The postpubertal outcome of a group of girls diagnosed of premature pubarche during childhood was assessed 1) to determine the incidence of functional ovarian hyperandrogenism (FOH) through the ovarian-steroidogenic response to the GnRH agonist leuprolide acetate, 2) to validate leuprolide acetate stimulation in FOH diagnosis, and 3) to ascertain whether FOH-predictive biochemical markers exist at the diagnosis of premature pubarche. Of 35 patients (age, 15.4 +/- 1.5 yr), 16 showed hirsutism, oligomenorrhea, and elevated baseline testosterone and/or androstenedione (delta 4-A) levels. Subcutaneous administration of leuprolide acetate (500 micrograms) produced similar increases in gonadotropin levels in oligomenorrheic patients, regularly menstruating patients (n = 19), and controls (n = 12; age, 15.3 +/- 1.3 yr) when tested at 6 h. Of all of the steroids measured, 17-hydroxyprogesterone (17-OHP) and delta 4-A levels 24 h postleuprolide acetate stimulation were significantly higher in oligomenorrheic patients than in the other two groups (P < 0.0001). No overlapping in 17-OHP responses occurred between oligomenorrheic patients and the other groups. Baseline dehydroepiandrosterone sulfate and delta 4-A levels at the diagnosis of premature pubarche correlated with 17-OHP values postleuprolide acetate challenge (r = 0.47; P < 0.005 and r = 0.67; P < 0.0001, respectively). These results show a distinct leuprolide acetate challenge response in 45% of the postpubertal premature pubarche girls studied, suggestive of an increased incidence of FOH, and support the need for continued routine postmenarcheal evaluation of this group of patients. Responses of 17-OHP to leuprolide acetate challenge facilitate the identification of FOH patients, establish this test as a reliable diagnostic tool in FOH diagnosis, and confirm the ovaries as the source of hyperandrogenemia in most patients with androgen excess. Although increased 17-OHP responses after leuprolide acetate stimulation seem to occur more frequently in girls with elevated dehydroepiandrosterone sulfate and/or delta 4-A levels at the diagnosis of premature pubarche, specific biochemical markers predictive of FOH in this group of patients are still lacking.
Since neurofibromatosis type 1 (NF1) is a well known cause of precocious puberty (PP), we reviewed 412 NF1 pediatric patients to evaluate the prevalence of PP, the association with optic pathway tumors (OPT), and other clinical, auxological and hormonal data. Thirty-one of 412 patients had OPT (7.5%), 10/412 PP (2.4%), and in seven of these PP was associated with OPT (7/31, 22.6%). OPT in patients with PP involved the chiasm in four patients, and the optic nerves alone in three patients. The age at the onset of puberty (or better at diagnosis) ranged from 5.2 to 7.5 yr in girls (n=6) and from 7.9 to 8.9 yr in boys (n=4). LHRH agonist therapy was used in only three children because in the others the predicted height at diagnosis was good, treatment was refused or the patients were referred to us too late. The three treated patients attained a final height within the familial range. In the untreated patients the progression of puberty was not too rapid and final height was slightly below the genetic target in four patients; however, three patients had a final height markedly below the familial range. In conclusion, the prevalence of PP is increased in children with NF1, and frequently but not exclusively is associated with OPT. Moreover, sexual precocity does not seem to be necessarily bound to chiasmatic OPT. Treatment seems to be useful in the children with younger age at the onset of puberty or with a progressive decline in predicted final height.
