Natural history and comorbidities of generalised and partial lipodystrophy syndromes in Spain

Natural history and comorbidities of generalised and partial lipodystrophy syndromes in Spain Antı ´a Ferna ´ndez-Pombo 1,2 , Sofı ´a Sa ´nchez-Iglesias 1 , Ana I. Castro-Pais 2,3 , Maria Jose ´Ginzo-Villamayor 4 , Silvia Cobelo-Go ´mez 1 , Teresa Prado-Moraña 1,2 , Everardo Josue ´Dı ´az-Lo ´pez 1,2 , Felipe F. Casanueva 3 , Lourdes Loidi 5 and David Arau ´jo-Vilar 1,2 * 1 Department of Psychiatry, Radiology, Public Health, Nursing and Medicine, IDIS-CiMUS, University of Santiago de Compostela, Santiago de Compostela, Spain, 2 Division of Endocrinology and Nutrition, University Clinical Hospital of Santiago de Compostela, Santiago de Compostela, Spain, 3 CIBER Fisiopatologı ´a de la Obesidad y la Nutricio ´n (CIBERobn), Madrid, Spain, 4 Department of Estatı ´stica, Ana ´lise Matema ´tica e Optimizacio ´n, University of Santiago de Compostela, Santiago de Compostela, Spain, 5 Galician Public Foundation for Genomic Medicine (SERGAS-Xunta de Galicia), Santiago de Compostela, Spain The rarity of lipodystrophies implies that they are not well-known, leading to delays in diagnosis/misdiagnosis. The aim of this study was to assess the natural course and comorbidities of generalised and partial lipodystrophy in Spain to contribute to their understanding. Thus, a total of 140 patients were evaluated (77.1% with partial lipodystrophy and 22.9% with generalised lipodystrophy). Clinical data were collected in a longitudinal setting with a median follow-up of 4.7 (0.5-17.6) years. Anthropometry and body composition studies were carried out and analytical parameters were also recorded. The estimated prevalence of all lipodystrophies in Spain, excluding Köbberling syndrome, was 2.78 cases/million. The onset of phenotype occurred during childhood in generalised lipodystrophy and during adolescence-adulthood in partial lipodystrophy, with the delay in diagnosis being considerable for both cohorts. There are specific clinical findings that should be highlighted as useful features to take into account when making the differential diagnosis of these disorders. Patients with generalised lipodystrophy were found to develop their first metabolic abnormalities sooner and a different lipid profile has also been observed. Mean time to death was 83.8 ± 2.5 years, being shorter among patients with generalised lipodystrophy. These results provide an initial point of comparison for ongoing prospective studies such as the ECLip Registry study. KEYWORDS generalised lipodystrophy, partial lipodystrophy, body composition, diabetes mellitus, hypertriglyceridaemia, atherosclerotic cardiovascular disease, mortality Frontiers in Endocrinology frontiersin.org01 OPEN ACCESS EDITED BY Milena Teles, University of São Paulo, Brazil REVIEWED BY Renan Magalhães Montenegro Jr., Federal University of Ceara, Brazil Cynthia Valerio, Instituto Estadual de Diabetes e Endocrinologia Luiz Capriglione, Brazil *CORRESPONDENCE David Arau ´jo-Vilar [email protected] RECEIVED 29 June 2023 ACCEPTED 10 October 2023 PUBLISHED 16 November 2023 CITATION Ferna ´ndez-Pombo A, Sa ´nchez-Iglesias S, Castro-Pais AI, Ginzo-Villamayor MJ, Cobelo-Go ´mez S, Prado-Moraña T, Dı ´az-Lo ´pez EJ, Casanueva FF, Loidi L and Arau ´jo-Vilar D (2023) Natural history and comorbidities of generalised and partial lipodystrophy syndromes in Spain. Front. Endocrinol. 14:1250203. doi: 10.3389/fendo.2023.1250203 COPYRIGHT ©2023Ferna ´ndez-Pombo, Sa ´nchez-Iglesias, Castro-Pais, Ginzo-Villamayor, Cobelo-Go ´mez, Prado-Moraña, Dı ´az-Lo ´pez, Casanueva, Loidi and Arau ´jo-Vilar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. TYPE Original Research PUBLISHED 16 November 2023 DOI 10.3389/fendo.2023.1250203 1 Introduction Lipodystrophy syndromes are a heterogeneous group of rare disorders distinguished by the selective loss of adipose tissue. They may be generalised if the loss of adipose tissue affects the whole body, or partial if only part of the body is affected (1,2). These generalised and partial lipodystrophy syndromes are also characterised by the ectopic accumulation of adipose tissue and the presence of insulin resistance and, consequently, by a variable degree of metabolic dysfunction, with diabetes mellitus (DM), dyslipidaemia, fatty liver disease, cardiovascular disease and reproductive dysfunction. In2017,therangeofworldwideprevalenceofall lipodystrophies (excluding human immunodeficiency virus (HIV)-related lipodystrophy) as determined by