Chapter 4.4 Non-AIDS Syndrome

Giuliano Enzi, Luca Busetto, Giuseppe Sergi, Sabrina Pigozzo

Lipodystrophies Acquired

Lipodystrophies (LDs) are clinically heteroge- Acquired Generalised Lipodystrophy neous acquired or inherited disorders charac- (Lipoatrophic Diabetes or Lawrence Syndrome) terised by a generalised or regional loss of adipose Acquired generalised lipodystrophy (AGLD) is a tissue. Generalised LDs, both inherited and rare, juvenile-onset lipodystrophy, first fully acquired, are associated with peripheral insulin described by Lawrence in 1946 [1], who reported resistance, glucose intolerance or overt diabetes, on a young female subject with ‘lipodystrophy, and hepatomegaly with diabetes, lipaemia and acanthosis nigricans, dyslipidaemia. Bone dem- other metabolic disturbances.’ To date, approxi- ineralisation and polycystic ovary syndrome are mately 80 patients with AGLD have been reported also part of these diseases. LDs can be classified as [2]. Like others LDs, AGLD is prevalent in females. acquired or congenital, and generalised or partial Lipoatrophy develops over a number of years, in (Table 1). childhood or in adolescence, so that the onset of the condition is later than that of congenital gen- Table 1.Classification of lipodystrophies (LDs) eralised lipodystrophy (CGLD). Extended areas of subcutaneous fat are involved, including the face, A. Acquired LDs arms, and legs. Less frequently mesenteric, 1. Acquired generalised LD or Lawrence syndrome retroperitoneal, perirenal and mediastinal fat 2. Acquired partial LD or Barraquer-Simons syndrome depots are involved, while retroorbital fat seems to be spared. Muscle mass, evaluated by dual ener- 3. Acquired localised LD gy X-ray analysis (DEXA), is preserved or even c. Hemifacial LD b. Cranial LD or Romberg syndrome increased compared to age-, sex- and body mass c. Other localised LDs index (BMI)-matched subjects. Therefore, in spite of the generalised atrophy of fat tissue the BMI in the majority of lipodystrophic patients falls into B. Congenital LDs the low-normal range. Resting energy expendi- 1. Congenital generalised LD or Berardinelli-Seip ture, independent of hyperthyroidism, is syndrome increased. This syndrome is associated with a. Type 1 b. Type 2 hyperinsulinaemia, insulin resistance, and acan- thosis nigricans, soon resulting in overt, non- 2. Congenital partial LDs ketotic diabetes mellitus. Hyperlipidaemia, name- a. Type 1 or Dunningam syndrome ly hypertriglyceridaemia, is a further metabolic b. Type 2 abnormality associated with AGLD. steato- 3. Mandibuloacral dystrophy sis, autoimmune hepatitis, splenomegaly, and, ulti- 4. Other inherited partial LDs mately, liver cirrhosis occur in some 20% of patients, often beginning in childhood [3, 4]. 5. LD associated with multiple symmetric lipomatosis Other autoimmune diseases, such as Sjögren’s 164 Giuliano Enzi, Luca Busetto, Giuseppe Sergi, Sabrina Pigozzo

