Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation.

To define the range of phenotypic expression in Treacher Collins syndrome (TCS; Franceschetti-Klein syndrome), we performed mutation analysis in the TCOF1 gene in 46 patients with tentative diagnosis of TCS and evaluated the clinical data, including a scoring system. A total of 27 coding exons of TCOF1 and adjacent splice junctions were analysed by direct sequencing. In 36 patients with a clinically unequivocal diagnosis of TCS, we detected 28 pathogenic mutations, including 25 novel alterations. No mutation was identified in the remaining eight patients with unequivocal diagnosis of TCS and 10 further patients, in whom the referring diagnosis of TCS was clinically doubtful. There is no overt genotype-phenotype correlation except that conductive deafness is significantly less frequent in patients with mutations in the 3' part of the open reading frame. Inter- and intrafamilial variation is wide. Some mutation carriers, parents of typically affected patients, are so mildly affected that the diagnosis might be overlooked clinically. This suggests that modifying factors are important for phenotypic expression. Based on these findings, minimal diagnostic criteria were defined: downward slanting palpebral fissures and hypoplasia of the zygomatic arch. The difficulties in genetic counselling, especially diagnosis of family members with a mild phenotype, are described.

Mutations in NSD1 are responsible for Sotos syndrome, but are not a frequent finding in other overgrowth phenotypes.

Recently, deletions encompassing the nuclear receptor binding SET-Domain 1 (NSD1) gene have been described as the major cause of Japanese patients with the Sotos syndrome, whereas point mutations have been identified in the majority of European Sotos syndrome patients. In order to investigate a possible phenotype-genotype correlation and to further define the predictive value of NSD1 mutations, we performed mutational analysis of the NSD1 gene in 20 patients and one familial case with Sotos syndrome, five patients with Weaver syndrome, six patients with unclassified overgrowth/mental retardation, and six patients with macrocephaly/mental retardation. We were able to identify mutations within the NSD1 gene in 18 patients and the familial case with Sotos syndrome (90%). The mutations (six nonsense, eight frame shifts, three splice site, one missense, one in-frame deletion) are expected to result in an impairment of NSD1 function. The best correlation between clinical assessment and molecular results was obtained for the Sotos facial gestalt in conjunction with overgrowth, macrocephaly, and developmental delay. In contrast to the high mutation detection rate in Sotos syndrome, none of the patients with Weaver syndrome, unclassified overgrowth/mental retardation and macrocephaly/mental retardation, harbored NSD1 mutations. We tested for large deletions by FISH analysis but were not able to identify any deletion cases. The results indicate that the great majority of patients with Sotos syndrome are caused by mutations in NSD1. Deletions covering the NSD1 locus were not found in the patients analyzed here.

Survival to adulthood and dominant inheritance of platyspondylic skeletal dysplasia, Torrance-Luton type.

We present a second family with survival to adulthood and dominant transmission of the Torrance-Luton type of platyspondylic chondrodysplasia, and demonstrate the radiographs at different ages together with radiographs and further data of the first family which was published in the Journal of Pediatrics (J Pediatr 136:411-413). Two families are described with survival to adulthood and dominant transmission of the Torrance-Luton type of platyspondylic chondrodysplasia. Although lethality is increased in patients with this disorder, mild expressions of the genetic defect are compatible with survival into adulthood. The heterogeneous group of platyspondylic lethal skeletal dysplasias (PLSD) originally included thanatophoric dysplasias (TD1/2: MIM 187600, 187100) as the most common forms of this condition, as well as TD variants San Diego type (PLSD-SD: MIM 270230) and Torrance-Luton type (PLSD-TL: MIM 151210). Fibroblast growth factor receptor 3 ( FGFR3) gene mutations have been detected in TD1/2 and PLSD-SD. Molecular studies in one of our two families with the Torrance-Luton type did not disclose mutations in the FGFR3 coding region, suggesting that this type of platyspondylic chondrodysplasia is not a thanatophoric dysplasia variant. In contrast to TD1/2 and PLD-SD, the Torrance-Luton type platyspondylic dysplasia is compatible with survival to adulthood.

Congenital disorder of glycosylation type 1a in a macrosomic 16-month-old boy with an atypical phenotype and homozygosity of the N216I mutation.

UNLABELLED: We report on a 16-month-old boy with congenital disorder of glycosylation type 1a (CDG-1a; OMIM 212065) showing an atypical phenotype. Whereas failure to thrive is known to be a prominent feature in this condition, our patient developed postnatal macrosomia with increase of weight, length and occipitofrontal circumference (OFC) above the 95th percentile within his 1st year of life. Thereafter, weight and length were close to the 90th and OFC at the 50th percentiles. In contrast to other CDG-1a patients, the child did not have abnormal fat pads or inverted nipples; but unusual eyebrows were present. CDG-1a was confirmed by isoelectric focusing of serum transferrin and measurement of phosphomannomutase activity in leucocytes and cultured fibroblasts (residual activity <5% of controls). Mutation analysis of the phosphomannomutase 2 gene (PMM2) revealed homozygosity for a 647A>T (N216I) mutation in our patient and heterozygosity in his consanguineous parents. CONCLUSION: This is the first report of macrosomia and of homozygosity for the 647A>T (N216I) mutation in a patient with congenital disorder of glycosylation type 1a which may allow further phenotype/genotype comparisons.

