axial skeleton. It illustrates the importance of specific genes in controlling the morphogenesis of individual skeletal elements in the tetrapod limb. We now report the isolation of three new members of the transforming growth factor-beta (TGF-beta) superfamily (growth/differentiation factors (GDF) 5,6 and 7) and show by mapping, expression patterns and sequencing that mutations in Gdf5 are responsible for skeletal alterations in bp mice. GDF5 and the closely related GDF6 and GDF7 define a new subgroup of factors related to known bone- and cartilage-inducing molecules, the bone morphogenetic proteins (BMPs). Studies of Bmp5 mutations in short ear mice have shown that at least one other BMP gene is also required for normal skeletal development. The highly specific skeletal alterations in bp and short ear mice suggest that different members of the BMP family control the formation of different morphological features in the mammalian skeleton.

750 759 short ear HP:0400005 910 919 short ear HP:0400005

7747758

To determine the spectrum of manifestations in neurofibromatosis 2 (NF2) and to assess possible heterogeneity, we evaluated 63 affected individuals from 32 families. Work-up included skin and neurologic examinations, audiometry, a complete ophthalmology examination with slit-lamp biomicroscopy of the lens and fundus, and gadolinium-enhanced MRI of the brain and, in some, of the spine. Mean age-at-onset in 58 individuals was 20.3 years; initial symptoms resulted from vestibular schwannomas (44.4%), other CNS tumors (22.2%), skin tumors (12.7%), and ocular manifestations including cataracts and retinal hamartomas (12.7%). Five asymptomatic individuals were diagnosed through screening. Vestibular schwannomas were documented in 62 individuals (98.4%); other findings included cataracts (81.0%), skin tumors (67.7%), spinal tumors (67.4%), and meningiomas (49.2%). Usually, clinical manifestations and course were similar within families but differed among families. To assess possible heterogeneity, we assigned affected individuals to three proposed subtypes (representing mild, intermediate, and severe NF2) based on age-at-onset, presence or absence of CNS tumors other than vestibular schwannomas, and presence or absence of retinal hamartomas. Comparisons among the three subtypes for many clinical parameters demonstrated that patients in the mild subtype differed from those in the other two subtypes for most parameters, but that none of the parameters distinguished patients in the intermediate subtype from those in the severe subtype. Thus, there are likely two rather than three subtypes of NF2. Classification of patients to subtype may aid in counseling about long-term prognosis and in formulating individualized guidelines for medical surveillance.

47 64 neurofibromatosis HP:0006746 96 109 heterogeneity HP:0001425 471 493 vestibular schwannomas HP:0009588 509 519 CNS tumors HP:0004375 529 540 skin tumors HP:0008069 554 575 ocular manifestations HP:0000478 586 595 cataracts HP:0000518 600 618 retinal hamartomas HP:0009594 692 714 Vestibular schwannomas HP:0009588 782 791 cataracts HP:0000518 801 812 skin tumors HP:0008069 822 835 spinal tumors HP:0010302 849 860 meningiomas HP:0002858 991 1004 heterogeneity HP:0001425 1162 1172 CNS tumors HP:0004375 1184 1206 vestibular schwannomas HP:0009588 1235 1253 retinal hamartomas HP:0009594

10196695

Angelman syndrome (AS) is a neurodevelopmental disorder caused by the absence of a maternal contribution to chromosome 15q11-q13. There are four classes of AS according to molecular or cytogenetic status: maternal microdeletion of 15q11-q13 (approximately 70% of AS patients); uniparental disomy (UPD); defects in a putative imprinting centre (IM); the fourth includes 20-30% of AS individuals with biparental inheritance and a normal pattern of allelic methylation in 15q11-q13. Mutations of UBE3A have recently been identified as causing AS in the latter group. Few studies have investigated the phenotypic differences between these classes. We compared 20 non-deletion to 20 age-matched deletion patients and found significant phenotypic differences between the two groups. The more severe phenotype in the deletion group may suggest a contiguous gene syndrome.

28 55 neurodevelopmental disorder HP:0000707 839 863 contiguous gene syndrome HP:0001466

7057963

Fifteen patients with bilateral acoustic neuromas are presented. Ten patients became symptomatic before age 21, and 9 of these patients developed additional central nervous system tumors. Cutaneous manifestations of neurofibromatosis and a positive family history of this disorder were absent in many of the patients. Most patients required multiple surgical procedures, and the timing, techniques, and results of these operations are reported. The pathogenesis of these tumors, the genetic aspects of this disorder, and potential treatment alternatives are discussed.

22 49 bilateral acoustic neuromas HP:0009589 157 186 central nervous system tumors HP:0100006 188 212 Cutaneous manifestations HP:0000951 216 233 neurofibromatosis HP:0006746 471 477 tumors HP:0002664

8923935

Since the group of disorders known as the distal arthrogryposes (DAs) were defined, additional disorders characterized by multiple congenital contractures of the distal limbs were described, and the distribution of phenotypic findings in the DAs has been expanded. The breadth of disorders labeled as DAs has diminished the usefulness of the DA classification. We propose a strict definition of DA and diagnostic criteria for DA disorders. Subsequently, we use these standards and propose a revised classification of discrete conditions that should be labeled DAs. Optimally, this serves as a framework for a DA classification based on underlying molecular and physiologic abnormalities.

