Importance of etiologic diagnosis of hydrocephalus as illustrated by a case of Walker Warburg syndrome

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Synpolydactyly and HOXD13 polyalanine repeat: addition of 2 alanine residues is without clinical consequences

<p>Abstract</p> <p>Background</p> <p>Type II syndactyly or synpolydactyly (SPD) is clinically very heterogeneous, and genetically three distinct SPD conditions are known and have been designated as SPD1, SPD2 and SPD3, respectively. SPD1 type is associated with expansion mutations in <it>HOXD13</it>, resulting in an addition of ≥ 7 alanine residues to the polyalanine repeat. It has been suggested that expansions ≤ 6 alanine residues go without medical attention, as no such expansion has ever been reported with the SPD1 phenotype.</p> <p>Methods</p> <p>We describe a large Pakistani and an Indian family with SPD. We perform detailed clinical and molecular analyses to identify the genetic basis of this malformation.</p> <p>Results</p> <p>We have identified four distinct clinical categories for the SPD1 phenotype observed in the affected subjects in both families. Next, we show that a milder foot phenotype, previously described as a separate entity, is in fact a part of the SPD1 phenotypic spectrum. Then, we demonstrate that the phenotype in both families segregates with an identical expansion mutation of 21 bp in <it>HOXD13</it>. Finally, we show that the HOXD13 polyalanine repeat is polymorphic, and the expansion of 2 alanine residues, evident in unaffected subjects of both families, is without clinical consequences.</p> <p>Conclusion</p> <p>It is the first molecular evidence supporting the hypothesis that expansion of ≤ 6 alanine residues in the HOXD13 polyalanine repeat is not associated with the SPD1 phenotype.</p

Fifteen years of research on oral–facial–digital syndromes: from 1 to 16 causal genes

Oral–facial–digital syndromes (OFDS) gather rare genetic disorders characterised by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFDS subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the OFD1 gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS. This effort has been greatly helped by the recent development of whole-exome sequencing (WES). Here, we present all our published and unpublished results for WES in 24 cases with OFDS. We identified causal variants in five new genes (C2CD3, TMEM107, INTU, KIAA0753 and IFT57) and related the clinical spectrum of four genes in other ciliopathies (C5orf42, TMEM138, TMEM231 and WDPCP) to OFDS. Mutations were also detected in two genes previously implicated in OFDS. Functional studies revealed the involvement of centriole elongation, transition zone and intraflagellar transport defects in OFDS, thus characterising three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the Meckel-Gruber syndrome module, a major component of the transition zone; and the CPLANE complex necessary for IFT-A assembly. OFDS now appear to be a distinct subgroup of ciliopathies with wide heterogeneity, which makes the initial classification obsolete. A clinical classification restricted to the three frequent/well-delineated subtypes could be proposed, and for patients who do not fit one of these three main subtypes, a further classification could be based on the genotype

Clinical profile and molecular diagnosis in patients of facioscapulohumeral dystrophy from Indian subcontinent

Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant muscular dystrophy. We retrospectively studied three families (two Indian, one Nepalese) with 12 affected members (male:female-7:5). Mean age at onset of weakness was 17.63 + 5.48 years. Patients were classified according to muscle groups affected (F-face, S-scapula, H-humeral, PG-pelvic girdle, P-peroneal, A-loss of independent ambulation): FSH-A (2), four FSH (4), SH (3), FSH-PG (2) and one: F (1). Progression of weakness was classified as F>S>P>PG in eight cases, S> F>P in one, static in three. Eleven patients had electromyographic findings suggestive of myopathy and one had features of neurogenic involvement. Molecular diagnosis was done by southern blotting using probe p13E-ni11 after digestion of genomic DNA with EcoRI and/or EcoRI/BlnI for twelve patients and three unaffected relatives. No EcoRI fragment smaller than 35 Kb was seen in unaffected subjects. Size of EcoRI fragment varied between 17 kb to 27 kb in affected subjects and was constant for affected members of the same family. Molecular diagnosis by southern blotting has helped to provide genetic counseling for the families

Further delineation of a new (Van Den Ende-Gupta) syndrome of blepharophimosis, contractural arachnodactyly, and characteristic face

We report on 2 unrelated Indian girls with blepharophimosis; arachnodactyly; digital contractures which improved spontaneously; elbow deformity; beaked nose; everted lips; large ears; findings similar to those in 2 cases reported previously by Van Den Ende et al. [99; Am J Med Genet 4:467-469]; Gupta et al. [995; J Med Genet :809-8]; thus delineating a new syndrome of contractural arachnodactyly with characteristic facial anomalies

Linear catch-up growth

Chronic diseases and malnutrition cause growth failure in childhood and adolescence. Correction of the cause of a growth deficiency is usually followed by catch-up growth. Capacity to catch-up is not only variable in different phases of growth, it is also different in different diseases and among different individuals suffering from the same disease: Catch-up growth is of three types. In type 1 catch-up growth, height deficit is swiftly eliminated after the growth restriction ceases. In type 2, after growth restriction ceases growth continues for longer than usual and growth arrest is compensated. Type 3 is a mixture of type 1 and type 2. Repeated episodes of growth inhibitory conditions result in lower catch-up rates in the subsequent periods. Although the exact mechanism regulating catch-up growth still remains a mystery, monitoring catch-up growth remains an important measure of the efficacy of the therapy and therefore of immense clinical importance