Congenital, hereditary, andneonatal diseasesandabnormalities;adrenalinsufficiency;frameshiftmutation;geneticcounseling Keywords A ins), levando à substituição pMet461Asp. substituição à levando ins), A mãe. No sequenciamento direto do da heterozigoto estado o e irmãos nos diagnóstico o confirmando mutação, a mostrou DAX1 gia molecular. gia etiolo- sua estabelecer para fatal, potencialmente doença rara (HAC), congênita adrenal plasia e andrógenos ao lado de níveis elevados de ACTH.de elevados níveis de lado ao andrógenos e criançasman- as porque 17-OH-progesteronade reduzidos plasmáticos níveis hormonal, tratamento o durante tiveram, foisuspeitado HAC de Odiagnóstico primária. adrenal suficiência in- para hormonal reposição de terapia receberam que neonatal período no sal de perdedora Objetivo: Resumo Arq Bras EndocrinolMetab.2009;53/6 Conclusion: substitution. pMet461Asp a to lead which ins), A (c1382-1383 base adenine an of insertion an nosis in the siblings and a heterozygous state in the mother. Direct sequencing of diag- the confirming mutation, whicha analysis, showed molecular by studied was DAX1 report: Case Objective: Abstract Rafael MachadoMantovani congênita adrenal hipoplasia de grave clínica forma com irmãos Identificação denovamutaçãonogeneDAX1/NR0B1Aemdois adrenal hypoplasiacongenita with severe clinicalpresentation of DAX1/NR0B1A geneintwosiblings Identification ofanovelmutationin aconselhamento genético Doenças congênitas, hereditáriaseneonataisanormalidades;insuficiência adrenal; mutaçãodafasedeleitura; Descritores implications forthelong-termmanagementofdisease. important have may aspects, clinical by only confirmed be disorder,cannot which,sometimes, gy of the AHC in the siblings, was identified. Obtaining a precise genetic diagnosis of this adrenal da doença. nas pelos aspectos clínicos, pode ter importantes implicações para o manuseio em longo prazo Um diagnóstico genético preciso deste distúrbio adrenal, frequentemente não confirmado ape­ gene no etiology of the adrenal hypoplasia congenita (AHC), a rare potentially life-threatening disorder.life-threatening potentially rare a (AHC), congenita hypoplasia adrenal the of etiology Vera MariaAlvesDias low plasma 17-OH progesterone (17-OHP) and androgens, despite high ACTH levels. ACTH high despite androgens, and (17-OHP) progesterone 17-OH plasma low hypothesis of AHC was suspected because the children maintained, during hormonal treatment, hormonalreplacementforprimaryadrenalinsufficiency.born periodandreceived Adiagnostic foi identificada, estabelecendo a etiologia molecular da HAC nos dois irmãos. dois nos HAC da molecular etiologia a estabelecendo identificada, foi DAX1 Pesquisar mutações no gene no mutações Pesquisar Tosearch in mutations for Arq BrasEndocrinolMetab. 2009;53(6):771-6 A novel frameshift mutation of DAX1 gene, which established the molecular etiolo- We describe two siblings who presented with salt-wasting syndrome in the new the in syndrome salt-wasting with presented who siblings two describe We Relato dos casos: dos Relato 1 , IvaniNovatoSilva 1 , IsabelaLeite Pezzuti São apresentados os relatos de dois irmãos com síndrome com irmãos dois de relatos os apresentados São DAX1 foi encontrada inserção de uma adenina (c1382-1383 DAX1/NR0B1A DAX1/NR0B1A Conclusão: 1

gene in siblings to establish the molecular molecular the establish to siblings in gene Resultados: em dois irmãos com suspeita de hipo­ de suspeita com irmãos dois em 1 Uma nova mutação da fase de leitura de fase da mutação nova Uma , Arq BrasEndocrinolMetab. 2009;53(6):771-6 A análise molecular do gene do molecular análise A DAX1 revealed Results:

- 1 clinical casereport Accepted inJuly/11/2009 Received in Aug/25/2008 [email protected] Av. Alfredo Balena, 190, sala267 Faculdade deMedicina,UFMG Departamento de Pediatria, Ivani Novato Silva Correspondence to: Belo Horizonte, MG,Brasil de MinasGerais(UFMG), Clínicas, Universidade Federal de Pediatria, das Hospital Pediátrica, Departamento DivisãodeEndocrinologia 771

