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8103288

Robertsonian translocations, occurring with a frequency of about 1 in 10,000 livebirths, may be an important cause of uniparental disomy as demonstrated for 13/15, 13/14, 14/14, and 22/22 translocations. Dysmorphogenesis and/or mental retardation provide clinical clues for uniparental disomy in apparently balanced offspring of translocation carriers. Research strategies for assessing frequency and implications of uniparental disomy in translocation carriers include a genetic register approach, study of abortuses from balanced translocation carriers, and parent-of-origin studies on de novo homologous Robertsonian translocations.

204 220 Dysmorphogenesis HP:0001999 228 246 mental retardation HP:0001249 588 595 de novo HP:0003745

2035528

A 9-year-old mentally retarded girl with multiple congenital anomalies was found to carry a balanced 13/14 Robertsonian translocation [45,XX,t(13q14q)] which was also present in her father. Her mother carried a balanced reciprocal translocation between chromosomes 1 and 14 [46,XX,t(1;14) (q32;q32)]. Both of her parents were phenotypically normal. Molecular studies were carried out to determine the parental origin of chromosomes 1, 13, and 14 in the patient. Using probes for D14S13 and D14S22, we could show that the patient inherited both chromosomes 14 from her father and none from her mother. Similar studies using probes for chromosomes 1 (D1S76) and 13 (D13S37) loci showed the presence of both maternal and paternal alleles in the patient. Our findings indicate that paternal uniparental heterodisomy for chromosome 14 most likely accounts for the phenotypic abnormalities observed in our patient. It is suggested that uniparental disomy may be the basis for abnormal development in at least some phenotypically abnormal familial balanced-translocation carriers.

13 30 mentally retarded HP:0001249 970 990 abnormal development HP:0001263

9012416

Distal arthrogryposis type 1 (DA1) and Freeman-Sheldon syndrome (FSS) are the two most common known causes of inherited multiple congenital contractures. We recently have characterized a new disorder (DA2B) with a phenotype intermediate between DA1 and FSS. We report the mapping of a gene that causes DA2B to chromosome 11p15.5-pter. Linkage analysis in a single kindred generated a positive LOD score of 5.31 at theta = 0 with the marker D11S922, and recombinants localize the gene to an approximately 3.5-6.5-cM region between the marker TH and the telomere. Analysis of additional families improves the LOD score to 6.45 at theta = 0 and suggests linkage homogeneity for DA2B.

0 21 Distal arthrogryposis HP:0005684 120 152 multiple congenital contractures HP:0005188

10861661

Among 25 patients diagnosed with Angelman syndrome, we detected 21 with deletion and 4 with paternal uniparental disomy (UPD), 2 isodisomies originating by postzygotic error, and 1 MII nondisjunction event. The diagnosis was obtained by molecular techniques, including methylation pattern analysis of exon 1 of SNRPN and microsatellite analysis of loci within and outside the 15q11-q13 region. Most manifestations present in deletion patients are those previously reported. Comparing the clinical data from our and published UPD patients with those with deletions we observed the following: the age of diagnosis is higher in UPD group (average 7 3/12 years), microcephaly is more frequent among deletion patients, UPD children start walking earlier (average age 2 9/12 years), whereas in deletion patients the average is 4 (1/2) years, epilepsy started later in UPD patients (average 5 10/12 years) than in deletion patients (average 1 11/12 years), weight above the 75th centile is reported mainly in UPD patients, complete absence of speech is more common in the deleted (88.9%) than in the UPD patients because half of the children are able to say few words. Thus, besides the abnormalities already described, the UPD patients have somewhat better verbal development, a weight above the 75th centile, and OFC in the upper normal range.

