Congenital generalized lipodystrophy type 2 (CGL2) is a rare metabolic disorder inherited in an autosomal recessive pattern. It has been related to mutations of the BSCL2 gene. Affected individuals are lacking body fat, are predisposed for metabolic complications like insulin resistance, diabetes mellitus, and hypertriglyceridemia, but are also likely to develop hypertrophic cardiomyopathy and mental retardation. Despite recent advances in CGL2 therapy - recombinant analogs of human leptin have been proven highly effective to control metabolic complications of the disease - life quality and expectancy of CGL2 patients remain decreased.
The near-total absence of body fat is characteristic of congenital generalized lipodystrophies and is usually apparent at birth. Less frequently, it is recognized in the neonatal period, in infancy or in childhood, as has been shown in a recently published study: The mean age of patients at the onset of fat loss has been reported to be 0.3 months, with a range of from birth to 12 years . At the same time, extreme muscularity is observed. Veins of arms and legs are rather prominent since they are not hidden by subcutaneous fat. The precise fat distribution pattern may raise suspicion as to the molecular type of lipodystrophy : CGL2 patients are essentially lacking all body fat, including mechanical adipose tissue such as fat pads on palms and soles, which are present in individuals suffering from congenital generalized lipodystrophy type 1 .
Hepatomegaly and splenomegaly may be found during the postnatal examination and may provoke umbilical prominence or even an umbilical hernia . In some patients, hepatosplenomegaly only develops during childhood. Initially, hepatic enlargement is due to the accumulation of fat in this organ, but liver disease may progress from hepatic steatosis to liver fibrosis, liver cirrhosis and liver failure. In some cases, hypertrophic cardiomyopathy has been reported .
Furthermore, acanthosis nigricans is typical of CGL2 and other types of congenital generalized lipodystrophy, but is not necessarily present before puberty. Predilection sites for this pigmentary anomaly are the neck, axillae and groin. Other skin areas may be affected, though. Acanthosis nigricans is considered an early indicator of insulin resistance and is usually detected years before diabetes mellitus becomes symptomatic . Indeed, CGL2-associated diabetes mellitus doesn't generally cause asthenia, weight loss, polyuria, or polydipsia until the second decade of life.
By the time CGL2 patients reach puberty, additional symptoms may manifest in females. Breast development is undisturbed with regards to glandular tissue, but subcutaneous fat is largely missing. Affected women often complain about irregular menstruation, but may also suffer from primary or secondary amenorrhea and polycystic ovary syndrome. Mild hirsutism and clitoromegaly may also be associated with the disease. Most female patients are unable to conceive while males are usually fertile. Teratozoospermia has occasionally been described, though.
Severe hypoleptinemia may induce an increase in appetite. In those patients suffering from hypertriglyceridemia, eruptive xanthomas can frequently been observed. This condition also predisposes for recurrent pancreatitis, particularly in case of poorly controlled diabetes mellitus.
Contrary to other types of congenital generalized lipodystrophy, CGL2 may be associated with mild mental retardation .
