A number sign (#) is used with this entry because of evidence that metaphyseal dysplasia and maxillary hypoplasia with or without brachydactyly (MDMHB) is caused by heterozygous duplication resulting in a gain of function in the RUNX2 gene (600211) on chromosome 6p21.

Heterozygous loss-of-function mutation in the RUNX2 gene results in cleidocranial dysplasia (CCD; 119600).

Metaphyseal dysplasia and maxillary hypoplasia with or without brachydactyly (MDMHB) is an autosomal dominant bone dysplasia characterized by metaphyseal flaring of long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, variable brachydactyly, and dystrophic teeth (summary by Moffatt et al., 2013).

Halal et al. (1982) reported a characteristic syndrome in 4 generations of a French Canadian family. The features were metaphyseal dysplasia with short stature (about 152 cm in both sexes); beaked nose, short philtrum, thin lips, maxillary hypoplasia, 'dystrophic' yellowish teeth with early loss and short metacarpal 5 and/or short middle phalanx of fingers 2 and 5. Skeletal roentgenograms in adults showed 'massive enlargement of the sternal ends of the clavicles; flaring of the metaphyses with thin cortex and osteoporosis most striking in the proximal humerus, distal femur and proximal tibia; platyspondyly, multiple small vertebral fractures, and osteoporosis of the vertebrae.' Male-to-male transmission was observed in 2 instances. Similarities to oculodentodigital dysplasia (164200) were noted, but important differences, particularly lack of ocular manifestations, in this syndrome speak for its distinctness.

Moffatt et al. (2013) studied a 4-generation French Canadian family that was from the same region of Quebec (Gaspesie) as the family reported by Halal et al. (1982) and had a very similar phenotype. Histomorphometric analysis of transiliac bone biopsy samples showed thin cortices and a low amount of trabecular bone. Mineral apposition rate, a marker of bone formation, was low, suggesting a defect in osteoblast function, whereas osteoclast surface, a marker of bone resorption, was normal. Biochemical parameters of bone and mineral metabolism were mostly within normal limits. Lumbar spine bone mineral density was low in some affected individuals but normal in others; however, peripheral quantitative CT of the radius showed that cortices were very thin at both the metaphysis and the diaphysis. In affected individuals, osteocyte density was 32% lower than that of age-matched controls, although the material density of trabecular bone was slightly increased compared to controls. Moffatt et al. (2013) noted that brachydactyly, which was an inconsistent feature in the family described by Halal et al. (1982), was not observed in affected individuals from this family.

Avela et al. (2014) described a 20-year-old Finnish patient with clinical and radiologic findings of MDMHB. The patient had a normal birth length, but by age 20 years, her height was at the 3rd centile. She had frequent bone pain, especially affecting her knees. Facial features included micrognathia, beaked nose, and thin lips. Radiographs showed a thick cranial vault, bilateral brachydactyly, metaphyseal flaring at multiple locations, widened clavicles, and irregularly shaped vertebrae. Bones were osteoporotic based on radiographs and bone densitometry. Teeth were small and fragile. Primary tooth resorption was deficient, requiring extraction, and eruption of permanent teeth was delayed. No teeth were missing congenitally. The patient also had a hypoplastic maxilla and retrognathic mandible. Her mother, who had short stature (155 cm at age 46 years), had no brachydactyly on clinical exam, but had oligodontia with 5 congenitally missing teeth. Teeth were small with browning enamel and short roots. She had a progenic mandible and retrusive maxilla. Both mother and daughter had normal psychomotor development.

Al-Yassin et al. (2018) reported 3 affected female members of a 3-generation family with MDMHB. The proband, her mother, and her maternal grandmother were short, with heights at the 0.4th, 9th, and 2nd centile, respectively. All 3 had dystrophic yellowish teeth, maxillary hypoplasia, metaphyseal dysplasia, and clavicular broadening. Two patients had delayed closure of the anterior fontanel, and 1 had osteoporosis and brachydactyly Al-Yassin et al. (2018) emphasized the importance of considering an underlying skeletal dysplasia in patients with significant dental problems and other suggestive features, including disproportionate short stature and digital anomalies.

The transmission pattern of MDMHB in the family reported by Moffatt et al. (2013) was consistent with autosomal dominant inheritance.

Using DNA from 5 affected and 4 unaffected members of a 4-generation French Canadian family segregating autosomal dominant metaphyseal dysplasia and maxillary hypoplasia with or without brachydactyly (MDMHB), Moffatt et al. (2013) performed whole-genome SNP genotyping and obtained the maximum achievable lod score of 2.1 for regions on chromosomes 6, 11, and 15.

In a 4-generation French Canadian family with MDMHB, Moffatt et al. (2013) analyzed SNP array data for copy number variation and found that all affected individuals had a 105-kb duplication within the linked region on chromosome 6 (chr6:45,308,920-45,413,885, GRCh37), comprising exons 3 to 5 of the RUNX2 gene (600211.0014), that was absent in unaffected family members.

In a 20-year-old Finnish woman with MDMHB, Avela et al. (2014) identified heterozygosity for an intragenic duplication in RUNX2 encompassing exons 3 to 5. Similar to the duplication reported by Moffatt et al. (2013), the duplication breakpoints were in intron 2 and intron 5; the location of the breakpoints differed, but the exact breakpoints in the Finnish patient were not identified.

In 3 affected members of a 3-generation family with MDMHB, Al-Yassin et al. (2018) identified heterozygosity for an intragenic tandem duplication of RUNX2 exons 3-6 (600211.0015). Further analysis showed that exon 3 was spliced to exon 6, confirming a tandem duplication, which was predicted to be in-frame.