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Mandibuloacral dysplasia

Orpha number ORPHA2457
Synonym(s) MAD
Prevalence <1 / 1 000 000
Inheritance
  • Autosomal recessive
Age of onset Neonatal/infancy
ICD-10
  • Q87.5
OMIM
UMLS -
MeSH -
MedDRA -
SNOMED CT
  • 109419009

Summary

Mandibuloacral dysplasia is characterized by postnatal growth retardation (late closure of the fontanelles), craniofacial anomalies and skeletal malformations, such as mandibular and clavicular hypoplasia (conferring an appearance of a receding chin and slopping shoulders), and mottled cutaneous pigmentation. Dental anomalies, acroosteolysis, joint rigidity and small stature have also been reported. They can be associated with adipose tissue loss in the limbs and sometimes with premature ageing (progeria), characterized by thin skin, sparse hair and ungual dysplasia. Two clinical forms differing in the extent of lipoatrophy have been described: type A in which partial lipoatrophy is predominant in the limbs and type B defined by a more generalized lipoatrophy. Mandibuloacral dysplasia is a very rare autosomal recessive disorder. Two types of genetic anomalies are responsible for this syndrome: homozygous missense mutations (Arg527His and Ala529Val) in the LMNA gene and compound heterozygous mutations in the ZMPSTE24 gene, coding for an endoprotease involved in lamin A maturation. Other loci are likely to be involved. Lamin is a nuclear envelope protein, but its exact role is unclear. It may interact with chromatin and an adipocyte differentiation factor. Conditions linked to mutations in the lamin A/C gene have a very heterogeneous phenotype and include partial lipoatrophy, muscular and cardiac dystrophies (Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy (LGMD 1B), nonobstructive cardiomyopathies (CMD 1A), Charcot-Marie-Tooth neuropathies, dermatological syndromes, acromandibular dysplasias and premature ageing syndromes (Hutchinson-Gilford progeria; see these terms). The three latter syndromes are accompanied by lipoatrophic features. Antenatal diagnosis can theoretically be performed, but it does not seem justified in view of the wide phenotypic heterogeneity of these affections. However, an early diagnosis allows detection and treatment of a metabolic syndrome potentially associated with the lipoatrophy. Treatment of the metabolic manifestations should follow the same guidelines as those used for other forms of insulin resistance: physical exercise, insulin-sensitising medication (metformin or glitazones) and insulin (or preferably insulin analogues). Clinical trails have shown that leptin is effective for the treatment of certain forms of lipodystrophy, but this treatment has not been tested for mandibuloacral dysplasia. The risk of cardiovascular disease is likely to be increased but the long-term prognosis is unknown.

Expert reviewer(s)

  • Dr Marie-Christine VANTYGHEM

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