659 671 microcephaly HP:0000252 836 844 epilepsy HP:0001250 1025 1042 absence of speech HP:0001617

7625442

We describe 47 patients with Angelman syndrome (AS) from Belgium and the Netherlands, including the anamnestic data, the clinical and the behavioral attributes at different ages. The clinical picture of AS is most distinct between the ages of 2-16 years. Most patients of this age group show at least 8 of the major characteristics (bursts of laughter, happy disposition, hyperactive behaviour, microcephaly, brachycephaly, macrostomia, tongue protrusion, mandibular prognathism, widely spaced teeth, stiff and puppetlike movements, typical stature, wide based gait) beside the mental retardation and (almost) absence of speech, which is a universal trait. The diagnosis in infants is based on only a limited number of clinical characteristics or on anamnestic data. However, if these occur in combination, they are indicative of AS. In older patients, the diagnosis may be hampered in part because of the changing behavioral characteristics and the decreasing frequency of fits. Other manifestations, such as scoliosis, may become more pronounced with age.

333 351 bursts of laughter HP:0000749 353 370 happy disposition HP:0100024 372 393 hyperactive behaviour HP:0000752 395 407 microcephaly HP:0000252 409 422 brachycephaly HP:0000248 424 435 macrostomia HP:0000181 437 454 tongue protrusion HP:0010808 456 478 mandibular prognathism HP:0000303 480 499 widely spaced teeth HP:0000687 511 531 puppetlike movements HP:0100022 550 565 wide based gait HP:0002136 578 596 mental retardation HP:0001249 610 627 absence of speech HP:0001617 661 681 diagnosis in infants HP:0003576 915 941 behavioral characteristics HP:0000708 1010 1019 scoliosis HP:0002650

8001963

Nevoid basal cell carcinoma syndrome (NBCCS, or Gorlin syndrome) is a cancer predisposition syndrome characterized by multiple basal cell carcinomas and diverse developmental defects. The gene responsible for NBCCS, which is most likely to be a tumor suppressor gene, has previously been mapped to 9q22.3-q31 in a 12-cM interval between the microsatellite marker loci D9S12.1 and D9S109. Combined multipoint and haplotype analyses of additional polymorphisms in this region in our collection of Australasian pedigrees have further refined the localization of the gene to between the markers D9S196 and D9S180, an interval reported to be approximately 2 cM.

7 27 basal cell carcinoma HP:0002671 70 76 cancer HP:0002664 127 148 basal cell carcinomas HP:0002671 161 182 developmental defects HP:0001263 245 250 tumor HP:0002664

3180506

We describe a new family with the Townes-Brocks syndrome, a dominantly inherited syndrome of anal, urorenal, ear and limb malformations. The proband shows the full spectrum of anomalies, including imperforate anus, prominent perineal raphe, rectoperineal fistula, triphalangeal thumb, preaxial hexadactyly, syndactyly, clinodactyly, preauricular protuberances, hypoplastic satyr ears, sensorineural hearing loss and urorenal anomalies. In contrast, the father shows only limb anomalies, sensorineural hearing loss and renal anomalies. Anorectal malformations, which are present in almost every patient with the Townes-Brocks syndrome, were absent in the father. This case report illustrates the intrafamilial variability of the Townes-Brocks syndrome. Consequently, careful examination of relatives of patients with this syndrome is necessary for the differential diagnosis with the sporadically inherited VA(C)TER(L) association.

60 80 dominantly inherited HP:0000006 93 135 anal, urorenal, ear and limb malformations HP:0004378 99 135 urorenal, ear and limb malformations HP:0000077 109 135 ear and limb malformations HP:0000598 117 135 limb malformations HP:0002813 197 213 imperforate anus HP:0002023 215 239 prominent perineal raphe HP:0003246 241 262 rectoperineal fistula HP:0004792 264 283 triphalangeal thumb HP:0001199 285 305 preaxial hexadactyly HP:0001177 307 317 syndactyly HP:0001159 319 331 clinodactyly HP:0030084 333 359 preauricular protuberances HP:0000384 361 383 hypoplastic satyr ears HP:0000377 385 411 sensorineural hearing loss HP:0000407 416 434 urorenal anomalies HP:0000079 471 485 limb anomalies HP:0002813 487 513 sensorineural hearing loss HP:0000407 518 533 renal anomalies HP:0000077 535 558 Anorectal malformations HP:0002034 695 720 intrafamilial variability HP:0003822

18285427

Naevoid basal cell carcinoma syndrome (NBCCS) is a pleiotropic, autosomal dominant disease. Growing evidence suggests that the disorder may result from mutations in genes of the Sonic hedgehog (Shh) signalling pathway. To investigate the pathogenic gene in a Chinese Han family with NBCCS. Mapping and mutation screening were used to investigate the candidate genes SHH, PTCH, PTCH2 and SMO. A GLI1 reporter gene and a cell growth curve were used to examine functional consequences of the detected mutant. One novel mutation, a G-->A transition (2157G-->A) in exon 15 of the PTCH2 gene, was identified in this family with NBCCS by direct sequencing and digestion with the AvaI restriction enzyme. The mutation was not found in normal family members or in 520 controls. The mutation led to an R719Q amino acid substitution in an extracellular loop of the PTCH2 protein. Functional studies revealed that the R719Q mutation resulted in inactivation of PTCH2 inhibitory activities. In contrast to wild type PTCH2, PTCH2-R719Q could not inhibit cell proliferation. PTCH2 (2157G-->A), a novel missense mutation, underlies NBCCS, resulting in the loss of PTCH2 inhibitory function in the Shh signalling pathway.

8 28 basal cell carcinoma HP:0002671 64 82 autosomal dominant HP:0000006

19557015

Basal cell nevus syndrome (BCNS or Gorlin syndrome, OMIM: 109400) is a rare autosomal dominant disorder with high penetrance. It is characterized by developmental anomalies and predisposition to tumors (for example, basal cell carcinoma (BCC) and medulloblastoma). PTCH1, the human homolog of the Drosophila patched gene, was identified as a gene responsible for BCNS. The PTCH1 protein is a Hedgehog (Hh) protein receptor and is pivotal for early development, stem cell maintenance and/or differentiation. We analyzed the six Japanese families with BCNS and identified six germline mutations in the PTCH1 gene. One family had a nonsense mutation (c.1196G>A), one had a 1-bp deletion (c.2029delA), two had 2-bp deletions (c.239_240delGA and c.1670_1671delCA) and one had a 58-bp duplication (c.1138_1195dup). They caused premature termination, resulting in the truncation of the PTCH1 protein. Analysis of a high-density single nucleotide polymorphism (SNP) mapping array showed a large approximately 1.2-Mb deletion, including the PTCH1 gene in one allele, in a family in which PTCH1 mutations were not identified at the sequence level. These data indicated that all the six families who were diagnosed with BCNS had mutations in the PTCH1 gene and that a single copy of a PTCH1 mutation causes BCNS.

0 16 Basal cell nevus HP:0002671 76 103 autosomal dominant disorder HP:0000006 195 201 tumors HP:0002664 216 236 basal cell carcinoma HP:0002671 247 262 medulloblastoma HP:0002885

1619642

Two sibs with the branchio-oculo-facial syndrome are reported. They both have orbital haemangiomatous cysts, which is a previously unreported feature. Both parents are clinically normal and unrelated. This disorder has been reported showing autosomal dominant transmission so this family could represent either an autosomal recessive form or germline mosaicism for the dominant gene.