electronic medical record (EMR) database searches has been estimated at 1.3 to 4.7 cases per million inhabitants. However, it has also been estimated that for partial Mendelian lipodystrophies the estimated prevalence is higher (3,4). The extreme rarity of lipodystrophy syndromes implies that they are not well-known. In addition, the clinical characterisation of these disorders is often deficient, there is a certain degree of phenotypical variability between the different subtypes of lipodystrophy and their aetiology is diverse, as are the pathogenetic mechanisms which lead to the alteration of adipose tissue. Thus, to date, they are considered to be underdiagnosed conditions, poorly understood by healthcare professionals, which often leads to long delays in diagnosis or misdiagnosis and to obstacles in the development of specific therapies. The knowledge we currently have about the natural history, burden of the disease and mortality of these patients is based fundamentally on studies limited to small samples or studies focused on a specific lipodystrophy subtype (5–12). To the best of our knowledge, only one study, focused on five specific centres across three countries (Turkey, Brazil and United States) included patients with both generalised and partial lipodystrophy with a larger sample size (13). In light of the previously-mentioned knowledge gap, the aim of this study was to assess the natural course and comorbidities of patients with generalised and partial lipodystrophies in Spain (both acquired and congenital) in an effort to contribute to the understanding of these syndromes. 2 Materials and methods 2.1 Study population Of a total of 343 patients with rare adipose tissue disorders, 140 subjects were diagnosed with lipodystrophy and evaluated between 2001 and 2020 in the leading management and treatment centre for lipodystrophies in Spain (UETeM, CiMUS), which receives patients from the whole country. Patients with localised lipodystrophy, lipomatosis and adiposis dolorosa were excluded from this analysis. Patients with HIV- related lipodystrophy are not evaluated at said centre and they were also not included in the analysis. Among patients with genetic lipodystrophy, subjects with familial partial lipodystrophy (FPLD) type 1 were also excluded taking into account the following reasons: its genetic origin is unknown and, therefore, its diagnosis is merely clinical; this specific FPLD subtype may be confused with android obesity in general practice and, therefore, it is rare for these patients to be referred for evaluation (80.6% of them come from the same geographic region in which the centre is located); the high number of patients with a diagnosis of FPLD type 1 would distort the prevalence results of the current study; most of the data on these patients have already been analysed and reported by our group (14). In addition, patients with progeroid syndromes associated with lipodystrophy and patients with a diagnosis of lipodystrophy but no signs of the disease taking into account their young age were only included for the demographic and epidemiological analysis, considering that their inclusion may also affect the prevalence results. More detailed data of the inclusion/exclusion of patients and the population evaluated can be seen in the flow diagram of Figure 1. On the other hand, it should be noted that twelve patients included in the analysis (11 with generalised lipodystrophy and one with partial lipodystrophy) started treatment with recombinant human leptin during follow-up. 2.2 Study design This is a retrospective, observational, longitudinal study, carried out in a single centre attending patients with lipodystrophy from all over Spain. All the analyses were executed for the overall sample, as well as for generalised and partial lipodystrophy cohorts. Clinical data were recorded for analysis from birth until loss of follow-up, death or closure of the database. This study was approved by the ethics review panel of the Red Gallega de ComitesdeE tica de la Investigacion (approval code 2017/477) and carried out according to the ethical guidelines of the Helsinki Declaration. 2.3 Diagnosis of lipodystrophy and clinical data collection The loss of adipose tissue and the affected regions were clinically confirmed by the same expert evaluator in all cases. Clinical diagnosis of lipodystrophy was also supported by body composition imaging. The pattern of partial or total fat loss and its onset was taken into consideration for each of the lipodystrophy subtypes. The absence of family history was also taken into account in the acquired forms. Molecular analysis was carried out in all patients evaluated in the centre in order to confirm or discard a genetic origin of the disorder. Other causes associated with wasting or weight loss (such as cancer cachexia, malnutrition, malabsorption, anorexia nervosa, thyrotoxicosis or chronic infections) were ruled out. Clinical data were obtained from the patients’electronic medical records and were evaluated by the same two examiners following a standardised and homogeneous protocol. Of the Ferna ´ndez-Pombo et al. 10.3389/fendo.2023.1250203 Frontiers in Endocrinology frontiersin.org02 patients evaluated, the proportion of subjects with more than three medical evaluations during follow-up was 62.1% in the overall sample (66.7% in the generalised lipodystrophy group and 50.4% in the partial lipodystrophy group). Physical examination was performed on all participants in the study, establishing a routine in their evaluation to enable a homogeneous comparison between the lipodystrophy subgroups. Regarding comorbidities, data collection focused on capturing organ abnormalities mainly related with adipose tissue dysfunction, ectopic fat accumulation and insulin resistance characteristic of the disease. In addition, other global defects found in these patients, extending beyond the key organ systems, were also recorded. DM and gestational diabetes were defined according to the 2022 American Diabetes Association criteria (15). Foot examination for the diagnosis of diabetic peripheral neuropathy, starting at diagnosis of diabetes and annually thereafter, included visual inspection and pedal pulses, as well as the 10-g monofilament exam, determination of vibration with a 128-Hz tuning fork, temperature and/or pinprick sensation. Symptoms of diabetic autonomic neuropathy were also assessed (16). Causes of neuropathy other than diabetes were discarded. Active screening of atherosclerotic vascular disease (ASCVD) and other cardiac abnormalities (including rhythm disturbances, hypertrophic cardiomyopathy and valvulopathies) was made only if symptoms or signs of any of these disorders were present and not on a routine basis in asymptomatic patients. Polycystic Ovary Syndrome (PCOS) was diagnosed based on the 2006 proposal of the Androgen Excess and PCOS Society: the presence of hyperandrogenism (hirsutism and/or hyperandrogenaemia) and ovulatory dysfunction (oligo-anovulation and/or polycystic ovarian disease assessed by ultrasound) (17). Hepatic steatosis was measured using high resolution ultra-sound B-mode imaging with a convex transducer (frequency of 3.5–5MHz).Forthe diagnosis of intellectual disability, cognitive evaluation tests, such as the Wechsler Adult Intelligence Scale (WAIS-IV), were carried out. The diagnosis of anxiety-depressive disorder was made according to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) and the 10 th revision of the FIGURE 1 Flow diagram of patients with lipodystrophy evaluated at the reference centre in Spain. *The group of patients with acquired partial lipodystrophy included 15 subjects with Barraquer-Simons syndrome and one subject with partial lipodystrophy after bone marrow transplantation and radiotherapy. CGL, congenital generalised lipodystrophy; CGL1, congenital generalised lipodystrophy type 1; CGL2, congenital generalised lipodystrophy type 2; FPLD, familial partial lipodystrophy; FPLD1, familial partial lipodystrophy type 1; FPLD2, familial partial lipodystrophy type 2; FPLD3, familial partial lipodystrophy type 3; FPLD4, familial partial lipodystrophy type 4; AGL, acquired generalised lipodystrophy; APL, acquired partial lipodystrophy; HGPS, Hutchinson-Gilford Progeria Syndrome; SHORT, short stature, hyperextensibility, ocular depression, Rieger anomaly, and teething delay; GL, generalised lipodystrophy; PL, partial lipodystrophy. Ferna ´ndez-Pombo et al. 10.3389/fendo.2023.1250203 Frontiers in Endocrinology frontiersin.org03 International Statistical Classification of Diseases and Related Health Problems (ICD-10) criteria (18). The ultimate diagnosis of the latter two conditions was made after referral to a psychiatry specialist in the centre. Progressive encephalopathy with or without lipodystrophy (PELD) was diagnosed in patients with pathogenic variants on chromosome 11q13 of the BSCL2 gene and developmental regression of motor and cognitive skills in the first years of life, leading to severe progressive neurodegeneration and death in the first decade of life (19). 