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. iopathic HH(23). prognosis compared with men fertility with isolated id- poor in resulting spermatogenesis, in defect intrinsic an sent pre may men affected that postulated been also control of gonadotropin pituitary secretion (22). It has and hypothalamic both in abnormalities by caused is It (21). development pubertal of lack of because tected de- usually AHC, X-linked with associated commonly symptoms of later inchildhoodorevenadulthood(14,18-20). onset progressive and insidious more to infancy early in presented insufficiency mineralocorticoid ranging from of severe salt-wasting with and glucocorticoid expression phenotypic wide a is mutations have been described elsewhere (11-18). There other many years, few last the In (10). deletions AHC, most of them being frameshift mutations and small of form X-linked the with patients in described been had apotentialnovelzincfinger(1,7-9). gion, toform Instead, it contains cysteines, positioned - in the same re region. N-terminal the at domain DNA-binding finger bers of the NR superfamily, but that lacks mem- the other typical zinc of domains ligand-binding the to mology ho- showing region C-terminal a contains which tein, gonadal axis (6). well and as at all levels of the hypothalamic-pituitary-adrenal as prostate, and breast skin, like tissues, many in bp, separated by a 3,385 bp (4,5). intron It is expressed by replaced zone, large cytomegalicvacuolatedeosinophiliccells(1). cortical adrenal adult permanent the of lack the to due failure adrenocortical primary in results It 1). member B, group 0, tor,superfamily NR, - chromo some, gene X 1), also called the on region critical AHC, reversal, sex of mutations by caused (3). between 1:140,000and1:1,200,000children form of AHC is much lower and might occur anywhere X-linked the of incidence true the that believe authors approximately 1:12,000 live (2). births However, some as quoted been has it although unknown, is incidence precise Its (1). morphologies adrenal different senting - pre forms both disease, X-linked or tosomal-recessive au- an as inherited be can condition The development. 772 A Background A novelmutationin yooaorpc yooaim H) s also is (HH) hypogonadism Hypogonadotropic in mutations 112 about 2003, Until 245 and 1,168 of exons two contains gene DAX1 is 300200) (OMIM: AHC of form X-linked The tentially life-threatening disorder of adrenal of disorder life-threatening tentially po- rare a is (AHC) congenita hypoplasia drenal DAX1/NR0B1A DAX1 encodes a 470-amino - acid pro gene (dosage-sensitive gene DAX1 insiblingswithAHC NR0B1 gene (nuclear - recep deficiency, DAX1 gene gene DAX1 DAX1

lar etiologyoftheAHC. in tions (24,25). replacement creasing mortality risk and allowing adequate hormonal de- crisis, adrenal of occurrence before asymptomatic males affected identify can early analysis or genetic Prenatal postnatal mothers. carrier known for seling coun- genetic of importance the underlines deficiency tisone 14 mg/m 14 tisone 11 years old, he was on steroid replacement (hydrocor at visit, last his On GP). - (Greulich-Pyle years 1.5 was two years of chronological age (CA), the bone age (BA) At events. unexpected other any or dehydration show didn’t he this, Besides µg/dl). 8.2 to 0.5 (cortisol: els lev- 2,437 to 3,940 pg/mL) and variable basal cortisol out his childhood, he maintained high ACTH (ACTH: normal-to-low androgen and 17-OHP levels. - Through the childwasdischarged. tenedione: 0.3 ng/mL), treatment was maintained and normalization of blood tests, 20 days later (Na later days 20 tests, blood of normalization and improvement clinical After initiated. was mg/day) ctt (0 mg/m (20 hydrocortisone acetate with replacement and suspected was (21-OHD) deficiency 21-OH to due hyperplasia, nal - adre congenital of diagnosis The ng/mL/h). 0.3-1.6 well as plasma renin activity (PRA) (27 ng/mL/h; RV: as pg/mL) 12-70 RV: pg/mL; (2,437 high very were found to be significantly elevated. Plasma ACTH levels were ng/mL) <1.6 RV: ng/mL; (6.5 levels tenedione ng/ - Andros elevated. mildly were (520 ng/dL) 6-496 RV: dL; concentrations testosterone 53-186 and RV: ng/dL) ng/dL; (440 (17-OHP) progesterone 17-OH Plasma mEq/L). (5.6 increased had on later etd ih eee yoarma (Na hyponatremia severe with sented thrive and generalized skin hyperpigmentation. He - pre to failure dehydration, vomiting, with admitted was he life, of days 30 At complications. perinatal of history without cm) 47 length: g; 2,820 (weight: age tational ges- for adequate newborn, term a was proband The Case report Subjects andmethos and normal potassium levels (K