Face-sparing Congenital Generalized Lipodystrophy Type 1 Associated With Nonclassical Congenital Adrenal Hyperplasia

Abstract

Context

Congenital generalized lipodystrophy, type 1 (CGL1), due to biallelic pathogenic variants in AGPAT2, is characterized by the near total loss of body fat from the face, trunk, and extremities. Patients develop premature diabetes, hypertriglyceridemia, hepatic steatosis, and polycystic ovary syndrome. However, sparing of the facial fat and precocious pubertal development has not been previously reported in CGL1.

Case Description

We report a 21-year-old woman of European descent with CGL1 who had sparing of the facial fat and premature thelarche at birth with premature pubarche and menstrual bleeding at age 3 years. Her serum 17-OH progesterone level rose to 1000 ng/dL (30.26 nmol/L) after cosyntropin stimulation test, suggestive of nonclassical congenital adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency. Hydrocortisone replacement therapy from age 3.5 to 10 years resulted in cessation of menstruation and growth of pubic hair, and a reduction of breast size. Sanger and whole-exome sequencing revealed compound heterozygous variants c.493-1G>C; p.(Leu165_Gln196del), and c.del366_588+534; p.(Leu123Cysfs*55) in AGPAT2 plus c.806G>C; p.(Ser269Thr) and c.844G>T; p.(Val282Leu) in CYP21A2. She developed diabetes at age 13 requiring high-dose insulin and had 7 episodes of acute pancreatitis due to extreme hypertriglyceridemia in the next 5 years. Metreleptin therapy was initiated at age 18 and after 3 years, she had remission of diabetes and hypertriglyceridemia; however, menstrual irregularity and severe hirsutism did not improve.

Conclusion

Concomitant NCAH in this CGL1 patient was associated with precocious pubertal development and sparing of facial fat. Metreleptin therapy drastically improved her hyperglycemia and hyperlipidemia but not menstrual irregularity and hirsutism.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near total loss of body fat from the face, trunk, and extremities and predisposition to develop premature diabetes mellitus, hypertriglyceridemia, hepatic steatosis, and polycystic ovary syndrome. Of the 4 genetically distinct subtypes of CGL, type 1 (CGL1; 1-acylglycerol-3-phosphate O-acyltransferase 2 [AGPAT2]-associated) and type 2 (CGL2; Berardinelli-Seip congenital lipodystrophy 2 [BSCL2]-associated) are the most frequent (1). Patients with CGL1 have near total absence of “metabolically active” adipose tissue located in subcutaneous regions (including the face, neck, arms, legs, and trunk), intra-abdominal and intrathoracic regions, and bone marrow, but “mechanical fat,” located in the orbits, periarticular regions, palms, and soles, is spared (2, 3). Furthermore, while some females with CGL1 develop polycystic ovary syndrome and have menstrual irregularity, hirsutism, and clitoromegaly (4, 5), precocious pubertal development in early childhood has not been reported. We report a young female with CGL1 who presented with sparing of the facial fat and precocious pubertal development most likely due to concomitant nonclassical congenital adrenal hyperplasia (NCAH) as a result of 21-hydroxylase deficiency. Metreleptin replacement therapy drastically improved hyperglycemia, hypertriglyceridemia, and hepatic steatosis in this patient, but not menstrual irregularity and hirsutism.

Materials and Methods

The protocol was approved by the institutional review board of UT Southwestern and the parents and the patient gave written informed consent to participate in the study.

Case Report

A 21-year-old woman of European descent was referred to the Pediatric Endocrinology Clinic of Hospital de Santa Maria, Lisbon, Portugal, when she was age 2.5 years, because of clinical suspicion of CGL. She was the only child of healthy, nonconsanguineous parents. She was born by cesarean delivery at the gestational age of 39 weeks with a birth weight of 2.53 kg, length of 45 cm, and head circumference of 32.5 cm. She had bilateral thelarche at birth. Soon thereafter at age 4.5 months, she was noted to have generalized loss of subcutaneous fat but with sparing of the face, apparent generalized muscle hypertrophy, umbilical prominence, and hypertrichosis (over the arms, legs, and posterior trunk).

