Frontometaphyseal Dysplasia 1

A number sign (#) is used with this entry because frontometaphyseal dysplasia-1 (FMD1) is caused by gain-of-function mutations in the gene encoding filamin A (FLNA; 300017) on chromosome Xq28.

Description

Frontometaphyseal dysplasia-1 is 1 of 4 otopalatodigital syndromes caused by mutations in the FLNA gene. The disorders, which include otopalatodigital syndrome-1 (OPD1; 311300), otopalatodigital syndrome-2 (OPD2; 304120), and Melnick-Needles syndrome (MNS; 309350), constitute a phenotypic spectrum. At the mild end of the spectrum, males with OPD1 have cleft palate and mild skeletal anomalies with conductive deafness caused by ossicular anomalies. FMD1 is characterized by a generalized skeletal dysplasia, deafness, and urogenital defects. Males with OPD2 have disabling skeletal anomalies in addition to variable malformations in the hindbrain, heart, intestines, and kidneys that frequently lead to perinatal death. The most severe phenotype, MNS, is characterized by a skeletal dysplasia in the heterozygote. Affected males exhibit severe malformations similar to those observed in individuals with OPD2, resulting in prenatal lethality or death in the first few months of life (review by Robertson, 2005). Verloes et al. (2000) suggested that these disorders constitute a single entity, which they termed 'frontootopalatodigital osteodysplasia.'

Genetic Heterogeneity of Frontometaphyseal Dysplasia

Frontometaphyseal dysplasia-2 (FMD2; 617137) is caused by mutation in the MAP3K7 gene (602614) on chromosome 6q15.

Clinical Features

Gorlin and Cohen (1969) described a male patient with extraordinarily marked frontal hyperostosis giving great prominence to the supraciliary ridges, underdeveloped mandible, cryptorchidism, subluxated radial heads, and metaphyseal dysplasia resembling that in Pyle disease (metaphyseal dysplasia). This may be the disorder present in the case described by Walker (1969). Striking overgrowth of bone in the superciliary region was repaired by removal of excess bone.

Holt et al. (1972) reported 2 unrelated patients. Danks et al. (1972) studied an isolated case in which progressive contracture of the fingers and lysis and fusion of carpal bones were features. The patient had progressive osteosclerosis also. Fibroblasts showed metachromasia. All 3 patients were males.

Weiss et al. (1976) observed the disorder in a black male whose mother had the same disorder. The thumbs in the son were strikingly broad. 'Metaphyseal' is a misnomer since striking diaphyseal changes with lack of molding of the shafts of the long bones are found.

Kassner et al. (1976) reported an affected 8-year-old whose mother was thought to have mild metaphyseal dysplasia and several minor skeletal abnormalities that have occurred in patients with the syndrome; they also described the disorder in maternal half brothers.

Medlar and Crawford (1978) described an affected male who presented with scoliosis and had 2 of 3 sibs with significant scoliosis and similar facial abnormalities.

Ullrich et al. (1979) reported the radiographic findings in a severely affected boy and his mildly affected mother.

Abuelo and Ehrlich (1981) described a typically affected male whose mother showed no evidence of the disorder in her facial features. However, x-rays revealed marked hyperostosis of the mandible, scoliosis, and other abnormalities.

Gorlin and Winter (1980) pointed out that dorsiflexion of the wrists and extension of the elbows are reduced, with very limited pronation and supination. Flexion deformities of the fingers and ulnar deviation of the wrists are progressive. Missing permanent teeth and retained deciduous teeth have been noted in most patients.

Beighton and Hamersma (1980) raised the question of whether osteodysplasty of Melnick and Needles is the same as frontometaphyseal dysplasia. They suggested that the disorder in males may be labeled frontometaphyseal dysplasia and that in females called osteodysplasty.

Fitzsimmons et al. (1982) reported 4 cases in 1 family: grandmother, mother, son and daughter. The male had obstructive uropathy at birth; the authors found reports of associated renal abnormalities in 3 other males. The male also had severe congenital stridor from subglottic stenosis and a tracheal web. Both children had recurrent respiratory tract infections.

Superti-Furga and Gimelli (1987) reexamined the patient reported as having FMD by Danks et al. (1972) and concluded that the findings were consistent with the diagnosis of otopalatodigital syndrome. A review of 10 male subjects with frontometaphyseal dysplasia and 13 male subjects with the OPD syndrome from the literature revealed substantial phenotypic overlap between the 2 disorders, which share an X-linked inheritance pattern. They suggested that these may be the same disorder.

On the basis of experience with 2 newborn sons of an affected mother, Glass and Rosenbaum (1995) commented on the difficulties in diagnosing FMD in the neonatal period. In both boys, bone density was generally increased, but most markedly so in the skull base. The coronal skull sutures were partially fused. The metaphyses of all the long bones were flared. As in the mother, the ribs were unusually shaped and there was an anterior bony spur from the mandible. Both boys died neonatally of severe congenital heart disease.

Franceschini et al. (1997) described a male infant in whom frontometaphyseal dysplasia was complicated by esophageal atresia with distal tracheoesophageal fistula. In a review of the literature they noted that malformation of the bronchial tree, respiratory distress and wheezing, narrowing of the subglottic area, and subglottic stenosis with anterior web had been reported in individual cases previously.

Morava et al. (2003) described 2 families in which both males and females showed the facial and skeletal characteristics of FMD in association with severe progressive scoliosis. Some also had hearing loss and urogenital anomalies, leading Morava et al. (2003) to suggest that these were examples of frontootopalatodigital osteodysplasia as described by Verloes et al. (2000).

Inheritance

Gorlin and Winter (1980) marshalled evidence for X-linked inheritance with severe manifestations in males and variable manifestations in females.

Molecular Genetics

Robertson et al. (2003) demonstrated gain-of-function mutations in the filamin A gene in patients with frontometaphyseal dysplasia; see, e.g., 300017.0011 (D1159A) and 300017.0015 (S1186L).

Giuliano et al. (2005) identified the S1186L mutation in the FLNA gene in affected members of a 3-generation family with FMD.

Robertson et al. (2006) performed clinical and molecular analysis of 23 unrelated probands with FMD. No mutation in the FLNA gene was identified in 10 of the 23 patients (43%), suggesting genetic heterogeneity.

Associations Pending Confirmation

See 605101.0001 for discussion of a possible assotiation between FMD and variation in the TAB2 gene.