Retinopathy and Uveitis in Congenital Generalized Lipodystrophy with Hypertriglyceridemia and Uncontrolled Diabetes (Berardinelli-Seip Syndrome).

Congenital lipodystrophy syndromes are characterized by a paucity of adipose tissue and are associated with metabolic abnormalities including insulin resistance, diabetes mellitus, and severe hypertriglyceridemia. Herein, we present a case of proliferative diabetic retinopathy with an attack of anterior uveitis in a young female with congenital generalized lipodystrophy - Berardinelli-Seip syndrome. To the best of our knowledge, this is the first description of ocular involvement in Berardinelli-Seip syndrome. Copyright:

Introduction

Congenital lipodystrophy syndromes are characterized by a paucity of adipose tissue and are associated with metabolic abnormalities including insulin resistance, diabetes mellitus, and severe hypertriglyceridemia. Additional findings include muscular hypertrophy, acanthosis nigricans, hepatomegaly, acromegaly, cardiac arrhythmias, impaired metabolism, and mental retardation.[1] The autosomal recessive form of the disease was reported initially by Berardinelli[2] and Seip.[3] Since then, over 300 patients have been reported in the literature including patients from consanguineous families.[45] Herein, we present a case of proliferative diabetic retinopathy with an attack of anterior uveitis in a young female with congenital generalized lipodystrophy (CGL).

Case Report

A 19-year-old Saudi female patient of healthy consanguineous (first cousins) parents was clinically diagnosed to have lipodystrophy during her early infancy. She was followed at the King Faisal Specialist Hospital and Research Center in Riyadh for generalized congenital lipodystrophy associated with insulin-resistant diabetes mellitus and dyslipidemia. She had one episode of pancreatitis in 2012. Her last serum triglycerides were reported to be 3675 mg/dL. Kidney function was normal. Genetic testing revealed homozygous mutation c.335del (p. Pro112Argfs*39) in Exon 3 of AGPAT2 gene consistent with CGL type 1. She had extensive eruptive xanthomas over her body [Figure 1]. She developed diabetes at the age of 14, was initially treated with oral hypoglycemic agents, but had been on insulin for the last 4 years with poor glucose control. Her glycated hemoglobin was 11.8%, and the fasting plasma glucose was 259 mg/dL. She also had features of polycystic ovarian syndrome with oligomenorrhea and irregular menstrual cycles. Additional findings included hypertension, a thyroid nodule, early nephropathy, acanthosis nigricans, mild acromegaly, and depression.

Figure 1

Slit-lamp anterior segment photographs of the right and left eyes at presentation showing conjunctival injection in the left eye (upper panels). Slit-lamp examination revealed +3 cells in the anterior chamber. External photograph of the patient's hands shows multiple eruptive xanthomas (lower panels)

She presented to the emergency room at the King Khaled Eye Specialist Hospital in Riyadh with an attack of anterior nongranulomatous uveitis in her left eye, decreasing her vision to 20/40 [Figure 1b]. Human leukocyte antigen typing was not performed. Fundus examination showed mild diabetic retinopathy in both eyes characterized by cotton wool spots. After topical corticosteroid therapy, her uveitis disappeared with restoration of visual acuity to 20/25. Four months later, she returned to the clinic with the same central vision but worsening of retinopathy [Figure 2]. Fundus fluorescein angiography revealed proliferative retinopathy with active neovascularization [Figure 2] for which the patient received panretinal laser photocoagulation bilaterally. At 1-year follow-up, retinopathy has been stable in both eyes, and she continues to be monitored.

Figure 2

Color fundus photograph of the right eye (a) with early frame of fluorescein angiogram of the same eye showing signs of proliferative diabetic retinopathy (b) with fluorescein leakage on late frames (c). Color fundus photograph of the left eye (d) of the same patient with similar signs of proliferative diabetic retinopathy on early (e) and late (f) frames of fluorescein angiogram in the left eye

Discussion

Berardinelli–Seip syndrome, also known as CGL, occurs in approximately 1 in 10 million of the world population and can result from mutation in four genes, giving rise to four clinically similar but distinguishable subsyndromes affecting fat metabolism.[6] CGL type 1 (OMIM#608594) is autosomal, is recessive, and is uniquely associated with mutation in the AGPAT2 gene encoding 1-acylglycerol-3-phosphate-O-acyltransferase 2.[7] This enzyme is integral to phospholipid biosynthesis, triglyceride/fat formation and storage, adipocyte formation, and fat metabolism pathways and has multiple molecular interaction partners.[6] CGL due to AGPAT2 gene (CGL type 1) and BSCL2 gene (CGL type 2) mutations is the most common variety of CGL and has been reported in patients of various ethnicities.[4] AGPATs are critical enzymes involved in the biosynthesis of triglyceride and phospholipids from glycerol-3-phosphate. AGPAT2 is highly expressed in adipose tissue, and its deficiency may cause lipodystrophy by limiting triglyceride or phospholipid biosynthesis there.[8]

This patient presented with a typical phenotype of CGL with involvement of multiple organs. In addition, she presented with an episode of anterior nongranulomatous uveitis, which could be attributed to the upregulation of pro-inflammatory pathways.[9] Later, she presented with rapid progression of diabetic retinopathy from mild nonproliferative to proliferative stage requiring panretinal photocoagulation for both eyes. Since then, retinopathy has been stable. While the association between CGL and uveitis is uncertain, the retinopathy is likely a consequence of prolonged hyperglycemia and hypertension.

To the best of our knowledge, this is the first description of ocular involvement in Berardinelli–Seip syndrome. Physicians should be vigilant about the ocular findings in long-standing CGL syndromes.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.