New genetic causes of primary adrenal insufficiency

Česká verzia

Authors: R. Pomahačová ¹; J. Sýkora ¹; J. Zamboryová ¹; P. Paterová ¹; J. Dort ²; E. Dortová ²; I. Šubrt ³
Authors place of work: Dětská klinika Lékařské fakulty v Plzni, Univerzity Karlovy v Praze a Fakultní nemocnice Plzeň ¹; Neonatologické oddělení Lékařské fakulty v Plzni, Univerzity Karlovy v Praze a Fakultní nemocnice Plzeň ²; Ústav lékařské genetiky Lékařské fakulty v Plzni, Univerzity Karlovy v Praze a Fakultní nemocnice Plzeň ³
Published in the journal: Čes-slov Pediat 2018; 73 (2): 100-103.
Category: Case Report

Věnováno významnému životnímu jubileu prof. MUDr. Lidky Lisé, DrSc.

Summary

The most frequent form of congenital adrenal hyperplasia (CAH) is 21-hydroxylase deficiency. The uncommon forms of CAH are defects at the beginning of steroidogenesis in the adrenal glands leading to either congenital lipoid adrenal hyperplasia (CLAH) caused by defect of steroidogenic acute regulatory protein (StAR protein) or P450scc deficiency caused by defect of cholesterol side-chain cleavage enzyme (P450scc). A classic form of both CLAH and P450scc deficiency is characterized by a severe disorder of steroidogenesis in the adrenal glands and in the gonads. All newborns have female external genitalia. The life-threatening adrenal insufficiency is manifested early after birth. In the nonclassic forms of CLAH and P450scc deficiency is a partial loss of function of StAR protein or P450scc. The patients present with late onset of primary adrenal insufficiency and undervirilised external genitalia in male patients (micropenis, cryptorchidism, hypospadias).

We characterized a case of congenital adrenal insufficiency caused by P450scc deficiency. The patient presented after birth with cardiopulmonary instability, hyponatremia, hyperkalemia, hypoglycemia and metabolic acidosis. There were no signs of the external genitalia virilism. The replacement therapy with glucocorticoids and mineralocorticoids led to normal laboratory. At the age of 12 years, we confirmed hypergonadotropic hypogonadism, which revealed disorder of steroidogenesis in the adrenal glands and in the gonads. The genetic testing confirmed mutation in the CYP11A1 gene leading to deficiency of cholesterol side-chain cleavage enzyme. The patient is compound heterozygote for the novel CYP11A1 missense mutation c.412G>A (p.Gly138Arg) in exon 2 and frameshift mutation c.508_509delCT (p.Leu170Valfs*30) in exon 3. So far, only 29 patients with CYP11A1 mutations causing P450scc deficiency have been reported worldwide. There are no related reports in the Czech Republic.

Key words:
lipoid congenital adrenal hyperplasia, P450scc deficiency, steroidogenic acute regulatory protein (StAR protein), cholesterol side-chain cleavage enzyme (P450scc), STAR gene, CYP11A1 gene, primary adrenal insufficiency, gonadal deficiency

Zdroje

1. Niranjan U, Natarajan A. Congenital adrenal hyperplasia in children – a survey on the current practice in the UK. JPEM 2015; 28 (7–8): 847–851.

2. Bens S, Mohn A, Yuksel B, et al. Congenital lipoid adrenal hyperplasia: Functional characterization of three novel mutations in the StAR gene. J Clin Endocrinol Metab 2010; 95: 1301–1308.

3. Kim CJ. Congenital lipoid adrenal hyperplasia. Ann Pediatr Endocrinol Metab 2014; 19 (4): 179–183.

4. Tee MK, Abramsohn M, Loewenthal N, et al. Varied clinical presentations of seven patients with mutations in CYP11A1 encoding the cholesterol side-chain cleavage enzyme, P450scc. J Clin Endocrinol Metab 2013; 98: 713–720.

