Congenital Generalized Lipodystrophy

Congenital Generalized Lipodystrophy

Overview

Congenital generalized lipodystrophy (CGL), also known as Berardinelli-Seip syndrome, is a rare genetic disorder characterized by the near total loss of body fat (adipose tissue) and extreme muscularity that is often present at birth or soon thereafter. CGL is associated with metabolic complications related to insulin resistance such as an inability to break down (metabolize) glucose intolerance (high blood glucose levels after oral glucose administration), elevated levels of triglycerides (fat) in the blood (hypertriglyceridemia) and diabetes. Diabetes associated with CGL is often very difficult to treat. Additional complications such as those affecting the liver and heart can also occur. The symptoms and severity of CGL can vary greatly from one person to another. There are four different subtypes of CGL each caused by changes (variants) in different genes. All the known types of CGL are inherited in an autosomal recessive pattern.

Lipodystrophy is a general term for a group of disorders that are characterized by complete (generalized) or partial loss of adipose tissue. In addition to CGL, there are other inherited forms of lipodystrophy. Some forms of lipodystrophy are not inherited but acquired at some point during life (acquired lipodystrophy). The degree of severity and the specific areas of the body affected can vary among the lipodystrophies. The loss of adipose tissue that characterizes these disorders is sometimes referred to as lipoatrophy rather than lipodystrophy by some physicians. CGL was first described in the medical literature by Dr. Berardinelli in 1954 and reviewed by Dr. Seip in 1959.

Symptoms

Infants with all forms of CGL have a near total absence of body fat at birth or soon thereafter. They also have an extremely muscular appearance and may have prominent superficial veins. During early childhood, most children grow at an accelerated rate and have slightly enlarged hands, feet and jaws (acromegaloid features). Infants and children have a markedly increased appetite and have been described as voracious eaters.

In individuals with CGL, fat deposits build up in areas of the body such as the muscles and liver. Consequently, affected individuals may develop abnormal enlargement of the muscles (muscular hypertrophy) or the liver (hepatomegaly). Some individuals may also have an abnormally enlarged spleen (splenomegaly). Hepatomegaly is often noticed during infancy. Fat accumulation in the liver (known as fatty liver or hepatic steatosis) may eventually cause scarring and damage to the liver (cirrhosis) and liver dysfunction. Ultimately, liver failure may develop in some people, necessitating a liver transplant.

Individuals with CGL develop metabolic complications associated with insulin resistance. Some individuals with CGL have a condition called acanthosis nigricans, a skin condition characterized by abnormally increased coloration (hyperpigmentation) and “velvety” thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck, groin and armpits (axillae). Other complications of insulin resistance may occur at a young age (often between 15-20 years of age) including glucose intolerance, hypertriglyceridemia and diabetes. These complications are often very difficult to control, and diabetes is often severe. Some individuals may have extreme hypertriglyceridemia and chylomicronemia, a condition characterized by the accumulation of chylomicrons (lipoprotein particles carrying fat) in the plasma. In some people, this can result in episodes of acute inflammation of the pancreas (pancreatitis). Acute pancreatitis can be associated with abdominal pain, chills, jaundice, weakness, sweating, vomiting and weight loss.

Intellectual disability can occur in CGL, especially in cases caused by variants of the BSCL2 gene (CGL type 2). However, the presence and/or severity of intellectual disability can vary dramatically from one person to another, even among members of the same family. Most people affected with CGL type 2 have mild or moderate intellectual disability. Intellectual disability is not common in other forms of CGL.

After puberty, some females with CGL may develop polycystic ovary syndrome (PCOS). PCOS is characterized by an imbalance of female sex hormones. Affected females may also have too much androgen, a male hormone, in the body. PCOS can result in irregular menstrual periods or a lack of menstruation, oily skin that is prone to acne, multiple cysts on the ovaries and mild hirsutism (a male pattern of hair growth). Hair may develop on the upper lip and chin. Most females with CGL are unable to conceive. However, there are a few reports of affected females who have had successful pregnancies. While some affected males may have normal reproductive capabilities, others may have morphological defects of sperm or a reduced sperm count.

Heart irregularities may occur in some people, especially abnormal thickening of the muscular walls of the lower left chamber of the heart (hypertrophic cardiomyopathy). This condition can obstruct the flow of blood in and out of the heart. Some individuals may have no associated symptoms; others may develop shortness of breath upon exertion, fatigue and excessive sweating. As affected individuals age, they may have chest pain or discomfort, irregular heartbeats, dizziness or fainting usually upon heavy exertion, and eventually, life-threatening complications such as congestive heart failure. Hypertrophic cardiomyopathy is most common in individuals with CGL types 2 and 4. It often develops in individuals around the age of 30 but has been reported in infants as well.

