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Mandibuloacral dysplasia type A-associated progeria caused by homozygous LMNA mutation in a family from Southern China.

ABSTRACT: Mandibuloacral dysplasia type A (MADA) is a rare autosomal recessive disorder, characterized by growth retardation, skeletal abnormality with progressive osteolysis of the distal phalanges and clavicles, craniofacial anomalies with mandibular hypoplasia, lipodystrophy and mottled cutaneous pigmentation. Some patients may show progeroid features. MADA with partial lipodystrophy, more marked acral, can be caused by homozygous or compound heterozygous mutation in the gene encoding lamin A and lamin C (LMNA). MADA and Hutchinson-Gilford progeria syndrome are caused by the same gene and may represent a single disorder with varying degrees of severity. MAD patients characterized by generalized lipodystrophy (type B) affecting the face as well as extremities and severe progressive glomerulopathy present heterozygous compound mutations in the ZMPSTE24 gene.We described a rare pedigree from Southern China, among them all three children presented with phenotypes of MADA associated progeria. The two elder sisters had developed severe mandibular hypoplasia associated progeria since the age of 1 year. The eldest sister showed a progressive osteolysis. The youngest son of 10 months showed severer lesions than those of his sisters at the same age, and presented possible muscle damage, and his symptoms progressed gradually. Three genes mutations including LMNA, ZMPSTE24 and BANF1 were tested in the family. LMNA gene sequencing revealed a homozygous missense mutation, c.1579C > T, p.R527C for all three siblings, and heterozygous mutations for their parents, whereas no mutations of ZMPSTE24 and BANF1 genes was detected among them.The same homozygous mutation of c.1579C > T of LMNA gene led to MADA associated progeria for the present family. The course of osteolysis for MADA is progressive.

SUBMITTER: Luo DQ

PROVIDER: S-EPMC4287574 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Mandibuloacral dysplasia type A-associated progeria caused by homozygous LMNA mutation in a family from Southern China.

Luo Di-Qing DQ Wang Xiao-Zhu XZ Meng Yan Y He Ding-Yang DY Chen Ying-Ming YM Ke Zhi-Yong ZY Yan Ming M Huang Yu Y Chen Da-Fang DF

BMC pediatrics 20141007

<h4>Background</h4>Mandibuloacral dysplasia type A (MADA) is a rare autosomal recessive disorder, characterized by growth retardation, skeletal abnormality with progressive osteolysis of the distal phalanges and clavicles, craniofacial anomalies with mandibular hypoplasia, lipodystrophy and mottled cutaneous pigmentation. Some patients may show progeroid features. MADA with partial lipodystrophy, more marked acral, can be caused by homozygous or compound heterozygous mutation in the gene encodin ...[more]

PMID: 25286833

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Project description:BACKGROUND:Mandibuloacral Dysplasia with type B lipodystrophy (MADB) is a rare premature aging disorder with an autosomal recessive inheritance pattern. MADB is characterized by brittle hair, mottled, atrophic skin, generalized lipodystrophy, insulin resistance, metabolic complications and skeletal features like stunted growth, mandibular and clavicular hypoplasia and acro-osteolysis of the distal phalanges. MADB is caused by reduced activity of the enzyme zinc metalloprotease ZMPSTE24 resulting from compound heterozygous or homozygous mutations in ZMPSTE24. METHODS:In 2012, and again in 2018, eight related patients from the remote tropical rainforest of inland Suriname were analysed for dysmorphic features. DNA analysis was performed and clinical features were documented. We also analysed all previously reported genetically confirmed MADB patients from literature (n =?12) for their clinical features. Based on the features of all cases (n =?20) we defined major criteria as those present in 85-100% of all MADB patients and minor criteria as those present in 70-84% of patients. RESULTS:All the Surinamese patients are of African descent and share the same homozygous c.1196A?>?G, p.(Tyr399Cys) missense variant in the ZMPSTE24 gene, confirming MADB. Major criteria were found to be: short stature, clavicular hypoplasia, delayed closure of cranial sutures, high palate, mandibular hypoplasia, dental crowding, acro-osteolysis of the distal phalanges, hypoplastic nails, brittle and/or sparse hair, mottled pigmentation, atrophic and sclerodermic skin, and calcified skin nodules. Minor criteria were (generalized or partial) lipoatrophy of the extremities, joint contractures and shortened phalanges. Based on our detailed clinical observations, and a review of previously described cases, we propose that the clinical diagnosis of MADB is highly likely if a patient exhibits ?4 major clinical criteria OR???3 major clinical criteria and???2 minor clinical criteria. CONCLUSIONS:We report on eight related Surinamese patients with MADB due to a homozygous founder mutation in ZMPSTE24. In low-income countries laboratory facilities for molecular genetic testing are scarce or lacking. However, because diagnosing MADB is essential for guiding clinical management and for family counselling, we defined clinical diagnostic criteria and suggest management guidelines.

Dataset Information

Mandibuloacral dysplasia type A-associated progeria caused by homozygous LMNA mutation in a family from Southern China.

Publications

Mandibuloacral dysplasia type A-associated progeria caused by homozygous LMNA mutation in a family from Southern China.

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