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11152153

A 1-year-old male with branchio-oculo-facial syndrome together with preaxial polydatyly and a white forelock at birth is described. This is only the second case where preaxial polydactyly has been described in branchio-oculo-facial syndrome. In both cases a diagnosis of Waardenburg syndrome had been considered.

68 87 preaxial polydatyly HP:0100258 94 108 white forelock HP:0002211 167 187 preaxial polydactyly HP:0001177

1672177

Angelman's syndrome and Prader-Willi syndrome are both causes of mental retardation with recognisable, but quite different, clinical phenotypes. Both are associated with deletions of chromosome 15q11-13, of maternal origin in Angelman's and paternal in Prader-Willi. Prader-Willi can arise by inheritance of two chromosomes 15 from the mother and none from the father (uniparental maternal disomy). In 2 patients with Angelman's syndrome we found evidence of uniparental paternal disomy. The phenotypic effects of maternal and paternal disomy of chromosome 15 are very different and inheritance of two normal 15s from one parent does not lead to normal development--strong evidence in man for genomic imprinting, in which the same gene has different effects dependent upon its parental origin.

65 83 mental retardation HP:0001249

3092103

The application of recombinant DNA techniques has identified two fundamental mechanisms of tumorigenesis in man. The first involves a qualitative or quantitative change in an oncogene (see ref. 1 for review). In the second, discovered in embryonal tumours, a primary mutation occurs which is recessive at the cellular level to the normal allele. The growth of a tumour ensues only after a secondary change, such as chromosome loss or mitotic recombination, eliminates the normal allele, thereby unmasking the altered allele. Because its effect is recessive, the primary mutation may also occur and be transmitted in the germ line, resulting in a familial pattern for the disease. In familial cases, independent bilateral tumours are common, since the tumours result from a single event--loss of the normal genes--which can occur in any cell. This contrasts with non-familial (sporadic) cases where solitary tumours result from the infrequent occurrence of two rare events within the same cell. By a molecular genetic approach we have now shown that acoustic neuroma, one of the most common tumours of the human nervous system, is specifically associated with loss of genes on human chromosome 22 and may result from the mechanism of tumorigenesis discovered in embryonal tumours. This finding might provide a clue to the chromosomal location of the defective gene in bilateral acoustic neurofibromatosis, an autosomal dominant disorder with the hallmark of bilateral acoustic neuromas. In view of the frequent occurrence of meningiomas in patients with bilateral acoustic neurofibromatosis and the association of meningioma with loss of chromosome 22 previously reported in cytogenetic studies, we suggest that a common event underlies tumorigenesis in acoustic neuroma and meningioma.

248 255 tumours HP:0002664 721 728 tumours HP:0002664 751 758 tumours HP:0002664 876 884 sporadic HP:0003745 907 914 tumours HP:0002664 1049 1065 acoustic neuroma HP:0009588 1090 1125 tumours of the human nervous system HP:0004375 1271 1278 tumours HP:0002664 1367 1403 bilateral acoustic neurofibromatosis HP:0009589 1408 1435 autosomal dominant disorder HP:0000006 1457 1484 bilateral acoustic neuromas HP:0009589 1524 1535 meningiomas HP:0002858 1553 1589 bilateral acoustic neurofibromatosis HP:0009589 1613 1623 meningioma HP:0002858 1753 1769 acoustic neuroma HP:0009588 1774 1784 meningioma HP:0002858

9024575

Brachydactyly type C is characterized by shortness of the second and fifth middle phalanges and the first metacarpal. It is inherited as an autosomal dominant trait, and is noted for its widely variable clinical phenotype both within and between families. In most families involvement is limited to the hands. However, in some families additional skeletal and non-skeletal findings have been reported. We report on 12 affected members from a 5 generation kindred that segregates a brachydactyly type C phenotype. All affected individuals had shortness principally affecting the second and fifth phalanges and first metacarpal. However, the metacarpal-phalangeal profile indicated that other digital elements were short as well. In addition, one affected individual had a bilateral Madelung deformity, but none had foot involvement. No other non-skeletal findings cosegregated with brachydactyly in this family. Recently, a gene for brachydactyly type C has been localized to 12q24. This was done by studying a large kindred first reported by Haws [1963], which manifests both hand and foot anomalies. Here we present linkage data which excludes the 12q24 locus in our kindred, indicating locus heterogeneity as one explanation for the interfamilial variability described in brachydactyly type C.

0 20 Brachydactyly type C HP:0009373 41 91 shortness of the second and fifth middle phalanges HP:0004220 140 164 autosomal dominant trait HP:0000006 187 254 widely variable clinical phenotype both within and between families HP:0003822 194 202 variable HP:0003813 347 381 skeletal and non-skeletal findings HP:0000924 481 501 brachydactyly type C HP:0009373 542 625 shortness principally affecting the second and fifth phalanges and first metacarpal HP:0009536 771 799 bilateral Madelung deformity HP:0003067 814 830 foot involvement HP:0001760 881 894 brachydactyly HP:0001156 932 952 brachydactyly type C HP:0009373 1076 1099 hand and foot anomalies HP:0001155 1085 1099 foot anomalies HP:0001760 1188 1207 locus heterogeneity HP:0001425 1235 1260 interfamilial variability HP:0003812 1274 1294 brachydactyly type C HP:0009373

8414026

Neurofibromatosis 2 (NF2) is a dominantly inherited disorder characterized by multiple tumors of the central nervous system, predominantly bilateral vestibular schwannomas. The gene for NF2 is located in the chromosomal region 22q12 between the loci D22S1 and D22S28. We have performed genetic linkage analysis on 13 NF2 families with a total of nine polymorphic DNA markers, including five which we have recently mapped to this region. Two loci, D22S32 and NEFH, are linked to the NF2 locus at 0% recombination (lod scores of 6.03 and 4.28, respectively). By multipoint linkage analysis, we assign the NF2 gene to an interval of 7 cM, between the loci D22S212 and D22S28. We have used this set of nine markers to construct chromosome 22 haplotypes for the 82 at-risk individuals in this pedigree set. It has been possible to determine, with a high degree of certainty, the carrier status of 70 (85%) of these at-risk individuals. Risk prediction was possible in every case where DNA was available from both parents. Fifty-three of the 70 (76%) informative individuals were assigned decreased risks of being carriers. The use of chromosome 22 probes for risk assessment should result in a greatly reduced number of individuals who require periodic screening for NF2.

0 17 Neurofibromatosis HP:0006746 31 51 dominantly inherited HP:0000006 87 123 tumors of the central nervous system HP:0100006 139 171 bilateral vestibular schwannomas HP:0009589

11338037

In this report we present a subject affected by nevoid basal cell carcinoma syndrome (NBCCS), showing also bilateral mandibular coronoid processes hyperplasia, a hitherto unreported association. Our observation of bilateral hyperplasia of the mandibular coronoid processes in a boy with NBCCS may prompt a retrospective and prospective review of other patients affected by this syndrome in order to establish if this anomaly is part of it.

55 75 basal cell carcinoma HP:0002671 107 158 bilateral mandibular coronoid processes hyperplasia HP:0000277 214 272 bilateral hyperplasia of the mandibular coronoid processes HP:0000277

15150776

Mutations have been found in the UBE3A gene (E6-AP ubiquitin protein ligase gene) in many Angelman syndrome (AS) patients with no deletion, no uniparental disomy, and no imprinting defect. UBE3A mutations are more frequent in familial than in sporadic patients and the mutations described so far seem to cause similar phenotypes in the familial affected cases. Here we describe two first cousins who have inherited the same UBE3A frameshift mutation (duplication of GAGG in exon 10) from their asymptomatic mothers but present discordant phenotypes. The proband shows typical AS features. Her affected cousin shows a more severe phenotype, with asymmetric spasticity that led originally to a diagnosis of cerebral palsy. Proband's brain MRI shows mild cerebral atrophy while her cousin's brain MRI shows severe brain malformation. This family demonstrates that, although brain malformation is unusual in AS, presence of a brain malformation does not exclude the diagnosis of AS. Also, this UBE3A mutation was transmitted from the cousin's grandfather to only two sisters among eight full siblings, raising the hypothesis of mosaicism for this mutation.

243 251 sporadic HP:0003745 656 666 spasticity HP:0001257 705 719 cerebral palsy HP:0100021 752 768 cerebral atrophy HP:0002059 871 889 brain malformation HP:0007319

8592325

Type A1 brachydactyly in humans is a recognisable syndrome characterised by shortening of the middle phalanx of all digits with occasional fusion of the middle and terminal phalanges. The purpose of this study was to evaluate candidate genes for type A1 brachydactyly in two families with multiple affected members. Several classes of genes have been implicated in the control of distal limb development including homeobox containing genes (MSX1, MSX2) some members of the homeobox gene family, and genes encoding growth factors of the FGF, TGF, and PDGF families. Homeobox (Hox) genes are a family of developmental control genes activated early in embryogenesis that encode positional information along the anterior-posterior body axis and specify distinct spatial domains within developing limbs. Growth factor genes can regulate the proliferation and differentiation of various embryonic structures including limb buds and have been shown to influence Hox gene expression. Candidate genes HOXD, MSX1, MSX2, FGF-1, and FGF-2 were excluded in one family. The brachydactyly type A1 gene or locus was not found in either of the two families studied.

0 21 Type A1 brachydactyly HP:0009371 76 122 shortening of the middle phalanx of all digits HP:0009843 139 182 fusion of the middle and terminal phalanges HP:0001204 246 267 type A1 brachydactyly HP:0009371 1060 1081 brachydactyly type A1 HP:0009371

1478663

Branchiootorenal syndrome is an autosomal dominant disorder that affects an estimated 2% of profoundly deaf children. In addition to hearing impairment, it is characterized by a lop-ear deformity, preauricular pits, branchial cleft sinus tracts, and renal anomalies. The pathogenesis of the disease remains unknown; however, the defective gene has been localized to chromosome 8q by family linkage studies.

32 59 autosomal dominant disorder HP:0000006 92 107 profoundly deaf HP:0000404 133 151 hearing impairment HP:0000365 178 195 lop-ear deformity HP:0000394 197 214 preauricular pits HP:0004467 216 244 branchial cleft sinus tracts HP:0100272 250 265 renal anomalies HP:0000077

9808466

The E6-AP ubiquitin ligase (human/mouse gene UBE3A/Ube3a) promotes the degradation of p53 in association with papilloma E6 protein, and maternal deficiency causes human Angelman syndrome (AS). Ube3a is imprinted with silencing of the paternal allele in hippocampus and cerebellum in mice. We found that the phenotype of mice with maternal deficiency (m-/p+) for Ube3a resembles human AS with motor dysfunction, inducible seizures, and a context-dependent learning deficit. Long-term potentiation (LTP) was severely impaired in m-/p+ mice despite normal baseline synaptic transmission and neuroanatomy, indicating that ubiquitination may play a role in mammalian LTP and that LTP may be abnormal in AS. The cytoplasmic abundance of p53 was increased in postmitotic neurons in m-/p+ mice and in AS, providing a potential biochemical basis for the phenotype through failure to ubiquitinate and degrade various effectors.

110 119 papilloma HP:0012740 392 409 motor dysfunction HP:0001270 421 429 seizures HP:0001250 455 471 learning deficit HP:0001328

18177466

Branchio-oto-renal (BOR) and Stickler (STL) syndromes are disorders that include hearing loss among their clinical features. STL syndrome type I (STL1) is a combination of ophthalmic, orofacial, articular, and auditory manifestations, caused by mutations in the COL2A1. BOR syndrome is an autosomal dominant trait encompassing branchial, otic and renal anomalies because of mutations in EYA1, SIX1 and SIX5. In this study, we have clinically and genetically diagnosed a proband that displayed STL1 and BOR syndromes. This patient and his younger brother exhibited hearing loss and cleft palate. Both siblings and their mother also showed myopia, congenital non-progressive vitreous anomaly and a flat face. Taken together, these clinical features are consistent with the diagnosis of a familial case of STL. Sequence analysis revealed in the three patients a novel COL2A1 mutation (c.1468_1475delinsT) that accounted for a STL1 phenotype. The proband also displayed pre-auricular pits, branchial fistulae and renal agenesis that define BOR syndrome. Interestingly, this patient carries an EYA1 mutation, p.R328X, which was not present in the two other patients or in his healthy father, supporting that the mutation arose de novo. In conclusion, this report highlights the importance of molecular testing and detailed clinical evaluation for the diagnosis of syndromes with overlapping phenotypic features.

81 93 hearing loss HP:0000365 172 233 ophthalmic, orofacial, articular, and auditory manifestations HP:0000478 184 233 orofacial, articular, and auditory manifestations HP:0000153 195 233 articular, and auditory manifestations HP:0001367 210 233 auditory manifestations HP:0000364 289 313 autosomal dominant trait HP:0000006 327 362 branchial, otic and renal anomalies HP:0009794 327 336 branchial HP:0009794 338 362 otic and renal anomalies HP:0000598 347 362 renal anomalies HP:0000077 564 576 hearing loss HP:0000365 581 593 cleft palate HP:0000175 638 644 myopia HP:0000545 673 689 vitreous anomaly HP:0007773 696 705 flat face HP:0000272 966 984 pre-auricular pits HP:0004467 986 1004 branchial fistulae HP:0009795 1009 1023 renal agenesis HP:0000104 1222 1229 de novo HP:0003745

9096762

We present an 8-year-old African-American boy with medulloblastoma and nevoid basal cell carcinoma syndrome (NBCCS) who exhibited the radiosensitive response of basal cell carcinoma (BCC) formation in the area irradiated for medulloblastoma. Such a response is well-documented in Caucasian NBCCS patients with medulloblastoma. The propositus was diagnosed with medulloblastoma at the age of 2 years and underwent surgery, chemotherapy, and craniospinal irradiation. At the age of 6 years, he was diagnosed with NBCCS following his presentation with a large odontogenic keratocyst of the mandible, pits of the palms and soles and numerous BCCs in the area of the back and neck that had been irradiated previously for medulloblastoma. Examination of other relatives showed that the propositus' mother also had NBCCS but was more mildly affected; in particular, she had no BCCs. This case illustrates complex gene-environment interaction, in that increased skin pigmentation in African-Americans is presumably protective against ultraviolet, but not ionizing, radiation. This case and other similar cases in the literature show the importance of considering NBCCS in the differential diagnosis of any patient who presents with a medulloblastoma, especially before the age of 5 years, and of examining other close relatives for signs of NBCCS to determine the patient's at-risk status. Finally, for individuals who are radiosensitive, protocols that utilize chemotherapy in lieu of radiotherapy should be considered.