2.4 Anthropometry and body composition analysis Height and weight were verified with digital scales and a stadiometer after 12 h overnight fasting and body mass index (BMI) was calculated. Waist and hip circumferences were determined using a soft tape measure by a single examiner. Waist circumference was calculated taking as a reference the superior border of the iliac crest, and hip circumference taking as a reference the greater trochanter. The patients’skinfolds were measured using a Lange skinfold calliper (Cambridge ScientificIndustries, Cambridge, MD, USA) in the same hemibody by a single examiner. The mean of three consecutive determinations was obtained. Determination of fat mass and fat-free mass (FFM), both total and segmental, was performed using Dual-energy X-ray absorptiometry (DXA) with a Lunar DPX model (GE Healthcare Lunar, Madison, WI, USA) between 8:30-10:30 a.m. after 12 h of overnight fasting, avoiding previous excessive physical effort. 2.5 Analytical measurements Laboratory results associated to metabolic complications were documented. Blood samples were taken between 8:00-9:00 a.m. after 12 h overnight fasting. Glucose, creatinine, creatinine kinase, triglycerides and total and fractionated cholesterol levels were measured by standardised methods with appropriate quality control and quality assurance procedures. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gglutamyl transpeptidase (GGT) were determined with enzymatic methods on an ADVIA analyser (Siemens, Bayer Diagnostics, Tarrytown, NY, USA). Glycated haemoglobin (HbA1c) was measured with ion-exchange high-performance liquid chromatography (Bio-Rad Laboratories Inc., Hercules, CA, USA). Plasma insulin concentrations were determined in duplicate by chemiluminescence using a commercial kit (Nichols Institute, San Juan Capistrano, CA, USA). The homeostatic model assessment for insulin resistance (HOMA-IR) was calculated using the following formula: (fasting glucose [mg/dL]/fasting insulin [mIU/L])/405. Plasma leptin levels and C-peptide were determined by enzymelinked immunosorbent assay (ELISA) (DRG International Inc., Springfield, NJ, USA). 2.6 Molecular analysis The search for variants in 26 genes involved in the aetiology of congenital lipodystrophies was made in all the patients evaluated in the centre by next-generation sequencing (NGS) (Ion torrent System, Thermo Fisher Scientific, Waltham, MA, USA) of the entire coding region of the genes and the flanking intronic regions (ADRA2A, AGPAT2, AKT2, BANF1, BLM, BSCL2, CAV1, CIDEC, ERCC6, ERCC8, FBN1, KCNJ6, LIPE, LMNA, MFN2, PCYT1A, PIK3R1, PLIN1, POLD1, POLR3A, PPARG, PSMB8, PTRF, SPRTN, WRN, ZMPSTE24). Patients with benign variants were discarded using databases such as Varsome, ClinVar, gnomAD and dbSNP. In cases in which no results were obtained, SIFT and Polyphen2 were used. If no reported damaging/deleterious variants were found in the databases evaluated, the characteristic phenotype of the disease was taken into consideration. Supplementary Table 1 lists the different variants in the genes that cause the disease in the patients with genetic lipodystrophy included in the study. 2.7 Statistical analysis Data are expressed as the mean ± standard deviation (SD), median and interquartile range (IQR) or as n (%) values. For each continuous variable, the hypothesis of a normal distribution was verified by the Kolmogorov-Smirnov test. The c 2 test and Fisher’s exact test were used to compare qualitative variables in two groups. The t test or Mann- Whitneytestwereusedtocompareaquantitativevariableintwo groups. The analysis of covariance was also conducted to eliminate the possible modifying effect of certain covariates such as age and gender. Time to the onset of phenotype, time to the diagnosis of lipodystrophy, DM and hypertriglyceridaemia, and overall survival were described using a Kaplan-Meier curve. Log-rank tests were conducted to make the comparisons between patients with generalised and partial lipodystrophy. The level of significance was set at p < 0.05. All statistical analyses were performed with the SPSS 22.0 program (Chicago, IL, USA). 