Autosomal dominant frontometaphyseal dysplasia: Delineation of the clinical phenotype

Abstract

Frontometaphyseal dysplasia (FMD) is caused by gain-of-function mutations in the X-linked gene FLNA in approximately 50% of patients. Recently we characterized an autosomal dominant form of FMD (AD-FMD) caused by mutations in MAP3K7, which accounts for the condition in the majority of patients who lack a FLNA mutation. We previously also described a patient with a de novo variant in TAB2, which we hypothesized was causative of another form of AD-FMD. In this study, a cohort of 20 individuals with AD-FMD is clinically evaluated. This cohort consists of 15 individuals with the recently described, recurrent mutation (c.1454C>T) in MAP3K7, as well as three individuals with missense mutations that result in substitutions in the N-terminal kinase domain of TGFβ-activated kinase 1 (TAK1), encoded by MAP3K7. Additionally, two individuals have missense variants in the gene TAB2, which encodes a protein with a close functional relationship to TAK1, TAK1-associated binding protein 2 (TAB2). Although the X-linked and autosomal dominant forms of FMD are very similar, there are distinctions to be made between the two conditions. Individuals with AD-FMD have characteristic facial features, and are more likely to be deaf, have scoliosis and cervical fusions, and have a cleft palate. Furthermore, there are features only found in AD-FMD in our review of the literature including valgus deformity of the feet and predisposition to keloid scarring. Finally, intellectual disability is present in a small number of subjects with AD-FMD but has not been described in association with X-linked FMD.

TAB2 c.1398dup variant leads to haploinsufficiency and impairs extracellular matrix homeostasis

“…The apparent overlap between TAB2 haploinsufficiency and CFCS due to TAK1 abnormalities can also be inferred by the allelic nature of selected TAB2 and TAK1 (MAP3K7) variants in the etiology of frontometaphyseal dysplasia (FMD), a skeletal dysplasia mostly characterized by hyperostosis of the torus frontalis, metaphyseal flaring, and joint contractures. In fact, FMD is a genetic heterogeneous disorder caused by heterozygous variants in FLNA, TAK1, or TAB2 genes(Robertson et al, 2003;Wade et al, 2017). Although the molecular pathogenesis explaining FMD is presumably different from that underlying TAB2 haploinsufficiency and CFCS, the documented locus heterogeneity for FMD suggests close relationships between TAB2 and TAK1 in health and disease.In order to formally demonstrate primary disarray of the ECM as the intermediate phenotype bridging the molecular finding to the clinical phenotype, we analyzed the effect of TAB2 loss-of-function on ECM organization and component expression in skin fibroblasts.…”

The X‐linked filaminopathies: Synergistic insights from clinical and molecular analysis

“…Substitutions in TAK1‐associated binding protein 2 (TAB2), also lead to a very similar form of FMD as those with the recurrent TAK1, p.(Pro485Leu) substitution (Wade et al, 2016, 2017; Figure 2J). All individuals with p.Pro485Leu‐associated FMD2 or FMD3 are isolated cases (Wade et al, 2017). Notably, a milder form of FMD exhibiting characteristic FMD facial features but with mostly unremarkable skeletal findings, is caused by substitutions affecting the N‐terminus of TAK1 distant from the site of the recurrent p.(Pro485Leu) substitution (Wade et al, 2016; Figure 2I).…”

“…(b–j) Representative clinical images for (b) PH, asterisks denote nodules of gray matter lining the cerebral ventricles, arrow highlights aortic dilation; (c) OPD1, distinctive facial features and undermodelling of the phalanges are shown; (d) FMD1, distinctive facial features, undermodelled phalanges, and skull base sclerosis are shown; (e) CKCO, showing contractures of the fingers and keloid scarring; (f) OPD2, lower limb deformities and skeletal abnormalities shown; (g) MNS, distinctive facial features and skeletal dysplasia are highlighted; (h) DCD, distinctive facial features, with facial lesions, and fibromas on the hands and feet are shown; (i) FMD2, distinctive facial features including the milder form of FMD2 (left panel), contractures of the fingers, and undermodelling of the phalanges is displayed; and (j) FMD3, characteristic facial features and arachnodactyly is shown. Images reproduced with permission from (Atwal et al, 2016; Gontijo et al, 2018; Lah et al, 2015; Robertson, 2005; Robertson, 2007; Wade et al, 2016; Wade et al, 2017). ABD, actin binding domain; CHD, calponin homology domain; CIPX, congenital intestinal pseudo‐obstruction; CKCO, syndrome consisting of contractures, keloid, cardiac defects and optic anomalies; DCD, digitocutaneous dysplasia; FCMPD, familial cardiac myxomatous polyvalvular dystrophy; FLNA, filamin A; FMD, frontometaphyseal dysplasia; IMT, isolated macrothrombocytopenia; MNS, Melnick‐needles syndrome; OPD, otopalatodigital syndrome; PH, periventricular heterotopia…”

“…A recurrent substitution in TGFβ‐activated kinase 1 (TAK1; (NM_003188.4:c.1454C>T, p.(Pro485Leu)) encoded by MAP3K7 , leads to the most severe form of FMD2 often manifesting with cardiac problems, cervical vertebral fusions, hearing loss, keloid and occasionally, intellectual disability (Wade et al, 2016). Females with more severe presentations of FMD are therefore most likely to have MAP3K7 pathogenic variants (Wade et al, 2017). Substitutions in TAK1‐associated binding protein 2 (TAB2), also lead to a very similar form of FMD as those with the recurrent TAK1, p.(Pro485Leu) substitution (Wade et al, 2016, 2017; Figure 2J).…”

“…Females with more severe presentations of FMD are therefore most likely to have MAP3K7 pathogenic variants (Wade et al, 2017). Substitutions in TAK1‐associated binding protein 2 (TAB2), also lead to a very similar form of FMD as those with the recurrent TAK1, p.(Pro485Leu) substitution (Wade et al, 2016, 2017; Figure 2J). All individuals with p.Pro485Leu‐associated FMD2 or FMD3 are isolated cases (Wade et al, 2017).…”