Case report https://doi.org/10.6065/apem.2020.25.1.46 Ann Pediatr Endocrinol Metab 2020;25:46­51 Nonclassic congenital lipoid adrenal hyperplasia diagnosed at 17 months in a Korean boy with normal male genitalia: emphasis on pigmentation as a diagnostic clue Hosun Bae, MD1, Congenital lipoid adrenal hyperplasia (CLAH) is one of the most fatal conditions Min-Sun Kim, MD1, caused by an abnormality of adrenal and gonadal steroidogenesis. CLAH results Hyojung Park, MD1, from loss-of-function mutations of the steroidogenic acute regulatory (STAR) Ja-Hyun Jang, MD, PhD2, gene; the disease manifests with electrolyte imbalances and hyperpigmentation Jong-Moon Choi, MD, PhD2, in neonates or young infants due to adrenocortical hormone deficiencies, and 46, Sae-Mi Lee, MD, PhD2, XY genetic male CLAH patients can be phenotypically female. Meanwhile, some Sung Yoon Cho, MD, PhD1, patients with STAR mutations develop hyperpigmentation and mild signs of adrenal insufficiency, such as hypoglycemia, after infancy. These patients are classified as Dong-Kyu Jin, MD, PhD1 having nonclassic CLAH (NCCLAH) caused by STAR mutations that retain partial 1Department of Pediatrics, Samsung activity of STAR. We present the case of a Korean boy with normal genitalia who Medical Center, Sungkyunkwan Univer­ was diagnosed with NCCLAH. He presented with whole-body hyperpigmentation sity School of Medicine, Seoul, Korea and electrolyte abnormalities, which were noted at the age of 17 months after 2GC Genome, Yongin, Korea an episode of sepsis with peritonitis. The compound heterozygous mutations p.Gly221Ser and c.653C>T in STAR were identified by targeted gene-panel sequencing. Skin hyperpigmentation should be considered an important clue for diagnosing NCCLAH. Keywords: Congenital lipoid adrenal hyperplasia, Nonclassic congenital lipoid adrenal hyperplasia, STAR, Pigmentation Introduction Congenital lipoid adrenal hyperplasia (CLAH) is a rare autosomal recessive disorder caused by defects in the steroidogenic acute regulatory (STAR) gene located on chromosome 8p11.2.1) Received: 10 May, 2019 Revised: 21 July, 2019 The true incidence of CLAH is unknown, but the literature suggests it is much higher among Accepted: 11 August, 2019 Japanese, Koreans, and Palestinians than other ethnic groups. The role of the STAR protein is to transfer cholesterols to the inner mitochondrial membrane from the outer mitochondrial Address for correspondence: membrane for the synthesis of pregnenolone.2) Thus, patients with CLAH have deficient levels Sung Yoon Cho, MD, PhD of glucocorticoids, mineralocorticoids, and sex hormones. Patients with classic CLAH develop Department of Pediatrics, Samsung adrenal failure within the first few months of life and show female external genitalia regardless Medical Center, Sungkyunkwan 3) of genetic sex. However, some patients with STAR mutations present with mild adrenal University School of Medicine, insufficiency, even after infancy. These patients are classified as having nonclassic CLAH 81 Irwon­ro, Gangnam­gu, Seoul 4) 06351, Korea (NCCLAH), which is caused by STAR mutations that retain partial STAR activity. Tel: +82­2­3410­3539 We present the case of a Korean boy who was diagnosed with NCCLAH at the age of 17 Fax: +82­2­3410­0043 months. During long-term hospitalization for nutritional support necessitated by short-bowel E­mail: [email protected] syndrome, whole-body hyperpigmentation and electrolyte abnormalities were noted at 17 https://orcid.org/0000­0003­2913­ months after an episode of sepsis with peritonitis. 059X This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// ISSN: 2287-1012(Print) creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any ISSN: 2287-1292(Online) medium, provided the original work is properly cited. ©2020 Annals of Pediatric Endocrinology & Metabolism Bae H, et al. • Nonclassic congenital lipoid adrenal hyperplasia in a Korean boy Case report male genitalia, and postaxial polydactyly of the left foot. He was able to ascend stairs with the support of a hand grasp. He could A male child was born at a gestational age of 39 weeks with stack 3 cubes, eat without assistance, and pronounce 10 words, no history of antenatal or perinatal problems. Apgar scores were meaning that the patient’s developmental status was normal for 9 points at one minute and 10 points at 5 minutes. His birth his age. Laboratory investigations revealed a slightly decreased weight and height were 3,800 g (z-score, +1 standard deviation sodium level (132 mmol/L) but normal potassium (4.8 mEq/ score [SDS]) and 52.5 cm (z-score, +1.4 SDS), respectively. L) and glucose (86 mg/dL) levels; complete blood count, blood There was no family history of consanguineous