Entire Body System
Disturbance of Growth
Complications include hypertrophic cardiomyopathy, a fatty liver with hepatic dysfunction, muscular hypertrophy, a number of endocrine disturbances (accelerated growth in infancy, precocious puberty etc .) and bone cysts with spontaneous fractures. [orpha.net]
Other clinical characteristics of this syndrome are prominent superficial veins, muscle hypertrophy, hirsuitism, abundant curly scalp hair, voracious appetite, accelerated skeletal growth with tall stature and precocious development of genitals. [peertechz.com]
Hepatomegaly and splenomegaly may be found during the postnatal examination and may provoke umbilical prominence or even an umbilical hernia. In some patients, hepatosplenomegaly only develops during childhood. [symptoma.com]
Splenomegaly and phlebomegaly (mostly in the extremities) is a feature.  There is also slight increase in the size of the external genitalia - the penis and the clitoris - since childhood.  Women may have hirsutism, oligomenorrhea, and polycystic [ijdvl.com]
He had a 5 cm non-tender firm hepatomegaly and no splenomegaly. His neurological examination was normal with normal intellectual faculties. Investigations revealed a normal hemogram and urine exam positive for reducing substance. [peertechz.com]
[…] throughout the body – mainly in the neck, trunk, and groin. The disorder also has characteristic features like hepatomegaly or an enlarged liver which arises from fatty liver and may lead to cirrhosis, muscle hypertrophy, lack of adipose tissue, splenomegaly [en.wikipedia.org]
In addition, patients may have umbilical prominence, hepatomegaly, and splenomegaly (Figs. 1 A and B). [ncbi.nlm.nih.gov]
Other characteristics include hepatomegaly affecting liver functions, gum hypertrophy, hypertriglyceridemia, arterial hypertension, acanthosis nigricans, hirsutism, cardiac hypertrophy, and nephropathy. [checkorphan.org]
The minor criteria are hypertrophic cardiomyopathy, mental retardation, hypertrichosis/hirsutism, precocious puberty in females, and bone cyst., Both of our patients fulfilled all major criteria and one minor criterion (hypertrichosis), but both [ijpd.in]
Minor criteria include hypertrophic cardiomyopathy, psychomotor retardation, hirsutism, precocious puberty in females, bone cysts, and phlebomegaly. [ijdvl.com]
Mild hirsutism and clitoromegaly may also be associated with the disease. Most female patients are unable to conceive while males are usually fertile. Teratozoospermia has occasionally been described, though. [symptoma.com]
After puberty, some affected females develop multiple cysts on the ovaries, an increased amount of body hair (hirsutism), and an inability to conceive (infertility), which are likely related to hormonal changes. [ghr.nlm.nih.gov]
We report BSCL type 2 in two siblings with several cutaneous manifestations like acanthosis nigricans, hypertrichosis, prominent subcutaneous veins, and increased lanugo hair. [idoj.in]
Advanced Bone Age
Symptoms Patients have accelerated growth, voracious appetite, and advanced bone age during early childhood. [checkorphan.org]
The 3 patients exhibited rapid growth with advanced bone age, dilation of the cerebral ventricles, hepatosplenomegaly with cirrhosis, generalized muscular overdevelopment, hypertrichosis, hypertension, punctate corneal opacities, and brownish pigmentation [emedicine.medscape.com]
Additional exams show advanced bone age, evidence of liver dysfunction (increase in aminotransferases), dyslipidemia (increase in triglycerides, decrease in HDL, with possible elevation of total cholesterol and LDL levels), glucose intolerance or diabetes [scielo.br]
Acromegaloid features include gigantism, muscular hypertrophy, advanced bone age, prognathism, prominent orbital ridges, enlarged hands and feet, clitoromegaly, and enlarged external genitalia in males. Hepatomegaly. [ncbi.nlm.nih.gov]
Affected individuals tend to have prominent bones above the eyes (orbital ridges), large hands and feet, and a prominent belly button (umbilicus). [ghr.nlm.nih.gov]
Adults may have large hands and feet and a strong, square jawbone if their hormone balance is off and they've kept growing. They could have larger than usual sex organs (clitoris and ovaries, penis and testicles). [webmd.com]
Congenital generalized lipodystrophies are hereditary disorders and thus, it should be determined whether family members have suffered from symptoms similar to those observed in the patient at hand . Also, consanguinity of the parents considerably increases the likelihood of diseases inherited in an autosomal recessive fashion, as is the case with CGL2.