5. Gucev ZS, Tee MK, Chitayat D, et al. Distinguishing deficiencies in the steroidogenic acute regulatory protein and the cholesterol side chain cleavage enzyme causing neonatal adrenal failure. J Pediatr 2013; 162: 819–822.

6. Prader A, Gurtner HP. The syndrome of male pseudohermaphroditism in congenital adrenocortical hyperplasia without overproduction of androgens (adrenal male pseudohermaphroditism). Helv Paed Acta 1955; 10: 397–412.

7. Lin D, Sugawara T, Strauss III JF, et al. Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. Science 1995; 267: 1828–1831.

8. Bose HS, Sugawara T, Strauss III JF, et al. The phatophysiology and genetics of congenital lipoid adrenal hyperplasia. N Engl J Med 1996; 335: 1870–1878.

9. Tajima T, Fujieda K, Kouda N, et al. Heterozygous mutation in the cholesterol side chain cleavage enzyme (P450scc) gene in a patient with 46, XY sex reversal and adrenal insufficiency. J Clin Endocrinol Metab 2001; 86: 3820–3825.

10. Miller WL. Steroidogenic acute regulatory protein (StAR), a novel mitochondrial cholesterol transporter. Biochim Biophys Acta 2007; 1771: 663–676.

11. Kim SO, Choi C, Kim CJ, et al. Lipoid congenital adrenal hyperplasia: pathologic features of the Testis. Urology 2010; 75 (1): 176–178.

12. Kim CJ, Lin L, Juany N, et al. Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc. J Clin Endocrinol Metab 2008; 93 (3): 696–702.

13. Baker BY, Lin L, Kim CJ, et al. Nonclassic congenital lipoid adrenal hyperplasia: a new disorder of the steroidogenic acute regulatory protein with very late presentation and normal male genitalia. J Clin Endocrinol Metab 2006; 91: 4781–4785.

14. Flück CE, Pandey AV, Dick B, et al. Characterization of novel StAR (steroidogenic acute regulatory protein) mutations causing non-classic lipoid adrenal hyperplasia. PLoS One 2011; 6: e20178.

15. Rubtsov P, Karmanov M, Sverdlova P, et al. A novel homozygous mutation in CYP11A1 gene is associated with late-onset adrenal insufficiency and hypospadias in 46, XY patient. J Clin Endocrinol Metab 2009; 94 (3): 936–939.

16. Sahakitrungruang T1, Tee MK, Blackett PR, et al. Partial defect in the cholesterol side chain cleavage enzyme P450scc resembling nonclassic congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab – Endocrine Research 2011; 96 (3): 792.

17. Sahakitrungruang T, Soccio RE, Lang-Muritano M, et al. Clinical, genetic and functional characterization of four patients carrying partial loss-of function mutations in the steroidogenic acute regulatory protein (StAR). J Clin Endocrinol Metab – Endocrine Research 2010; 95 (7): 3352–3359.

18. Abdulhadi-Atwan M, Jean A, Chung WK, et al. Role of a founder c.201_202delCT mutation and new phenotypic features of congenital lipoid adrenal hyperplasia in Palestinians. J Clin Endocrinol Metab 2007; 92 (10): 4000–4008.

19. Katsumata N, Ohtake M, Hojo T, et al. Compound heterozygous mutations in the cholesterol side- chain cleavage enzyme gene (CYP11A) cause congenital adrenal insufficiency in humans. J Clin Endocrinol Metab 2002; 87: 3808–3813.

20. Hiort O, Holterhus PM, Werner R, et al. Homozygous disruption of P450 side-chain cleavage (CYP11A1) is associated with prematurity, complete 46, XY sex reversal, and severe adrenal failure. J Clin Endocrinol Metab 2005; 90: 538–541.

21. Hauffa BP, Miller WL, Grumbach MM, et al. Congenital adrenal hyperplasia due to deficient cholesterol side-chain cleavage activity (20,22 desmolase) in a patient treated for 18 years. Clin Endocrinol (Oxf) 1985; 23: 481–493.