51 66 medulloblastoma HP:0002885 78 98 basal cell carcinoma HP:0002671 134 157 radiosensitive response HP:0003079 161 181 basal cell carcinoma HP:0002671 225 240 medulloblastoma HP:0002885 310 325 medulloblastoma HP:0002885 361 376 medulloblastoma HP:0002885 557 595 odontogenic keratocyst of the mandible HP:0010603 597 614 pits of the palms HP:0010610 597 624 pits of the palms and soles HP:0010612 716 731 medulloblastoma HP:0002885 944 971 increased skin pigmentation HP:0000953 1226 1241 medulloblastoma HP:0002885 1415 1429 radiosensitive HP:0003079

9556704

Prader-Willi and Angelman syndromes are 2 clinically distinct disorders associated with multiple anomalies and mental retardation. They are only discussed together because they share a similar and uncommon genetic basis: they involve genes that are located in the same region in the genome and are characterized by genetic imprinting. This normal process has contributed to these 2 complex and severe conditions through inactivation of 1 copy of the genes relevant to each disorder: the maternally derived copy of genes for Prader-Willi syndrome in proximal 15q are normally silent, and a paternally derived copy of 1 gene for Angelman syndrome in 15q is normally silent. For both disorders, when the normally active copy of the gene or genes is missing, abnormality results. Since the genes for these 2 disorders are located very close together, and since the center involved in inactivating the genes involved in imprinting may be the same, both these disorders usually result from the same chromosomal deletion; which disorder results depends on the parent of origin of the chromosome 15 that becomes deleted. Both Prader-Willi and Angelman syndrome can also occur as a result of having both members of the chromosome 15 pair derived from 1 parent, a condition known as uniparental disomy. Both can also result from a structural abnormality of the imprinting center, known as an imprinting mutation. In addition, Angelman syndrome can be caused by a mutation in the gene that causes it; a comparable cause is not present in Prader-Willi syndrome since it results from abnormality in more than 1 gene. Finally, despite the complexity of possible causes, all but the single gene mutation of the Angelman syndrome gene can be detected through methylation-sensitive DNA probes, since DNA methylation is the process by which the genes for these 2 disorders are imprinted. This unusual property of specific areas of the DNA holds promise for future treatment of these and other disorders related to imprinting through reversal of the imprinting process.

111 129 mental retardation HP:0001249

18220287

Branchio-oto-renal syndrome (BOR) is an autosomal dominant disorder characterized by the association of branchial and external ear malformations, hearing loss, and renal anomalies. The phenotype varies from ear pits to profound hearing loss, branchial fistulae, and kidney agenesis. The most common gene mutated in BOR families is EYA1, a transcriptional activator. Over 80 different disease-causing mutations have been published (www.healthcare.uiowa.edu/labs/pendredandbor/, last accessed 20 November 2007). We analyzed the EYA1 coding region (16 exons) from 435 families (345 at the University of Iowa [UI] and 95 at Boys Town National Research Hospital [BTNRH], including five at both) and found 70 different EYA1 mutations in 89 families. Most of the mutations (56/70) were private. EYA1 mutations were found in 31% of families (76/248) fitting established clinical criteria for BOR and 7% of families with questionable BOR phenotype (13/187). Severity of the phenotype did not correlate with type of mutation nor with the domain involved. These results add considerably to the spectrum of EYA1 mutations associated with BOR and indicate that the BOR phenotype is an indication for molecular studies to diagnose EYA1-associated BOR.

40 67 autosomal dominant disorder HP:0000006 104 144 branchial and external ear malformations HP:0009794 104 113 branchial HP:0009794 118 144 external ear malformations HP:0000356 146 158 hearing loss HP:0000365 164 179 renal anomalies HP:0000077 207 215 ear pits HP:0004467 219 240 profound hearing loss HP:0000365 242 260 branchial fistulae HP:0009795 266 281 kidney agenesis HP:0000104

7747785

We review 43 patients (15 new, 28 literature) with the branchio-oculo-facial (BOF) syndrome, which has a distinctive phenotype ranging from mild to severe forms, consisting of eye, ear, oral, and craniofacial anomalies. Virtually ubiquitous and possibly pathognomonic are the cervical/infra-auricular skin defects. Much less common are supra-auricular defects occurring as isolated anomalies or with cervical defects. Regardless of location, these lesions may have aplastic, "hemangiomatous," or otherwise abnormal overlying skin, and draining sinus fistulae. Renal malformations are frequent, but congenital heart and central nervous system defects are rare. Psychomotor performance is usually normal, but development delays, hypotonia, and visual, hearing, and speech problems are common. Autosomal dominant inheritance seems likely. Overlap between the BOF and branchio-otorenal syndromes has been observed, but elucidation of its molecular basis is not yet available. This article also discusses 5 patients with atypical manifestations considered to be possibly affected or probably unaffected, who are sufficiently unusual to be excluded from the final data analysis.

176 218 eye, ear, oral, and craniofacial anomalies HP:0000478 181 218 ear, oral, and craniofacial anomalies HP:0000598 186 218 oral, and craniofacial anomalies HP:0000153 196 218 craniofacial anomalies HP:0002260 276 313 cervical/infra-auricular skin defects HP:0009794 285 313 infra-auricular skin defects HP:0000356 336 359 supra-auricular defects HP:0000383 506 529 abnormal overlying skin HP:0000951 535 558 draining sinus fistulae HP:0004467 560 579 Renal malformations HP:0000792 598 649 congenital heart and central nervous system defects HP:0002564 619 649 central nervous system defects HP:0007319 707 725 development delays HP:0001263 727 736 hypotonia HP:0001252 742 778 visual, hearing, and speech problems HP:0000478 750 778 hearing, and speech problems HP:0000364 763 778 speech problems HP:0002116 791 821 Autosomal dominant inheritance HP:0000006

8102569

RFLP typing of members of a neurofibromatosis type 2 (NF2) family suggested that affected individuals were hemizygous at the neurofilament heavy chain (NEFH) locus, possibly as a result of a disease-associated deletion. Conventional karyotyping revealed no evidence for a deletion and all or a majority of the affected family members were heterozygous for closely linked markers which mapped proximal to the NEFH locus (D22S1 and D22S56) and for the distal marker D22S32. FISH analysis confirmed a disease-associated germinal deletion on 22q which encompassed the NEFH locus, which is known to be very closely linked to NF2, but did not extend as far as the proximal Ewing sarcoma region or the distal leukaemia factor (LIF) locus. PFGE analysis with a LIF cosmid subclone identified patient-specific NotI and MluI fragments and suggested that the deletion is about 700 kb in length. Although this large deletion could be expected to eliminate a considerable fraction, and possibly all of the NF2 gene, the resulting phenotype is the mild, so-called Gardner subtype of NF2. The deletion should provide a useful mapping resource for characterising the chromosomal region containing the NF2 locus.

28 45 neurofibromatosis HP:0006746 673 680 sarcoma HP:0100242

6882181

We report 9 subjects from 2 families with the syndrome of cerebral gigantism, seven of the patients also had jaw cyst basal cell naevoid syndrome. Neurological, radiological, somatic and biochemical features of this hitherto unreported association are described. Neurological symptoms included mild hydrocephalus, ventricular malformation, cerebellar syndrome, intracranial calcification, oculomotor disturbances, EEG abnormalities and rarely, mild peripheral nervous disorders. A disturbance of calcium metabolism appears to be a prominent feature of the genetically determined nonprogressive syndrome.

58 76 cerebral gigantism HP:0002060 109 117 jaw cyst HP:0010603 118 136 basal cell naevoid HP:0002671 299 312 hydrocephalus HP:0000238 314 338 ventricular malformation HP:0002118 340 359 cerebellar syndrome HP:0001317 361 387 intracranial calcification HP:0002514 389 412 oculomotor disturbances HP:0006860 414 431 EEG abnormalities HP:0002353 449 477 peripheral nervous disorders HP:0000759 496 514 calcium metabolism HP:0004363 579 593 nonprogressive HP:0003680

712760

A family is described in which 16 individuals in 3 generations have Charcot-Marie-Tooth disease. At least 6 family members also have the naevoid basal cell carcinoma syndrome. In addition, 1 subject with both disorders has 2 young daughters with the naevoid basal cell carcinoma syndrome.

145 165 basal cell carcinoma HP:0002671 258 278 basal cell carcinoma HP:0002671

1683160

DNA deletion studies using 5 DNA markers localized at 15q11-q12 were performed in 14 Angelman syndrome (AS) patients (9 sporadic and 5 familial cases). A one-copy density for one or more of the 5 loci was detected in 8 (57.1%) of the 14 patients. A deletion of only the D15S11 locus was detected in one sporadic patient, that involving only the D15S10 in 3 familial patients (sibs in a family), that spanning 3 loci (D15S11, D15S10, D15S12) in one sporadic patient, and that spanning 4 loci (D15S9, D15S11, D15S10, D15S12) in the other 3 sporadic patients. The deletion common to our patients as well as to the reported patients may be confined to a segment between D15S11 and D15S10, if the 5 loci are ordered as cen-D15S18-(D15S9-D15S11-D15S10)-D15S12-qt er. This site overlaps but is more distal to the common deletion site in Prader-Willi syndrome (PWS) patients. In the family of the 3 sibs, both of the phenotypically normal mother and maternal grandfather also have deletions of the D15S10 locus. These results were consistent with the genomic imprinting hypothesis for the occurrence of AS, i.e., the lack of a maternally derived locus leads to AS, but may not support a model that AS is the alternative phenotype of PWS at the identical locus.

120 128 sporadic HP:0003745 135 149 familial cases HP:0000005 303 311 sporadic HP:0003745 448 456 sporadic HP:0003745 538 546 sporadic HP:0003745

9811917

Stereotactic radiosurgery is the principal alternative to microsurgical resection for acoustic neuromas (vestibular schwannomas). The goals of radiosurgery are the long-term prevention of tumor growth, maintenance of neurologic function, and prevention of new neurologic deficits. Although acceptable short-term outcomes have been reported, long-term outcomes have not been well documented. We evaluated 162 consecutive patients who underwent radiosurgery for acoustic neuromas between 1987 and 1992 by means of serial imaging tests, clinical evaluations, and a survey between 5 and 10 years after the procedure. The average dose of radiation to the tumor margin was 16 Gy, and the mean transverse diameter of the tumor was 22 mm (range, 8 to 39). Resection had been performed previously in 42 patients (26 percent); in 13 patients the tumor represented a recurrence of disease after a previous total resection. Facial function was normal in 76 percent of the patients before radiosurgery, and 20 percent had useful hearing. The rate of tumor control (with no resection required) was 98 percent. One hundred tumors (62 percent) became smaller, 53 (33 percent) remained unchanged in size, and 9 (6 percent) became slightly larger. Resection was performed in four patients (2 percent) within four years after radiosurgery. Normal facial function was preserved in 79 percent of the patients after five years (House-Brackmann grade 1), and normal trigeminal function was preserved in 73 percent. Fifty-one percent of the patients had no change in hearing ability. No new neurologic deficits appeared more than 28 months after radiosurgery. An outcomes questionnaire was returned by 115 patients (77 percent of the 149 patients still living). Fifty-four of these patients (47 percent) were employed at the time of radiosurgery, and 37 (69 percent) remained so. Radiosurgery was believed to have been successful by all 30 patients who had undergone surgery previously and by 81 (95 percent) of the 85 who had not. Thirty-six of the 115 patients (31 percent) described at least one complication, which resolved in 56 percent of those cases. Radiosurgery can provide long-term control of acoustic neuromas while preserving neurologic function.

86 103 acoustic neuromas HP:0009588 105 127 vestibular schwannomas HP:0009588 188 193 tumor HP:0002664 461 478 acoustic neuromas HP:0009588 651 656 tumor HP:0002664 715 720 tumor HP:0002664 837 842 tumor HP:0002664 1039 1044 tumor HP:0002664 1110 1116 tumors HP:0002664 1569 1588 neurologic deficits HP:0000707 2183 2200 acoustic neuromas HP:0009588

7762579

The index case was a Maori bushman who presented with severe congenital spinal stenosis and manifestations of distal arthrogryposis. His offspring and 8 of his 9 sibs and most of their offspring were interviewed and examined. Of those examined 7 individuals with definite and 2 with probable distal arthrogryposis were identified in 4 of the families. A tenth relative with distal arthrogryposis and contractural arachnodactyly had died. There was marked variability in the severity and nature of manifestations with 2 having severe hand and foot involvement in addition to craniofacial changes compatible with a diagnosis of Freeman-Sheldon syndrome. Other apparently unrelated hereditary disorders in the family included ectrodactyly, biliary atresia, and Brachmann-de Lange syndrome. This is the first report of arthrogryposis in a Maori family.

72 87 spinal stenosis HP:0003416 110 131 distal arthrogryposis HP:0005684 292 313 distal arthrogryposis HP:0005684 374 395 distal arthrogryposis HP:0005684 400 427 contractural arachnodactyly HP:0001166 448 511 marked variability in the severity and nature of manifestations HP:0003815 455 466 variability HP:0003812 533 558 hand and foot involvement HP:0001155 542 558 foot involvement HP:0001760 574 594 craniofacial changes HP:0002260 723 735 ectrodactyly HP:0100257 737 752 biliary atresia HP:0005912 815 829 arthrogryposis HP:0001390

6741990

This is a report on a child with sensorineural deafness, imperforate anus with rectovaginal fistula, hypoplastic thumb, and congenital heart defect. This pattern of congenital anomalies is similar to that described in patients with the Townes-Brocks syndrome, although the present patient has characteristics that have not been reported previously in this syndrome. It is proposed that the clinical spectrum of the Townes-Brocks syndrome must be extended to include congenital heart defect, auricular changes differing from those previously described, and anomalies of other internal organs. The syndrome is an autosomal dominant trait. The present case may represent a de novo mutation.

33 55 sensorineural deafness HP:0000407 57 73 imperforate anus HP:0002023 79 99 rectovaginal fistula HP:0000143 101 118 hypoplastic thumb HP:0009778 124 147 congenital heart defect HP:0002564 466 489 congenital heart defect HP:0002564 491 508 auricular changes HP:0000383 575 590 anomalies of other internal organs HP:0000118 611 635 autosomal dominant trait HP:0000006 670 686 de novo mutation HP:0003745

18000979

Mutations in SALL1 and GLI3 are responsible for human limb malformation syndromes. The molecular pathophysiology of these mutations is incompletely understood, and many conclusions have been drawn from studies performed in the mouse. We identified truncating mutations in SALL1 and GLI3 in patients with limb malformation and studied the contribution of nonsense-mediated decay (NMD) to the expression of mutant mRNA in patient-derived fibroblasts. Quantification of the relative proportions of mutant and wild-type alleles was performed by pyrosequencing. In SALL1, a mutant allele causing Townes-Brocks syndrome was unexpectedly resistant to NMD, whereas a different mutation causing a much milder phenotype was susceptible to NMD. In GLI3, all three mutant alleles tested were susceptible to NMD. This work provides novel insights into the molecular pathophysiology of SALL1 and GLI3 mutations, extends the phenotypic spectrum of SALL1 mutations, and provides an example of a human mutation which does not follow the usual accepted positional rules governing mammalian NMD. (c) 2007 Wiley-Liss, Inc.

54 71 limb malformation HP:0002813 304 321 limb malformation HP:0002813

1003450

A syndrome of brachydactyly (absence of some middle or distal phalanges), aplastic or hypoplastic nails, symphalangism (ankylois of proximal interphalangeal joints), synostosis of some carpal and tarsal bones, craniosynostosis, and dysplastic hip joints is reported in five members of an Italian family. It may represent a previously undescribed autosomal dominant trait.

14 27 brachydactyly HP:0001156 29 71 absence of some middle or distal phalanges HP:0009881 74 103 aplastic or hypoplastic nails HP:0001798 86 103 hypoplastic nails HP:0001792 105 118 symphalangism HP:0100264 120 163 ankylois of proximal interphalangeal joints HP:0008090 166 208 synostosis of some carpal and tarsal bones HP:0009702 210 226 craniosynostosis HP:0001363 232 253 dysplastic hip joints HP:0001385 346 370 autosomal dominant trait HP:0000006

1750770

Two very preterm infants (born at 29 and 25 weeks, respectively) were found to have abnormal ribs. Though this was thought unimportant at the time, it was subsequently shown to indicate that some members of their families had a dominantly inherited risk of developing skin cancer and other serious problems.

