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Congenital generalized lipodystrophy type 2(CGL2)

MedGen UID:
318593
Concept ID:
C1720863
Congenital Abnormality
Synonyms: BERARDINELLI SYNDROME; Berardinelli-Seip Congenital Lipodystrophy Type 2; BRUNZELL SYNDROME, BSCL2-RELATED; CGL2; SEIP SYNDROME
 
Gene (location): BSCL2 (11q12.3)
 
Monarch Initiative: MONDO:0010020
OMIM®: 269700

Disease characteristics

Excerpted from the GeneReview: Berardinelli-Seip Congenital Lipodystrophy
Berardinelli-Seip congenital lipodystrophy (BSCL) is usually diagnosed at birth or soon thereafter. Because of the absence of functional adipocytes, lipid is stored in other tissues, including muscle and liver. Affected individuals develop insulin resistance and approximately 25%-35% develop diabetes mellitus between ages 15 and 20 years. Hepatomegaly secondary to hepatic steatosis and skeletal muscle hypertrophy occur in all affected individuals. Hypertrophic cardiomyopathy is reported in 20%-25% of affected individuals and is a significant cause of morbidity from cardiac failure and early mortality. [from GeneReviews]
Authors:
Lionel Van Maldergem   view full author information

Additional descriptions

From OMIM
Congenital generalized lipodystrophy (CGL), also known as Berardinelli-Seip syndrome, is an autosomal recessive disorder characterized by marked paucity of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis and early onset of diabetes (Garg, 2004). For a general description and a discussion of genetic heterogeneity of congenital generalized lipodystrophy, see CGL1 (608594).  http://www.omim.org/entry/269700
From MedlinePlus Genetics
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.  https://medlineplus.gov/genetics/condition/congenital-generalized-lipodystrophy