78 107 orbital haemangiomatous cysts HP:0001144 241 259 autosomal dominant HP:0000006 251 272 dominant transmission HP:0000006 314 338 autosomal recessive form HP:0000007 342 360 germline mosaicism HP:0001442 369 377 dominant HP:0000006

17353411

To gain insight into the pathogenesis of neurofibromatosis type 2 (NF2) by investigating the ocular manifestations of this disease. Using standard histologic techniques, immunohistochemistry, and electron microscopy, we described the ocular pathologic findings of a 34-year-old woman who died from complications of NF2. We identified 3 types of NF2-associated lesions: juvenile posterior subcapsular cataracts, epiretinal membranes, and an intrascleral schwannoma. Our analysis indicated that dysplastic lens cells accumulate just anterior to the posterior lens capsule in juvenile posterior subcapsular cataracts and that dysplastic Müller cells may be a major component of NF2-associated epiretinal membranes. Clinical Relevance Our findings suggest that a subset of glial cells with epithelial features (Schwann cells, ependymal cells, and Müller cells) may be particularly sensitive to loss of the NF2 gene. Understanding the molecular basis for this sensitivity may lead to novel strategies for treating NF2.

41 58 neurofibromatosis HP:0006746 93 114 ocular manifestations HP:0000478 235 261 ocular pathologic findings HP:0000478 380 411 posterior subcapsular cataracts HP:0007787 413 433 epiretinal membranes HP:0100014 442 465 intrascleral schwannoma HP:0100011 585 616 posterior subcapsular cataracts HP:0007787 693 713 epiretinal membranes HP:0100014 694 714 epiretinal membranes HP:0100014

7835901

Four disease genes (NBCCS, ESS1, XPAC, FACC) map to 9q22.3-q31. A fine map of this region was produced by linkage and haplotype analysis using 12 DNA markers. The gene for nevoid basal cell carcinoma syndrome (NBCCS, Gorlin) has an important role in congenital malformations and carcinogenesis. Phase-known recombinants in a study of 133 meioses place NBCCS between (D9S12/D9S151) and D9S176. Haplotype analysis in a two-generation family suggests that NBCCS lies in a smaller interval of 2.6 cM centromeric to D9S287. These flanking markers will be useful clinically for gene tracking. Recombinants also map FACC (Fanconi anemia, group C) to the same region, between (D9S196/D9S197) and D9S287. The recombination rate between (D9S12/D9S151) and D9S53 in males is 8.3% and 13.2% in females, giving a sex-specific male:female ratio of 1:1.6 and a sex-averaged map distance of 10.4 cM. No double recombinants were detected, in agreement with the apparently complete level of interference predicted from the male chiasmata map.

179 199 basal cell carcinoma HP:0002671

1456285

We report on a female patient with bilateral acoustic neurinomas and other tumors in the central nervous system (neurofibromatosis type 2: NF2) and the constitutional translocation, t(4;22) (q12;q12.2). The precise identification of the translocation breakpoint (q12.2) on chromosome 22 implies the refined localization of a gene responsible for NF2, and would provide a clue to its molecular characterization and to the isolation of the gene. Chromosomes of a paraspinal neurinoma from the patient were also analyzed, and the same karyotype as seen in cultured peripheral lymphocytes was found. The patient's father was also a carrier of the translocation, but he had no clinical symptoms of NF2, nor did other relatives. Several explanations are offered for the different expression of the translocation between the patient and her father.

35 64 bilateral acoustic neurinomas HP:0009589 69 81 other tumors HP:0003008 75 111 tumors in the central nervous system HP:0100006 113 130 neurofibromatosis HP:0006746 461 481 paraspinal neurinoma HP:0006751

11342693

A retrospective review of 29 consecutive unselected patients referred for neuro-ophthalmic evaluation after the diagnosis of neurofibromatosis type 2 (NF2) showed that four of them had a monocular elevator paresis. In two of the four MRI demonstrated lesions, presumed to be schwannomas, of the third nerve. These findings indicate that monocular elevator paresis is a common neuro-ophthalmic finding in NF2, which the authors suspect is probably a sign of third nerve infiltration or compression by a schwannoma.