syndrome and dermatomyositis, have been reported in association with AGLD, suggesting an immunomediated fat loss as a possible patho- genetic basis [3]. , characterised by a granulomatous infiltration of , may be an early manifestation of the disease [5]. Acute viral often precede AGLD onset. A high- er frequency than casually expected of astrocy- tomas of the third ventricle have been reported. Low levels of leptin and adiponectin have also been described in these patients [6]. a Acquired Partial Lipodystrophy (Barraquer-Simons Syndrome) Acquired partial lipodystrophy (APLD) was first b described by Mitchell in 1885 [7] as a ‘singular case of absence of adipose tissue in the upper part Fig. 1a, b. A patient with acquired partial lipodystrophy. of the body,’ and then as segmental atrophy of the Lipoatrophy exclusively involves the upper body segment and face (a), while a marked increase in subcutaneous fat subcutaneous fat layer by Barraquer [8] in 1907, depots is evident in the lower body segment (b) and as ‘lipodystrofia progressiva’ by Simons in 1911 [9]. APLD is phenotypically characterised by a loss of fat in the upper body segment, namely, in the face, trunk, and arms. In the lower body seg- ment, the subcutaneous fat depots are spared or even increased. Bichat’s fat pad is also involved, giv- ing the face an extremely lean appearance (Fig. 1). may be suggested when psychological discomfort Women are affected three times more frequently impairs the patient’s quality of life. than men. A mesangiocapillary glomerulonephri- tis [10] develops in some 30% of affected subjects within 8–15 years after the onset of the disease, Acquired Localised Lipodystrophies leading to renal failure [10], associated with low levels of serum C3 complement fraction [11–13]. Hemifacial Lipoatrophy A slight increase of a circulating polyclonal IgG, a Hemifacial lipoatrophy (HFLD) asymmetrically C3 nephritic factor, causes activation of the alter- involves the left or right half of the face. No pecu- native complement pathway and increased con- liar symptoms are associated with HFLD, and aes- sumption of the C3 fraction. C3 nephritic factor thetic discomfort is the main consequence. HFLD could induce fat cell lysis, and then a loss of sub- affects mainly females of any age, from childhood cutaneous fat [14]. Other autoimmune disorders, to adulthood. such as , temporal arteritis, Atrophy of the subcutaneous fat makes the face dermatomyositis, thyroiditis, coeliac disease, and asymmetrical due to depression of the cheek and systemic , have been reported the supramandibular region. Cutis, muscles, and to be associated with APLD [15–18]. No informa- bones are unaffected. No renal, neurological, or tion has been offered so far to explain the seg- autoimmune diseases have been reported in associ- mental involvement of subcutaneous fat and the ation with HFLD. Skull X-ray rules out involvement female prevalence, and no effective therapy is cur- of the facial bones. Electromyography reveals no rently available. Cosmetic surgical procedures sensory or motor abnormalities of the facial mus- 4.4 Non-AIDS Lipodystrophy Syndrome 165 cles. Lipofilling procedures can improve the aesthet- described several cases of a progressive centrifu- ic appearance. gal loss of subcutaneous fat at the abdominal wall [20]. The age of onset is infancy. Histological stud- ies show an accumulation of lymphocytes and his- Progressive Cranial Lipodystrophy (Romberg Disease) tiocytes at the edge of the lipoatrophic area, with Progressive cranial lipodystrophy (PCLD) repre- a satellite lymphadenopathy. The disease usually sents the most important differential diagnosis regresses spontaneously in a few months or years. from HFLD. PCLD is characterised by abnormali- The aetiology is unknown, but an inflammatory ty of the cranial basal angle, with monolateral reaction to unknown agents seems to be the most atrophy of all the structures of the face, including credible hypothesis. muscles, bones, cartilaginous tissues, and subcu- taneous fat. Damage of the nerves manifests as Congenital Lipodystrophies trigeminal neuropathy and facial palsy. Cranial X- ray and electromyography easily discriminate Congenital Generalised Lipodystrophy (Berardinelli–Seip between PCLD and HFLD. Syndrome or Lipoatrophic Diabetes) Congenital generalised lipodystrophy (CGLD) is Other Acquired Localised Lipoatrophies an autosomal recessive, transmitted disease char- acterised by a pronounced loss of subcutaneous Other atrophies of small, circumscribed areas of and visceral fat tissue manifested since birth. The subcutaneous fat layers can appear after a local condition is associated with acromegalic traits trauma or prolonged pressure, or at the site of (Fig. 2), accelerated growth with normal hGH drug (mainly of protein structure) injection. Extractive hormones, e.g. bovine insulin, growth hormone, ACTH, calcitonin, and vasopressin, have been reported to be responsible for this form of fat atrophy at injection sites. Local formation of immunocomplexes, or protein precipitate or acti- vation of complement fractions could induce a local lipolytic response mediated by inflammatory agents, and may explain the zonal loss of subcuta- neous fat. Tumour necrosis factor (TNF)-α release induced by insulin may mediate adipocyte atro- phy [19]. An asymptomatic, discoid or funnel- shaped depression appears. Microscopic examina- tion of samples of tissue from atrophic area shows the disappearance of fat cells. A dedif- ferentiation of fat cells to fibroblast-like cells can be postulated, rather than adipocyte necrosis. In fact, the subcutaneous fat may reappear sponta- neously or after topical steroid treatment. Recently, the recombinant technology used for hormonal drug production has made local fat atrophy unusual. Localised lipoatrophies of unknown origin, not belonging to any of other previously reported Fig. 2. A patient with congenital lipodystrophy or lipoat- rophic diabetes. There is evidence of a pronounced loss of LD, have been defined as localised involutional subcutaneous fat, acromegaloid aspect, and phlebomegaly LDs. For example, in 1984, Imamura et al. (for details, see Table 3, patient GF) 166 Giuliano Enzi, Luca Busetto, Giuseppe Sergi, Sabrina Pigozzo

