Berardinelli-Seip congenital

Author: Professor Lionel Van Maldergem1 Creation Date: November 2001

Scientific Editor: Professor Didier LACOMBE

1Centre de Génétique Humaine, Institut de Pathologie et de Génétique, 41, Allée des Templiers, Loverval, 6280, Belgium. [email protected]

Abstract Keywords Disease name and synonyms Excluded diseases Diagnostic criteria Differential diagnosis Prevalence Clinical description Management Handling Etiology Diagnostic methods Genetic counseling Prenatal diagnosis Unresolved questions References

Abstract Berardinelli-Seip congenital lipodystrophy (BSCL) is a very rare autosomal recessive disorder determining the triad of lipoatrophy, , hepatomegaly and acromegaloid features. It is associated with resistance resulting in clinically overt mellitus with onset during the second decade. Complications include hypertrophic cardiomyopathy, a fatty liver with hepatic dysfunction, muscular hypertrophy and a number of endocrine disturbances (accelerated growth in infancy, precocious puberty, ...) and cysts with spontaneous fractures. There are at least three loci among which two are localized (BSCL1 in 9q34 and BSCL2 in 11q13) and one gene already cloned (seipin for BSCL2). Mental retardation is observed in a majority of BSCL2 patients. Treatment consists of low diet and handling of and diabetes.

Keywords - diabetes mellitus - mental retardation - seipin - triglycerides -autosomal recessive inheritance.

Disease name and synonyms syndrome have also been used, although the It is called Berardinelli-Seip syndrome after latter designates in principle the so-called Berardinelli from Brazil described the first acquired form. it is usually called lipoatrophic patients in 1954. The syndrome was confirmed diabetes in the United States. It has received the in 1959 in Norway were Seip described a new OMIM number 269700. Brunzell syndrome is the series of patients originating from the county of association of bone cysts and lipoatrophic Rogaland. In the European literature, the terms diabetes described in five affected African- generalized lipodystrophy, congenital Americans from the same sibship. A separate lipodystrophy or total lipodystrophy have also OMIM entry (272500) was given but it is now been coined. Seip syndrome, or Lawrence generally admitted that bone cysts represent a

Van Maldergem, L., Berardinelli-Seip congenital lipodystrophy. Orphanet encyclopedia. November 2001. http://www.orpha.net/data/patho/GB/uk-berard.pdf 1

rare of Berardinelli-Seip congenital Differential diagnosis lipodystrophy (BSCL). In the infant Excluded diseases • Short syndrome. Slit lamp examination. • Lawrence syndrome . • Dunnigan partial lipodystrophy • Neonatal progeroid syndrome. Prominent • Barraquer-Simons syndrome veins of the scalp. Premature teeth. Pseudo • Partial congenital lipodystrophy with hydrocephaloid appearance. elevated C3 nephritic factor • Neurometabolic lysosomal storage disorder: • Rabson-Mendenhall syndrome Gaucher type 2, Krabbe disease. Abnormal • Launois-Bensaude syndrome neurological examination. • Wiedemann-Rautenstrausch Glucocerebrosidase and • SHORT syndrome galactocerebrosidase on peripheral • AIDS lipodystrophy leukocytes or cultured fibroblasts. • Russell diencephalic syndrome • Russell diencephalic syndrome. Brain MRI

