Global Adrenal Insufficiency in Two Independent Patients Carrying the Same Homozygous c.172A>G, p.(Thr58Ala) Mutation in the TBX19 Gene.

INTRODUCTION: TBX19 mutations cause isolated ACTH-deficiency. While this classically results in severe hypocortisolism, potential consequences for mineralocorticoid biosynthesis have not been described to date. Liquid chromatography mass spectrometry (LC-MS/MS) and gas chromatography mass spectrometry (GC-MS) allow novel insights into the steroid metabolism of pediatric endocrine diseases. CASE PRESENTATION: Patient 1 (female) presented right after birth with hypoglycemia and hyponatremia (minimum sodium 126 mmol/L). She recovered under therapy with hydrocortisone, fludrocortisone and initial NaCl. Patient 2 (male) presented after birth with prolonged cholestatic jaundice. Only at the age of 3.5 months, repeated episodes of hypoglycemia occurred. Both patients showed severely reduced ACTH. LC-MS/MS analyses on plasma samples demonstrated combined reduced glucocorticoid- and mineralocorticoid biosynthesis confirmed by GC-MS analyses on spot urine. In contrast to patient 1, patient 2 (currently 8 years old) never suffered from hyponatremia. Both patients carry the same homozygous c.172A>G, p.(Thr58Ala) mutation in the TBX19 gene proving isolated ACTH-deficiency. CONCLUSION: Isolated ACTH-deficiency can be associated with reduced mineralocorticoids and hyponatremia. We hypothesize that sufficient pituitary ACTH secretion is an important predisposition for regular adrenal mineralocorticoid biosynthesis.

Gonadotropin- and Adrenocorticotropic Hormone-Independent Precocious Puberty of Gonadal Origin in a Patient with Adrenal Hypoplasia Congenita Due to DAX1 Gene Mutation - A Case Report and Review of the Literature: Implications for the Pathomechanism.

BACKGROUND/AIMS: Mutations in the DAX1 gene cause X-linked adrenal hypoplasia congenita (AHC) classically associated with hypogonadotropic hypogonadism. Unexpectedly, precocious puberty (PP) has been reported in some cases, its mechanism remaining unclear. METHODS: We longitudinally studied a boy with AHC due to DAX1 gene mutation who developed peripheral PP at age 4.5 years. Initially he presented pubic hair, penile enlargement, advanced bone age and elevated testosterone levels. PP progressed with acne, body odour and ejaculations. In addition, we summarized reported findings of patients with DAX1 mutations and PP in the literature in a structured manner providing a basis to discuss possible pathomechanisms of PP in DAX1 patients. RESULTS: In our patient, hydrocortisone treatment was increased to 20 mg/m2/day as suggested in similar published cases. However, despite the suppression of adrenocorticotropic hormone (ACTH), this remained without clinical effect or change in laboratory results. The progression of symptoms of pubertal development was well suppressed under cyproterone acetate treatment. Twenty-four-hour steroid urine excretion rate measurements excluded an effect of adrenal androgens and showed a prepubertal rise of excreted testosterone. Testes size remained small. GnRH testing showed peripheral PP. CONCLUSION: We hypothesize that an intrinsic, gonadotropin- and ACTH-independent activation of steroidogenesis in the DAX1 deficient testes leads to PP in AHC patients with DAX1 mutations.