Atypical Progeroid Syndrome and Partial Lipodystrophy Due to LMNA Gene p.R349W Mutation

Abstract

Atypical progeroid syndrome (APS) comprises heterogeneous disorders characterized by variable degrees of fat loss, metabolic alterations, and comorbidities that affect skeleton, muscles, and/or the heart. We describe 3 patients that were referred to our center for the suspicion of lipodystrophy. They had precocious aging traits such as short stature, mandibular hypoplasia, beaked nose, and partial alopecia manifesting around 10 to 15 years of age recurrently associated with: (1) partial lipodystrophy; (2) proteinuric nephropathy; (3) heart disease (rhythm disorders, valvular abnormalities, and cardiomyopathy); and (4) sensorineural hearing impairment. In all patients, genetic testing revealed a missense heterozygous lamin A/C gene (LMNA) mutation c.1045 C > T (p.Arg349Trp). Ten patients with LMNA p.R349W mutation have been reported so far, all presenting with similar features, which represent the key pathological hallmarks of this subtype of APS. The associated kidney and cardiac complications occurring in the natural history of the disease may reduce life expectancy. Therefore, in these patients a careful and periodic cardiac and kidney function evaluation is required.

Keywords: LMNA mutation; atypical progeroid syndrome; lipodystrophy.

Figure 1.

Phenotypic characteristics of patients with heterozygous LMNA p.R349W mutation. All patients show partial lipodystrophy involving mostly the face and the extremities and progeroid appearance: beaked nose, skin atrophy, thin lips, and mandibular hypoplasia. (A) Anterior and lateral view of patient 1, a 46-year-old woman. (B) Anterior and lateral view of patient 2, a 14-year-old boy. (C) Anterior and lateral view of patient 3, a 37-year-old man. LMNA, lamin A/C gene.

Figure 2.

Cardiac magnetic resonance imaging of patient 3. At late gadolinium enhancement, the patient presented a subendocardial scar (arrows) involving the (A) basal, (B) mid, and (C) apical segments of the anterior and anterolateral walls of the left ventricle. His previous coronary angiography had shown 3-vessel atherosclerosis, with multiple calcified plaques not hemodynamically significant.