Diagnostic criteria In the child • Dunningan lipodystrophy. Spares the face. Major Cushingoid appearance. in the • Lipoatrophy affecting both trunk and limbs. lamin gene. Gives an athletic appearance, especially • Rabson-Mendenhall. Pure insulin-resistance when muscle hypertrophy is also syndrome present.Secondary phlebomegaly. • Insulin-dependent diabetes mellitus Involvement of the face (empty cheeks due to absence of Bichat's pads) may be absent In the adult at birth and appear during the first months of • Barraquer-Simons syndrome. Asymmetric. life. • AIDS. HIV testing • Acromegaloid features : it includes • Partial lipodystrophy. C3 nephritic factor prognathism, salient orbital ridges, enlarged • Lawrence syndrome hands and feet, macrogenitosomia, gigantism, muscular hypertrophy and Prevalence advanced bone age. Estimated at 1 per 12 millions by Garg in USA • Hepatomegaly secondary to fatty liver and, 1 per million in Norway in late course of the disease, cirrhosis. 1 per 200 000 in Lebanon • Elevated serum concentration of 1 per 500 000 in Portugal triglycerides (up to 80g /Liter), sometimes according to the number of registered cases of associated to . the Berardinelli-Seip study group. • Insulin resistance : may be limited to Clinical description elevated serum concentration of insulin and C-peptide in the first years of life. Will usually Neonatal or infantile presentation determine overt clinical diabetes during the Severe forms may be of prenatal onset with second decade. Its early clinical expression intrauterine growth retardation. When diagnosed is of the groins, neck at birth (rare), it is usually because of and axillae which may take, in some cases, lipoatrophy. Reason for referral in the first a verruquous appearence. months of life include failure to thrive, or conversely gigantism, hepatomegaly, Minor lipoatrophy, facial dysmorphia, enlarged tongue • Hypertrophic cardiomyopathy. May be or developmental delay. present in infancy or develop later in life. • Psychomotor or mental retardation. Affects a Juvenile presentation majority of BSCL2 patients. Mild (IQ 50-70) Accelerated growth, lipoatrophy or cognitive to moderate(IQ 35-50) impairment are major modes of presentation in • : low frontal and posterior early childhood while diabetes mellitus hairlines, hypertrichosis of the trunk manifested by weight loss, polydipsy, polyuria or • Precocious puberty in the female. asthenia is frequently the cause in the second • Bone cysts. Polycyclic appeareance on X- decade. rays. Located in epiphyseal and metaphyseal regions of long . Often diagnosed during the second decade.

Van Maldergem, L., Berardinelli-Seip congenital lipodystrophy. Orphanet encyclopedia. November 2001. http://www.orpha.net/data/patho/GB/uk-berard.pdf 2

Adult presentation insufficient. The other drugs, including Presents rarely in early adulthood with diabetes fenfluramine, have no proven efficiency and mellitus. The plastic surgery clinic for cosmetic should be avoided. improvement of facial lipoatrophy, the cardiologic The patient will have to be followed in a clinics or gastroenterologic clinics may be also diabetology clinic for possible retinal, peripheral the first through which the patient comes to nerve and renal complications one outpatient medical attention. consultation every six months. Cardiac and liver ultrasound will have to be Management repeated every six months. Special education will be required for most Diagnostic work-up BSCL2 patients Family history, including a three generation pedigree and the locality of origin of the Etiology grandparents needs to be investigated. Specific Rare autosomal recessive disorder with at least questions on parental consanguinity should be three loci identified: asked for. BSCL1:prevalent in Africa, Maghreb and African Clinical examination includes the pubertal status populations from North America and Caribbean. according to Tanner's charts, a complete Also described in Western European neurological examination and search for signs of populations. Apparently less severe phenotype liver dysfunction and cardiac failure. Attention than BSCL2. Onset of lipoatrophy may being the must also be paid to possible orthopedics second or third decade. No or low frequency of problems (reduced hip mobility, genu valgum). mental retardation. Linkage to 9q34 established by an Anglo-American consortium in 1999. Addtitional investigations No gene with disease-causing • Clinical chemistry : Complete blood count, identified up to now. electrolytes, serum glucose concentration, BSCL2:prevalent in Portugal and its ancient insulin, aspartate transaminase, alanine colonies, Lebanon and Norway. Lipoatrophy of transaminase, serum proteins and invariable neonatal onset. More severe than electrophoresis, urea, creatinine, C-peptide, BSCL1. A majority of patients (two-thirds) triglycerides, cholesterol, Oral glucose mentally retarded, especially those with a tolerance test. When appropriate : clamp nonsense or a splice-site mutation affecting the glucose homeostasis study, GH, IgG, A, M, first half of the gene. Missense mutations E, C3 nephritic factor, CH50, C3, C4, reportedly less harmful. In a recent survey of 45 apolipoproteins, hypothalamo-pituitary BSCL2 patients, 7 premature deaths were dynamic tests. observed, from and liver failure. Through • Cardiac ultrasound the study of patients from an international • Liver ultrasound consortium, a gene has been cloned in 2001. It • Skeletal survey, especially long bones. encodes a protein of unknown function, mainly Search for osteopenia and bone cysts. Bone expressed in the brain, termed seipin (Magré et age maturation al 2001) • Kidney ultrasound BSCL3:some rare families appear unlinked to • Complete ophtalmological examination, neither 11q13 nor 9q34. If we also consider a including biomicroscopy and slit lamp patient with unconclusive segregation study, it examination seems associated with a severe phenotype (two • Wechsler testing of IQ premature deaths at 16 months and 7 years in • DNA testing ( search for a BSCL2 mutation two Czech patients). However, these are very or 9q34 microsatellites segregation study). scarce data and awaits confirmation on Collect also leukocytes from unaffected additional families siblings and parents after informed consent (15 ml EDTA purple top tubes) Diagnostic methods Dysmorphology Handling Clinical examination Restriction of total fat intake between 20 and Blood chemistry 30% is often sufficient to maintain a normal triglycerides serum concentration. Genetic counseling Hypercholesterolemia is rarely in the range Recurrence risk 25% requiring anticholesterol drugs. Medium chain Microsatellites segregation study and mutation triglycerides may provide an additional effect and screening mandatory to refine counseling. should be used when low fat diet alone is