9 24 preterm infants HP:0001622 84 97 abnormal ribs HP:0000772 228 248 dominantly inherited HP:0000006 268 279 skin cancer HP:0008069

8576558

We studied the seizure and polygraphic patterns of 18 patients with Angelman's syndrome. All patients showed movement problems. Eleven patients were also reported to have long-lasting periods of jerky movements. The polygraphic recording showed a myoclonic status epilepticus in nine of them. Seven patients had partial seizures with eye deviation and vomiting, similar to those of childhood occipital epilepsies. These seizures and electroencephalographic patterns suggest that Angelman's syndrome occurs in most of the patients as a nonprogressive, age-dependent myoclonic encephalopathy with a prominent occipital involvement. These findings indicate that, whereas ataxia is a constant symptom in Angelman's syndrome, the occurrence of a transient myoclonic status epilepticus may account for the recurrence of different abnormal movements, namely the jerky ones.

15 22 seizure HP:0001250 109 126 movement problems HP:0100022 195 210 jerky movements HP:0007087 247 275 myoclonic status epilepticus HP:0002123 312 328 partial seizures HP:0007359 334 347 eye deviation HP:0000496 352 360 vomiting HP:0002013 382 391 childhood HP:0011463 402 412 epilepsies HP:0001275 420 428 seizures HP:0001250 433 465 electroencephalographic patterns HP:0002353 535 589 nonprogressive, age-dependent myoclonic encephalopathy HP:0007030 668 674 ataxia HP:0001251 751 779 myoclonic status epilepticus HP:0002123 824 865 abnormal movements, namely the jerky ones HP:0007087

8808282

Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by branchial abnormality, hearing loss, and renal anomalies. Recently, the disease gene has been localized to chromosome 8q. Here, we report genetic studies that further refine the disease gene region to a smaller interval and identify several YACs from the critical region. We studied two large, clinically well-characterized BOR families with a set of 13 polymorphic markers spanning the D8S165-D8S275 interval from the chromosome 8q region. Based on multipoint analysis, the highest likelihood for the location of the BOR gene is between markers D8S543 and D8S530, a distance of about 2 cM. YACs that map in the BOR critical region have been identified and characterized by fluorescence in situ hybridization and pulsed-field gel electrophoresis. A YAC contig, based on the STS content map, that covers a minimum of 4 Mb of human DNA in the critical region of BOR is assembled. This lays the groundwork for the construction of a transcriptional map of this region and the eventual identification of genes involved in BOR syndrome.

40 67 autosomal dominant disorder HP:0000006 85 106 branchial abnormality HP:0009794 108 120 hearing loss HP:0000365 126 141 renal anomalies HP:0000077

16957682

Heterozygous missense mutations in the serine-threonine kinase receptor BMPR1B result typically in brachydactyly type A2 (BDA2), whereas mutations in the corresponding ligand GDF5 cause brachydactyly type C (BDC). Mutations in the GDF inhibitor Noggin (NOG) or activating mutations in GDF5 cause proximal symphalangism (SYM1). Here, we describe a novel mutation in BMPR1B (R486Q) that is associated with either BDA2 or a BDC/SYM1-like phenotype. Functional investigations of the R486Q mutation were performed and compared with the previously reported BDA2-causing mutation R486W and WT BMPR1B. Overexpression of the mutant receptors in chicken micromass cultures resulted in a strong inhibition of chondrogenesis with the R486Q mutant, showing a stronger effect than the R486W mutant. To investigate the consequences of the BMPR1B mutations on the intracellular signal transduction, we used stably transfected C2C12 cells and measured the activity of SMAD-dependent and SMAD-independent pathways. SMAD activation after stimulation with GDF5 was suppressed in both mutants. Alkaline phosphatase induction showed an almost complete loss of activation by both mutants. Our data extend the previously known mutational and phenotypic spectrum associated with mutations in BMPR1B. Disturbances of NOG-GDF5-BMPR1B signaling cascade can result in similar clinical manifestations depending on the quantitative effect and mode of action of the specific mutations within the same functional pathway.

99 127 brachydactyly type A2 (BDA2) HP:0009372 186 206 brachydactyly type C HP:0009373 208 211 BDC HP:0009373 296 318 proximal symphalangism HP:0100264 320 324 SYM1 HP:0006152 411 415 BDA2 HP:0009372 421 424 BDC HP:0009373 425 434 SYM1-like HP:0006152

10569966

Neurofibromatosis type 2 (NF2) is a highly penetrant autosomal dominant condition predisposing affected individuals to schwannomas and meningiomas. The proportion of children presenting with meningioma or schwannoma who have NF2 is not well described, and neither is the mode of presentation in most children with the inherited disease. To determine the frequency of childhood meningioma and schwannoma cases caused by NF2 and the mode of presentation. The records of the Manchester Children's Tumour Registry from 1954 were searched for cases of meningioma and schwannoma. Paediatric presentation in a large UK series of NF2 was also studied. 18% (61/334) of patients with NF2 on the UK database presented in the paediatric age group (0-15 years), frequently with the symptoms of an isolated tumour. More than half had no family history to alert the clinician to their susceptibility. Three of 22 children presenting with a meningioma on the Manchester Children's Tumour Registry have gone on to develop classic features of NF2. Clinicians should suspect NF2 in children presenting with meningioma, schwannoma, and skin features, such as neurofibromas/schwannomas, but fewer than 6 café au lait patches, who thus fall short of a diagnosis of neurofibromatosis type 1.

0 17 Neurofibromatosis HP:0006746 53 71 autosomal dominant HP:0000006 119 130 schwannomas HP:0100008 135 146 meningiomas HP:0002858 191 201 meningioma HP:0002858 205 215 schwannoma HP:0100008 368 377 childhood HP:0011463 378 388 meningioma HP:0002858 393 403 schwannoma HP:0100008 496 502 Tumour HP:0002664 549 559 meningioma HP:0002858 564 574 schwannoma HP:0100008 796 802 tumour HP:0002664 928 938 meningioma HP:0002858 968 974 Tumour HP:0002664 1092 1102 meningioma HP:0002858 1104 1114 schwannoma HP:0100008 1120 1133 skin features HP:0000951 1143 1156 neurofibromas HP:0001067 1157 1168 schwannomas HP:0100008 1187 1208 café au lait patches HP:0000957 1247 1264 neurofibromatosis HP:0006746 1248 1265 neurofibromatosis HP:0006746

8379998

Neurofibromatosis type 2 (NF2) is a monogenic dominantly inherited disease predisposing carriers to develop nervous system tumours. To identify the genetic defect, the region between two flanking polymorphic markers on chromosome 22 was cloned and several genes identified. One is the site of germ-line mutations in NF2 patients and of somatic mutations in NF2-related tumours. Its deduced product has homology with proteins at the plasma membrane and cytoskeleton interface, a previously unknown site of action of tumour suppressor genes in humans.

0 17 Neurofibromatosis HP:0006746 46 66 dominantly inherited HP:0000006 108 130 nervous system tumours HP:0004375 369 376 tumours HP:0002664 515 521 tumour HP:0002664

7468659

Nineteen of 421 white children in Montreal schools for the deaf had preauricular pits. The branchio-oto-renal (BOR syndrome was identified in four of the nine families who agreed to family investigation, including audiograms and intravenous pyelograms (IVPs) and may have been present in several others. The penetrance of this autosomal dominant syndrome appears to be high. It is estimated that severe renal dysplasia occurs in about 6% of heterozygotes. The presence of a preauricular pit at birth suggests that the child has at least one chance in 200 of severe hearing loss, and this warrants a careful family history, as well as alertness for any signs of hearing impairment. Offspring of affected individuals are eligible for parental diagnosis of renal dysplasia.

59 63 deaf HP:0000404 68 85 preauricular pits HP:0004467 327 345 autosomal dominant HP:0000006 403 418 renal dysplasia HP:0000110 474 490 preauricular pit HP:0004467 565 577 hearing loss HP:0000365 661 679 hearing impairment HP:0000365 754 769 renal dysplasia HP:0000110

2888021

Bilateral acoustic neurofibromatosis (BANF) is a severe autosomal dominant disorder involving development of multiple tumours of the nervous system including meningiomas, gliomas, neurofibromas and particularly bilateral acoustic neuromas. We have used genetic linkage analysis with DNA markers to establish that the defective gene causing BANF is on chromosome 22, and is therefore distinct from the gene for the von Recklinghausen form of neurofibromatosis, which maps to chromosome 17. Linked DNA markers will be particularly valuable in BANF, facilitating early detection of tumours and thereby permitting more effective surgical intervention. In view of the reported loss of genes on chromosome 22 in meningiomas and acoustic neuromas, the genetic localization of the primary BANF defect strongly supports the concept that the disease locus encodes a 'tumour suppressor' gene. Isolation of this gene should provide insights into the pathogenesis of acoustic neuromas and other nervous system tumours, as well as into the control of proliferation and differentiation of neural crest cells.

0 36 Bilateral acoustic neurofibromatosis HP:0009589 38 42 BANF HP:0009589 56 83 autosomal dominant disorder HP:0000006 118 147 tumours of the nervous system HP:0004375 158 169 meningiomas HP:0002858 171 178 gliomas HP:0009733 180 193 neurofibromas HP:0001067 211 238 bilateral acoustic neuromas HP:0009589 441 458 neurofibromatosis HP:0006746 579 586 tumours HP:0002664 706 717 meningiomas HP:0002858 722 739 acoustic neuromas HP:0009588 857 863 tumour HP:0002664 954 971 acoustic neuromas HP:0009588 982 1004 nervous system tumours HP:0004375

1348213

Gorlin syndrome is an autosomal dominant disorder that predisposes to basal cell carcinomas of the skin, ovarian fibromas, and medulloblastomas. Unlike other hereditary disorders associated with cancer, it features widespread developmental defects. To investigate the possibility that the syndrome is caused by mutation in a tumor suppressor gene, we searched for loss of heterozygosity in 16 sporadic basal cell carcinomas, 2 hereditary basal cell carcinomas, and 1 hereditary ovarian fibroma and performed genetic linkage studies in five Gorlin syndrome kindreds. Eleven sporadic basal cell carcinomas and all 3 hereditary tumors had allelic loss of chromosome 9q31, and all informative kindreds showed tight linkage between the Gorlin syndrome gene and a genetic marker in this region. Loss of heterozygosity at this chromosomal location, particularly in hereditary tumors, implies that the gene is homozygously inactivated and normally functions as a tumor suppressor. In contrast, hemizygous germline mutations lead to multiple congenital anomalies.

22 49 autosomal dominant disorder HP:0000006 70 103 basal cell carcinomas of the skin HP:0002671 105 121 ovarian fibromas HP:0010618 127 143 medulloblastomas HP:0002885 195 201 cancer HP:0002664 226 247 developmental defects HP:0001263 325 330 tumor HP:0002664 393 401 sporadic HP:0003745 402 423 basal cell carcinomas HP:0002671 438 459 basal cell carcinomas HP:0002671 478 493 ovarian fibroma HP:0010618 573 581 sporadic HP:0003745 582 603 basal cell carcinomas HP:0002671 625 631 tumors HP:0002664 869 875 tumors HP:0002664 955 960 tumor HP:0002664

18629882

Brachydactyly type A1 is a limb malformation characterized by a uniform shortening of the middle phalanges in all digits. Mutations in the Indian hedgehog (IHH) gene were shown to be the cause of this autosomal dominant disorder. The IHH protein is known to be an important signaling molecule involved in chondrocyte formation. So far, only missense mutations in IHH have been reported to cause BrachydactylyA1. We report here on the first deletion in IHH, p.delE95, causing mild BrachydactylyA1 in a small Dutch family. This brings the total number of different mutations found to cause BDA1 to 7.

0 21 Brachydactyly type A1 HP:0009371 27 44 limb malformation HP:0002813 72 120 shortening of the middle phalanges in all digits HP:0010240 201 228 autosomal dominant disorder HP:0000006

16871364

Brachydactyly type A1 (BDA1) is caused by mutations in the Indian hedgehog gene, IHH, on chromosome 2q35-36. In this study, a large five-generation Chinese family with BDA1 was identified and characterized. All affected family members demonstrated significant homogeneous phenotype and some unique clinical features different from those associated with the reported BDA1 mutations in IHH. Linkage analysis showed that the BDA1 gene in the family was linked to marker D2S126 close to IHH with a LOD score of 4.74 at a recombination fraction of 0. DNA sequence analysis revealed a heterozygous C to T transition at nucleotide 461 of IHH, resulting in a novel T154I substitution. The T154I mutation co-segregated with all affected individuals in the family, and was not present in normal family members or 200 normal controls. These results expand the spectrum of clinical phenotype associated with IHH mutations.

0 21 Brachydactyly type A1 HP:0009371 23 27 BDA1 HP:0009371 248 281 significant homogeneous phenotype HP:0003813

1456287

We report on the 12-year development of a child with branchio-oculo-facial syndrome who was initially referred at age 5 months. Of note is his normal intelligence, regular class placement, hypernasal speech, and continued growth along the third centile. The importance of serial observations of patients with rare genetic disorders is emphasized.

189 206 hypernasal speech HP:0001611 212 252 continued growth along the third centile HP:0004322

3185841

The diagnosis, size and operation results in 41 acoustic neurinomas (26 females and 15 males) are presented. In one case the tumor was bilateral. Out of the total of 41 tumors, 12.5% were small acoustic neurinomas. As a rule, at diagnosis the tumors were larger in females than in males. Ten of the small and medium size acoustic neurinomas had no brain stem and cerebellar symptoms or signs at all, only the 8th cranial nerve was affected. All large tumors already had brain stem symptoms and one-third of them also had cerebellar symptoms, lesions of further cranial nerves and increasing intracranial pressure. All these findings were always present in giant tumors. Neurootological functional laboratory examinations cannot be replaced by CT because of the possibility of false negative findings in the smallest acoustic neurinomas. CT and functional neurootological laboratory examinations are complementary to each other and they are not screening procedures at all. As regards morbidity and mortality, the surgical results are comparable with those of other authors using microsurgical techniques. As regards the preservation of hearing, the results are among the best particularly in tumors that were diagnosed as small or medium in this series. Thus it is apparent that the size of a diagnosed acoustic neurinoma is more important for surgical results than the chosen approach to the tumor.

48 67 acoustic neurinomas HP:0009588 125 130 tumor HP:0002664 169 175 tumors HP:0002664 194 213 acoustic neurinomas HP:0009588 243 249 tumors HP:0002664 321 340 acoustic neurinomas HP:0009588 363 382 cerebellar symptoms HP:0001317 409 426 8th cranial nerve HP:0009591 451 457 tumors HP:0002664 470 489 brain stem symptoms HP:0002363 521 540 cerebellar symptoms HP:0001317 542 575 lesions of further cranial nerves HP:0001291 580 612 increasing intracranial pressure HP:0002516 662 668 tumors HP:0002664 816 835 acoustic neurinomas HP:0009588 1192 1198 tumors HP:0002664 1303 1321 acoustic neurinoma HP:0009588 1393 1398 tumor HP:0002664

14717907

The association between ear and kidney anomalies is not usually due to an insult to the embryo. In recent years, many essential development control genes that coordinate the assembly and function of kidney and ear have been discovered through the generation of animal mutants and have increased our understanding of the mechanisms of human oto-renal diseases. Here, we describe ear and kidney clinical syndromes and their molecular expression.

