Craniometaphyseal Dysplasia, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive craniometaphyseal dysplasia (CMDR) is caused by homozygous mutation in the GJA1 gene (121014) on chromosome 6q22.

Description

Craniometaphyseal dysplasia is an osteochondrodysplasia characterized by hyperostosis and sclerosis of the craniofacial bones associated with abnormal modeling of the metaphyses. Sclerosis of the skull may lead to asymmetry of the mandible, as well as to cranial nerve compression, that may finally result in hearing loss and facial palsy (summary by Nurnberg et al., 1997).

The delineation of separate autosomal dominant (CMDD; 123000) and autosomal recessive forms of CMD by Gorlin et al. (1969) was confirmed by reports that made it evident that the dominant form is relatively mild and comparatively common, whereas the recessive form is rare, severe, and possibly heterogeneous.

Clinical Features

Case 4 of Jackson et al. (1954) was blind from optic atrophy at 15 months.

Reardon et al. (1991) reported a brother and sister with identical facies consisting of prominent supraorbital ridges and hypertelorism, with prominent mandible giving the face a square profile; bilateral mixed hearing loss; mental retardation; and radiologic changes in the skeleton involving the metaphyses and the ribs, which were widened.

Elcioglu and Hall (1998) illustrated and discussed the changes in a patient with autosomal recessive craniometaphyseal dysplasia followed from infancy to the age of 17 years.

Iughetti et al. (2000) reported a 4-generation consanguineous Brazilian family in which 10 individuals were affected with autosomal recessive craniometaphyseal dysplasia. They suggested that the diaphyseal involvement in the recessive form is more severe than that in the dominant form. The family also segregated another disorder, autosomal recessive spondylocostal dysplasia (277300). One affected individual had both disorders.

Hu et al. (2013) restudied the family with CMDR reported by Iughetti et al. (2000), noting that affected individuals showed relatively mild symptoms, with nasal flattening and hypertelorism. Three-dimensional CT and radiography showed sclerosis of the cranial vault and cranial base. Facial bones were hyperostotic. Affected members displayed diaphyseal hyperostosis in limb bones with mild metaphyseal widening. Hu et al. (2013) also described a 3-year-old boy from a consanguineous Indian family who was referred for evaluation of left-sided epiphora and dysmorphic facial features. He had relative macrocephaly, hypertelorism, an unusual thick bony wedge over the bridge of the nose, and a depressed and flattened nasal bridge. The ophthalmologic examination revealed secondary nasolacrimal duct obstruction bilaterally. Skull x-rays showed significant sclerosis of the skull base, and 3D MRI of the paranasal sinuses and orbits showed bilateral dense sclerotic thickening in parietal, occipital, and ethmoid bones as well as in the frontal process of maxillary and zygomatic bones. Serum calcium, phosphorus, and alkaline phosphatase levels were normal. Hu et al. (2013) stated that all affected individuals had difficulty breathing, probably due to hyperostosis, but none showed loss of vision or hearing loss.

Inheritance

Affected sibs were described by Millard et al. (1967) and by Lehmann (1957) and parental consanguinity was recorded by Lievre and Fischgold (1956). Penchaszadeh et al. (1980) reported 2 families, each with 2 affected sibs.

Iughetti et al. (2000) reported that all 10 affected members of a 4-generation Brazilian family with CMD were born to consanguineous healthy parents; this finding, together with the equal sex ratio among affected individuals and the occurrence of only normal individuals among their offspring, indicated that the disease in this family was an autosomal recessive trait.

Cytogenetics

Yamada et al. (1987) described a sporadic case of CMD in a female child with a translocation t(12;18)(q13;q12). Nurnberg et al. (1997) stated that the severity of the clinical manifestations in this child suggested the autosomal recessive form of the disorder.

Mapping

Through genomewide scanning, Iughetti et al. (2000) mapped the locus for autosomal recessive CMD in a Brazilian family to a 7-cM interval at 6q21-q22. They excluded COL10A1 (120110) as a candidate gene.

Molecular Genetics

By exome sequencing in the proband from a consanguineous Portuguese family with craniometaphyseal dysplasia, Hu et al. (2013) identified homozygosity for a missense mutation in the GJA1 gene (R239Q; 121014.0021) that segregated with disease in the family and was not found in the dbSNP, HGMD, 1000 Genomes Project, or NHLBI Exome Sequencing Project databases. They identified homozygosity for the same variant in affected individuals from the Brazilian family reported by Iughetti et al. (2000), in the proband from an Indian CMD family, and in a sporadic Brazilian CMD patient.