Case Report
Clinical Genetics 1990: 38: 391-395
Partial lipodystrophy syndromes - a further male case w.REARDON', I. K. TEMPLE',
H. MACKINNON', J.
v. LEONARD'
AND
M. BARAITSER2
'Mothercare Department of Paediatric Genetics and 4Department of Child Health, Institute of Child Health; *Department of Clinical Genetics, Hospitals For Sick Children, Gt. Ormond St.; and 'Department of Paediatrics, Whittington Hospital, London, UK Details are presented of a boy with partial lipodystrophy. Only one male case has previously been described with this condition. The spectrum of partial lipodystrophy syndromes and the inheritance thereof are discussed in relation to our case. Received 20 February, revised 21 April, accepted for publication 25 April 1990 Key words: Lipodystrophy
Inherited lipodystrophy has been documented in two forms - the Seip-Berardinelli syndrome (McKusick No. 26970) and the Kobberling-Dunnigan syndrome (McKusick No. 15166). The former syndrome is an autosomal recessive condition essentially characterised by generalised lipodystrophy noted in the first 2 years of life, marked hyperlipidaemia and advanced growth in the early years (Seip 1975). The latter syndrome describes a condition of partial lipodystrophy, variable hyperlipidaemia and glucose intolerance of adult onset which may be associated with acanthosis nigricans (Kobberling & Dunnigan 1986). Due to the preponderance of females among cases documented, it has been suggested that the mode of inheritance is X-linked dominant with lethality in males (Kobberling & Dunnigan 1986). We present a male with congenital lipodystrophy who does not fit into either of these categories, making classification and genetic counselling difficult.
Case Report
The male proband was born to Irish parents at 37 weeks of gestation. Birth weight was 3000 g (50th centile). His mother was concerned from the first month of life at his abdominal protrusion and thin buttocks. Clinical examination at 6 weeks of age, and subsequently, demonstrated a striking absence of subcutaneous fat over the trunk, limbs and buttocks (see Fig. 1 and 2). Limb musculature was very well developed (see Fig. 1). The hands and feet were spared and were noted to be large and puffy (see Fig. 2 and 3). Subcutaneous fat was also spared on the face (see Fig. 4). The liver and spleen were noted to be enlarged. Radiological examination of the limbs revealed normal metaphyses and normal skeletal age. The clinical impression of large hands and feet was confirmed radiologically when marked soft tissue prominence was noted. Haematological and biochemical parameters were
392
REARDON ET A L
normal except for serum AST of 83 IU/I (normal for age 15-45). Liver echogram showed a normal pattern. Chromosomal analysis was normal. Cholesterol was normal but serum triglycerides were elevated at 3.3 mmol/l (normal adult range 0.3-1 3). Lipid electrophoresis showed an increase in the pre-Betalipoprotein band. Glucose tolerance test and growth hormone response to a glucose load were normal. Serum complement levels were normal but with increased C3 fraction of > 1000 iu/ml (normal C3 range= 107465) on one occasion. CT scan of the brain gave no evidence for a diencephalic tumour.
Fig. 1. The proband aged 2 years demonstrating absence of cutaneous fat over the trunk, limbs and buttocks. Note the muscularity of the legs.
Subsequent clinical examinations at 1 and 2 years of age have confirmed the clinical findings. Growth is between the 50th and 75th centiles, as is weight gain (50th-75th centile). Psychomotor development is normal. Both parents and an older male sibling have been examined and are clinically unremarkable. Discussion
Our patient has clinical features which are unlike the Seip-Berardinalli syndrome in that the lipodystrophy is partial rather than generalised, and the face, hands and feet are
Fig, 2. Note the complete absence of buttock fat and the sparing and puffiness of the hand.