plasma levels, hypertrichosis, mild virilisation, cholesterol plasma levels are part of the syn- liver enlargement, reduced glucose tolerance or drome. Total cholesterol levels are not constantly overt diabetes, heat intolerance, and increased increased, but occasionally can be remarkably perspiration (Table 2) [21–23]. high [25] (Table 3). Muscle mass, evaluated by DEXA, is preserved on even increased compared The loss of fat involves the mesenteric, perire- with age-, sex- and BMI-matched subjects. The nal, and paracardiac adipose tissue depots [24]. increase in resting energy expenditure is related to Orbital and perirenal fat depots are spared. the higher fat-free mass/body mass ratio. Two sub- Acanthosis nigricans and hyperinsulinaemia are types of CGLD have been identified and are distin- the rule. Accelerated growth in early childhood guished according to the mode of inheritance and advanced bone development compared with [26–29]. Type 1 CGLD is related to an autosomal age-matched controls have been reported, but recessive genetic defect in AGPAT2 isoform. This adult body height is normal or only slightly enzyme, involved in the biosynthesis of triglyc- increased. In one patient (e.g., DMM, Table 3) a erides and phospholipids, is expressed at high lev- defect in adipose tissue lipoprotein lipase in a els in adipose tissue. Thus, a defect in AGAPT func- small residual lobule of omental tissue obtained tion may reduce triglyceride synthesis in fat cells. during surgery was observed [25]. In all four Type 2 CGLD is related to an autosomal recessive patients in our series, post-heparin plasma involvement of seipin, a protein of unknown func- lipoprotein lipase activity was blunted or near tion [30]. Mutation of the seipin gene has been absent. Elevated triglyceride and reduced HDL reported to cluster in a large consanguineous pedi-

Table 2. Clinical aspects of the most important lipodystrophies (LDs)

Generalised Partial Generalised Partial congenital congenital acquired acquired LD LD LD LD Eponym Berardinelli Dunningam Lawrence Barraquer Simons Seip syndrome syndrome syndrome syndrome

Inheritance Autosomal Autosomal - - recessive dominant Gene involved Type 1 AGPAT2 LMNA Type 2 Seipin PPARγ Age at onset Birth Puberty Any age Youth Sex prevalence = Women Women Women Insulin resistance Usual Usual Frequent Unusual Glucose tolerance Reduced Reduced Reduced Normal Acanthosis nigricans Frequent Frequent Unusual Absent Hypertrichosis Frequent Frequent Unusual Absent Genital hypertrophy Frequent Frequent Unusual Absent Somatic growth Precocious Normal Precocious Normal (if early manifestation) Liver enlargement Frequent Frequent Frequent Absent Hypertriglyceridaemia Usual Usual Usual Absent Basal metabolic rate Increased Increased Increased Normal Polycystic ovary syndrome Frequent Frequent Frequent Absent C3 deficiency Absent Absent Absent Frequent 4.4 Non-AIDS Lipodystrophy Syndrome 167 gree [31]. A high level of seipin RNA expression in in Scotland. An autosomal dominant transmission the brain of affected subjects suggests an involve- of the disease was reported in five families. To ment of the cerebral nervous system. This hypothe- date, some 200 cases of the disease have been sis seems to be supported by the association of reported, with a higher prevalence in females. type 2 CGLD with mild mental retardation. Atrophy of the subcutaneous fat layer usually CGLD can manifest with different expression manifests at puberty, involving the arms, legs, and of and with different degrees buttocks. The subcutaneous adipose tissue of the of severity of the metabolic abnormalities (Table face, neck, and intra-abdominal area may be pre- 3). Insulin resistance usually evolves into overt served, giving patients a silhouette of visceral diabetes. Micro- and macroangiopathies and keto- obesity. An increase in intramuscular fat has been sis are unusual in lipoatrophic diabetes. An reported. Insulin resistance, reduced glucose tol- increased resting energy expenditure without erance, overt diabetes, hypertriglyceridaemia, and abnormalities of thyroid function has been low levels of HDL cholesterol are associated with reported. Liver steatosis, liver fibrosis, portal Dunningam syndrome and lead to early onset of hypertension, and oesophageal varices are late- atherosclerotic vascular diseases. Acute pancreati- onset complications, possibly leading to death. tis and liver steatosis may complicate the clinical picture. The identification of missense mutations on chromosome 1q 21–22, involving genes encod- Congenital Partial Lipodystrophy: ing lamins A and C, in affected members of a fam- Type 1 (Dunningam Syndrome) ily suggests the molecular basis of the disease This LD variety was first described by Dunningam [33]. Lamins provide structural integrity to the in 1974 [32] in females belonging to two families nuclear membrane, such that mutations in the