24 48 ear and kidney anomalies HP:0000598 32 48 kidney anomalies HP:0000077 378 411 ear and kidney clinical syndromes HP:0000598 386 411 kidney clinical syndromes HP:0000077

9949213

Transcribed, low-copy repeat elements are associated with the breakpoint regions of common deletions in Prader-Willi and Angelman syndromes. We report here the identification of the ancestral gene ( HERC2 ) and a family of duplicated, truncated copies that comprise these low-copy repeats. This gene encodes a highly conserved giant protein, HERC2, that is distantly related to p532 (HERC1), a guanine nucleotide exchange factor (GEF) implicated in vesicular trafficking. The mouse genome contains a single Herc2 locus, located in the jdf2 (juvenile development and fertility-2) interval of chromosome 7C. We have identified single nucleotide splice junction mutations in Herc2 in three independent N-ethyl-N-nitrosourea-induced jdf2 mutant alleles, each leading to exon skipping with premature termination of translation and/or deletion of conserved amino acids. Therefore, mutations in Herc2 lead to the neuromuscular secretory vesicle and sperm acrosome defects, other developmental abnormalities and juvenile lethality of jdf2 mice. Combined, these findings suggest that HERC2 is an important gene encoding a GEF involved in protein trafficking and degradation pathways in the cell.

972 999 developmental abnormalities HP:0001263 1004 1022 juvenile lethality HP:0004149

263442

A pedigree of branchio-oto-renal dysplasia (the BOR syndrome) is reported, including the documentation by serial audiometric studies of the onset and rapid progression of hearing loss in the twin sister of an affected child. The literature on this syndrome is analyzed to derive some figures for use in genetic counseling of such families. Branchio-oto-renal dysplasia is an autosomal dominant disorder in which affected individuals may have preauricular pits, lachrymal duct stenosis, hearing loss, branchial fistulas or cysts, structural defects of the outer, middle, and inner ear, and renal anomalies, which may range from mild hypoplasia to complete absence. Not all features of the syndrome are expressed in all carriers of the gene, but few carriers lack all the features, and the pits, branchial clefts, and hearing loss, are frequently expressed. Those offspring of affected persons who have pits or fistulas are likely (about 80%) to have hearing loss of varying degrees of severity. A minority of heterozygotes (about 7%) may have hearing loss without pits or fistulas. The risk of severe renal malformation is probably fairly low. Whether families that show dominant inheritance of pits, clefts, and deafness without renal anomalies represent variants of the BOR syndrome or a separate entity (the BO syndrome), is still not clear. At present, any individual with preauricular pits and branchial clefts deserves both otologic and renal investigation.

27 42 renal dysplasia HP:0000110 150 167 rapid progression HP:0003678 171 183 hearing loss HP:0000365 353 368 renal dysplasia HP:0000110 375 402 autosomal dominant disorder HP:0000006 442 459 preauricular pits HP:0004467 461 484 lachrymal duct stenosis HP:0007925 486 498 hearing loss HP:0000365 500 527 branchial fistulas or cysts HP:0009796 500 518 branchial fistulas HP:0009795 529 583 structural defects of the outer, middle, and inner ear HP:0000598 589 604 renal anomalies HP:0000077 788 792 pits HP:0004467 794 810 branchial clefts HP:0009794 816 828 hearing loss HP:0000365 901 905 pits HP:0004467 909 917 fistulas HP:0009794 949 961 hearing loss HP:0000365 1042 1054 hearing loss HP:0000365 1063 1067 pits HP:0004467 1100 1118 renal malformation HP:0000792 1170 1190 dominant inheritance HP:0000006 1194 1198 pits HP:0004467 1200 1206 clefts HP:0009794 1212 1220 deafness HP:0000404 1229 1244 renal anomalies HP:0000077 1376 1393 preauricular pits HP:0004467 1398 1414 branchial clefts HP:0009794 1429 1437 otologic HP:0000598 1442 1461 renal investigation HP:0000077

3287922

We report the prenatal diagnosis of distal arthrogryposis type I by ultrasound at 18 wk gestation in a family with two other affected members (mother and sister of the fetus). The pregnancy was followed with serial ultrasounds, and the diagnosis was confirmed after birth. The clinical findings in all affected family members are described. A literature survey of prenatally diagnosed cases of multiple joint contractures is presented. These include cases with many different diagnoses. This is the first report of the prenatal diagnosis of distal arthrogryposis type I. It helps to illustrate the variability and prenatal natural history of the condition and the subtlety of the prenatal ultrasound findings.

36 57 distal arthrogryposis HP:0005684 364 390 prenatally diagnosed cases HP:0003660 394 421 multiple joint contractures HP:0002828 541 562 distal arthrogryposis HP:0005684 598 609 variability HP:0003812

9831341

We had previously described a patient with an overgrowth syndrome and the chromosome constitution 45,XY,t(15q15q) (Wajntal et al., DNA Cell Biol 1993: 12: 227-231). Clinical reassessment and the use of molecular studies, including methylation analysis with an SNRPN probe, microsatellite analyses of D15S11, GABRB3 and D15S113 loci, and fluorescence in situ hybridization (FISH) using the SNRPN and GABRB3 probes, are consistent with a diagnosis of Angelman syndrome (AS) due to paternal isodisomy. This is the fourth report case of a translocation 15q15q with paternal uniparental disomy (UPD). Our findings suggest that some patients with clinical features of AS have hyperphagia and obesity with overgrowth, and that these features should not rule out a diagnosis of AS.

46 56 overgrowth HP:0001548 670 681 hyperphagia HP:0002591 686 693 obesity HP:0001513 699 709 overgrowth HP:0001548

1307249

Branchio-oto-renal syndrome (BOR) is an autosomal dominant disorder with variable clinical manifestations affecting branchial, renal and auditory development. Varying clinical expression of the disease between different families suggests that multiple loci may be involved. However, the possibility of genetic heterogeneity as the cause of clinical variability cannot be resolved until the gene(s) causing BOR syndrome are mapped. DNA from four generations of a family with autosomal dominant BOR syndrome have been typed with a series of genetic markers on the long arm of chromosome 8. Using two point linkage analysis, a significant lod score of Z = 4.0 at theta = 0.05 was obtained with the D8S165 microsatellite marker. Multipoint analyses with 8q markers place the gene for BOR between the markers D8S87 and D8S165.

40 67 autosomal dominant disorder HP:0000006 73 81 variable HP:0003813 91 132 manifestations affecting branchial, renal HP:0000077 91 157 manifestations affecting branchial, renal and auditory development HP:0000364 302 323 genetic heterogeneity HP:0001425 340 360 clinical variability HP:0003812 474 492 autosomal dominant HP:0000006

18701717

Angelman syndrome is a neurological disorder whose symptoms include severe mental retardation, loss of motor coordination, and sleep disturbances. The disease is caused by a loss of function of UBE3A, which encodes a HECT-domain ubiquitin ligase. Here, we generate a Drosophila model for the disease. The results of several experiments show that the functions of human UBE3A and its fly counterpart, dube3a, are similar. First, expression of Dube3a is enriched in the Drosophila nervous system, including mushroom bodies, the seat of learning and memory. Second, we have generated dube3a null mutants, and they appear normal externally, but display abnormal locomotive behavior and circadian rhythms, and defective long-term memory. Third, flies that overexpress Dube3a in the nervous system also display locomotion defects, dependent on the ubiquitin ligase activity. Finally, missense mutations in UBE3A alleles of Angelman syndrome patients alter amino acid residues conserved in the fly protein, and when introduced into dube3a, behave as loss-of-function mutations. The simplest model for Angelman syndrome is that in the absence of UBE3A, particular substrates fail to be ubiquitinated and proteasomally degraded, accumulate in the brain, and interfere with brain function. We have generated flies useful for genetic screens to identify Dube3a substrates. These flies overexpress Dube3a in the eye or wing and display morphological abnormalities, dependent on the critical catalytic cysteine. We conclude that dube3a mutants are a valid model for Angelman syndrome, with great potential for identifying the elusive UBE3A substrates relevant to the disease.

23 44 neurological disorder HP:0000707 68 93 severe mental retardation HP:0002187 95 121 loss of motor coordination HP:0002275 127 145 sleep disturbances HP:0002360

10982040

Angelman syndrome is a neuro-developmental disorder caused by genetic abnormalities affecting the maternal gene expression in the chromosome region 15q11-q13. In a study group of 45 Finnish Angelman patients, a recurrence of a del(15)(q11q13) was detected in one family. The mother's chromosomes 15 were structurally normal, whereas the patients and their unaffected brother shared an identical maternally derived haplotype outside the deletion region. These findings are suggestive of maternal germ-line mosaicism of del(15)(q11q13).

23 51 neuro-developmental disorder HP:0012759

11896453

Six breakpoint regions for rearrangements of human chromosome 15q11-q14 have been described. These rearrangements involve deletions found in approximately 70% of Prader-Willi or Angelman's syndrome patients (PWS, AS), duplications detected in some cases of autism, triplications and inverted duplications. HERC2-containing (HEct domain and RCc1 domain protein 2) segmental duplications or duplicons are present at two of these breakpoints (BP2 and BP3) mainly associated with deletions. We show here that clusters containing several copies of the human chromosome 15 low-copy repeat (LCR15) duplicon are located at each of the six described 15q11-q14 BPs. In addition, our results suggest the existence of breakpoints for large 15q11-q13 deletions in a proximal duplicon-containing clone. The study reveals that HERC2-containing duplicons (estimated on 50-400 kb) and LCR15 duplicons ( approximately 15 kb on 15q11-q14) share the golgin-like protein (GLP) genomic sequence. Through the analysis of a human BAC library and public databases we have identified 36 LCR15 related sequences in the human genome, most (27) mapping to chromosome 15q and being transcribed. LCR15 analysis in non-human primates and age-sequence divergences support a recent origin of this family of segmental duplications through human speciation.

257 263 autism HP:0000717

11312426

Nevoid basal cell carcinoma syndrome (NBCCS) is a genodermatosis with autosomal dominant inheritance. In identified kindreds the diagnosis is relatively easy, but for the patients without family history of this syndrome a high clinical suspicion is necessary for diagnosis. Acrochordons are distinctly uncommon in childhood. Our purpose was to evaluate skin tags that develop at an early age. This is a retrospective series evaluation of 7 children who presented with pedunculated papules (acrochordon-like growths). A full history was then correlated with biopsy results in each patient. Clinically, lesions consisted of flesh-colored and pigmented pedunculated papules. Histopathologic examination of these papules showed basal cell carcinomas in each biopsy specimen. We consider that "skin tag"-like basal cell carcinomas in childhood may represent a marker for NBCCS. Early diagnosis of this syndrome and early sun protection of the affected children could help decrease the number of lifetime tumors. Biopsy should be performed on acrochordons in children because they may be the presenting sign of NBCCS. Because these tags may precede other stigmata of the NBCCS, recognition may facilitate early diagnosis and allow early treatment and sun protection.

7 27 basal cell carcinoma HP:0002671 70 100 autosomal dominant inheritance HP:0000006 315 324 childhood HP:0011463 354 363 skin tags HP:0010609 383 392 early age HP:0003593 470 490 pedunculated papules HP:0200034 727 748 basal cell carcinomas HP:0002671 793 801 skin tags HP:0010609 808 829 basal cell carcinomas HP:0002671 833 842 childhood HP:0011463 1003 1009 tumors HP:0002664 1041 1053 acrochordons HP:0010609

391043

Short stature may be a component of the brachydactyly C syndrome. A family is presented in which the propositus has brachydactyly C, short stature, and hip dysplasia.

0 13 Short stature HP:0004322 40 55 brachydactyly C HP:0009373 116 131 brachydactyly C HP:0009373 133 146 short stature HP:0004322 152 165 hip dysplasia HP:0001385

10712204

Brachydactyly type A-1 (BDA1) was, in 1903, the first recorded example of a human anomaly with Mendelian autosomal dominant inheritance. Two large families, the affected members of which were radiographed, were recruited in the study we describe here. Two-point linkage analysis for pedigree 1 (maximum LOD score [Zmax] 6.59 at recombination fraction [theta] 0.00) and for pedigree 2 (Zmax=5.53 at straight theta=0.00) mapped the locus for BDA1 in the two families to chromosome 2q. Haplotype analysis of pedigree 1 confined the locus for family 1 within an interval of <8.1 cM flanked by markers D2S2248 and D2S360, which was mapped to chromosome 2q35-q36 on the cytogenetic map. Haplotype analysis of pedigree 2 confined the locus for family 2 within an interval of <28. 8 cM flanked by markers GATA30E06 and D2S427, which was localized to chromosome 2q35-q37. The two families had no identical haplotype within the defined region, which suggests that the two families were not related.

0 22 Brachydactyly type A-1 HP:0009371 24 28 BDA1 HP:0009371 105 135 autosomal dominant inheritance HP:0000006

3547011

The nevoid basal-cell carcinoma syndrome is characterized by major manifestations, such as multiple basal-cell carcinomata, cysts of the jaws, and skeletal--specifically, rib--abnormalities. Findings in 53 patients and a review of the literature document both major and lesser-known manifestations of the disorder. The odontogenic keratocyst, which usually appears during adolescence, has a marked tendency to recur. In addition to the skin tumors, milia, epidermoid cysts, chalazia, comedones, and palmar and plantar pits are frequent. The skin tumors, originally thought to be independent of sun exposure, are more common in sun-exposed areas and are far less frequent and occur at a much later age in blacks than in whites. There is some evidence that radiation of the skin promotes the appearance of skin cancers in this disorder. Unilateral linear nevoid basal-cell carcinomas with comedones may represent postzygotic somatic mutation. A proclivity to other forms of neoplasia exists. Patients with this syndrome have had medulloblastoma, meningioma, ovarian fibroma, ovarian fibrosarcoma, fibrosarcoma of the jaws, cardiac fibroma, fetal rhabdomyoma, and lymphatic or chylous cysts of the mesentery. In addition to the usual modalities of treatment, topical immunotherapy and topical 5-fluorouracil have been used with success. Oral synthetic retinoids, such as 13-cis-retinoic acid, have been used to prevent new lesions from appearing and to arrest the growth of older lesions by inducing differentiation. The independent observations of increased prostaglandin levels associated both with odontogenic keratocyst expansion and aggression of basal cell cancers merit further investigation both as a fundamental cellular mechanism and as a possible basis for treatment (e.g., with antiprostaglandins). The key to pre- and early postnatal diagnosis of the disorder--as well as to an understanding of the basic abnormality--lies in molecular genetics. Prime attention should be given to finding the site of the gene through the use of DNA and other markers.