PARTIAL LIPODYSTROPHY SYNDROME
393
hands and feet being of normal size and shape. Various forms of hyperlipoproteinaemia and a variable age of adult onset diabetes mellitus were common but not invariable in the patients described. Although the subject of this report has a partial loss of subcutaneous fat, it extends beyond the limb involvement which is the hallmark of type 1 Kobberling-Dunnigan syndrome. Type 2 Kobberling-Dunnigan syndrome shows loss of subcutaneous fat on the trunk as well as on the limbs. The face is said to Fig. 3. The feet are spared. be broad, the hands and feet normal. As with type 1, hyperlipoproteinaemia of nonspecific nature is a variable feature of the spared. Indeed, one of the most striking syndrome. Glucose intolerance ranging features in the child presented here is the from asymptomatic impairment of glucose tolerance test to insulin-resistant diabetes presence of large “fleshy” hands and feet. Kobberling & Dunnigan in 1986 delin- has been described (Kobberling & Dunnieated two forms of familial partial lipo- gan 1986). Serum complement investigadystrophy in adult patients. Type 1 IS tions in two families with this condition recharacterised by absence of subcutaneous vealed normal fractions. One of the problems in comparing our fat from the arms and legs only, with the patient to those with the Kobberling-Dunnigan syndrome is that this syndrome has been documented in adults only. However, the lipodystrophy was thought to have been present since “early childhood”. The subject of this report has partial lipodystrophy suggestive of type 2 Kobberling-Dunnigan syndrome, in that it involves the limbs and trunk. The additional striking feature of buttock lipodystrophy sets him apart. The abnormalities described of soft tissue hypertrophy of the hands and feet are also inconsistent with this diagnosis. Among the variable features of the Kobberling-Dunnigan syndrome (types 1 and 2) are acanthosis nigricans and insulin-resistant diabetes mellitus (Kobberling & Dunnigan 1986). The coexistence of diabetes with acanthosis nigricans is a common finding in insulin resistance syndromes (Flier et al. 1979) and is frequently due to disorders involving the insulin receptor (Editorial, LanFig. 4. Note the facial sparing. cet 1987). Although obesity and hyperan-
394
REARDON ET AL.
drogenaemia (Richards et al. 1985) and ovarian dysfunction (Flier et al. 1980) have all been documented in the spectrum of disorders occurring with insulin resistance and acanthosis nigricans, none of the cases described appear to have had lipodystrophy. The subject of this report has lipodystrophy but no evidence of glucose intolerance, although this may develop in the post-puberta1 period as is the case in the Seip-Berardinelli syndrome (Seip 1975). Indeed, one of the features common to the Seip-Berardinelli and Kobberling-Dunnigan syndromes is the occurrence of glucose intolerance, which is often accompanied by acanthosis nigricans. A further feature common to both syndromes is hyperlipidaemia. However, the hyperlipidaemia is nonspecific and highly variable from patient to patient. The hypertriglyceridaemia and elevated prebetalipoprotein band seen in our patient are features of both Seip-Berardinelli and KobberlingDunnigan syndromes and are unhelpful in classifying our patient. Several authors have described cases with partial lipodystrophy. Aarskog and colleagues (1983) described a 3-generation pedigree with partial lipodystrophy. However, the striking feature of the lipodystrophy in this report was the total absence of facial fat. In addition, the affected individuals had Rieger’s eye anomaly and short stature. The triad of partial lipodystrophy, Rieger’s anomaly and short stature had been previously documented in separate reports (Gorlin et al. 1975, Sensenbrenner et al. 1975). As with the Aarskog report these two reports document patients in whom there was marked loss of facial fat. The normal growth parameters, absence of eye disease and strikingly different fat distribution in our case set this patient apart from those alluded to above. The cases which most resemble the patient in this report were those described by
