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Congenital generalized lipodystrophy type 3(CGL3; BSCL3)

MedGen UID:
436541
Concept ID:
C2675861
Disease or Syndrome
Synonym: BERARDINELLI-SEIP CONGENITAL LIPODYSTROPHY, TYPE 3
 
Gene (location): CAV1 (7q31.2)
 
Monarch Initiative: MONDO:0012923
OMIM®: 612526

Definition

Congenital generalized lipodystrophy, 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). [from OMIM]

Additional description

From MedlinePlus Genetics
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.

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.

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.

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.  https://medlineplus.gov/genetics/condition/congenital-generalized-lipodystrophy

Clinical features

From HPO
Primary amenorrhea
MedGen UID:
115918
Concept ID:
C0232939
Disease or Syndrome
Abnormally late or absent menarche in a female with normal secondary sexual characteristics.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Hepatosplenomegaly
MedGen UID:
9225
Concept ID:
C0019214
Sign or Symptom
Simultaneous enlargement of the liver and spleen.
Hepatic steatosis
MedGen UID:
398225
Concept ID:
C2711227
Disease or Syndrome
Steatosis is a term used to denote lipid accumulation within hepatocytes.
Lipodystrophy
MedGen UID:
6111
Concept ID:
C0023787
Disease or Syndrome
Degenerative changes of the fat tissue.
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.
Generalized lipodystrophy
MedGen UID:
1369615
Concept ID:
C4317112
Disease or Syndrome
Generalized degenerative changes of the fat tissue.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Diabetes mellitus
MedGen UID:
8350
Concept ID:
C0011849
Disease or Syndrome
A group of abnormalities characterized by hyperglycemia and glucose intolerance.
Hypercholesterolemia
MedGen UID:
5687
Concept ID:
C0020443
Disease or Syndrome
An increased concentration of cholesterol in the blood.
Hypocalcemia
MedGen UID:
5705
Concept ID:
C0020598
Disease or Syndrome
An abnormally decreased calcium concentration in the blood.
Insulin resistance
MedGen UID:
43904
Concept ID:
C0021655
Pathologic Function
Increased resistance towards insulin, that is, diminished effectiveness of insulin in reducing blood glucose levels.
Hypertriglyceridemia
MedGen UID:
167238
Concept ID:
C0813230
Finding
An abnormal increase in the level of triglycerides in the blood.
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).

Professional guidelines

PubMed

Araujo-Vilar D, Sánchez-Iglesias S, Guillín-Amarelle C, Castro A, Lage M, Pazos M, Rial JM, Blasco J, Guillén-Navarro E, Domingo-Jiménez R, del Campo MR, González-Méndez B, Casanueva FF
Endocrine 2015 May;49(1):139-47. Epub 2014 Nov 4 doi: 10.1007/s12020-014-0450-4. PMID: 25367549Free PMC Article
Agarwal AK, Garg A
Annu Rev Med 2006;57:297-311. doi: 10.1146/annurev.med.57.022605.114424. PMID: 16409151

Recent clinical studies

Etiology

Yildirim Simsir I, Tuysuz B, Ozbek MN, Tanrikulu S, Celik Guler M, Karhan AN, Denkboy Ongen Y, Gunes N, Soyaltin UE, Altay C, Nur B, Ozalkak S, Akgun Dogan O, Dursun F, Pekkolay Z, Eren MA, Usta Y, Ozisik S, Ozgen Saydam B, Adiyaman SC, Unal MC, Gungor Semiz G, Turan I, Eren E, Kayserili H, Jeru I, Vigouroux C, Atik T, Onay H, Ozen S, Arioglu Oral E, Akinci B
Diabetes Obes Metab 2023 Jul;25(7):1950-1963. Epub 2023 Apr 11 doi: 10.1111/dom.15061. PMID: 36946378
Adiyaman SC, V Schnurbein J, De Laffolie J, Hahn A, Siebert R, Wabitsch M, Kamrath C
J Pediatr Endocrinol Metab 2022 Jul 26;35(7):946-952. Epub 2022 Apr 11 doi: 10.1515/jpem-2022-0022. PMID: 35405042
Sorkina E, Chichkova V
Presse Med 2021 Nov;50(3):104075. Epub 2021 Sep 22 doi: 10.1016/j.lpm.2021.104075. PMID: 34562560
Capeau J, Magré J, Caron-Debarle M, Lagathu C, Antoine B, Béréziat VR, Lascols O, Bastard JP, Vigouroux C
Endocr Dev 2010;19:1-20. Epub 2010 Jun 15 doi: 10.1159/000316893. PMID: 20551664Free PMC Article
Park JY, Chong AY, Cochran EK, Kleiner DE, Haller MJ, Schatz DA, Gorden P
J Clin Endocrinol Metab 2008 Jan;93(1):26-31. Epub 2007 Oct 16 doi: 10.1210/jc.2007-1856. PMID: 17940115Free PMC Article