11 31 basal-cell carcinoma HP:0002671 100 122 basal-cell carcinomata HP:0002671 124 141 cysts of the jaws HP:0010603 147 169 skeletal--specifically HP:0000924 171 189 rib--abnormalities HP:0000772 319 341 odontogenic keratocyst HP:0010603 357 383 appears during adolescence HP:0003590 436 447 skin tumors HP:0008069 449 454 milia HP:0001056 456 472 epidermoid cysts HP:0200040 474 482 chalazia HP:0010605 484 493 comedones HP:0000951 499 522 palmar and plantar pits HP:0010610 510 522 plantar pits HP:0010612 541 552 skin tumors HP:0008069 804 816 skin cancers HP:0008069 860 881 basal-cell carcinomas HP:0002671 887 896 comedones HP:0000951 923 939 somatic mutation HP:0001428 972 981 neoplasia HP:0002664 1027 1042 medulloblastoma HP:0002885 1044 1054 meningioma HP:0002858 1056 1071 ovarian fibroma HP:0010618 1073 1093 ovarian fibrosarcoma HP:0000137 1095 1119 fibrosarcoma of the jaws HP:0000209 1121 1136 cardiac fibroma HP:0010617 1144 1155 rhabdomyoma HP:0009730 1598 1620 odontogenic keratocyst HP:0010603 1635 1645 aggression HP:0000718 1649 1667 basal cell cancers HP:0002671

8533848

Branchiootorenal (BOR) syndrome is a variable, autosomal-dominant disorder of the first and second embryonic branchial arches, kidneys, and urinary tract. We describe the phenotype in 45 individuals, highlighting differences and similarities reported in other studies. Characteristic temporal bone findings include cochlear hypoplasia (4/5 of normal size with only 2 turns), dilation of the vestibular aqueduct, bulbous internal auditory canals, deep posterior fossae, and acutely-angled promontories.

37 45 variable HP:0003813 47 65 autosomal-dominant HP:0000006 109 125 branchial arches HP:0009794 284 306 temporal bone findings HP:0009911 315 334 cochlear hypoplasia HP:0008586 375 410 dilation of the vestibular aqueduct HP:0000359 412 444 bulbous internal auditory canals HP:0004458 446 467 deep posterior fossae HP:0000359 473 500 acutely-angled promontories HP:0000359

8092198

Branchio-oto-renal (BOR) syndrome is an autosomal dominant condition of branchial arch anomalies, deafness and renal dysplasia. Clinical manifestations tend to have considerable intrafamilial and interfamilial variability. Previous linkage studies had localized the gene responsible for BOR syndrome to a broad region of chromosome 8q. Using 10 microsatellite markers, we have further refined the localization of this disorder by establishing tight linkage to two markers, D8S279 and D8S530 (Zmax = 3.91 and Zmax = 2.83 respectively at theta = 0.00). These markers are within 1 cM of one another. Multipoint analysis, involving 7 loci, placed the gene between these markers, with a lod-1 confidence interval 0.7 cM proximal to D8S530 and 0.6 cM distal to D8S279.

40 58 autosomal dominant HP:0000006 72 96 branchial arch anomalies HP:0009794 98 106 deafness HP:0000404 111 126 renal dysplasia HP:0000110 178 221 intrafamilial and interfamilial variability HP:0003822 196 221 interfamilial variability HP:0003812

12404110

Branchio-Oto-Renal (BOR) syndrome is transmitted as an autosomal dominant disorder, affects an estimated 2% of profoundly deaf children, and is caused by mutations in the human EYA1 gene. However, in up to half of the reported cases, EYA1 mutation screening is negative. This finding has been taken as evidence of genetic heterogeneity. Mutation screening of the coding region of EYA1 in a panel of families linked to chromosome 8 was conducted using SSCP and direct sequencing. Only one point mutation in five probands was detected. However, complex rearrangements, such as inversions or large deletions, were discovered in the other four patients using Southern blot analysis. These data suggest that more complex rearrangements may remain undetected in EYA1 since SSCP and sequencing were commonly used to detect mutations in this gene.

55 82 autosomal dominant disorder HP:0000006 111 126 profoundly deaf HP:0000404 314 335 genetic heterogeneity HP:0001425

8092199

Branchiootorenal (BOR) syndrome is a common autosomal dominant form of hearing impairment previously mapped to 8q. This report refines the localization of the BOR syndrome gene by haplotype analysis to the interval flanked by markers D8S553 and D8S286. By multipoint linkage analysis, the disease locus most likely is flanked by markers D8S530 and D8S279.

44 67 autosomal dominant form HP:0000006 71 89 hearing impairment HP:0000365

3943073

Six patients with typical features of the multiple basal cell nevus syndrome were studied cytogenetically, using prometaphase G-banding and C-banding. Three patients were from one family and the others were sporadic cases. No cytogenetic marker of the disease was identified using these techniques.

51 76 basal cell nevus syndrome HP:0002671 207 221 sporadic cases HP:0003745

3281570

We report a type C brachydactyly transmitted through four generations, with incomplete penetrance and feet abnormalities in the proposita.

12 32 type C brachydactyly HP:0009373 76 97 incomplete penetrance HP:0003829 102 120 feet abnormalities HP:0001760

7091188

We report studies of six patients with the Angelman "Happy Puppet" syndrome and compare the data with those from previous reports. The results confirm the classic findings of severe mental retardation, "puppet-like" gait, characteristic craniofacial abnormalities, and frequent episodes of laughter and suggest that this syndrome is more common than previously thought. Computerized axial tomographs of the brain demonstrating unilateral cerebellar atrophy in one patient constitute the first direct evidence of cerebellar abnormalities in this syndrome.

53 65 Happy Puppet HP:0100024 175 200 severe mental retardation HP:0002187 202 220 "puppet-like" gait HP:0001288 237 263 craniofacial abnormalities HP:0001999 269 298 frequent episodes of laughter HP:0000749 427 456 unilateral cerebellar atrophy HP:0001272 512 536 cerebellar abnormalities HP:0001317

12384778

Brachydactyly type A1 (BDA1) was the first disorder described in terms of autosomal dominant Mendelian inheritance. Early in the 1900s Farabee and Drinkwater described a number of families with BDA1. Examination of two of Drinkwater's families has revealed that, although they are not known to be related, both share a common mutation within the Indian hedgehog gene ( IHH). This novel mutation is a guanine to adenine transition at nucleotide 298, resulting in an Asn100Asp amino acid substitution. Both families demonstrate significant intrafamilial phenotypic heterogeneity among the affected individuals. Examination of single nucleotide polymorphisms (SNP) has shown that the affected individuals in both families share SNPs within IHH consistent with that of a common founder. The identification of the same mutation in these families has answered a question that is nearly a century old about the genetic cause of their disease and supports the hypothesis that IHH plays a pivotal role in normal human skeletogenesis.

0 21 Brachydactyly type A1 HP:0009371 23 27 BDA1 HP:0009371 74 92 autosomal dominant HP:0000006 538 575 intrafamilial phenotypic heterogeneit HP:0003822 563 576 heterogeneity HP:0001425

3799714

The family on which this report is based is of interest because it contains individuals with the branchio-oto-renal (BOR) syndrome who have renal hypoplasia or malformations of the kidney or collecting system including duplication; only branchial and ear anomalies; and apparent nonpenetrance of the syndrome. This report provides evidence to support the hypothesis that in some families variable expressivity includes duplication of the urinary collecting system in individuals with other manifestations of the BOR syndrome as well as individuals with branchial and ear anomalies who have apparently normal kidneys.

140 156 renal hypoplasia HP:0000089 160 208 malformations of the kidney or collecting system HP:0004742 160 230 malformations of the kidney or collecting system including duplication HP:0000081 160 187 malformations of the kidney HP:0000792 237 246 branchial HP:0009794 251 264 ear anomalies HP:0000598 279 292 nonpenetrance HP:0003829 388 409 variable expressivity HP:0003828 419 463 duplication of the urinary collecting system HP:0000081 553 580 branchial and ear anomalies HP:0009794 567 580 ear anomalies HP:0000598

15190457

Neurofibromatosis 2 (NF2) is an autosomal dominant disease that is characterized by tumors on the vestibular branch of the VIII cranial nerve, but other types of nervous system tumors usually occur as well. Genotype-phenotype correlations are well documented for overall NF2 disease severity but have not been definitively evaluated for specific types of non-VIII nerve tumors. We evaluated genotype-phenotype correlations for various types of non-VIII nerve tumors in 406 patients from the population-based United Kingdom NF2 registry, using regression models with the additional covariates of current age and type of treatment center (specialty or nonspecialty). The models also permitted consideration of intrafamilial correlation. We found statistically significant genotype-phenotype correlations for intracranial meningiomas, spinal tumors, and peripheral nerve tumors. People with constitutional NF2 missense mutations, splice-site mutations, large deletions, or somatic mosaicism had significantly fewer tumors than did people with constitutional nonsense or frameshift NF2 mutations. In addition, there were significant intrafamilial correlations for intracranial meningiomas and spinal tumors, after adjustment for the type of constitutional NF2 mutation. The type of constitutional NF2 mutation is an important determinant of the number of NF2-associated intracranial meningiomas, spinal tumors, and peripheral nerve tumors.

0 17 Neurofibromatosis HP:0006746 32 50 autosomal dominant HP:0000006 84 141 tumors on the vestibular branch of the VIII cranial nerve HP:0009591 162 183 nervous system tumors HP:0004375 364 376 nerve tumors HP:0004375 453 465 nerve tumors HP:0004375 806 830 intracranial meningiomas HP:0100009 832 845 spinal tumors HP:0010302 851 874 peripheral nerve tumors HP:0100007 970 987 somatic mosaicism HP:0001442 1012 1018 tumors HP:0002664 1160 1184 intracranial meningiomas HP:0100009 1189 1202 spinal tumors HP:0010302 1366 1390 intracranial meningiomas HP:0100009 1392 1405 spinal tumors HP:0010302 1411 1434 peripheral nerve tumors HP:0100007

8923936

We describe the clinical findings of 15 individuals in a large kindred affected with distal arthrogryposis type 1A (DA1A). The most consistent findings among individuals were overlapping fingers at birth, abnormal digital flexion creases, and foot deformities, including talipes equinovarus and vertical talus. There was marked intrafamilial variation in the expression of DA1A. Linkage mapping of the locus for DA1A suggests that the use of strict diagnostic criteria excludes unaffected individuals rigorously, but can produce incomplete ascertainment of affected individuals. In the context of an affected family, the range of phenotypes consistent with a diagnosis of DA1A needs to be expanded.

85 106 distal arthrogryposis HP:0005684 175 203 overlapping fingers at birth HP:0010557 205 237 abnormal digital flexion creases HP:0006143 243 259 foot deformities HP:0001760 271 290 talipes equinovarus HP:0001762 295 309 vertical talus HP:0001838 321 351 marked intrafamilial variation HP:0003822

7039311

We report on 44 patients (18 with additional affected family members), with congenital distal limb contractures identified from a large study of over 350 patients with congenital joint contractures. Fourteen propositi (seven familial cases, seven isolated cases) had a newly recognized form of arthrogryposis, which we have designated distal arthrogryposis type 1, with the predominant manifestations of autosomal dominant inheritance; tightly clenched fists at birth, with medially overlapping fingers, ulnar deviation, and camptodactyly in adults; and positional foot deformities. Contractures at other major joints are variable. There are no associated visceral anomalies; intelligence is normal. There can be marked intrafamilial and interfamilial variability. Twenty-two propositi with similar distal contractures had additional findings and were classified into five subcategories of distal arthrogryposis (type IIA-E). Among type II patients cleft palate, cleft lip, small tongue, trismus, ptosis, epicanthal folds, keratoconus, short stature, scoliosis, a unique hand position, and dull normal intelligence were seen. These characteristics were seen in various combinations and patterns and allowed sorting into groups that were the basis for the categorization. The remaining eight propositi were recognized to have previously described conditions with distal contractures and autosomal dominant inheritance, ie, the Freeman-Sheldon syndrome, trismus-pseudo-camptodactyly syndrome, congenital contractural arachnodactyly, and familial camptodactyly. Pathogenetically we postulate similar underlying defects of abnormal tendon attachments, attenuation, and absence; careful nosologic comparisons are important for prognostic counseling and habilitative management.

76 111 congenital distal limb contractures HP:0002803 168 197 congenital joint contractures HP:0002803 225 239 familial cases HP:0000005 247 261 isolated cases HP:0001420 294 308 arthrogryposis HP:0001390 335 356 distal arthrogryposis HP:0005684 404 434 autosomal dominant inheritance HP:0000006 436 458 tightly clenched fists HP:0001188 474 502 medially overlapping fingers HP:0010557 504 519 ulnar deviation HP:0001193 525 538 camptodactyly HP:0012385 554 581 positional foot deformities HP:0005656 583 595 Contractures HP:0001371 622 630 variable HP:0003813 656 674 visceral anomalies HP:0002012 720 763 intrafamilial and interfamilial variability HP:0003822 738 763 interfamilial variability HP:0003812 799 818 distal contractures HP:0005684 890 911 distal arthrogryposis HP:0005684 949 961 cleft palate HP:0000175 963 972 cleft lip HP:0100333 974 986 small tongue HP:0000171 988 995 trismus HP:0000211 997 1003 ptosis HP:0000508 1005 1021 epicanthal folds HP:0000286 1023 1034 keratoconus HP:0000563 1036 1049 short stature HP:0004322 1051 1060 scoliosis HP:0002650 1064 1084 unique hand position HP:0001155 1362 1381 distal contractures HP:0005684 1386 1416 autosomal dominant inheritance HP:0000006 1452 1459 trismus HP:0000211 1467 1480 camptodactyly HP:0012385 1502 1529 contractural arachnodactyly HP:0001166 1544 1557 camptodactyly HP:0012385

18478600

Popliteal pterygium syndrome (PPS) and Van der Woude syndrome (VWS) are caused by mutations in the gene interferon regulatory factor 6 (IRF6). Skeletal, genital malformations and involvement of the skin occur in PPS and orofacial clefting and lip pits occur in both. We report on a patient with unilateral cleft lip and palate, ankyloblepharon, paramedian lip pits, unilateral renal aplasia, and a coronal hypospadias. By sequencing IRF6, we detected a novel missense mutation (Arg339Ile). The other family members were unaffected and had no IRF6 mutations, including the patient's brother who was also born with hypospadias. The patient and his brother were both conceived by in vitro fertilization (IVF). It is discussed whether the renal malformation in the patient is related to the IVF procedure or to the IRF6 mutation.

0 19 Popliteal pterygium HP:0009756 143 174 Skeletal, genital malformations HP:0000924 179 202 involvement of the skin HP:0000951 220 238 orofacial clefting HP:0000202 243 251 lip pits HP:0000196 295 326 unilateral cleft lip and palate HP:0100334 295 315 unilateral cleft lip HP:0100333 306 326 cleft lip and palate HP:0000175 328 343 ankyloblepharon HP:0009755 345 364 paramedian lip pits HP:0100269 366 390 unilateral renal aplasia HP:0000122 398 417 coronal hypospadias HP:0008743 613 624 hypospadias HP:0000047 735 753 renal malformation HP:0000792

9425907

Townes-Brocks syndrome (TBS, OMIM #107480) is a rare autosomal-dominant malformation syndrome with a combination of anal, renal, limb and ear anomalies. Cytogenetic findings suggested that the gene mutated in TBS maps to chromosome 16q12.1, where SALL1 (previously known as HSAL1), a human homologue of spalt (sal), is located. SAL is a developmental regulator in Drosophila melanogaster and is conserved throughout evolution. No phenotype has yet been attributed to mutations in vertebrate sal-like genes. The expression patterns of sal-like genes in mouse, Xenopus and the fish Medaka, and the finding that Medaka sal is regulated by Sonic hedgehog (Shh; ref. 11), prompted us to examine SALL1 as a TBS candidate gene. Here we demonstrate that SALL1 mutations cause TBS in a family with vertical transmission of TBS and in an unrelated family with a sporadic case of TBS. Both mutations are predicted to result in a prematurely terminated SALL1 protein lacking all putative DNA binding domains. TBS therefore represents another human developmental disorder caused by mutations in a putative C2H2 zinc-finger transcription factor.

