Meckel-Gruber syndrome (MKS, OMIM #249000) is a multiple congenital malformation syndrome that represents the severe end of the ciliopathy phenotypic spectrum. Despite the relatively common occurrence of this syndrome among Arabs, little is known about its genetic architecture in this population. This is a series of 18 Arab families with MKS, who were evaluated clinically and studied using autozygome-guided mutation analysis and exome sequencing. We show that autozygome-guided candidate gene analysis identified the underlying mutation in the majority (n ¼ 12, 71%). Exome sequencing revealed a likely pathogenic mutation in three novel candidate MKS disease genes. These include C5orf42, Ellis-van-Creveld disease gene EVC2 and SEC8 (also known as EXOC4), which encodes an exocyst protein with an established role in ciliogenesis. This is the largest and most comprehensive genomic study on MKS in Arabs and the results, in addition to revealing genetic and allelic heterogeneity, suggest that previously reported disease genes and the novel candidates uncovered by this study account for the overwhelming majority of MKS patients in our population.
Mutations of the GDF5 gene cause a variable phenotype including brachydactyly type C. A review of the literature showed that it is caused either by heterozygous frameshift mutations within the prodomain or heterozygous missense/nonsense mutations within the active domain. Only a single patient with a homozygous mutation (c.517A > G, which predicts p. Met173Val) has been reported in this disorder. In this paper, we report two children with novel homozygous missense mutations in the GDF5 gene associated with brachydactyly type C: one mutation was within the region coding for the prodomain (c.608C > A, which predicts p.Thr203Asn) and the other was within the region coding for the active domain (c.1456 G > A, which predicts p.Val486Met). The genotype-phenotype correlations in the mutational spectrum of the GDF5 gene are discussed.
BackgroundFibro-osseous pseudotumor (FOPD) of the digit is a rare benign lesion of subcutaneous tissue characterized by fibroblastic proliferation and osteoid formation. Herein, we present a case of massive FOPD lesion in the base of ring finger with extensive involvement of the neurovascular bundles with challenging surgical approach.Case descriptionA 27-year old female patient, presented with 7-months history of a progressively enlarging mass on her left hand. Upon assessment, the mass was located over the proximal phalanx of the left ring finger with extensive involvement of the 4th web space. Her neurovascular examination was normal. Radiological investigations showed partial involvement of the radial sided bundle together with complete involvement of the ulnar sided neurovascular bundle. The patient was bothered by the mass being painful with overlying skin ulceration. She was taken afterwards to the operating room where the mass was dissected freely from those bundles while preserving the radial and ulnar structures. The resected margins were however, positive for residual lesions due to the extensive nature of the mass. The patient was informed about the need for close follow-ups for both clinical and radiological signs of lesion recurrence pending early surgical intervention.ConclusionFOPD although benign, a soft tissue osteosarcoma is one of the differential diagnosis. Meticulous attention to the clinical, pathological and histological features of FOPD is required. Early diagnosis and treatment of FOPD is very crucial in optimizing the overall outcome. Pre-operative planning with various radiological modalities was of great help anticipating the surgical course.
The diaphysial axis-metacarpal head angle (DHA) is the angle formed between the longitudinal axis of the diaphysis of the proximal phalanx and central point of the metacarpal head. The normal DHA ranges from 177.1° and 180.0°. There were no significant differences between DHA measurements when taken by the same observer at two separate occasions (P = 0.986) or when taken by two different observers (P = 0.948). We have put an algorithm of management of paediatric phalangeal base fractures incorporating the DHA in the decision making. A prospective study of 92 children (5-14 years) with phalangeal base fractures was conducted. Closed reduction was possible in all but one case in which open reduction and K-wire fixation was required. Closed reduction of the remaining 91 fractures yielded a 'good' reduction in 80 cases (no finger deformity on clinical examination with a post-reduction DHA greater than 177°). After a mean follow-up of 4.2 months, all these 80 cases qualified for an excellent outcome as per Al-Qattan's criteria. The remaining 11 children were considered to have an 'acceptable' reduction (no scissoring, but there was a mild residual lateral deviation of the finger with a DHA angle of 169.4° to 176.2°). At a mean follow-up of 28 months, all these 11 mal-united fractures remodelled with normalization of the DHA; and all 11 children qualified for an excellent outcome as per Al-Qattan's criteria. The current series stresses on the advantages of using DHA in the objective assessment of paediatric phalangeal base fractures and demonstrates the remodelling of fractures with about 10° of lateral deviation.
The pathogenesis of ulnar polydactyly in humans is not known. There are numerous syndromes that are associated with ulnar polydactyly. We have noted that the genetic defects in these syndromes lead to a disturbance of the normal balance between the two forms of the Gli3 protein (the active and repressor forms of Gli3, which are known as Gli3-A and Gli3-R, respectively), leading to a relative increase in the Gli3-R protein. We offer the hypothesis of a unified pathogenesis of ulnar polydactyly through the relative predominance of Gli3-R.
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