42 63 distal arthrogryposes HP:0005684 122 154 multiple congenital contractures HP:0005188 142 174 contractures of the distal limbs HP:0003121

1496981

The neurofibromatosis type 2 (NF2) gene has been hypothesized to be a recessive tumor suppressor, with mutations at the same locus on chromosome 22 that lead to NF2 also leading to sporadic tumors of the types seen in NF2. Flanking markers for this gene have previously been defined as D22S1 centromeric and D22S28 telomeric. Identification of subregions of this interval that are consistently rearranged in the NF2-related tumors would aid in better defining the disease locus. To this end, we have compared tumor and constitutional DNAs, isolated from 39 unrelated patients with sporadic and NF2-associated acoustic neuromas, meningiomas, schwannomas, and ependymomas, at eight polymorphic loci on chromosome 22. Two of the tumors studied revealed loss-of-heterozygosity patterns, which is consistent with the presence of chromosome 22 terminal deletions. By using additional polymorphic markers, the terminal deletion breakpoint found in one of the tumors, an acoustic neuroma from an NF2 patient, was mapped within the previously defined NF2 region. The breakpoint occurred between the haplotyped markers D22S41/D22S46 and D22S56. This finding redefines the proximal flanking marker and localizes the NF2 gene between markers D22S41/D22S46 and D22S28. In addition, we identified a sporadic acoustic neuroma that reveals a loss-of-heterozygosity pattern consistent with mitotic recombination or deletion and reduplication, which are mechanisms not previously seen in studies of these tumors. This finding, while inconsistent with models of tumorigenesis that invoke single deletions and their gene-dosage effects, lends further support to the recessive tumor-suppressor model.

4 21 neurofibromatosis HP:0006746 80 85 tumor HP:0002664 181 189 sporadic HP:0003745 190 196 tumors HP:0002664 424 430 tumors HP:0002664 509 514 tumor HP:0002664 581 589 sporadic HP:0003745 609 626 acoustic neuromas HP:0009588 628 639 meningiomas HP:0002858 641 652 schwannomas HP:0100008 658 669 ependymomas HP:0002888 726 732 tumors HP:0002664 952 958 tumors HP:0002664 963 979 acoustic neuroma HP:0009588 1285 1293 sporadic HP:0003745 1294 1310 acoustic neuroma HP:0009588 1487 1493 tumors HP:0002664 1656 1661 tumor HP:0002664

6973119

The results of a systematic study of the otological aspects in 13 cases of earpit-deafness syndrome are reported. The audiometric, radiological and vestibular findings as well as the results of exploratory tympanotomies with and without stapedectomies are discussed together with the results reported in the literature. A convincing explanation of the poor results of exploratory tympanotomies in cases with mixed hearing loss is not furnished. If the hearing loss is confined to conduction and ankylosis of the stapes or a disconnection of the ossicular chain is suspected, exploratory tympanotomy can be expected to be successful.

75 81 earpit HP:0004467 82 90 deafness HP:0000404 408 426 mixed hearing loss HP:0000410 452 464 hearing loss HP:0000365 480 490 conduction HP:0000405 495 518 ankylosis of the stapes HP:0000381 524 560 disconnection of the ossicular chain HP:0004452

19533801

Gorlin syndrome (GS) is inherited in an autosomal dominant pattern with high-penetrance and is characterized by a range of developmental anomalies and increased risk of developing basal cell carcinoma and medulloblastoma. Between 50% and 85% of patients with GS harbor germ line mutations in the only susceptibility gene identified to date, PTCH1, a key component in the Sonic Hedgehog signaling pathway. Another component in this pathway, SUFU, is known to be involved in susceptibility to medulloblastoma but has never been reported in GS patients to date. We have identified the known c.1022 + 1G>A SUFU germ line splicing mutation in a family that was PTCH1-negative and who had signs and symptoms of GS, including medulloblastoma. This is the first report of a germ line SUFU mutation associated with GS.

40 58 autosomal dominant HP:0000006 180 200 basal cell carcinoma HP:0002671 205 220 medulloblastoma HP:0002885 491 506 medulloblastoma HP:0002885 719 734 medulloblastoma HP:0002885

9546330

We compared epilepsy phenotypes with genotypes of Angelman syndrome (AS), including chromosome 15q11-13 deletions (class I), uniparental disomy (class II), methylation imprinting abnormalities (class III), and mutation in the UBE3A gene (class IV). Twenty patients were prospectively selected based on clinical cytogenetic and molecular diagnosis of AS. All patients had 6 to 72 hours of closed-circuit television videotaping and digitized electroencephalogrpahic (EEG) telemetry. Patients from all genotypic classes had characteristic EEGs with diffuse bifrontally dominant high-amplitude 1- to 3-Hz notched or triphasic or polyphasic slow waves, or slow and sharp waves. Class I patients had severe intractable epilepsy, most frequently with atypical absences and myoclonias and less frequently with generalized extensor tonic seizures or flexor spasms. Epileptic spasms were recorded in AS patients as old as 41 years. Aged-matched class II, III, and IV patients had either no epilepsy or drug-responsive mild epilepsy with relatively infrequent atypical absences, myoclonias, or atonic seizures. In conclusion, maternally inherited chromosome 15q11-13 deletions produce severe epilepsy. Loss-of-function UBE3A mutations, uniparental disomy, or methylation imprint abnormalities in AS are associated with relatively mild epilepsy. Involvement of other genes in the chromosome 15q11-13 deletion, such as GABRB3, may explain severe epilepsy in AS.