Davidson & Young in 1975. Three females were observed with absent subcutaneous fat over the arms, buttocks and lower limbs but present on the face and upper trunk. Although male diabetics were seen in this pedigree, no male was observed with lipodystrophy. Based on the preponderance of females reported with partial lipodystrophy (Davidson & Young 1975, Kobberling & Dunnigan 1986) Kobberling & Dunnigan have suggested that published reports of partial lipodystrophy are consistent with an X-linked dominant pattern of inheritance with male lethality. Only one male case has previously been documented with partial lipodystrophy (Burn & Baraitser 1986). We now add a further male case. References Aarskog, D.,L. Ose, H. Pande & N. Eide (1983). Autosomal dominant partial lipodystrophy associated with Rieger’s anomaly, short stature and insulinopenic diabetes. Am. J . Med. Genet. 15, 29-38. Bum, J . & M. Baraitser (1986). Partial lipoatrophy with insulin resistant diabetes and hyperlipidaemia (Dunnigan syndrome). 1. Med. Genet. 23, 128-130. Davidson. M. B. & R. T. Young (1975). Mctabolic studies in familial partial lipodystrophy of the lower trunk and extremities. Diubetologiu 11, 561-568. Editorial (1987). Beyond the insulin response. Lancet i. 81-82. Flier, J. S., C . R. Kahn & J. Roth (1 979). Receptors, antireceptor antibodies and mechanisms of insulin resistance. N . Engl. J. Med. 330, 413-419. Flier, J. S., J. B. Young & L. Landsberg (1980). Familial insulin resistance with acanthosis nigricans, acral hypertrophy and muscle cramps. N . Engl. J. Med. 303, 970-973. Gorlin, R., J. Cervenka, K. Moller, M. Horrobin & C. Witkop (1975). Rieger anomaly and growth retardation (the S-H-0-R-T syndrome). Birth Defects XI, 4 6 4 8 . Kobberling, J. & M. D. Dunnigan (1986). Familial partial lipodystrophy: two types of an X-linked dominant syndrome, lethal in the hemizygous male. J . Med. Genet. 23, 120127.
PARTIAL LIPODYSTROPHY SYNDROME Richards. G.. A. Cavallo. W. J. Mevel, M. J. Prince,’E. J: Peters, C. A: Stuart & E R. Smith (1 985). Obesity, acanthosis nigricans, insulin resistance and hyperandrogenemia: pediatric perspective and natural history. J . Pediatr. 107, 893-897. Seip, M. (1975). The syndrome of generalised lipodystrophy. Birth Defects 11, 325-327. Sensenbrenner, J. A. I. E. Hussels & L. S. Levin (1975). CC - a low birthweight syndrome? Rieger syndrome. Birth Defects XI, 423-442.
Address: Dr. u! Reardon Morhercare Dept. of Paediatric Genetics Inst. of Child Health 30 Guilford St. London WCIN IEH U.K.
395
Clinical Genetics 1990: 38: 391-395
Partial lipodystrophy syndromes - a further male case w.REARDON', I. K. TEMPLE',
H. MACKINNON', J.
v. LEONARD'
AND
M. BARAITSER2
'Mothercare Department of Paediatric Genetics and 4Department of Child Health, Institute of Child Health; *Department of Clinical Genetics, Hospitals For Sick Children, Gt. Ormond St.; and 'Department of Paediatrics, Whittington Hospital, London, UK Details are presented of a boy with partial lipodystrophy. Only one male case has previously been described with this condition. The spectrum of partial lipodystrophy syndromes and the inheritance thereof are discussed in relation to our case. Received 20 February, revised 21 April, accepted for publication 25 April 1990 Key words: Lipodystrophy
Inherited lipodystrophy has been documented in two forms - the Seip-Berardinelli syndrome (McKusick No. 26970) and the Kobberling-Dunnigan syndrome (McKusick No. 15166). The former syndrome is an autosomal recessive condition essentially characterised by generalised lipodystrophy noted in the first 2 years of life, marked hyperlipidaemia and advanced growth in the early years (Seip 1975). The latter syndrome describes a condition of partial lipodystrophy, variable hyperlipidaemia and glucose intolerance of adult onset which may be associated with acanthosis nigricans (Kobberling & Dunnigan 1986). Due to the preponderance of females among cases documented, it has been suggested that the mode of inheritance is X-linked dominant with lethality in males (Kobberling & Dunnigan 1986). We present a male with congenital lipodystrophy who does not fit into either of these categories, making classification and genetic counselling difficult.
