Frontometaphyseal Dysplasia 2

A number sign (#) is used with this entry because of evidence that frontometaphyseal dysplasia-2 (FMD2) is caused by heterozygous mutation in the MAP3K7 gene (602614) on chromosome 6q15.

Cardiospondylocarpofacial syndrome (CSCF; 157800), which encompasses features overlapping those of FMD2, is also caused by mutation in the MAP3K7 gene.

Description

Frontometaphyseal dysplasia (FMD) is a progressive sclerosing skeletal dysplasia characterized by supraorbital hyperostosis, undermodeling of the small bones, and small and large joint contractures, as well as extraskeletal developmental abnormalities, primarily of the cardiorespiratory system and genitourinary tract. Patients with FMD2 appear to have a propensity for keloid formation (summary by Wade et al., 2016).

For a discussion of genetic heterogeneity of frontometaphyseal dysplasia, see FMD1 (305620).

Clinical Features

Morava et al. (2003) described 2 Hungarian families in which both males and females showed the facial and skeletal characteristics of frontometaphyseal dysplasia in association with severe progressive scoliosis. Some also had hearing loss and urogenital anomalies, leading Morava et al. (2003) to suggest that these might represent cases of frontootopalatodigital osteodysplasia as described by Verloes et al. (2000); see OPD1 (311300).

Basart et al. (2015) described 7 unrelated patients, 6 females and 1 male, who had features of FMD as well as keloid formation but no mutation in the FMD1-associated gene FLNA (300017). The patients all displayed the major clinical and radiologic features of FMD, including prominent supraorbital ridges, underdeveloped sinuses, luxation of the radial head, small lateral epicondyle of the femora, underdevelopment of the carpals and tarsals, and undermodeling of the metacarpals, metatarsals, and phalanges. Five patients had scoliosis, 2 had a mandibular spur, and 2 showed mild bowing of the long bones. All 7 patients also exhibited findings that were not typical of FMD, including hypertrophic keloid scars, coxa valga, and pes equinovarus. Other uncommon features included congenital large joint dislocations, primarily of the hips, in 5 of the patients; muscular underdevelopment in 5; cleft palate in 4, and occurring as part of Robin sequence in 2; hirsutism in 3; intellectual disability in 3; and eye abnormalities in 2, with thickening or opacification of the cornea in both and absent anterior eye chamber in 1.

Wade et al. (2016) studied 19 patients with FMD, including a Hungarian girl originally reported by Morava et al. (2003) and 5 of the patients previously described by Basart et al. (2015). Core features included prominent supraorbital ridges, hyperostosis, downslanting palpebral fissures, hypertelorism, wide nasal bridge, and small pointed chin. Progressive contractures of the joints were common, especially in the fingers and wrists. Radiographs revealed a dense skull, especially at the frontal bone and skull base. Long bones of the hands and feet were undermodeled, frequently with sclerotic cortices. Patients often presented with mild to severe scoliosis, and had undermodeled, deformed ribs, sometimes in a 'coat-hanger' configuration. Long bones had dense cortices and splaying of the metaphyses. Three of the patients had a somewhat milder skeletal phenotype, 1 of whom also lacked some of the facial characteristics but still showed prominent supraorbital ridges. In addition, 8 patients exhibited keloid scarring that was occasionally progressive and severe; it formed spontaneously as well as after surgical trauma.

Molecular Genetics

Wade et al. (2016) performed exome analysis and targeted Sanger sequencing in 19 unrelated patients from diverse ethnic backgrounds with FMD, including a Hungarian girl originally reported by Morava et al. (2003) and 5 patients of Korean, Turkish, Mexican, English, and Australian-European origin, respectively, previously described by Basart et al. (2015). Wade et al. (2016) identified heterozygosity for a recurrent missense mutation in the MAP3K7 gene (P485L; 602614.0001) in 15 of the patients, including all 8 who exhibited keloid scarring. In addition, 3 patients with a 'notably' milder phenotype were heterozygous for 3 MAP3K7 missense mutations located in the kinase domain of TAK1: E70Q (602614.0002), V100E (602614.0003), and G168R (602614.0004). In 7 patients for whom parental DNA was available, the mutations were shown to have arisen de novo, but 2 mutations (E70Q and V100E) were inherited from affected mothers. The remaining patient was heterozygous for a de novo missense mutation in the TAK1-binding protein gene (TAB2; see 605101.0003). Noting that the latter patient demonstrated a phenotype that was indistinguishable from MAP3K7-associated FMD, Wade et al. (2016) suggested that this might represent a third form of FMD, which they designated 'FMD3.'