Opsismodysplasia

A number sign (#) is used with this entry because of evidence that opsismodysplasia is caused by homozygous or compound heterozygous mutation in the INPPL1 gene (600829) on chromosome 11q13.

Description

Opsismodysplasia is a rare skeletal dysplasia involving delayed bone maturation. Clinical signs observed at birth include short limbs, small hands and feet, relative macrocephaly with a large anterior fontanel, and characteristic craniofacial abnormalities including a prominent brow, depressed nasal bridge, a small anteverted nose, and a relatively long philtrum. Death in utero or secondary to respiratory failure during the first few years of life has been reported, but there can be long-term survival. Typical radiographic findings include shortened long bones with delayed epiphyseal ossification, severe platyspondyly, metaphyseal cupping, and characteristic abnormalities of the metacarpals and phalanges (summary by Below et al., 2013 and Fradet and Fitzgerald, 2017).

Clinical Features

Opsismodysplasia was suggested by Maroteaux et al. (1982) as the designation for a skeletal dysplasia that shows late bone maturation; the Greek root for the first part of the word means 'delayed maturation.' The disorder was observed at birth; predominantly rhizomelic micromelia, facial dysmorphia, prominent brow, large fontanels, depressed nasal bridge, small anteverted nose with long philtrum, and short feet and hands with sausage-like fingers were features. Death from pulmonary infection was frequent. Growth of the limbs and vertebrae was slow. One patient, aged 3 years and 9 months, showed no femoral, tibial, or carpal nuclei. Maroteaux et al. (1982) studied 4 cases. They referred to a fifth possible case reported by Zonana et al. (1977). One set of parents had ages 44 and 38; consanguinity in other cases suggested autosomal recessive inheritance. Consistent with the designation, the characteristic radiographic signs include very retarded bone maturation, as well as marked shortness of the bones of the hands and feet with concave metaphyses and thin, lamellar vertebral bodies. In studies of the growth cartilage in 1 case, Maroteaux et al. (1984) found a wide hypertrophic area containing thick connective tissue septa, irregular provisional calcification, and vascular invasion. Type I collagen was detected in the hypertrophic area by immunohistochemical and microchemical tests.

Beemer and Kozlowski (1994) described the disorder in a 2-year-old boy with first-cousin parents. At 16 months, there were no carpal or tarsal ossification centers and the bones of the hands and feet showed severe abnormalities. There was also absence of ossification in the distal femur and proximal tibia.

Santos and Saraiva (1995) described a typical case in a Portuguese male infant born to consanguineous parents. Macrostomia was the only finding in this patient that had not previously been reported in this disorder.

Cormier-Daire et al. (2003) described 12 cases in 9 families, all of which had major delay in epiphyseal ossification, platyspondyly, metaphyseal cupping, and very short metacarpals and phalanges. Six cases were diagnosed by prenatal ultrasound and the pregnancies were terminated; of the 6 other cases, one died at 3 months of age of respiratory illness, but the other 5 were still alive and were aged 28 months to 15 years, demonstrating that patients with this disease can survive well beyond the neonatal period. Initial radiographic findings were characteristic of the disease; x-ray follow-up of the survivors showed persistence of an extremely delayed epiphyseal ossification with dysplastic carpal ossification, marked shortness of the metacarpals, and metaphyseal irregularities in the knee. Histopathologic examination of fetal bones and cartilage showed wide and numerous epiphyseal vascular canals; chondrocyte density in the resting cartilage was increased, many cells were arranged in clusters, and some of them were ballooned. At the growth plate level, the proliferative zone was very disorganized, with a nearly absent columnar organization. The mineralized matrix trabeculae were thick and irregular. These anomalies were observed in all cases but varied markedly in severity among cases, paralleling the variability of the x-ray manifestations.

Lee et al. (2015) provided details of a 33-week-gestation hydropic stillborn (ISDR R02-170) with a clinical diagnosis of Schneckenbecken dysplasia (269250) who was previously reported by Hiraoka et al. (2007). The patient had midfacial hypoplasia, handlebar clavicles, short ribs, hypoplastic vertebrae with rounded anterior ends, short long bones with widened metaphyseal ends, and a snail-like projection in the ileum. Histomorphology of the cartilage growth plate showed poor hypertrophic column formation with fibrous septae between the columns, areas of hypercellularity with decreased extracellular matrix and hypervascularity, chondrocytes with central round nuclei, as well as thickened primary trabeculae and a fibrous band entering the growth plate from the growth collar.