125 142 neurofibromatosis HP:0006746 187 213 monocular elevator paresis HP:0006860 275 306 schwannomas, of the third nerve HP:0001291 337 363 monocular elevator paresis HP:0006860 502 512 schwannoma HP:0100008

6928117

A family with the Popliteal Pterygium Syndrome is presented. The father was born with a cleft of the palate and lower lip pits. Two of the three offspring showed extensive involvement of the palate, gums, and lips with minimal involvement of the lower limbs, genitalia, and nails.

18 37 Popliteal Pterygium HP:0009756 88 107 cleft of the palate HP:0000175 112 126 lower lip pits HP:0000196 172 213 involvement of the palate, gums, and lips HP:0000159 172 197 involvement of the palate HP:0000174 227 279 involvement of the lower limbs, genitalia, and nails HP:0001597 227 268 involvement of the lower limbs, genitalia HP:0000078

657583

Three families are presented, one with branchio-oto-renal dysplasia (BOR) and two with branchio-oto dysplasia (BO). The former syndrome is characterized by external ear malformations, cervical fistulae, mixed hearing loss and renal anomalies of varying severity. The latter syndrome differs in that there are no renal anomalies and that the sensorineural component of the hearing loss may be absent. The external ear malformations are quite variable in both syndromes. Evidence is presented which supports the idea that these two syndromes are not phenotypic variants of the same autosomal dominant mutation but distinct disease entities. The BOR syndrome appears to belong to a larger group of hereditary ear dysplasia-renal adysplasia syndromes that must be carefully ruled out in all patients with familial branchial arch malformations as well as in the parents and siblings of infants with "Potter facies" in the presence of auricular malformation and renal adysplasia.

52 67 renal dysplasia HP:0000110 156 182 external ear malformations HP:0000356 184 201 cervical fistulae HP:0009795 203 221 mixed hearing loss HP:0000410 226 241 renal anomalies HP:0000077 312 327 renal anomalies HP:0000077 372 384 hearing loss HP:0000365 404 430 external ear malformations HP:0000356 441 449 variable HP:0003813 580 598 autosomal dominant HP:0000006 706 719 ear dysplasia HP:0000598 720 736 renal adysplasia HP:0000110 810 838 branchial arch malformations HP:0009794 895 908 Potter facies HP:0002009 929 951 auricular malformation HP:0000356 956 972 renal adysplasia HP:0000110

1415348

We report on a woman who was diagnosed with branchio-oto-renal (BOR) syndrome after 2 pregnancies complicated by oligohydramnios due to renal hypoplasia and agenesis. Both babies died neonatally of pulmonary hypoplasia. Histopathology of the temporal bones of the second child showed marked immaturity of the middle ear cleft, ossicles, facial nerve and canal, and cochlear nerve. Maternal renal ultrasound study was normal although intravenous pyelography indicated renal hypoplasia. The frequency of BOR syndrome among cases of recurrent fetal renal hypoplasia/dysplasia or agenesis is unknown, and parental renal ultrasonography may not identify a heritable renal defect. Investigations should include a family history, and examination of relatives to look for preauricular pits, lacrimal duct stenosis, and branchial fistulae and/or cysts. Hearing studies and IVP may be indicated.

113 128 oligohydramnios HP:0001562 136 152 renal hypoplasia HP:0000089 136 165 renal hypoplasia and agenesis HP:0008680 179 194 died neonatally HP:0003811 198 218 pulmonary hypoplasia HP:0002089 291 349 immaturity of the middle ear cleft, ossicles, facial nerve HP:0010827 291 379 immaturity of the middle ear cleft, ossicles, facial nerve and canal, and cochlear nerve HP:0000375 467 483 renal hypoplasia HP:0000089 546 572 renal hypoplasia/dysplasia HP:0000110 546 562 renal hypoplasia HP:0000089 546 584 renal hypoplasia/dysplasia or agenesis HP:0000104 661 673 renal defect HP:0000077 764 781 preauricular pits HP:0004467 783 805 lacrimal duct stenosis HP:0007925 811 829 branchial fistulae HP:0009795 811 842 branchial fistulae and/or cysts HP:0009796 844 859 Hearing studies HP:0000365

