Unusual clinical features associated with congenital generalized lipodystrophy type 4 in a patient with a novel E211X CAVIN1 gene variant

Abstract

Background: Congenital generalized lipodystrophy (CGL) is a rare disorder characterized by the lack of adipose tissue and metabolic complications with predominantly autosomal recessive inheritance. There are 6 different genes known to cause CGL with 4 main types recognized to date, which differ by the degree of fat loss, association with mental retardation and metabolic disorders, with CGL type 1 and 2 being the most common. Twenty seven cases of СGL type 4 from Japan, Oman, UK, Turkey, Mexico, Saudi Arabia, USA were reported previously. This report details our clinical experience with the first patient from Russia with CGL type 4. Case presentation: A 36-year-old patient, who has been suffering from generalized lipoatrophy since the first months of life and myopathy and gastrointestinal dysmotility since early childhood, developed dysmenorrhea and diabetes mellitus at the age of 19, bilateral cataracts when she was only 22 y.o., osteoporosis with vitamin D deficiency and hypocalcemia at the age of 28, diabetic foot syndrome and hyperuricemia when she was 35 y.o. Sequencing of lipodystrophy candidate genes detected a novel pathogenic homozygous variant p.631G < T: p.E211X in the CAVIN1 gene, confirming the diagnosis of CGL type 4. Conclusions: In comparison with previously reported patients with CGL type 4, our patient has diabetes mellitus, vitamin D deficiency, hypocalcemia, bilateral cataracts and hyperuricemia. All these manifestations are known to be associated with other lipodystrophy syndromes, but to our knowledge it is the first time they have been reported to be associated with CGL type 4.

Metabolic and other morbid complications in congenital generalized lipodystrophy type 4

“…Only two patients were older than 35 years. One patient, whose initial presentation was previously reported by Sorkina et al (2020) developed diabetes at the age 19, had multiple surgeries for dolichosigmoid, perforation of diverticula and peritonitis between the ages of 17 and 20, and then developed foot ulcers on the right lower extremity at 35 years of age. Her condition deteriorated significantly after being affected by a severe COVID‐19 infection that required a month‐long stay in the intensive care unit.…”

“…At age 16, she developed sepsis and died due to multiorgan dysfunction (Gunes et al, 2020). Patient 14 died at age 39 due to nonhealing diabetic foot ulcers complicated with decubitus ulcers and sepsis as described above (Sorkina et al, 2020).…”

“…The protocol was further reviewed at individual centers as necessary. Clinical and laboratory data on some patients have been published previously and we report follow-up information on these patients (Acar et al, 2022;Adiyaman et al, 2022;Akinci et al, 2016Akinci et al, , 2017Babalola et al, 2022;Gunes et al, 2020;Mancioppi et al, 2023;Patni et al, 2019;Shastry et al, 2010;Sorkina et al, 2020) Hypertriglyceridemia was defined as serum triglyceride level 150 mg/ dL or higher. Low HDL cholesterol was defined as <40 mg/dL for men and <50 mg/dL for women.…”

“…A few patients have reportedly died of cardiac disease, mainly due to the development of ventricular arrhythmias but not congestive heart failure (Akinci et al, 2016; Patni et al, 2019; Rajab et al, 2010). While congenital pyloric stenosis requiring early surgery has been reported in some patients, other gastrointestinal complications are not well recognized (Akinci et al, 2016; Gunes et al, 2020; Munoz et al, 2019; Shastry et al, 2010; Sorkina et al, 2020).…”

Analysis of disease characteristics of a large patient cohort with congenital generalized lipodystrophy from the Middle East and North Africa

“…Generalized fat loss in CGL typically occurs at birth or soon thereafter, leading to diagnosis in infancy for some cases as supported here and by earlier work [ 2 , 17 , 26 , 34 ]. However, some patients do not receive a definitive diagnosis of CGL until puberty or adulthood by which stage severe metabolic disease may have developed [ 11 , 17 , 26 , 39 – 41 ]. In the MENA cohort, 19% of patients were diagnosed ≥ 12 years of age.…”