Cerebral manifestations, hemihypertrophy and lymphoedema of one leg in a child with epidermal nevus syndrome (Schimmelpenning-Feuerstein-Mims).

The report focuses on a rare variant form of epidermal nevus syndrome (ENS) (Schimmelpenning-Feuerstein-Mims syndrome) describing lesions involving the skin, eyes, skeleton, heart and brain in an 11-year-old boy. Despite his evident brain pathology, the boy lacks neurological symptoms and mental retardation. We describe his unusual MRI appearances and radiographic skeletal findings. To our knowledge this is the first report of ENS with lymphoedema occurring together in the same individual.

Familial MCA/MR syndrome due to inherited submicroscopic translocation t(18;21)(q22.1q21.3) with breakpoint at the Down syndrome critical region.

We report three generation family that includes two patients with severe mental retardation and additional anomalies who have been studied, clinically, cytogenetically, and molecular cytogenetically. A clinical diagnosis could not be made in the propositus, but facial anomalies of Down syndrome (DS) were recognized in the maternal uncle of the propositus. In view of a strong family history of recurrent miscarriage, a familial translocation was highly suggestive. Standard cytogenetic analysis did not reveal any abnormalities. Fluorescence in situ hybridization (FISH) using subtelomeric DNA probes identified a familial cryptic translocation of chromosomes 18 and 21, resulting in partial trisomy 21 and partial monosomy 18q in both patients. FISH analysis of obligate carriers demonstrated a balanced translocation between the terminal parts of 18q and 21q. Including this family, a total of six different familial cases with cryptic or subtle subtelomeric translocations of chromosome 21q has been reported, of which three involved terminal parts of chromosome 18q. The remarkable similarity of the chromosomal breakpoints of our patients and the described families prompted us to refine the breakpoints and to discuss phenotypic differences between these patients. Our results reinforce the role of cryptic subtelomeric rearrangements in patients with mental retardation associated with physical anomalies and stress the importance of FISH technology to supplement routine cytogenetics.

Pigmentary mosaicism of the hyperpigmented type in two half-brothers.

Pigmentary mosaicism is a heterogeneous cutaneous phenotype that is often associated with extracutaneous anomalies. It is widely accepted that these phenotypes arise de novo as a result of a postzygotic mutation, leading to a mosaic status of the embryo. In the vast majority of cases, the occurrence of pigmentary mosaicism is sporadic. We report two paternal half-brothers affected with pigmentary mosaicism of the hyperpigmented type. The hyperpigmentation in both patients is distributed along the lines of Blaschko. In addition, mental retardation, facial asymmetry, short stature, scoliosis, and short fingers with clinodactyly of the 5th digit were noted in one of them. Chromosome analysis in this 15-year-old patient demonstrated a mosaic 46,XY,dup(3)(p21.3;pter)/46,XY with 12% aberrant cells in lymphocytes and 2% in skin fibroblasts derived from a hyperpigmented area. His nine-year-old half-brother had similar systematized hyperpigmented skin lesions, macrocephaly, facial asymmetry, and clinodactyly of the 5th digit. Chromosome analysis of peripheral lymphocytes showed a normal karyotype 46,XY. A skin biopsy could not be obtained. So far, some familial cases of hypopigmentation along the lines of Blaschko have been reported, but familial occurrence of the hyperpigmented type of pigmentary mosaicism appears to be extremely unusual. It is difficult to establish a causal relationship with the chromosomal mosaicism as observed in patient 1. Paradominant transmission seems unlikely because this would likewise imply that the chromosomal mosaicism is an incidental finding.

ABCD syndrome is caused by a homozygous mutation in the EDNRB gene.

ABCD syndrome is an autosomal recessive syndrome characterized by albinism, black lock, cell migration disorder of the neurocytes of the gut (Hirschsprung disease [HSCR]), and deafness. This phenotype clearly overlaps with the features of the Shah-Waardenburg syndrome, comprising sensorineural deafness; hypopigmentation of skin, hair, and irides; and HSCR. Therefore, we screened DNA of the index patient of the ABCD syndrome family for mutations in the endothelin B receptor (EDNRB) gene, a gene known to be involved in Shah-Waardenburg syndrome. A homozygous nonsense mutation in exon 3 (R201X) of the EDNRB gene was found. We therefore suggest that ABCD syndrome is not a separate entity, but an expression of Shah-Waardenburg syndrome.