12235555

To evaluate clinical and molecular predictors of the risk of mortality in people with neurofibromatosis 2 (NF2), we analyzed the mortality experience of 368 patients from 261 families in the United Kingdom NF2 registry, using the Cox proportional-hazards model and the jackknife method. Age at diagnosis, intracranial meningiomas, and type of treatment center were informative predictors of the risk of mortality. In Cox models, the relative risk of mortality increased 1.13-fold per year decrease in age at diagnosis (95% confidence interval [CI] 1.08-1.18) and was 2.51-fold greater in people with meningiomas compared with those without meningiomas (95% CI 1.38-4.57). The relative risk of mortality in patients treated at specialty centers was 0.34 compared with those treated at nonspecialty centers (95% CI 0.12-0.98). In a separate model, the relative risk of mortality in people with constitutional NF2 missense mutations was very low compared with those with other types of mutations (nonsense or frameshift mutations, splice-site mutations, and large deletions), but the CI could not be well quantified because there was only one death among people with missense mutations. We conclude that age at diagnosis, the strongest single predictor of the risk of mortality, is a useful index for patient counseling and clinical management (as are intracranial meningiomas). To ensure optimal care, we recommend that people with NF2 be referred to specialty treatment centers.

86 103 neurofibromatosis HP:0006746 305 329 intracranial meningiomas HP:0100009 600 611 meningiomas HP:0002858 640 651 meningiomas HP:0002858 1349 1373 intracranial meningiomas HP:0100009

2164325

This paper reports on a family with popliteal pterygium syndrome (PPS), which was ascertained through a baby with most of the major signs of the syndrome. The mother, who had a repaired cleft palate and toe syndactyly, had been aware that her syndactyly was familial, but her unpreparedness for the birth of a child with PPS led to interest in, and a subsequent review of, the differnetial diagnosis and the variable expression of the clinical manifestations of this syndrome. Upon review, some earlier reported cases were excluded as PPS, and certain ascertainment and reporting biases that could affect such an analysis were considered.

36 55 popliteal pterygium HP:0009756 186 198 cleft palate HP:0000175 203 217 toe syndactyly HP:0001770 243 253 syndactyly HP:0001159 408 427 variable expression HP:0003828

12868482

A mother and daughter with Gorlin syndrome with similar neuroradiological findings are reported. These include calcification of the falx cerebri and tentorium cerebelli and dysgenesis of the corpus callosum and vermis. Vermian dysgenesis was detected in both mother and daughter suggesting a previously unrecognized finding associated with Gorlin syndrome.

111 168 calcification of the falx cerebri and tentorium cerebelli HP:0007352 111 144 calcification of the falx cerebri HP:0005462 173 217 dysgenesis of the corpus callosum and vermis HP:0002195 173 206 dysgenesis of the corpus callosum HP:0006996 219 237 Vermian dysgenesis HP:0002195

509397

We have reviewed a series of 36 patients with the basal cell nevus syndrome seen at Roswell Park Memorial Institute from 1950 to 1978. Among these patients a number of disastrous complications occurred. These include extensive uncontrolled basal cell epithelioma of the face resulting in one death from direct cerebral invasion via the orbit, one facial nerve palsy, two bilateral and two unilateral eye enucleations, and several severe facial mutilations in young patients. There were three patients who developed severe bradycardia and hypotension during induction of general anesthesia required postponement of the intended operation, and one patient with congenital hemiparesis who on investigation was found to have an absent internal carotid artery. A review of the syndrome complex is presented with a plan for recognition and management.