Van Maldergem, L., Berardinelli-Seip congenital lipodystrophy. Orphanet encyclopedia. November 2001. http://www.orpha.net/data/patho/GB/uk-berard.pdf 3

Prenatal diagnosis 13. Craig JW and Miller M (1960) Lipoatrophic Based on the identification of the mutation in the diabetes in Williams RH : Diabetes. New York, index patients or carriers. Hoeber Publ. Chorionic Villus Sampling between 9 and 12 14. Das GP, Lakshmi M (1991) Seip-Berardinelli weeks. syndrome. Indian J Pediatr 58 : 551-5 Ethical issue of terminating a pregnancy for the 15. Dorasamy DS (1980) Congenital apparently milder BSCL1 subtype where mental lipodystrophy. A case report. S Afr Med J retardation is rare. 58:417-20. 16. Dreyer M, Seemanova E, Schmidt-Preuss U, Unresolved questions Rudiger HW (1992) Clinical and biochemical Function of the protein characterization of syndromes associated with Pathophysiology of the disease defects of the insulin receptor. Acta Univ Carol Med 38 :49-66 References 17. Floret D, Longin B, Plauchu H, Gaillard L, 1. Anand JS (1966) Lipodystrophic muscular Hermier M, François R (1975) Diabete hypertrophy with arthrogryposis multiplex lipoatrophique. Pédiatrie , 30:837-849. congenita. Indian J Pediatr 33:152-6. 18. Fontan A, Verger P, Couteau D, Pery M 2. Arico M, Ricordi A, Caselli D, et al (1987) (1956) Hypertrophie musculaire généralisée à Insulin receptor evaluation in congenital début précoce, avec lipodystrophie faciale, generalized lipodystrophy. Case report of an hépatomégalie et hypertrophie clitoridienne chez infant. Helv Paediatr Acta 42:167-71. une fille de 11 ans. Arch Fr Pédiat 13:27. 3. Asano S, Matzuki S, Ozawa Y et al (1966) A 19. Garg A, Wilson R, Barnes R, Arioglu E, Zaidi case of Seip-Lawrence syndrome with Z, Gurakan F, Kocak N, et al (1999) A gene for acanthosis nigricans. Keio J Med 15:101-10. congenital lipodystrophy maps to human 4. Bamatter F (1964) Leprechaunisme. Rev Med chromosome 9q34. J Clin Endocrinol Metab Suisse Romande 84:494-502. 84:3390-4. 5. Berardinelli W (1954) An undiagnosed 20. Garg A (2000) . Am J Med endocrinometabolic syndrome : report of two 108:143-152 cases. J Clin Endocrinol Metab 14:193-204. 21. Gedde-Dahl Jr T, Trygstad O, Van 6. Berge T, Brun A, Hansing B, Kjellman B Maldergem L, Magré J, van der Hagen CB, (1976) Congenital generalized lipodystrophy. Olaisen B, Sternesen M, et al (1996) of Report on one case, with special reference to the Berardinelli-Seip syndrome (congenital postmortem findings. Acta Pathol Microbiol generalized lipodystrophy) in Norway : Scand [A] 84:47-54. epidemiology and gene mapping. Acta Paediatr 7. Beylot M, Sautot G, Laville M, Cohen R (1988) Suppl 413:52-58. Metabolic studies in : 22. Ghanem Q (1993) Percussion myoedema in mechanism of and evidence of a Pakistani boy with Berardinelli Seip resistance to insulin of . Diabete lipodystrophy syndrome. Clin Genet 44:277-8. Metab 14:20-4. 23. Gonzales JRG, Martin EA, Hildalgo BA et al 8. Brubaker MM, Levan NE, Collipp PJ (1965) (1970) Lipodistrofia generalizada congénita. Acanthosis nigricans and congenital total Reporte de 6 casos. Rev Cubana Med 9:187- lipodystrophy. Associated anomalies observed in 204. two siblings. Arch Dermatol 91:320-25. 24. Gordon H, Pimstone BL, Leary PM, Gordon 9. Brunzell JD, Shangle SW, Bethune JE (1968) W (1971) Congenital generalized lipodystrophy Congenital generalized lipodystrophy with abnormal homeostasis. accompanied by cystic angiomatosis. Ann intern Arch Dermatol 104:551-9. Med 69:501-16. 25. Griffiths HJ and Rossini AA (1975) A case of 10. Casali RE, Resnick J, Goetz F, Simmons RL, Lipoatrophic diabetes. Radiology 114:329-30. Najarian JS, Kjellstrand C (1978) Renal 26. Guihard J, Tessier R, Laniece M, Foucault transplantation in a patient with lipoatrophic JP, Sibireff JJ, L'Hirondel J (1971) Lipoatrophic diabetes. A case report. Transplantation 26:174- diabetes (Lawrence's syndrome) :a new case. 7 Ann Pediatr (Paris) 18:633-43 11. Choo KE, Sharifah A, Ariffin WA, Mafauzy M 27. Harendra da Silva DG (1984) Congenital (1990) Generalised lipodystrophy. Singapore lipodystrophy (Seip syndrome) in Sri Lanka. Med J 31:289-92. Ceylon Med J 29:205-7. 12. Choremis KB, Constantinides B, Kattamis 28. Howard BV, Mott DM, Hidaka H, Fields RM, CA (1965) Congenital type of generalized Katzeff H, Howard WJ, Bennett PH (1981) Cell lipodystrophy. Acta Paediatr scand 54:175-9. culture studies of a patient with congenital lipoatrophic diabetes--normal insulin binding with

