E-Poster Presentation 63rd Endocrine Society of Australia Annual Scientific Meeting 2020

We report a mother-daughter pair with clinical features suggestive of familial partial lipodystrophy (FPL). Our case discusses a young woman presenting with metabolic syndrome with a recent history of hypertriglyceridaemia-induced pancreatitis. Her mother has a similar body habitus, metabolic phenotype and recurrent episodes of hypertriglyceridaemia-induced pancreatitis with additional symptoms of a progressive neuromuscular disorder. Maternal genetic testing revealed two novel missense mutations in the PTRF gene of uncertain pathogenic significance. Mutations in the PTRF gene cause congenital generalized lipodystrophy type 4 (CGL4) which is associated with myopathy. There have been no reports of PTRF gene variants associated with FPL. This kindred may present with a novel gene variant causing FPL.

Background

The lipodystrophies are a rare heterogeneous group of disorders characterized by generalized or selective lipoatrophy of adipose tissue. FPL presents with selective loss of subcutaneous fat in the arms and legs with excess subcutaneous fat accumulation in other areas of the body, especially the neck and face resulting in a cushingoid appearance. Lipodystrophy is commonly associated with a variety of metabolic complications including dyslipidaemia, hypertriglyceridaemia, hyperglycaemia, insulin resistance, diabetes mellitus, hepatic steatosis, central adiposity and increased cardiovascular risk [1]. Mild to moderate myopathies, cardiomyopathies and conduction system abnormalities indicative of a multisystem dystrophy can occur in FPL.

Several genes are associated with FPL with five subtypes identified. In subtypes 2-5 the causative gene is known, however, the variant in FPL1 remains unknown and many novel FPL genes remain to be discovered [2,3,4].

The PTRF (polymerase I and transcript release factor) gene encodes cavin-1. Cavin-1 is a highly abundant caveolae component and is suggested to play an essential role in caveolar formation. Caveolae are involved in several important cellular processes, including clathrin-independent endocytosis, regulation and transport of cellular cholesterol and signal transduction. Mice lacking PTRF do not have morphologically detectable caveolae and mimic lipodystrophy in humans with considerably reduced adipose tissue mass, high triglyceride levels, glucose intolerance and hyperinsulinaemia [2,3,4,5,6].

Homozygous variants in PTRF have recently been found to cause CGL4, an autosomal recessive form of congenital generalised lipodystrophy. CGL4 is characterised by generalised absence of adipose tissue and is associated with hypertriglyceridaemia and diabetes mellitus. Characteristic to this type of lipodystrophy is myokymia, muscle weakness and raised CK. Secondary features include cardiac arrhythmias, skeletal abnormalities, atlantoaxial instability, hepatomegaly, reduction of growth hormone levels, immunoglobulin A deficiency, and umbilical prominence. Since the characterisation of CGL4 in 2010, all affected individuals have been homozygous for truncating mutations in the PTRF gene [2,3,4,5, 6].

 Case Report

A 31-year-old woman was referred for assistance with weight reduction in the setting of metabolic syndrome. Her prior medical history included obesity, type 2 diabetes mellitus, polycystic ovarian syndrome, hepatic steatosis with bridging fibrosis and a recent hospitalisation for severe hypertriglyceridaemia-related pancreatitis requiring intensive care admission. Her obesity had been a life-long issue in the setting of chronic binge and purge behaviours, longstanding anxiety, depression and Tourette syndrome. She was a non-smoker and denied alcohol consumption. Current medications included Fenofibrate 145mg daily, Ezetimibe/ Rosuvastatin 10/20mg daily, Metformin 1000mg BD, Venlafaxine 225mg daily, Clonidine 100mg daily, Candesartan 4mg daily, Propranolol 20mg BD, Pregabalin 75mg BD, Melatonin 6mg nocte, Rabeprazole 20mg daily, Quetiapine 25mg nocte and Oxybutynin 5mg nocte.