Clinical features

From HPO
Polycystic ovaries
MedGen UID:
10836
Concept ID:
C0032460
Disease or Syndrome
Polycystic ovary syndrome is a condition that affects women in their child-bearing years and alters the levels of multiple hormones, resulting in problems affecting many body systems.\n\nMost women with polycystic ovary syndrome produce excess male sex hormones (androgens), a condition called hyperandrogenism. Having too much of these hormones typically leads to excessive body hair growth (hirsutism), acne, and male pattern baldness.\n\nHyperandrogenism and abnormal levels of other sex hormones prevent normal release of egg cells from the ovaries (ovulation) and regular menstrual periods, leading to difficulty conceiving a child (subfertility) or a complete inability to conceive (infertility). For those who achieve pregnancy, there is an increased risk of complications and pregnancy loss. Due to irregular and infrequent menstruation and hormone abnormalities, affected women have an increased risk of cancer of the uterine lining (endometrial cancer).\n\nIn polycystic ovary syndrome, one or both ovaries can contain multiple small, immature ovarian follicles that can appear as cysts on medical imaging. Normally, ovarian follicles contain egg cells, which are released during ovulation. In polycystic ovary syndrome, abnormal hormone levels prevent follicles from growing and maturing to release egg cells. Instead, these immature follicles accumulate in the ovaries. Affected women can have 12 or more of these follicles. The number of these follicles usually decreases with age.\n\nAbout half of all women with polycystic ovary syndrome are overweight or have obesity and are at increased risk of a fatty liver. Additionally, many women with polycystic ovary syndrome have elevated levels of insulin, which is a hormone that helps control levels of blood glucose, also called blood sugar. By age 40, about 10 percent of overweight women with polycystic ovary syndrome develop abnormally high blood glucose levels (type 2 diabetes), and up to 35 percent develop prediabetes (higher-than-normal blood glucose levels that do not reach the cutoff for diabetes). Obesity and increased insulin levels (hyperinsulinemia) further increase the production of androgens in polycystic ovary syndrome.\n\nWomen with polycystic ovary syndrome are also at increased risk for developing metabolic syndrome, which is a group of conditions that include high blood pressure (hypertension), increased belly fat, high levels of unhealthy fats and low levels of healthy fats in the blood, and high blood glucose levels. About 20 percent of affected adults experience pauses in breathing during sleep (sleep apnea). Women with polycystic ovary syndrome are more likely than women in the general popluation to have mood disorders such as depression.
Decreased fertility in females
MedGen UID:
57728
Concept ID:
C0151639
Finding
Clitoral hypertrophy
MedGen UID:
57848
Concept ID:
C0156394
Finding
Hypertrophy of the clitoris.
Nephrolithiasis
MedGen UID:
98227
Concept ID:
C0392525
Disease or Syndrome
The presence of calculi (stones) in the kidneys.
Labial hypertrophy
MedGen UID:
96054
Concept ID:
C0404531
Pathologic Function
Decreased fertility
MedGen UID:
452706
Concept ID:
C0729353
Finding
Large hands
MedGen UID:
98097
Concept ID:
C0426870
Finding
Long foot
MedGen UID:
154365
Concept ID:
C0576225
Finding
Increased back to front length of the foot.
Hypertrophic cardiomyopathy
MedGen UID:
2881
Concept ID:
C0007194
Disease or Syndrome
Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased ventricular wall thickness or mass in the absence of loading conditions (hypertension, valve disease) sufficient to cause the observed abnormality.
Ventricular septal hypertrophy
MedGen UID:
138013
Concept ID:
C0344955
Finding
The dividing wall between left and right sides of the heart, thickens and bulges into the left ventricle.
Tall stature
MedGen UID:
69137
Concept ID:
C0241240
Finding
A height above that which is expected according to age and gender norms.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Cirrhosis of liver
MedGen UID:
7368
Concept ID:
C0023890
Disease or Syndrome
A chronic disorder of the liver in which liver tissue becomes scarred and is partially replaced by regenerative nodules and fibrotic tissue resulting in loss of liver function.
Prominent umbilicus
MedGen UID:
324875
Concept ID:
C1837795
Finding
Abnormally prominent umbilicus (belly button).
Hepatic steatosis
MedGen UID:
398225
Concept ID:
C2711227
Disease or Syndrome
Steatosis is a term used to denote lipid accumulation within hepatocytes.
Macrotia
MedGen UID:
488785
Concept ID:
C0152421
Congenital Abnormality
Median longitudinal ear length greater than two standard deviations above the mean and median ear width greater than two standard deviations above the mean (objective); or, apparent increase in length and width of the pinna (subjective).
Polyphagia
MedGen UID:
9369
Concept ID:
C0020505
Finding
A neurological anomaly with gross overeating associated with an abnormally strong desire or need to eat.
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
High pitched voice
MedGen UID:
66836
Concept ID:
C0241703
Finding
An abnormal increase in the pitch (frequency) of the voice.
Elevated hemoglobin A1c
MedGen UID:
892798
Concept ID:
C4073162
Finding
An increased concentration of hemoglobin A1c (HbA1c), which is the product of nonenzymatic attachment of a hexose molecule to the N-terminal amino acid of the hemoglobin molecule. This reaction is dependent on blood glucose concentration, and therefore reflects the mean glucose concentration over the previous 8 to 12 weeks. The HbA1c level provides a better indication of long-term glycemic control than one-time blood or urinary glucose measurements.
Umbilical hernia
MedGen UID:
9232
Concept ID:
C0019322
Anatomical Abnormality
Protrusion of abdominal contents through a defect in the abdominal wall musculature around the umbilicus. Skin and subcutaneous tissue overlie the defect.
Lipodystrophy
MedGen UID:
6111
Concept ID:
C0023787
Disease or Syndrome
Degenerative changes of the fat tissue.
Accelerated skeletal maturation
MedGen UID:
154262
Concept ID:
C0545053
Finding
An abnormally increased rate of skeletal maturation. Accelerated skeletal maturation can be diagnosed on the basis of an estimation of the bone age from radiographs of specific bones in the human body.
Generalized muscular appearance from birth
MedGen UID:
373412
Concept ID:
C1837799
Finding
Reduced subcutaneous adipose tissue
MedGen UID:
387876
Concept ID:
C1857657
Finding
A reduced amount of fat tissue in the lowest layer of the integument. This feature can be appreciated by a reduced skinfold thickness.
