Clinical and Molecular Update on the Fourth Reported Family with Hamamy Syndrome.

We report on 2 cousins, a girl and a boy, born to first-cousin Lebanese parents with Hamamy syndrome, exhibiting developmental delay, intellectual disability, severe telecanthus, abnormal ears, dentinogenesis imperfecta, and bone fragility. Whole-exome sequencing studies performed on the 2 affected individuals and one obligate carrier revealed the presence of a homozygous c.503G>A (p.Arg168His) missense mutation in IRX5 in both sibs, not reported in any other family. Review of the literature and differential diagnoses are discussed.

A novel mutation in the PORCN gene underlying a case of almost unilateral focal dermal hypoplasia.

BACKGROUND: Focal dermal hypoplasia (also known as Goltz syndrome) is an X-linked dominant syndrome characterized by patchy hypoplastic skin with soft-tissue, skeletal, dental, and ocular defects that are secondary to mutations in the PORCN gene. To our knowledge, only 5 cases of focal dermal hypoplasia with unilateral presentation have been reported, and molecular studies were not performed in any of the cases. OBSERVATIONS: A 17-year-old girl was seen with features of almost unilateral focal dermal hypoplasia. These included left cleft hand, dental dysplasia, left mammary hypoplasia, deviation of the sacral line, raspberrylike papillomas in the perianal region, syndactyly of the second and third digits of the left foot, and linear streaks of dermal hypoplasia and pigmented lesions on her left hemibody. CONCLUSIONS: Mutation analysis of PORCN revealed a novel heterozygous mutation in exon 10, c.854-855insACCTGAC; [p.T285fsX316], resulting in a premature stop signal. Analysis of the X-chromosome inactivation status was performed on blood and skin DNA samples, showing random inactivation in blood and unaffected skin and skewed inactivation in affected skin, highlighting the role of X-chromosome inactivation in X-linked disease expression.

Mutation in WNT10A is associated with an autosomal recessive ectodermal dysplasia: the odonto-onycho-dermal dysplasia.

Odonto-onycho-dermal dysplasia is a rare autosomal recessive syndrome in which the presenting phenotype is dry hair, severe hypodontia, smooth tongue with marked reduction of fungiform and filiform papillae, onychodysplasia, keratoderma and hyperhidrosis of palms and soles, and hyperkeratosis of the skin. We studied three consanguineous Lebanese Muslim Shiite families that included six individuals affected with odonto-onycho-dermal dysplasia. Using a homozygosity-mapping strategy, we assigned the disease locus to an ~9-cM region at chromosome 2q35-q36.2, located between markers rs16853834 and D2S353, with a maximum multipoint LOD score of 5.7. Screening of candidate genes in this region led us to identify the same c.697G-->T (p.Glu233X) homozygous nonsense mutation in exon 3 of the WNT10A gene in all patients. At the protein level, the mutation is predicted to result in a premature truncated protein of 232 aa instead of 417 aa. This is the first report to our knowledge of a human phenotype resulting from a mutation in WNT10A, and it is the first demonstration of an ectodermal dysplasia caused by an altered WNT signaling pathway, expanding the list of WNT-related diseases.

New autosomal recessive syndrome with short stature and facio-auriculo-thoracic malformations.

Two sibs, a boy and a girl, from a Lebanese consanguineous family presented with short stature, microcephaly, ptosis, small, dysplastic, low set ears, short neck, and pectum excavatum and carinatum. In addition, the boy had a high arched palate, a cardiac malformation, and at the X-rays an absence of fusion of the posterior hemi-arches of C7 and a fusion between L5 and S1 with a sagittal-cleft vertebral body of L5, while his sister had a cleft lip/palate and at the X-rays an abnormal odontoid peg and a malformation of the articular facets between C1 and C2, and bilateral cervical ribs. Other laboratory and radiological investigations were normal. Sequencing of PTPN11 exons 2, 3, 4, 7, 8, 12, and 13 did not reveal any variations. Two other sibs presented almost the same dysmorphic features; one girl died at age 6(1/4) years after an acute episode of renal insufficiency, and one boy died at 40 days of age. Differential diagnosis is discussed and the possibility of the report of a new autosomal recessive syndrome with variable expressivity is raised.

Further delineation of the odonto-onycho-dermal dysplasia syndrome.

We report on three boys, two brothers and their maternal cousin, presenting with dry hair, pilar keratosis, severe hypodontia, smooth tongue, onychodysplasia, and keratoderma and hyperhidrosis of palms and soles. Histology of the skin showed orthokeratotic, hyperkeratosis, hypergranulosis, and mild acanthosis in the epidermis. Scanning electron microscopic examination of the hair showed longitudinal depressions in some hair. These features are close to a rare entity: the odonto-onycho-dermal dysplasia but with some differing features.