50 66 basal cell nevus HP:0002671 240 274 basal cell epithelioma of the face HP:0000271 347 365 facial nerve palsy HP:0002008 400 416 eye enucleations HP:0000478 437 455 facial mutilations HP:0000271 459 473 young patients HP:0003593 522 533 bradycardia HP:0001662 538 549 hypotension HP:0002615 659 681 congenital hemiparesis HP:0001269 724 754 absent internal carotid artery HP:0005290

730159

The basal cell nevus syndrome is characterized by multiple basal cell nevi and basal cell carcinoma, cysts of the jaw, anomalies of ribs and spine, abnormal calcifications, and additional anomalies of the facial skull. A German family is described with manifestations of the syndrome in the mother and her three daughters. Expressivity was variable, in part due to age effects. The observation conforms to the assumed autosomal dominant mode of inheritance with high penetrance.

4 29 basal cell nevus syndrome HP:0002671 50 74 multiple basal cell nevi HP:0001054 79 99 basal cell carcinoma HP:0002671 101 117 cysts of the jaw HP:0010603 119 136 anomalies of ribs HP:0000772 119 146 anomalies of ribs and spine HP:0000925 148 171 abnormal calcifications HP:0004348 188 211 anomalies of the facial HP:0000271 340 348 variable HP:0003813 418 456 autosomal dominant mode of inheritance HP:0000006

9236523

To evaluate patients with multiple endocrine neoplasia type 1 (MEN 1) for cutaneous manifestations. Survey during a 3-year period. The National Institutes of Health, a tertiary referral research hospital in Bethesda Md. A consecutive sample of 32 individuals with previously diagnosed MEN1 who were not preselected for the presence of skin lesions were examined for cutaneous abnormalities. None of the patients or family members were diagnosed as having tuberous sclerosis. Lesions were identified by clinical appearance, photographed, and confirmed histologically. To determine the frequency of skin lesions in patients with MEN1. Multiple facial angiofibromas were observed in 28 (88%) of the patients with MEN1, with 16 patients (50%) having 5 or more. Angiofibromas were clinically and histologically identical to those in individuals with tuberous sclerosis. Collagenomas were observed in 23 patients (72%). Also observed were cafe au lait macules in 12 patients (38%), lipomas in 11 patients (34%), confetti-like hypopigmented macules in 2 patients (6%), and multiple gingival papules in 2 patients (6%). Multiple angiofibromas, collagenomas, lipomas, confetti-like hypopigmented macules and multiple gingival papules are cutaneous manifestations of MEN1 and should be looked for in both family members of patients with MEN1 and individuals with hyperparathyroidism of other MEN1-associated tumors. Multiple angiofibromas can no longer be considered pathognomonic for tuberous sclerosis. The observation of angiofibromas in individuals without tuberous sclerosis necessitates further biochemical testing for MEN1.

35 54 endocrine neoplasia HP:0100568 74 98 cutaneous manifestations HP:0000951 338 350 skin lesions HP:0011355 369 392 cutaneous abnormalities HP:0000951 602 614 skin lesions HP:0011355 648 668 facial angiofibromas HP:0009720 763 776 Angiofibromas HP:0010615 871 883 Collagenomas HP:0000951 939 959 cafe au lait macules HP:0000957 982 989 lipomas HP:0001012 1012 1047 confetti-like hypopigmented macules HP:0007449 1081 1097 gingival papules HP:0000168 1128 1141 angiofibromas HP:0010615 1143 1155 collagenomas HP:0000951 1157 1164 lipomas HP:0001012 1166 1201 confetti-like hypopigmented macules HP:0007449 1215 1231 gingival papules HP:0000168 1236 1260 cutaneous manifestations HP:0000951 1360 1379 hyperparathyroidism HP:0000843 1405 1411 tumors HP:0002664 1422 1435 angiofibromas HP:0010615 1521 1534 angiofibromas HP:0010615

9225971

The case of a seriously disabled and retarded female patient with neurofibromatosis type 2 (NF2) is reported. She suffered from bilateral vestibular schwannomas, multiple intracranial meningiomas and neurinomas. The constitutional karyotype of the patient was 46, XX, r(22)/45,XX,-22. A constitutional G to A transition in the proximal 3' untranslated region of isoforms 1 and 2 was identified in the patient's NF2 gene and shown not to affect differential splicing or mRNA stability. The instability of the ring chromosome 22 with the associated loss of tumor suppressor genes on chromosome 22, in particular the loss of the NF2 gene, are assumed to have caused multiple tumorigenesis in this patient.