12 20 epilepsy HP:0001250 521 540 characteristic EEGs HP:0002353 566 574 dominant HP:0000006 701 721 intractable epilepsy HP:0001275 744 761 atypical absences HP:0007270 766 776 myoclonias HP:0001336 802 837 generalized extensor tonic seizures HP:0002069 841 854 flexor spasms HP:0004305 856 872 Epileptic spasms HP:0011097 980 988 epilepsy HP:0001250 1013 1021 epilepsy HP:0001250 1049 1066 atypical absences HP:0007270 1068 1078 myoclonias HP:0001336 1083 1098 atonic seizures HP:0010819 1181 1189 epilepsy HP:0001250 1324 1332 epilepsy HP:0001250 1433 1441 epilepsy HP:0001250

11343340

The diagnosis of Angelman syndrome (AS) can be confirmed by genetic laboratory in about 80% of cases. In 20%, the diagnosis remains clinical, but often there is uncertainty about the correctness of the clinical diagnosis and alternative diagnoses may be investigated. In evaluating individuals for AS in our center since 1989, we have encountered several mimicking conditions, and additional ones have been reported in the literature. Mimicking conditions can be grouped into the areas of chromosome, single gene, and symptom complex anomalies. Microdeletions or microduplications include chromosome regions 2,4,17, 22, and 15. Single gene conditions include methylene tetrahydrofolate reductase deficiency (MTHFR), Rett syndrome, alpha-thalassemia retardation syndrome (ATR-X), and Gurrieri syndrome. Symptom complexes include cerebral palsy, static encephalopathy, Lennox-Gastaut syndrome, autism spectrum disorder, pervasive developmental delay (PDD), and mitochondrial disorders. We present a review of these mimicking disorders to increase the awareness about conditions that can lead to an incorrect clinical diagnosis of AS.

749 760 retardation HP:0001249 828 842 cerebral palsy HP:0100021 851 865 encephalopathy HP:0001298 892 916 autism spectrum disorder HP:0000729 918 947 pervasive developmental delay HP:0000729

17307835

Neurofibromatosis type 2 (NF2) is almost unique among inherited disorders in the frequency of mosaicism in the first affected generation. However, the implications of this on transmission risks have not been fully elucidated. The expanded database of 460 families with NF2 and 704 affected individuals was analysed for mosaicism and transmission risks to offspring. 64 mosaic patients, with a projected mosaicism rate of 33% for sporadic classical NF2 with bilateral vestibular schwannoma at presentation and 60% for those presenting unilaterally, were identified. Offspring risks can be radically reduced on the basis of a sensitive mutation analysis of blood DNA including multiple ligation-dependent probe amplification (MLPA, which detects 15% of all mutations), but even MLPA cannot detect high levels of mosaicism. The chances of mosaicism in NF2 and the resultant risks of transmission of the mutation to offspring in a number of different clinical situations have been further delineated. The use of MLPA in this large NF2 series is also reported for the first time.

0 17 Neurofibromatosis HP:0006746 94 103 mosaicism HP:0001442 320 329 mosaicism HP:0001442 405 414 mosaicism HP:0001442 431 439 sporadic HP:0003745 459 490 bilateral vestibular schwannoma HP:0009589 839 848 mosaicism HP:0001442

11837604

Intrafamilial clinical variability in type C brachydactyly: In this report we describe a 4-generation family in which three members present variable clinical and radiological manifestations of brachydactyly type C. The observation of 'skipped generations' in the present family and in a few other families reported previously, may indicate that brachydactyly type C is not a true autosomal dominant condition due to mutations in a single gene.

0 34 Intrafamilial clinical variability HP:0003822 38 58 type C brachydactyly HP:0009373 140 148 variable HP:0003813 193 213 brachydactyly type C HP:0009373 345 358 brachydactyly HP:0001156 380 398 autosomal dominant HP:0000006

3688021

Two unrelated females, age 15 and 5 years respectively, were studied cytogenetically because of severe mental retardation, seizures and ataxia-like incoordination. A similar deletion of the proximal long arm of chromosome 15 was found in both patients. Re-evaluation showed no voracious appetite or obesity; normal size of hands and feet, minimal to no hypotonia by history or examination and facial features not typical of the Prader-Willi syndrome. However, the facial appearance of the girls was similar to each other with mild hypertelorism. The similarity of these girls and dissimilarity to Prader-Willi syndrome suggest a different syndrome, perhaps the result of deletion of a different segment of 15q. The findings of ataxic-like movements, frequent, unprovoked and prolonged bouts of laughter and facial appearance are more compatible with the diagnosis of Angelman syndrome.