At age 2 years and 8 months, premature pubarche was noted (Fig. 1). At age 3 years and 4 months, menstrual bleeding ensued. Vaginal bleeding was scarce (spotting) and occurred twice, in the same month, 21 days apart. Pelvic ultrasound showed prepubertal uterus (uterine size 3.8 cm). Basal serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were less than 0.3 U/L and less than 0.07 U/L, respectively, and the intravenous LH-releasing hormone (45 µg, 2.5 µg/kg for a body weight of 17 kg) stimulation test showed mainly a rise in FSH level to 13.42 U/L with a stimulated LH level of 2.44 U/L. Gonadotropin-releasing hormone (GnRH) stimulation test was repeated and was still negative (there was no significant increase of LH nor an LH/FSH ratio > 0.66). She had an advanced bone age of 5 years and 9 months at chronological age 3 years and 5 months. Her plasma Δ 4-androstenedione level was 0.78 ng/mL (2.72 nmol/L) (normal range, 0.3-3.3 ng/mL or 1.05-11.5 nmol/L); dehydroepiandrosterone sulfate was less than 30 µg/dL (0.81 µmol/L) (16-96 µg/dL or 0.43-2.61 µmol/L for prepubertal females from Mayo Medical Laboratories); 11-deoxy-cortisol was 2.8 ng/mL (8.08 nmol/L) (normal values, mean ± SD: 0.3 ± 0.29 ng/mL or 0.86 ± 0.84 nmol/L) for ages 1 to 5 years); estradiol 17.3 pg/mL (83.5 pmol/L) (normal range, 11-165 pg/mL or 40.3-605.8 pmol/L); insulin 6.7 mU/L (46.5 pmol/L) (normal range, 6-27 mU/L or 41.7-187.5 pmol/L); cortisol 13.5 µg/dL (372.4 nmol/L) (normal range, 4.3-23 µg/dL or 118.6-634.5 nmol/L); and 17-OH progesterone was 172 ng/dL (5.2 nmol/L) (normal range < 100 ng/dL or 3.03 nmol/L). Considering the negative GnRH stimulation test, it was hypothesized that the clinical manifestations of pubarche, growth acceleration, and advanced bone age could be due to congenital adrenal hyperplasia (CAH). An adrenocorticotropin (ACTH) stimulation test was performed.

Figure 1.

Clinical features of the patient at various ages. A and B, Anterior view of the patient at age 5 years and 2 months showing scarce subcutaneous adipose tissue, pseudomuscular hypertrophy, and pubarche. C and D, Lateral and anterior views of the patient at age 16 years and 6 months, before metreleptin treatment, with persistent face-sparing scarce subcutaneous adipose tissue, pseudomuscular hypertrophy, umbilical prominence, and acromegaloid features. E, Anterior view of the patient at age 21 years showing weight loss, decrease of acanthosis nigricans, and acromegaloid features. Abdominal protuberance seen previously in C and D is absent now.

On cosyntropin (synthetic ACTH) stimulation test (175 µg intravenously), the patient’s 17-OH progesterone level rose to 1000 ng/dL (30.26 nmol/L) at 60 minutes, which was interpreted to be compatible with NCAH due to 21-hydroxylase deficiency. She was started on hydrocortisone at a dose of 11 mg/m²/day (7.5 mg/day) at age 3.5 years. After initiation of hydrocortisone therapy, she did not have any further menstrual periods, a reduction of breast size was noted, and the pubic hair stopped growing, all of these suggesting arrest of pubertal progression. At the time of normal puberty (age 10 years), hydrocortisone was stopped.

Until age 3.5 years, her serum triglycerides were normal or slightly higher than 200 mg/dL (2.26 mmol/L) but afterward were as high as 929 mg/dL (10.5 mmol/L) (normal range < 150 mg/dL [< 1.70 mmol/L]) (Fig. 2). Insulin resistance (fasting plasma insulin level of 80 mU/L [555.6 pmol/L]) and a plasma glucose/insulin ratio of 1.2 was noted at age 9 years and she was started on metformin 500 mg twice a day at age 10 years and 8 months. Her maximum serum triglycerides (3410 mg/dL, 38.5 mmol/L) were at age 13 years when she developed diabetes mellitus and presented with polyuria and polydipsia with a blood glycated hemoglobin A_1c (HbA_1c) of 6.9%. She was started on insulin therapy with a dose of 0.6 U/kg/day (multiple daily injections) and required progressively higher doses.

Figure 2.

