Background Congenital adrenal hyperplasia is caused mostly by 21-hydroxylase deficiency (>90%) and 11ß-hydroxylase deficiency (5–8%). Both enzymes are required for cortisol synthesis and the non classical (NC) phenotype of both deficiencies is characterized by hyper-androgenic manifestations in childhood/adolescence. Objectives To complete the characterization of a NC case in which the identified CYP21A2 mutations do not mach completely the phenotype by analysis of the CYP11B1 gene. Population and/or methods Case: female that present: precocious puberty at 5,5 yrs; at 6,7 yrs advanced bone age (10 yrs), hypertrophic clitoris and the following hormonal data: 17-OHP 8200/14600 ng/dl, ACTH 66 pg/ml; T 0.98 ng/ml; Cortisol 190/170 ng/ml; D4-A 315/377 ng/dl. A therapy with hydrocortisone (5 mg x3/die) has been started. A first clinical diagnosis of NC-21OHD was made. Genetic analysis of CYP21A2 and CYP11B1 genes was performed as previously described. Results The sequencing analysis of CYP21A2 gene revealed the presence of 3 mutations: Q318X (null), A391T (mild) and *13 G>A 3’UTR (very mild) all carried by the maternal allele. Complete sequencing of the paternal CYP21A2 gene do not show any alterations. The MLPA analysis of the family revealed a normal arrangement of the locus, therefore all the 3 maternal mutations lie on a unique gene. In order to identify other possible molecular causes, we performed the CYP11B1 gene analysis even without a complete hormonal profile, as the patient was in therapy. This analysis revealed the presence of 2 mutations: R43Q and A386V, both present on the paternal allele and individually reported as mild. Conclusions The patient, with the standard clinical NC-CAH manifestations, resulted to be heterozygous for both the deficiencies. We suggest therefore the possibility of a cumulative effect on the phenotype of the two mutants as previously reported in other conditions for enzymes catalyzing consecutive reactions on the same pathway. This is the first report of a di-genic inheritance in CAH.

CYP21A2 AND CYP11B1: FIRST REPORT OF A DIGENIC INHERITANCE IN CAH.

MENABO', SOARA;BALDAZZI, LILIA;NICOLETTI, ANNALISA;PIRAZZOLI, PIERO;BALSAMO, ANTONIO
2012

Abstract

Background Congenital adrenal hyperplasia is caused mostly by 21-hydroxylase deficiency (>90%) and 11ß-hydroxylase deficiency (5–8%). Both enzymes are required for cortisol synthesis and the non classical (NC) phenotype of both deficiencies is characterized by hyper-androgenic manifestations in childhood/adolescence. Objectives To complete the characterization of a NC case in which the identified CYP21A2 mutations do not mach completely the phenotype by analysis of the CYP11B1 gene. Population and/or methods Case: female that present: precocious puberty at 5,5 yrs; at 6,7 yrs advanced bone age (10 yrs), hypertrophic clitoris and the following hormonal data: 17-OHP 8200/14600 ng/dl, ACTH 66 pg/ml; T 0.98 ng/ml; Cortisol 190/170 ng/ml; D4-A 315/377 ng/dl. A therapy with hydrocortisone (5 mg x3/die) has been started. A first clinical diagnosis of NC-21OHD was made. Genetic analysis of CYP21A2 and CYP11B1 genes was performed as previously described. Results The sequencing analysis of CYP21A2 gene revealed the presence of 3 mutations: Q318X (null), A391T (mild) and *13 G>A 3’UTR (very mild) all carried by the maternal allele. Complete sequencing of the paternal CYP21A2 gene do not show any alterations. The MLPA analysis of the family revealed a normal arrangement of the locus, therefore all the 3 maternal mutations lie on a unique gene. In order to identify other possible molecular causes, we performed the CYP11B1 gene analysis even without a complete hormonal profile, as the patient was in therapy. This analysis revealed the presence of 2 mutations: R43Q and A386V, both present on the paternal allele and individually reported as mild. Conclusions The patient, with the standard clinical NC-CAH manifestations, resulted to be heterozygous for both the deficiencies. We suggest therefore the possibility of a cumulative effect on the phenotype of the two mutants as previously reported in other conditions for enzymes catalyzing consecutive reactions on the same pathway. This is the first report of a di-genic inheritance in CAH.
Hormone Research
250
250
HORMONE RESEARCH IN PAEDIATRICS
Menabò S.; Marsigli A.; Baldazzi L.; Nicoletti A.; Pirazzoli P.; Balsamo A.
File in questo prodotto:
Eventuali allegati, non sono esposti

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/127402
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact