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Blomstrand osteochondrodysplasia (BOCD) is a rare autosomal recessive sclerosing skeletal dysplasia characterized by accelerated chondrocyte differentiation. In this article, we discuss three cases where lethal skeletal dysplasia was suspected and Blomstrand dysplasia was diagnosed by autopsy. Antenatal ultrasound findings include increased nuchal translucency, tetramicromelia and polyhydramnios. Radiological hallmark is advanced skeletal maturation and bone sclerosis. Histology of long bones revealed narrow cartilagenous cap and changes in the physeal growth zone which showed severe hypoplasia and disorganization of proliferative phase and hypertrophic phase. Homozygous and compound heterozygous mutations in PTHR1 gene have been implicated in the pathogenesis of this chondrodysplasia. [ABSTRACT FROM PUBLISHER]

Cartilage-hair hypoplasia is a rare, autosomal recessive skeletal dysplasia, caused by mutations in the RMRP gene. The skeletal abnormalities include irregular metaphyses and cone shaped epiphyses of the hands. Molecular diagnosis confirmed two novel RMRP mutations in a compound heterozygous state in two siblings with this condition. [ABSTRACT FROM AUTHOR]

Pyridoxine-dependent epilepsy (PDE) is an inborn error of metabolism resulting from antiquitin deficiency. There is marked elevation of α-amino adipic semi-aldehyde (αAASA), piperidine-6-carboxylate (P6C) and pipecolic acid. The diagnosis can be confirmed by identifying the mutation in the ALDH7A1 gene in chromosome 5q3l. An 8-year-old Indian girl presented with severe developmental delay and seizures and was found to have pyridoxine-dependent epilepsy owing to an antiquitin mutation. Genetic evaluation of the parents allowed antenatal diagnosis to be made during the next pregnancy. [ABSTRACT FROM AUTHOR]

Joubert syndrome (JBTS) is a recessive ciliopathy in which a subset of affected individuals also have the skeletal dysplasia Jeune asphyxiating thoracic dystrophy (JATD). Here, we have identified biallelic truncating CSPP1 (centrosome and spindle pole associated protein 1) mutations in 19 JBTS-affected individuals, four of whom also have features of JATD. CSPP1 mutations explain ∼5% of JBTS in our cohort, and despite truncating mutations in all affected individuals, the range of phenotypic severity is broad. Morpholino knockdown of cspp1 in zebrafish caused phenotypes reported in other zebrafish models of JBTS (curved body shape, pronephric cysts, and cerebellar abnormalities) and reduced ciliary localization of Arl13b, further supporting loss of CSPP1 function as a cause of JBTS. Fibroblasts from affected individuals with CSPP1 mutations showed reduced numbers of primary cilia and/or short primary cilia, as well as reduced axonemal localization of ciliary proteins ARL13B and adenylyl cyclase III. In summary, CSPP1 mutations are a major cause of the Joubert-Jeune phenotype in humans; however, the mechanism by which these mutations lead to both JBTS and JATD remains unknown. [ABSTRACT FROM AUTHOR]

Distal arthrogryposis (DA) syndromes are the most common of the heritable congenital-contracture disorders, and ∼50% of cases are caused by mutations in genes that encode contractile proteins of skeletal myofibers. DA type 5D (DA5D) is a rare, autosomal-recessive DA previously defined by us and is characterized by congenital contractures of the hands and feet, along with distinctive facial features, including ptosis. We used linkage analysis and whole-genome sequencing of a multiplex consanguineous family to identify in endothelin-converting enzyme-like 1 (ECEL1) mutations that result in DA5D. Evaluation of a total of seven families affected by DA5D revealed in five families ECEL1 mutations that explain ∼70% of cases overall. ECEL1 encodes a neuronal endopeptidase and is expressed in the brain and peripheral nerves. Mice deficient in Ecel1 exhibit perturbed terminal branching of motor neurons to the endplate of skeletal muscles, resulting in poor formation of the neuromuscular junction. Our results distinguish a second developmental pathway that causes congenital-contracture syndromes. [Copyright &y& Elsevier]