Exaggerated 17-hydroxyprogesterone response to short-term adrenal stimulation and evidence for CYP21B gene point mutations in true precocious puberty

Mariangela Cisternino, Elisabetta Dondi, Miryam Martinetti, Renata Lorini, Laura Salvaneschi, Mariaclara Cuccia, Francesca Severi

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Abstract

OBJECTIVE: Following the observation of two patients affected by true precocious puberty who went on to develop polycystic ovary syndrome (PCOS) and who were found to be heterozygotes (carriers) for 21-hydroxylase deficiency (21-OHD), we decided to evaluate the frequency of heterozygosity for adrenal 21-OHD in patients with true precocious puberty. STUDY DESIGN: We investigated 32 girls affected by true precocious puberty, by the single- dose ACTH stimulation test, HLA typing and the molecular analysis of the CYP21B gene encoding for the 21-OH enzyme. In order to detect gene deletions or point mutations. Twenty-eight cases were on LHRH analogue treatment and the remaining four, untreated owing to parental refusal, were investigated 0- 5-1.5 years after spontaneous menarche. RESULTS: After ACTH testing, 13 out of the 32 (41%) cases displayed higher 17-hydroxyprogesterone (17OHP) levels than normal but less than those found in patients affected by nonclassical adrenal hyperplasia (CAH); these levels were similar to those observed in obligate heterozygotes for CAH due to 21-hydroxylase deficiency (21-OHD). HLA typing showed a significantly increased frequency of the HLA alleles A28 and B14 which are peculiar to the HLA haplotypes of nonclassical CAH due to 21- OHD. Molecular analysis of the CYP21B gene showed that in four out of the 10 tested patients with an exaggerated 17-OHP response there were heterozygous point mutations of the CYP21B gene. In contrast, no CYP21B gene abnormalities were detected in the eight tested patients with normal 17-OHP. No differences were found between carriers and non-carriers of the 21-OHD with regard to age at onset of precocious puberty, clinical features, bone age acceleration and gonadal suppression induced by LH-RH analogue treatment. Two out of the four untreated patients who were investigated after menarche were found to be carriers of the 21OHD; these girls showed signs of androgen excess, irregular menses and polycystic ovaries. CONCLUSIONS: A high frequency of heterozygosity for adrenal steroid 21-OHD was found in our patients with true precocious puberty. This adrenal defect does not seem to influence the pattern of central precocious puberty, but these patients require long-term follow-up as they might go on to develop polycystic ovary syndrome (PCOS). Whether or not heterozygosity of the 21-OHD may be related to the premature activation of the hypothalamo-pituitary-gonodal axis remains to be defined.

Original languageEnglish
Pages (from-to)555-560
Number of pages6
JournalClinical Endocrinology
Volume48
Issue number5
DOIs
Publication statusPublished - 1998

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17-alpha-Hydroxyprogesterone
Precocious Puberty
Point Mutation
Genes
Histocompatibility Testing
Menarche
Polycystic Ovary Syndrome
Heterozygote
Gonadotropin-Releasing Hormone
Adrenocorticotropic Hormone
HLA-B14 Antigen
Menstruation
Sequence Deletion
Gene Deletion
Age of Onset
Gene Frequency
Haplotypes
Androgens
Hyperplasia
Ovary

ASJC Scopus subject areas

  • Endocrinology

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Exaggerated 17-hydroxyprogesterone response to short-term adrenal stimulation and evidence for CYP21B gene point mutations in true precocious puberty. / Cisternino, Mariangela; Dondi, Elisabetta; Martinetti, Miryam; Lorini, Renata; Salvaneschi, Laura; Cuccia, Mariaclara; Severi, Francesca.

In: Clinical Endocrinology, Vol. 48, No. 5, 1998, p. 555-560.

Research output: Contribution to journalArticle

Cisternino, Mariangela ; Dondi, Elisabetta ; Martinetti, Miryam ; Lorini, Renata ; Salvaneschi, Laura ; Cuccia, Mariaclara ; Severi, Francesca. / Exaggerated 17-hydroxyprogesterone response to short-term adrenal stimulation and evidence for CYP21B gene point mutations in true precocious puberty. In: Clinical Endocrinology. 1998 ; Vol. 48, No. 5. pp. 555-560.
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AU - Lorini, Renata

AU - Salvaneschi, Laura

AU - Cuccia, Mariaclara

AU - Severi, Francesca

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