Table 1 summarizes the baseline characteristics of patients and controls. Among the 19 patients with CGL, 12 had generalized fat loss caused by pathogenic variants in acyltransferase 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2), 4 had seipin (BSCL2), 2 had caveolae associated protein 1 (CAVIN-1), and 1 had lamin A/C (LMNA) (Table 2).

Among 29 patients with FPLD, 12 had typical Dunnigan syndrome due to heterozygous LMNA variants (Table 2). Partial lipodystrophy was characterized by fat loss primarily affecting the limbs with preservation/accumulation of fat in the upper portion of the body and/or face and neck in these patients. Fat loss was more severe in one patient with a pathogenic variant in LMNA c.1456 A > G, p.(K486E). This patient previously presented with generalized fat loss and coinciding systemic lymphoma [15]. Peroxisome proliferator-activated receptor gamma (PPARG) variants c.452 A > G, p.(Y151C) and c.1346 A > T, p.(H477L) were observed in two individuals. A slight fat loss affecting their limbs was noted in these two patients.

Of the remaining 14 patients with FPLD, seven exhibited phenotypic characteristics of the Kobberling variant (FPLD1). Genetic studies are typically unable to assist with the diagnosis of patients with FPLD1. Consequently, FPLD1 was diagnosed based on clinical features, including metabolic abnormalities, truncal obesity, fat loss predominantly affecting the extremities, and the presence of a palpable “ledge” between lipodystrophic and non-lipodystrophic areas. Furthermore, radiological studies, including whole-body MRI, were conducted to demonstrate fat loss or accumulation in specific body areas [16].

On the other hand, no pathogenic variant was identified in the genes currently associated with FPLD in the remaining seven patients with a phenotype indicating Mendelian FPLD (FPLDX). Historically, Sanger sequencing was used to study patients with lipodystrophy at our center. Typically, our FPLD genetic testing approach started with LMNA followed by PPARG sequencing. If these two genes did not yield disease-causing variants, Sanger sequencing was performed for other FPLD genes on a case-by-case basis based on phenotype. Over the past 8 years, our algorithm has shifted to the use of a genetic panel consisting of nine lipodystrophy genes.

Median glucose, aspartate aminotransferase (AST), alanine transaminase (ALT), and triglyceride levels were higher (P < .001, P = .001, P < .001, and P < .001, respectively), whereas the median high-density lipoprotein (HDL) levels were lower in patients with lipodystrophy than in controls (P < .001) (Table 1). Patients with GL were younger and had a lower BMI than the control group (P < .001). Conversely, glucose, AST, ALT, triglyceride, and LDL levels were higher in patients with GL than in the control group. Patients with FPLD were older and had a higher BMI than those with GL (P < .001 and P = .004, respectively). Although glucose, AST, triglyceride, and LDL levels were similar in both groups, patients with FPLD had higher levels of total cholesterol, HDL cholesterol, leptin, and adiponectin, and lower levels of ALT than patients with GL (Table 1). Among subtypes of FPLD, patients with FPLD1 had higher levels of leptin (P = .009) and lower levels of triglyceride (P = .036) compared to patients with FPLD2 (Table 3).

Median AOM distance was 10.9 (IQR: 6.6–16.1) mm in patients with lipodystrophy and 11.3 (IQR: 8.4–15.5) mm in the control group (P = .587). Patients with CGL had a lower AOM distance (8.1, IQR, 6.0–10.8 mm) compared with controls (11.3, IQR, 8.4–15.5 mm; P = .016) and patients with FPLD (vs. 13.0, IQR, 8.8–18.1 mm; P = .023). The AOM distance was numerically higher in patients with FPLD1 than in those with FPLD2, but this was not statistically significant. Figure 1 shows representative AOM distance measurements in T1-weighted MR scans from patients with two subtypes of lipodystrophy and healthy controls.

MR images showing aortomesenteric distance in healthy controls and patients with subtypes of genetic lipodystrophies (T1-weighted axial image at the level of left renal vein). The AOM distance was 4.9 mm in a 31-year-old female patient with CGL due to an AGPAT2 pathogenic variant (A), 10.6 mm in a 32-year-old female patient with FPLD due to an LMNA pathogenic variant (B), and 11.8 mm in a 34-year-old female healthy control (C)

BMI was positively correlated with the AOM distance, both in the overall sample (r = .397, P < .001) and in patients with lipodystrophy (r = .505, P < .001) (Fig. 2). BMI was found to be a significant predictor of the AOM distance in multivariate linear regression analysis including an age- and sex-adjusted model (beta = 0.537, 95% confidence interval [CI]:0.277–0.798, P < .001). No correlation was observed between height and AOM distance in all subjects (P = .976), among patients with lipodystrophy (P = .319), or in the control group (P = .364).

