Mandibuloacral dysplasia type A in childhood

Abstract

Mandibuloacral dysplasia type A (MADA) is characterized by growth retardation, postnatal onset of craniofacial anomalies with mandibular hypoplasia, progressive acral osteolysis, and skin changes including mottled pigmentation, skin atrophy, and lipodystrophy. Owing to its slowly progressive course, the syndrome has been recognized in adults, and pediatric case reports are scarce. We present the clinical case of two children in whom the diagnosis of MADA was made at an unusually early age. A 5-year-old boy presented with ocular proptosis, thin nose, and short and bulbous distal phalanges of fingers. A 4-year-old girl presented with round face and chubby cheeks, thin nose, bulbous fingertips, and type A lipodystrophy. In both, a skeletal survey showed wormian bones, thin clavicles, short distal phalanges of fingers and toes with acro-osteolysis. Both children were found to be homozygous for the recurrent missense mutation, c.1580G>A, (p.R527H) in exon 9 of the LMNA gene. Thus, the phenotype of MADA can be manifest in preschool age; diagnosis may be suggested by short and bulbous fingertips, facial features, and lipodystrophy, supported by the finding of acral osteolysis, and confirmed by mutation analysis.

A novel homozygous p.Arg527Leu LMNA mutation in two unrelated Egyptian families causes overlapping mandibuloacral dysplasia and progeria syndrome

“…The most common genetic cause of MADA is the homozygous p.Arg527His LMNA mutation. 1,3,4 Furthermore, the homozygous p.Arg527Cys LMNA mutation results in early and severe MAD and progeria. 7 According to the computational structure prediction, a basic arginine at position 527 of the wildtype lamin A, forms a salt bridge with the glutamate at position 537, thus stabilizing the structure of the conserved C-terminal IG-like domain of this protein.…”

“…2 The most common mutation reported in patients with MADA is the homozygous p.Arg527His substitution in exon 9 of the LMNA gene. 1,3,4 Other LMNA mutations resulting in MAD are homozygous p.Ala529Val and compound p.Arg527His/Val440Met. 5,6 MAD with progeria-like features was described in relation to the homozygous p.Arg527Cys, homozygous p.Lys542Asn, homozygous p.Arg471Cys, compound p.Thr528Met/Met540Thr, and compound p.Arg471Cys/ Arg527Cys LMNA mutations.…”

Mandibuloacral dysplasia and LMNA A529V mutation in Turkish patients with severe skeletal changes and absent breast development

“…Primers were designed from published sequence information (Garg et al, 2005). PCR was performed as described previously (Garavelli et al, 2009). The amplicons were analyzed by direct sequencing with ABI Prism (Life Technologies, Waltham, Massachusetts, USA).…”

“…Mandibuloacral dysplasia (MAD; MIM 248370) is a rarely encountered autosomal recessive disorder that is involved in progeroid syndromes and laminopathies (Novelli et al, 2002;Jacob and Garg, 2006;Garavelli et al, 2009). MAD is characterized by acroosteolysis (resorption of terminal phalanges), skin changes (hyperpigmentation, skin atrophy), clavicular hypoplasia, craniofascial anomalies such as mandibular hypoplasia with overcrowded teeth, a hook nose, and prominent eyes, along with delayed closures of the cranial sutures (Novelli et al, 2002;Shen et al, 2003;Garavelli et al, 2009).…”

“…MAD is characterized by acroosteolysis (resorption of terminal phalanges), skin changes (hyperpigmentation, skin atrophy), clavicular hypoplasia, craniofascial anomalies such as mandibular hypoplasia with overcrowded teeth, a hook nose, and prominent eyes, along with delayed closures of the cranial sutures (Novelli et al, 2002;Shen et al, 2003;Garavelli et al, 2009). Hypogonadism, delayed puberty, bilateral sensory neural deafness, high-arched palate, alopecia, and cutaneous calsinosis are less commonly encountered (Novelli et al, 2002;Garavelli et al, 2009). MAD patients have a normal physical appearance as well as normal height and weight measurements at birth.…”