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DAX1 and X-Linked Adrenal Hypoplasia Congenita

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DAX1 and X-Linked Adrenal Hypoplasia Congenita European Journal of Endocrinology (2006) 154 685–689 ISSN 0804-4643 CLINICAL STUDY DAX1 and X-linked adrenal hypoplasia congenita: clinical and molecular analysis in five patients Giovanna Mantovani1, Ernesto De Menis2, Giorgio Borretta3, Giorgio Radetti4, Sara Bondioni1, Anna Spada1, Luca Persani1,5 and Paolo Beck-Peccoz1 1Institute of Endocrine Sciences, University of Milan, Padiglione Granelli, Ospedale Maggiore IRCCS, Via F. Sforza 35, 20122 Milan, Italy, 2 I Divisione Medica, Ospedale Generale, Treviso, Italy, 3 Endocrinology Unit, Ospedale S. Croce e Carle, Cuneo, Italy, 4 Department of Pediatrics, Ospedale Generale Regionale, Bolzano, Italy and 5 Laboratory of Endocrinological Research, Istituto Auxologico Italiano IRCCS, Milan, Italy (Correspondence should be addressed to G Mantovani; Email: [email protected]) Abstract Objective: Mutations in the gene coding for the orphan nuclear receptor DAX1 cause X-linked adrenal hypoplasia congenita (AHC). Affected boys usually present with primary adrenal failure in early infancy or childhood. Impaired sexual development due to hypogonadotropic hypogonadism becomes manifest at the time of puberty. Moreover, evidence from Dax1 knockout mice and a limited number of patients with AHC, suggests that mutations in DAX1 may directly cause abnormalities in spermato- genesis. The aim of this study was to characterize clinically and genetically five patients with AHC. Design: DNA sequencing analysis, endocrine testing, testicular ultrasound and semen analysis with 1- year follow-up after gonadotropin treatment. Methods: We report on five men with classic AHC manifestations. Genomic DNA was extracted from patients’ peripheral blood leukocytes and the coding region, splice sites, and promoter (2240 bp) region of DAX1 were directly sequenced. Results: Three known and two novel mutations were detected in the DAX1 coding sequence in these patients. Semen analysis was performed in four of the five patients and showed azoospermia. Twelve- month treatment with gonadotropins did not restore fertility in these patients. All patients showed a normal testicular Doppler ultrasound, in contrast with that observed in Dax1-deficient mice, which display abnormalities in the rete testis. Conclusions: These cases further expand the number of DAX1 mutations reported in the literature, as well as our clinical knowledge of this rare disease. European Journal of Endocrinology 154 685–689 Introduction or frameshift mutations causing premature truncation of the protein (7–9). The orphan nuclear receptor DAX1 plays a crucial role During the last years, other variant phenotypes in the development and function of the adrenal gland including an adult-onset form of AHC (10–12), isolated and the hypothalamic–pituitary–gonadal axis (1–4). HH in a female homozygous for a DAX1 mutation and Mutations in the gene encoding DAX1 (DAX1, OMIM: extreme pubertal delay in heterozygous female carriers 300473) cause X-linked adrenal hypoplasia congenita have been described (6, 13). Moreover, evidence from (AHC, OMIM: 300200) (1, 2). AHC is an inherited dis- both Dax1 knockout mice (14) and a limited number order of adrenal gland development, characterized by of patients with AHC (6, 10–12), suggests that lack of the permanent zones of the adrenal cortex. mutations in DAX1 may directly cause abnormalities Boys with this condition usually present with severe in spermatogenesis. In particular, either Sertoli cell (15) or Leydig cell (16) ‘rescue’ of Dax1 expression primary adrenal failure in infancy or childhood. Hypo- showed that these rescued animals have restored ferti- gonadotropic hypogonadism (HH) becomes apparent at lity, although abnormalities in testicular architecture puberty and infertility results from gonadotropin persist. The way in which DAX1 affects fertility seems deficiency in combination with a primary defect in sper- to be, at least in part, mediated by blockage of the matogenesis (5, 6). Over 80 different mutations in rete testis, with subsequent dilatation of the proximal DAX1 have been described, most of which are nonsense efferent ductules (17). Dilatation or ectasia of the rete q 2006 Society of the European Journal of Endocrinology DOI: 10.1530/eje.1.02132 Online version via www.eje-online.org Downloaded from Bioscientifica.com at 10/01/2021 09:41:13AM via free access 686 G Mantovani and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 154 testis, that is the anastomosing spaces where the tubuli levels in the presence of low/normal follicle-stimulating recti enter the mediastinum testis, is a rare and benign hormone and luteinizing hormone (LH) levels, and both condition that may be visualized on scrotal sonography. were