Delayed Presentation of Berardinelli-Siep Lipodystrophy in an Adolescent Female

Abstract

Berardinelli-Siep syndrome (BSS) is a form of congenital generalized lipodystrophy that disrupts the pathways of lipid metabolism. It presents with physical exam findings, including muscular hypertrophy and lipoatrophy as well as serious metabolic consequences such as diabetes mellitus, hypertriglyceridemia, acute pancreatitis, hepatomegaly, and hepatic steatosis. Diagnosis generally occurs soon after birth or in childhood. The case presented is significant for a delayed diagnosis of suspected BSS Type 1 which is rather uncommon in a developed country. Due to the detrimental complications of BSS, such as hypertrophic cardiomyopathy, pancreatitis, and liver disease, early diagnosis and intervention are crucial. Pediatric providers must be knowledgeable about physical features of BSS and common presentations such as new onset diabetes, hypertriglyceridemia, or pancreatitis throughout early childhood and adolescence in order to avoid delayed diagnoses.

Introduction

Diagnosis of Berardinelli-Siep syndrome (BSS), a form of congenital generalized lipodystrophy that disrupts pathways of lipid metabolism resulting in deleterious metabolic complications, generally occurs soon after birth or in childhood due to severe lipoatrophy warranting further clinical investigation. ¹ The case presented herein will focus on a patient with suspected AGPAT2 mutation (BSS Type 1) and is significant for the delayed diagnosis of BSS Type 1 at the age of 16 years through an acute presentation of diabetes mellitus with associated phenotypic changes. Upon review of the literature, while late-onset diabetes mellitus is common among BSS patients and there is one case of an adolescent diagnosis of BSS described in a rural area of South America, a case with delayed presentation in a developed country with adequate familial health care access such as this has yet to be described. ¹

Case Presentation

A 16-year-old female with no known past medical history presented to her primary care physician due to a 2-month history of labial pruritis, polyuria, polyphagia, and polydipsia. She also had 1 week duration of dysuria, white vaginal discharge, right labial swelling, and bilateral lower quadrant abdominal pain without fevers, activity change, vomiting, diarrhea, or sick contacts. Her last known menstrual cycle was 2 months prior to this presentation but occurs irregularly at baseline. Her point-of-care blood glucose exceeded readable levels, and she was subsequently found to have glucosuria (>1000) and ketonuria (40), prompting referral to the emergency department (ED).

The patient’s physical exam findings were remarkable for tall stature, coarse facial features including a long triangular shaped face with prominent large jaw, broad forehead, hypertelorism, enlarged hands and feet, prominent veins, increased muscularity with low adiposity (Images 1 and 2), abdominal protuberance (Image 3), and slowed, delayed verbal responses with poor eye contact. She did not exhibit signs of acanthosis nigricans or hirsutism. Her breast development, pubic hair, and axillary hair were Tanner stage V. Growth parameters were a body mass index (BMI) of 21.6 (63rd percentile), height of 172 cm (93rd percentile), and a weight of 64 kg (81st percentile).

Image 1.

Lipoatrophy with muscular hypertrophy right upper extremity.

Image 2.

Lipoatrophy with muscular hypertrophy left upper extremity.

Image 3.

Abdominal protuberance with subsequently found hepatomegaly.

In the ED, laboratory workup yielded a hemoglobin A1C of >14, hyperglycemia (>500 mg/dL), hyponatremia, glucosuria, and ketonuria without acidemia. Importantly, the initial blood sample was notable for a fine supernatant fat layer in the vial, which warranted addition of a lipid panel. The panel reported hypercholesterolemia (374 mg/dL), severe hypertriglyceridemia (>4000 mg/dL), low high-density lipoprotein (HDL) (38), and an low-density lipoprotein (LDL) unable to be calculated. Leptin and adiponectin levels were not obtained. Furthermore, she had a mildly elevated aspartate aminotransferase (AST) (61 units/L), normal alanine transaminase (ALT), and hypoalbuminemia (1.7 g/dL). Liver ultrasound revealed hepatomegaly (18.2 cm cranial-caudal span) with trace ascites justified concern for fatty liver disease. Echocardiogram findings were benign, without evidence of hypertrophic cardiomyopathy. Pediatric endocrinology team began an insulin regimen with long-acting and sliding scale insulin as well as a low carbohydrate diet. Diflucan was prescribed for vaginal candidiasis. Reported oligomenorrhea was suspected to be due to hypothalamic-pituitary axis immaturity with anovulation. Transvaginal ultrasound was normal without abnormal findings that may be seen with polycystic ovarian syndrome (PCOS); the uterus was also normal in morphology and echogenicity.