53 71 autosomal-dominant HP:0000006 116 151 anal, renal, limb and ear anomalies HP:0004378 138 151 ear anomalies HP:0000598 852 860 sporadic HP:0003745

14735582

Brachydactyly type C (BDC) is characterized by shortening of the middle phalanges of the index, middle, and little finger with hyperphalangy, usually of the index and middle finger. Heterozygous mutations of the cartilage derived morphogenetic protein-1 (CDMP1) resulting in a loss of function have been reported in BDC. We here describe a large kindred with a semi-dominant form of BDC and pronounced ulnar deviation of the second and third digits. In this family a novel homozygous missense mutation was identified (517A > G) changing methionine to valine at amino acid position 173. The mutation is located within a highly conserved seven amino acid region of the prodomain of CDMP1. Hand radiographs of heterozygous mutation carriers showed mild shortening of the metacarpals IV and V; a finding confirmed by the analysis of their metacarpophalangeal profiles (MCPPs). The mutation described here points toward an important function of the prodomain for the folding, secretion, and availability of biologically active CDMP1.

0 20 Brachydactyly type C HP:0009373 22 25 BDC HP:0009373 47 121 shortening of the middle phalanges of the index, middle, and little finger HP:0004220 127 180 hyperphalangy, usually of the index and middle finger HP:0009495 127 140 hyperphalangy HP:0010235 366 379 dominant form HP:0000006 402 448 ulnar deviation of the second and third digits HP:0009464 402 417 ulnar deviation HP:0001193 750 788 shortening of the metacarpals IV and V HP:0010047

8317476

Familial Angelman syndrome (AS) can result from mutations in chromosome 15q11q13 that, when transmitted from father to child, result in no phenotypic abnormality but, when transmitted from mother to child, cause AS. These mutations therefore behave neither as dominant nor as recessive mutations but, rather, show an imprinted mode of inheritance. We have analyzed two sibling pairs with AS and a larger family with four AS offspring of three sisters with several recently described microsatellite polymorphisms in the AS region. AS siblings inherited the same maternal alleles at the GABRB3 and GABRA5 loci, and the unaffected siblings of AS individuals inherited the other maternal alleles at these loci. In one of the AS sibling pairs, analysis of a recombination event indicates that the mutation responsible for AS is distal to locus D15S63. This result is consistent with a previously described imprinted submicroscopic deletion causing AS, a deletion that includes loci D15S10, D15S113, and GABRB3, all distal to D15S63. The analysis of the larger AS family provides the first clear demonstration of a new mutation in nondeletion AS. Analysis of linkage of AS to GABRB3 in these three families, on the assumption of imprinted inheritance (i.e., penetrance of an AS mutation is 1 if transmitted maternally and is 0 if transmitted paternally), indicates a maximum lod score of 3.52 at theta = 0.

139 161 phenotypic abnormality HP:0000118 260 268 dominant HP:0000006 327 346 mode of inheritance HP:0000005

10482951

The clinical features of Angelman syndrome (AS) comprise severe mental retardation, postnatal microcephaly, macrostomia and prognathia, absence of speech, ataxia, and a happy disposition. We report on seven patients who lack most of these features, but presented with obesity, muscular hypotonia and mild mental retardation. Based on the latter findings, the patients were initially suspected of having Prader-Willi syndrome. DNA methylation analysis of SNRPN and D15S63, however, revealed an AS pattern, ie the maternal band was faint or absent. Cytogenetic studies and microsatellite analysis demonstrated apparently normal chromosomes 15 of biparental inheritance. We conclude that these patients have an imprinting defect and a previously unrecognised form of AS. The mild phenotype may be explained by an incomplete imprinting defect or by cellular mosaicism.

57 82 severe mental retardation HP:0002187 84 106 postnatal microcephaly HP:0005484 108 119 macrostomia HP:0000181 124 134 prognathia HP:0000303 136 153 absence of speech HP:0001617 155 161 ataxia HP:0001251 169 186 happy disposition HP:0100024 268 275 obesity HP:0001513 277 295 muscular hypotonia HP:0001252 300 323 mild mental retardation HP:0001256

1248162

The present report concerns a two-generation family of nine individuals in which the father and three of the six living children all had: (1) a mixed hearing loss with a Mondini type cochlear malformation and stapes fixation; (2) cup-shaped, anteverted pinnae with bilateral prehelical pits: (3) bilateral branchial cleft fistulas; and (4) bilateral renal dysplasia and anomalies of the collecting system. The father and one affected son also had aplasia of the lacrimal ducts. A fourth child who died at 5 months of age was reported to have branchial cleft fistulas and bilateral polycystic kidneys at autopsy. In addition, the concept of noso-embryologic communities is presented. Such groups are composed of syndromes whose total phenotypic spectra not only overlap but also share common elements in embryogenesis. This concept is illustrated with a group of branchial arch syndromes that are related in this way.

144 162 mixed hearing loss HP:0000410 170 204 Mondini type cochlear malformation HP:0000376 209 224 stapes fixation HP:0000381 230 259 cup-shaped, anteverted pinnae HP:0000378 275 290 prehelical pits HP:0004467 306 330 branchial cleft fistulas HP:0009795 340 365 bilateral renal dysplasia HP:0012582 370 404 anomalies of the collecting system HP:0004742 447 476 aplasia of the lacrimal ducts HP:0007993 542 566 branchial cleft fistulas HP:0009795 571 599 bilateral polycystic kidneys HP:0000113 862 886 branchial arch syndromes HP:0009794

1745350

We studied two families with an unusual variant of neurofibromatosis (NF). The first family had spinal neurofibromas and café au lait spots (CLS), the second spinal neurofibromas without CLS. Other signs of NF1 or NF2, such as cutaneous tumors, Lisch nodules, or acoustic tumors, were absent. The inheritance pattern in both pedigrees was consistent with autosomal dominant inheritance. Using genetic linkage analysis with DNA markers tightly linked to the NF1 and NF2 loci, we determined that the likely location for the mutation in the first family was in the NF1 gene with odds of 97:1, whereas the mutation in the second family was excluded from the NF1 locus with odds greater than 100,000:1. Families such as these, in which a defined subset of the NF phenotype is passed on, are important for understanding the functional consequences of particular mutations in the NF genes.

51 68 neurofibromatosis HP:0006746 96 116 spinal neurofibromas HP:0009735 121 145 café au lait spots (CLS) HP:0000957 158 178 spinal neurofibromas HP:0009735 227 243 cutaneous tumors HP:0008069 245 258 Lisch nodules HP:0009737 263 278 acoustic tumors HP:0009588 355 385 autosomal dominant inheritance HP:0000006

6829601

Two unrelated children (one male, the other female) had unusual craniofacial anomalies consisting of hemangiomatous branchial clefts, lip pseudoclefts, and identical unusual facial appearance. One also had unilateral microphthalmia and both had congenital nasolacrimal duct obstruction. Two similar, sporadic cases from the literature were also identified. These four cases form the basis of a new, distinctly recognizable pattern of malformation.

56 86 unusual craniofacial anomalies HP:0002004 101 132 hemangiomatous branchial clefts HP:0009794 134 150 lip pseudoclefts HP:0000159 166 191 unusual facial appearance HP:0002004 217 231 microphthalmia HP:0000568 256 285 nasolacrimal duct obstruction HP:0000579 300 314 sporadic cases HP:0003745

6859100

We report two families in which propositi had severe bilateral sensorineural hearing loss, a preauricular pit or tag, and duplication of the ureters or bifid renal pelvices. Other relatives had one or more of these anomalies in a pattern suggesting autosomal dominant inheritance with reduced penetrance and variable expressivity. We suggest the term "branchio-oto-ureteral syndrome" to designate this condition.

53 89 bilateral sensorineural hearing loss HP:0008619 93 116 preauricular pit or tag HP:0000384 93 109 preauricular pit HP:0004467 122 148 duplication of the ureters HP:0000073 152 172 bifid renal pelvices HP:0005580 249 279 autosomal dominant inheritance HP:0000006 285 303 reduced penetrance HP:0003829 308 329 variable expressivity HP:0003828

11748306

Angelman syndrome (AS) is a severe neurobehavioural disorder caused by defects in the maternally derived imprinted domain located on 15q11-q13. Most patients acquire AS by one of five mechanisms: (1) a large interstitial deletion of 15q11-q13; (2) paternal uniparental disomy (UPD) of chromosome 15; (3) an imprinting defect (ID); (4) a mutation in the E3 ubiquitin protein ligase gene (UBE3A); or (5) unidentified mechanism(s). All classical patients from these classes exhibit four cardinal features, including severe developmental delay and/or mental retardation, profound speech impairment, a movement and balance disorder, and AS specific behaviour typified by an easily excitable personality with an inappropriately happy affect. In addition, patients can display other characteristics, including microcephaly, hypopigmentation, and seizures. We restricted the present study to 104 patients (93 families) with a classical AS phenotype. All of our patients were evaluated for 22 clinical variables including growth parameters, acquisition of motor skills, and history of seizures. In addition, molecular and cytogenetic analyses were used to assign a molecular class (I-V) to each patient for genotype-phenotype correlations. In our patient repository, 22% of our families had normal DNA methylation analyses along 15q11-q13. Of these, 44% of sporadic patients had mutations within UBE3A, the largest percentage found to date. Our data indicate that the five molecular classes can be divided into four phenotypic groups: deletions, UPD and ID patients, UBE3A mutation patients, and subjects with unknown aetiology. Deletion patients are the most severely affected, while UPD and ID patients are the least. Differences in body mass index, head circumference, and seizure activity are the most pronounced among the classes. Clinically, we were unable to distinguish between UPD and ID patients, suggesting that 15q11-q13 contains the only significant maternally expressed imprinted genes on chromosome 15.

35 60 neurobehavioural disorder HP:0000707 520 539 developmental delay HP:0001263 547 575 mental retardation, profound HP:0002187 567 593 profound speech impairment HP:0002167 597 626 movement and balance disorder HP:0100022 706 734 inappropriately happy affect HP:0100024 803 815 microcephaly HP:0000252 817 833 hypopigmentation HP:0007513 839 847 seizures HP:0001250 1077 1085 seizures HP:0001250 1350 1358 sporadic HP:0003745 1769 1776 seizure HP:0001250

8658145

The basal cell nevus syndrome (BCNS) is characterized by developmental abnormalities and by the postnatal occurrence of cancers, especially basal cell carcinomas (BCCs), the most common human cancer. Heritable mutations in BCNS patients and a somatic mutation in a sporadic BCC were identified in a human homolog of the Drosophila patched (ptc) gene. The ptc gene encodes a transmembrane protein that in Drosophila acts in opposition to the Hedgehog signaling protein, controlling cell fates, patterning, and growth in numerous tissues. The human PTC gene appears to be crucial for proper embryonic development and for tumor suppression.

4 29 basal cell nevus syndrome HP:0002671 57 84 developmental abnormalities HP:0001263 140 161 basal cell carcinomas HP:0002671 192 198 cancer HP:0002664 243 259 somatic mutation HP:0001428 265 273 sporadic HP:0003745 619 624 tumor HP:0002664

7849713

The analysis of a de novo 8q12.2-q21.2 deletion led to the identification of a proposed previously undescribed contiguous gene syndrome consisting of Branchio-Oto-Renal (BOR) syndrome, Duane syndrome, hydrocephalus and trapeze aplasia. This is the first reported localization of the genes responsible for Duane syndrome and this dominant form of hydrocephalus. In contrast, we report a new localization for the gene responsible for BOR syndrome which is more telomeric to an initial placement. Linkage analysis of affected families consistently mapped the gene responsible for BOR and Branchio-Oto (BO) syndromes to within the deletion. Using new algorithms, a YAC contig was constructed and used to localize the breakpoint of another chromosomal rearrangement associated with BO syndrome to a 500 kb interval within the deletion. The 8q12.2-q21.2 deletion suggests that reduced dosage of the relevant genes is sufficient to cause Duane syndrome, BOR syndrome and this dominant form of hydrocephalus.

18 25 de novo HP:0003745 111 135 contiguous gene syndrome HP:0001466 185 199 Duane syndrome HP:0009921 201 214 hydrocephalus HP:0000238 219 234 trapeze aplasia HP:0006106 305 319 Duane syndrome HP:0009921 329 337 dominant HP:0000006 346 359 hydrocephalus HP:0000238 931 945 Duane syndrome HP:0009921 969 982 dominant form HP:0000006 986 999 hydrocephalus HP:0000238

8981943

The human homologue of the Drosophila segment polarity gene patched is implicated in the development of nevoid basal cell carcinoma syndrome (NBCCS) and in the genesis of sporadic basal cell carcinomas. In order to examine the phenotypic variability in NBCCS and to highlight functionally important domains of the PTCH protein, we have now screened 71 unrelated NBCCS individuals for mutations in the PTCH exons. We identified 28 mutations that are distributed throughout the entire gene, and most (86%) cause protein truncation. As part of this analysis, we demonstrate that failure of one NBCCS family to show clear linkage to chromosome 9q22.3-31 is most likely due to germinal mosaicism. We have identified three families bearing identical mutations with variable phenotypes, suggesting phenotypic variability in NBCCS is a complex genetic event. No phenotype genotype correlation between the position of truncation mutations and major clinical features was evident. Two missense mutations have been identified, and their location within transmembrane domains supports the notion that PTCH may have a transport function. The preponderance of truncation mutants in the germ line of NBCCS patients suggests that the developmental defects associated with the disorder are most likely due to haploinsufficiency.

111 131 basal cell carcinoma HP:0002671 171 179 sporadic HP:0003745 180 201 basal cell carcinomas HP:0002671 227 249 phenotypic variability HP:0003812 759 778 variable phenotypes HP:0003813 791 813 phenotypic variability HP:0003812 1218 1239 developmental defects HP:0001263

12357473

Growth/differentiation factor-5 (GDF5), also known as cartilage-derived morphogenetic protein-1 (CDMP-1), is a secreted signaling molecule that participates in skeletal morphogenesis. Heterozygous mutations in GDF5, which maps to human chromosome 20, occur in individuals with autosomal dominant brachydactyly type C (BDC). Here we show that BDC is locus homogeneous by reporting a GDF5 frameshift mutation segregating with the phenotype in a family whose trait was initially thought to map to human chromosome 12. We also describe heterozygous mutations in nine additional probands/families with BDC and show nonpenetrance in a mutation carrier. Finally, we show that mutant GDF5 polypeptides containing missense mutations in their active domains do not efficiently form disulfide-linked dimers when expressed in vitro. These data support the hypothesis that BDC results from functional haploinsufficiency for GDF5.

277 295 autosomal dominant HP:0000006 296 316 brachydactyly type C HP:0009373 318 321 BDC HP:0009373 610 623 nonpenetrance HP:0003829

1347096

The Gorlin (naevoid-basal-cell-carcinoma) syndrome is an autosomal dominant disorder characterised by multiple naevoid basal-cell carcinomas, recurrent odontogenic keratocysts, skeletal anomalies, intracranial calcification, and developmental malformations. Characterisation of the gene that causes the syndrome may improve our understanding of the pathogenesis of other basal-cell carcinomas. By linkage analysis, we have shown that the gene is located on chromosome 9q22.3-q31; the most likely position is between DNA markers D9S12 and D9S53. Location of the gene for Gorlin syndrome offers the possibility that DNA markers can be used in risk estimation and presymptomatic identification of patients for surveillance.