Van Maldergem, L., Berardinelli-Seip congenital lipodystrophy. Orphanet encyclopedia. November 2001. http://www.orpha.net/data/patho/GB/uk-berard.pdf 4

alterations in intracellular glucose metabolism 41. Montenovesi P, Altichieri M, Silvestri R and insulin action. Metabolism 30:845-52. (1971) Generalized congenital lipodystrophy as 29. Huseman C, Johanson A, Varma M, Blizzard a part of congenital diencephalic syndrome. RM (1978) Congenital lipodystrophy: An Minerva Pediatr 23:1259-69. endocrine study in three siblings. I. Disorders of 42. Mora PF, Ramirez LC, Lender D, Raskin P carbohydrate metabolism. J Pediatr 93:221-6. (1993) Insulin requirements in lipodystrophic 30. Jolliff JW and Craig JW (1967) Lipoatrophic diabetes. Diabet Med 10:863-5. diabetes and mental illness in three siblings. 43. Mosely N, Bogdonoff MD, Kirschner N et al Diabetes 16:708-14. (1964) Lipodystrophic muscular hypertrophy 31. Keenan BS, Kirland RT, Garber AJ, (lipoatrophic diabetes). J Pediatr 65:1105. Rubenstein AH, Holcombe JH, Potts VE, Clayton 44. Orlandi B, Baldassarre M, Camponozzi FA, GW (1980) The effect of diet upon carbohydrate Di Stanislao C, Poccia G, De Donatis D (1992) metabolism, insulin resistance, and blood Congenital generalized lipodystrophy associated pressure in congenital total lipoatrophic diabetes. with multiple sclerosis. Ital J Neurol Sci 13:161- Metabolism 29:1214-24. 4. 32. Klar A, Livni N, Gross-Kieselstein E, Navon 45. Pachioli R, Olivi O, Genova R ( 1966) La P, Shahin A, Branski D (1987) Ultrastructural lipodistrofia, un quadro di paniperpituitarismo abnormalities of the liver in total lipodystrophy. anteriore nell'infanza. Minerva Pediatr 18:1387- Arch Pathol Lab Med 111:197-9. 94. 33. Klein S, Jahoor F, Wolfe RR, Stuart CA 46. Pandit A, Bhave S, Sanghvi A (1979) (1992) Generalized lipodystrophy: in vivo Congenital generalized lipodystrophy (a case evidence for hypermetabolism and insulin- report). Indian Pediatr 16:459-61. resistant lipid, glucose, and kinetics. 47. Reed WB, Dexter R, Corley C et al (1965) Metabolism 41:893-6. Congenital lipodystrophic diabetes with 34. Kodama S, Kasuga M, Seki A, Ninomiya M, acanthosis nigricans. The Seip-Lawrence Sakurai T, Morishita Y, Matsuo M, Matsuo T syndrome. Arch Dermatol 91:326-34 (1978) Congenital generalized lipodystrophy with 48. Robert JJ, Rakotoambinina B, Cochet I, insulin-resistant diabetes. Eur J Pediatr 127:111- Foussier V, Magre J, Darmaun D, Chevenne D, 9. Capeau J (1993) The development of 35. Kulayat NA, Narchi HH, Baalbaki SA, hyperglycaemia in patients with insulin-resistant Tunnessen WW Jr (1998) Generalized generalized lipoatrophic syndromes. lipodystrophy. Picture of the month. Arch Pediatr Diabetologia 36:1288-92. Adolesc Med 152 :405-6. 