Additional findings have been reported in individuals with CGL including excessive sweating (hyperhidrosis). Some findings are more likely to be associated with a specific subtype of CGL such as the formation of bone cysts after puberty (more common in types 1 and 2), which can cause individuals to be prone to spontaneous fractures; bone marrow fat loss (more common in types 1 and 2); and osteoporosis and problems with vitamin D, reported patients with CGL type 3. CGL type 3 patients may have swallowing difficulty due to large esophagus with reduced motility (achalasia), short stature and amenorrhea. Muscular dystrophy, a general term for disorders that cause muscle weakness and loss of muscle tissue, and pyloric stenosis (constriction of the opening of stomach into duodenum) is seen in individuals with CGL type 4. Intense exercise-induced irregular heartbeats (cardiac arrhythmias) and sudden death have also been associated with CGL type 4.

Individuals with CGL type 1 lack metabolically active fat, which is the fat that plays a role in the storage and release of energy and is located in subcutaneous regions, intermuscular regions, the bone marrow and areas within the abdomen and chest (thoracic cavity), but mechanical fat is well preserved. Mechanical fat is the fat that supports and protects regions subjected to mechanical insults and is located in the palms, soles, eye sockets (orbits), scalp and around the joints. Individuals with CGL type 2 are prone to having a more severe form of lipodystrophy because they also experience the loss of mechanical fat.

Causes

CGL is caused by changes (disease-causing variants) of specific genes. Variants in four genes cause CGL including the AGPAT2 gene (CGL type 1), BSCL2 gene (CGL type 2), CAV1 gene (CGL type 3) and the CAVIN1 gene (CGL type 4). Some individuals with CGL do not have a variant in any of these genes, suggesting that variants in additional, as yet unidentified genes can cause the disorder.

The AGPAT2 gene contains instructions for creating (encoding) the enzyme AGPAT2, which is involved in the creation (synthesis) of triglycerides and fatty substances called phospholipids.

The BSCL2 gene encodes a protein known as seipin. Recent data suggest a role of seipin in fusion of lipid droplets and in fat cell differentiation.

The CAV1 gene encodes caveolin-1, which is expressed in caveolae, tiny structures on the surface of cells. Caveolae play a role in the formation of lipid droplets, most likely by transporting lipids and phospholipids from outside the cell to inside the cell. Lipid droplets are organelles, specialized subunits found within cells that have specific functions. One function of lipid droplets is the storage of lipids.

The CAVIN1 (previously known as PTRF) gene encodes cavin 1, an essential protein factor in the creation (biogenesis) of caveolae.

Researchers think that various genes and gene products associated with CGL are involved with the proper creation, function and/or health of lipid droplets within adipocytes. Adipocytes are fat cells. Each adipocyte has a lipid droplet that accounts for approximately 90% of its cell volume. An adipocyte stores fats (triglycerides) within its lipid droplet. Biallelic (on both the maternal and paternal chromosomes) variants in the above-mentioned genes ultimately lead to a loss of adipocytes and an inability to store fat. Consequently, fat is stored in other tissues of the body such as the liver and skeletal muscle causing symptoms such as liver disease and insulin resistance. The cause of other symptoms sometimes associated with CGL such as cardiomyopathy is unknown. More research is necessary to understand the exact, underlying mechanisms that ultimately cause CGL and its associated symptoms.

CGL is inherited as an autosomal recessive condition. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

Affected populations

Approximately 500-600 people with CGL have been reported in the medical literature. The estimated worldwide prevalence ranges from 1 in a million to 1 in 10 million individuals in the general population. The disorder has been reported in individuals of every ethnic group. A higher prevalence has been reported in Peru, Lebanon, Turkey and Brazil, most likely due to increased consanguinity (marriage between people related by blood).

Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of CGL. Comparisons may be useful for a differential diagnosis.

Familial partial lipodystrophy (FPLD) is a rare genetic disorder characterized by selective, progressive loss of body fat (adipose tissue) in various areas of the body. Individuals with FPLD often have reduced subcutaneous fat in the arms and legs and the chest and trunk of the body. Conversely, affected individuals may also have excess subcutaneous fat deposits in other areas of the body, especially the neck, face and intra-abdominal regions. In most people, adipose tissue loss begins during puberty. FPLD can be associated with a variety of metabolic abnormalities. The extent of adipose tissue loss usually determines the severity of the associated metabolic complications. These complications can include glucose intolerance, hypertriglyceridemia and diabetes. Additional findings can occur in some people. Eight genetically distinct subtypes of FPLD have been identified. Each subtype is caused by variants in a different gene. Six forms of FPLD are inherited in an autosomal dominant pattern. Three forms are inherited in an autosomal recessive pattern. The mode of inheritance of one form is not fully understood.

Acquired lipodystrophy is a general term for types of lipodystrophy that are not inherited but rather acquired at some point during life. Acquired lipodystrophies do not have a direct genetic cause, but rather many different factors may be involved. Acquired lipodystrophies may be caused by medications, autoimmunity or for unknown reasons (idiopathic). Subtypes of acquired lipodystrophy include localized lipodystrophy, acquired generalized lipodystrophy (Lawrence syndrome), acquired partial lipodystrophy (Barraquer-Simons syndrome) and highly active antiretroviral therapy induced lipodystrophy, which may develop in HIV-infected individuals undergoing a specific form of treatment. The onset of acquired forms of lipodystrophy can occur during childhood, adolescence or adulthood. Affected individuals develop characteristic loss of body fat (adipose tissue) affecting certain areas of the body, especially the arms, legs, face, neck and chest or thoracic regions. In some people, metabolic complications associated with insulin resistance may occur. Such complications include an inability to break down glucose (glucose intolerance), elevated levels of triglycerides (a type of fat) in the blood (hypertriglyceridemia), diabetes and fat accumulation in the liver (fatty liver or hepatic steatosis).

