Lawrence–Seip syndrome

Overview

Lawrence–Seip syndrome, also known as congenital generalized lipodystrophy (CGL), is a rare autosomal recessive genetic disorder characterized by a near-total absence of body fat from birth or early infancy. This condition leads to abnormal fat distribution, insulin resistance, severe metabolic disturbances, and muscular prominence due to the lack of subcutaneous adipose tissue. First described by Drs. Lawrence and Seip, the syndrome is classified into several types based on the specific gene mutation involved. Affected individuals are prone to developing diabetes, hypertriglyceridemia, and fatty liver disease at a young age.

Causes

Lawrence–Seip syndrome is caused by mutations in genes responsible for the development and function of adipose tissue. The most commonly involved genes include:

• AGPAT2 – associated with CGL type 1

• BSCL2 – associated with CGL type 2 (more severe)

• CAV1 – associated with CGL type 3 (rare)

• PTRF – associated with CGL type 4 (rare)

The disorder follows an autosomal recessive inheritance pattern, meaning a child must inherit two defective copies of the gene (one from each parent) to be affected. Carriers typically show no symptoms.

Symptoms

Signs and symptoms of Lawrence–Seip syndrome usually begin in infancy or early childhood and may include:

• Generalized absence of subcutaneous fat – resulting in a muscular, well-defined appearance

• Prominent veins and musculature – due to the lack of overlying fat

• Insulin resistance – often progressing to early-onset diabetes mellitus

• Hypertriglyceridemia – elevated blood triglyceride levels

• Hepatomegaly – enlargement of the liver due to fatty infiltration (hepatic steatosis)

• Acanthosis nigricans – dark, velvety patches of skin, often around the neck or armpits

• Hyperphagia (increased appetite)

• Delayed puberty or reproductive issues

In more severe types (especially CGL type 2), neurological deficits and intellectual disability may also occur.

Diagnosis

Diagnosis of Lawrence–Seip syndrome is based on clinical presentation, metabolic testing, and genetic confirmation. Common diagnostic approaches include:

• Physical examination – identifying absence of fat, muscular appearance, and skin changes

• Blood tests – to assess glucose, insulin, lipid profile, and liver enzymes

• Imaging studies – such as MRI or ultrasound to evaluate fat distribution and liver involvement

• Genetic testing – confirms the diagnosis by identifying mutations in known CGL-associated genes

• Family history – to evaluate potential inheritance patterns

Treatment

There is no cure for Lawrence–Seip syndrome, so treatment is aimed at managing metabolic complications and preventing long-term organ damage. Management strategies include:

• Dietary modifications – low-fat, balanced diet to control triglycerides and blood sugar

• Insulin therapy or oral hypoglycemics – to manage diabetes

• Lipid-lowering agents – such as fibrates or omega-3 fatty acids

• Metreleptin therapy – a synthetic leptin analog that helps improve insulin sensitivity and lipid profile in some patients

• Liver monitoring – regular evaluation for hepatic steatosis or fibrosis

• Endocrinological support – for managing pubertal or hormonal abnormalities

Prognosis

The prognosis for individuals with Lawrence–Seip syndrome depends on the severity of metabolic complications and access to specialized care. Early diagnosis and proper management can significantly reduce the risk of complications such as diabetes, cardiovascular disease, and liver failure. However, without treatment, the disorder can lead to life-threatening consequences in childhood or early adulthood. Lifelong monitoring and multidisciplinary care are essential for improving outcomes and maintaining quality of life.