Hipoplasia adrenal, hipogonadismo y talla baja por una nueva mutación del gen DAX-1 (pGly168fsX17)

Pérez Rodríguez, O.; Ruibal Francisco, J.L.; Loidi Fernández de Trocóniz, L.; Parajes Castro, S.; Martín Rojas-Marcos, P.

doi:10.1157/13089927

Article information

Varios genes intervienen en la morfogénesis de la corteza suprarrenal, entre ellos el gen DAX-1. Presentamos una nueva mutación del gen DAX-1 en un varón de 18 años que padeció fracaso suprarrenal completo en el período neonatal, hipogonadismo hipogonadotropo y talla baja patológica.

Ingresó a los 16 días por presentar un síndrome pierde-sal con hiperpotasemia. Se mantuvo sin tratamiento hasta los 2 años, cuando comenzó progresivamente con anorexia, avidez por la sal, desmedro, hiperpigmentación cutánea y finalmente choque, hipoglucemia, hiponatremia, acidosis metabólica e hiperpotasemia.

Inició espontáneamente el desarrollo puberal, pero fue incompleto. Recibió tratamiento con testosterona-depot. El volumen testicular definitivo alcanzado fue de 6¦ml con una pubarquia V. Su talla final ha sido 150¦cm (talla diana 164¦cm).

El estudio genético del gen DAX-1 mostró la mutación g 2080-2081 ins a en la primera posición del codón 168, que produce una parada prematura de la proteína DAX en la posición 184.

Palabras clave:

Hipoplasia adrenal congenital

DAX-1

Hipogonadismo hipogonadotropo

Mutación

Talla baja

Various genes play a role in the morphogenesis of the adrenal cortex, among them the DAX-1 gene. We report an 18-year-old man who showed complete adrenal failure in the neonatal period, hypogonadotropic hypogonadism and pathological short stature associated with a mutation of the DAX-1 gene that has not previously been described. The patient was admitted to hospital at the age of 16 days due to salt-losing syndrome with hyperpotassemia. After this episode, he received no treatment for 2 years, when he began to show progressive anorexia, salt avidity, asthenia, cutaneous hyperpigmentation and finally shock, with hypoglycemia, hyponatremia, metabolic acidosis and hyperpotassemia.

Puberal development was spontaneous but incomplete. The patient received treatment with testosterone-depot. He reached a definitive testicular volume of 6 ml and pubarche V. His final height is 150 cm (target height 164¦cm).

Amplification of the DAX-1 gene showed mutation g 2080-2081 insertion in the first position of codon 168, which produces a premature shutdown of protein DAX-1 at position 184.

Key words:

Congenital adrenal hypoplasia

DAX-1

Hypogonadotropic hypogonadism

Mutation

Short stature

Full text is only aviable in PDF

Bibliografía

[1.]

Mc-Cabe ERB. Adrenal hypoplasias and aplasias. En: Scriver. Beaudet. Valle. Sly. Childs. Kinzler. Vogelstein. The metabolic and molecular bases of inherited disease. 8.ª ed. Mc-Graw-Hill. 2001;167:4263-74.

[2.]

J.C. Achermann, J.J. Meeks, J.L. Jameson.

Phenotypic spectrum of mutations in DAX-1 and SF-1.

Mol Cell Endocrinol, 185 (2001), pp. 17-25

Medline

[3.]

E. Zazopoulos, E. Lalii, D.M. Stocco, P. Sassone-Corsi.

DNA binding and transcriptional repression by DAX-1 blocks steroidogenesis.

Nature, 390 (1997), pp. 311-315

http://dx.doi.org/10.1038/36899 | Medline

[4.]

G.B. Kletter, J.L. Gorski, R.P. Kelch.

Congenital adrenal hypoplasia and isolated gonadotropin deficiecy.

Trends Endocrinol Metab, 2 (1991), pp. 123-128

[5.]

F. Muscatelli, T.M. Strom, A.P. Walker, E. Zanaria, D. Recan, A. Meindl, et al.

Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism.

Nature, 372 (1994), pp. 672-676

http://dx.doi.org/10.1038/372672a0 | Medline

[6.]

E. Zanaria, F. Muscatelli, B. Bardoni, T.M. Strom, S. Guioli, W. Guo, et al.

An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita.

Nature, 372 (1994), pp. 635-641

http://dx.doi.org/10.1038/372635a0 | Medline

[7.]

W. Guo, T.P. Burris, E.R. McCabe.

Expression of DAX-1, the gene responsible for X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism, in the hypothalamic-pituitary-adrenal/gonadal axis.

Biochem Mol Med, 56 (1995), pp. 8-13

Medline

[8.]

A. Swain, E. Zanaria, A. Hacker, R. Lovell-Badge, G. Camerino.

Mouse Dax1 expression is consistent with a role in sex determination as well as in adrenal and hypothalamus function.