37 45 retarded HP:0001263 66 83 neurofibromatosis HP:0006746 128 160 bilateral vestibular schwannomas HP:0009589 162 195 multiple intracranial meningiomas HP:0003008 200 210 neurinomas HP:0009588 555 560 tumor HP:0002664 663 685 multiple tumorigenesis HP:0003008

1360768

Eleven patients with Angelman syndrome (AS) and their parents from 5 families have been studied with high resolution chromosome analysis and molecular probes from region 15q11-13 in an attempt to elucidate the mode of inheritance in familial AS. No deletions were detected. All families were informative with a combination of different short arm cytogenetic markers. All sets of sibs inherited the same maternal chromosome 15, but in 3 families sibs inherited different paternal 15s. Analysis of 6 polymorphic DNA markers supported the conclusion that AS sibs inherit the same maternal 15, but often different paternal 15s. These data make autosomal recessive inheritance at a 15q11-13 locus very unlikely and support the hypothesis that familial AS is due to maternal transmission of a mutation within 15q11-13.

210 229 mode of inheritance HP:0000005 233 244 familial AS HP:0000005 640 671 autosomal recessive inheritance HP:0000007

8326488

There are many potential complications which have been reported in association with the naevoid basal cell carcinoma syndrome. We have been able to show the relative frequencies of these problems in a population based study of 84 cases in the north west of England. The major complications of basal cell carcinomas and jaw cysts occur in over 90% of patients by 40 years of age, but may both occur before 10 years of age. Less well described complications are ovarian calcification or fibroma (24%), medulloblastoma (5%), cardiac fibroma (3%), cleft palate (5%), and ophthalmic abnormalities such as squint or cataract (26%). This study more clearly defines the possible complications of the syndrome and gives clearer guidelines for counselling and screening affected and at risk persons.

96 116 basal cell carcinoma HP:0002671 293 314 basal cell carcinomas HP:0002671 319 328 jaw cysts HP:0010603 460 481 ovarian calcification HP:0008657 460 492 ovarian calcification or fibroma HP:0010618 500 515 medulloblastoma HP:0002885 522 537 cardiac fibroma HP:0010617 544 556 cleft palate HP:0000175 567 591 ophthalmic abnormalities HP:0000478 600 606 squint HP:0000486 610 618 cataract HP:0000518

2667456

The authors report a new case of Townes-Brocks syndrome with cardiac defect, ossicular anomalies and dominant transmission. The intrafamilial variability of the phenotype and the difficulty of diagnosis in isolated cases are underlined.

61 75 cardiac defect HP:0001627 77 96 ossicular anomalies HP:0001759 101 122 dominant transmission HP:0000006 128 170 intrafamilial variability of the phenotype HP:0003822 206 220 isolated cases HP:0001420

2893543

A female with cystic fibrosis and short stature was investigated for molecular or cytogenetic abnormalities that might explain the combined phenotype. Analysis with polymorphic DNA markers indicated that the father did not contribute alleles to the propositus for markers near the CF locus or for centromeric markers on chromosome 7. High-resolution cytogenetic analysis was normal, and the result could not be explained on the basis of nonpaternity or a submicroscopic deletion. All of the data indicate that the propositus inherited two identical copies of maternal sequences for much or all of chromosome 7. The occurrence of uniparental disomy could be explained by models postulating postfertilization error, gamete complementation, monosomic conception with subsequent chromosome gain, or trisomic conception followed by chromosome loss. Uniparental disomy in an individual with a normal chromosome analysis is a novel mechanism for the occurrence of human genetic disease.

34 47 short stature HP:0004322