3 Results 3.1 Demographic and epidemiological data Atotalof140patientswereevaluatedinthereferencecentrefor lipodystrophies in Spain, with a median follow-up of 4.7 (0.5-17.6) years. Of these patients, 102 (72.9%) were women and 38 (27.1%) men (3:1 ratio). Age at first visit ranged from 5 months to 81.9 years of age. A total of 117 (83.4%) patients presented genetic lipodystrophy and 23 (16.4%) acquired. According to the pedigree analysis, 62 index cases led to the detection of the rest of their affected relatives after cascade testing. As far as fat distribution is concerned, 108 (77.1%) patients presented partial lipodystrophy and 32 (22.9%) generalised lipodystrophy. As for the different lipodystrophy subtypes, 17 (12.1%) patients had congenital generalised Ferna ´ndez-Pombo et al. 10.3389/fendo.2023.1250203 Frontiers in Endocrinology frontiersin.org04 lipodystrophy (CGL), 92 (65.7%) FPLD, 7 (5.0%) acquired generalised lipodystrophy (AGL), 16 (11.4%) acquired partial lipodystrophy (APL) and 8 (5.7%) patients had a progeroid syndrome. The most frequent disease was FPLD type 2 (57.9%), followed by Barraquer-Simons syndrome (10.7%) and CGL type 2 (8.6%). More detailed data on the distribution of the different lipodystrophy subtypes can be seen in Figure 1. The estimated prevalence of all lipodystrophy cases in Spain was 2.95 cases/million. When separated into generalised and partial lipodystrophy, the estimated prevalence was 0.51 and 2.28 cases/ million, respectively (1.94 cases/million for FPLD, 0.34 cases/ million for APL, 0.36 cases/million for CGL and 0.15 cases/ million for AGL) (Figure 2). In order to properly evaluate the natural course and comorbidities of lipodystrophies, subjects with progeroid syndrome, four prepuberal subjects with FPLD and 13 patients with FPLD and no data were discarded from the following analysis and, therefore, a total of 115 patients (91 with partial lipodystrophy and 24 with generalised lipodystrophy, 77.4% women, 45.2 ± 20.0 years of age) were subsequently analysed. The presence of women was predominant in the diagnosis of partial lipodystrophy (82.4%) in comparison with generalised lipodystrophy (58.3%) (p = 0.012), and patients with partial lipodystrophy were generally older (49.8 ± 18.4 vs 27.1 ± 15.5 years of age, p <0.0001), which is why the following non-demographic data were calculated after age and gender adjustment. 3.2 Clinical features The onset of phenotype occurred during childhood in 95.6% of patients with generalised lipodystrophy (4.7 ± 11.5 years of age; 47.8% at birth), and during adolescence-adulthood in 91.7% of patients with partial lipodystrophy (16.5 ± 10.8 years of age), p < 0.0001. The delay in diagnosiswas7.4±8.1yearsfor patients with generalised lipodystrophy and 23.8 ± 17.1 years for patients with partial lipodystrophy (p < 0.0001) (Figure 3). Table 1 summarises the lipodystrophy-associated clinical features of the patients evaluated. Consanguinity was present in 4 out of 24 (16.7%) patients with generalised lipodystrophy and in only one case (1.1%) with partial lipodystrophy. The most frequent clinical features in the overall sample were phlebomegaly (70 patients; 60.9%), followed by muscle hypertrophy (62 patients; 53.9%) and then by signs of insulin resistance such as acanthosis nigricans (48 patients; 41.7%). Among patients with generalised lipodystrophy, phlebomegaly and umbilical protrusion/hernia were the most commonly reported clinical features (70.8% and 62.5%, respectively), whereas in the partial lipodystrophy cohort, phlebomegaly and muscle hypertrophy were the most frequent clinical characteristics reported (58.2% and 59.3%, respectively). Furthermore, there were several distinctive features of the generalised lipodystrophy group in comparison with the partial lipodystrophy group, such as acromegaloid features (7/24 patients [29.2%] with generalised lipodystrophy vs 4/91 patients [4.4%], p = 0.004), prognathism (4/24 patients [16.7%] with generalised lipodystrophy vs 2/91 patients [2.2%] with partial lipodystrophy, p = 0.043) and the presence of umbilical protrusion/hernia (15/24 patients [62.5%] with generalised lipodystrophy vs 4/91 [4.4%] patients with partial lipodystrophy, p <0.0001). 