Berardinelli–Seip syndrome: highlight of treatment challenge

Abstract

Berardinelli–Seip congenital lipodystrophy (BSCL) syndrome is a rare autosomal-recessive disease characterised by lipoatrophy and associated with deregulations of glycidic and lipid metabolism. We report three BSCL cases with its typical clinical picture and complications. Clinically, they all show marked atrophy of adipose tissue, acromegaly, acanthosis nigricans and tall stature. Two cases present attention deficit hyperactivity and developmental learning disorders; another patient has hypertrophic myocardiopathy and polycystic ovary syndrome. In all the cases AGPAT2 was the identified mutation. All the cases present hypertriglyceridemia. One case has developed hyperinsulinism controlled with metformin and another case already has type 2 diabetes with a difficult clinical control. There is no curative treatment and the current treatment options are based only on symptomatic control of the complications. Recently, published studies showed that leptin-replacement therapy appears a promising tool in the metabolic correction of BSCL complications, highlighting the importance of further investigations in BSCL treatment.

Background

Generalised congenital lipoatrophy or Berardinelli–Seip congenital lipodystrophy (BSCL) syndrome was first described in 1954 by Berardinelli,¹ in a 2-year-old boy in Brazil.¹ Later in 1959, Seip² described the same syndrome in three other patients. BSCL is a rare syndrome with an estimated prevalence of 1 in every 10 million births.³ It is inherited as an autosomal recessive trait, with frequent parental consanguinity. At least three molecularly distinct forms of BSCL have been defined, with the mutations of AGPAT2 and BSCL2 being responsible for 95% of reported cases.^3–5

BSCL is characterised by the lack of adipose tissue with its consequent deregulations in lipid and carbohydrate metabolism. The absence of adipose tissue is responsible for extremely low levels of leptin, an adipocytokine responsible for the regulation of energy metabolism. This plays an important role in the pathophysiology of the disease characterised by hypertriglyceridemia, hepatic steatosis, hyperglycemia, insulin resistance and the development of diabetes mellitus and microvascular complications.^{6 7}

There is no standardised treatment. The treatment options are based on symptomatic control of the complications, in order to slow down the life-threatening progression of the disease.⁸ We report three patients with BSCL followed in our unit, highlighting the difficulties in the clinical follow-up and therapy of these cases.

Case presentation

The three cases of BSCL are all from the same family with multiple consanguine relations and with positive history of congenital lipoatrophies (figure 1).

Figure 1.

Familial relations of the three Berardinelli–Seip congenital lipodystrophy cases.

Case 1

A 19-year-old girl is followed up in our unit since she was 7 months old. Her antenatal history was unremarkable. In the perinatal period generalised lipoatrophy, muscle hypertrophy and clitoris hypertrophy were noticed, allowing for the diagnosis of BSCL. Arterial hypertension was diagnosed at the age of 5 months, she was referred to the paediatric cardiologist and myocardial hypertrophy was diagnosed.

Clinically her height was always higher than her target height. She developed hirsutism, acromegaloid appearance and acanthosis nigricans. Hepatomegaly was noticed when she was 3 years old. Lipoatrophy and muscle hypertrophy increased markedly during the years (figure 2).

Figure 2.

Picture of case 1, showing the lipoatrophy, marked muscle hypertrophy, hirsutism and acanthosis nigricans lesions in the armpits.

By the age of 14, she was referred to the gynaecologist for menstrual irregularities and polycystic ovary syndrome was diagnosed.

Case 2

An 11-year-old girl is followed up in our unit since she was 2 months old. Her antenatal history was unremarkable. When she was born, lipoatrophy, muscle hypertrophy and clitoris hypertrophy were noticed. Clinically her height was always higher than her target height. She developed hirsutism, an acromegaloid appearance and acanthosis nigricans lesions. Hepatomegaly was noticed when she was 5 years old. She had a gradual and progressive increase in lipoatrophy and muscle hypertrophy (figure 3).

