Long-Term Follow-Up in a Chinese Child with Congenital Lipoid Adrenal

Zhao et al. BMC Endocrine Disorders (2018) 18:78 https://doi.org/10.1186/s12902-018-0307-6 CASEREPORT Open Access Long-term follow-up in a Chinese child with congenital lipoid adrenal hyperplasia due to a StAR gene mutation Xiu Zhao1,ZheSu1* , Xia Liu1,JianmingSong2,YungenGan3, Pengqiang Wen4,ShoulinLi5,LiWang1 and Lili Pan1 Abstract Background: Congenital lipoid adrenal hyperplasia (CLAH) is an extremely rare and the most severe form of congenital adrenal hyperplasia. Typical features include disorder of sex development, early-onset adrenal crisis and enlarged adrenal glands with fatty accumulation. Case presentation: We report a case of CLAH caused by mutations in the steroidogenic acute regulatory protein (StAR) gene. The patient had typical early-onset adrenal crisis at 2 months of age. She had normal-appearing female genitalia and a karyotype of 46, XY. The serum cortisol and adrenal steroids levels were always nearly undetectable, but the adrenocorticotropic hormone levels were extremely high. Genetic analysis revealed compound heterozygous mutations at c. 229C > T (p.Q77X) in exon 3 and c. 722C > T (p.Q258X) in exon 7 of the StAR gene. The former mutation was previously detected in only two other Chinese CLAH patients. Both mutations cause truncation of the StAR protein.Thecasereportedhereappearstobeaclassicexample of CLAH with very small adrenal glands and is the second reported CLAH case with small adrenal glands thus far. In a 15-year follow-up, the patient’sheight wasapproximatelyaverageforfemalesbeforeage4andfellto− 1 SDS at 10 years of age. Her bone age was similar to her chronological age from age 4 to age 15 years. Conclusions: In conclusion, this is a classic case of CLAH with exceptionally small adrenal glands. Q77X mutation seems to be more common in Chinese CLAH patients. Additionally, this is the first report of the growth pattern associated with CLAH after a 15-year follow-up. Keywords: Congenital lipoid adrenal hyperplasia, Steroidogenic acute regulatory protein, Mutation, Growth Background of cholesterol to pregnenolone (P). All affected indi- Congenital lipoid adrenal hyperplasia (CLAH, OMIM viduals with classic CLAH are phenotypically female 201710) is the most severe form of congenital adrenal regardless of their gonadal sex [1]. Hormone replace- hyperplasia (CAH) and may cause 46, XY disorders of ment enables long-term survival for these patients, sex development (DSD). CLAH is an autosomal reces- but the literature regarding their long-term outcomes sive inherited disorder caused by mutations of the ste- is limited. roidogenic acute regulatory protein (StAR;OMIM Here, we report a 15-year follow-up of a Chinese pa- 600617) gene [1]. Currently, more than 83 different tient with typical clinical manifestations of CLAH except mutations of the StAR gene have been reported in ap- for small adrenal glands. proximately 190 patients [2]. However, only 17 cases of CLAH have been reported in Chinese patients [3–9]. Case presentation The clinical features include severe adrenal and gonadal The patient was Chinese individual who was raised as a steroidogenesis defects due to disorder of the conversion female. She was born full-term by vaginal delivery. She was the fourth child of nonconsanguineous parents. * Correspondence: [email protected] She was admitted to our hospital at 2 months of age 1Department of Endocrinology, Shenzhen Children’s Hospital, 7019# Yitian Road, Futian District, Shenzhen 518038, Guangdong Province, China with recurrent vomiting, diarrhea and dehydration. She Full list of author information is available at the end of the article was found to have hyperpigmentation, hyponatremia © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zhao et al. BMC Endocrine Disorders (2018) 18:78 Page 2 of 10 (sodium 114 mmol/L) and hyperkalemia (potassium hormone and Inhibin b. The patient’s karyotype was 46, 6.98 mmol/L). The serum adrenocorticotropic hormone XY (big Y). Ultrasonography revealed the presence of (ACTH) level was greater than 1250 pg/ml accompan- testes-like masses in the pelvic cavity (1.4 cm × 0.8 cm × ied by very low levels of cortisol (0.17 μg/dl) and aldos- 1.0 cm on the left and 1.5 cm × 0.6 cm × 1.0 cm on the terone (4.21 pg/ml). The levels of all adrenal steroids, right). Neither ovaries nor a uterus was identified. After including testosterone (T), P, dehydroepiandrosterone 13 years of steroid replacement therapy, the patient sulfate, androstenedione and 17-hydroxyprogesterone, underwent an