Lipodystrophic Laminopathies: From Dunnigan Disease to Progeroid Syndromes

Abstract

Lipodystrophic laminopathies are a group of ultra-rare disorders characterised by the presence of pathogenic variants in the same gene (LMNA) and other related genes, along with an impaired adipose tissue pattern and other features that are specific of each of these disorders. The most fascinating traits include their complex genotype-phenotype associations and clinical heterogeneity, ranging from Dunnigan disease, in which the most relevant feature is precisely adipose tissue dysfunction and lipodystrophy, to the other laminopathies affecting adipose tissue, which are also characterised by the presence of signs of premature ageing (Hutchinson Gilford-progeria syndrome, LMNA-atypical progeroid syndrome, mandibuloacral dysplasia types A and B, Nestor-Guillermo progeria syndrome, LMNA-associated cardiocutaneous progeria). This raises several questions when it comes to understanding how variants in the same gene can lead to similar adipose tissue disturbances and, at the same time, to such heterogeneous phenotypes and variable degrees of metabolic abnormalities. The present review aims to gather the molecular basis of adipose tissue impairment in lipodystrophic laminopathies, their main clinical aspects and recent therapeutic strategies. In addition, it also summarises the key aspects for their differential diagnosis.

Keywords: Dunnigan disease; FPLD; Hutchinson-Gilford progeria syndrome; Nestor-Guillermo progeria syndrome; adipose tissue; atypical progeroid syndrome; laminopathies; lipodystrophy; mandibuloacral dysplasia; progeria.

Figure 1

Phenotypic features of patients with lipodystrophic laminopathies. (A) 48-year-old woman with Dunnigan disease and classic phenotype due to the p.(Arg482Trp) variant in exon 8 of the LMNA gene (FPLD2 #1); (B) 62-year-old woman with Dunnigan disease and atypical phenotype due to the p.(Thr528Met) variant in exon 9 of the LMNA gene (FPLD2 #2); (C) Classic FPLD2 is usually characterised by the accumulation of fat in the face and neck, giving a Cushingoid appearance; (D) Signs of insulin resistance such as acanthosis nigricans are common features in FPLD2; (E) The presence of subcutaneous lipomas and a concordant phenotype can guide the diagnosis in patients with FPLD2, as is the case of this subject, who developed lipomas within 3 months of follow-up; (F) 7-year-old boy with Hutchinson-Gilford progeria syndrome diagnosed at birth due to the 1822G > A, p.(G608S) variant in the LMNA gene (HGPS #1), showing the following phenotypical characteristics: generalised lipodystrophy, generalised alopecia, leucomelanodermal macules affecting the entire body, prominent cranial venous tree (H), bulging eyes due to the absence of retroorbital fat, small and sharp nose, small ears of normal implantation, dental malposition and absence of teeth, micrognathia and nasal voice. He presented a distended abdomen, with a reducible umbilical hernia and no hepatosplenomegaly. He showed marked veins in the lower limbs. Apparently normal clavicles, nail dysplasia and coxa valga could also be observed. Regarding comorbidities, he presented recurrent infections, bronchial asthma, subclinical hypothyroidism, myopia and, at the age of 5, he was hospitalised due to an occlusive dissection of the left internal carotid artery; (G) 16-year-old woman with Hutchinson-Gilford progeria syndrome diagnosed at birth due to the c.1824C > T, p.(G608G) variant in the LMNA gene (HGPS #2), showing the following phenotypical characteristics: generalised lipodystrophy, cutaneous sclerosis, generalised alopecia, small and sharp nose, small mouth with dental crowding and micrognathia (I). She presented apparently normal clavicles, dysplastic nails, joint stiffness and coxa valga. Regarding comorbidities, she only showed mild aortic insufficiency. However, at the age of 16 she presented an acute myocardial infarction; (K) 17-year-old man with LMNA-atypical progeroid syndrome diagnosed at 6 months of age due to the heterozygous c.29C > T, p.(Thr10Ile) variant in the LMNA gene, showing the following phenotypic characteristics: generalised lipodystrophy affecting palms and soles (J,L), with thin skin, leucomelanodermal macular lesions (M) and a progeroid facies with proptotic eyeballs as a consequence of the probable absence of retro-orbital fat, a pointed nasal pyramid, high-pitched voice and slight crowding of teeth. Hepatomegaly and splenomegaly were palpable. He had joint contractures affecting the upper and lower limbs and metatarsophalangeal stiffness. He presented pseudodislocation of the ankle joint which conditions talus-valgus feet. There was no resorption of the distal phalanges and he had normal nails. He had mild scoliosis, normal clavicles and no mandibular hypoplasia. He presented phlebomegaly in the limbs (L). Regarding comorbidities, he was diagnosed with diabetes mellitus, hypertriglyceridaemia, dilated cardiomyopathy with moderate pulmonary hypertension, for which he underwent a heart transplant, and he developed central nervous system lymphoma following the immunosuppressive therapy received. The images included here are of patients from our Lipodystrophy Unit (UETeM reference centre) and have not previously been published elsewhere.

Figure 2

Body composition determined by Dual-Energy X-Ray Absorptiometry of patients with lipodystrophic laminopathies and a non-lipodystrophic subject. Colour mapped, total body composition scans via whole-body Dual-Energy X-Ray Absorptiometry of (A) a 42-year-old non-lypodystrophic woman, showing normal fat distribution; (B) a 48-year-old woman with classical FPLD2 (FPLD2 #1) and loss of fat in the upper and lower limbs and its accumulation in the face, neck and pubic area; (C) a 62-year-old woman with atypical FPLD2 (FPLD2 #2) showing loss of fat in the upper and lower limbs and less accumulation in the face and neck; (D) a 7-year-old boy with Hutchinson-Gilford progeria syndrome (HGPS #1), presenting with severe generalised lipodystrophy, including palms and soles as well as muscle atrophy; (E) a 16-year-old woman with Hutchinson-Gilford progeria syndrome (HGPS #2), presenting with severe generalised lipodystrophy, including palms and soles, and muscle atrophy; (F) a 17-year-old man with LMNA-atypical progeroid syndrome, showing generalised lipodystrophy, with preserved adipose tissue in the palms, loss of fat in the soles and muscle mass atrophy. Green represents an area of low level % fat (0–25%), yellow an area of medium level % fat (25–60%), and red an area of high level % fat (60–100%). These are original data from patients of our Lipodystrophy Unit (UETeM reference centre) and have not previously been published elsewhere. FPLD2: familial partial lipodystrophy type 2; HGPS: Hutchinson-Gilford progeria syndrome; APS: LMNA-atypical progeroid syndrome; BMI: body mass index; FM: fat mass; FFM: fat-free mass.