ABSTRACT. The adrenocorticotropin (ACTH), cortisol, and dehydroepiandrosterone responses to synthetic human corticotropin-releasing factor (CRF) were studied in 28 endocrinologically healthy children (age 1-16 yr) and in six adult volunteers (age 24-42 yr). CRF was given as an intravenous bolus (I pg/kg body weight) between 0900 and 1000 hr. Significant increments in ACTH and cortisol levels after CRF were observed in all subjects, with an ACTH peak value of 48.2 2 3.4 pg/ml at 10 min Cp < 0.001). The ACTH and cortisol response patterns after CRF did not change with age or pubertal maturation and did not differ in children and in adults. In contrast, the dehydroepiandrosterone response to CRF clearly was related to the stage of pubertal development. The peak value after CRF significantly increased from puberty stage 1 to puberty stage 5 (164 +. 18 versus 779 +. 86 ng/100 ml, p < 0.001). In adults, the mean dehydroepiandrosterone peak value after CRF did not differ from that of P5 children.These results show that CRF can be given safely to children. The absence of age-dependent ACTH and cortisol responses and a dehydroepiandrosterone response changing with pubertal maturation points to the existence of factors involved in the control of adrenal androgen production other than ACTH. CRF, corticotropin-releasing factorSince the isolation and characterization of CRF (1)(2)(3) several studies of its use in humans have been published (4-1 1). Synthetic CRF 1-41 has been reported to be highly potent in stimulating the release of ACTH-and proopiomelanocortinderived peptides from the pituitary of rodents and of humans (12, 13). Furthermore, the CRF-induced ACTH increase stimulates the concomitant release of cortisol and aldosterone from the adrenals (4-1 1, 14). Because of these effects and of its relative safety during clinical studies, CRF provides a powerful tool for studying ACTH secretion in normal as well as pathological situations. Several recent studies describe use of the CRF test in the evaluation of Cushing syndrome (1 5-1 7), Nelson syndrome (1 9, isolated pituitary ACTH deficiency and adrenal insufficiency (19,20). Data on the administration of CRF to children are limited so far to two reports (2 1, 22). In one study, Ross et al.(21) could find no age-dependent changes in the ACTH or cortisol responses to CRF in a group of normal children.In the present study, CRF was administered to hospitalized but endocrinologically healthy children, and the CRF-induced activation of the pituitary-adrenal axis was studied in relation to pubertal maturation. DHEA responses as well as ACTH and cortisol responses to CRF were assessed since the maturation of adrenal androgen production is associated with pubertal development (23-26). SUBJECTS AND METHODS Subjects.Approval for studies was obtained from the ethical committees of the three pediatric clinics in Tiibingen, Bonn, and Parma. The parents of all hospitalized but endocrinologically healthy children gave informed consent before the test was done. The normal children had...
Triple A (Allgrove) syndrome was first described by Allgrove in 1978 in two pairs of siblings. Since then, about 100 cases have been reported, all of them displaying an autosomal recessive pattern of inheritance. Clinical picture is characterized by achalasia, alacrimia and ACTH-resistant adrenal failure. A progressive neurological syndrome including central, peripheral and autonomic nervous system impairment, and mild mental retardation is often associated. The triple A syndrome gene, designated AAAS, is localized on chromosome 12q13. It consists of 16 exons, encoding for a 546 aminoacid protein called ALADIN (Alacrimia-Achalasia-aDrenal Insufficiency Neurologic disorder).We report on a 13 year-old boy presenting with Addison’s disease, dysphagia, muscle weakness, excessive fatigue and recent onset gait ataxia. The analysis of the AAAS gene revealed a homozygous missense mutation in exon 12. It was a T > G transversion at nucleotide position 1224, resulting in a change of leucine at amino acid position 381 into arginine (Leu381Arg or L381R). Brain appearance was found normal at magnetic resonance imaging (MRI) and functional spectroscopy analysis showed normal levels of the main metabolites. Spine MRI showed a cystic cavity within the spinal cord (syringomyelia), localized between the sixth cervical vertebra and the first thoracic vertebra. Cerebellar tonsils descended 7 mm caudal to foramen magnum, consistently with a mild type 1 Chiari malformation. Mild posterior inter-vertebral disk protrusions were evident between T9 and T10 and between L4 and L5.To our knowledge, this is the first report describing type 1 Chiari malformation and multiple spinal cord abnormalities in a patient with Allgrove syndrome.
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