levels potassium normal and day), with good adherence to treatment. Physical ex- Physical treatment. to adherence good with day), mEq/L; K The objective of this study was to search for muta- for search to was study this of objective The of expression phenotypic of variability This From that moment on, his blood analyses showed analyses blood his on, moment that From DAX1 + : 4.8 mEq/L; 17-OHP: 31 ng/dL; - andros in two siblings to establish the molecu- the establish to siblings two in 2 rtisone 0.05 mg/ 0.05 rtisone fludroco plus /day 2 /day) and fludrocortisone (0.1 fludrocortisone and /day) Arq BrasEndocrinol Metab.2009;53/6 + : 3.6 mEq/L), which mEq/L), 3.6 : + 13 mEq/L) 103 : DAX1 + : 140 : - the 90 the cortisone cortisone acetate (20 mg/m - hydro with replacement hormonal adequate by lowed fol- support fluid and electrolyte proper with managed promptly be could which hyponatremia, presented He sufficiency was suspected, following his brother pattern. sive Care Unit (ICU), where the diagnosis of adrenal in- profile was not available, as the child stayed in an Inten- - re he infection, mained in the hospital for 45 tract days. His initial hormonal urinary for treatment needed he Because complications. prenatal of history no with cm), 47 length: g; 2.680 (weight: age gestational for normal. were electrolytes Plasma µg/dL). (6.6 range normal in were levels were high (670 pg/mL), and levels basal cortisol ACTH Again, thighs. internal and areas cervical both in skin dry and hyperpigmentation was There stage. I old, he had 14.3 mg/m 14.3 had he old, years four was he When events. unexpected other no an episode of adrenal insufficiency at seven months, but high(38.901pg/mL). very were levels ACTH and elevated mildly were ng/mL/h) 2.3 (maximum: levels PRA ng/mL). 0.7 (maximum dione testosterone (maximum: 294 ng/dL), and - androstene ng/dL), 20 (maximum: 17-OHP plasma of levels low showed he life, of year first his During mg/day). (0.1 in order toestablishtheetiologyofAHC. in order levels, so that we searched for mutations in ACTH high very despite androgens, plasma and OHP concentrations. electrolyte normal were sol levels were in normal range (12.3 µg/dL) and there remained very high (1,201 pg/mL); plasma basal - corti levels ACTH brother, his for As (GP). years four was Arq Bras EndocrinolMetab.2009;53/6 the for parents from obtained was consent informed Written follow-up. their accomplish better to order in AHC, of etiology molecular the establishing impor of tance the about informed were parents Children’s Molecular analysis kg/m 20.9 was (BMI) index mass 0.3). body The = SD cm; 139.8 (height: stature adequate and =0.82), SD kg; (40.9 overweight revealed amination BMI of 19.1 kg/m 19.1 of BMI and 0.34) = SD cm; (106.5 height statural adequate 1.72), = SD kg; (22.5 overweight revealed amination ex- Physical mg/day). (0.05 fludrocortisone and tate His younger brother In spite of adequate treatment, this child presented presented child this treatment, adequate of spite In During treatment, the patients maintained low 17- low maintained patients the treatment, During th centile. He had prepubertal testes, at Tanner at testes, prepubertal had He centile. 2 (above the 97 the (above was a term newborn, adequate 2 /day of hydrocortisone ace- hydrocortisone of /day 2 /day) and fludrocortisone th centile). His BA His centile). DAX1 gene 2 above , - 00000169297 sequence. automatic sequencer. 310 PRISM ABI an in CA) City, Foster Biosystems, Applied (PE Kit Reaction Ready Sequencing Cycle tor Termina- BigDye™ the using sequenced directly and OH) Cleveland, Corp, Biochemical States (United I exonuclease and phosphatase alkaline shrimp of tion combina- enzymatic an with pretreated were products primers specific PCR The (26). previously described as conditions, and using (PCR) reaction bypoly- chain merase amplified were sequences flanking intronic of exons Both mother. their and siblings two the of leukocytes blood peripheral from publication. and study frameshift mutation (ATG – AAT) at codon 461 (pMet461Asp); (C) mother mother (C) (pMet461Asp); 461 codon at AAT) (heterozygous carrier). – (ATG mutation frameshift (normal individual); (B) index case: (Figure 1). (Figure state heterozygous in mutation same the of presence the confirmed DNA mother’s of study The 470. tion → tion of a metionin to an asparagine at codon 461 (ATG substitu- the causes insA) (c1382-1383 1382 position at insertion adenine An siblings. two the in identified of 2 exon in mutation frameshift novel A Results Figure 1. Figure AAT), determining a loss of the stop codon at posi- at codon stop the of loss AAT),a determining DAX1/NR0B1A sequence was compared to ENSG Sequence analysis of exon 2 of the of 2 exon of analysis Sequence A novelmutationin A nucleotide insertion at position 1382, leading a eoi DA a isolated was DNA Genomic DAX1/NR0B1A NR0B1A/DAX1 gene and the and gene DAX1 insiblingswithAHC gene in (A) control (A) in gene was DAX1 773