Figure 3.

Picture of case 2, showing the lipoatrophy and moderate muscle hypertrophy.

At the age of 5, she was diagnosed with attention deficit hyperactivity disorder associated with developmental learning disabilities.

Case 3

An 11-year-old boy is followed up in our unit since he was 5 months old.

His antenatal period was unremarkable. In the neonatal period, a generalised atrophy of subcutaneous tissue, marked muscular hypertrophy and voracious appetite were noticed. Clinically his height was always higher than his target height and he developed progressive acromegaloid features and hirsutism.

At the age of 7, he was diagnosed with attention deficit hyperactivity disorder associated with developmental learning disability.

Investigations

In all cases, the same AGPAT2 mutation was identified.

Case 1

Cardiological investigation revealed moderate hypertrophic cardiomyopathy.

Annual lipid metabolism evaluation always showed low high-density lipoprotein (HDL) cholesterol (minimum 0.62 mmol/l) with normal total cholesterol. By the age of 10 she developed hypertriglyceridemia (triglycerides 2 mmol/l) with progressive increase reaching a maximum of 5.4 mmol/l by the age of 14.

At the age of 11, she developed alterations in glycidic metabolism with hyperinsulinism (fasting insulin 229 pmol/l) and insulin resistance (homeostatic model assessment (HOMA) 8.07). There was a gradual deterioration and by the age of 15, type 2 diabetes was diagnosed.

By the age of 12, positive microalbuminuria was detected (microalbuminuria 4.3 µg/mg) with gradual increase reaching a maximum of 442 µg/mg by the age of 17.

Hepatic function evaluation showed only a slight increase in alanine aminotransferase (ALT) 47 UI/l) by the age of 18, with normal aspartate aminotransferase.

Abdominal ultrasound showed moderate hepatomegaly with no signs of steatosis.

Case 2

Cardiological investigation was normal.

Annual lipid metabolism evaluation also showed low HDL cholesterol (minimum 0.62 mmol/l) with normal total cholesterol. By the age of 10 she developed hypertriglyceridemia (triglycerides 3.3 mmol/l) with progressive value increase, reaching a maximum of 5.2 mmol/l by the age of 11.

At the age 10, laboratory evaluation showed hyperinsulinism (fasting insulin 729.2 pmol/l) and insulin resistance (HOMA 24.79). Fasting glucose levels, glycated haemoglobin (HbA1c) and oral glucose tolerance test (OGTT) remained normal.

Hepatic function routine evaluation showed no alterations.

Abdominal ultrasound revealed moderate hepatomegaly without steatosis.

Case 3

Cardiological investigation was normal.

Annual lipid metabolism evaluation showed low HDL cholesterol (minimum 0.85 mmol/l) with normal total cholesterol. By the age of 10 he developed hypertriglyceridemia (triglycerides 3.6 mmol/l).

Laboratory evaluations of glicid metabolism and hepatic function have been normal so far.

Treatment

All cases have regular nutritional support with a strict hypolipidic diet.

Case 1

Propanolol was started at 5 months, by the time of arterial hypertension diagnosis.

At the age of 10, metformin was introduced in order to control insulin resistance and has been gradually increased, since the diagnosis of type 2 diabetes (present dose is 6000 mg/day).

At the age of 12, when microalbuminuria was detected, nephroprotective treatment with lisinopril was started.

At the age of 17, when the hypertriglyceridemia reached its maximum, treatment with fenofibrate was started.

Case 2

At the age of 10, metformin treatment (2000 mg/day) was started in order to control insulin resistance.

Metylphenidate was prescribed at the time of the diagnosis of attention deficit hyperactivity disorder, with good clinical result.

Case 3

He has regular nutritional support with a strict hypolipidic diet.

Metylphenidate was prescribed at the age of 7, with good clinical result.

Outcome and follow-up

Case 1

Arterial hypertension has been adequately controlled with propanolol.