The patient’s physical exam warranted investigation for acromegaly, however, serum insulin-like growth factor (IGF)-1 level (177 ng/mL) was within normal limits; hand x-rays demonstrated appropriate bone age. Cushing’s syndrome was lowered on the differential with morning cortisol levels measured over 2 consecutive days (22.6 and 17.0 µg/dL). A few days later, further outpatient chart review of the family history revealed an older brother with a formal diagnosis of Berardinelli-Siep lipodystrophy with biallelic variants in AGPAT2

Due to familial history and clinical presentation a working clinical diagnosis of hereditary lipodystrophy was made. Patient was discharged on a fibrate, omega 3 fatty acid supplementation, and insulin regimen of a long-acting insulin with sliding scale. One week after discharge, the patient suffered an episode of pancreatitis believed to be secondary to severe hypertriglyceridemia. At that time, she had hypertriglyceridemia (>4000 mg/dL), an elevated lipase (741 units/L), and an abdominal computed tomography (CT) with contrast which revealed an enlarged, edematous pancreas with stranding and peripancreatic fluid without focal areas of necrosis. In addition, she was found to be in mild diabetic ketoacidosis (DKA) with pH of 7.28, a bicarbonate of 18 mEq/L, an elevated anion gap (19.7mEq/L), and ketonemia (1.3 mmol/L). She was started on an insulin drip to correct the DKA and hypertriglyceridemia and was later transitioned to subcutaneous insulin consisting of a total daily dose of 2.19 units/kg/day meeting classification for severe insulin resistance. Her hypertriglyceridemia resolved inpatient with an inpatient low-fat diet. Patient non-compliance with appropriate home diet was believed to be a significant contributing factor to her readmission, and therefore, a statin and insulin sensitizers such as metformin were not felt to be warranted at that time.

The patient’s data from the primary care physician are unavailable as it was performed at an outside institution. The information about the brother’s diagnosis was not provided by the mother to the inpatient care team during the initial intake history. Additionally, the mother mentioned that her daughter’s physical build had always appeared secondary to her athletic endeavors and that it was of low concern to her as she “looks like her father and brother,” raising the suspicion that poor health literacy and comprehension of pertinent family history were at play. While the mother did endorse that the patient had been followed regularly with a physician throughout her life for routine checkups, without access to these records, it is undetermined at what age the patient began to exhibit physical manifestations of BSS, and whether there was a clinical suspicion for this syndrome earlier.

Discussion

Berardinelli Siep syndrome is a form of congenital generalized lipodystrophy that disrupts pathways of lipid metabolism resulting in deleterious metabolic complications such as type 2 diabetes mellitus, hypertriglyceridemia, acute pancreatitis, hepatomegaly, and hepatic steatosis as witnessed in this patient’s presentation. Phenotypic changes appear as muscular hypertrophy, appreciable lipoatrophy, increased height, and acromegaly all of which were observed in this patient. ² Case reports have mentioned associations with learning disorders, attention deficit hyperactivity, hypertrophic cardiomyopathy, and PCOS. ³ Though the patient did not participate in special education with evident learning disabilities, she did exhibit signs of social immaturity and slowed, age-inappropriate verbal communication. Intrafamilial variations in intellectual manifestations are common. ⁴ Thus, multiple affected children may present differently on the intellectual spectrum further masking the diagnosis of subsequent children. This patient’s affected sibling exhibited no intellectual concerns per mother’s report; standardized neuropsychological testing should be considered if cognitive delays become apparent. Furthermore, the patient’s abdominal protuberance with bilateral lower quadrant pain, oligomenorrhea, and hypertrophic muscularity warranted gynecological workup to reassure absence of PCOS.

