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

Di-Qing Luo,Ming Yan,Zhi-Yong Ke,Yan Meng,Da-Fang Chen,Yu Huang,Xiao-Zhu Wang,Ying-Ming Chen,Ding-Yang He

doi:10.1186/1471-2431-14-256

Abstract

BackgroundMandibuloacral 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.Cases presentationsWe 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 1year. 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.ConclusionsThe 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.

Highlights

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
The same homozygous mutation of c.1579C > T of LMNA gene led to MADA associated progeria for the present family
We described a pedigree from Southern China, among them all three siblings presented with phenotype of MAD associated progeria and lipodsystophy, with the same homozygous mutation in LMNA gene mimicking the case reported by Agarwal et al [18], while their parents showed healthy appearance with heterozygous mutations

Summary

Conclusions

The present pedigree showed severe phenotype of MADA associated with progeria syndrome in all of three siblings. The present siblings had the same R527C mutation as Agarwal et al [18] described, but their clinical phenotypes were different, we speculated that such conditions may result from different inherited backgrounds in different populations, and may result from a variable expressivity of LMNA gene in the various cases Both clinical phenotypes and progressions of patient 1 and 2 were similar, but patient 3 had earlier onset (only 8 months old) with more progressive development, and presented atypical symptoms with possibility of muscle damage.

Background

Results