Serum triglycerides levels from birth until age 21 years in our patient. Duration of hydrocortisone, ciprofibrate, insulin, and metreleptin therapy is shown in horizontal bars. Arrow head: diagnosis of diabetes. Arrows: acute pancreatitis episodes. Duration of contraceptive pills (P1: 2 mg cyproterone acetate + 0.035 mg ethinyl estradiol, 21 days/month; P2: 3 mg drospirenone + 0.02 mg ethinyl estradiol; and P3: 1-3 mg estradiol valerate + 2-3 mg dienogest).

She has been taking ciprofibrate 100 to 200 mg/day since age 14 years (see Fig. 2). She also had hepatic steatosis (diagnosed by abdominal ultrasound with the liver measuring a maximum of 24 cm in the midclavicular line) since age 11 years and had maximum elevation of serum aspartate transaminase of 82 U/L (0-34 U/L) and alanine transaminase of 75 U/L (10-49 U/L) at age 14 years.

Menarche occurred at age 12 years. A pelvic ultrasound revealed plurifollicular, microcystic ovaries. She had irregular menstrual periods, with scarce bleeding. She had excess facial hair and mild facial acne and her serum total testosterone level was high (91.8 ng/dL, 3.18 nmol/L; normal range < 20 ng/dL, or < 0.69 nmol/L). There was no clitoromegaly and breast development was at Tanner stage 4. She was started on oral contraceptive (2.0 mg of cyproterone acetate + 0.035 mg ethinyl estradiol, 21 days/month) to improve hirsutism; but stopped 8 months later because of extreme hypertriglyceridemia. She had amenorrhea and worsening hirsutism and was started again on oral contraceptive (3 mg drospirenone + 0.02 mg ethinyl estradiol) at age 13 years and 11 months that was again stopped 3 months later because of hypertriglyceridemia (serum triglycerides 1792 mg/dL, 20.24 mmol/L). She had her first documented episode of acute pancreatitis at age 14 years and 3 months, with serum triglycerides of 5360 mg/dL (60.6 mmol/L), requiring intensive care. Abdominal ultrasound and a computed tomography (CT) scan of the abdomen showed acute pancreatic inflammatory changes (peripancreatic fluid and pancreatic heterogeneity). At age 14 years and 6 months, serum triglycerides were 209 mg/dL (2.36 mmol/L) and oral contraceptive (estradiol valerate 1-3 mg + dienogest 2-3 mg) was started, which resulted in regular menstrual periods and improvement of hirsutism but she had 2 episodes of acute pancreatitis, therefore it was stopped at age 16 years and 6 months (see Fig. 2).

The patient had a total of 7 acute pancreatitis episodes of variable severity. An abdominal CT angiogram was performed at age 19 years and revealed obliteration of the distal two-thirds of the splenic vein. She also developed gastric varices and had 6 episodes of upper gastrointestinal bleeding, all requiring blood transfusions. Therefore, she underwent splenectomy, without complications.

At age 18 years, just before starting metreleptin, her weight was 66.6 kg and her height was 166.7 cm (body mass index of 23.9) with normal blood pressure of 120/50 mm Hg. She had severe acanthosis nigricans in the posterior cervical region, acromegaloid features (that affected both the hands and feet), prominent veins, hepatomegaly (palpable at 8 cm below the costal margin), hirsutism, oligomenorrhea, hyperphagia, and depression. She required 208 units of subcutaneous insulin daily (120 units of glargine insulin and 22 units of glulisine insulin given 4 times daily, total insulin dose 3 units/kg/day), metformin 2 g/day, fish oil 9 g/day, ciprofibrate 200 mg/day, and pravastatin 40 mg/day. Fasting serum triglycerides were 1315 mg/dL (14.86 mmol/L), and total cholesterol, uric acid, aspartate transaminase, and alanine transaminase were within the normal range. HbA_1c was 8.9% and her 24-hour urinary albumin excretion was 1882 mg/g creatinine (normal range < 30 mg/g).

