COMMENTARY (SEE STRICKLAND ET AL., P. 2247) Novel Forms of Lipodystrophy Why should we care? ipodystrophies are a heterogeneous A/C, a protein, which is important for than others with similar degrees of obesity Lgroup of conditions in which indi- the integrity and function of the nuclear or type 2 diabetes, implying that this lip- viduals never develop or progres- envelope. It is entirely unclear why some odystrophy has clinical significance. With sively lose adipose tissue in parts or all of white adipocytes are affected and others greater awareness and more detailed clin- their bodies (1,2) (Table 1). In this com- are not. Dunnigan syndrome is character- ical studies including laboratory testing mentary, we will make the case that 1) ized by accumulation of fat in the neck and determination of body composition, defining lipodystrophy is a work in prog- area and loss of subcutaneous fat only in it will become evident whether this phe- ress; 2) not all forms of lipodystrophy are the limbs or the gluteal region—parts of notype is a circumscribed entity. Ques- very rare; 3) lipodystrophy and obesity the body often not revealed on a brief tions to be addressed are whether adipose can occur simultaneously and their met- clinical examination (Table 1). Thus, tissue in the distal extremities is lost or abolic consequences are similar and pos- some patients have been misdiagnosed never gained, whether these patients are sibly synergistic; 4) leptin treatment can as having Cushing syndrome and others leptin deficient or have other adipokine have impressive therapeutic effects; and have suffered from delayed recogni- abnormalities, and whether affected indi- 5) these conditions provide useful para- tion and therapy of their marked hyper- viduals benefit from early recognition and digms to explore the role of the adipose triglyceridemia and treatment-resistant intervention to lower their risk of devel- tissue on metabolic homeostasis and to diabetes associated with severe insulin re- oping diabetes or to more aggressively investigate pathways leading from dis- sistance. Recently, it has been reported treat their overt diabetes. Thus far, the tinct genetic mutations to very different that individuals with metabolic syn- etiology, heredity, and prevalence of this clinical phenotypes. drome but without classical findings of condition remain to be determined. What is lipodystrophy? A recent Dunnigan syndrome had a surprisingly The novel description of a presumably consensus statement by the American high prevalence of mutations in LMNA more common form of lipodystrophy is Association of Clinical Endocrinologists and ZMPSTE24 (a gene encoding one of contrasted by the recent identification of acknowledges the difficulty in determin- the lamin A processing enzymes) (4). Thus, an exceedingly rare form, part of an auto- ing quantitative criteria and concludes as often in medicine, it appears that cer- inflammatory condition: CANDLE (chronic that “lipodystrophy is a condition charac- tain genetically determined conditions neutrophilic dermatosis with lipodystrophy terized by regional or total loss or absence when associated with milder pheno- and elevated temperature) syndrome (7). of subcutaneous fat. This can occur either types are much more common than ini- Infants as young as 2 weeks of age (and at in the presence or absence of metabolic tially anticipated. the latest by 12 months of age) present with abnormalities, and with diverse clinical In this issue of Diabetes Care,Strick- skin rashes, accompanied by episodic fe- presentations. While generalized forms of land et al. (5) describe a novel form vers, anemia, and eventual development lipodystrophy are often diagnosed during termed “partial lipodystrophy of the of partial lipodystrophy, predominantly childhood or adolescence, some forms of limbs” (PLL). In comparison with other affecting the face, wrists, ankles, and distal lipodystrophy, particularly familial partial forms of lipodystrophy, which are ex- parts of fingers and toes. Joint contrac- lipodystrophy, may bear some resem- tremely rare (e.g., congenital generalized tures may develop early, and affected blance to common metabolic disorders lipodystrophy has an estimated preva- children fail to thrive. Again, incorrect di- managed by adult endocrinologists” (3). lence of 1 in 10 million), this condition agnoses ranging from Lyme disease to cu- There are no specific cutoff levels for per- (PLL), similar to lipodystrophy associated taneous myelogenous leukemia have led cent body fat or leptin concentrations, and with antiretroviral treatment of HIV (6), to unnecessary and harmful treatments it often requires time and long-term follow- may affect larger numbers of individuals. such as whole-body radiation and pro- up to confirm the