Lipodystrophy with mandibulo-acral dysplasia E88.10

Lipodystrophy with mandibuloacral dysplasia, or MAD, is a rare autosomal recessive systemic disorder occurring in several ethnic groups and characterized by growth retardation, craniofacial anomalies with mandibular hypoplasia, skeletal abnormalities with progressive osteolysis of the distal phalanges and clavicles, pigmentary abnormalities of the skin, and adipose tissue loss in the extremities (+face and trunk in MADB). Some patients present with progeria-like symptoms. Additional metabolic complications may occur due to insulin resistance and diabetes mellitus (Young et al. 1971; Garavelli et al. 2009).

Due to different genotypes and largely identical phenotypes, lipodystrophy with mandibulo-acral dysplasia is classified into 2 clinical pictures:

• Lipodystrophy with mandibulo-acral dysplasia type A: Mutations in the laminin A gene (LMNA; chromosome 1q22), which codes for laminin A, have been shown.
• Lipodystrophy with mandibulo-acral dysplasia type B: Mutations in the zinc metalloprotease gene (ZMPSTE24; chromosome 1p34.2) coding for a zinc metalloprotease have been detected.

Novelli et al (2002) detected a homozygous mutation in the laminin A gene (LMNA gene). In a patient with a MADA-like phenotype but without clavicle hypoplasia or metabolic disorders, Lombardi et al (2007) found a heterozygous mutation for missense mutations in the LMNA gene.

Lombardi et al (2008) found significantly higher levels (about 4.7-fold) of the active enzyme forms of MMP9 (120361) in the serum of 5 patients with MADA. The results suggest a pathogenic role of MMP9 in the skeletal manifestations of the disease.

In a woman with MAD and generalized lipodystrophy, Agarwal et al (2003) detected mutations in the ZMPSTE24 gene. The unaffected parents and 2 unaffected siblings of the patients were heterozygous for one of the two mutations each.

Miyoshi et al. (2008) identified heterozygous mutations in the ZMPSTE24 gene in 2 Japanese sisters with severe MAD (606480.0004 and 606480.0005).

Young et al (1971) described 2 boys with a hypoplastic mandible resulting in acroosteolysis, joint dysplasia, atrophy of the skin over the hands and feet, and hypoplastic clavicles. Furthermore, persistent wide cranial sutures were noted. Diffuse alopecia and short stature were other features of the progeria-like syndrome.

Cutler et al (1991) described 2 patients with extreme insulin resistance and marked hypermetabolism later published as Werner syndrome (Cohen et al, 1973). Hearing loss was present in all 3 patients.

Cogulu et al (2003) described a 13-year-old girl with mandibuloacral dysplasia who had no breast development, although pubic and axillary hair were normal. Menarche began at 10 years, normal menstrual cycles. Evidence of insulin resistance was present.

Afifi and El-Bassyouni (2005) discussed the differential diagnosis of MAD and noted phenotypic overlap with several disorders, including HGPS, Werner syndrome, Gottron acrogeria, Hallermann-Streiff syndrome (234100), and Hajdu-Cheney syndrome.

Lombardi et al (2007) identified a patient with an apparent MADA phenotype without clavicular hypoplasia or metabolic abnormalities. Furthermore, there was a hypoplastic mandible, acroosteolysis, pointed nose, partial loss of subcutaneous adipose tissue, and a progeria-like appearance.

Kosho et al. (2007) reported a 56-year-old Japanese woman, born to consanguineous parents, with MAD and type A lipodystrophy.

Garavelli et al. (2009) reported 2 unrelated patients with childhood onset MADA features. Furthermore, osseous facial dysplasia with protruding cheeks, mild micrognathia, overbite, and type A lipodystrophy were detectable, combined with acral fat loss in the shoulder region.

Mutations in the LMANA gene cause several different diseases including familial partial lipodystrophy type 2 (OMIM 151660), a disorder characterized by subcutaneous fat loss and invariably associated with insulin resistance and diabetes.

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