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. 774 con- metabolic disorders, steroidogenic when failure, adrenal salt-losing with presenting infant male any in the patients. DAX1 gene was essential for the definitive diagnosis of the of Analysis hyperpigmentation. and levels ACTH high very despite androgens, plasma and 17-OHP low childhood, their throughout maintained, patients the since suspected was AHC of diagnosis A children. the of improvement with initiated was replacement coid - mineralocorti and Glucocorticoid 21-OHD. of form seeninneonateswiththesalt-losing the onescurrently of plasma 17-hydroxyprogesterone levels, not similar to elevation inexpressive very but crisis, salt-losing sented - pre patient the period, newborn the brother.In elder the in made firstly was hyperplasia adrenal congenital of hypothesis diagnostic a report, present the In ing. counsel- genetic and management steroid course, clini- cal their in differ they because important is orders dis- two these Distinguishing (29). fetocortex adrenal persisting neonates’ by production steroids by caused probably life, of weeks first the in results confusing to lead often with may determinations patients steroid in plasma AHC, Moreover, com- (19,29). more disorder this mon having as misdiagnosed frequently are and 21-OHD of form salt-losing the in those observed from indistinguishable are that symptoms and adulthood(12). they reach however, adrenal insufficiency may not be evident until patients, some In life. of months first the in mentation hyperpig- skin and hypoglycemia, acidosis), metabolic and hyperkalemia (hyponatremia, syndrome wasting salt- thrive, to failure with present patients the of Most in the differential diagnosis in a context of adrenal crisis. considered not is it if overlooked be can and ognizable (16,21). guity andsexreversal infancy (28), testicular enlargement (29), genital ambi- in secretion testosterone prolonged (19,27), ficiency de- mineralocorticoid isolated include also may tions insufficiency in childhood (3). Other clinical manifesta- adrenal primary of cause rare a AHC, cause may factor transcription this in Mutations function. and opment devel- adrenal in role important an plays gene DAX1 disorders. developmental and metabolic autoimmune, including etiologies, of range a by caused be can that condition life-threatening a is failure nal adre Primary Discussion A novelmutationin uainl nlss of analysis Mutational signs present generally boys period, neonatal the In - rec clearly always not is AHC of diagnosis Clinical DAX1/NR0B1A insiblingswithAHC be worthwhile worthwhile be may DAX1 pituitary-gonadal tifying associated features. Although the hypothalamic- iden- for and management long-term for implications den death. Moreover, a correct diagnosis has important sud- preventing and morbidity diminishing placement, (1). maleoffspring ment oftheiraffected to all women in reproductive age, to allow earlier - treat ing according to their carrier status should be proposed counsel- and diagnosis genetic families, such In males. in death unexpected or disorders adrenal of history ily been excluded (3). have hemorrhage adrenal and infection iatrogenic causes, disease, autoimmune syndromes, ditions, Lalli and cols. showed that two that showed cols. and Lalli (32). NRs other of activity transcriptional the inhibits perfamily member, acting as a protein coregulatory that (5,10,21,30,31). transcriptional repression impair or localization nuclear and folding protein pair im- either to shown been have and gene the of region nonsense or frameshift are mutations in the C-terminal in tations mu- of majority The embryogenesis. adrenal in ment tant region