Congenital adrenal hyperplasia caused by compound heterozygosity of two novel CYP11B1 gene variants.

BACKGROUND: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder caused by pathogenic variants in seven genes involved in the cortisol and aldosterone biosynthetic pathway. The second most common cause, 11ß-hydroxylase deficiency (11ßOHD), is attributed to pathogenic variants in the CYP11B1 gene encoding for the enzyme 11ß-hydroxylase (11ßOH). CASE PRESENTATION: A 13-year-old girl was referred to the pediatric endocrinologist due to a syncopal episode. She is the third child of non-consanguineous parents. She presented with premature adrenarche at the age of 6 years and menarche at the age of 12 years. On physical examination, her height was 154.5 cm and weight 50 kg, while she presented with acne, hirsutism, clitoromegaly, and normal blood pressure. Laboratory investigation revealed increased androgen levels and poor cortisol response to the ACTH stimulation test. From the family history, the mother was diagnosed with CAH at the age of 10 years and was under treatment with methylprednisolone. Previous molecular investigation of the CYP21A2 gene was negative. Due to the increased androstenedione levels in the index patient, the suspicion of 11ßOH was raised, and she was investigated for 11-deoxycortisol, 11-deoxycorticosterone, and CYP11B1 gene pathogenic variants. The patient and her mother were found to be compound heterozygous for two novel variants of the CYP11B1 gene. CONCLUSION: We present a case of CAH due to compound heterozygosity of two novel pathogenic variants of the CYP11B1 gene, emphasizing the importance of molecular investigation in order to confirm clinical diagnosis and allow proper genetic counseling of the family.

Spontaneous ovulation in a true hermaphrodite with normal male phenotype and a rare 46,XX/47,XXY Klinefelter's mosaic karyotype.

BACKGROUND: Most true hermaphrodite patients--characterized by the presence of both ovarian and testicular tissue--demonstrate ambiguous genitalia and are diagnosed at birth, most commonly bearing a 46,XX karyotype. PATIENT AND METHODS: We report on a 13-year-old boy presenting with left scrotal hemorrhage. He had a left inguinal hernia, a palpable testis in the right, normal male external genitalia and significant gynecomastia. During operation, the left gonad and adjacent tissue were removed for histological examination, which revealed the presence of a normal ovary, rich in follicles and a ruptured corpus luteum, suggestive of spontaneous ovulation, with a normal ipsilateral adnexa and semi-uterus. Biopsy of the right gonad revealed a dysgenetic testicle. Endocrinological assessment postoperatively depicted high FSH, pubertal testosterone and low estradiol levels. Cytogenetic analysis in peripheral blood lymphocytes and FISH of the right gonad revealed a 46,XX (70-60%)/47,XXY (30-40%) karyotype, respectively, while molecular analysis verified the presence of SRY and azoospermia factor genes. CONCLUSION: The importance of full histological, cytogenetic and molecular investigation and of interdisciplinary approach in every single patient with sex differentiation disorders is highlighted by this rare case of spontaneous ovulation in a true hermaphrodite with normal male external genitalia and Klinefelter mosaicism.

Early growth, pubertal development, body mass index and final height of patients with congenital adrenal hyperplasia: factors influencing the outcome.

OBJECTIVE: The management of children with congenital adrenal hyperplasia (CAH) remains a challenge, especially with regard to growth potentials. The objective of our analysis was to uncover the factors that influence the growth and final height of patients with CAH. DESIGN: The linear growth pattern and body mass index (BMI) at different developmental stages (birth to 2 years, 2 years to puberty initiation and puberty initiation to final height) and the final height achieved were analysed retrospectively in 48 patients with 21-hydroxylase deficiency; 17 with the salt-wasting (SW) form, 25 with the simple virilizing (SV) and six with the nonclassical (NC) form. RESULTS: Mean final height (FH) and FH-SDS were, respectively, 170.8 +/- 5.6 m and -0.57 +/- 0.8 in males and 156.7 +/- 6 cm and -0.61 +/- 1 in females with the SW form, 166.1 +/- 6.1 cm and -1.05 +/- 1 in males and 151.6 +/- 5.4 cm and -1.4 +/- 1 in females with the SV form and 159.7 +/- 6.9 cm and 0.3 +/- 1.4 in females with the NC form. In subjects with the SW form, height SDS at 2 years, at puberty initiation and at FH were -0.18 +/- 0.9, 0.11 +/- 1.28 and -0.6 +/- 1.0, respectively. FH achieved was not different from target height (TH) in the SW group, but it was significantly lower than TH in the SV group (P = 0.003). FH in the SW group showed a positive correlation to the height achieved at 2 years of age (r = 0.68, P = 0.019), and height at 2 years was negatively related to the hydrocortisone dose in the birth to 2-year period (r = -0.79, P = 0.011). FH showed no correlation to hydrocortisone dose at any of the three developmental periods studied. BMI-SDS were not different in the various forms of CAH and showed no correlation to FH or hydrocortisone dose. Age at menarche was comparable to that in our general population. CONCLUSIONS: Under our conditions of management, the final height of patients with the salt-wasting form was comparable to the target height and to the most favourable literature data. The patients with the simple virilizing form fare less well, mainly due to delayed diagnosis and consequent advancement of bone age and early puberty. In salt-wasting patients, height at 2 years is comparable to normals, it is influenced by the hydrocortisone dose and is related to the final height. Some height is lost during puberty. Hence, monitoring treatment over the first 2 years and during puberty is critical for the outcome in these patients.