Feist et al. (2016) reported 2 fetuses of phenotypically normal parents with a lethal skeletal dysplasia consistent with severe opsismodysplasia. Findings included short limbs with flared metaphyses, bowed radii, femora, and tibiae, irregular ossification of hands and feet, and marked platyspondyly. One of the fetuses also had progressive ventriculomegaly and developed hydrops.

Fradet and Fitzgerald (2017) found that the outcomes in 31 reported patients with opsismodysplasia caused by mutation in the INPPL1 gene varied widely from fetal deaths and deaths in the newborn period to one individual who was 24 years old at the time of evaluation.

Inheritance

Maroteaux et al. (1984) favored autosomal recessive transmission because 2 affected sibs with first-cousin parents were observed by Zonana et al. (1977). Tyler et al. (1999) described a family with 2 marriages of first cousins with a total of 5 children with opsismodysplasia. The diagnosis was based on clinical, radiologic, and immunohistochemical findings. Testing with type I collagen antibodies showed abnormally high levels in the hypertrophic area of growth cartilage. This family substantiated the hypothesis of autosomal recessive inheritance.

Molecular Genetics

In a consanguineous family in which 2 sibs had opsismodysplasia, Below et al. (2013) performed linkage analysis and whole-genome sequencing and identified a missense mutation in the candidate gene INPPL1 (600829.0001) that was homozygous in both affected sibs and heterozygous in the parents. Sanger sequencing of INPPL1 in an unrelated family with opsismodysplasia revealed that the affected child was homozygous for a nonsense mutation (600829.0002). Screening the INPPL1 gene in 10 more unrelated opsismodysplasia families identified homozygous or compound heterozygous mutations in 7 (see, e.g., 600829.0003 and 600829.0004). In each of 5 families for which parental DNA was available, heterozygosity was confirmed in the unaffected parents. Overall, INPPL1 mutations were found in 7 (58%) of 12 families studied. Below et al. (2013) noted that the clinical characteristics of individuals with INPPL1-related opsismodysplasia were indistinguishable from those without INPPL1 mutations and included individuals with severe renal phosphate wasting and those in whom no such abnormality was reported.

In the probands from 3 unrelated families with opsismodysplasia in whom mutation in the SBDS (607444), SLC35D1 (610804), and TRIP11 (604505) genes had been excluded, Huber et al. (2013) performed exome capture-sequencing and identified a single gene, INPPL1, in which homozygous or compound heterozygous mutations were present in all 3 (see, e.g., 600829.0005-600829.0008). Screening of INPPL1 in 7 additional opsismodysplasia families revealed 7 additional mutations for a total of 12 distinct INPPL1 mutations in the 10 families. All 16 patients clearly fulfilled the diagnostic criteria for opsismodysplasia, but were variable in severity: 7 pregnancies were terminated based on prenatal findings including hygroma, short long bones, short extremities, and narrow thorax; 4 children died in infancy (see, e.g., 600829.0009); and the 5 remaining patients ranged in age from 3 to 19 years and had normal cognitive development, severe short stature, lower limb deformity, and severe scoliosis, with atlantoaxial instability in 1 patient.

In a 33-week-gestation hydropic stillborn (ISDR R01-170) with a clinical diagnosis of Schneckenbecken dysplasia (SHNKND; 269250) in whom Hiraoka et al. (2007) had excluded mutation in the SLC35D1 gene (610804), Lee et al. (2015) identified homozygosity for a splice site mutation in the INPPL1 gene (600829.0004). The authors suggested that this represented a second locus for SHNKND; however, Fradet and Fitzgerald (2017) concluded that additional families with SHNKND would be needed to confirm a role for INPPL1 in that disorder.

In 2 fetuses of phenotypically normal parents with severe opsismodysplasia, Feist et al. (2016) identified compound heterozygous mutations in the INPPL1 gene. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.

Fradet and Fitzgerald (2017) reviewed the variants in the INPPL1 gene identified in patients with opsismodysplasia. The 25 mutations found in 20 families were spread throughout the gene and included 3 nonsense, 1 in-frame, 7 missense, 9 frameshift, and 5 splice site mutations. The majority of the mutations (17/25) were expected to lead to premature stop codons, resulting in a null allele. Six of the 7 missense mutations were located in the catalytic domain and presumably inactivated the phosphatase function of the SHIP2 protein. All patients had mutations in homozygous or compound heterozygous state and heterozygous parents were unaffected, suggesting that SHIP2 needs to be disabled for complete penetrance of the phenotype. No clear genotype-phenotype correlation was noted. The oldest surviving patient reported in the literature was 24 years old and was compound heterozygous for a frameshift and a missense mutation (Gln251His) located outside the catalytic domain, leading the authors to speculate that a small amount of enzyme activity might be enough to ameliorate the severity of the phenotype.