of impor this in sequence acid amino new Probably,this 470. position at codon stop and the of codon loss a determining 461 at forward acids amino of sequence the changing nucleotide, 1382 at insertion adenine in consisting mutation frameshift novel The protein. mal of 2 exon in mutation (23). fertility impaired have may patients the and ineffective often are therapy gonadotropin and GnRH spermatogenesis. pulsatile Thus, and development testis affect may sexual characteristics. In addition, secondary of development normal for replacement one testoster require will patients These puberty. arrested or impaired with adolescence, during apparent comes be- usually disorder, this of feature associated an HH, calization, undergoes allosteric conformational changes lo- nuclear and dimerization, binding, ligand mediates domain) which domain, C-terminal [AF2] of acids amino These (33). 2 function activation the loop, including short intermediary the and regions H12 H11, (minimally of portion (final domain domain C-terminal a and region) H3 N-terminal the activity: this for - re hormonal of start early ensures diagnosis Early fam- previous no was there report, present the In has a unique role as a homologous NR su- NR homologous a as role unique a has DAX1 a confirmed analysis molecular the patients, our In causing AHC/HH reported to date to reported AHC/HH causing DAX1 DAX1 protein prevented its accomplish-

(HPG) axis is often intact in infancy,in intact often is axis (HPG) that generated an abnor an generated that DAX1 Arq BrasEndocrinol Metab.2009;53/6

domains are necessary necessary are domains DAX1 abnormalities - - - Arq Bras EndocrinolMetab.2009;53/6 References was reported. Disclosure: no potential conflict ofrelevant interest to this article assistance. Medicina of Universidade de São Paulo, Brazil, for their technical de Faculdade the of Clínicas das Hospital the of 42, cular/LIM Mole- Genética e Hormônios de Laboratório Desenvolvimento, do Endocrinologia de Unidade the from Mendonça, B. renice Acknowledgments: the authors thank Sorahia Domenice and Be- with associated variability and function (36,37). of complexities the highlight studies about is the correlation of raised genotype to question phenotype. Recent important an level, molecular a on As more and more monogenetic disorders are explained with an early and severe clinical pattern of presentation. dependent functions,asdimerization(35). binding- ligand the involved that structure domain the affect could domain, AF2 the includes which region, this in mutation (34), a Thus, 461-466. domain codons at AF2 located its of transactivation dependent hormone- the through binding, ligand to response in 2. 1. priate familycounseling. investigating possible associated features and for - appro prognosis, predicting for long-term disease, the the of management for implications important have may sometimes cannot be confirmed only by clinical aspects, precise genetic diagnosis of this adrenal disorder, which literature. the in scribed found. was 1383 A ins), which lead to a pMet461Asp substitution, (c1382- base adenine an of insertion An levels. OHP 17- of elevation inexpressive very the despite CAH, of as if they had the diagnosis of 21-OHD salt-losing form in the (38). cannot beeasilypredicted correlation genotype-phenotype date, To (36). ences mental illnesses (intercurrent and other stressors) influ- - environ and penetrance) and , expressivity in variability (modifier ofgenetic a combination reflecting

hs oe mtto dsrbd ee s associated is here described mutation novel This In conclusion, we presented a frameshift mutation frameshift a presented we conclusion, In nal hypoplasia. ObstetGynecol.1973;41(5):655-64. Laverty CR, Fortune DW, Beischer NA. Congenital idiopathic adre- Res. 2006;65(4):163-8. Horm family. multigenerational large, a from example ficiency: de- DAX1 of diagnosis genetic of Importance al. et RC, Gaillard R, PuttingerM, VoirolMJ, Lang-Muritano R, Salvi S, Ostermann DAX1 gene in two siblings being initially treated This mutation had not been previously de- previously been not had mutation This There There is considerable phenotypic e eiv ta otiig a obtaining that believe We DAX1 mutations, probably probably mutations, regulation regulation DAX1 10. 9. 8. 7. 6. 5. 4. 3. 19. 18. 7. 1 16. 15. 14. 13. 12. 11.