adrenal computed tomography (CT) scan were always nearly undetectable. She was diagnosed at the age of 13.2 years. Adrenal CT scans revealed that with primary adrenal insufficiency and was prescribed the adrenal glands on both sides were much smaller hydrocortisone and 9ɑ-fludrocortisone orally [10]. than normal (Fig. 1). Magnetic resonance imaging of However, her treatment compliance was poor. She the abdominal and pelvic cavities showed no uterus or often did not take the medications on time or at the ovaries. The patient’s bone age (BA) was 13.5 years old recommended dose. She was followed up irregularly. (Fig. 2). Several episodes of adrenal crisis occurred, and she was The patient was given hydrocortisone (17.3 mg/m2 admitted again at the age of 13.2 years. On admission, of body surface area per day) and 9ɑ-fludrocortisone her blood pressure was 90/60 mmHg, and her height, (0.1 mg/day) regularly. Her hyperpigmentation was weight and body mass index (BMI) were 148.7 cm (− slightly alleviated, and she had no adrenal crisis epi- 1.3 SDS), 35.3 kg (− 1.5 SDS) and 15.96 kg/m2 (− 1.0 sodes thereafter. At the age of 15.2 years, the patient SDS), respectively. Hyperpigmentation was found on began estrogen replacement therapy. After 4 months her tongue, gums, face, trunk, elbows, knees, palms, of estrogen treatment, her breasts began developing. and soles. The patient was in Tanner stage 1. External Photos of the patient are shown in Fig. 3. Laboratory female genitalia were observed, including a normal- and treatment data were collected during the 15-year sized clitoris and a normal urethral orifice and vaginal follow-up and are shown in Table 1.Growthdataare orifice. No palpable gonads were identified in the in- shown in Table 2. Compared to healthy Chinese girls guinal or labial regions. No pubic or axillary hair was [11], the patient’s growth charts were drawn and are observed. She had a high ACTH level and lower levels shown in Fig. 4. At 15.5 years old, she nearly reached of cortisol, adrenal steroids and aldosterone. She exhib- her final adult height (154 cm), which was similar to ited gonadal dysgenesis, including: 1) high baseline levels her midparent height (152.5 cm) but shorter than the of luteinizing hormone (38.2 mIU/ml) and follicle-stimu- heights of her two sisters (156 cm, 160 cm). lating hormone (68.3 mIU/ml); 2) very low levels of The patient had no other diseases and exhibited nor- baseline T (< 0.35 nmol/L) and T after administration mal intelligence. One of her elder sisters died during of the human chorionic gonadotropin stimulation test infancy from an unknown cause. Her parents and her (0.47 nmol/L); and 3) low levels of anti-Müllerian other two sisters were healthy and underwent normal Fig. 1 At the age of 13.2-year adrenal computed tomography (CT) scans revealed that the adrenal glands on both sides were much smaller than normal. The yellow arrows indicate the adrenal gland Zhao et al. BMC Endocrine Disorders (2018) 18:78 Page 3 of 10 Fig. 2 Bone age of the patient. CA chronological age, BA bone age, yrs. = years old puberty. Her mother died in a traffic accident when she Gene analysis was 10 years old. No family history of DSD was noted. The sex-determining region on the Y chromosome gene Considering the above clinical picture, an initial diag- was positive. Gene sequencing was performed with med- nosis of 46, XY DSD caused by severe deficiency of ad- ical exome sequencing. The interpretation of the se- renal and gonadal steroids was established. The most quence variants and pathogenicity was conducted plausible causes of the patient’s condition include some according to guidelines set by the American College of specific types of CAH (3β-hydroxysteroid dehydrogenase Medical Genetics and Genomics [13]. The Human Gene deficiency, 17 hydroxysteroid dehydrogenase deficiency, Mutation Database (HGMD), db SNP database, and CLAH) and congenital adrenal hypoplasia caused by 1000 database were used to identify whether the ob- mutations of the NR0B1 or NR5A1 genes [12]. Medical served mutations have been reported previously. Com- exome sequencing was the method of choice for a clear pound heterozygous mutations were found in the StAR diagnosis. gene, with c. 229C > T (p. Q77X) in exon 3 and c. Fig. 3 Photos of the patient with CLAH. (a) Photos at age 13.2 years, (b) Photos at age 15.5 years Zhao et al. BMC Endocrine Disorders (2018)18:78 Table 1 Laboratory test results and treatment of the patient during the 15-year follow-up Age Variable

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