20 40 basal-cell-carcinoma HP:0002671 57 84 autosomal dominant disorder HP:0000006 102 140 multiple naevoid basal-cell carcinomas HP:0001054 152 175 odontogenic keratocysts HP:0010603 177 195 skeletal anomalies HP:0000924 197 223 intracranial calcification HP:0002514 229 256 developmental malformations HP:0001263 371 392 basal-cell carcinomas HP:0002671

3134615

At least eight provisional categories of neurofibromatosis have been proposed. Among these, neurofibromatosis 1 (von Recklinghausen's disease or peripheral neurofibromatosis) and neurofibromatosis 2 (central or bilateral acoustic neurofibromatosis) have been established as distinct disorders. We studied 15 affected male and 8 affected female members of one large kindred with neurofibromatosis 2. None of the patients met the diagnostic criteria for neurofibromatosis 1. Between the ages of 15 and 53 years, the patients had multiple central nervous system tumors of various types--mainly, bilateral acoustic neuromas. Two or more tumors eventually developed in 20 of the patients; 9 had evidence of only bilateral acoustic neuromas. Meningiomas and ependymomas were more common among the young patients; those who initially presented with acoustic neuromas were nearly a decade older. Intracranial nontumoral calcifications were present in most patients and were also found in symptom-free children. The presence of such lesions is probably a prodromic feature of neurofibromatosis 2. Simultaneous analysis of D22S1 and IGLV DNA markers for coinheritance with neurofibromatosis 2 indicates that the locus for the disease is near the center of the long arm of chromosome 22 (22q11.1----22q13.1). The eventual isolation of this disease gene may reveal a cause of the most common intracranial tumors in humans.

41 58 neurofibromatosis HP:0006746 92 109 neurofibromatosis HP:0006746 156 173 neurofibromatosis HP:0006746 179 196 neurofibromatosis HP:0006746 211 247 bilateral acoustic neurofibromatosis HP:0009589 378 395 neurofibromatosis HP:0006746 452 469 neurofibromatosis HP:0006746 536 565 central nervous system tumors HP:0100006 592 619 bilateral acoustic neuromas HP:0009589 631 639 tumors HP:0002664 707 734 bilateral acoustic neuromas HP:0009589 736 747 Meningiomas HP:0002858 752 763 ependymomas HP:0002888 791 805 young patients HP:0003593 842 859 acoustic neuromas HP:0009588 888 926 Intracranial nontumoral calcifications HP:0002514 1067 1084 neurofibromatosis HP:0006746 1163 1180 neurofibromatosis HP:0006746 1380 1399 intracranial tumors HP:0100006

12900905

We present the case of a 14-year-old Japanese girl who had both Gorlin syndrome and ulcerative colitis. She had complained of blood stools for 6 months and severe scoliosis from her infancy. Physical examination revealed multiple nevi, palmar and plantar pits, jaw cysts, and calcification of the falx cerebri, leading to the diagnosis of Gorlin syndrome. Total colonoscopy revealed an edematous and spotty bleeding mucosa extending from the anus to the transverse colon. Histological examination was also compatible with ulcerative colitis. Thus, we diagnosed her as having Gorlin syndrome with ulcerative colitis. Gene analysis revealed a mutation, 1247InsT, in the human patched gene (PTCH), resulting in the truncation of PTCH protein. Since Gorlin syndrome and ulcerative colitis are rare disorders in childhood, this association is interesting, suggesting a correlation between the hedgehog signaling and intestinal disorders.

84 102 ulcerative colitis HP:0100279 126 138 blood stools HP:0002255 163 172 scoliosis HP:0002650 182 189 infancy HP:0003576 221 234 multiple nevi HP:0001054 236 259 palmar and plantar pits HP:0010610 247 259 plantar pits HP:0010612 261 270 jaw cysts HP:0010603 276 309 calcification of the falx cerebri HP:0005462 386 422 edematous and spotty bleeding mucosa HP:0004295 522 540 ulcerative colitis HP:0100279 596 614 ulcerative colitis HP:0100279 766 784 ulcerative colitis HP:0100279 807 816 childhood HP:0011463 911 931 intestinal disorders HP:0002012

9207339

Neurofibromatosis 1 and neurofibromatosis 2 are autosomal dominant genetic disorders in which affected individuals develop both benign and malignant tumors at an increased frequency. Since the original National Institutes of Health Consensus Development Conference in 1987, there has been significant progress toward a more complete understanding of the molecular bases for neurofibromatosis 1 and neurofibromatosis 2. Our objective was to determine the diagnostic criteria for neurofibromatosis 1 and neurofibromatosis 2, recommendations for the care of patients and their families at diagnosis and during routine follow-up, and the role of DNA diagnostic testing in the evaluation of these disorders. Published reports from 1966 through 1996 obtained by MEDLINE search and studies presented at national and international meetings. All studies were reviewed and analyzed by consensus from multiple authors. Peer-reviewed published data were critically evaluated by independent extraction by multiple authors. The main results of the review were qualitative and were reviewed by neurofibromatosis clinical directors worldwide through an Internet Web site. On the basis of the information presented in this review, we propose a comprehensive approach to the diagnosis and treatment of individuals with neurofibromatosis 1 and neurofibromatosis 2.

0 17 Neurofibromatosis HP:0006746 24 41 neurofibromatosis HP:0006746 48 66 autosomal dominant HP:0000006 149 155 tumors HP:0002664 374 391 neurofibromatosis HP:0006746 398 415 neurofibromatosis HP:0006746 478 495 neurofibromatosis HP:0006746 502 519 neurofibromatosis HP:0006746 1083 1100 neurofibromatosis HP:0006746 1306 1323 neurofibromatosis HP:0006746 1330 1347 neurofibromatosis HP:0006746

9643284

Blood samples from 125 unrelated families with classical type 2 neurofibromatosis (NF2) with bilateral vestibular schwannomas have been analysed for mutations in the NF2 gene. A further 17 families fulfilling modified criteria for NF2 have also been analysed. Causative mutations have been identified in 54 (43%) classical families and six (35%) of those fulfilling modified criteria. Forty-two cases from 38 families with truncating mutations had an average age at onset of symptoms of 19 years and diagnosis at 22.4 years. Fifty-one cases from 16 families with splice site mutations (15 from six), missense mutations (18 from six), and large deletions (18 from five) had an average age of onset of 27.8 years and at diagnosis of 33.4 years. Subjects with truncating mutations were significantly more likely to have symptoms before 20 years of age (p<0.001) and to develop at least two symptomatic CNS tumours in addition to vestibular schwannoma before 30 years (p<0.001). There were also significantly fewer multigenerational families with truncating mutations. Four further truncating mutations were in mosaic form and were associated with milder disease than other similar mutations. This large study has confirmed the previous impression that truncating mutations are associated with severe disease, but caution has to be exercised in using mutation type to predict disease course.

64 81 neurofibromatosis HP:0006746 93 125 bilateral vestibular schwannomas HP:0009589 899 910 CNS tumours HP:0100006 926 947 vestibular schwannoma HP:0009588 1128 1187 associated with milder disease than other similar mutations HP:0003813

9182785

Undiagnosed institutionalised patients were reviewed in an attempt to identify those with Angelman syndrome (AS). The aim was to test these patients for deletion of chromosome 15(q11-13) and to describe the adult phenotype. The selection criteria included severe intellectual disability, ataxic or hypermotoric limb movements, lack of speech, a "happy" demeanour, epilepsy, and facial appearance consistent with the diagnosis. Patients were examined, medical records perused, and patients' doctors contacted as required. Genetic tests performed included routine cytogenetics, DNA methylation analysis (with probe PW71B), and fluorescence in situ hybridisation (with probes D15S10, GABRbeta3, or SNRPN). A deletion in the AS region was detected in 11 patients (9 males and 2 females) of 22 tested. The mean age at last review (March 1996) was 31.5 years (range 24 to 36 years). Clinical assessment documented findings of large mouth and jaw with deep set eyes, and microcephaly in nine patients (two having a large head size for height). No patient was hypopigmented; 1/11 patients was fair. Outbursts of laughter occurred in all patients but infrequently in 7/11 (64%) and a constant happy demeanour was present in 5/11 (46%). All had epilepsy, with improvement in 5/11 (46%), no change in 4 (36%), and deterioration in 2 (18%). The EEG was abnormal in 10/10 patients. Ocular abnormalities were reported in 3/8 patients (37.5%) and 4/11 (36%) had developed kyphosis. Two had never walked. All nine who walked were ataxic with an awkward, clumsy, heavy, and/or lilting gait. No patient had a single word of speech but one patient could use sign language for two needs (food and drink). Our data support the concept that AS resulting from deletion is a severe neurological syndrome in adulthood. The diagnosis in adults may not be straightforward as some manifestations change with age. Kyphosis and keratoconus are two problems of older patients.

263 286 intellectual disability HP:0001249 288 294 ataxic HP:0001251 288 325 ataxic or hypermotoric limb movements HP:0002070 298 325 hypermotoric limb movements HP:0002276 327 341 lack of speech HP:0001617 345 362 "happy" demeanour HP:0100024 364 372 epilepsy HP:0001250 378 395 facial appearance HP:0001999 920 939 large mouth and jaw HP:0000303 920 931 large mouth HP:0000181 945 958 deep set eyes HP:0000490 964 976 microcephaly HP:0000252 1008 1018 large head HP:0000256 1052 1065 hypopigmented HP:0001010 1091 1112 Outbursts of laughter HP:0000749 1175 1199 constant happy demeanour HP:0100024 1235 1243 epilepsy HP:0001250 1369 1389 Ocular abnormalities HP:0000284 1457 1465 kyphosis HP:0002808 1475 1487 never walked HP:0002540 1514 1520 ataxic HP:0001251 1885 1893 Kyphosis HP:0002808 1898 1909 keratoconus HP:0000563

12567410

CDMP-1, a cartilage-specific member of the TGFss superfamily of secreted signaling molecules, plays a key role in chondrogenesis, growth and patterning of the developing vertebrate skeleton. Homozygous CDMP-1 mutations cause Hunter-Thompson and Grebe types of acromesomelic chondrodysplasia and DuPan syndrome in humans, as well as brachypodism in mice, while heterozygous mutations cause brachydactyly type C (BDC). We present clinical and radiographic data from three unrelated families in which 12 members share the same heterozygous CDMP-1 mutation, an insertion (insG206), resulting in a frameshift predicted to cause functional haploinsufficiency. Although eight mutation carriers display BDC, four have normal hands and feet, confirming nonpenetrance of BDC with CDMP-1 mutations. In addition, several carriers have other skeletal abnormalities, including severe bilateral vertical talus (in two), developmental hip dysplasia (in one), and short stature (in two, who are otherwise unaffected). Premature vertebral end-plate disease was observed in four mutation carriers and was associated with spondylolysis and spondylolisthesis in three of these. Axial skeletal involvement has not been previously reported in association with CDMP-1 mutations. This finding is consistent with CDMP-1 expression in human hypertrophic chondrocytes, which are present in the ring epiphyses of vertebral end plates. Phenotypic variation in BDC has previously been attributed either to locus heterogeneity or to the varied functional effects of different CDMP-1 mutations. The remarkable range of phenotypes caused by this identical CDMP-1 mutation in these families emphasizes the crucial role of genetic background, stochastic variation and/or environmental factors in modifying the observed phenotype. Our findings illustrate that nonpenetrance for the typical features of BDC can be appreciable and that atypical skeletal features that have been reported in some patients with BDC (i.e., clubfoot, short stature, spondylolysis) may also result from CDMP-1 mutation.

389 409 brachydactyly type C HP:0009373 744 757 nonpenetrance HP:0003829 829 851 skeletal abnormalities HP:0000924 880 894 vertical talus HP:0001838 905 932 developmental hip dysplasia HP:0001385 947 960 short stature HP:0004322 1001 1038 Premature vertebral end-plate disease HP:0008419 1102 1115 spondylolysis HP:0003304 1120 1137 spondylolisthesis HP:0003302 1157 1183 Axial skeletal involvement HP:0009121 1406 1426 Phenotypic variation HP:0003812 1475 1494 locus heterogeneity HP:0001425 1823 1836 nonpenetrance HP:0003829 1981 1989 clubfoot HP:0001762 1991 2004 short stature HP:0004322 2006 2019 spondylolysis HP:0003304

2918545

The inheritance of Angelman's syndrome, a disorder characterised by mental retardation, epilepsy, ataxia, and a happy disposition, is debated because affected sibs occur less frequently than expected with autosomal recessive inheritance. After discovering two unrelated patients with a small deletion of the proximal long arm of chromosome 15, 10 further patients with Angelman's syndrome were reassessed. Five had apparently normal karyotypes, four had a deletion within 15q11-13, and one had a pericentric inversion, inv(15)(p11q13) involving the same chromosomal region. In the latter case, the healthy mother had the same pericentric inversion, indicating that the patient also had a submicroscopic mutation on his other chromosome 15. These data map the Angelman locus to 15q11-13 and suggest that de novo visible deletions (associated with a low recurrence risk) and autosomal recessively inherited cases combine to give an overall sib recurrence risk of less than 25%.

68 86 mental retardation HP:0001249 88 96 epilepsy HP:0001250 98 104 ataxia HP:0001251 112 129 happy disposition HP:0100024 205 236 autosomal recessive inheritance HP:0000007 803 810 de novo HP:0003745 873 894 autosomal recessively HP:0000007

3100017

In situ hybridization with a c-sis probe was performed on peripheral lymphocytes of a man with neurofibromatosis and a ring 22 chromosome. Hybridization was observed on both the normal #22 and the ring 22, indicating that the patient is not constitutionally hemizygous for c-sis. The implications of a ring 22 constitution and the neurofibromatosis phenotype are discussed.

95 112 neurofibromatosis HP:0006746 331 348 neurofibromatosis HP:0006746

955942

Six cases of this syndrome previously reported in Great Britain and in Canada are reviewed in relation to a personal case, a 17-month-old boy. The syndrome's main features are microbrachycephaly and peculiar face, mental deficiency with euphoria and laughter, ataxia and epilepsy consisting in infantile spasms and grand-mal attacks. Though its precise nature and cause still remain unknown, the syndrome seems neither familial nor progressive.

176 194 microbrachycephaly HP:0002258 199 212 peculiar face HP:0002004 214 231 mental deficiency HP:0001249 237 245 euphoria HP:0000708 250 258 laughter HP:0000748 260 266 ataxia HP:0001251 271 279 epilepsy HP:0001250 294 310 infantile spasms HP:0002391 315 332 grand-mal attacks HP:0002069

6631421

A young girl 12 old, sent to us for obesity, and coxa-epiphysiolysis showed signs of mental retardation and bilateral thumb ankylosis. The fact that the mother was also affected by both of these signs, led to a more detailed genetic research. The latter revealed that not only the daughter, the mother, but also their own mother and may be, the sister, the grand-mother and the great-aunt of the patient had a retardation, a slight dysmorphia, a type A brachydactylia, signs of obesity and an identical ankylosis of both thumbs. This vertical inheritance, affecting apparently females only, but not associated with a high rate of miscarriage, has, it seems, never been reported. The characteristics of this family are being considered and discussed.