Concerning her family history, her mother had suspected partial lipodystrophy given her Cushingoid habitus and background of hypercholesterolaemia, type 2 diabetes mellitus, obstructive sleep apnoea and severe hypertriglyceridaemia complicated by multiple episodes of pancreatitis. Her mother additionally had proximal myopathy, peripheral neuropathy and ataxia with cerebellar hypoplasia on CT scan Lipodystrophy testing found two novel missense mutations in the PTRF gene, the significance of which was unknown. There was a maternal family history of neuromuscular disorder, described as progressive ataxia, with a pattern of inheritance suggestive of a mitochondrial disorder (Figure 1). She was unaware of her father’s medical history and she had one unaffected half-sister with a different father.  

On physical examination, she had a lipodystrophic habitus with marked lipoatrophy of her arms and legs, appearing muscular with prominent visible surface veins. There was central adiposity and a moon-shaped face. Acanthosis nigricans was present on her neck and axillae. She did not have hirsutism or acne and there were no biochemical features of hyperandrogenism. She was 163 cm tall, with weight 92.1 kg, body mass index 34.7 kg/m² and waist circumference was 114.5 cm.  

Her in-hospital laboratory results included: HbA1c 6.7% with a peak total cholesterol of 20.4 mmol/L (<5.5); triglycerides 84.8mmol/L (<2); and HDL-C, <0.08mmol/L (>1.2). She had a mild transaminitis with ALT 42 U/L (10-35), AST 41 U/L (10–35) and a raised GGT 102 U/L (5–35). She was treated with an insulin infusion in ICU, with excellent resolution of triglyceride levels.(Figure 2)

Owing to the presence of an elevated HbA1c, the patient was commenced on Empagliflozin and given lifestyle management advice including diet and exercise. In the setting of her hypertriglyceridaemia, she was commenced on fish oil. Genetic testing has been arranged to confirm her suspected diagnosis of FPL with assessment for PTRF gene mutation and family co-segregation studies.

Discussion

Lipodystrophic syndromes are a rare cause of type 2 diabetes with severe insulin resistance. This case demonstrates the need for awareness of this rare condition. Features suggestive of a diagnosis of partial lipodystrophy in a patient with metabolic syndrome include early onset diabetes, fatty liver disease, requirement of excessive doses of insulin, and persistently elevated triglycerides refractory to lifestyle and therapeutic interventions. Our case with suspected FPL demonstrated manifestations of both lipodystrophic habitus and metabolic derangements associated with metabolic syndrome, namely, diabetes mellitus, PCOS, NAFLD fibrosis and hypertriglyceridaemia, all of which are known to manifest in patients with FPL. These clinical manifestations are consistent with the lipid overflow hypothesis, in which excess triglycerides from reduced peripheral storage capacity accumulate in the liver, skeletal muscles and preserved visceral depots, subsequently leading to peripheral and hepatic insulin resistance and often, eventual diabetes mellitus [7,8,9].

For patients with a constellation of metabolic conditions and clinical features suggestive of lipodystrophy, consideration of genetic sequencing and molecular diagnosis may be useful [10]. A novel aspect of this case is the family history of a progressive neuromuscular disorder which led to the finding of two missense mutations in the PTRF gene in the mother. The first of these variants (c.923A>G) results in the substitution of a tyrosine to cysteine at position 308 in cavin-1. Of note, this tyrosine has been identified as a highly insulin-responsive phosphorylation site on the cavin-1 protein, suggesting that this may be a functional mutation, responsible for the phenotype observed in this mother-daughter pair. Although the clinical features of the kindred reported here are not consistent with CGL4, it is possible that they may have a milder spectrum of PTRF-related lipodystrophy. 

Take Home Messages

• Familial partial lipodystrophy involves selective loss of subcutaneous fat in the arms and legs and abnormal accumulation of subcutaneous fat in other areas
• Lipodystrophy is commonly associated with a variety of metabolic complications including dyslipidaemia, hypertriglyceridaemia, hyperglycaemia, insulin resistance, diabetes mellitus, hepatic steatosis, increased central adiposity and increased cardiovascular risk.
• Many novel FPL genes remain to be discovered. We report a novel mutation in PTRF which may be pathogenic for FPL.