96 121 severe mental retardation HP:0002187 123 131 seizures HP:0001250 136 142 ataxia HP:0001251 148 162 incoordination HP:0002311 277 295 voracious appetite HP:0002591 299 306 obesity HP:0001513 353 362 hypotonia HP:0001252 464 481 facial appearance HP:0001999 531 544 hypertelorism HP:0000316 727 748 ataxic-like movements HP:0001251 750 802 frequent, unprovoked and prolonged bouts of laughter HP:0000749 794 802 laughter HP:0000748 807 824 facial appearance HP:0001999

12473765

Four sets of clinical diagnostic criteria for neurofibromatosis 2 (NF2) have been developed by groups of expert clinicians, but sensitivity has never been formally assessed. The sets of criteria differ for people without bilateral vestibular schwannomas, which are pathognomonic for NF2. To empirically evaluate the four existing sets of clinical diagnostic criteria for NF2. The study was based on 163 of 403 people in the United Kingdom NF2 registry (41%) who presented without bilateral vestibular schwannomas. The authors applied the sets of criteria to each person at initial assessment and at the most recent clinical evaluation (mean +/- SE length of follow-up, 13 +/- 1 years). In people with "definite NF2" and a negative family history of NF2, the 1987 US NIH and 1991 NIH criteria each identify 78% of people at the most recent clinical evaluation but 0% at initial assessment. The National Neurofibromatosis Foundation (NNFF) criteria and the Manchester criteria each identify higher proportions at both time points (NNFF criteria, 91% and 10%; Manchester criteria, 93% and 14%), but the proportions at initial assessment are still low. None of the existing sets of criteria are adequate at initial assessment for diagnosing people who present without bilateral vestibular schwannomas as having NF2, particularly people with a negative family history of NF2. The authors recommend that a single, revised set of diagnostic criteria be devised to replace all of the existing sets of criteria.

46 63 neurofibromatosis HP:0006746 221 253 bilateral vestibular schwannomas HP:0009589 482 514 bilateral vestibular schwannomas HP:0009589 1268 1300 bilateral vestibular schwannomas HP:0009589

19206155

Branchio-oto-renal syndrome is a heterogeneous disorder inherited in an autosomal dominant pattern, characterized by branchial arch abnormalities, hearing loss and renal abnormalities, with mutations in EYA1 reported in 30-70% of patients. We have applied a molecular testing strategy of sequencing of the complete coding region/flanking intronic regions and multiple ligation probe amplification analysis of EYA1 to a pediatric branchio-oto-renal proband cohort. EYA1 mutations were identified in 82% (14/17) of the probands. We also describe a novel recurrent EYA1 mutation c.867 + 5G > A found in five unrelated affected patients. RNA analysis showed that c.867 + 5G > A affects EYA1 splicing, producing an aberrant mRNA transcript lacking exon 8 and resulting in premature termination in exon 9. The aberrant transcript was present at approximately 50% level of wild-type EYA1 mRNA in fibroblasts, and is predicted to encode an EYA1 protein retaining the amino terminal transcriptional coactivator region but lacking the conserved carboxy terminal Eya phosphatase domain. Patients with the c.867 + 5G > A mutation were found to have more severe renal abnormalities than probands with other mutations in this cohort. Analysis of the c.867 + 5G > A mutation suggests that certain transcripts of EYA1 escape nonsense-mediated decay and encode truncated EYA proteins that may be capable of dominant-negative interactions producing distinct phenotypic features within the branchio-oto-renal spectrum.

33 46 heterogeneous HP:0001425 72 90 autosomal dominant HP:0000006 117 145 branchial arch abnormalities HP:0009794 147 159 hearing loss HP:0000365 164 183 renal abnormalities HP:0000077

12136076

Mutations of the neurofibromatosis 2 (NF2) tumor suppressor gene cause the inherited disorder NF2 and are also common in malignant mesothelioma, which is not a characteristic feature of NF2. The authors report an asbestos-exposed person with NF2 and malignant mesothelioma. Immunohistochemical analysis of the mesothelioma confirmed loss of expression of the NF2 protein, and comparative genomic hybridization revealed losses of chromosomes 14, 15, and 22, and gain of 7. The authors propose that a person with a constitutional mutation of an NF2 allele is more susceptible to mesothelioma.

17 34 neurofibromatosis HP:0006746 43 48 tumor HP:0002664 121 143 malignant mesothelioma HP:0100001 250 272 malignant mesothelioma HP:0100001 310 322 mesothelioma HP:0100001 562 589 susceptible to mesothelioma HP:0006741

19476995

Neurofibromatosis type 2 is an autosomal-dominant multiple neoplasia syndrome that results from mutations in the NF2 tumour suppressor gene located on chromosome 22q. It has a frequency of one in 25,000 livebirths and nearly 100% penetrance by 60 years of age. Half of patients inherit a germline mutation from an affected parent and the remainder acquire a de novo mutation for neurofibromatosis type 2. Patients develop nervous system tumours (schwannomas, meningiomas, ependymomas, astrocytomas, and neurofibromas), peripheral neuropathy, ophthalmological lesions (cataracts, epiretinal membranes, and retinal hamartomas), and cutaneous lesions (skin tumours). Optimum treatment is multidisciplinary because of the complexities associated with management of the multiple, progressive, and protean lesions associated with the disorder. We review the molecular pathogenesis, genetics, clinical findings, and management strategies for neurofibromatosis type 2.