A comprehensive metabolic panel should be obtained in order to detect characteristic anomalies even in the absence of the respective clinical symptoms . The triad of insulin resistance with or without overt diabetes mellitus, hypertriglyceridemia and hepatic steatosis - associated with abnormal liver function tests - is considered to be characteristic of, yet no specific for congenital generalized lipodystrophies  . In detail, biochemical analyses typically yield the following results :
Diagnostic imaging may provide valuable hints on the molecular type of congenital generalized lipodystrophy. Whole-body magnetic resonance imaging allows for the assessment of body fat distribution. In CGL2 patients, a near total absence of body fat is to be expected. Sonography is the technique of choice to assess the overall size of the liver and the progress of fibrotic remodeling in follow-ups. Lytic lesions along the long bones, a condition that predisposes for pathological fractures and that is frequently observed in patients suffering from congenital generalized lipodystrophy type 1, are not usually observed in people affected by CGL2, as can be seen in images obtained by means of radiography and computer tomography.
Genetic analyses have to be conducted to identify the causal mutation of the BSCL2 gene.
There is no causal therapy for CGL2. Metabolic complications that arise due to the genetic disorder have to be treated symptomatically, by putting into practice dietary measures and by means of pharmacotherapy:
- In general, patients suffering from congenital generalized lipodystrophy are recommended to avoid excessive food intake and restrict the ingestion of fat and carbohydrates. Due to the lack of adipose tissue, energy storage is limited and fluctuations in energy supply are poorly compensated.
- Before recombinant analogs of human leptin have been used to treat generalized lipodystrophies, conventional antidiabetics and lipid-lowering drugs had been the mainstay of therapy . However, adequate control of metabolic anomalies has rarely been achieved. By contrast, leptin analogs significantly improve insulin resistance and diabetes mellitus as well as hypertriglyceridemia and related complications.
- Still, many patients require additional medication, either because they never respond satisfactorily to leptin analogs or because the efficacy of that therapy decreases due to the formation of antibodies against the recombinant hormone . With regards to mitigating insulin resistance and hyperglycemia, thiazolidinediones such as pioglitazone and troglitazone have been shown to be more effective than metformin. However, in severe cases, glycemic control can only be achieved by high doses of insulin .
Diabetes mellitus, heart disease, and hepatopathy are frequent complications of CGL2 and decrease the life expectancy of affected individuals . CGL2 patients are at particularly high risks of cardiovascular accidents, liver cirrhosis, and hepatocellular carcinoma . According to a meta-analysis published recently, the mean age at mortality was 12.5 years for patients suffering from any congenital generalized lipodystrophy .
CGL2 has been associated with mutations of the BSCL2 gene. BSCL2 stands for Bernardinelli-Seip congenital lipodystrophy type 2 protein, and this gene encodes for a protein of as of yet unknown function. It is located in the endoplasmic reticulum and presumably plays a major role in lipid droplet formation and adipocyte differentiation. Both null and missense mutations of the BSCL2 gene have been described in CGL2 patients, but distinct types of mutation could not yet be related with phenotypic differences.
To date, about 500 cases of congenital generalized lipodystrophy have been described. The overall prevalence of those diseases comprised in this group has been roughly estimated to 1 in 10,000,000 inhabitants , but it may be even lower . Reliable data regarding incidence and prevalence of single types of congenital generalized lipodystrophy cannot be provided, though.
CGL2 is the second most common subtype of congenital generalized lipodystrophy. Most cases have been reported in Lebanese families, but also in individuals of European, Mediterranean and Middle Eastern Arabic, and Japanese origin. Consistent with the fact that CGL2 and other types of congenital generalized lipodystrophy are inherited in an autosomal recessive pattern, consanguineous marriage and low genetic variability considerably increase the risk of homozygosity in offspring .
Individuals suffering from congenital generalized lipodystrophy lack functional adipocytes. Consequently, lipids are stored in other tissues, namely in muscles and liver, and in fact, patients may present with skeletal muscle hypertrophy and hepatomegaly at birth  . Nevertheless, the mean percentage of body fat remains below 10%  . In other studies, mean values of less than 6% have been reported . Furthermore, CGL2 is not only associated with abnormal lipid storage but also with considerable metabolic disturbances. This can be explained by the fact that adipose tissue plays an important role in endocrine processes and secretes a variety of hormones. One of those hormones is leptin, a proinflammatory adipokine and regulator of appetite and energy expenditure . Unsurprisingly though, metabolic complications start to arise soon after birth in those affected by congenital generalized lipodystrophy:
- Insulin resistance and hyperinsulinemia may be detected in affected infants and children, while diabetes mellitus rarely manifests before puberty. CGL2 patients suffer from ketosis-resistant diabetes mellitus . Furthermore, about three out of four patients affected by CGL2 develop hypertriglyceridemia during late childhood or adolescence. It has been speculated that enhanced lipolysis and defective energy storage contribute to the development of this type of dyslipidemia, but further research is necessary to understand how these processes are related to each other .