Cystic angiomatosis of bone
MedGen UID:
867384
Concept ID:
C4021749
Finding
Disseminated multifocal hemangiomatous or lymphangiomatous lesions of the skeleton. The lesions are lytic, well-defined, round or oval lesions within the medullary cavity, and they have an intact cortex, and manifest variable peripheral sclerosis and may exhibit endosteal scalloping.
Reduced intrathoracic adipose tissue
MedGen UID:
1378187
Concept ID:
C4476537
Finding
An abnormally reduced amount of adipose tissue in the thoracic cavity.
Reduced intraabdominal adipose tissue
MedGen UID:
1369752
Concept ID:
C4476602
Finding
An abnormally reduced amount of adipose tissue in the abdominal cavity.
Acute pancreatitis
MedGen UID:
7872
Concept ID:
C0001339
Disease or Syndrome
A acute form of pancreatitis.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Type 2 diabetes mellitus
MedGen UID:
41523
Concept ID:
C0011860
Disease or Syndrome
Type 2 diabetes mellitus is distinct from maturity-onset diabetes of the young (see 606391) in that it is polygenic, characterized by gene-gene and gene-environment interactions with onset in adulthood, usually at age 40 to 60 but occasionally in adolescence if a person is obese. The pedigrees are rarely multigenerational. The penetrance is variable, possibly 10 to 40% (Fajans et al., 2001). Persons with type 2 diabetes usually have an obese body habitus and manifestations of the so-called metabolic syndrome (see 605552), which is characterized by diabetes, insulin resistance, hypertension, and hypertriglyceridemia. Genetic Heterogeneity of Susceptibility to Type 2 Diabetes Susceptibility to T2D1 (601283) is conferred by variation in the calpain-10 gene (CAPN10; 605286) on chromosome 2q37. The T2D2 locus (601407) on chromosome 12q was found in a Finnish population. The T2D3 locus (603694) maps to chromosome 20. The T2D4 locus (608036) maps to chromosome 5q34-q35. Susceptibility to T2D5 (616087) is conferred by variation in the TBC1D4 gene (612465) on chromosome 13q22. A mutation has been observed in hepatocyte nuclear factor-4-alpha (HNF4A; 600281.0004) in a French family with NIDDM of late onset. Mutations in the NEUROD1 gene (601724) on chromosome 2q32 were found to cause type 2 diabetes mellitus in 2 families. Mutation in the GLUT2 glucose transporter was associated with NIDDM in 1 patient (138160.0001). Mutation in the MAPK8IP1 gene, which encodes the islet-brain-1 protein, was found in a family with type 2 diabetes in individuals in 4 successive generations (604641.0001). Polymorphism in the KCNJ11 gene (600937.0014) confers susceptibility. In French white families, Vionnet et al. (2000) found evidence for a susceptibility locus for type 2 diabetes on 3q27-qter. They confirmed the diabetes susceptibility locus on 1q21-q24 reported by Elbein et al. (1999) in whites and by Hanson et al. (1998) in Pima Indians. A mutation in the GPD2 gene (138430.0001) on chromosome 2q24.1, encoding mitochondrial glycerophosphate dehydrogenase, was found in a patient with type 2 diabetes mellitus and in his glucose-intolerant half sister. Mutations in the PAX4 gene (167413) have been identified in patients with type 2 diabetes. Triggs-Raine et al. (2002) stated that in the Oji-Cree, a gly319-to-ser change in HNF1-alpha (142410.0008) behaves as a susceptibility allele for type 2 diabetes. Mutation in the HNF1B gene (189907.0007) was found in 2 Japanese patients with typical late-onset type 2 diabetes. Mutations in the IRS1 gene (147545) have been found in patients with type 2 diabetes. A missense mutation in the AKT2 gene (164731.0001) caused autosomal dominant type 2 diabetes in 1 family. A (single-nucleotide polymorphism) SNP in the 3-prime untranslated region of the resistin gene (605565.0001) was associated with susceptibility to diabetes and to insulin resistance-related hypertension in Chinese subjects. Susceptibility to insulin resistance has been associated with polymorphism in the TCF1 (142410.0011), PPP1R3A (600917.0001), PTPN1 (176885.0001), ENPP1 (173335.0006), IRS1 (147545.0002), and EPHX2 (132811.0001) genes. The K121Q polymorphism of ENPP1 (173335.0006) is associated with susceptibility to type 2 diabetes; a haplotype defined by 3 SNPs of this gene, including K121Q, is associated with obesity, glucose intolerance, and type 2 diabetes. A SNP in the promoter region of the hepatic lipase gene (151670.0004) predicts conversion from impaired glucose tolerance to type 2 diabetes. Variants of transcription factor 7-like-2 (TCF7L2; 602228.0001), located on 10q, have also been found to confer risk of type 2 diabetes. A common sequence variant, rs10811661, on chromosome 9p21 near the CDKN2A (600160) and CDKN2B (600431) genes has been associated with risk of type 2 diabetes. Variation in the PPARG gene (601487) has been associated with risk of type 2 diabetes. A promoter polymorphism in the IL6 gene (147620) is associated with susceptibility to NIDDM. Variation in the KCNJ15 gene (602106) has been associated with T2DM in lean Asians. Variation in the SLC30A8 gene (611145) has been associated with susceptibility to T2D. Variation in the HMGA1 gene (600701.0001) is associated with an increased risk of type 2 diabetes. Mutation in the MTNR1B gene (600804) is associated with susceptibility to type 2 diabetes. Protection Against Type 2 Diabetes Mellitus Protein-truncating variants in the SLC30A8 (611145) have been associated with a reduced risk for T2D.
Hypertriglyceridemia
MedGen UID:
167238
Concept ID:
C0813230
Finding
An abnormal increase in the level of triglycerides in the blood.
Insulin-resistant diabetes mellitus at puberty
MedGen UID:
373411
Concept ID:
C1837792
Disease or Syndrome
Elevated hepatic transaminase
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Mandibular prognathia
MedGen UID:
98316
Concept ID:
C0399526
Finding
Abnormal prominence of the chin related to increased length of the mandible.
Triangular face
MedGen UID:
324383
Concept ID:
C1835884
Finding
Facial contour, as viewed from the front, triangular in shape, with breadth at the temples and tapering to a narrow chin.
Acanthosis nigricans
MedGen UID:
54
Concept ID:
C0000889
Disease or Syndrome
A dermatosis characterized by thickened, hyperpigmented plaques, typically on the intertriginous surfaces and neck.
Hirsutism
MedGen UID:
42461
Concept ID:
C0019572
Disease or Syndrome
Abnormally increased hair growth referring to a male pattern of body hair (androgenic hair).
Hyperinsulinemia
MedGen UID:
43779
Concept ID:
C0020459
Disease or Syndrome
An increased concentration of insulin in the blood.
Decreased serum leptin
MedGen UID:
373413
Concept ID:
C1837802
Finding
A decreased concentration of leptin in the blood.

