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Familial Partial Lipodystrophy: Two Types of an X Linked Dominant Syndrome, Lethal in the Hemizygous State

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Familial Partial Lipodystrophy: Two Types of an X Linked Dominant Syndrome, Lethal in the Hemizygous State J Med Genet: first published as 10.1136/jmg.23.2.120 on 1 April 1986. Downloaded from Journal of Medical Genetics 1986, 23, 120-127 Familial partial lipodystrophy: two types of an X linked dominant syndrome, lethal in the hemizygous state J KOBBERLING* AND M G DUNNIGANt From *the Department of Medicine, University of Gottingen, Germany; and tthe Division of General Medicine, Medical Unit B, Stobhill General Hospital, Glasgow, Scotland. SUMMARY Familial lipodystrophy (referred to in publications as the Kobberling-Dunnigan syndrome) comprises at least two clinical phenotypes which are consistent within each pedigree. In type 1 familial lipodystrophy, loss of subcutaneous fat is confined to the limbs, sparing the face and trunk. In type 2 familial lipodystrophy, the trunk is also affected with the exception of the vulva, giving an appearance of labial hypertrophy. Diabetes mellitus, hyperlipoproteinaemia, and acanthosis nigricans are present to a variable degree in some but not all patients with familial lipodystrophy, and the abnormal distribution of subcutaneous fat is the essential hallmark of the syndrome. In addition to a survey of published reports, new cases with the syndrome are described. Both types of partial lipodystrophy, occurring either as familial disease or as sporadic cases, have onlycopyright. been observed in female patients. Study of the pedigrees of five families with familial lipodystrophy (two Scottish and three German) suggests an X linked dominant mode of transmission, lethal in the hemizygous (XY) state. The two clinical phenotypes with their variably expressive metabolic abnormalities are consistent either with different mutants of the same allele or with two genes on adjacent loci. Other clinical phenotypes of familial lipodystrophy may exist due to further mutations of the same allele or of genes on adjacent loci. http://jmg.bmj.com/ The nature of the disorder in patients with familial lipodystrophy usually escapes recognition for many years and the syndrome is almost certainly much commoner than the few families described to date suggest. Before the description of the syndrome which forms within the first two years of life. This condition is the subject of the present communication, three commonly associated with parental consanguinity on September 27, 2021 by guest. Protected clinical syndromes were recognised which share as and is recessively inherited. The sexes are equally their common distinguishing feature the partial or affected. Hepatosplenomegaly, hypertrichosis, total absence of subcutaneous fat (lipoatrophy or acanthosis nigricans, and genital hypertrophy are lipodystrophy). In progressive ,partial lipodystrophy usual, and neurological, cardiac, and renal (Barraquer-Simon syndrome' ) fat is lost from the abnormalities are frequent. Hyperlipidaemia and face and, in most cases, from the trunk with normal abnormal glucose tolerance are commonly associated or excessive fat deposition on the pelvic girdle and metabolic abnormalities. Lawrence5 described lower limbs. Most affected subjects are female and acquired lipoatrophic diabetes which usually begins show no other abnormality; a minority develop in adolescence or early adult life, predominantly in glomerulonephritis, diabetes, or hyperlipidaemia. females, and is sporadic. This syndrome shares The condition is usually sporadic. Seip3 and certain features with congenital lipodystrophy, such Berardinelli4 described congenital lipodystrophy in as hepatosplenomegaly, leading to frank cirrhosis in which total loss of subcutaneous fat was noted some cases, and acanthosis nigricans. Hyper- lipidaemia and insulin resistant diabetes mellitus are invariable but neurological, cardiac, and renal Received for publication 12 Fcheruarv 1985. Revised version accepted for publication 8 May 1985. abnormalities are absent. 120 J Med Genet: first published as 10.1136/jmg.23.2.120 on 1 April 1986. Downloaded from Familial partial lipodystrophy 121 In 1974 Dunnigan et al6 described a syndrome of syndrome is thus the abnormality of subcutaneous 'familial lipoatrophic diabetes'. Three female mem- fat distribution itself. The phenotype is variable but bers of one Scottish family and one female member consistent within each pedigree. More detailed of another family showed the complete absence of descriptions of the two clinical phenotypes seen in subcutaneous fat from the limbs and trunk with our German and Scottish families are given below. normal or excessive adipose tissue on the face and These may be designated as limb lipodystrophy neck. All four patients had hyperlipoproteinaemia (familial lipodystrophy type 1) and