Table 3. Main clinical aspects of four patients with congenital lipoatrophic generalised lipodystrophy

DMM GF GI TV Sex F F F F Age (years) 18 35 31 24 BMI 22.0 21.6 22.2 15.5 Glucose tolerance Diabetes Diabetes Reduced glucose tolerance Diabetes Blood glucose 335 168 106 165 Plasma insulin 28 20 16 37 Total cholesterol 415 154 158 250 HDL cholesterol 18 30 35 24 Triglycerides 471 201 270 310 9.3 5.4 5.8 6.8 Lipoatrophy +++ ++ - ++ - +++ Resting energy expenditure +28% +14% +18% +16% Muscle hypertrophy +++ +-- +++ --- Liver steatosis +++ +-- ++ - +-- Bone cysts +++ ++- +-- ---

GF and GI: sisters. DMM: cousin of GF and GI. The father of GF and GI and the mother of DMM are cousins 168 Giuliano Enzi, Luca Busetto, Giuseppe Sergi, Sabrina Pigozzo

gene could result in disruption of the nuclear lam- Other Inherited Partial Lipodystrophies ina in adipocytes and subsequently cell death. The Other varieties of LD have been described in Dunningam’s variety of familial partial LD seems small series of patients. A syndrome characterised to be a heterogeneous disorder with a slightly dif- by a low birth weight, short stature, defective ocu- ferent clinical expression. The site of missense lar development, mental retardation, delayed mutations could explain these differences. A vari- teething, hyperextensible joints, and atrophy of ety of this congenital LD was described by the subcutaneous fat layer at the arms and trunk, Köbberling in 1975 [34]. sparing any other site, called the SHORT syn- drome, was reported by Sensenbrenner et al. in Familial Partial Lipodystrophy Associated with a PPARg 1975 [42]. Gene Mutation A LD characterised by a near absence of sub- cutaneous fat from birth, sparing the adipose tis- Garg et al. recently reported on a missense het- sue of the sacral and gluteal fat deposits, has been erozygous mutation, Arg397Cys, in peroxisome- reported in newborns affected by a neonatal proliferator-activated receptor-gamma (PPARγ) progeroid syndrome [43]. gene in a 64-year-old woman with diabetes, Recently, a new clinical condition was report- hypertriglyceridaemia, hypertension, hirsutism, ed, characterised by generalised lipoatrophy, and marked subcutaneous fat loss, more promi- insulin-resistant diabetes, disseminated leukome- nent in her forearms and calves than in her upper lanodermal papules, liver steatosis, and cardiomy- arms and thighs [35]. opathy. The condition was linked to lamin A and C Other heterozygous mutations in the PPARγ mutations [44]. gene were subsequently recognised in subjects with familial partial LD [36, 37]. PPARγ is highly expressed in adipose tissue and plays a role in adi- Lipoatrophy Associated with Multiple Symmetric pogenesis and adipocyte differentiation. However, Lipomatosis (Launois-Bensaude Syndrome or Madelung the localised atrophy of adipose tissue has yet to Collar) be explained. Multiple symmetric lipomatosis (MSL) is charac- terised by the growth of fat masses symmetrically Familial Partial Lipodystrophy Associated with located at the neck, shoulders, deltoid and supras- Mandibuloacral Dysplasia capular regions, proximal segments of the arms This type of dystrophy was first identified by and legs, and at the thoracic inlet, a distribution Young et al. in 1971 [38] as ‘a new syndrome mani- reminiscent of the location of brown adipose tis- fested by mandibular hypoplasia, acroosteolysis sue in the foetus. The remaining subcutaneous fat (at the extremities), stiff joints and cutaneous layer is markedly atrophic, allowing MSL to be atrophy, a bird-like face associated to lipoatrophy included in the group of LDs (Fig. 3). MSL is at the arms and legs, in two unrelated boys.’ reported to be highly prevalent in men, but sever- Metabolic abnormalities, namely insulin-resistant al cases of MSL in women have recently been diabetes mellitus, hypermetabolism, and the reported [45]. molecular basis of the disease were subsequently In a series of 69 patients, the male to female demonstrated [39, 40]. Two different patterns of ratio was 7:1. MSL appears in adulthood (range: mandibuloacral dysplasia (MAD) have been 29–65 years), has a slowly progressive course, and reported. Type A is characterised by a homozy- is an autosomal dominant inherited disorder that gous Arg527His mutation in the LMNA gene [40]. primarily affects adipose tissue. Previous observa- Type B heterozygous mutations in the zinc metal- tions suggested lipomatous cells as brown-adi- loproteinase ZMPSTE24 gene [41] were observed pose-tissue-derived cells [46, 47]. Almost all in a patient whose generalised LD and MAD were patients have a high alcohol intake, usually red associated with progeria and renal failure. wine, suggesting a specific role for ethanol or 4.4 Non-AIDS Lipodystrophy Syndrome 169