A variety of syndromic disorders may be associated with lipodystrophy and/or have symptoms similar to CGL including Rabson-Mendenhall syndrome, SHORT syndrome, mandibuloacral dysplasia, Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome), Hutchinson-Gilford progeria syndrome, Werner syndrome and leprechaunism. Lipodystrophy should also be differentiated from anorexia nervosa, cachexia, diencephalic syndrome, multiple symmetric lipomatosis and other disorders that affect growth and development. NORD has individual reports on most of these disorders.

Diagnosis

A diagnosis of CGL is based upon identification of characteristic symptoms, a detailed patient history and a thorough clinical evaluation. A lipodystrophy diagnosis should be suspected in individuals who are lean or “non-obese” and who present with early diabetes, severe hypertriglyceridemia, hepatic steatosis, hepatosplenomegaly, acanthosis nigricans and/or polycystic ovarian syndrome.

Molecular genetic testing can confirm a diagnosis of CGL in most patients when variants in specific genes that cause CGL are identified.

Clinical Testing and Workup

Although the diagnosis of lipodystrophy is primarily clinical, a variety of tests can be used to aid in the diagnosis and/or rule out other conditions. A blood chemical profile may be conducted to assess the levels of glucose, lipids, liver enzymes and uric acid.

The characteristic pattern of fat loss in CGL can be noted on magnetic resonance imaging (MRI). X-rays can show the presence of lytic bones lesions that occur in some individuals with CGL.

Individuals with CGL may be evaluated to determine their leptin levels. Leptin is a hormone found in adipocytes. Some affected individuals have low levels of leptin. Although not a diagnostic test, determining leptin levels may help physicians predict a person’s response to leptin replacement therapy.

Standard Therapies

Treatment

The treatment of CGL is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, endocrinologists, nutritionists and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.

Individuals with CGL and their families are encouraged to seek counseling after a diagnosis and before treatment because the diagnosis can cause anxiety, stress and extreme psychological distress. Psychological support and counseling both professionally and through support groups is recommended for affected individuals and their families.

Genetic counseling is recommended for affected individuals and their families as well.

Individuals with CGL are encouraged to follow a high carbohydrate, low-fat diet. Such a diet can improve chylomicronemia associated with acute pancreatitis. However, such diets may also raise very low-density lipoprotein triglyceride concentration. It is important that children still consume a diet that provides sufficient energy for proper growth and development. Regular exercise and maintaining a healthy weight are also encouraged to decrease the chances of developing diabetes. Individuals with CGL type 4 should avoid intense or strenuous exercise.

Leptin is a hormone found in adipocytes. Severe lipodystrophy is sometimes associated with leptin deficiency. In 2014, the U.S. Food and Drug Administration approved metreleptin (Myalept) as replacement therapy to treat the complications of leptin deficiency in addition to diet, in patients with congenital generalized or acquired generalized lipodystrophy. Metreleptin is a recombinant analogue (laboratory-created form) of human leptin and is taken once a day by subcutaneous (under the skin) injection. It has been found to help improve metabolic complications such as diabetes and hypertriglyceridemia. The most common side effects are low blood sugar (hypoglycemia), headache and decreased weight. Other side effects can be local reactions at injection site, the possibility of developing leptin antibodies (which could result in severe infections or loss of treatment effectiveness) and rare cases of T-cell lymphoma. It is contraindicated in patients with general obesity not associated with congenital leptin deficiency and with prior severe hypersensitivity reactions to metreleptin or any of the product components. Myalept is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) which requires prescriber and pharmacy certification and special documentation.

Individuals with extreme hypertriglyceridemia may be treated with fibric acid derivatives, statins, or n-3 polyunsaturated fatty acids from fish oils. The characteristic loss of adipose tissue in individuals with CGL cannot be reversed. Consequently, cosmetic surgery may be helpful to improve appearance. Individuals with severe facial lipodystrophy can undergo reconstructive facial surgery including fascial grafts from the thighs, free flaps from the anterolateral thigh, anterior abdomen or temporalis muscle.

In some people, liver disease can ultimately require a liver transplantation.

Additional therapies to treat individuals with CGL are symptomatic and supportive and follow regular, standard guidelines. Diabetes is treated with standard therapies. After the onset of diabetes, hyperglycemic drugs such as metformin and sulfonylureas may be recommended to treat hyperglycemia. Insulin can also be used to treat individuals with CGL and diabetes, although extremely high doses are often required. Although drug therapy is commonly used, there have been no clinical trials to establish the optimal use of drug therapy to treat the metabolic complications associated with CGL.

Special remedial education may be necessary for individuals with intellectual disability. Psychosocial support for the entire family is essential as well.

Type of Doctor Department : An endocrinologist