3.3 Anthropometric measurements and body composition analysis After age and gender adjustment, anthropometric parameters such as height, weight, waist and hip circumferences, as well as the FIGURE 2 Estimated prevalence of lipodystrophies in Spain. Values above the bars report the prevalence. The estimated prevalence was calculated taking into account the population in Spain in 2020 according to the Instituto Nacional de Estadı stica (Spanish National Statistics Institute). Familial partial lipodystrophy type 1 has not been taken into account in the calculation of prevalence. LD, lipodystrophies; GL, generalised lipodystrophy; PL, partial lipodystrophy; AGL, acquired generalised lipodystrophy; CGL, congenital generalised lipodystrophy; APL, acquired partial lipodystrophy; FPLD, familial partial lipodystrophy. Ferna ´ndez-Pombo et al. 10.3389/fendo.2023.1250203 Frontiers in Endocrinology frontiersin.org05 skinfolds in the triceps, biceps, subscapular area, suprailiac area and thigh, were significantly lower in the generalised lipodystrophy cohort compared to the partial lipodystrophy cohort. However, no significant differences were found when measuring the skinfold of the calf in both groups. Regarding the DXA measurement of fat content, as expected, it was observed that, in patients with generalised lipodystrophy, this was significantly reduced both in total and in the limbs and trunk, compared to the partial lipodystrophy group. Patients with generalised lipodystrophy also presented higher FFM in the trunk, with no differences in the global analysis or in the upper and lower limbs (Table 2). 3.4 Prevalence of main comorbidities Data on the prevalence of lipodystrophy-associated comorbidities are shown in Table 3. Throughout the follow-up, DM was reported in 50 individuals (43.5%) in the overall sample, with no differences among the groups. Prevalence of DM complications was of 36.0% in the case of nephropathy (16.0% presenting renal failure and the rest of them isolated albuminuria, one patient with partial lipodystrophy required dialysis) and 20.0% in the case of retinopathy and peripheral neuropathy. Mean age at diagnosis of DM (Figure 3) was 30.2 ± 3.1 years in the overall sample (12.6 ± 1.6 years in patients with generalised lipodystrophy and 35.5 ± 3.2 years in patients with partial lipodystrophy; p <0.0001). As regards cardiovascular disease (Table 3), ischemic cardiopathy was present in 14 patients (15.4%) with partial lipodystrophy. Valvulopathy and hypertrophic cardiomyopathy were distinctive comorbidities associated to the generalised lipodystrophy group (eight patients [33.3%] and seven patients [29.2%], respectively) in comparison with the partial lipodystrophy cohort (p <0.0001). As far as neurological disease is concerned, intellectual disability was also more frequent among subjects with generalised lipodystrophy (11 patients [45.8%] vs one patient [1.1%] in the partial lipodystrophy group, p<0.0001). In addition, four (16.7%) patients with generalised lipodystrophy were diagnosed with PELD and, therefore, presented encephalopathy and gait disturbances. Hepatic steatosis was the most common liver abnormality identified, affecting 49 patients (42.6%) in the overall sample, with no differences among the groups. Episodes of acute pancreatitis were reported in three patients (12.5%) with generalised lipodystrophy and seven patients (7.7%) with partial lipodystrophy. As far as gynaecological disorders are concerned, 20 women (24.4%) manifested oligo/amenorrhea (four women [20.0%] in the generalised group and 16 [22.2%] in the partial lipodystrophy A BD C FIGURE 3 Time to the onset of phenotype, the diagnosis of the disease and the diagnosis of comorbidities in generalised and partial lipodystrophy. Time to the onset of phenotype (A), time to diagnosis of the disease (B) and time to the diagnosis of diabetes mellitus (C) and hypertriglyceridaemia (D) in generalised and partial lipodystrophy. Subjects with progeroid syndrome, prepuberal subjects with familial partial lipodystrophy and patients with familial partial lipodystrophy and no data were excluded from this analysis. Ferna ´ndez-Pombo et al. 10.3389/fendo.2023.1250203 Frontiers in Endocrinology frontiersin.org06 group) and 13 (15.9%) were diagnosed with PCOS. Anxietydepressive disorder was diagnosed in 18 subjects (15.7%) of the overall sample, with 10 of them receiving chronic antidepressant and/or anxiolytic treatment. In all these cases patients related psychological distress due to their physical appearance as one of the causes. Other disorders detected with relative frequency in these patients are also shown in Table 3. 