Terminal Osseous Dysplasia

A number sign (#) is used with this entry because of evidence that terminal osseous dysplasia (TOD) is caused by mutation in the FLNA gene (300017) on chromosome Xq28.

Description

Terminal osseous dysplasia is an X-linked dominant male-lethal disease characterized by skeletal dysplasia of the limbs, pigmentary defects of the skin, and recurrent digital fibroma during infancy (Sun et al., 2010).

Clinical Features

Zhang et al. (2000) identified a novel limb-malformation syndrome in a 4-generation family. The syndrome was characterized by abnormal and delayed ossification of bones in the hands and feet, leading to brachydactyly, camptodactyly, and clinodactyly, severe limb deformities, and joint contractures. In addition, affected individuals had pigmentary skin lesions on the face and scalp, dysmorphic features including hypertelorism, and multiple frenula. The phenotype was reminiscent of those described by Bloem et al. (1974) and Horii et al. (1998) in sporadic cases.

Bacino et al. (2000) gave a full description of the family reported by Zhang et al. (2000). The syndrome was present in 10 females in 4 generations. It was ascertained through a 4-month-old female with multiple anomalies including hypertelorism, iris colobomas, low-set ears, midface hypoplasia, 'punched-out' pigmentary abnormalities over the face and scalp, generalized brachydactyly, and digital fibromatosis. Affected females had a reduced male-to-female ratio of liveborn offspring, and some of them also had a history of multiple miscarriages. Some of the affected family members showed mesomelic bowing and/or shortening of arms and legs, suggesting that the skeletal dysplasia may not be limited to the hands and feet. The digital fibromata observed in the proband was reported to be present in most of the affected females but regressed with age. In some instances, affected females had vestigial and linear scar-like lesions on the fingertips. The lack of affected males, decreased number of male progeny in the pedigree, and the number of spontaneous abortions in the family supported a male-lethal X-linked dominant etiology.

Breuning et al. (2000) described 5 female patients with this condition, 2 of whom were related (a mother and her daughter). The mother, previously described by Bloem et al. (1974), had recurrent digital fibromas, ptosis of the right eyelid, and pigmentary anomalies of the forehead. Her daughter had focal dermal hypoplasia, coloboma of the iris and eyelids, anal stenosis, and extensive limb malformations; she developed digital fibromas at age 3 months. The 3 sporadic cases, one of whom was previously described by Bloem et al. (1974), had multiple digital fibromas, pigmented lesions in the temporal region, and limb malformations.

Baroncini et al. (2007) described a 2-year-old Italian girl with full expression of the syndrome, including skin defects, skeletal anomalies, and recurrent fibromatosis of fingers and toes. Her mother had only multiple hypertrophic oral frenula. X-chromosome inactivation studies revealed extremely skewed X inactivation (100%) with silencing of the maternal X chromosome in the daughter; the mother also had extremely skewed X inactivation (100%).

Kokitsu-Nakata et al. (2008) described a Brazilian girl with typical features of this disorder, including skin defects, skeletal anomalies, and recurrent fibromatosis of fingers and toes.

Brunetti-Pierri et al. (2010) restudied the family with terminal osseous dysplasia and pigmentary defects originally reported by Zhang et al. (2000), reviewing clinical and radiologic characteristics. The digital fibromata originally observed in the proband were not present at later evaluations, and she had particularly striking carpal and tarsal coalitions that were not noted in the earlier reports, because the carpal bones had not yet ossified. Although the skeletal manifestations of the disorder mostly involve hands and feet, Brunetti-Pierri et al. (2010) observed a more generalized bone involvement including bowing, mesomelic shortening, abnormal bony texture, areas of localized osteoporosis, cystic-like lesions, and amorphous ossification that suggested a possible defect of matrix degradation. They also noted that in this family, the degree of hand and foot involvement was more severe laterally compared to medially.

Mapping

Using a methylation assay at the androgen receptor locus for evaluation of X inactivation, Zhang et al. (2000) found that all 7 affected females studied demonstrated preferential inactivation of their maternal X chromosomes carrying the mutation, whereas 2 unaffected females showed a random pattern. This finding indicated that the disorder is linked to the X chromosome. In linkage studies, a maximum lod score of 3.16 at a recombination fraction of zero was obtained for 5 markers mapping to Xq27.3-q28.

Brunetti-Pierri et al. (2010) restudied the family with terminal osseous dysplasia and pigmentary defects originally reported by Zhang et al. (2000), obtaining a maximum multipoint lod score of 2.9 from marker rs1860929 to qter; an identical haplotype was found only in affected individuals. The reduced genetic interval was refined to Xq28-qter, a region containing more than 100 genes.

Molecular Genetics

In a family with terminal osseous dysplasia and pigmentary defects mapping to Xq28-qter, originally reported by Zhang et al. (2000), Brunetti-Pierri et al. (2010) sequenced the intron-exon junctions and exons of the candidate FAM58A (300708) and FLNA genes but did not find any mutations.

In affected members of 3 families segregating terminal osseous dysplasia, 2 of which were previously described by Breuning et al. (2000) and Baroncini et al. (2007), and in 3 sporadic case individuals, who were previously described by Horii et al. (1998), Drut et al. (2005), and Breuning et al. (2000), Sun et al. (2010) identified a causative mutation in the FLNA gene: a 5217G-A transition activated a cryptic splice site, removing the last 48 nucleotides from exon 31 and resulting in a loss of 16 amino acids (300017.0029). In the families, the variant segregated with the disease. Sun et al. (2010) showed that because of nonrandom X chromosome inactivation, the mutant allele was not expressed in the patient fibroblasts. RNA expression of the mutant allele was detected only in cultured fibroma cells obtained from 15-year-old surgically removed material. The mutation was not found in 400 control X chromosomes, pilot data from 1000 Genomes Project, or the FLNA gene variant database. Because the mutation was predicted to remove a sequence at the surface of filamin repeat 15, Sun et al. (2010) suggested that the missing region in the filamin A protein affects or prevents the interaction of filamin A with other proteins.