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Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. 776 A novelmutationin 28. 27. 26. 25. 24. 23. 22. 21. 20. enlargement. MolGenetMetab.2003;78(1):79-81. testis prepubertal with associated gene DAX1 the of 434 (1301delT) codon at deletion base single novel A J. Jameson Larry Soriano-Guillén L, M, Muñoz J,Teresa Pozo G, Ozisik J, Argente Pediatr EndocrinolMetab.2001;14(8):1093-6. J congenita. hypoplasia adrenal X-linked of presentation riable JL, AchermannJC. Jameson C, VaRoddaJ, Couper - E, Wiltshire dism. JClinEndocrinolMetab.1996;81(2):530-5. congenital adrenal hypoplasia and hypogonadotropic hypogona - mutations of DAX1 genes in two Japanese patients with X-linked New H. Nawata K, Nishi Y, Ohe Yanase K, T, Oba R, Takayanagi by analysis ofDAX1. congenita JPediatr. 2000;137(6):878-81. hypoplasia adrenal Xlinked of diagnosis tomatic Achermann JC, Silverman BL, Habiby RL, Jameson JL. Presymp- tations inDAX1 andSF-1. MolCellEndocrinol.2001;185(1-2):17-25. Achermann JC, Meeks JJ, Jameson JL. Phenotypic spectrum of mu- J congenita. Clin EndocrinolMetab.2002;87(1):44-8. hypoplasia adrenal X-linked late-onset of feature presenting a as hypogonadism Hypogonadotropic al. et L, sani Mantovani G, Ozisik G, Achermann JC, Romoli R, Borretta G, Per J ClinInvest. 1996;98(4):1055-62. production. gonadotropin in defects pituitary and hypothalamic hypogonadism: evidencethatDAX1 mutationsleadtocombined meson JL. Adrenal hypoplasia congenita with hypogonadotropic P,Boepple RL, Habiby Jr Crowley PM, WF,NachtigallSluss L, Ja- Endocrinol Metab.1999;84(12):4501-9. Clin J females. and males in spectrum phenotypic the expands DAX1 in mutation a congenita: hypoplasia adrenal X-linked Jr. Seminara SB, Achermann JC, Genel M, Jameson JL, Crowley WF nadism. JClinInvest. 2000;105(3):321-8. adrenal insufficiency and incomplete hypogonadotropic hypogo- delayed-onset causes DAX1 in mutation novel A al. et S, Maitre Christin- X, Bex V,Bertagna D, Recan TabarinJC, AchermannA, DAX1/NR0B1A insiblingswithAHC - 38. 37. 36. 35. 34. 33. 32. 31. 30. 29. docrinol Metab.2001;86(7):3171-5. En- Clin J repression. transcriptional impair and DAX1 of region carboxyl-terminal the within cluster mutations Missense al. et A, Rosler S, Pang RL, Habiby BL, Silverman M, Ito JC, Achermann MolEndocrinol.2006;20(10):2326-42. terodimers. (NR0B2) form homodimers individually, as well as DAX1-SHP he- me, gene 1 (DAX1) (NR0B1) and small heterodimer partner (SHP) chromosoX - the on region critical congenita hypoplasia adrenal reversal sex Dosage-sensitive ER. McCabe YH, Zhang AK, Iyer vel nuclearreceptor. MolCellEndocrinol.2007;265-266:179-82 no- this of roles the in complexity Increasing DAX1: ER. McCabe three-dimensional model. AM JHumGenet.1998; 62(4):855-64. DAX1 mutations map to putative structural domains in a deduced Zhang YH, Guo W, Wagner RL, Huang BL, McCabe L, Vilain E, et al. Genet Metab.2004;83(1-2):60-73. Iyer AK, McCabe ER. Molecular mechanisms of DAX1 action. Mol Endocrinol. Mol congenita. 1997;11(13):1950-60. hypoplasia adrenal mu- causes whose DAX-1 tation in domain silencing transcriptional A al. et Strom D, E, JM, ZazopoulosMoras Wurtz B, TM, Bardoni E, Lalli Mol GenetMetab.2005;86(1-2):70-83. role. novel and function, origin, DAX1 ER. McCabe KK, Niakan DAX-1 protein.Proc Natl Acad Sci US A. 2002;99(12):8225-30. the of localization nuclear abnormal by caused is congenita sia P.Sassone-Corsi E, Lalli hypoplaSG, - adrenal Lehmann X-linked 2000;53(2):249-55. mutations new (Oxf). Endocrinol hypoplasia:Clin patients. three in follow-up long-term and adrenal congenital X-linked MB. Ranke SchwarzeCP,M, H, G, WollmannPeterStrom Binder TM, Endocrinol Metab.1998;83(8):2666-74. Clin J gene. DAX1 the of mutations point new on report and sis, hypoplasia: clinical spectrum, experience with hormonal diagno- M, PeterPartsch M, Viemann Sippell adrenal CJ, Congenital WG. Arq BrasEndocrinol Metab.2009;53/6