0 17 Neurofibromatosis HP:0006746 31 49 autosomal-dominant HP:0000006 50 68 multiple neoplasia HP:0003008 117 123 tumour HP:0002664 358 374 de novo mutation HP:0003745 379 396 neurofibromatosis HP:0006746 422 444 nervous system tumours HP:0004375 446 457 schwannomas HP:0100008 459 470 meningiomas HP:0002858 472 483 ependymomas HP:0002888 485 497 astrocytomas HP:0009592 503 516 neurofibromas HP:0001067 519 540 peripheral neuropathy HP:0009830 542 566 ophthalmological lesions HP:0000478 568 577 cataracts HP:0000518 579 599 epiretinal membranes HP:0100014 605 623 retinal hamartomas HP:0009594 630 647 cutaneous lesions HP:0000951 649 661 skin tumours HP:0008069 935 952 neurofibromatosis HP:0006746

8751853

Neurofibromatosis 2 (NF2) features bilateral vestibular schwannomas, other benign neural tumors, and cataracts. Patients in some families develop many tumors at an early age and have rapid clinical progression, whereas in other families, patients may not have symptoms until much later and vestibular schwannomas may be the only tumors. The NF2 gene has been cloned from chromosome 22q; most identified germ-line mutations result in a truncated protein and severe NF2. To look for additional mutations and clinical correlations, we used SSCP analysis to screen DNA from 32 unrelated patients. We identified 20 different mutations in 21 patients (66%): 10 nonsense mutations, 2 frameshifts, 7 splice-site mutations, and 1 large in-frame deletion. Clinical information on 47 patients from the 21 families included ages at onset and at diagnosis, numbers of meningiomas, spinal and skin tumors, and presence of cataracts and retinal abnormalities. We compared clinical findings in patients with nonsense or frameshift mutations to those with splice-site mutations. When each patient was considered as an independent random event, the two groups differed (P < or = .05) for nearly every variable. Patients with nonsense or frameshift mutations were younger at onset and at diagnosis and had a higher frequency and mean number of tumors, supporting the correlation between nonsense and frameshift mutations and severe NF2. When each family was considered as an independent random event, statistically significant differences between the two groups were observed only for mean ages at onset and at diagnosis. A larger data set is needed to resolve these discrepancies. We observed retinal hamartomas and/or epiretinal membranes in nine patients from five families with four different nonsense mutations. This finding, which may represent a new genotype-phenotype correlation, merits further study.

0 17 Neurofibromatosis HP:0006746 35 67 bilateral vestibular schwannomas HP:0009589 82 95 neural tumors HP:0004375 101 110 cataracts HP:0000518 146 157 many tumors HP:0003008 164 173 early age HP:0003593 290 312 vestibular schwannomas HP:0009588 329 335 tumors HP:0002664 855 866 meningiomas HP:0002858 879 890 skin tumors HP:0008069 908 917 cataracts HP:0000518 1183 1191 variable HP:0003813 1325 1331 tumors HP:0002664 1675 1693 retinal hamartomas HP:0009594 1701 1721 epiretinal membranes HP:0100014

8929945

We report the clinical features in 27 Australasian patients with Angelman syndrome (AS), all with a DNA deletion involving chromosome 15(q11-13), spanning markers from D15S9 to D15S12, about 3 center dot 5 Mb of DNA. There were nine males and 18 females. All cases were sporadic. The mean age at last review (end of 1994) was 11 center dot 2 years (range 3 to 34 years). All patients were ataxic, severely retarded, and lacking recognisable speech. In all patients, head circumference (HC) at birth was normal but skewed in distribution, with 62 center dot 5% at the 10th centile. At last review HC was around the 50th centile in three patients (12 center dot 5%) while 15 had poor postnatal head growth. Short stature was not invariable, 5/26 (19%) were on or above the 50th centile. Hypotonia at birth was recorded in 15/24 (63%) and neonatal feeding difficulties were recorded in 20/26 (77%). Epilepsy was present in 26/27 (96%) with onset by the third year of life in 20 patients (83%). Improvement in epilepsy was reported in 11/16 patients (69%) with age. An abnormal EEG was reported in 25/25 patients. Hypopigmentation was present in 19/26 (73%). One patient had oculocutaneous albinism. Five patients could not walk independently. Of the remaining 22 who could walk, age of onset of walking ranged from 2 to 8 years. Disrupted sleep patterns were present in 18/21 patients (86%), with improvement in 9/12 patients (75%) over 10 years of age. The clinical features in this group of deletional AS patients were similar to previous reports, but these have not separated patients into subgroups based on DNA studies. In our group of deletional cases, 100% showed severe mental retardation, ataxic movements, absent language, abnormal EEG, happy disposition (noted in infancy in 95%), normal birth weight and head circumference at birth, and a large, wide mouth. These features occurred with a higher frequency than in AS patients as a whole. Our study also provided information on the evolution of the phenotype. The data can act as a benchmark for comparisons of AS resulting from other genetic mechanisms.