Positive correlation between BMI and AOM distance in all subjects (A) and in patients with lipodystrophy (B)

The TF-SMA and TF-RR distances, representing mesenteric and retroperitoneal adipose tissues, respectively, were significantly lower in patients with CGL than in patients with FPLD and controls (Table 1). Although patients with FPLD had a lower TF-SMA distance than the controls (P = .016), the TF-RR distance was similar between the two groups. Among patients with FPLD subtypes, those with FPLD1 had higher TF-SMA and TF-RR distances compared to those with FPLD2 (Table 3). BMI and AOM distance were positively correlated with TF-SMA (r = .429, P < .001 and r = .493, P < .001, respectively) and TF-RR (r = .488, P < .001 and r = .503, P < .001, respectively) distances in all subjects. Similar correlations were found when patients with lipodystrophy were analyzed separately. BMI and AOM distance were positively correlated with TF-SMA (r = .633, P < .001 and r = .545, P < .001, respectively) and TF-RR (r = .581, P < .001 and r = .490, P < .001, respectively) distances in patients with lipodystrophy. Representative mesenteric and retroperitoneal fat measurements on T1-weighted MR scans from patients with two subtypes of lipodystrophy and healthy controls are shown in Fig. 3.

MR images showing the distance between the transversalis facia and the superior mesenteric artery (TF-SMA) at the level of the umbilicus which estimates mesenteric fat tissue thickness in healthy controls and patients with subtypes of genetic lipodystrophies (T1-weighted axial image). Retroperitoneal fat tissue thickness was estimated by measuring the distance from the end of the right renal lower pole to the transversalis facia (TF-RR). Mesenteric (A) and retroperitoneal (B) fat tissues were almost completely lost in a 29-year-old female patient with CGL due to an AGPAT2 pathogenic variant. The TF-SMA and TF-RR distances were 19.3 mm (C) and 33.7 mm (D) in a 33-year-old female patient with FPLD lacking a pathogenic variant, and 23.4 mm (E) and 24.6 mm (F) in a 34-year-old female healthy control, respectively

Leptin levels were lower in patients with CGL (0.3 ng/mL, IQR, 0.1–0.7 ng/mL) than in patients with FPLD (3.4 ng/mL, IQR, 1.3–8.2 ng/mL; P < .001). Leptin was positively correlated with AOM distance in patients with lipodystrophy (r = .513, P < .001). A positive correlation was observed between leptin levels and AOM distance in patients with FPLD (r = .551, P = .005). Leptin levels were positively correlated with TF-SMA and TF-RR distances in patients with lipodystrophy (r = .717, P < .001 and r = .721, P < .001, respectively). In addition, adiponectin levels were lower in patients with CGL than in those with FPLD (P = .003). Adinopectin was positively correlated with leptin (r = .554, P < .001), but there was no correlation between AOM distance and adiponectin.

Of the 19 patients with CGL, 12 (63%) had an AOM distance of less than 10 mm, a risk factor that may predispose to SMA syndrome development. Among these patients, four were admitted to the emergency room or hospital with abdominal pain or GI symptoms: two with confirmed pancreatitis, one diagnosed with intestinal perforation, and one patient had an undetermined etiology of abdominal pain. Our medical chart review identified a patient with symptoms suggestive of SMA syndrome in addition to recurrent pancreatitis. A 37-year-old female patient with CGL due to an APGAT2 variant (BMI: 16.9 kg/m2) underwent seven hospitalizations for abdominal pain, all of which were attributed to episodes of pancreatitis secondary to hypertriglyceridemia. The patient was initiated on metreleptin at a dose of 5 mg/day. The patient remained on the same dose as we observed continuous desirable benefits from the treatment with no significant side effects. Her severe abdominal pain episodes were resolved with metreleptin treatment, and thereby, no further hospitalization was required.

Upon reviewing her medical charts, amylase and lipase levels and CT assessments were incompatible with acute pancreatitis in at least two of these hospitalizations. During symptom examinations focusing on periods outside hospitalization episodes, the patient reported chronic abdominal pain for years, describing postprandial epigastric pain accompanied by nausea. Vomiting would occasionally follow abdominal pain, typically radiating from the midline of the abdomen to the waist. The CT could not measure the AOM angle because of low body weight. Transabdominal Doppler USG was performed, which revealed an AOM angle of 16.1º, indicating a severely narrowed AOM angle that can lead to SMA syndrome (Fig. 4).

MR images and Doppler ultrasonography of a 37-year-old woman with CGL due to an AGPAT2 pathogenic variant. (A) Abdominal MR images showing aortomesenteric distance of 4 mm (fat-saturated T1-weighted axial image at the level of left renal vein). (B) Doppler Ultrasonography showing the aortomesenteric angle of 16.1º

One additional patient had an undetermined etiology of abdominal pain, with a 28º AOM angle measured in CT images from her medical records. Unfortunately, further symptom reviews or diagnostic testing could not be conducted because the patient died.

Eight of 29 (27%) patients with FPLD had an AOM distance of 10 mm. Among them, two were hospitalized several times with clinical symptoms of acute pancreatitis due to severe hypertriglyceridemia. Notably, no other patients with FPLD reported symptoms suggestive of SMA syndrome or displayed an AOM angle of < 25º on available CT images in the medical charts.