She was started on 0.075 mg/kg/d of metreleptin (5 mg) administered once daily, subcutaneously. Her compliance has been excellent. The patient reported an early disappearance of hyperphagia within 2 weeks of metreleptin therapy, while a notable decrease of acanthosis nigricans by 2 months and she noted reduction in the size of her hands and feet. Her menstrual periods resumed but remained irregular, with scarce bleeding, and amenorrhea for periods of 3 to 10 months. Her liver size reduced to 3 cm below the costal margin after 4 months of metreleptin therapy and the liver was not palpable after 6 months of therapy. There was no evidence of hepatic steatosis on abdominal CT scan 1 year after metreleptin was started. Serum triglyceride levels were normal at 106 mg/dL (1.20 mmol/L) after 9 months and microalbuminuria normalized during the third year of therapy (23.6 mg/g creatinine). She stopped taking pravastatin 9 months after metreleptin was started, ciprofibrate after 1 year, and fish oil after 1 year and 6 months.

Despite reducing the insulin dosage, she had frequent hypoglycemic episodes (none were severe, some were asymptomatic). Insulin dose was progressively reduced to 104 U/day (91 U glargine + 13 U glulisine) after 1 year of metreleptin therapy. After 12 months of metreleptin, blood HbA_1c level was 5.9%. Insulin therapy was discontinued after 3 years of metreleptin therapy when HbA_1c level was 5.8%.

She did not notice any substantial improvement in severe hirsutism and her menstrual periods remained irregular, so she resumed oral contraceptive therapy (0.02 mg ethinyl estradiol with 0.075 mg gestodene, 21 d/mo) at age 20 years and 10 months. Her serum triglycerides have remained within normal range (72-149 mg/dL [0.81-1.68 mmol/L]). Her hirsutism has progressively improved with less need for laser hair removal.

There has been a progressive weight loss (total weight loss of 16.6 kg) and metreleptin dosage was lowered to 4 mg once a day (0.08 mg/kg/d) at age 21 years and 7 months, and she gained 1 kg in the next 4 months.

Genotyping

The proband and her parents underwent Sanger sequencing for variants in AGPAT2 and CYP21A2. In addition, the proband underwent whole-exome sequencing (WES) using the IDT xGen Exome capture kit on the Illumina platform. Sequencing read length was paired-end 2 × 100 bp. Sequences were aligned to the human reference genome b37. The median coverage of the targeted regions was 127-fold. In addition, for detection of large CYP21A2 copy number variants (CNVs), a multiplex ligation-dependent probe amplification (MLPA) assay was conducted using the SALSA MLPA Probemix P050 CAH (MRC Holland).

Results

Genotyping confirmed the diagnosis of CGL1. We first conducted the Sanger sequencing of coding sequence of AGPAT2, and the result was interpreted to be a homozygous pathogenic variant c.493-1G>C also known as c.IVS3-1G>C, p.(Leu165_Gln196del); rs606231168 (6, 7). However, genotyping of the parents revealed that only the mother had the heterozygous c.493-1G>C variant; the father did not. This observation led us to perform CNV analysis of the WES using ExomeDepth (8), which indicated a heterozygous deletion of exon 4 in the proband. We further confirmed the heterozygous AGPAT2 variant c.del366_588+534; p.(Leu123Cysfs*55) in the proband and her father by Sanger sequencing using the 3 primers as suggested by Magré et al (9) (Fig. 3). She also had a heterozygous missense variant c.299G>A, (rs764260414), p.(Ser100Asn), which is in strong linkage disequilibrium with the c.493-1G>C variant and may not be pathogenic.

Figure 3.

Pedigree and the variants in CYP21A2 and AGPAT2 in the proband and her parents. A, Pedigree of the proband (CGL 120.3) showing variants in CYP21A2 and AGPAT2. Circles denote females and square denotes male. WT, wild-type allele. B, Chromatogram of a portion of CYP21A2 from Sanger sequencing showing the c.806G>C heterozygous (het) variant in the proband with the WT chromatogram underneath. C, Chromatogram of a portion of CYP21A2 from Sanger sequencing showing the c.844G>T het variant in the proband with the WT chromatogram underneath. D, Chromatogram of a portion of AGPAT2 from Sanger sequencing showing the c.493-1G>C variant in the proband that was initially interpreted as homozygous but was present in the mother (CGL 120.2) but not in the father (CGL 120.1), E, Chromatogram of a portion of AGPAT2 from Sanger sequencing showing the c.del366_588+534 heterozygous variant in the proband using the 3 primer pairs as suggested by Magré et al (9).