After the implementation of lisinopril there was a decrease in microalbuminuria and a recent evaluation showed a microalbuminuria of 33 µg/mg.

Hypertriglyceridemia had also an adequate response to the therapy with fenofibrate with a reduction to the current values of 2 mmol/l.

Glucose homeostasis has not improved in spite of the increases in metformin dose. A recent evaluation showed a HOMA of 9.63 and an HbA1c of 7.5%, therefore implementation of insulinotherapy is now considered.

Case 2

After the introduction of therapy with metformin, insulin resistance improved. Nevertheless, the most recent evaluation of the glycidic metabolism showed a fasting insulin of 597 pmol/l and HOMA of 18.78.

Hypertriglyceridemia has been difficult to control and remains within high values (5 mmol/l), and therefore reinforcement of nutritional guidelines has been tried.

Case 3

Hypertriglyceridemia improved with the implementation of a strict hypolipidic diet.

Discussion

AGPAT2 mutations have been found in the three reported cases, therefore they can all be classified as BSCL type 1 cases. AGPAT2 has been mapped to chromosome 9q34 and encodes the enzyme responsible for the acylation of lysophosphatidic acid into phosphatidic acid, a key intermediate in the biosynthesis of triacylglyceride and glycerophospholipids. BSCL type 1 is more frequently found in patients of African ancestry, frequent among Portuguese population.³ The other frequent mutation is BSCL2 which is responsible for type 2 BSCL cases. This mutation has been mapped to chromosome 11q13 and encodes a protein called Seipin that is critical for normal adipogenesis and induction of the expression of key lipogenic transcription factors. The majority of BSCL2 variants are null mutations that are predicted to result in severe disruption of the protein function.⁹ A novel nonsense mutation, W107X, in exon 3 of the BSCL2 gene has been recently reported.¹⁰ BSCL type 2 is more frequent in patients of European and Middle Eastern origins.⁴

Recent reports provide evidence for at least two additional loci resulting from mutations in CAV1 and PTRF, constituting BSCL type 3 and type 4, respectively. These new mutations account for less than 5% of all the BSCL cases.⁹

Several studies have been made to assess the BSCL genotype–phenotype relationship. Individuals with type 2 BSCL seem to present more severe and premature symptoms than those who have mutations in type 1 with a higher incidence of intellectual deficiency in type 2 BSCL. That can be explained by the fact that seipin is expressed variably in several tissues such as liver, skeletal muscle, kidney, pancreas, testicles and a high expression in the central nervous system while AGTPA2 is a tissue-restricted enzyme, occurring at high levels in adipose tissue, liver and cardiac tissue, but almost undetectable in the brain.^11–13

The three reported cases illustrate the clinical manifestations and complications of BSCL.

The clinical typical picture of typical BSCL is the absence of subcutaneous fat from most subcutaneous areas, abdomen and thorax, that is noticed soon after birth. The lipoatrophy spares certain anatomical regions, such as buccal region, tongue, palm of the hand and sole of the feet, scalp, articular regions and epidural areas, where normal deposition of adipose tissue occurs.¹⁴ During childhood these patients have a voracious appetite, accelerated linear growth and an increased metabolic and anabolic rate. The anabolic processes are responsible for the acromegaloid characteristics, due to insulin-like growth factor 1 (IGF 1) hypersecretion and for the organomegaly with hepatomegaly due to fatty infiltration. With disease progression, hepatomegaly usually progresses to non-alcoholic steatohepatitis and associated liver chirrosis.⁸

Increase in external genitalia—labia majora hypertrophy and clitoromegaly—is also commonly seen as part of the organomegaly.¹⁵ This is generally accompanied by other virilisation signs such as hirsutism. Precocious puberty and polycystic ovary syndrome are common and can be explained by the hyperandrogenism related to insulin resistance.^{16 17}

