Diaphanospondylodysostosis

A number sign (#) is used with this entry because of evidence that diaphanospondylodysostosis is caused by homozygous or compound heterozygous mutation in the BMPER gene (608699) on chromosome 7p14.

Description

Diaphanospondylodysostosis is a rare, recessively inherited, perinatal lethal skeletal disorder. The primary skeletal characteristics include small chest, abnormal vertebral segmentation, and posterior rib gaps containing incompletely differentiated mesenchymal tissue. Consistent craniofacial features include ocular hypertelorism, epicanthal folds, depressed nasal bridge with short nose, and low-set ears. The most commonly described extraskeletal finding is nephroblastomatosis with cystic kidneys, but other visceral findings have been described in some cases (summary by Funari et al., 2010).

Clinical Features

Prefumo et al. (2003) described 3 sibs, born to nonconsanguineous parents, with absent intrauterine ossification of the spinal column, rib abnormalities with unossified segments and posterior gaps, thoracic hypoplasia, and multiple intralobar nephrogenic rests in the kidneys. Whole body roentgenograms showed complete absence of ossification of the vertebral bodies throughout the spine and no ossification of the vertebral pedicles below the thoracic region. Autopsy revealed a normal spinal column in the lumbar and sacral regions that were cartilaginous and unossified. First trimester fetal nuchal translucency was measured in 2 of the pregnancies. Prefumo et al. (2003) proposed autosomal recessive inheritance since both sexes were affected. They also suggested that the dizygotic twins reported by Nisbet et al. (1999) may have had the same disorder.

Gonzales et al. (2005) reported 4 patients from 3 families with similar radiologic findings comprising absent or severely delayed ossification of vertebral bodies. Other manifestations included a short neck, short and wide thorax, normally shaped limbs, hypoplastic nails, and nephroblastomatosis. The babies were stillborn or died soon after birth of respiratory insufficiency. One of the patients had previously been described by Maroteaux and Le Merrer (2002). Two patients were sibs born to consanguineous Malian parents. Gonzales et al. (2005) proposed to name this lethal autosomal recessive syndrome diaphanospondylodysostosis.

Vatanavicharn et al. (2007) reported 6 additional patients from 4 families with diaphanospondylodysostosis. Typical facial features included hypertelorism, a short nose, depressed nasal bridge, low-set ears, and webbed neck. Other congenital anomalies in their patients were polymicrogyria, and trilobed liver. The majority of cases died in the neonatal period of respiratory insufficiency. One male patient was alive at 9 months of age with severe developmental delay and generalized hypotonia. Characteristic radiographic findings included unossified vertebral bodies below the T12 level to the sacrum, posterior rib gaps, missing ribs, and downward tilting pubic rami. The skull and long bones were normal. Histology of the rib gaps revealed cartilage interrupted by fasicles of skeletal muscle and dense fibrous tissue and patchy areas of skeletal ossification. Molecular analysis of PAX1 (167411) and MEOX1 (600147) exons and flanking intronic sequences excluded these 2 candidate genes.

Mapping

Funari et al. (2010) tested DNA samples from 4 unrelated cases of diaphanospondylodysostosis for autozygosity using whole-genome SNP data and identified 1 case in which there were 2 blocks of homozygosity larger than 5 Mbps that were not shared with an unaffected sib, on chromosomes 1 and 7, respectively. The 2 regions contained 35 Mb and comprised 166 known genes.

Molecular Genetics

Using a targeted capture-and-resequencing approach on DNA from a proband with diaphanospondylodysostosis, in whom 2 autozygous intervals had been found on chromosomes 1 and 7, Funari et al. (2010) identified homozygosity for a nonsense mutation in the BMPER gene (Q309X; 608699.0001) within the region of homozygosity on chromosome 7. Homozygosity was confirmed by Sanger sequencing in the proband, and both unaffected parents and an unaffected sib were heterozygous carriers of the mutation. Analysis of the BMPER gene in 3 additional unrelated probands with diaphanospondylodysostosis revealed compound heterozygosity for a deletion/insertion mutation and a splice site mutation in 1 proband (608699.0002 and 608699.0003, respectively) and for a missense (608699.0004) and a nonsense mutation (C546X; 608699.0005) in another proband. In the third proband, only a single nonsense mutation (Q172X) was found, suggesting that the other allele either resulted in a deletion or did not reside within the coding region.