270 278 sporadic HP:0003745 389 395 ataxic HP:0001251 397 414 severely retarded HP:0010864 420 448 lacking recognisable speech. HP:0001617 677 703 poor postnatal head growth HP:0000241 705 718 Short stature HP:0004322 785 803 Hypotonia at birth HP:0001319 836 865 neonatal feeding difficulties HP:0008872 896 904 Epilepsy HP:0001250 1006 1014 epilepsy HP:0001250 1065 1077 abnormal EEG HP:0002353 1110 1126 Hypopigmentation HP:0007513 1171 1194 oculocutaneous albinism HP:0001107 1210 1238 could not walk independently HP:0002540 1326 1350 Disrupted sleep patterns HP:0002360 1668 1693 severe mental retardation HP:0002187 1695 1711 ataxic movements HP:0001251 1713 1728 absent language HP:0002463 1730 1742 abnormal EEG HP:0002353 1744 1761 happy disposition HP:0100024 1772 1779 infancy HP:0003576 1855 1865 wide mouth HP:0000154

9863591

Patients who present with unilateral vestibular schwannomas either at a young age or with additional features of type 2 neurofibromatosis (NF2) are at risk of developing bilateral disease and transmitting a risk of neurogenic tumours to their offspring. We have identified 15 patients from a series of 537 with unilateral vestibular schwannomas who also had one or more of the following: other tumours (10/15), features of NF2 (3/15), or a family history of neurogenic tumours (5/15). No germline NF2 mutations were detected and in 7/9 cases where tumour material was available for analysis a germline mutation in the NF2 gene has been excluded. Although a possibility of gonosomal mosaicism still exists, exclusion tests for the offspring are now possible. We suggest a general strategy, based on analysis of tumour DNA, for distinguishing sporadic and familial cases of tumours caused by two hit mechanisms. Application of this strategy suggests that most instances of unilateral vestibular schwannoma which do not fulfil criteria for NF2 represent chance occurrences.

26 59 unilateral vestibular schwannomas HP:0009590 72 81 young age HP:0003593 120 137 neurofibromatosis HP:0006746 170 187 bilateral disease HP:0009589 215 233 neurogenic tumours HP:0004375 311 344 unilateral vestibular schwannomas HP:0009590 394 401 tumours HP:0002664 458 476 neurogenic tumours HP:0004375 548 554 tumour HP:0002664 810 816 tumour HP:0002664 841 849 sporadic HP:0003745 854 868 familial cases HP:0000005 872 879 tumours HP:0002664 971 1003 unilateral vestibular schwannoma HP:0009590

7628117

Three successive generations in two families affected with the popliteal pterygium syndrome are reported. While expression of the syndrome was relatively mild in the first and second generation, the patients in the third generation showed the full-blown syndrome. Differential diagnosis between mildly affected patients with the popliteal pterygium syndrome and those with Van der Woude syndrome is difficult and may even be impossible. The present observations further support the hypothesis that both syndromes may in fact represent variants of the same condition.

63 82 popliteal pterygium HP:0009756 329 348 popliteal pterygium HP:0009756

7450780

Two siblings with the "happy puppet" syndrome are presented. Their clinical features are quite similar and closely resemble those of previously reported cases. These features include severe mental retardation, epileptic seizures, easily provoked and prolonged paroxysms of laughter, atactic jerky movements, hypotonia, large mandible with prognathia, and 2-3 cps spike and wave activity in the EEG. The occurrence of this syndrome in the two siblings suggests a genetic etiology possible as an autosomal recessive trait.

23 35 happy puppet HP:0100024 183 208 severe mental retardation HP:0002187 210 228 epileptic seizures HP:0002133 230 281 easily provoked and prolonged paroxysms of laughter HP:0000749 260 281 paroxysms of laughter HP:0000749 283 306 atactic jerky movements HP:0001251 308 317 hypotonia HP:0001252 319 333 large mandible HP:0000303 325 349 mandible with prognathia HP:0000303 355 397 2-3 cps spike and wave activity in the EEG HP:0010848 494 513 autosomal recessive HP:0000007

1479598

A clinical and genetic study of type 2 neurofibromatosis (NF2) has been carried out in the United Kingdom. Virtually complete ascertainment of cases in the north-west of England was achieved and suggests a population incidence of 1 in 33,000 to 40,000. In the UK as a whole, 150 cases have been identified and been used to study the clinical and genetic features of NF2. The autosomal dominant inheritance of NF2 was confirmed, 49% of cases were assessed as representing new mutations, and the mutation rate was estimated to be 6.5 x 10(-6). Evidence to support a maternal gene effect was found in that age at onset was 18.17 years in 36 maternally inherited cases and 24.5 in 20 paternally inherited cases (p = 0.027). The preponderance of maternally inherited cases was also significant (p = 0.03). Data are presented which suggest that there are two types of NF2, one with later onset and bilateral vestibular schwannomas as the only usual feature, and the other with earlier onset and multiple other tumours. A considerable number of cases did not fall easily into one or other group and other factors such as maternal effect on severity and anticipation need to be considered.