pharyngeal accumulation of fat tissue. In some 20% of MSL patients, fat infiltration of the pha- ryngeal and tracheal wall was found to be respon- sible for an obstructive apnoea syndrome during sleep. Metabolic abnormalities include hyper- triglyceridaemia and high levels of circulating HDL cholesterol. Hyperuricaemia and reduced glucose tolerance or overt diabetes occur at a fre- quency slightly higher than casually expected. A defect in adrenergic-stimulated lipolysis [50] and an increase in lipoprotein lipase activity of adi- pose tissue [51] have been demonstrated in sam- ples of lipomatous tissue. No information is avail- able on the metabolic activity in uninvolved sub- cutaneous adipose tissue, due to the fat atrophy which makes fat sampling extremely difficult. There is evidence for a mitochondrial dysfunc- tion in muscle fibres. Levels of respiratory-chain enzyme show a significant decrease of cytochrome-c oxidase, succinic dehydrogenase, and citrate synthase activity [52]. Reduced mito- chondrial enzyme activity could provide the pathogenetic basis of the multisystemic clinical manifestations of MSL. Cultured MSL adipocytes synthesise UCP-1, the selective marker of brown adipocyte, but unlike in normally functioning Fig. 3. A patient with multiple symmetric lipomatosis. The brown fat cells, UCP-1 gene expression was not presence of lipomatous masses localised at the neck, significantly induced by noradrenaline. Thus, MSL occipital region, and lower part of the abdomen is associ- may be the consequence of a defective noradren- ated with a marked loss of the subcutaneous fat layer at ergic modulation of proliferation and differentia- the limbs tion of brown fat cells [53]. other wine components in revealing a genetic Therapeutic Approaches to Lipodystrophies defect. MSL was considered slowly progressive and benign, but a recent longitudinal study No specific treatment is currently available for LD. demonstrated a significant disease-specific mor- In some patients, therapy has to be addressed to tality [48]. The main complications include medi- coexisting comorbidities or to correcting cosmet- astinal occupation by lipomatous tissue, with ic appearance. compression and infiltration of the muscles of the Hyperglycaemia is treated with conventional neck and mediastinal structures, and a somatic medication. Insulin is used for overt diabetes. and autonomic neuropathy. Symptoms of sensory High doses of regular or long-acting insulin may and autonomic neuropathies are frequently asso- be required when a pronounced resistance is pres- ciated with the disease [49]. In a 15-year follow-up ent. Metformin has been suggested to improve of 70 patients, sudden death, in the absence of insulin sensitivity and the control of hyperphagia. coronary heart disease, was recorded in three out Liver steatosis and polycystic ovary syndrome of 11 patients, related to severe autonomic neu- may be additional indications for metformin ropathy [48]. A further clinical sign of MSL is the treatment. 170 Giuliano Enzi, Luca Busetto, Giuseppe Sergi, Sabrina Pigozzo

Dyslipidaemia requires close adherence to a low- and liver steatosis. Alcoholic beverages should be fat diet (no more than 15% of calories). Adequate avoided.Cosmetic appearance can only be improved control of diabetes will improve or even normalise in localised LD, as in Barraquer-Simons syndrome plasma lipid levels. Hypertriglyceridaemia occurs in and HFLD. Cosmetic surgery including silicon or the majority of congenital LD patients. Fibrates and collagen implants or isolated fat-cell transplanta- high doses of ω-3 polyunsaturated fatty acids are tion from the gluteal region can be used to correct mandatory to minimise the risk of vascular disease sunken cheeks and asymmetry.

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