Fifteen days later, his sister was admitted to our hospital for jaundice. The patient was 27 days old, G4P2, and delivered by caesarean section after 40 weeks and 4 days of gestation. Her Apgar score at 5 min and 10min after birth was 9 and 10. her birth weight was normal (4000 g). She was also born with skin hyperpigmentation ( Figures 1C, D ) but never had hypoglycemia.
Jaundice appeared four days after birth. It was initially relieved by phototherapy, but gradually worsened after phototherapy was stopped. Laboratory examination revealed that the cortisol level was low, and extremely high morning ACTH was observed ( Supplementary Table 2 ). She had normal glucose, electrolytes and renin levels ( Supplementary Table 1 ). Thyroid hormone levels were normal, but elevated total bilirubin (Tbil), direct bilirubin (DBIL), indirect bilirubin (IBIL), and total bile acid (TBA) were observed, cardiac ultrasound revealed that she suffered from mild mitral and tricuspid regurgitation, while the electrocardiogram was normal ( Supplementary Table 2 ). Sanger sequencing confirmed that the sister had the same homozygotic variants in c.712C>T/p.H238Y in MC2R ( Figure 1E ). The pedigree of the family is shown in  Figure 2 . The sister received oral hydrocortisone at a dose of 10 mg/m2 body surface area. To date, no readily visible side effects have been observed. Informed consent was obtained from the parents for the publication of this case.
This variant was located in the transmembrane domain (PM1) and not reported in the dbSNP152, gnomAD, 1000 Genome Database, or Exome Variant Server (PM2). In-silico tools predicted this variant would be pathogenic (SIFT: Damaging, Mutation taster: Disease causing, Polyphen-2: Probably damaging, CADD: Pathogenic and Revel: Damaging), and it was located at a highly conserved site (PP3), the protein model was constructed and polar contacts of wild-type and mutated amino acid residues were compared ( Supplement Figure 1 ). A previous work showed it to be a causal variant for FGD1[8], and it was observed in the trans position against other MC2R pathogenic variants R145C (PM3). The variant was observed in both affected siblings (PP1). Thus, the variant produced PM1+PM2+PM3+PP1+PP3, which met pathogenic criteria.