Case Report
The male proband was born to Irish parents at 37 weeks of gestation. Birth weight was 3000 g (50th centile). His mother was concerned from the first month of life at his abdominal protrusion and thin buttocks. Clinical examination at 6 weeks of age, and subsequently, demonstrated a striking absence of subcutaneous fat over the trunk, limbs and buttocks (see Fig. 1 and 2). Limb musculature was very well developed (see Fig. 1). The hands and feet were spared and were noted to be large and puffy (see Fig. 2 and 3). Subcutaneous fat was also spared on the face (see Fig. 4). The liver and spleen were noted to be enlarged. Radiological examination of the limbs revealed normal metaphyses and normal skeletal age. The clinical impression of large hands and feet was confirmed radiologically when marked soft tissue prominence was noted. Haematological and biochemical parameters were
392
REARDON ET A L
normal except for serum AST of 83 IU/I (normal for age 15-45). Liver echogram showed a normal pattern. Chromosomal analysis was normal. Cholesterol was normal but serum triglycerides were elevated at 3.3 mmol/l (normal adult range 0.3-1 3). Lipid electrophoresis showed an increase in the pre-Betalipoprotein band. Glucose tolerance test and growth hormone response to a glucose load were normal. Serum complement levels were normal but with increased C3 fraction of > 1000 iu/ml (normal C3 range= 107465) on one occasion. CT scan of the brain gave no evidence for a diencephalic tumour.
Fig. 1. The proband aged 2 years demonstrating absence of cutaneous fat over the trunk, limbs and buttocks. Note the muscularity of the legs.
Subsequent clinical examinations at 1 and 2 years of age have confirmed the clinical findings. Growth is between the 50th and 75th centiles, as is weight gain (50th-75th centile). Psychomotor development is normal. Both parents and an older male sibling have been examined and are clinically unremarkable. Discussion
Our patient has clinical features which are unlike the Seip-Berardinalli syndrome in that the lipodystrophy is partial rather than generalised, and the face, hands and feet are
Fig, 2. Note the complete absence of buttock fat and the sparing and puffiness of the hand.
PARTIAL LIPODYSTROPHY SYNDROME
393
hands and feet being of normal size and shape. Various forms of hyperlipoproteinaemia and a variable age of adult onset diabetes mellitus were common but not invariable in the patients described. Although the subject of this report has a partial loss of subcutaneous fat, it extends beyond the limb involvement which is the hallmark of type 1 Kobberling-Dunnigan syndrome. Type 2 Kobberling-Dunnigan syndrome shows loss of subcutaneous fat on the trunk as well as on the limbs. The face is said to Fig. 3. The feet are spared. be broad, the hands and feet normal. As with type 1, hyperlipoproteinaemia of nonspecific nature is a variable feature of the spared. Indeed, one of the most striking syndrome. Glucose intolerance ranging features in the child presented here is the from asymptomatic impairment of glucose tolerance test to insulin-resistant diabetes presence of large “fleshy” hands and feet. Kobberling & Dunnigan in 1986 delin- has been described (Kobberling & Dunnieated two forms of familial partial lipo- gan 1986). Serum complement investigadystrophy in adult patients. Type 1 IS tions in two families with this condition recharacterised by absence of subcutaneous vealed normal fractions. One of the problems in comparing our fat from the arms and legs only, with the patient to those with the Kobberling-Dunnigan syndrome is that this syndrome has been documented in adults only. However, the lipodystrophy was thought to have been present since “early childhood”. The subject of this report has partial lipodystrophy suggestive of type 2 Kobberling-Dunnigan syndrome, in that it involves the limbs and trunk. The additional striking feature of buttock lipodystrophy sets him apart. The abnormalities described of soft tissue hypertrophy of the hands and feet are also inconsistent with this diagnosis. Among the variable features of the Kobberling-Dunnigan syndrome (types 1 and 2) are acanthosis nigricans and insulin-resistant diabetes mellitus (Kobberling & Dunnigan 1986). The coexistence of diabetes with acanthosis nigricans is a common finding in insulin resistance syndromes (Flier et al. 1979) and is frequently due to disorders involving the insulin receptor (Editorial, LanFig. 4. Note the facial sparing. cet 1987). Although obesity and hyperan-
394
REARDON ET AL.
