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.

Is it possible to achieve an acceptable disease control by dietary therapy alone in Berardinelli Seip type 1? Experience from a case report

“…In the case described, the patient presented the homozygous mutation c.493-1G>C in the AGPAT2 gene, which has also been described in the literature (20,21). The genetic alteration substitutes G for C at position-1 of intron 3, located in a highly conserved 3' splicing acceptor site.…”

“…Notable generalized lipodystrophy with upper limb phlebomegaly. (20,21). NGS analysis also detected a heterozygous variant located in LIPE gene c.666G>C, leading to amino acid substitution p.Trp222Cys.…”

“…Serum leptin showed undetectable levels ( Table 1 ), as expected for BSCL ( 1 ). NGS analysis was conducted, and the patient was found to carry the pathogenic variant c.493-1G>C in AGPAT2 gene in a homozygous state ( 20 , 21 ). NGS analysis also detected a heterozygous variant located in LIPE gene c.666G>C, leading to amino acid substitution p.Trp222Cys.…”

Lysophosphatidic acid triggers inflammation in the liver and white adipose tissue in rat models of 1-acyl-sn-glycerol-3-phosphate acyltransferase 2 deficiency and overnutrition

“…No direct evidence addresses the loss of adipose tissues during the perinatal period in human CGL1 patients due to AGPAT2 mutations. Some case reports regarding human CGL1 infants due to AGPAT2 mutations described no remarkable change at birth ( 26 – 28 ). Generalized loss of adipose was noted at 2 mo, 4.5 mo, or 7 y, respectively, in these case reports.…”

Role of Different Members of the AGPAT Gene Family in Milk Fat Synthesis in Bubalus bubalis

“…Among them, AGPAT4/LPAATδ is a physiologically essential enzyme that catalyzes the conversion of LPA (lysophosphatidic acid) to PA (phosphatidic acid), and is an essential component of the fission-inducing machinery driven by the protein BARS [34]. AGPAT2 mutations can lead to congenital lipodystrophy [35], which indicates that other family members cannot replace the AGPAT2 function. No significant differences in energy metabolism, food intake, and fat synthesis were observed in AGPAT4 knockout mice, suggesting that the AGPAT4 function may be compensated by other genes.…”