Acanthosis nigricans is present in almost all individuals, with symmetrical hyperkeratotic and hyperpigmented lesions, appearing mainly in the nape, armpit, groin, neck, breast and other areas suffering flexion.¹⁸

As reported in case 1, ventricular dysfunction and hypertrophic cardiomyopathy are often observed. These are correlated with the high plasmatic insulin levels that activate the IGF1 receptors, present in large quantities in the myocardial tissue.¹⁹

Psychomotor retardation or mild-to-moderate cognitive impairment can also occur, being more frequent in BSCL type 2. It can also be present in approximately 10% of type 1 BSCL, as reported in cases 2 and 3.²⁰ Apart from the cognitive impairment, the absence of adipose tissue in the brain has also been recently associated with abnormal response to highly fat-soluble anaesthetic agents, reflecting the difficulties in conducting a safe anaesthesia in these patients.²¹

The metabolic complications in BSCL develop as the disease progresses. Metabolic complications seem to be related to a reduced concentration of adipocytokines resulting from the total body fat reduction. Leptin is an adipocytokine which seem to play an important role in BSCL and whose low levels are strongly correlated with lipid and glycidic metabolism changes. Lipid alterations are characterised by a severe hypertriglyceridemia with deposition of triglycerides in lymphoreticular tissues, especially in the liver. The glycidic metabolism disorders are aggravated as a result of the limited capacity for the storage of glucose in the form of fat. Glucose is then stored in the form of glycogen in hepatic, skeletal and cardiac muscle with a consequent disturbance in glucose homeostasis and the appearance of a slight resistance to insulin during childhood. Insulin resistance increases rapidly between the age of 8 and 10 years, and diabetes usually appears around the age12, as in our cases.⁸

Recently, neonatal-onset diabetes has also been reported in BSCL, representing an early form of glycidic metabolism deregulation of the syndrome.¹⁰

Strict dietary regimen is primordial in the management of BSCL. Calorie-controlled regimen with strict restriction of total fat intake restriction is indicated for the control of dyslipidemia. Severe hypertriglyceridemia may be controlled with the use of fibric acid derivatives such as fenofibrate, as it was in case 1.⁸

Metformin is the drug of choice for the management of BSCL as it controls the glycidic metabolism as well as contributing for an appetite reduction and improvement of hepatic steatosis and polycystic ovary syndrome. In some cases, as it is being considered in case 1, insulinotherapy may also be necessary to improve the management of type 2 diabetes.^{22 23}

Currently these are the available treatment strategies for BSCL, which are only based on the symptomatic treatment of the disease complications. No curative treatment is yet established and, as we can see in our case reports, the disease evolution and its complications bring to light the treatment challenges in BSCL.

In the last years, several studies reported the use of recombinant leptin in BSCL.^24–29 The first studies in adults with lipodystrophy showed that leptin-replacement therapy improved glycaemic control and decreased triglyceride levels, therefore allowing for the discontinuation or a large reduction in antidiabetes therapy.²⁹ They also proved that leptin treatment was able to correct hepatic steatosis and reverse insulin resistance²⁴ with benefits sustained for at least 12 months of treatment.²⁵

In 2007, Beltrand et al,²⁶ published the first study concerning leptin-replacement therapy in children with BSCL, demonstrating that leptin replacement was able to reverse metabolic complications in the majority of children with BSCL and insulin resistance or dyslipidemia before the development of overt diabetes.

Leptin-replacement therapy appears as a promising tool in the treatment and metabolic correction of Berardinelli–Seip congenital lipoatrophy. Further investigation is needed regarding the treatment challenge in these cases.

Learning points.

• Berardinelli–Seip congenital lipodystrophy (BSCL) syndrome is a rare autosomal disease characterised by congenital lipoatrophy with lipid and glycidic metabolism deregulations.

• BSCL treatment currently is only symptomatic and does not prevent the disease complications.

• Leptin treatment in BSCL should be considered an important promising new curative therapy.

• Further investigation is needed regarding BSCL treatment challenges.