Skeletal phenotype of mandibuloacral dysplasia associated with mutations in ZMPSTE24

Mandibuloacral dysplasia (MAD) is a rare recessively inherited premature aging disease characterized by skeletal and metabolic anomalies. It is part of the spectrum of diseases called laminopathies and results from mutations in genes regulating the synthesis of the nuclear laminar protein, lamin A. Homozygous or compound heterozygous mutations in the LMNA gene, which encodes both the precursor protein prelamin A and lamin C, are the commonest cause of MAD type A. In a few cases of MAD type B, mutations have been identified in the ZMPSTE24 gene encoding a zinc metalloproteinase important in the post-translational modification of lamin A. Here we describe a new case of MAD resulting from compound heterozygote mutations in ZMPSTE24 (p.N256S/p.Y70fs). The patient had typical skeletal changes of MAD, but in addition a number of unusual skeletal features including neonatal tooth eruption, amorphous calcific deposits, submetaphyseal erosions, vertebral beaking, severe cortical osteoporosis and delayed fracture healing. Treatment with conventional doses of pamidronate improved estimated volumetric bone density in the spine but did not arrest cortical bone loss. We reviewed the literature on cases of MAD associated with proven LMNA and ZMPSTE24 mutations and found that the unusual features described above were all substantially more prevalent in patients with mutations in ZMPSTE24 than in those with LMNA mutations. We conclude that MAD associated with ZMPSTE24 mutations has a more severe phenotype than that associated with LMNA mutations—probably reflecting the greater retention of unprocessed farnesylated prelamin A in the nucleus, which is toxic to cells.