Two unrelated families with variable expression of Fraser syndrome due to the same pathogenic variant in the FRAS1 gene.

We report on two unrelated families of Polish origin with variable expression of Fraser syndrome (FS; MIM#219000) due to homozygosity for the same pathogenic variant, c.6963_6964dup, of FRAS1. In one family, the disorder presented with perinatal and prenatal lethality. One affected female from family 2 who was followed-up for 32 years, represented a relatively favorable long-term outcome. She displayed the typical craniofacial dysmorphism, including right cryptophthalmos, cutaneous syndactyly, abnormalities of the stomathognatic system, bilateral atresia of the external ear canals resulting in conductive hearing loss, and malformations of the larynx, spleen, kidney, and genitourinary tract. Her intellectual capacities were normal. Our observations illustrate that expression and severity of FS, even when caused by the same pathogenic variant, may be quite different ranging from a lethal disorder to a condition with multiple physical malformations but normal psychomotor development. In addition, we propose that the FRAS1 c.6963_6964dup variant may be a founder mutation in the Polish population. Therefore, it would be reasonable to test specifically for this variant first in any FS1 patient of Polish ancestry.

A 23-year follow-up of a male with Hajdu-Cheney syndrome due to NOTCH2 mutation.

We present a natural history of a 32-year-old man with Hajdu-Cheney syndrome (HJCYS), because of the de novo truncating mutation in the exon 34 of NOTCH2 (c.6424-6427delTCTG, p.Ser2142ArgfsX4), who has been followed up for a period of 23 years (between 9 and 32 years). During follow-up, we observed abnormalities of vision, hearing, voice, and progression of craniofacial features in the form of skeletal dysplasia with affected skull, dentition, spine, limbs, fingers, and toes. Low bone mineral density and history of fragility fractures also suggested primary osteoporosis being a clinical manifestation. According to Stengel-Rutkowski, Schimanek, and Wernheimer (1984; Human Genetics, 6, 272-295), systematic data acquisition has been used for quantitative analysis of anthropological, radiographic, and clinical features at childhood, adolescence, and young adulthood separately. A detailed phenotype description together with the results of reanalysis of 14 reports so far published on patients with HJCYS and NOTCH2 mutation showed similar phenotype evolution with age. The spectrum of observed features may improve diagnostic tools for HJCYS at different periods of the lifespan.

Interstitial deletion 9q22.32-q33.2 associated with additional familial translocation t(9;17)(q34.11;p11.2) in a patient with Gorlin-Goltz syndrome and features of Nail-Patella syndrome.

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