3.5 Analytical parameters As for analytical measurements at first visit (Table 4), mean HbA1c among individuals with DM was 7.9 ± 2.2% in the overall sample, with HbA1c levels >7% occurring in around half of the patients (26 patients [52.0%]). Analytical parameters such as HOMA-IRshowedresultsrelatedwithsignificant insulin resistance in these subjects. In terms of lipid profile, hypertriglyceridaemia was present both in patients with generalised and partial lipodystrophy. However, severe hypertriglyceridaemia was observed more frequently in the generalised lipodystrophy cohort, with triglyceride levels >500 mg/dl occurring in 7 out of 24 (29.2%) subjects with generalised lipodystrophy vs 5 out of 91 (5.5%) subjects with partial lipodystrophy, p = 0.011. In addition, mean age at diagnosis of hypertriglyceridaemia was 30.4 ± 3.3 in the overall sample (7.3 ± 2.9 years in patients with generalised lipodystrophy and 36.9 ± 3.1 years in patients with partial lipodystrophy; p <0.0001) (Figure 3). On the other hand, low-density lipoprotein cholesterol (LDL-C) and highdensity lipoprotein cholesterol (HDL-C) levels were also significantly lower in the generalised group of subjects, with no differences in non-HDL-C or total cholesterol. As expected, lower leptin levels were observed in patients with generalised lipodystrophy in comparison with partial lipodystrophy. No differences were found regarding transaminase levels in both groups. The rest of the metabolic parameters analysed are shown in Table 4. 3.6 Comparison between the two main subtypes of partial lipodystrophy Taking into account the differences in the adipose tissue phenotype between the two main partial lipodystrophy subtypes (FPLD and APL), a subanalysis was made in order to compare body TABLE 1 Clinical features of patients with generalised and partial lipodystrophy. Overall (n=115) Generalised lipodystrophy (n=24) Partial lipodystrophy (n=91) P value Age (years) 45.2 ± 20.0 27.1 ± 15.5 49.8 ± 18.4 <0.0001 † Gender n (% women) 89 (77.4) 14 (58.3) 75 (82.4) 0.012 † Consanguinity n (%) 5 (4.3) 4 (16.7) 1 (1.1) 0.004 † Acromegaloid features n (%) 11 (9.6) 7 (29.2) 4 (4.4) 0.004 † Prognathism n (%) 6 (5.2) 4 (16.7) 2 (2.2) 0.043 † Ogival palate n (%) 5 (4.3) 3 (12.5) 2 (2.2) 0.171 Alopecia n (%) 7 (6.1) 0 (0.0) 7 (7.7) 0.538 Hirsutism n (%) 17 (14.8) 8 (33.3) 9 (9.9) 0.310 Hypoacusia n (%) 5 (4.3) 3 (12.5) 2 (2.2) 0.075 Acanthosis nigricans n (%) 48 (41.7) 13 (54.2) 35 (38.5) 0.978 Acrochordons n (%) 21 (18.3) 7 (29.2) 14 (15.4) 0.298 Hepatomegaly n (%) 42 (36.5) 12 (50.0) 30 (33.0) 0.075 Splenomegaly n (%) 9 (7.8) 5 (20.8) 4 (4.4) 0.056 Umbilical protrusion/hernia n (%) 19 (16.5) 15 (62.5) 4 (4.4) <0.0001 † Phlebomegaly n (%) 70 (60.9) 17 (70.8) 53 (58.2) 0.213 Muscle hypertrophy n (%) 62 (53.9) 8 (33.3) 54 (59.3) 0.077 Myopathy n (%) 7 (6.1) 1 (4.2) 6 (6.6) 0.757 Muscle pain n (%) 25 (21.7) 4 (16.7) 21 (23.1) 0.799 Muscle contractures n (%) 6 (5.2) 1 (4.2) 5 (5.5) 0.999 Polyphagia n (%) 25 (21.7) 12 (50.0) 13 (14.3) 0.031 † Data are mean ± SD and n (%) values. Subjects with progeroid syndrome, prepuberal subjects with familial partial lipodystrophy and patients with familial partial lipodystrophy and no data were excluded from this analysis. Age and gender were used as covariables. † p < 0.05. Ferna ´ndez-Pombo et al. 10.3389/fendo.2023.1250203 Frontiers in Endocrinology frontiersin.org07 composition analysis and metabolic abnormalities (Table 5). Although there were no statistically significant differences in leptin levels or in the percentage of total fat, as expected, fat distribution differed between the two partial lipodystrophy subtypes. Thus, while the percentage of lower-limb fat was lower in the patients with FPLD, patients with APL showed lower trunk fat percentage. Consistent with this, subjects with FPLD also showed lower thigh and calf skinfolds and subjects with APL showed lower subscapular and suprailiac skinfolds (data not shown). A greater BMI was observed in the FPLD population, mainly based on greater FFM (both in total and in the limbs). The presence of phlebomegaly and muscle hypertrophy were also especially characteristic of the FPLD cohort (observed in 64.0% and 70.7% of these subjects, respectively). While DM was diagnosed in 37 (49.3%) patients with FPLD, it was only diagnosed in two (12.5%) patients with APL (p = 0.006), with worse metabolic control in the FPLD population (HbA1c 7.7 ± 2.2 vs 6.9 ± 0.0 in subjects with APL, p = 0.029). Although no statistically significant differences were found regarding organ abnormalities, peripheral arterial disease was only diagnosed in the FPLD cohort (10.7%) and a tendency towards greater triglyceride levels and towards a greater prevalence of hepatic steatosis was also observed for the FPLD subjects (44.0% vs 18.8% in comparison with patients with APL, p = 0.052). In addition, PCOS was likewise only diagnosed in women with FPLD (20.0%). 