Professional guidelines

PubMed

Mainieri F, Tagi VM, Chiarelli F
Front Endocrinol (Lausanne) 2022;13:879979. Epub 2022 May 4 doi: 10.3389/fendo.2022.879979. PMID: 35600578Free PMC Article
Araújo-Vilar D, Santini F
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Gupta N, Asi N, Farah W, Almasri J, Barrionuevo P, Alsawas M, Wang Z, Haymond MW, Brown RJ, Murad MH
J Clin Endocrinol Metab 2017 Feb 1;102(2):363-374. doi: 10.1210/jc.2016-2271. PMID: 27967300Free PMC Article

Recent clinical studies

Etiology

Craveiro Sarmento AS, Gomes Lima J, de Souza Timoteo AR, Galvão Ururahy MA, Antunes de Araújo A, Carvalho Vasconcelos R, Cândido Dantas VK, Fassarella Agnez-Lima L, Araújo de Melo Campos JT
Biochim Biophys Acta Mol Cell Biol Lipids 2020 Apr;1865(4):158610. Epub 2020 Jan 7 doi: 10.1016/j.bbalip.2020.158610. PMID: 31917334
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Neuromuscul Disord 2017 Oct;27(10):923-930. Epub 2017 Jun 1 doi: 10.1016/j.nmd.2017.05.015. PMID: 28754454

Diagnosis

Ferranti S, Lo Rizzo C, Renieri A, Galluzzi P, Grosso S
Neurol Sci 2020 Nov;41(11):3345-3348. Epub 2020 May 21 doi: 10.1007/s10072-020-04418-1. PMID: 32440981
Akinci G, Topaloglu H, Demir T, Danyeli AE, Talim B, Keskin FE, Kadioglu P, Talip E, Altay C, Yaylali GF, Bilen H, Nur B, Demir L, Onay H, Akinci B
Neuromuscul Disord 2017 Oct;27(10):923-930. Epub 2017 Jun 1 doi: 10.1016/j.nmd.2017.05.015. PMID: 28754454
Opri R, Fabrizi GM, Cantalupo G, Ferrarini M, Simonati A, Dalla Bernardina B, Darra F
Seizure 2016 Nov;42:1-6. Epub 2016 Sep 5 doi: 10.1016/j.seizure.2016.08.008. PMID: 27632409

Therapy

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Prognosis

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Clinical prediction guides

Ferranti S, Lo Rizzo C, Renieri A, Galluzzi P, Grosso S
Neurol Sci 2020 Nov;41(11):3345-3348. Epub 2020 May 21 doi: 10.1007/s10072-020-04418-1. PMID: 32440981
Craveiro Sarmento AS, Gomes Lima J, de Souza Timoteo AR, Galvão Ururahy MA, Antunes de Araújo A, Carvalho Vasconcelos R, Cândido Dantas VK, Fassarella Agnez-Lima L, Araújo de Melo Campos JT
Biochim Biophys Acta Mol Cell Biol Lipids 2020 Apr;1865(4):158610. Epub 2020 Jan 7 doi: 10.1016/j.bbalip.2020.158610. PMID: 31917334
Akinci G, Topaloglu H, Demir T, Danyeli AE, Talim B, Keskin FE, Kadioglu P, Talip E, Altay C, Yaylali GF, Bilen H, Nur B, Demir L, Onay H, Akinci B
Neuromuscul Disord 2017 Oct;27(10):923-930. Epub 2017 Jun 1 doi: 10.1016/j.nmd.2017.05.015. PMID: 28754454

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