49. Schwartz R, Schafer IA, Renold AE (1960) 36. Lestradet C, Massol J, Plouvier E, Narboni Generalized lipoatrophy, hepatic cirrhosis, G, Raffi A (1985) Congenital generalized disturbed carbohydrate metabolism and lipodystrophy. Lipid changes. Therapeutic trials. accelerated growth (lipoatrophic diabetes) Am J Arch Fr Pediatr 42:705-7. Med 28:973-985. 37. Lieberman-Leigh S and Davis JA (1984) 50. Seip M (1959) Lipodystrophy and gigantism Generalized lipodystrophy. J R Soc Med 77:246- with associated endocrine manifestations: a new 8. diencephalic syndrome? Acta Paediatr Scand 38. Magré J, Hilbert P, Desbois-Mouton C, 48:555-74. Vigouroux C, Fauré S, Weissenbach J, Capeau 51. Seip M, Trygstad O (1996) Generalized J, Bonnicci A, Nivelon-Chevalier A, Gedde-Dahl lipodystrophy, congenital and acquired T, O'Rahilly S, D'Abronzo FH, Bachy A, Van (lipoatrophy). Acta Paediatr Suppl 413:2-28. Maldergem L and the Berardinelli-Seip Study 52. Seip M, Trygstad O (1963) Generalized Group (1996) Search for the gene(s) responsible lipodystrophy. Arch Dis Child 38:447-53. for Lipoatrophic Diabetes. Eur J Hum Genet 4 : 53. Seip M (1971) Generalized lipodystrophy. 165 (abstract) Ergeb Inn Med Kinderheilkd 31:59-95 Review. 39. Magré J, Délépine M, Khallouf E, Gedde- 54. Senior B, Gellis SS (1964) The syndromes of Dahl T, Van Maldergem L, Sobel E, Papp J, total lipodystrophy and of partial lipodystrophy. Meier M, CGL Working Group, Lathrop M, 33:593-612. Capeau J (2001) Identification of the gene 55. Senior B (1961) Lipodystrophic muscular altered in Berardinelli-Seip congenital hypertrophy. Arch Dis Child 36:426-31 lipodystrophy on chromosome 11q13. Nat 56. Tanner JM, Whitehouse RH, Takaishi M Genet. 28: 365-70. (1966). Arch Dis Child 41. 40. Miyahara R, Tsutamura C, Sugihara M 57. Torikai T, Fukuchi S, Sasaki C et al (1965) (1965) A case of generalized lipodystrophy. Two sibling cases with lipoatrophic diabetes. Hiroshima J Med Sci 14:31-9. Endocrinol Jpn 12:197-208.

Van Maldergem, L., Berardinelli-Seip congenital lipodystrophy. Orphanet encyclopedia. November 2001. http://www.orpha.net/data/patho/GB/uk-berard.pdf 5

58. Tourniaire J, Guinet P, Mornex R et al (1968) Syndrome of lipoatrophic diabetes , vitamin D Lipoatrophic diabetes. Clinical and biological resistant rickets and persistent Mullerian ducts study of an atypical case. Sem Hop 44:3289-97. syndrome in a Turkish boy born to 59. Tsukahara H, Kikuchi K, Kuzuya H et al consanguineous parents. Am J Med Genet 64 : (1988) Insulin resistance in a boy with congenital 506-13. generalized lipodystrophy. Pediatr Res 24:668- 61. Van Maldergem L, Da Silva H, Freitas P, 72. D'Abronzo FH (1998) Berardinelli-Seip 60. Van Maldergem L, Bachy A, Feldman D, syndrome : a new Portuguese Disease ? Eur J Bouillon R, Maassen JA, Dreyer et al (1996) Hum Genet 6: 74 (abstract)

Van Maldergem, L., Berardinelli-Seip congenital lipodystrophy. Orphanet encyclopedia. November 2001. http://www.orpha.net/data/patho/GB/uk-berard.pdf 6