Advertisement

Hormones

, Volume 14, Issue 1, pp 160–166 | Cite as

A novel mutation in the NR0B1 gene in a family with monozygotic twin sisters and congenital adrenal hypoplasia affected children

  • Roberta Minari
  • Alessandra Vottero
  • Francesco Tassi
  • Isabella Viani
  • Tauro Maria Neri
  • Maria Elisabeth Street
  • Lucia Ghizzoni
  • Sergio Bernasconi
  • Davide Martorana
Case report
  • 4 Downloads

Abstract

OBJECTIVE: Congenital adrenal hypoplasia (CAH) is a rare disorder that can be inherited in an X-linked or autosomal recessive pattern. CAH is frequently associated with hypogonadotropic hypogonadism (HHG) with absent or arrested puberty and impaired fertility caused by abnormalities in spermatogenesis. It is estimated that more than 50% of boys with idiopathic adrenal insufficiency have mutations in the NR0B1 gene product, DAX1. CASE REPORT: The proband is a young boy born after an uneventful pregnancy and delivery to non-consanguineous parents. At age 4 years and 4 months he came to our attention because of severe vomiting, abdominal pain, dehydration, and asthenia. The proband underwent a detailed clinical investigation including genetic testing. Sequencing analysis of the NR0B1 gene coding region from the affected child revealed a novel hemizygous deletion [c.385delC; p.(Leu129Cysfs*135)]. This mutation was also present in the heterozygous healthy mother and in her twin sister and in the first cousin of the proband. Monozygosity of the twin sisters was demonstrated. This suggests a de novo mutation and gonadal mosaicism for the deletion. CONCLUSIONS: Adrenal hypoplasia typically presents as adrenal insufficiency during the first few months of life, however, not necessarily as shown by our index case. HHG is thought to affect all NR0B1 mutated patients who reach puberty and, as understanding of the disease has improved, more of these patients survive while presenting different features of the disease, this emphasizing the value of genetic testing in boys with primary adrenal insufficiency and suspected X-linked CAH.