2 7 young HP:0003593 36 43 obesity HP:0001513 49 68 coxa-epiphysiolysis HP:0006461 85 103 mental retardation HP:0001249 118 133 thumb ankylosis HP:0001172 410 421 retardation HP:0001249 425 442 slight dysmorphia HP:0004675 446 468 type A brachydactylia, HP:0009370 478 485 obesity HP:0001513 503 527 ankylosis of both thumbs HP:0001172

3063533

We report on seven children with Angelman syndrome presenting with psychomotor retardation during the 1st year of life. Seizures developed in six patients, and computed tomography (CT) scanning showed diffuse atrophy of the brain in five patients. We conclude that diagnosis is difficult in the first years of life. A review of the literature is given.

67 90 psychomotor retardation HP:0001255 91 118 during the 1st year of life HP:0003576 120 128 Seizures HP:0001250 201 229 diffuse atrophy of the brain HP:0002283

6846397

We report a man who had the branchio-oto-renal (BOR) syndrome with crossed renal ectopia. His three children were born with bilateral renal agenesis and the so-called Potter syndrome. This case illustrates the potential severity of the renal anomalies in the BOR syndrome and the inadequacy of oligohydramnios and maternal serum alpha-fetoprotein as screening methods for renal agenesis. This case also implies strongly the necessity for meticulous search for renal anomalies in individuals with the BOR syndrome and proper counseling regarding the possibility of lethal bilateral renal agenesis.

75 88 renal ectopia HP:0000086 124 148 bilateral renal agenesis HP:0010958 167 182 Potter syndrome HP:0002009 236 251 renal anomalies HP:0000077 294 309 oligohydramnios HP:0001562 372 386 renal agenesis HP:0000104 460 475 renal anomalies HP:0000077 571 595 bilateral renal agenesis HP:0010958

8954778

Brachydactyly type C is an autosomal dominant disorder characterized by abnormal segmentation of the index and middle fingers segregating with a high degree of variable expression in members of the same family. We have followed up and studied members of the large kindred segregating with the brachydactyly type C phenotype described by Virgil Haws in 1963, and using genetic linkage analysis, we localized the susceptibility gene to human chromosome 12q24.

0 20 Brachydactyly type C HP:0009373 27 54 autosomal dominant disorder HP:0000006 72 125 abnormal segmentation of the index and middle fingers HP:0004100 145 209 high degree of variable expression in members of the same family HP:0003822 293 313 brachydactyly type C HP:0009373

10767004

In addition to craniofacial, auricular, ophthalmologic, and oral anomalies, the distinctive phenotype of the branchio-oculo-facial (BOF) syndrome (MIM 113620) includes skin defects in the neck or infra/supra-auricular region. These unusual areas of thin, erythematous wrinkled skin differ from the discrete cervical pits, cysts, and fistulas of the branchio-oto-renal (BOR) syndrome (MIM 113650). Although the BOF and BOR syndromes are sufficiently distinctive that they should not be confused, both can be associated with nasolacrimal duct stenosis, deafness, prehelical pits, malformed pinna, and renal anomalies. Furthermore, a reported father and son [Legius et al., 1990, Clin Genet 37:347-500] had features of both conditions. It was not clear whether they had an atypical presentation of either BOR or BOF syndrome, or represented a private syndrome. In light of these issues, we selected the BOR locus (EYA1) as a possible gene mutation for the BOF syndrome. In five BOF patients, there were no mutations detected in the EYA1 gene, suggesting that it is not allelic to the BOR syndrome.

15 74 craniofacial, auricular, ophthalmologic, and oral anomalies HP:0002260 29 74 auricular, ophthalmologic, and oral anomalies HP:0000377 40 74 ophthalmologic, and oral anomalies HP:0000478 60 74 oral anomalies HP:0000153 168 192 skin defects in the neck HP:0000464 196 224 infra/supra-auricular region HP:0000356 232 281 unusual areas of thin, erythematous wrinkled skin HP:0000951 307 341 cervical pits, cysts, and fistulas HP:0009795 307 327 cervical pits, cysts HP:0009796 333 341 fistulas HP:0009794 523 549 nasolacrimal duct stenosis HP:0007678 551 559 deafness HP:0000404 561 576 prehelical pits HP:0004467 578 593 malformed pinna HP:0000377 599 614 renal anomalies HP:0000077

8042673

One hundred eighteen cases of nevoid basal cell carcinoma syndrome (NBCCS, Gorlin's syndrome or basal cell nevus syndrome) are presented in this study. In aiming to ascertain all the affected families in Australia, we have examined the largest series to date. Relative frequencies of associated complications are presented and compared with those of the recent English survey by Evans et al. [J Med Genet 30:460-464, 1993]. The frequencies of most manifestations are similar. However, one major difference is that the multiple basal cell carcinomas are manifest from an earlier age in the Australian population, which probably reflects greater exposure to ultraviolet radiation. Of the 64 families ascertained, 37 represented simplex cases, and, accordingly, the apparent new mutation rate is surprisingly high (14-81%) given the lack of impact of NBCCS on reproductive capabilities. There is some evidence to suggest that this may be attributable to anticipation.

37 57 basal cell carcinoma HP:0002671 96 112 basal cell nevus HP:0002671 527 548 basal cell carcinomas HP:0002671

8755929

Gorlin syndrome is an autosomal dominant disorder characterized by multiple basal cell carcinomas, medulloblastomas, ovarian fibromas, and a variety of developmental defects. All affected individuals share certain key features, but there is significant phenotypic variability within and among kindreds with respect to malformations. The gene (NBCCS) maps to chromosome 9q22, and allelic loss at this location is common in tumors from Gorlin syndrome patients. Two recessive cancer-predisposition syndromes, xeroderma pigmentosum group A (XPAC) and Fanconi anemia group C (FACC), map to the NBCCS region; and unusual, dominant mutations in these genes have been proposed as the cause of Gorlin syndrome. This study presents cytogenetic and molecular characterization of germ-line deletions in one patient with a chromosome 9q22 deletion and in a second patient with a deletion of 9q22-q3l. Both have typical features of Gorlin syndrome plus additional findings, including mental retardation, conductive hearing loss, and failure to thrive. That Gorlin syndrome can be caused by null mutations (deletions) rather than by activating mutations has several implications. First, in conjunction with previous analyses of allelic loss in tumors, this study provides evidence that associated neoplasms arise with homozygous inactivation of the gene. In addition, dominant mutations of the XPAC and FACC1 genes can be ruled out as the cause of Gorlin syndrome, since the two patients described have null mutations. Finally, phenotypic features that show variable expression must be influenced by genetic background, epigenetic effects, somatic mutations, or environmental factors, since these two patients with identical alterations (deletions) of the Gorlin syndrome gene have somewhat different manifestations of Gorlin syndrome.

22 49 autosomal dominant disorder HP:0000006 76 97 basal cell carcinomas HP:0002671 99 115 medulloblastomas HP:0002885 117 133 ovarian fibromas HP:0010618 152 173 developmental defects HP:0001263 241 301 significant phenotypic variability within and among kindreds HP:0003822 253 275 phenotypic variability HP:0003812 422 428 tumors HP:0002664 474 480 cancer HP:0002664 971 989 mental retardation HP:0001249 991 1014 conductive hearing loss HP:0000405 1020 1037 failure to thrive HP:0001508 1230 1236 tumors HP:0002664 1283 1292 neoplasms HP:0002664 1544 1563 variable expression HP:0003828

3321995

We observed an autosomal dominant disorder of abnormal upper lip, which resembles a poorly repaired cleft lip, malformed nose with broad bridge and flattened tip, lacrimal duct obstruction, malformed ears, and branchial cleft sinuses and/or linear skin lesions behind the ears in several persons in 3 families. In each of the 3 families, an affected parent had at least one affected child. Father-to-son transmission in one of these families ruled out X-linked inheritance. Other anomalies include coloboma, microphthalmia, auricular pits, lip pits, highly arched plate, dental anomalies, and subcutaneous cysts of the scalp. Premature graying of hair occurred in the affected adults. Growth retardation, developmental delay, and hand anomalies are variable components of the syndrome.

15 42 autosomal dominant disorder HP:0000006 46 64 abnormal upper lip HP:0000177 100 109 cleft lip HP:0100333 111 125 malformed nose HP:0000366 131 143 broad bridge HP:0000431 148 161 flattened tip HP:0000437 163 188 lacrimal duct obstruction HP:0000579 190 204 malformed ears HP:0000377 210 233 branchial cleft sinuses HP:0009794 241 276 linear skin lesions behind the ears HP:0004464 452 472 X-linked inheritance HP:0001417 498 506 coloboma HP:0000589 508 522 microphthalmia HP:0000568 524 538 auricular pits HP:0004467 540 548 lip pits HP:0000196 550 569 highly arched plate HP:0000156 571 587 dental anomalies HP:0000164 593 611 subcutaneous cysts HP:0200040 606 624 cysts of the scalp HP:0001965 626 651 Premature graying of hair HP:0002216 685 703 Growth retardation HP:0001510 705 724 developmental delay HP:0001263 730 744 hand anomalies HP:0001155 749 757 variable HP:0003813

1789288

We report on a family in which individuals at risk for NF 2 were investigated with the use of gadolinium-enhanced MRI. This technique has allowed the diagnosis of small (less than 8 mm) acoustic neuromas in two asymptomatic children (age 7 and 11), one of whom had normal audiometric and brainstem-evoked response testing. To our knowledge these are the youngest asymptomatic patients in whom the diagnosis of NF 2 has been demonstrated. It is possible that acoustic neuromas develop at an early age more commonly than recognized previously. The early diagnosis of acoustic neuromas with the use of gadolinium-enhanced MRI may lead to better outcome following surgery. This technique will provide the opportunity to better determine the natural course of this disease.

186 203 acoustic neuromas HP:0009588 458 475 acoustic neuromas HP:0009588 490 499 early age HP:0003593 565 582 acoustic neuromas HP:0009588

10593995

Popliteal pterygium syndrome (PPS) is a rare autosomal dominant disorder, thought to occur with an incidence of approximately 1 in 300 000 live births. The main clinical manifestations are popliteal webbing, cleft lip, cleft palate, lower lip pits, syndactyly, and genital and nail anomalies. This report describes the clinical features in two families with PPS and one isolated case, showing the range of anomalies found both within and between the families. PPS has some features in common with Van der Woude syndrome (VWS), also inherited as an autosomal dominant condition, with cleft lip/palate and, more distinctively, lower lip pits. Although the gene for VWS has not yet been identified, it has been localised to within 1.6 cM in the region 1q32-41. To determine whether PPS and VWS represent allelic forms of the same gene, three families were genotyped for markers flanking and within the critical region. A multipoint lod score of 2.7 was obtained, with no evidence of recombination, supporting the hypothesis that these two disorders are allelic.

0 19 Popliteal pterygium HP:0009756 45 72 autosomal dominant disorder HP:0000006 189 206 popliteal webbing HP:0009756 208 231 cleft lip, cleft palate HP:0000202 233 247 lower lip pits HP:0000196 249 259 syndactyly HP:0001159 265 291 genital and nail anomalies HP:0000078 277 291 nail anomalies HP:0001597 370 383 isolated case HP:0001420 548 566 autosomal dominant HP:0000006 583 599 cleft lip/palate HP:0000202 583 592 cleft lip HP:0100333 625 639 lower lip pits HP:0000196

2105641

Neurofibromatosis 2 or bilateral acoustic neurofibromatosis (NF2) is a severe autosomal dominant disorder characterized by the development of multiple tumors of the nervous system, including meningiomas, gliomas, neurofibromas, ependymomas, and particularly acoustic neuromas. Polymorphic DNA markers have revealed frequent loss of one copy of chromosome 22 in the tumor types associated with NF2. Family studies have demonstrated that the primary defect in NF2 is linked to DNA markers on chromosome 22, suggesting that it involves inactivation of a tumor suppressor gene. We have employed a combination of multipoint linkage analysis and examination of deletions in primary tumor specimens to precisely map the NF2 locus between flanking polymorphic DNA markers on chromosome 22. The 13-cM region bracketed by these markers corresponds to 13% of the genetic length of the long arm of chromosome 22 and is expected to contain less than 5 x 10(6) bp of DNA. The delineation of flanking markers for NF2 should permit accurate presymptomatic and prenatal diagnosis for the disorder and greatly facilitate efforts to isolate the defective gene on the basis of its location.

0 17 Neurofibromatosis HP:0006746 23 59 bilateral acoustic neurofibromatosis HP:0009589 78 105 autosomal dominant disorder HP:0000006 151 179 tumors of the nervous system HP:0004375 191 202 meningiomas HP:0002858 204 211 gliomas HP:0009733 213 226 neurofibromas HP:0001067 228 239 ependymomas HP:0002888 258 275 acoustic neuromas HP:0009588 365 370 tumor HP:0002664 551 556 tumor HP:0002664 676 681 tumor HP:0002664

15385437

Angelman syndrome is a neurogenetic disorder caused by the loss of function of the imprinted UBE3A gene in 15q11-q13. In a small group of patients, the disease is due to an imprinting defect (ID) that silences the maternal UBE3A allele. The presence of a faint maternal band detected by methylation-specific PCR analysis of the SNURF-SNRPN locus in approximately one-third of patients who have an ID but no imprinting center deletion suggested that these patients are mosaics of ID cells and normal cells. In two patients studied, somatic mosaicism was proven by molecular and cellular cloning, respectively. X inactivation studies of cloned fibroblasts from one patient suggest that ID occurred before the blastocyst stage. To quantify the degree of mosaicism, we developed a novel quantitative methylation assay based on real-time PCR. In 24 patients tested, the percentage of normal cells ranged from <1% to 40%. Regression analysis suggests that patients with a higher percentage of normally methylated cells tend to have milder clinical symptoms than patients with a lower percentage. In conclusion, we suggest that the role of mosaic imprinting defects in mental retardation is underestimated.

531 548 somatic mosaicism HP:0001442 1162 1180 mental retardation HP:0001249

6261046

A 17-year-old girl presented with an enlarged cardiac silhouette on routine chest roentgenogram. After clinical evaluation, echocardiography, and pericardiocentesis failed to provide a diagnosis, exploratory thoracotomy and biopsy revealed an unresectable left ventricular fibroma. The tumor continued to enlarge and began causing ventricular arrhythmia. Therefore, she underwent cardiac transplantation 2 years after the initial diagnosis was made. She is now alive nd well 18 months following transplantation.

37 64 enlarged cardiac silhouette HP:0001627 256 280 left ventricular fibroma HP:0010617 286 291 tumor HP:0002664 331 353 ventricular arrhythmia HP:0004308

2705922

This study of 47 patients from 11 families with neurofibromatosis type 2 (NF 2) confirms our previously reported association between posterior capsular cataract and NF 2. A highly significant statistical association was found between the presence of posterior capsular lens opacities and the presence of NF 2 as determined by magnetic resonance imaging or pathologic diagnosis. This association was not present for other types of lens opacities that could be the result of age-related or nonspecific changes. When considering the diagnosis of NF 2, this finding now makes it essential to use a careful dilated biomicroscopic examination of the lens to evaluate known, suspected, or at-risk individuals for this potentially early associated manifestation.

48 65 neurofibromatosis HP:0006746 133 160 posterior capsular cataract HP:0100020 250 283 posterior capsular lens opacities HP:0007787 430 444 lens opacities HP:0000518 723 753 early associated manifestation HP:0003593