Adrenal Hypoplasia Congenita Presenting as Congenital Adrenal Hyperplasia

Hindawi Publishing Corporation Case Reports in Endocrinology Volume 2013, Article ID 393584, 4 pages http://dx.doi.org/10.1155/2013/393584 Case Report Adrenal Hypoplasia Congenita Presenting as Congenital Adrenal Hyperplasia Jennifer L. Flint1 and Jill D. Jacobson2 1 Department of Pediatrics, Children’s Mercy Hospitals and Clinics, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA 2 Division of Endocrinology and Diabetes, Children’s Mercy Hospitals and Clinics, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA Correspondence should be addressed to Jill D. Jacobson; Received 7 December 2012; Accepted 16 January 2013 Academic Editors: T. Cheetham, M. P. Kane, and T. Usui Copyright © 2013 J. L. Flint and J. D. Jacobson. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We report on a patient with genetically confirmed adrenal hypoplasia congenita (AHC) whose presentation and laboratory abnormalities were consistent with the more common condition, congenital adrenal hyperplasia (CAH). The patient presented with failure to thrive and salt wasting. General appearance showed marked hyperpigmentation and normal male genitalia. He displayed mildly elevated 17-hydroxyprogesterone and markedly elevated 11-deoxycortisol levels at baseline and with ACTH stimulation testing. Results were consistent with 11𝛽-hydroxylase deficiency. He required glucocorticoids and high doses of mineralocorticoids. The marked elevation in 11-deoxycortisol directed our clinical reasoning away from a hypoplastic condition and towards a hyperplasic adrenal condition. Sequencing of the DAX1 gene (named for dosage-sensitive sex reversal (DSS) locus and the AHC locus on the X chromosome) revealed a missense mutation. A review of the literature revealed that elevated 11-deoxycortisol levels have been noted in kindreds with DAX1 mutations, but only when measured very early in life. A mouse model has recently been described that displays elevated 11-deoxycorticosterone levels and evidence for hyperplasia of the zona glomerulosa of the adrenal gland. We conclude that DAX1 testing may be considered in patients with laboratory evidence of 11𝛽-hydroxylase deficiency, especially in those with severe salt wasting. 1. Introduction The X-linked form of adrenal hypoplasia congenita (AHC) is a rare inherited disorder in which the adult cortical zone of the adrenal gland fails to develop [1]. Its cause is an inactivating mutation in the DAX1 gene [2]. The gene is also known as the NROB1 gene (nuclear receptor subfamily 0, group B, member 1). DAX1 is expressed in the adrenal glands, ovaries, testes, and the developing hypothalamus and pituitary. This gene works as a repressor of steroidogenesis factor 1 (SF1), thereby playing a crucial role in suppressing steroidogenesis [3, 4]. Given the role of DAX1 in repressing steroidogenesis, the symptoms in patients with inactivating mutations in DAX1 appear paradoxical. Patients with Xlinked adrenal hypoplasia congenita present with signs of combined glucocorticoid and mineralocorticoid deficiency [5]. Its distinction from congenital adrenal hyperplasia is imperative, as the treatments and prognoses differ. 2. Case Report A 21-day-old white male presented to the primary pediatrician for poor feeding, who noted that he had not regained his birth weight. Electrolytes were ordered as part of a failure to thrive workup, which revealed a sodium of 106 mmol/L, a potassium of 7.1 mmol/L, and a glucose of 1.8 mmol/L. After having a 17-OH progesterone level drawn, the infant was transferred to our tertiary referral hospital for electrolyte 2 derangements with the presumptive diagnosis of salt-wasting congenital adrenal hyperplasia. Birth history was significant for an uneventful pregnancy and delivery. Birth length was 51 cm (65th Percentile). Birth weight was 3.35 kg (37th percentile). Apgar scores were 8 and 9. Hyperpigmentation of the scrotum was noted at birth. Hypoglycemia was noted on the first day of life. He was discharged on the second day of life. The past medical history was significant for two previous admissions for unconjugated hyperbilirubinemia with a maximum bilirubin of 367 𝜇mol/L. He was treated with phototherapy on both occasions. His parents noted that his skin seemed to be progressively more pigmented over the first three weeks of life. This “bronzing” was attributed to phototherapy. Physical exam upon arrival revealed normal vital signs and a blood pressure of 68/33 mmHg. His weight was 3.1 kg (7th Percentile). No dysmorphic features were noted. Genital exam revealed normal male genitalia with both testes descended. Phallus was normal in length and caliber with the urethral meatus at the tip. Physical exam was remarkable for marked bronzing of the skin. Once in the pediatric intensive care unit, the patient was started on fludrocortisone and intravenous fluid support. He underwent a high-dose ACTH stimulation test and then was begun on glucocorticoid treatment at an initial dose of 28 mg/m2 /day. Severe hyponatremia persisted despite the administration of 400 mcg/day of fludrocortisone in addition to 20 mEq/kg/day of sodium chloride. Diarrhea ensued. Escalating doses of glucocorticoid up to 54 mg/m2 were used. By the age of 5 months, he was weaned off of salt supplementation, and hydrocortisone doses were weaned to physiologic levels. Fludrocortisone doses have been gradually reduced. The 11-deoxycortisol values of the ACTH stimulation became available early in this hospitalization and were consistent with 11𝛽-hydroxylase deficiency with markedly elevated baseline and stimulated levels of 11-deoxycortisol (see Table 1). The 17-hydroxyprogesterone obtained from his primary care physician returned at 5.6 pmol/L (normal up to 2.9 pmol/L). As 11-deoxycorticosterone (DOC) and 11deoxycortisol have been reported to be elevated in 21hydroxylase deficiency and because salt wasting does not occur in 11-hydroxylase deficiency, 21-hydroxylase deficiency remained the presumptive diagnosis. The following day the baseline and stimulated 17-hydoxy progesterone levels returned to normal levels (4.5 nmol/L), arguing against 21hydroxylase deficiency. He was evaluated for possible 11𝛽hydroxylase deficiency. A repeat 11-deoxycortisol after 12 days of hydrocortisone treatment returned to 1.49 nmol/L (normal range <.346–4.5). Genetic testing was sent for CYP11B1 gene. The coding exons and the flanking intronic sequences were PCR amplified and sequenced in forward and reverse directions, using automated fluorescent dideoxy sequencing methods and the mRNA isoform NM 000497 as the reference sequence. Case Reports in Endocrinology Genetic testing was also performed for the DAX1 (NROB1) gene associated with X-linked congenital adrenal hypoplasia. The coding exo (...truncated)