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      A patient with DAX1  mutation presenting with elevated testosterone in early infancy

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      World Journal of Pediatrics
      Springer Singapore

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          Abstract

          Dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome 1 (DAX1) deficiency is a rare disorder presents X-Linked adrenal hypoplasia congenital, impaired sexual development and infertility. Mutational gene of DAX1 was identified as NROB1 [1] which expresses in adrenal gland and hypothalamic–pituitary–gonad axis, restrains progenitor stem cells from differentiating into steroidogenic cells prematurely. Therefore, DAX1 deficiency usually manifests primary adrenal insufficiency and hypogonadotropic hypogonadism. However, we observed a patient whose testosterone elevated in early infancy. With uneventful pregnancy and birth history, the patient got intractable jaundice. There is a maternal uncle died young suddenly in the family history. Biochemical findings showed persistent hyponatremia (120.9–133 mmol/L), hyperkalemia (6.4–9.1 mmol/L) and hyperbilirubinemia. His blood sugar, 17-hydroxyprogesterone, creatine kinase, very-long-chain fatty acid and gas chromatography mass spectrometry were normal. First hormone analysis showed adrenal insufficiency and elevated testosterone (Table 1). Ultrasound showed adrenal region got hypoechoic nodule that recognized as small adrenal gland. Genetic test found a pathogenic mutation of c.1169-1G>T in NROB1 from his mother. Table 1 Hormones levels and medication dosages Age Weight (kg) ACTH (pg/mL) Cortisol (nmol/L) Aldosterone (pg/mL) Renin (pg/mL) LH (mIU/mL) FSH (mIU/mL) Testosterone (nmol/L) Androstendione (ng/mL) Hydrocortisone (mg/d) Fludrocortisone Episodes 1 d 3 14 d 2.78 1.24 22 d 172 5.94 243 3.85 3 0.05 mg bid 47 d 11.7 5.72 57 d 119 6.28 68 d 4.6 320.3 179.68 1.32 6.96 5.93 12.5–20 Lower respiratory 77 d 5 3.29 > 1750 38.76 1.69 6.57 5.41 15 infection 3 mon 1613 2.72 8 4.5 mon 3.71 1220 0.98 6 mon 7.7 4.99 576 <0 .09 5 0.05 mg bid 9 mon 34.78 497.6 < 0.09 5 1 y 2 mon 11.2 176.5 627.6 < 0.09 5 0.05 mg bid 1 y 7 mon 764 453 < 0.09 2 y 1 mon 845.8 146.5 < 0.09 3 y 169.7 531.1 < 0.09 3 y 3 mon 20 443.7 159.9 <0 .087 6.25–10 0.05-0.025 mg bid 4 y 127.3 480.2 62.01 88.3 < 0.088 10 0.033 mg bid 4 y 5 mon 23 196.1 1.12 31.29 32.05 < 0.09 12.5 0.033 mg bid 5 y 1 mon 29.2 > 2000 0.71 68.44 120.98 < 0.1 0.9 < 0.087 < 0.3 12.5 0.075 mg qd Reference value: adrenocorticotropic hormone (ACTH): 7.2–63.3 pg/mL, cortisol: 171–536 nmol/L, aldosterone: 40–310 pg/mL, renin: 4–38 pg/mL, luteinizing hormone (LH): 0.2–1.4 mIU/mL, follicle-stimulating hormone (FSH): 0.2–3.8 mIU/mL After treatment with hydrocortisone, fludrocortisone and sodium salt replacement, his electrolyte gradually adjusted to normal in a month, and testosterone reduced to normal in 4 months (Table 1). Growth and development were under our observation as well. Delayed bone age and smaller testes were consistent with his disease. Primary adrenal insufficiency combined with high testosterone tends to be diagnosed as congenital adrenal hyperplasia. From this case, we summarize DAX1 deficiency’s differential points as normal 17-hydroxyprogesterone, delayed bone age and confirmation of mutation in NROB1.Adrenal ultrasound also has certain value for distinguishing it from congenital adrenal hyperplasia. Although most patients manifest sexual development failure, many reports broaden its clinical spectrum. Spontaneous or even precocious puberty happen but basically suspend in Tanner stage 2 to 3 [2, 3]. In this case, we observed elevated sexual hormones initially. Minipuberty was found in one case as well caused by a mutation of c.518del23 [4]. Another case was found with elevated testosterone since 9 months old with Trp291Arg in NROB1 [5]. As testicular histological examination has been reported as intact in affected neonate [6], and testosterone can also be stimulated by human chorionic gonadotropin during early time [2], testicular structure and function can be normal but progressively impaired as increasing age. Excluding ectopic secretory tissue, testes can be reasonable origin for testosterone in early life. Overall, although patients with DAX1 deficiency commonly present hypogonadism, individual case may have temporal elevated testosterone which confuses its diagnosis.