39 56 neurofibromatosis HP:0006746 375 405 autosomal dominant inheritance HP:0000006 892 924 bilateral vestibular schwannomas HP:0009589 1004 1011 tumours HP:0002664

18283415

Growth/differentiation factor 5 (GDF5) is a secreted growth factor that plays a key regulatory role in embryonic skeletal and joint development. Mutations in the GDF5 gene can cause different types of skeletal dysplasia, including brachydactyly type C (BDC) and proximal symphalangism (SYM1). We report two novel mutations in the GDF5 gene in Chinese families with distinct limb malformations. In one family affected with BDC, we identified a novel nonsense mutation, c.1461T > G (p.Y487X), which is predicted to truncate the GDF5 precursor protein by deleting 15 amino acids at its C-terminus. In one family with SYM1, we found a novel missense mutation, c.1118T > G (p.L373R), which changes a highly conserved amino acid in the prodomain of GDF5. We transfected COS-7 cells with retroviral constructs to express human wild-type or mutant GDF5 cDNAs. The mature GDF5 protein was detected, as in the wild-type, in supernatant derived from the p.L373R mutant GDF5 transfected cells, but not in the supernatant from the p.Y487X mutant transfected cells, indicating that the two mutations led to different fates of the mutant GDF5 proteins, thereby producing distinct limb phenotypes.

201 219 skeletal dysplasia HP:0002652 231 251 brachydactyly type C HP:0009373 253 256 BDC HP:0009373 262 284 proximal symphalangism HP:0100264 374 392 limb malformations HP:0002813

6774282

Neurofibromatosis includes the common "peripheral" form and a recently documented "central" form. We describe the central form in 130 cases from 9 kindreds personally studied and 15 reported kindreds. Central neurofibromatosis with bilateral acoustic neuroma is an autosomal dominant disorder beginning about 20 years of age, accompanied by mild skin changes. In three kindreds with central neurofibromatosis, we measured nerve growth factor in serum by radioimmunoassay and radioreceptor assay. Only the antigenic activity of nerve growth factor was increased. In contrast, in peripheral neurofibromatosis, only the functional activity of nerve growth factor has been reported increased. Central and peripheral forms of neurofibromatosis are closely related but discrete diseases which appear to have separate alterations in nerve growth factor activity.

0 17 Neurofibromatosis HP:0006746 209 226 neurofibromatosis HP:0006746 232 258 bilateral acoustic neuroma HP:0009589 265 292 autosomal dominant disorder HP:0000006 346 358 skin changes HP:0000951 391 408 neurofibromatosis HP:0006746 589 606 neurofibromatosis HP:0006746 721 738 neurofibromatosis HP:0006746

11078565

We present a child with mild to moderate global developmental delay including severe speech impairment, inappropriate happy demeanor, wide-based gait, frequent ear infections with mild hearing loss, deep-set eyes, a wide mouth, widely-spaced teeth, normal head circumference, and no seizures. Results of peripheral blood lymphocyte chromosomal analysis with GTG banding were normal. However, fluorescence in situ hybridization (FISH) studies showed mosaicism for a deletion of probes (D15S10 and SNRPN) from the Angelman syndrome (AS) critical region with approximately 40% of peripheral lymphocytes having the deletion. The deleted chromosome 15 also showed centromeric duplication, which was detected with a D15Z1 probe [46,XX, dic(15)(pter-->q11.1::p11.2-->q11. 1::q13-->qter)]. The same duplication pattern was observed in 30% of the nuclei obtained from a buccal smear. Methylation studies using polymerase chain reaction with sodium bisulfite-treated DNA demonstrated a normal biparental methylation pattern. To the best of our knowledge, this is the first case with AS and a FISH detectable deletion in a mosaic pattern. We recommend FISH studies for the detection of mosaicism in the patients with AS clinical findings even if results of the methylation studies are normal.

24 67 mild to moderate global developmental delay HP:0011342 85 102 speech impairment HP:0002167 104 132 inappropriate happy demeanor HP:0100024 134 149 wide-based gait HP:0002136 151 174 frequent ear infections HP:0000403 185 197 hearing loss HP:0000365 199 212 deep-set eyes HP:0000490 216 226 wide mouth HP:0000154 228 247 widely-spaced teeth HP:0000687 283 291 seizures HP:0001250

