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A rare multiple congenital anomalies/dysmorphic syndrome characterized by anomalous ossification and skeletal patterning of the axial and appendicular skeleton, facial dysmorphism and conductive and sensorineural hearing loss.
ORPHA:1826Classification level: Disorder
To date, over 100 cases have been described in the literature.
Frontometaphyseal dysplasia (FMD) is a congenital disorder and the cardinal manifestations in males are skeletal dysplasia (skull base sclerosis; distal phalangeal hypoplasia; progressive contractures of the hand over the first two decades resulting in marked limitation of movement at the interphalangeal, metacarpophalangeal joints, wrists, elbows, knees, and ankles); mild but progressive scoliosis; limb bowing; campomelia), facial dysmorphism (supraorbital hyperostosis, downslanting palpebral fissures, ocular hypertelorism, broad nasal bridge and nasal tip, hypodontia, oligodontia and occasionally craniosynostosis) and conductive and sensorineural hearing loss. Extraskeletal manifestations include congenital heart malformation (interauricular communication, ventricular septal defect, congenital pulmonary valve stenosis, aortic dilatation), congenital subglottic stenosis, an asthenic build, and underdevelopment of the musculature, most notably around the shoulder girdle and in the intrinsic muscles of the hands (common). Males with FMD can present with ureteric and/or urethral obstruction most frequently at the vesicoureteric junction (leading to hydronephrosis). Intelligence is normal. Females are less severely affected and present the characteristic craniofacial features, scoliosis but absent or attenuated digital, cardiorespiratory, and urologic anomalies.
The exact pathogenesis of FMD is still unknown, however around half of cases of FMD are caused by gain of function mutations in the gene FLNA (Xq28) that encodes filamin A. There is evidence for a second autosomal locus for FMD that to date remains uncharacterized. FMD is allelic with 4 other skeletal dysplasias (otopalatodigital syndrome type 1 and 2 (OPD1 and OPD2, respectively), terminal osseous dysplasia - pigmentary defects (TOD) and Melnick-Needles syndrome (MNS)).
Many pedigrees are consistent with X-linked dominant inheritance. Male-to-male transmission has not been reported. The risk of transmitting the mutation in each pregnancy is 50%; males inheriting the mutation will be affected while females who inherit the mutation are less severely affected.
- Clinical genetics review
- English (2019)