Diagnosis

Mancioppi V, Daffara T, Romanisio M, Ceccarini G, Pelosini C, Santini F, Bellone S, Mellone S, Baricich A, Rabbone I, Aimaretti G, Akinci B, Giordano M, Prodam F
Front Endocrinol (Lausanne) 2023;14:1212729. Epub 2023 Jul 12 doi: 10.3389/fendo.2023.1212729. PMID: 37501786Free PMC Article
Costa S, Sampaio L, Berta Sousa A, Xing C, Agarwal AK, Garg A
J Clin Endocrinol Metab 2022 Aug 18;107(9):2433-2438. doi: 10.1210/clinem/dgac406. PMID: 35857714Free PMC Article
Sorkina E, Chichkova V
Presse Med 2021 Nov;50(3):104075. Epub 2021 Sep 22 doi: 10.1016/j.lpm.2021.104075. PMID: 34562560
Craveiro Sarmento AS, Ferreira LC, Lima JG, de Azevedo Medeiros LB, Barbosa Cunha PT, Agnez-Lima LF, Galvão Ururahy MA, de Melo Campos JTA
Mutat Res Rev Mutat Res 2019 Jul-Sep;781:30-52. Epub 2019 Mar 23 doi: 10.1016/j.mrrev.2019.03.005. PMID: 31416577
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

Adiyaman SC, V Schnurbein J, De Laffolie J, Hahn A, Siebert R, Wabitsch M, Kamrath C
J Pediatr Endocrinol Metab 2022 Jul 26;35(7):946-952. Epub 2022 Apr 11 doi: 10.1515/jpem-2022-0022. PMID: 35405042
Brener A, Zeitlin L, Wilnai Y, Birk OS, Rosenfeld T, Chorna E, Lebenthal Y
Acta Diabetol 2022 May;59(5):711-719. Epub 2022 Feb 8 doi: 10.1007/s00592-022-01854-7. PMID: 35137278
Dantas de Medeiros Rocha E, Dantas Leite L, de Fátima Paiva Baracho M, Goretti do Nascimento Santos M, de Araújo DM, Cavalcante França M, da Silva CA, das Graças Almeida M, Rezende AA, Marchini JS, Brandão-Neto J
Ann Nutr Metab 2010;57(1):9-17. Epub 2010 Jul 8 doi: 10.1159/000313932. PMID: 20616542
Park JY, Chong AY, Cochran EK, Kleiner DE, Haller MJ, Schatz DA, Gorden P
J Clin Endocrinol Metab 2008 Jan;93(1):26-31. Epub 2007 Oct 16 doi: 10.1210/jc.2007-1856. PMID: 17940115Free PMC Article
Kodama S, Kasuga M, Seki A, Ninomiya M, Sakurai T, Morishita Y, Matsuo M, Matsuo T
Eur J Pediatr 1978 Jan 17;127(2):111-9. doi: 10.1007/BF00445766. PMID: 203464

Prognosis

Vatier C, Vantyghem MC, Storey C, Jéru I, Christin-Maitre S, Fève B, Lascols O, Beltrand J, Carel JC, Vigouroux C, Bismuth E
Curr Med Res Opin 2019 Mar;35(3):543-552. Epub 2018 Nov 9 doi: 10.1080/03007995.2018.1533459. PMID: 30296183
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
Araujo-Vilar D, Sánchez-Iglesias S, Guillín-Amarelle C, Castro A, Lage M, Pazos M, Rial JM, Blasco J, Guillén-Navarro E, Domingo-Jiménez R, del Campo MR, González-Méndez B, Casanueva FF
Endocrine 2015 May;49(1):139-47. Epub 2014 Nov 4 doi: 10.1007/s12020-014-0450-4. PMID: 25367549Free PMC Article
Antuna-Puente B, Boutet E, Vigouroux C, Lascols O, Slama L, Caron-Debarle M, Khallouf E, Lévy-Marchal C, Capeau J, Bastard JP, Magré J
J Clin Endocrinol Metab 2010 Mar;95(3):1463-8. Epub 2010 Jan 22 doi: 10.1210/jc.2009-1824. PMID: 20097706
Park JY, Chong AY, Cochran EK, Kleiner DE, Haller MJ, Schatz DA, Gorden P
J Clin Endocrinol Metab 2008 Jan;93(1):26-31. Epub 2007 Oct 16 doi: 10.1210/jc.2007-1856. PMID: 17940115Free PMC Article

Clinical prediction guides

Adiyaman SC, V Schnurbein J, De Laffolie J, Hahn A, Siebert R, Wabitsch M, Kamrath C
J Pediatr Endocrinol Metab 2022 Jul 26;35(7):946-952. Epub 2022 Apr 11 doi: 10.1515/jpem-2022-0022. PMID: 35405042
Lima JG, Nobrega LHC, Lima NN, Dos Santos MCF, Baracho MFP, Bandeira F, Capistrano L, Freire Neto FP, Jeronimo SMB
J Clin Densitom 2018 Jan-Mar;21(1):61-67. Epub 2016 Nov 25 doi: 10.1016/j.jocd.2016.10.002. PMID: 27894728
Faria CA, Moraes RS, Sobral-Filho DC, Rego AG, Baracho MF, Egito ES, Brandão-Neto J
Europace 2009 Jun;11(6):763-9. Epub 2009 Apr 17 doi: 10.1093/europace/eup095. PMID: 19376819
Taleban S, Carew HT, Dichek HL, Deeb SS, Hollenback D, Weigle DS, Cummings DE, Brunzell JD
Metabolism 2008 Aug;57(8):1155-61. doi: 10.1016/j.metabol.2008.04.008. PMID: 18640396Free PMC Article
Agarwal AK, Garg A
Annu Rev Med 2006;57:297-311. doi: 10.1146/annurev.med.57.022605.114424. PMID: 16409151

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