Key words

Congenital Adrenal Hypoplasia de novo mutation Gonadal mosaicism NR0B1 gene 

References

  1. 1.
    Weiss L, Meilinger RC, 1970 Congenital adrenal hypoplasia—an X-linked disease. J Med Genet 7: 27–32.CrossRefGoogle Scholar
  2. 2.
    McKusick VA, Francomano CA, Antonarakis SE, 1992 Mendelian inheritance in man: Vol 1. Catalogs of autosomal dominant, autosomal recessive, and X-linked phenotypes.Google Scholar
  3. 3.
    Hay ID, Smail PJ, Forsyth CC, 1981 Familial cytomegalic adrenocortical hypoplasia: an X-linked syndrome of pubertal failure. Arch Dis Child 56: 715–721.CrossRefGoogle Scholar
  4. 4.
    Reutens AT, Achermann JC, Ito M, et al, 1999 Clinical and functional effects of mutations in the DAX-1 gene in patients with adrenal hypoplasia congenita. J Clin Endocrinol Metab 84: 504–511.PubMedGoogle Scholar
  5. 5.
    Tabarin A, Achermann JC, Recan D, et al, 2000 A novel mutation in DAX1 causes delayed-onset adrenal insufficiency and incomplete hypogonadotropic hypogonadism. J Clin Invest 105: 321–328.CrossRefGoogle Scholar
  6. 6.
    Muscatelli F, Strom TM, Walker AP, et al, 1994 Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature 372: 672–676.CrossRefGoogle Scholar
  7. 7.
    Zanaria E, Muscatelli F, Bardoni B, et al, 1994 An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature 372: 635–641.CrossRefGoogle Scholar
  8. 8.
    Iyer AK, McCabe ER, 2004 Molecular mechanisms of DAX1 action. Mol Genet Metab 83: 60–73.CrossRefGoogle Scholar
  9. 9.
    Jadhav U, Harris RM, Jameson JL, 2011 Hypogonadotropic hypogonadism in subjects with DAX1 mutations. Mol Cell Endocrinol 346: 65–73.CrossRefGoogle Scholar
  10. 10.
    Wheeler B, George PM, Mackenzie K, Hunt P, Potter HC, Florkowski CM, 2008 Three cases of congenital adrenal hypoplasia with novel mutations in the (NROB1) DAX-1 gene. Ann Clin Biochem 45: 606–609.CrossRefGoogle Scholar
  11. 11.
    Achermann JC, Ito M, Silverman BL, et al, 2001 Missense mutations cluster within the carboxyl-terminal region of DAX-1 and impair transcriptional repression. J Clin Endocrinol Metab 86: 3171–3175.PubMedGoogle Scholar
  12. 12.
    Ostermann S, Salvi R, Lang-Muritano M, et al, 2006 Importance of genetic diagnosis of DAX-1 deficiency: example from a large, multigenerational family. Horm Res 65: 163–168.PubMedGoogle Scholar
  13. 13.
    Wildeman M, van Ophuizen E, den Dunnen JT, Taschner PE, 2008 Improving sequence variant descriptions in mutation databases and literature using the Mutalyzer sequence variation nomenclature checker. Hum Mutat 29: 6–13.CrossRefGoogle Scholar
  14. 14.
    Xiao W, Oefner PJ, 2001 Denaturing high-performance liquid chromatography: A review. Hum Mutat 17: 439–474.CrossRefGoogle Scholar
  15. 15.
    McCabe ER, 1996 Sex and the single DAX1: too little is bad, but can we have too much? J Clin Invest 98: 881–882.CrossRefGoogle Scholar
  16. 16.
    Phelan JK, McCabe ER, 2001 Mutations in NR0B1 (DAX1) and NR5A1 (SF1) responsible for adrenal hypoplasia congenita. Hum Mutat 18: 472–487.CrossRefGoogle Scholar
  17. 17.
    Guo W, Lovell RS, Zhang YH, et al, 1996 Ahch, the mouse homologue of DAX1: cloning, characterization and synteny with GyK, the glycerol kinase locus. Gene 178: 31–34.CrossRefGoogle Scholar
  18. 18.
    Verrijn Stuart AA, Ozisik G, de Vroede MA, et al, 2007 An amino-terminal DAX1 (NROB1) missense mutation associated with isolated mineralocorticoid deficiency. J Clin Endocrinol Metab 92: 755–761.CrossRefGoogle Scholar
  19. 19.
    Peter M, Viemann M, Partsch CJ, Sippell WG, 1998 Congenital adrenal hypoplasia: clinical spectrum, experience with hormonal diagnosis, and report on new point mutations of the DAX-1 gene. J Clin Endocrinol Metab 83: 2666–2674.CrossRefGoogle Scholar
  20. 20.
    Zhang YH, Guo W, Wagner RL, et al, 1998 DAX1 mutations map to putative structural domains in a deduced three-dimensional model. Am J Hum Genet 62: 855–864.CrossRefGoogle Scholar
  21. 21.
    McCabe ER, 2007 DAX1: Increasing complexity in the roles of this novel nuclear receptor. Mol Cell Endocrinol 265–266: 179–182.CrossRefGoogle Scholar

Copyright information

© Hellenic Endocrine Society 2015

Authors and Affiliations

  • Roberta Minari
    • 1
  • Alessandra Vottero
    • 1
  • Francesco Tassi
    • 1
  • Isabella Viani
    • 1
  • Tauro Maria Neri
    • 2
  • Maria Elisabeth Street
    • 3
  • Lucia Ghizzoni
    • 4
  • Sergio Bernasconi
    • 1
  • Davide Martorana
    • 2
  1. 1.Departments of Clinical and Experimental MedicineUniversity of ParmaParmaItaly
  2. 2.Unit of Molecular GeneticsUniversity Hospital of ParmaParmaItaly
  3. 3.Departments of PaediatricsUniversity Hospital of ParmaParmaItaly
  4. 4.Division of Endocrinology and Metabolism, Department of Internal MedicineUniversity of TurinTurinItaly

Personalised recommendations