3.7 Overall survival Duringthefollow-up,therewereatotalofeightdeaths(6.8%);four (3.4%) in patients with generalised lipodystrophy and four (3.4%) in patients with partial lipodystrophy. Mortality status was unknown for 15 patients. Overall mean time to death was 83.8 ± 2.5 years (Figure 4). Furthermore, mean time to death was shorter among patients with generalised lipodystrophy in comparison to patients with partial lipodystrophy (55.3 ± 3.8 vs 86.2 ± 2.3 years, respectively; p <0.0001). The causes of death of the patients with generalised lipodystrophy (CGL and AGL) were fundamentally respiratory TABLE 2 Adjusted anthropometric and body composition data determined by Dual-energy X-ray absorptiometry (DXA) of lipodystrophy syndromes. Overall (n=115) Generalised lipodystrophy (n=24) Partial lipodystrophy (n=91) P value Height (cm) 157.7 ± 17.3 148.1 ± 31.4 159.8 ± 11.7 0.033 † Weight (kg) 63.3 ± 19.5 48.5 ± 21.9 66.5 ± 17.6 0.003 † BMI (kg/m 2 ) 24.8 ± 6.3 20.7 ± 5.5 25.8 ± 6.1 0.008 † Waist perimeter (cm) 83.3 ± 16.0 70.9 ± 16.2 85.7 ± 14.9 0.004 † Hip perimeter (cm) 90.2 ± 13.3 79.5 ± 9.5 92.3 ± 13.0 0.003 † Triceps skinfold (mm) 8.9 ± 8.7 4.5 ± 2.9 9.9 ± 9.3 0.036 † Biceps skinfold (mm) 6.1 ± 5.2 2.8 ± 0.8 6.7 ± 5.4 0.012 † Subscapular skinfold (mm) 21.9 ± 15.7 7.7 ± 4.4 24.4 ± 15.5 0.001 † Suprailiac skinfold (mm) 13.6 ± 13.3 5.2 ± 1.9 15.3 ± 14.0 0.027 † Thigh skinfold (mm) 11.5 ± 13.9 5.7 ± 4.2 12.8 ± 14.9 0.033 † Calf skinfold (mm) 7.3 ± 8.3 4.2 ± 2.2 7.9 ± 9.0 0.051 Total fat (kg) 16.8 ± 10.8 4.4 ± 2.1 19.9 ± 9.8 <0.0001 † Total fat (%) 25.3 ± 11.8 9.9 ± 3.4 29.4 ± 9.6 <0.0001 † Upper-limb fat (kg) 1.8 ± 1.2 0.6 ± 0.4 2.1 ± 1.2 0.002 † Upper-limb fat (%) 24.4 ± 11.5 11.7 ± 6.7 27.8 ± 10.4 <0.0001 † Lower-limb fat (kg) 4.3 ± 3.6 1.4 ± 0.6 5.1 ± 3.6 0.003 † Lower-limb fat (%) 21.4 ± 11.9 10.9 ± 2.7 24.1 ± 11.9 <0.0001 † Trunk fat (kg) 9.9 ± 7.8 1.6 ± 1.1 12.1 ± 7.3 <0.0001 † Trunk fat (%) 26.8 ± 14.1 7.3 ± 4.2 31.9 ± 10.9 <0.0001 † Total FFM (kg) 42.4 ± 12.1 40.3 ± 17.8 42.9 ± 10.3 0.586 Upper-limb FFM (kg) 4.7 ± 1.8 4.4 ± 2.6 4.7 ± 1.5 0.634 Lower-limb FFM (kg) 13.0 ± 4.0 12.1 ± 6.0 13.3 ± 3.3 0.752 Trunk FFM (kg) 15.7 ± 7.8 21.0 ± 8.7 14.3 ± 7.8 <0.0001 † Data are mean ± SD values. Subjects with progeroid syndrome, prepuberal subjects with familial partial lipodystrophy and patients with familial partial lipodystrophy and no data were excluded from this analysis. Age and gender were used as covariables. † p < 0.05. BMI, body mass index; FFM, fat-free mass. Ferna ´ndez-Pombo et al. 10.3389/fendo.2023.1250203 Frontiers in Endocrinology frontiersin.org08 TABLE 3 Lifetime prevalence of organ abnormalities and comorbidities. Overall (n=115) Generalised lipodystrophy (n=24) Partial lipodystrophy (n=91) P value Diabetes mellitus and microvascular complications Gestational diabetes* n (%) 10 (12.2) 2 (20.0) 8 (11.1) 0.327 DM n (%) 50 (43.5) 11 (45.8) 39 (42.9) 0.066 DM complications - Retinopathy n (%) 10 (20.0) 1 (9.1) 9 (23.1) 0.880 - Nephropathy n (%) 18 (36.0) 5 (45.5) 13 (33.3) 0.814 Renal failure n (%) 8 (16.0) 1 (9.1) 7 (17.9) 0.739 - Peripheral neuropathy n (%) 10 (20.0) 3 (27.3) 7 (17.9) 0.720 Cardiovascular disease Ischemic cardiopathy n (%) 14 (12.2) 0 (0.0) 14 (15.4) 0.495 Arrhythmia n (%) 4 (3.5) 1 (4.2) 3 (3.3) 0.793 Hypertrophic cardiomyopathy n (%) 7 (6.1) 7 (29.2) 0 (0.0) <0.0001 † Valvulopathy n (%) 13 (11.3) 8 (33.3) 5 (5.5) <0.0001 † Peripheral arterial disease n (%) 9 (7.8) 1 (4.2) 8 (8.8) 0.442 Neurological disease Encephalopathy n (%) 4 (3.5) 4 (16.7) 0 (0.0) 0.002 † Intellectual disability n (%) 12 (10.4) 11 (45.8) 1 (1.1) <0.0001 † Gait disturbances n (%) 5 (4.3) 5 (20.8) 0 (0.0) <0.0001 † Stroke n (%) 2 (1.7) 0 (0.0) 2 (2.2) 0.858 Abdominal abnormalities Hepatic steatosis n (%) 49 (42.6) 13 (54.2) 36 (39.6) 0.198 Cirrhosis n (%) 1 (0.9) 0 (0.0) 1 (1.1) 0.760 Cholelithiasis n (%) 6 (5.2) 0 (0.0) 6 (6.6) 0.503 Pancreatitis n (%) 10 (8.7) 3 (12.5) 7 (7.7) 0.492 Gynaecological disorders Oligo/amenorrhea* n (%) 20 (24.4) 4 (40.0) 16 (22.2) 0.431 PCOS* n (%) 13 (15.9) 1 (10.0) 12 (16.7) 0.319 Pregnancy loss* n (%) 11 (13.4) 0 (0.0) 11 (15.3) 0.314 Uterine polyps/fibroids* n (%) 9 (7.8) 1 (4.2) 8 (8.8) 0.815 Other disorders Hypertension n (%) 19 (16.5) 4 (16.7) 15 (16.5) 0.572 Anxiety-depressive disorder n (%) 18 (15.7) 1 (4.2) 17 (18.7) 0.418 Carpal tunnel Sd n (%) 8 (7.0) 1 (4.2) 7 (7.7) 0.617 Hypothyroidism n (%) 7 (6.1) 2 (8.3) 5 (5.5) 0.615 Goiter n (%) 13 (11.3) 1 (4.2) 12 (13.2) 0.530 Sleep apnoea n (%) 5 (4.3) 0 (0.0) 5 (5.5) 0.190 Malignancy n (%) 10 (8.7) 0 (0.0) 10 (11.0) 0.850 Data are n (%) values. 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