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Frontometaphyseal dysplasia

Synonym(s) -
Prevalence <1 / 1 000 000
Inheritance X-linked dominant
or Autosomal dominant
Age of onset Neonatal
  • Q78.5
  • C0265293
  • C538064
MedDRA -


Disease definition

Frontometaphyseal dysplasia (FMD) belongs to the otopalatodigital syndrome spectrum disorder (see this term) and is characterized by anomalous ossification and skeletal patterning of the axial and appendicular skeleton, facial dysmorphism and conductive and sensorineural hearing loss.


To date, over 100 cases have been described in the literature.

Clinical description

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 (see this term)) and conductive and sensorineural hearing loss. Extraskeletal manifestations include congenital heart malformation (interauricular communication, ventricular septal defect, congenital pulmonary valve stenosis (see these terms), aortic dilatation), congenital subglottic stenosis (see this term), 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) (see these terms)).

Genetic counseling

Many pedigrees are consistent with X-linked dominant inheritance. Male-to-male transmission has not been reported. The chance 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.

Expert reviewer(s)

  • Pr Stephen ROBERTSON

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Detailed information

Clinical genetics review
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