Given the persistence of marked hirsutism, menstrual irregularities, and facial acne, we examined the WES data for variants in CAH candidate genes. Two missense variants in the cytochrome P450 family 21 subfamily A member 2 (CYP21A2) gene were identified: c.844G>T, p.(Val282Leu) (rs6471; minor allele frequency [MAF]: 0.00795 in Europeans), which is frequently observed in individuals with NCAH, and c.806G>C, p.(Ser269Thr) (rs6472; MAF: 0.06491 in Europeans), which is considered benign (10). These 2 variants were in trans with c.806G>C inherited from the mother and c.844G>T from the father (see Fig. 3). In addition, she had 2 other heterozygous synonymous variants c.747C>G; p.(Leu249Leu); (rs6477, MAF: 0.09230) and c.1125C>T, p.(Ser375Ser); (rs6469; MAF: 0.19041) in CYP21A2. The MLPA assay for CYP21A2 revealed no deletions, duplications, or chimeras. No pathogenic variants were identified in CYP11B1, CYP17A1, HSD3B2, CYP11A1, STAR, or POR.

Discussion

This patient presented with many of the typical clinical features of CGL1, since birth and over the years, such as near total lack of body fat, hyperphagia, prominent muscles and subcutaneous veins, acanthosis nigricans, acromegaloid features, hepatomegaly, umbilical prominence, menstrual irregularity, and hirsutism (1). She also developed severe metabolic abnormalities such as hypertriglyceridemia (which led to recurrent episodes of acute pancreatitis), hyperinsulinemia, diabetes mellitus requiring high-dose insulin therapy, hepatic steatosis, and microalbuminuria. However, she had some unusual clinical features not previously reported in CGL1 patients, namely sparing of the facial fat, and thelarche since birth, and pubarche and menstrual bleeding as early as age 3 years, confirming precocious pubertal development. Previously, some females with CGL1 have been reported to develop clitoromegaly, hirsutism, and menstrual irregularity due to polycystic ovary syndrome (4, 5) but not precocious pubertal development.

Precocious pubertal development in our patient was related to NCAH (11). The ACTH stimulation test provided biochemical evidence of 21-hydroxylase deficiency. Furthermore, WES revealed compound heterozygous missense nonsynonymous variants in CYP21A2; however, only one of those is considered pathogenic while the other is considered benign. By WES, we did not identify CNVs in the region, which can be observed in approximately 32% of patients with CAH (12). Because WES is not sensitive enough to detect heterozygous CNVs, we performed MLPA for CYP21A2, which revealed no CNVs.

Serum LH increments greater than or equal to 4 to 5 IU/L at 30 to 60 minutes after GnRH administration are well-known criteria to diagnose central precocious puberty, and to further support diagnosis, a peak LH to FSH ratio greater than 0.66 has been added to the criteria (13). Basal serum LH has an equally crucial role as levels greater than 1.0 IU/L have been demonstrated to have a positive predictive value for central precocious puberty of 96.4% (13). In confirmed cases of NCAH with precocious puberty, the presence of gonadotropin response with pubertal changes suggests development of central precocious puberty, which was not the case in our patient. The self-limited menstrual bleeding and thelarche could be due to a transitory activation of the hypothalamic-pituitary-gonadal axis, and therefore a pubertal variant. Persistence of hyperandrogenism and irregular menstruation despite metreleptin therapy could also be due to NCAH (14). NCAH is usually associated with an estimated in vitro 21-hydroxylase activity of 5% to 30% (15).

It is possible that the sparing of the facial fat in this patient with CGL1 was most likely also due to associated NCAH, which can result in high concentrations of 17-OH progesterone, progesterone, and other adrenal steroids. Progesterone and 17-OH progesterone also bind to glucocorticoid receptor (GR) with reduced relative binding affinity: progesterone (43%) and 17-OH progesterone (27%) to that of cortisol (100%) (16, 17). Recently, 17-OH progesterone was reported to elicit a dramatic induction in GR transactivation activity and treatment of lean mice with 17-OH progesterone promoted hyperglycemia and insulin resistance (18). Thus, high serum 17-OH progesterone levels due to concomitant 21-hydroxylase deficiency in our patient may have caused sparing of facial adipose tissue similar to excess glucocorticoids increasing facial fat in patients with Cushing syndrome. Also, high serum 17-OH progesterone levels could have exacerbated insulin resistance and caused the premature onset of diabetes. A direct measurement of GR affinity for progesterone and 17-OH progesterone in the adipose tissue/adipocytes, especially from region in future may provide further evidence of the role of NCAH in sparing of facial fat in this patient.

