Two Decades after Mandibuloacral Dysplasia Discovery: Additional Cases and Comprehensive View of Disease Characteristics

Abstract

Pathogenic variants in the LMNA gene cause a group of heterogeneous genetic disorders, called laminopathies. In particular, homozygous or compound heterozygous variants in LMNA have been associated with "mandibuloacral dysplasia type A" (MADA), an autosomal recessive disorder, characterized by mandibular hypoplasia, growth retardation mainly postnatal, pigmentary skin changes, progressive osteolysis of the distal phalanges and/or clavicles, and partial lipodystrophy. The detailed characteristics of this multisystemic disease have yet to be specified due to its rarity and the limited number of cases described. Here, we report three unrelated Egyptian patients with variable severity of MAD features. Next-generation sequencing using a gene panel revealed a homozygous c.1580G>A-p.Arg527His missense variant in LMNA exon 9 in an affected individual with a typical MADA phenotype. Another homozygous c.1580G>T-p.Arg527Leu variant affecting the same amino acid was identified in two additional patients, who both presented with severe manifestations very early in life. We combined our observations together with data from all MADA cases reported in the literature to get a clearer picture of the phenotypic variability in this disease. This work raises the number of reported MADA families, argues for the presence of the founder effect in Egypt, and strengthens genotype-phenotype correlations.

Keywords: LMNA; acro-osteolysis; genotype–phenotype correlation; lipodystrophy; mandibuloacral dysplasia.

Figure 1

Proband 1 shows an oval-shaped, bird-like face; wide prominent eyes; full cheeks; submental obesity; arched, heavy eyebrows; a narrow, prominent nasal bridge and shallow philtrum (A); a beaked nose and severe mandibular hypoplasia (B); bulbous fingertips and nail dystrophy (C,D); marked bilateral clavicular hypoplasia evident on chest X-ray (E); and marked abdominal obesity and reticular/mottled hyperpigmentation (F).

Figure 2

Proband 2 showing an oval face; wide eyes with periocular hyperpigmentation; arched eyebrows; a short, thin, upturned nose; a small mouth with limited opening (A); submental obesity and microretrognathia (B); narrow, sloping shoulders and prominent scapular wings (C); abnormal facility in opposing shoulders (D); short fingers with drumstick-shaped distal phalanges (E); flexed fingers with atrophic shiny overlying skin; hypopigmentation over the knuckles and broad, short, dystrophic nails (F); and round toe tips, nail dystrophy, and visible veins (G). Chest radiograph demonstrating severely hypoplastic/absent clavicles bilaterally (H).

Figure 3

Proband 3 shows a receding anterior hairline; scanty scalp hair; bulbous cheeks with visible veins; wide eyes with periocular hyperpigmentation; a pointed nose; a small mouth and micrognathia (A); occipital alopecia and prominent scalp veins (B); round-tipped terminal phalanges of fingers (C); atrophic shiny skin on the dorsum of hands and broad, short, dystrophic nails (D); mild rounding of toe tips and broad, short nails (E); hyperpigmented thin skin over knees (F); and hyper- and hypopigmented patches on axilla (G).