Homozygous and Heterozygous Nuclear Lamin A p.R582C Mutation: Different Lipodystrophic Phenotypes in the Same Kindred

Abstract

Background: Dunnigan-type familial partial lipodystrophy (FPLD2) is a rare autosomal dominant disease caused by heterozygous mutations in the LMNA gene that results in regional loss of subcutaneous adipose tissue with onset in puberty. However, a generalized lipodystrophy phenotype has also been associated with heterozygous mutations in this gene, demonstrating the noticeable phenotypic heterogeneity of this disease. Methods: We report and describe clinical and metabolic features of four patients from the same family with the p.R582C LMNA mutation, three homozygous and one in the heterozygous state that present with three distinct lipodystrophic phenotypes. Results: Case description: The proband was a 12-year-old girl who developed severe subcutaneous fat atrophy in limbs and abdomen followed by a remarkable dorsocervical fat accumulation in adulthood along with diabetes at age 23. The proband's sister was a phenotypically normal girl who developed hypertriglyceridemia at age 8, progressive features of partial lipodystrophy at age 11, and diabetes at age 22. The proband's mother was first examined at age 32, presenting diabetes and a severe generalized lipodystrophic phenotype; she developed kidney failure at age 41 and died due to diabetic complications. The proband's father was a 50-year-old man with abdominal fat concentration that was initially considered phenotypically normal. Massively parallel sequencing using a platform of genes related to genetic lipodystrophies, followed by Sanger sequencing, revealed the transversion c.1744C>T at exon 11 of the LMNA gene (p.R582C) in the homozygous (mother and daughters) and heterozygous (father) states. Conclusion: We documented three distinct phenotypes of the homozygous and heterozygous p. R582C LMNA mutation in the same kindred, illustrating that FPLD2 linked to mutations in this gene is a disease of great clinical heterogeneity, possibly due to associated environmental or genetic factors.

Keywords: Dunnigan; FPLD2; LMNA; generalized lipodystrophy; partial lipodystrophy; phenotypic heterogen.

Figure 1

Patient 1 (proband) with familial partial lipodystrophy bearing the homozygous p.R582C lamin A mutation at (a,b) age 12 with decompensated hypothyroidism. (c) One year after levothyroxine treatment. Adulthood (d) acanthosis nigricans, (e,f) fat accumulation in the neck and dorsocervical region, and (g,h) loss of subcutaneous tissue in the limbs and abdomen. Morphea hypochromic cutaneous lesions can be seen in the abdomen and trunk.

Figure 2

Patient 2 (proband's sister) with familial partial lipodystrophy bearing the homozygous p.R582C lamin A mutation in adulthood showing loss of subcutaneous tissue in limbs and abdomen, fat accumulation in neck and dorsocervical region, and notable acanthosis nigricans.

Figure 3

Patient 3 (proband's mother) bearing the homozygous p.R582C lamin A mutation (a,b) at age 32 showing a phenotype of apparently generalized lipodystrophy without fat accumulation in the neck and face and without acanthosis nigricans. (c) Mother and daughters (from L–R: patients 1, 3, and 2) at ages 19, 32, and 15 years old (L–R).

Figure 4

Proband's father bearing the heterozygous p.R582C lamin A mutation at age 50 and showing a subtle decrease in subcutaneous fat in the limbs and fat accumulation in the abdomen, without fat accumulation in the neck.

Figure 5

Pedigree of the family with lipodystrophy due to the p.R582C lamin A mutation.

Figure 6

T1-weighted magnetic resonance imaging of the (1) homozygous proband's sister and (2) the heterozygous father at the levels of (a) orbits and scalp, (b) anterior neck, (c) dorsocervical, (d) thoracolumbar spine, (e) abdomen, (f) pelvis and thighs, (g) knees, and (h) feet. It is worth noting that the sister and father's body mass indices are 20.7 and 24.9 kg/m², respectively. Note the diffuse absence in subcutaneous tissue of the homozygous proband's sister (indicated by the arrows in a,d–h) and excess fat deposition in the neck and dorsocervical area (indicated by the arrows in b,c).