The conventional approach to treatment of CGL patients includes lifestyle modification and the use of oral antidiabetics and insulin, lipid-lowering drugs, and other medications (19). Hypertriglyceridemia is usually treated with fibrates, long-chain polyunsaturated omega-3 fatty acids from fish oils, and statins, all of which were given to our patient (19). These drugs were relatively well tolerated by the patient, but there was no significant lowering of serum triglycerides. The patient’s diabetes mellitus was treated with metformin and insulin, but like in the vast majority of cases with CGL1, she developed severe insulin resistance and required large doses of insulin (up to 208 U/day) and still had an elevated HbA_1c (19).

Metreleptin replacement therapy has become the mainstay of treating metabolic complications in patients with CGL (20). The patient started metreleptin at age 18, before it was officially approved by the European Union, as an off-label administration through an early access program. This was the first patient treated with metreleptin in Portugal. At the time, there were reported cases of earlier use with positive outcomes (21, 22), and additional studies demonstrated the sustained efficacy of metreleptin therapy on metabolic imbalance in cohorts of adults and children with CGL (23). Metreleptin improved hyperphagia resulting in a total weight loss of 13 kg over the first year in our patient. Her serum triglyceride levels were normal (66-116 mg/dL [0.75-1.31 mmol/L]) after 9 months of metreleptin treatment, consequently reverting completely the risk for acute pancreatitis episodes, which had caused the splenic vein thrombosis and were potentially life-threatening. Our patient also experienced hypoglycemic episodes after metreleptin therapy, which is a reported side effect due to improved insulin action. Consequently, her insulin dose was gradually reduced and insulin was eventually stopped. Metreleptin also improved hepatic steatosis, reduced liver volume, and normalized serum liver enzyme levels in our patient as reported previously (20, 21, 24). The benefits in renal function, namely improvement of proteinuria and hyperfiltration with metreleptin, were also observed in our patient (24).

A previous study of metreleptin therapy on ovarian function in generalized lipodystrophy patients (that included 7 CGL patients) reported that all patients with grossly irregular menstruation achieved regular menstrual cycles following 12 months of therapy (24). Although normalized gonadotropin secretion and decrease of androgen level are generally expected with metreleptin therapy in CGL patients (24), even though there was a decrease in serum total testosterone level from 80 to 50.6 ng/dL (2.77 to 1.75 nmol/L) in our patient, she continued to experience irregular menstruation, hirsutism, and acne, which could be related to NCAH (25).

In conclusion, we report the first case of CGL1 with NCAH presenting with precocious pubertal development and sparing of facial fat. Owing to overlapping features of CGL and CAH, it was difficult to diagnose NCAH in our patient. Metreleptin therapy drastically improved hyperglycemia and hyperlipidemia but not menstrual irregularity and hirsutism in this patient.

Glossary

Abbreviations

ACTH

adrenocorticotropin;

CAH

congenital adrenal hyperplasia;

CGL

congenital generalized lipodystrophy;

CGL1

congenital generalized lipodystrophy type 1;

CNV

copy number variant;

CT

computed tomography;

FSH

follicle-stimulating hormone;

GnRH

gonadotropin-releasing hormone;

GR

glucocorticoid receptor;

HbA_1c

glycated hemoglobin A_1c;

LH

luteinizing hormone;

MAF

minor allele frequency;

MLPA

multiplex ligation-dependent probe amplification;

NCAH

nonclassical congenital adrenal hyperplasia;

WES

whole-exome sequencing

Financial Support

This work was supported by the National Institutes of Health (grant No. R01-DK105448) and the Southwestern Medical Foundation. The funding sources were not involved in the study design, analysis and interpretation of data, writing of the paper, or the decision to submit the article for publication.

Conflict of Interest

A.G. consults for Amryt Pharma plc, Regeneron, Kyttaro Limited, and Third Rock Ventures, and has received grant support from Amryt Pharma plc, Regeneron, Quintiles, Akcea Pharmaceuticals, and Intercept Pharmaceuticals. A.G. is a co-holder of patents for the use of leptin for treating human lipoatrophy and methods of determining predisposition to said treatment but receives no financial benefit. The remaining authors have nothing to disclose.

Data Availability

Restrictions apply to the availability of some or all data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data be provided.