unresponsive to gonadotropin releasing hormone Interestingly, among all patients described to date in the (GnRH) stimulation test. All of them, with the excep- literature, only one has been reported to show abnorm- tion of patient 2 who is still growing, reached a alities of the rete testis, and in particular ectasia of the normal final height, consistent with their target rete testis at testicular ultrasound (12), although most height (Table 1). Androstenedione, progesterone and of these patients are not usually investigated for such 17-hydroxyprogesterone were below the normal an alteration. range. An abdominal computed tomography scan Here, we report clinical and molecular analysis of five revealed small adrenal glands. Anti-adrenocortical young males with classic AHC manifestations and HH antibodies were negative, and very-long-chain fatty due to DAX1 mutations, two of which have not pre- acids were normal, thus excluding autoimmune Addi- viously been reported in the literature. This study son’s disease and adrenoleukodystropy respectively. further expands the present knowledge about the dis- Moreover, all patients underwent a testicular Doppler ease and reports two novel alterations in this gene. ultrasound. The typical appearance of the rete testis is an echogenic structure communicating from the med- iastinum testis to the epididymal head. The rete is Materials and methods usually located at the posterolateral aspect of the DNA sequencing and mutational analysis testis. Occasionally, the rete may be anechoic with numerous tiny round or tubular structures, indicating After obtaining written consent, genomic DNA was tubular ectasia of the rete testis. Ultrasound of the five extracted from peripheral blood leukocytes using stan- patients included in the study did not detect any dard procedures. Both exons of DAX1 (GenBank acces- abnormality of the rete testis. sion no. NM_000475) were amplified by PCR using Treatment with cortisone acetate and/or hydrocorti- specific oligonucleotide primer pairs and conditions sone and testosterone was started in all patients. Semen described previously (11, 12). Direct sequencing of PCR analysis was performed in four patients (1, 3, 4 and 5) products was performed using a Taq big dye terminator and showed azoospermia. In these four patients, testos- sequencing kit and an ABI310 automated sequencer terone replacement was withdrawn and treatment with (PE Applied Biosystems, Foster City, CA, USA). exogenous gonadotropins was started and maintained Informed consent was obtained in all cases, after pro- for at least one year (human chorionic gonadotropin ject approval by the local Ethics Committee. 2000 IU and urofollitropin 75 IU, three times weekly). In all patients, this treatment failed to improve the sperm count and restore fertility. Consequently, intra- Testicular ultrasound muscular testosterone enanthate (250 mg every Ultrasound of the scrotum has been reported to be 4 weeks) replacement was restored. Of note, while highly sensitive in the detection of rete testis blockage 1-year treatment induced normalization of testosterone (18) and it consisted of imaging the testes, epididy- levels in patient 4, patients 1, 3 and 5 did not respond mides, paratesticular structures and spermatic cords either in terms of hormonal testing, or in terms of tes- in a systematic fashion. The examination was per- ticular volume. formed with the patient supine and the scrotum elev- No patient had a family history of affected males. ated by a sheet wrapped around the patient’s pelvis. Clinical and endocrine details are given in Table 1. A 7 to 15 MHz. transducer was used. Transverse and longitudinal images were obtained, and color and spec- Mutational analysis tral Doppler ultrasound was performed. Direct DNA sequencing analysis of DAX1 in patients 1, 2 and 4 revealed three frameshift alterations, of which Results two are deletions, the first novel to the literature, and Patients one an insertion (1011delC, codon 337; 543delA, codon 181; 259insAGCG, codon 86) (19, 20). All The five patients presented either at neonatal age lead to premature stop codons at positions 371 (patient 2) or childhood (patients 1, 3, 4 and 5) with (1011delC) and 263 (543delA and 259insAGCG), a history of fatigue, nausea, dehydration and weight thus resulting in non-functional truncated proteins. loss. Patient 4 has been extensively described in a pre- Patient 3 revealed a missense mutation in the C-term- vious report (19). Clinical laboratory investigations inal region of DAX1 (K382N), which has already revealed hypocortisolemia, hypoaldosteronism and been reported and shown to result in a protein devoid elevated adrenocorticotropin (ACTH) in all boys, con- of repressor activity (21). In patient 5, we detected a sistent with primary adrenal failure. All patients later C-terminal missense mutation
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