diagnosis. The BMI of people with PLL is described longed suffering of the affected child. Much progress has been made in to cover a wide range from normal to CANDLE syndrome is caused by muta- identifying the genetic etiologies of obese. Affected individuals have dispro- tions in the proteasome gene PSMB8, many lipodystrophy forms (1). How portionately slender forearms with or which had been reported earlier by Garg missing or abnormal gene products pre- without slender calves (and at times et al. (8) to cause JMP syndrome (joint vent adipocyte development or cause dis- thighs) compared with the rest of their contractures, muscle atrophy, microcytic appearance of adipose tissue in distinct bodies. Since huge physiological varia- anemia, and panniculitis-induced child- regions of the human body, however, re- tions in quantity and distribution of hood onset lipodystrophy) in adults mains mostly unknown. An excellent ex- body fat exist among healthy humans, it (8,9). A promising treatment trial (clinical ample is familial partial lipodystrophy or is necessary to provide evidence that a trial reg. no. NCT01724580) is underway Dunnigan syndrome, in which numerous variant is harmful in order to classify it at the National Institutes of Health to test mutations of the LMNA gene have been as pathological. Strickland et al. make whether the Janus kinase 1/2 inhibitor bar- found. LMNA is expressed in a tissue- the case that patients with PLL are more icitinib is beneficial. Janus kinases phos- dependent manner and encodes lamin insulin resistant and have worse glycemia phorylate activated cytokine receptors, 2142 DIABETES CARE, VOLUME 36, AUGUST 2013 care.diabetesjournals.org care.diabetesjournals.orgTable 1—Phenotypic characterization of lipodystrophy subtypes D with inclusion of genotype (if available) Approximate Lipodystrophy subtype Genetic cause Clinical presentation Metabolic features Associated conditions population frequency Fat distribution Congenital generalized Recessive: AGPAT2, Muscular appearance Severe insulin Cardiomyopathy, ,1 per million (1) lipodystrophy BSCL2, CAV1, PTRF with or without resistance/diabetes, bone cysts, (Berardinelli-Seip hepatomegaly and acanthosis, proteinuria, focal syndrome) umbilical prominence hypertriglyceridemia segmental in infancy with or without glomerulosclerosis pancreatitis, PCOS/ hyperandrogenism with infertility (women), steatohepatitis Acquired generalized None Gradual loss of Severe insulin Autoimmune diseases 250 cases reported (1) lipodystrophy subcutaneous fat in resistance/diabetes, (e.g., hepatitis, type 1 (Lawrence childhood or adulthood; acanthosis, diabetes, juvenile syndrome) may be preceded by hypertriglyceridemia dermatomyositis, panniculitis with or without Hashimoto pancreatitis, PCOS/ thyroiditis), hyperandrogenism lymphoma, with infertility immunodeficiency (women), steatohepatitis Familial partial Dominant: LMNA, Unusual body fat Insulin resistance/ Rarely myopathy, ,1 per million (1) lipodystrophy PPARg, AKT2, PLIN1; distribution, insulin diabetes, acanthosis, cardiomyopathy, (Kobberling and Recessive: CIDEC resistance, PCOS often hypertriglyceridemia cardiac conduction Dunnigan noted during with or without abnormalities (1) syndromes) adolescence. Men have pancreatitis, PCOS/ much milder phenotype hyperandrogenism IABETES and are rarely with reduced fertility diagnosed (women), steatohepatitis, Acquired partial Not yet determined Gradual loss of Usually mild or absent Autoimmune diseases, ,1 per million (1) C ARE lipodystrophy subcutaneous fat MPGN type 2, low , (Barraquer-Simons progressing in complement 3 + C3 VOLUME syndrome) a cephalocaudal nephritic factor direction with variable 36, A lower limit with or without increased fat UGUST accumulation in lower Rother and Brown body 2013 Continued on p. 2144 2143 Commentary which subsequently recruit STAT tran- scription factors known to modulate gene transcription. Thus, it is proposed that the inflammatory cascade is interrupted. Making the correct diagnosis may have vital consequences for patients with lipodystrophy. For familial forms of lip- odystrophy, genetic counseling is essen- (5) ” tial, and in all cases, patients should be screened for known comorbidities, in- cluding but not limited to metabolic abnormalities such as diabetes, hyper- Approximate triglyceridemia, and steatohepatitis, as 70% of patients with not uncommon well as cardiomyopathy (10) and kidney population frequency Fat distribution – “ HIV receiving ART (6) 100 cases reported (7) Unknown but probably 13 , disease (11). Making a diagnosis of lipodys- trophy may also be critical for medical management. Conventional therapies for hyperlipidemia or diabetes are often inef- fective, especially in patients with extreme metabolic disturbances.