Multiple genetic mutations have been linked to the disorder notably the AGPAT2 (BSS Type 1) and BSCL2 (BSS Type 2) genes. AGPAT2 plays a role in triglyceride and glycerophospholipid synthesis due to its role in the conversion of lysophosphatidic acid into phosphatidic acid. ⁵ BSCL2 encodes the siepin protein involved in lipid droplet synthesis in the endoplasmic reticulum and synthesis of triglycerides and phospholipids. ⁶ Mutations in both genes are inherited in an autosomal recessive pattern. This patient’s AGPAT2 gene study was denied during insurance prior authorization due to high cost of the study and overall insignificance in altering treatment course, especially due to significant family history. Thus, the diagnosis of BSS Type 1 in this patient is a genetically unconfirmed clinical diagnosis. Berardinelli-Siep syndrome is diagnosed by having 3 major criteria or 2 major with 2 minor criteria present. Major criteria include lipoatrophy affecting trunk, limbs, face, acromegaloid features, hepatomegaly, elevated serum triglycerides, and insulin resistance. Minor criteria include hypertrophic cardiomyopathy, mild to moderate intellectual impairment, phlebomegaly, bone cysts, hirsutism, or precocious puberty in females. It is also diagnosed by identifying biallelic pathogenic variants in AGPAT2 and BSCL2. ⁴ This patient received a clinical diagnosis of BSS Type 1 by presenting with 5 major criteria: lipoatrophy of the limbs, acromegaloid features, hepatomegaly, elevated serum triglycerides, and insulin resistance with 1 minor criteria of phlebomegaly.

As aforementioned, new onset insulin-resistant diabetes mellitus is an expected presentation among BSS Type 1 adolescents in the second decade of life according to prior literature. ⁷ A case such as this one with such delayed diagnosis of a classic phenotypical presentation has yet to be described in the literature except for one such case in Suriname, South America where a 15-year-old girl of African descent presented to a rural clinic with similar findings such as new onset severely insulin-resistant diabetes and classic BSS physical examination findings. ⁸ Importantly, this case was in a rural, under-developed area with minimal familial access to healthcare, in stark contrast to our case. In our case, the physical examination findings of lipoatrophy, acromegaly, and muscular hypertrophy should warrant clinical suspicion in a regular follow-up visit or annual sports physical. This case report highlights the importance of educating physicians on BSS phenotypic clues that may have resulted in an earlier diagnosis prior to significant metabolic changes. Low familial health literacy may have also contributed to this patient’s delayed diagnosis as her family believed for years that her appearance was due to resemblance of masculine family members and athleticism rather than an underlying disorder; this highlights the importance of close medical follow-up, and the provision of family education, including adequate genetic counseling in cases of genetic disorders such as BSS, when diagnosed in immediate family members.

Hypertrophic cardiomyopathy, though not seen in this case, is a deleterious complication of the disease and warrants serial echocardiograms. Patients without current hypertrophic cardiomyopathy should still have regular cardiology follow-up to monitor for this disease presentation. Early diagnosis and follow-up are of the upmost importance as cardiac failure mortality has been reported around 30 years of age with one of the earliest deaths at 19 months old. ⁴ One study reports that the average age of death among 20 deceased patients with BSS was 27.1 years of age, and the most common causes were infection and hepatic disease with less common causes being myocardial infarction and renal failure. This study estimated a loss of life expectancy of 35.6 years. ⁹

Conclusion

The delayed diagnosis of BSS increases patients’ risk of significant comorbidities and reduced life expectancy. Early diagnosis places BSS patients in coordinated clinical care to monitor subsequent metabolic complications. This allows for faster intervention for hypertriglyceridemia and hyperglycemia and possible prevention of complications such as liver disease and pancreatitis, as seen in this patient. Thus, early intervention may play a key role in preventing premature death due to the detrimental complications of BSS. As such, primary care physicians must be aware of the salient physical features and continue to maintain clinical suspicion for BSS throughout early childhood and adolescence in order to adequately identify these patients.