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          Minipuberty of infancy and adolescent pubertal function in adrenal hypoplasia congenita.

          An infant and his uncle, both with adrenal hypoplasia congenita, shared the same DAX1 mutation. The adolescent uncle had hypogonadotropic hypogonadism, but the infant had a normal minipuberty of infancy. These observations suggest differences in the physiologic mechanisms regulating the hypothalamic-pituitary-gonadal axis in infancy and adolescence.
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            Identification of a novel missense mutation that is as damaging to DAX-1 repressor function as a nonsense mutation.

            Mutations in the DAX-1 (NROB1) gene result in X-linked congenital adrenal hypoplasia (AHC) and hypogonadotropic hypogonadism. The clinical presentation is usually as adrenal insufficiency in early life, with hypogonadotropic hypogonadism detected at the time of expected puberty. In this study we identified mutations in the DAX-1 gene of two patients with AHC. One mutation, Y399X, resulted in a premature stop codon and was associated with loss of Leydig cell responsiveness to human chorionic gonadotropin. The second, L297P, was a missense mutation, and human chorionic gonadotropin responsiveness was maintained. Kindred analysis established that the mutations had been inherited from the proband's mothers. The L297P has not been described previously and occurs within a highly conserved binding motif (LLXLXL). Transient transfection assays demonstrated that both mutations resulted in a severe loss of DAX-1 repressor activity. Immunohistochemical analysis of testicular tissue obtained from an affected sibling of the subject with the Y399X mutation, who had died with adrenal failure as a neonate, showed normal testicular morphology and expression of DAX-1, steroidogenic factor-1, and anti-Mullerian hormone protein. These data extend the clinical and molecular information on DAX-1 mutations, confirm normal testicular development at the neonatal stage, and illustrate variability in Leydig cell function.
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              Longitudinal Evaluation of the Hypothalamic-Pituitary-Testicular Function in 8 Boys with Adrenal Hypoplasia Congenita (AHC) Due to NR0B1 Mutations

              Background Boys carrying mutations in the NR0B1 gene develop adrenal hypoplasia congenita (AHC) and impaired sexual development due to the combination of hypogonadotropic hypogonadism (HH) and primary defects in spermatogenesis. Methods We analysed the evolution of hypothalamic-pituitary-testicular function of 8 boys with AHC due to NR0B1 mutations. Our objective was to characterize and monitor the progressive deterioration of this function. Results The first symptoms appeared in the neonatal period (n = 5) or between 6 months and 8.7 years (n = 3). Basal plasma adrenocorticotrophic hormone (ACTH) concentrations increased in all boys, whilst cortisol levels decreased in one case. The natremia was equal or below 134 mmol/L and kaliemia was over 5 mmol/L. All had increased plasma renin. In 3 of 4 patients diagnosed in the neonatal period and evaluated during the first year, the basal plasma gonadotropins concentrations, and their response to gonadotropin releasing hormone (GnRH) test (n = 2), and those of testosterone were normal. The plasma inhibin B levels were normal in the first year of life. With the exception of two cases these concentrations decreased to below the normal for age. Anti-Müllerian hormone concentrations were normal for age in all except one case, which had low concentrations before the initiation of testosterone treatment. In 3 of the 8 cases the gene was deleted and the remaining 5 cases carried frameshift mutations that are predicted to introduce a downstream nonsense mutation resulting in a truncated protein. Conclusions The decreases in testosterone and inhibin B levels indicated a progressive loss of testicular function in boys carrying NR0B1 mutations. These non-invasive examinations can help to estimate the age of the testicular degradation and cryopreservation of semen may be considered in these cases as investigational procedure with the aim of restoring fertility.
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                Author and article information

                Contributors
                18505329889 , drlitang@hotmail.com
                Journal
                World J Pediatr
                World J Pediatr
                World Journal of Pediatrics
                Springer Singapore (Singapore )
                1708-8569
                1867-0687
                20 March 2019
                20 March 2019
                2019
                : 15
                : 3
                : 309-311
                Affiliations
                [1 ]ISNI 0000 0001 0455 0905, GRID grid.410645.2, Medical Department, , Qingdao University, ; Qingdao, China
                [2 ]Department of Pediatric Endocrinology and Genetic Metabolic Diseases, Qingdao Women and Children’s Hospital, Qingdao, China
                Article
                236
                10.1007/s12519-019-00236-4
                6597599
                30891672
                b16becfe-7331-4bf8-a94c-20c2f0a96788
                © The Author(s) 2019

                Open AccessThis 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.

                History
                : 25 December 2018
                : 4 February 2019
                Categories
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                © Children's Hospital, Zhejiang University School of Medicine 2019

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