limb and trunk of varing severity, three had diabetes mellitus, and lipodystrophy (familial lipodystrophy type 2) respec- one showed impaired glucose tolerance. Other dead tively. female members of both families were reported to have been affected and the disorder involved four LIMB LIPODYSTROPHY (TYPE 1) generations in one family and three generations in Patients with this form of familial lipodystrophy the other, suggesting a dominant mode of inheri- show the complete absence of visible or palpable tance. subcutaneous fat from the arms and legs. The In 1975 Kobberling et af7 described three female subcutaneous veins appear prominent and the mus- members of a German family who showed complete cles hypertrophied. In contrast, subcutaneous fat is absence of subcutaneous fat from the limbs with normal on the face and trunk and some patients normal fat on the face and trunk. In this family, the show moderate truncal obesity (fig 1). The face does disorder also appeared to be inherited in a dominant not show the broad, acromegaloid, or rounded fashion over two generations. Only the proband also features frequently found in the type 2 variety of the showed diabetes mellitus and severe hyperlipo- syndrome (see below) and the hands and feet are of proteinaemia. A second family was later described normal size and shape. The genitalia are normal and by the same authors.8 A mother and two of her there is no apparent hypertrophy of the labia three daughters showed limb lipodystrophy but majora, minora, or clitoris. No other clinical or only the former exhibited hyperlipidaemia and metabolic abnormalities are consistently associated copyright. diabetes. Since the description of the cases cited above, the syndrome of familial partial lipodystrophy has been referred to as the Kobberling-Dunnigan syndrome.' 9-11 There is some doubt, however, about the similarities and differences between the families described by Kobberling et al7 in Germany http://jmg.bmj.com/ and by Dunnigan et a16 in Scotland. The present communication clarifies these and reports a further German family with the 'Scottish' variety of the syndrome. A new interpretation of the genetics of familial lipodystrophy is proposed, together with a review of other case reports of familial lipodys- trophy. on September 27, 2021 by guest. Protected The clinical phenotype of familial lipodystrophy The terms lipoatrophy and lipodystrophy are often used synonymously. In the syndromes in which lipoatrophy is present in one part of the body, subcutaneous fat may be present in excess in other sites. The more comprehensive term lipodystrophy is used in the present report to describe the abnormal distribution of subcutaneous fat, whether absent or present in excess. The only condition common to all affected patients with familial lipodystrophy is the abnormal distribution of subcutaneous fat. Metabolic abnor- FIG 1 Proband ofthe second German family with familial malities show varying degrees of expressivity, being lipodystrophy type I (fig 2, family 4, No I). Lack of absent in some patients and present in severe degree subcutaneous fat on the legs with prominent veins and in others. The essential clinical phenotype of the musculature but well developedfat on the trunk. J Med Genet: first published as 10.1136/jmg.23.2.120 on 1 April 1986. Downloaded from 122 J Kobberling and M G Dunnigan with all cases of the syndrome. Acanthosis nigricans test showed a degree of insulin resistance, but occurs only in patients with diabetes and hyperlipo- insulin receptors on the patient's monocytes were proteinaemia. All affected patients were aware that normal (H W Rudiger, 1980, personal communica- they had an unusual appearance and that their loss tion). The hyperlipoproteinaemia varied over a of subcutaneous fat had been present since early number of years, conforming to Fredrickson types childhood. There was no history of parental consan- III, IV, and V on different occasions. Lipid lowering guinity in any of the affected patients. drugs were ineffective and the hyperlipoproteinaemia Insulin dependent diabetes mellitus developed in responded partially to a carbohydrate restricted diet; the proband of the first family (fig 2, family 3, No 2) low fat diets were ineffectual. From the age of 27 at 11 years of age.7 At 16 years of age the patient years the patient eventually developed severe com- developed tuberous xanthomata on the buttocks, plications associated with poor control of both her hands, and extensor aspects of the limbs associated diabetes and hyperlipoproteinaemia. She became with gross hyperlipoproteinaemia. The patient's blind from advanced proliferative retinopathy, had a diabetes remained poorly controlled despite large limb amputation because of severe peripheral vascu- doses of insulin. An intravenous insulin tolerance lar disease, and was eventually dialysed because of 0 0 1 2g copyright. 34 51 61 7
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