- Insulin resistance has also been related to hyperandrogenism  and hyperandrogenism interferes with ovary function in women suffering from congenital generalized lipodystrophy . Additionally, irregular luteinizing hormone
stimulation presumably contributes to anovulation and infertility in affected females .
Affected families may benefit from genetic counseling. Those with a positive family history of hereditary diseases should be informed about the risks inherent in consanguineous marriage, and in case CGL2 has been diagnosed in family members, genetic analyses may help to assess the precise risk for any couple to engender a child homozygous for BSCL2 mutations.
The term congenital generalized lipodystrophy refers to a heterogeneous group of disorders, all of which are inherited in an autosomal recessive manner. In general, individuals suffering from congenital generalized lipodystrophy lack adipose tissue from birth and are prone to metabolic disease. Most patients develop severe insulin resistance and diabetes mellitus, hypertriglyceridemia, hepatic steatosis, polycystic ovary syndrome, acanthosis nigricans and
hypertension . There are four types of congenital generalized lipodystrophy, which differ with regards to their etiology, but largely coincide clinically:
- Congenital generalized lipodystrophy type 1 results from mutations in the AGPAT2 gene.
- CGL2 is associated with mutations of the BSCL2 gene and will be discussed in this article.
- Congenital generalized lipodystrophy type 3 is caused by sequence anomalies within the CAV1 gene.
- Congenital generalized lipodystrophy type 4 develops due to mutations of the CAVIN1 or PTRF gene.
Alternative denominations of CGL2 include Berardinelli-Seip congenital lipodystrophy type 2, BSCL2-related Brunzell syndrome, total lipodystrophy and acromegaloid gigantism, and congenital lipatrophic diabetes.
Congenital generalized lipodystrophy type 2 (CGL2) is an inherited disease associated with anomalies of fat storage and metabolism affecting the whole body. In detail, children who inherit defective allels of a gene named BSCL2 from both their parents will suffer from CGL2. A near-total absence of body fat and extreme muscularity are characteristic of the disease and usually apparent at birth. Furthermore, affected individuals may show umbilical prominence or even have umbilical hernia due to an enlarged liver. These observations can be explained by the fact that functional adipose tissue can only be formed by those disposing of at least one "healthy" BSCL2 gene. In CGL2 patients, however, adipose tissue is largely missing and lipids are stored in muscles and liver.
Because adipose tissue plays an important role in endocrine processes and secretes a variety of hormones, CGL2 predisposes for metabolic complications such as insulin resistance, hyperinsulinemia, and diabetes mellitus as well as hypertriglyceridemia. In turn, these conditions render CGL2 patients prone to cardiovascular disease and interfere with fertility. Acanthosis nigricans and eruptive xanthomas may result from CGL2, but also irregular menstruation, amenorrhea, polycystic ovary syndrome and pancreatitis.
In order to decrease the risk of such potentially life-threatening complications, metabolic anomalies as described above have to be corrected. Recombinant analogs of human leptin, i.e., of one of those hormones secreted by normal adipose tissue, as well as antidiabetic and lipid-lowering drugs are applied to this end. In some cases, patients require high doses of insulin to sufficiently lower blood glucose concentrations. Still, treatment shouldn't rely on medication alone and needs to be complemented by an appropriate diet. Those suffering from CGL2 are recommended to restrict fat and carbohydrate intake in order to maintain blood lipid levels within desirable ranges and to avoid complications due to fluctuations in energy supply that cannot be compensated.
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