Congenital generalized lipodystrophy

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Congenital generalized lipodystrophy (also called Berardinelli-Seip congenital lipodystrophy) is a rare condition characterized by an almost total lack of fatty (adipose) tissue in the body and a very muscular appearance. Adipose tissue is found in many parts of the body, including beneath the skin and surrounding the internal organs. It stores fat for energy and also provides cushioning. Congenital generalized lipodystrophy is part of a group of related disorders known as lipodystrophies, which are all characterized by a loss of adipose tissue. A shortage of adipose tissue leads to the storage of fat elsewhere in the body, such as in the liver and muscles, which causes serious health problems.

The signs and symptoms of congenital generalized lipodystrophy are usually apparent from birth or early childhood. One of the most common features is insulin resistance, a condition in which the body's tissues are unable to recognize insulin, a hormone that normally helps to regulate levels of blood glucose, also called blood sugar. Insulin resistance may develop into a more serious disease called diabetes mellitus. Most affected individuals also have high levels of fats called triglycerides circulating in the bloodstream (hypertriglyceridemia), which can lead to the development of small yellow deposits of fat under the skin called eruptive xanthomas and inflammation of the pancreas (pancreatitis). Additionally, congenital generalized lipodystrophy causes an abnormal buildup of fats in the liver (hepatic steatosis), which can result in an enlarged liver (hepatomegaly) and liver failure. Some affected individuals develop a form of heart disease called hypertrophic cardiomyopathy, which can lead to heart failure and an abnormal heart rhythm (arrhythmia) that can cause sudden death.

People with congenital generalized lipodystrophy have a distinctive physical appearance. They appear very muscular because they have an almost complete absence of adipose tissue and an overgrowth of muscle tissue. A lack of adipose tissue under the skin also makes the veins appear prominent. Affected individuals tend to have prominent bones above the eyes (orbital ridges), large hands and feet, and a prominent belly button (umbilicus). Affected females may have an enlarged clitoris (clitoromegaly), an increased amount of body hair (hirsutism), irregular menstrual periods, and multiple cysts on the ovaries, which may be related to hormonal changes. Many people with this disorder develop acanthosis nigricans, a skin condition related to high levels of insulin in the bloodstream. Acanthosis nigricans causes the skin in body folds and creases to become thick, dark, and velvety.

Researchers have described four types of congenital generalized lipodystrophy, which are distinguished by their genetic cause. The types also have some differences in their typical signs and symptoms. For example, in addition to the features described above, some people with congenital generalized lipodystrophy type 1 develop cysts in the long bones of the arms and legs after puberty. Type 2 can be associated with intellectual disability, which is usually mild to moderate. Type 3 appears to cause poor growth and short stature, along with other health problems. Type 4 is associated with muscle weakness, delayed development, joint abnormalities, a narrowing of the lower part of the stomach (pyloric stenosis), and severe arrhythmia that can lead to sudden death.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Mutations in the AGPAT2, BSCL2, CAV1, and CAVIN1 genes cause congenital generalized lipodystrophy types 1 through 4, respectively. The proteins produced from these genes play important roles in the development and function of adipocytes, which are the fat-storing cells in adipose tissue. Mutations in any of these genes reduce or eliminate the function of their respective proteins, which impairs the development, structure, or function of adipocytes and makes the body unable to store and use fats properly. These abnormalities of adipose tissue disrupt hormones and affect many of the body's organs, resulting in the varied signs and symptoms of congenital generalized lipodystrophy.

Some of the genes associated with congenital generalized lipodystrophy also play roles in other cells and tissues. For example, the protein produced from the BSCL2 gene is also present in the brain, although its function is unknown. A loss of this protein in the brain may help explain why congenital generalized lipodystrophy type 2 is sometimes associated with intellectual disability.

In some people with congenital generalized lipodystrophy, no mutations have been found in any of the genes listed above. Researchers are looking for additional genetic changes associated with this disorder.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Congenital generalized lipodystrophy has an estimated prevalence of 1 in 10 million people worldwide. Between 300 and 500 people with the condition have been described in the medical literature. Although this condition has been reported in populations around the world, it appears to be more common in certain regions of Lebanon and Brazil.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Adipose tissue loss · Very frequent (99-80%)

A reduction in the amount of adipose tissue (fat) compared with the amount previously present in an individual.

Hepatomegaly · Very frequent (99-80%)

Abnormally increased size of the liver.

Insulin resistance · Very frequent (99-80%)

Increased resistance towards insulin, that is, diminished effectiveness of insulin in reducing blood glucose levels.

Lipodystrophy · Very frequent (99-80%)

Degenerative changes of the fat tissue.

Skeletal muscle hypertrophy · Very frequent (99-80%)

Abnormal increase in muscle size and mass not due to training.

Diabetes mellitus · Frequent (79-30%)

A group of abnormalities characterized by hyperglycemia and glucose intolerance.

Hypertrichosis · Frequent (79-30%)

Hypertrichosis is increased hair growth that is abnormal in quantity or location.

Hypertriglyceridemia · Frequent (79-30%)

The concentration of triglyceride in the blood circulation is above the upper limit of normal.

Other findings in the same source

From: Orphanet

Additional reported features include Intellectual disability (Frequent (79-30%)); Abnormal facial shape (Occasional (29-5%)); Acanthosis nigricans (Occasional (29-5%)); Accelerated skeletal maturation (Occasional (29-5%)); Bone cyst (Occasional (29-5%)); Cirrhosis (Occasional (29-5%)); Clitoral hypertrophy (Occasional (29-5%)); Congestive heart failure (Occasional (29-5%)); Failure to thrive (Occasional (29-5%)); Global developmental delay (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Congenital generalized lipodystrophy is Endocrinology, with a endocrinologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which hormone or metabolic finding is important in this case?
• How should test timing and current medicines be taken into account?
• What follow-up would show whether the care plan is working?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Congenital generalized lipodystrophy. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.