12011146

Neurofibromatosis type 2 (NF2) must be suspected in patients presenting with a unilateral vestibular schwannoma at a young age who are therefore at theoretical risk of developing bilateral disease. We identified 45 patients aged 30 years or less at the onset of symptoms of a unilateral vestibular schwannoma. Molecular genetic analysis of the NF2 gene was completed on peripheral blood samples in all 45 and on 28 tumour samples. No pathogenic NF2 mutations were identified in any of the blood samples. NF2 point mutations were identified in 21/28 (75%) tumour samples and loss of heterozygosity (LOH) in 21/28 (75%) tumour samples. Both mutational hits were identified in 18/28 (65%) tumour samples. In one multilobular tumour, one (presumably first hit) mutation was confirmed which was common to different foci of the tumour, while the second mutational event differed between foci. The molecular findings in this patient were consistent with somatic mosaicism for NF2 and the clinical diagnosis was confirmed with the presence of two meningiomas on a follow up MRI scan. A further patient developed a contralateral vestibular schwannoma on a follow up MRI scan in whom neither of the truncating mutations in the vestibular schwannoma were present in blood. It is important when counselling patients with unilateral vestibular schwannomas to identify (1) those at risk of bilateral disease, (2) those at risk of developing other tumours, and (3) other family members at risk of developing NF2. Comparing tumour and blood DNA cannot exclude mosaicism in the index case and cannot, therefore, be used to predict those at risk of developing further tumours. However, identification of both mutations or one mutation plus LOH in the tumour and exclusion of those mutations in the blood samples of the sibs or offspring of the affected case may be sufficient to render further screening unnecessary in these relatives.

0 17 Neurofibromatosis HP:0006746 79 111 unilateral vestibular schwannoma HP:0009590 117 126 young age HP:0003593 179 196 bilateral disease HP:0009589 276 308 unilateral vestibular schwannoma HP:0009590 415 421 tumour HP:0002664 555 561 tumour HP:0002664 618 624 tumour HP:0002664 686 692 tumour HP:0002664 722 728 tumour HP:0002664 822 828 tumour HP:0002664 947 964 somatic mosaicism HP:0001442 1039 1050 meningiomas HP:0002858 1106 1141 contralateral vestibular schwannoma HP:0009589 1217 1238 vestibular schwannoma HP:0009588 1309 1342 unilateral vestibular schwannomas HP:0009590 1376 1393 bilateral disease HP:0009589 1433 1440 tumours HP:0002664 1508 1514 tumour HP:0002664 1650 1657 tumours HP:0002664 1733 1739 tumour HP:0002664

11382639

To describe the ophthalmic and systemic features in a series of patients initially seen with eyelid basal cell carcinoma associated with Gorlin-Goltz syndrome. Retrospective noncomparative case series. Of 105 consecutive patients with eyelid basal cell carcinoma managed at an Ocular Oncology Center between January 1973 and December 1999, four patients with Gorlin-Goltz syndrome were identified. The ophthalmic and systemic features, management, and outcome of patients with eyelid basal cell carcinoma associated with Gorlin-Goltz syndrome were analyzed. The published literature on Gorlin-Goltz syndrome, specifically related to genetics, systemic features, ophthalmic associations, and prophylactic management strategies, was reviewed. Response of the eyelid basal cell carcinoma to treatment and the final systemic condition were the main outcome measures. All four patients had a family history of Gorlin-Goltz syndrome. The systemic manifestations included multiple basal cell carcinomas in all the patients, frontal bossing or increased occipitofrontal circumference in three patients, palmar pits in two patients, odontogenic keratocyst in one patient, ectopic calcification in one patient, and bifid rib in one patient. The mean age at the detection of the first basal cell carcinoma was 30 years (range, 16-38 years). All four patients had multiple basal cell carcinomas on the face and elsewhere. The eyelid basal cell carcinoma was advanced with orbital infiltration in three patients, one of whom opted for palliative radiotherapy, whereas the other two underwent orbital exenteration. The fourth patient, who had localized recurrent basal cell carcinoma in the upper eyelid, was treated with excision and eyelid reconstruction. At the final follow-up (mean, 41 months), eyelid basal cell carcinoma was cured in three patients and stable in one patient. No patient had life-threatening sequelae of Gorlin-Goltz syndrome. Gorlin-Goltz syndrome is a rare autosomal dominant cancer predisposition syndrome that may be associated with eyelid basal cell carcinoma. The associated systemic findings may be a clue to the diagnosis of this condition. It is important to recognize Gorlin-Goltz syndrome when a patient has multiple basal cell carcinomas or when a young patient with eyelid basal cell carcinoma is seen by an ophthalmologist, because lifelong monitoring is essential for patient management.

100 120 basal cell carcinoma HP:0002671 244 264 basal cell carcinoma HP:0002671 487 507 basal cell carcinoma HP:0002671 768 788 basal cell carcinoma HP:0002671 979 1000 basal cell carcinomas HP:0002671 1022 1037 frontal bossing HP:0002007 1041 1080 increased occipitofrontal circumference HP:0000256 1100 1111 palmar pits HP:0010610 1129 1151 odontogenic keratocyst HP:0010603 1168 1189 ectopic calcification HP:0010766 1210 1219 bifid rib HP:0000892 1279 1299 basal cell carcinoma HP:0002671 1366 1399 basal cell carcinomas on the face HP:0000271 1426 1446 basal cell carcinoma HP:0002671 1654 1674 basal cell carcinoma HP:0002671 1798 1818 basal cell carcinoma HP:0002671 1974 1992 autosomal dominant HP:0000006 1993 1999 cancer HP:0002664 2059 2079 basal cell carcinoma HP:0002671 2243 2264 basal cell carcinomas HP:0002671 2275 2280 young HP:0003593 2301 2321 basal cell carcinoma HP:0002671