drogenaemia (Richards et al. 1985) and ovarian dysfunction (Flier et al. 1980) have all been documented in the spectrum of disorders occurring with insulin resistance and acanthosis nigricans, none of the cases described appear to have had lipodystrophy. The subject of this report has lipodystrophy but no evidence of glucose intolerance, although this may develop in the post-puberta1 period as is the case in the Seip-Berardinelli syndrome (Seip 1975). Indeed, one of the features common to the Seip-Berardinelli and Kobberling-Dunnigan syndromes is the occurrence of glucose intolerance, which is often accompanied by acanthosis nigricans. A further feature common to both syndromes is hyperlipidaemia. However, the hyperlipidaemia is nonspecific and highly variable from patient to patient. The hypertriglyceridaemia and elevated prebetalipoprotein band seen in our patient are features of both Seip-Berardinelli and KobberlingDunnigan syndromes and are unhelpful in classifying our patient. Several authors have described cases with partial lipodystrophy. Aarskog and colleagues (1983) described a 3-generation pedigree with partial lipodystrophy. However, the striking feature of the lipodystrophy in this report was the total absence of facial fat. In addition, the affected individuals had Rieger’s eye anomaly and short stature. The triad of partial lipodystrophy, Rieger’s anomaly and short stature had been previously documented in separate reports (Gorlin et al. 1975, Sensenbrenner et al. 1975). As with the Aarskog report these two reports document patients in whom there was marked loss of facial fat. The normal growth parameters, absence of eye disease and strikingly different fat distribution in our case set this patient apart from those alluded to above. The cases which most resemble the patient in this report were those described by
Davidson & Young in 1975. Three females were observed with absent subcutaneous fat over the arms, buttocks and lower limbs but present on the face and upper trunk. Although male diabetics were seen in this pedigree, no male was observed with lipodystrophy. Based on the preponderance of females reported with partial lipodystrophy (Davidson & Young 1975, Kobberling & Dunnigan 1986) Kobberling & Dunnigan have suggested that published reports of partial lipodystrophy are consistent with an X-linked dominant pattern of inheritance with male lethality. Only one male case has previously been documented with partial lipodystrophy (Burn & Baraitser 1986). We now add a further male case. References Aarskog, D.,L. Ose, H. Pande & N. Eide (1983). Autosomal dominant partial lipodystrophy associated with Rieger’s anomaly, short stature and insulinopenic diabetes. Am. J . Med. Genet. 15, 29-38. Bum, J . & M. Baraitser (1986). Partial lipoatrophy with insulin resistant diabetes and hyperlipidaemia (Dunnigan syndrome). 1. Med. Genet. 23, 128-130. Davidson. M. B. & R. T. Young (1975). Mctabolic studies in familial partial lipodystrophy of the lower trunk and extremities. Diubetologiu 11, 561-568. Editorial (1987). Beyond the insulin response. Lancet i. 81-82. Flier, J. S., C . R. Kahn & J. Roth (1 979). Receptors, antireceptor antibodies and mechanisms of insulin resistance. N . Engl. J. Med. 330, 413-419. Flier, J. S., J. B. Young & L. Landsberg (1980). Familial insulin resistance with acanthosis nigricans, acral hypertrophy and muscle cramps. N . Engl. J. Med. 303, 970-973. Gorlin, R., J. Cervenka, K. Moller, M. Horrobin & C. Witkop (1975). Rieger anomaly and growth retardation (the S-H-0-R-T syndrome). Birth Defects XI, 4 6 4 8 . Kobberling, J. & M. D. Dunnigan (1986). Familial partial lipodystrophy: two types of an X-linked dominant syndrome, lethal in the hemizygous male. J . Med. Genet. 23, 120127.
PARTIAL LIPODYSTROPHY SYNDROME Richards. G.. A. Cavallo. W. J. Mevel, M. J. Prince,’E. J: Peters, C. A: Stuart & E R. Smith (1 985). Obesity, acanthosis nigricans, insulin resistance and hyperandrogenemia: pediatric perspective and natural history. J . Pediatr. 107, 893-897. Seip, M. (1975). The syndrome of generalised lipodystrophy. Birth Defects 11, 325-327. Sensenbrenner, J. A. I. E. Hussels & L. S. Levin (1975). CC - a low birthweight syndrome? Rieger syndrome. Birth Defects XI, 423-442.
Address: Dr. u! Reardon Morhercare Dept. of Paediatric Genetics Inst. of Child Health 30 Guilford St. London WCIN IEH U.K.
395
