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Congenital generalized lipodystrophy type 4(CGL4)

MedGen UID:
412871
Concept ID:
C2750069
Disease or Syndrome
Synonym: BERARDINELLI-SEIP CONGENITAL LIPODYSTROPHY, TYPE 4, WITH MUSCULAR DYSTROPHY
SNOMED CT: Generalized congenital lipodystrophy with myopathy (1156814008); Generalized congenital lipodystrophy type 4 (1156814008)
 
CAVIN1 (17q21.2)
 
Monarch Initiative: MONDO:0013225
OMIM®: 613327
Orphanet: ORPHA228429

Definition

Congenital generalized lipodystrophy type 4 (CGL4) combines the phenotype of classic Berardinelli-Seip lipodystrophy (608594) with muscular dystrophy and cardiac conduction anomalies (Hayashi et al., 2009). For a general description and a discussion of genetic heterogeneity of congenital generalized lipodystrophy, see CGL1 (608594). [from OMIM]

Additional description

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.

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.

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

Clinical features

From HPO

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

Recent clinical studies

Etiology

Akinci G, Alyaarubi S, Patni N, Alhashmi N, Al-Shidhani A, Prodam F, Gagne N, Babalola F, Al Senani A, Muniraj K, Elsayed SM, Beghini M, Saydam BO, Allawati M, Vaishnav MS, Can E, Simsir IY, Sorkina E, Dursun F, Kamrath C, Cavdar U, Chakraborty PP, Dogan OA, Al Hosin A, Al Maimani A, Comunoglu N, Hamed A, Huseinbegovic T, Scherer T, Curtis J, Brown RJ, Topaloglu H, Simha V, Wabitsch M, Tuysuz B, Oral EA, Akinci B, Garg A
Am J Med Genet A 2024 Jun;194(6):e63533. Epub 2024 Jan 17 doi: 10.1002/ajmg.a.63533. PMID: 38234231Free PMC Article
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
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

Diagnosis

Akinci G, Alyaarubi S, Patni N, Alhashmi N, Al-Shidhani A, Prodam F, Gagne N, Babalola F, Al Senani A, Muniraj K, Elsayed SM, Beghini M, Saydam BO, Allawati M, Vaishnav MS, Can E, Simsir IY, Sorkina E, Dursun F, Kamrath C, Cavdar U, Chakraborty PP, Dogan OA, Al Hosin A, Al Maimani A, Comunoglu N, Hamed A, Huseinbegovic T, Scherer T, Curtis J, Brown RJ, Topaloglu H, Simha V, Wabitsch M, Tuysuz B, Oral EA, Akinci B, Garg A
Am J Med Genet A 2024 Jun;194(6):e63533. Epub 2024 Jan 17 doi: 10.1002/ajmg.a.63533. PMID: 38234231Free PMC Article
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
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
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
Murakami N, Hayashi YK, Oto Y, Shiraishi M, Itabashi H, Kudo K, Nishino I, Nonaka I, Nagai T
Neuromuscul Disord 2013 May;23(5):441-4. Epub 2013 Mar 13 doi: 10.1016/j.nmd.2013.02.005. PMID: 23489663

Therapy

Zaffina S, Piano Mortari E, Di Prinzio RR, Cappa M, Novelli A, Agolini E, Raponi M, Dallapiccola B, Locatelli F, Perno CF, Carsetti R
Front Immunol 2022;13:869042. Epub 2022 Apr 6 doi: 10.3389/fimmu.2022.869042. PMID: 35464479Free PMC Article
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

Prognosis

Akinci G, Topaloglu H, Akinci B, Onay H, Karadeniz C, Ergul Y, Demir T, Ozcan EE, Altay C, Atik T, Garg A
Eur J Med Genet 2016 Jun;59(6-7):320-4. Epub 2016 May 7 doi: 10.1016/j.ejmg.2016.05.001. PMID: 27167729Free PMC Article

Clinical prediction guides

Zaffina S, Piano Mortari E, Di Prinzio RR, Cappa M, Novelli A, Agolini E, Raponi M, Dallapiccola B, Locatelli F, Perno CF, Carsetti R
Front Immunol 2022;13:869042. Epub 2022 Apr 6 doi: 10.3389/fimmu.2022.869042. PMID: 35464479Free PMC Article
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
Ishiguro K, Nakayama T, Yoshioka M, Murakami T, Kajino S, Shichiji M, Sato T, Hino-Fukuyo N, Kuru S, Osawa M, Nagata S, Okubo M, Murakami N, Hayashi YK, Nishino I, Ishigaki K
Neuromuscul Disord 2018 Oct;28(10):857-862. Epub 2018 Jul 31 doi: 10.1016/j.nmd.2018.07.010. PMID: 30174172
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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