Nat Genet, 12 (1996), pp. 404-409

http://dx.doi.org/10.1038/ng0496-404 | Medline

[9.]

E. Lalli, B. Bardoni, E. Zazopoulos, J.M. Wurtz, T.M. Strom, D. Moras, et al.

A transcripcional silencing dom in DAX-1 whose mutation causes adrenal hypoplasia congenita.

Mol Endocrinol, 11 (1997), pp. 1950-1960

http://dx.doi.org/10.1210/mend.11.13.0038 | Medline

[10.]

A. Hossain, C. Li, G.F. Saunders.

Generation of two distinct functional isoforms of dosage-sensitive sex reversal-adrenal hypoplasia congenital-critical region on the X chromosome gene 1 (DAX-1) by alternative splicing.

Mol Endocrinol, 18 (2004), pp. 1428-1437

http://dx.doi.org/10.1210/me.2003-0176 | Medline

[11.]

R. Salvi, F. Gómez, M. Fiaux, D. Schorderet, J.L. Jameson, J.C. Achermann, et al.

Progressive onset of adrenal insufficiency and hypogonadism of pituitary origin caused by a complex genetic rearrangement within DAX-1.

J Clin Endocrinol Metab, 87 (2002), pp. 4094-4100

http://dx.doi.org/10.1210/jc.2001-011930 | Medline

[12.]

J. Nakae, S. Abe, T. Tajima, N. Shinohara, M. Murashita, Y. Igarashi, et al.

Three novel mutations and de novo deletion mutation of the DAX-1 gene in patients with X-linked adrenal hypoplasia congenital.

J Clin Endocrinol Metab, 82 (1997), pp. 3835-3841

http://dx.doi.org/10.1210/jcem.82.11.4342 | Medline

[13.]

S.G. Lehmann, E. Lalli, P. Sassone-Corsi.

X-linked adrenal hypoplasia congenita is caused by abnormal nuclear localization of the DAX-1 protein.

P Nac Academ Sci, 99 (2002), pp. 8225-8230

[14.]

M. Ito, R. Yu, J.L. Jameson.

DAX-1 inhibits SF-1-mediated transactivation via a carboxy-terminal domain that is deleted in adrenal hypoplasia congenital.

Mol Cell Biol, 17 (1997), pp. 1476-1483

Medline

[15.]

P.A. Crawford, C. Dorn, Y. Sadovsky, J. Milbrandt.

Nuclear receptor DAX-1 recruits nuclear receptor corepressor N-CoR to steroidogenic factor 1.

Mol Cell Biol, 18 (1998), pp. 2949-5629

Medline

[16.]

S.G. Lehmann, J.M. Wurtz, J.P. Renaud, P. Sassone-Corsi, E. Lalli.

Structure-function analysis reveals the molecular determinants of the impaired biological function of DAX-1 mutants in AHC patients.

Human Molecular Genetics, 9 (2003), pp. 1063-1072

[17.]

H. Mizusaki, K. Kawabe, T. Mukai, E. Ariyoshi, M. Kasahara, H. Yoshioka, et al.

DAX-1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1) gene transcription is regulated by wnt4 in the female developing gonad.

Molec Endocrinol, 17 (2003), pp. 507-519

[18.]

E. Casado de Frías, J.L. Ruibal Francisco, G. Bueno Lozano, G. Pinel Simón, F. Reverte Blanc, J. Benítez Ortiz.

Síndrome de deleción de genes continuos en Xp-21 (déficit complejo de glicerol-cinasa) e hipoplasia suprarrenal congénita.

An Esp Pediatr, 47 (1997), pp. 639-642

Medline

[19.]

A. Tabarin, J.C. Acherman, D. Recan, V. Bex, X. Bertagna, S. Christin-Maitre, et al.

A novel mutation in DAX-1 causes delayed onset adrenal insufficiency and incomplete hypogonadotrpic hypogonadism.

J Clin Invest, 105 (2000), pp. 321-328

http://dx.doi.org/10.1172/JCI7212 | Medline

[20.]

J. Argente, G. Ozisik, J. Pozo, M.T. Muñoz, L. Soriano-Guillén, J.L. Jameson.

A novel single base deletion at codon 434 (1301delT) of the DAX-1 gene associated with prepubertal testis enlargement.

Mol Genet Metab, 78 (2003), pp. 79-81

Medline

[21.]

A. Francese, N. Brunetti-Pierri, R. Spadaro, T. Mukai, G. Valerio.

Inappropiate tall stature and renal ectopy in a male patient with X-linked congenital adrenal hypoplasia due to a novel missense mutation in the DAX-1 gene.

Am J Med Genet, 135A (2005), pp. 72-74

Indexed in:

Follow us:

Indexed in:

Follow us:

Subscribe to our newsletter