marriages. The gas profile, hepatic and renal function, thyroid function test patient was born with an imperforate anus and a colostomy was and sex hormone levels were obtained. Decreased cortisol (1.0 performed the day after birth. He had normal male genitalia, μg/dL) and markedly elevated adrenocorticotropic hormone with both testes palpable, and postaxial polydactyly of the left (ACTH) (16,064 pg/mL) levels were noted. The patient's foot. A grade 2 systolic murmur was heard in the left upper cortisol levels did not respond to stimulation with ACTH (125 2 sternal border and echocardiography revealed a patent ductus µg [250 µg/m ]) (Table 1). Meanwhile, he presented a normal arteriosus. Bilateral grade 3 vesicoureteral reflux (VUR) was 17-hydroxyprogesterone level (0.42 ng/mL). Plasma renin revealed via voiding cystourethrography. Spine ultrasound activity and aldosterone levels were 7.28 ng/mL/hr (normal revealed no vertebral anomalies, and tracheoesophageal range, 1.0–6.5 ng/mL/hr) and 0.1 ng/dL (normal range, 3–35 fistula was not suspected clinically. Based on this clinical ng/dL), respectively. The abdominal ultrasound revealed no information, including anal atresia, renal anomalies, and limb abnormalities, such as adrenal enlargement, hydronephrosis, abnormalities, he was diagnosed with VACTERL association distal ureter dilatation, or bowel wall thickening. Based on which is defined by the presence of at least 3 of the following the patient’s symptoms and laboratory results, we considered congenital malformations: vertebral defects, anal atresia, several genetic causes for primary adrenal insufficiency, and the cardiac defects, tracheo-esophageal fistula, renal anomalies, causative genes of candidate diseases were listed as STAR for and limb abnormalities. Laboratory test results, including NCCLAH and CYP11A1 for congenital adrenal insufficiency. electrolyte levels, were normal. Neonatal screening tests for Additionally, melanocortin-2 receptor (MC2R) and MC2R metabolic disease were also normal, including the 17-alpha- accessory protein for familial glucocorticoid deficiency (FGD) hydroxyprogesterone level. Chromosome analysis revealed were listed as candidate genes with a low probability because the a 46, XY karyotype. He was discharged from the neonatal patient did not have elevated aldosterone. intensive care unit at 21 days of age. At the age of 3 months, the Targeted gene-panel sequencing was performed to check patient was admitted to the hospital for colostomy takedown, for pathogenic variants in those genes responsible for primary anorectoplasty, and endoscopic dextranomer/hyaluronic acid adrenal insufficiency. Genomic DNA was extracted from copolymer injection for VUR. After the surgery, the patient the peripheral blood of the patient and both parents. Library was febrile and hypotensive and his abdomen was distended preparation was done using the TruSight One Sequencing and discolored. An exploratory laparotomy revealed bowel Panel (Illumina, Inc., San Diego, CA, USA), which enriches a necrosis. Bowel resection with colostomy and jejunostomy was 12-Mb region spanning 62,000 target exons of a total of 4,813 performed 3 times, which resulted in short-bowel syndrome. genes. Massively parallel sequencing was performed on the He could not be discharged because parenteral nutrition was Illumina NextSeq platform. Sequence reads were mapped to the required. The remnant small bowel extended from the Treitz UCSC hg19 standard database for comparative analysis. The ligament to the jejunocolonic anastomosis and the length of average depth of the panel was 85.86X, and percentages of bases the remnant bowel was only 40 cm. At the age of 7 months, a above 10X of CYP11A1 and STAR were 99.37%, and 100%, takedown of the colostomy and jejunostomy was performed. respectively. Meanwhile, no pathogenic variants were detected The patient’s mother observed slight bronzing of the patient’s in CYP11A1 genes. skin after repeated surgeries. The exome-sequencing results revealed compound heterozy- At 17 months of age, the patient had an episode of sepsis gous mutations for c.653C>T and c.661G>A (p.Gly221Ser) and peritonitis secondary to Acinetobacter baumannii infection in exon 6 of the STAR gene. Sanger sequencing confirmed the and an exploratory laparotomy was performed to check for presence of these variants and each of the same heterozygous bowel necrosis. At this time, generalized hyperpigmentation variant was found in his father and mother, respectively (Fig. 1). was noted by the doctor and the mother stated that the child's This variant has been previously reported in association with hyperpigmentation was markedly exacerbated after exploratory laparotomy