A novel missense (R80W) mutation in 17-beta-hydroxysteroid dehydrogenase type 3 gene associated with male pseudohermaphroditism.

OBJECTIVE: Deficit of the testosterone converting enzyme 17-beta-hydroxysteroid dehydrogenase (17beta-HSD) has been shown to be responsible for male pseudohermaphroditism (MPH). We analysed the gene encoding 17beta-HSD type 3 (17beta-HSD3) in a patient with MPH. METHODS: We studied a 46, XY new-born diagnosed as having MPH. The child also had other congenital disorders, including a giant omphalocele and Fallot's tetralogy, and died of post-surgical complications at age 4.5 months. Basal hormonal levels, and after human chorionic gonadotrophin stimulation, suggested a deficiency in 17beta-HSD as the biochemical defect underlying this MPH. PCR amplification and subsequent sequencing of all coding exons of the 17beta-HSD3 gene were performed on genomic DNA from the patient and both parents. Messenger RNA was extracted from the patient's testis and 17beta-HSD3 cDNA was synthesized, PCR amplified and sequenced. RESULTS: Sequencing revealed the presence of a homozygous missense mutation (R80W) in exon 3 of the 17beta-HSD3 gene, which was also present in single doses in both parents, in accordance with the recessive inheritance of the defect. No other mutation was found, and cDNA sequencing confirmed correct synthesis and processing of 17beta-HSD3 mRNA. CONCLUSIONS: Confirming the abnormal delta4-androstenedione/testosterone ratios that suggested 17beta-HSD deficiency, a homozygous missense mutation in the gene coding for this enzyme was identified in the patient with MPH. This study adds further genetic evidence to the role of 17beta-HSD3 in male sexual development. There is no evidence supporting the association of this mutation in 17beta-HSD3 with the congenital malformations other than MPH present in the child.

A novel postzygotic nonsense mutation in SRY in familial XY gonadal dysgenesis.

The Y chromosome gene SRY plays an important role in normal male sexual development and is thought to be the testis-determining factor. We describe a familial nonsense mutation in SRY, shared by two XY sisters with complete gonadal dysgenesis and, in a mosaic manner, by their father. This mutation, consisting of a C to T transition in position 1 of codon 97 of SRY, results in a truncated peptide with an incomplete DNA-binding domain. The mutation is also present in the father of the two cases, but a portion of wild-type SRY also remains. Our data suggest that the father suffered a postzygotic mutation early in development, but that he retained a remnant of functional SRY protein that accounts for his normal development.

Hypogonadotrophic hypogonadism with hyposmia, X-linked ichthyosis, and renal malformation syndrome.

OBJECTIVE: The aim of this study was the endocrinological, enzymatic, and genetic evaluation of a family with a complex syndrome associating hypogonadotrophic hypogonadism with hyposmia, X-linked ichthyosis and renal malformation. DESIGN: Hypothalamic-pituitary-testicular function, olfaction, steroid sulphatase activity, and morphological renal studies were assessed. DNA molecular analyses were carried out in all the patients. PATIENTS: Two brothers and their maternal uncle showed the clinical picture of congenital ichthyosis, hypogonadism, hyposmia and unilateral renal maldevelopment. MEASUREMENTS: LH and FSH were determined by RIA basally and after GnRH stimulation, and the test repeated after a period of GnRH priming. Testosterone response to hCG was measured. Arylsulphatase C assay was performed as a measure of steroid sulphatase activity. DNA amplification analysis and Southern blot analysis of four Xp22.3 loci were performed. RESULTS: Low levels of gonadotophins, basally and after acute GnRH, increased clearly after GnRH priming. Low testosterone levels increased promptly after hCG. Subnormal levels of arylsulphatase C were detected. Hyposmia and renal hypoplasia or aplasia were demonstrated. A large Xp 22.3 deletion including the genes responsible for X-linked ichthyosis (steroid sulphatase deficiency) and Kallmann syndrome was demonstrated. CONCLUSIONS: The absence of the gene encoding steroid sulphatase accounts for the X-linked ichthyosis in these patients, whereas the absence of the Kallmann syndrome gene accounts for hypogonadism, anosmia and for the single kidney found in two of the three patients.

Oral dexamethasone administration: new pharmacological test for the assessment of growth hormone secretion.

Acute intravenous (i.v.) dexamethasone administration has been described recently as a new test for the diagnosis of growth hormone (GH) deficiency. In the present study, a new protocol of dexamethasone administration was evaluated. Twelve normal adults and 18 normal prepubertal children were studied. The dexamethasone i.v. test was performed in six adults at a dose of 4 mg and 12 children at a dose of 2 mg/m2. Blood samples were collected 15 min before, at time zero and every 15 or 30 min during 5 h, resulting in a total of 16 samples. In the remaining six adults and six children, 8 and 4 mg, respectively, of dexamethasone were administered orally at the subject's home, and blood sampling started 90 min later when they arrived at the hospital. Plasma GH was measured by radioimmunoassay. The dexamethasone-induced GH response (mean +/- SEM, micrograms/l) to the i.v. or oral protocol did not differ in either the adults (i.v. 8.2 +/- 2.1; oral 8.0 +/- 1.6) or the children (i.v. 14.9 +/- 1.3; oral 13.6 +/- 1.8). It is concluded that the simpler protocol of acute oral dexamethasone administration hereby presented can be a safe and suitable test of GH secretion.

[Other indications for growth hormone treatment: chronic kidney failure and Turner's syndrome]. / Otras indicaciones de tratamiento con hormona de crecimiento: insuficiencia renal crónica y síndrome de Turner.

Recently, it has been demonstrated that treatment with growth hormone (GH) can accelerate height velocity in children with chronic renal insufficiency (CRI), after kidney transplantation and in Turner syndrome. The pathogenesis of growth retardation in CRI is complex. Possibly the most important factor involved is the presence of peripheral resistance to insulin-like growth factors. The administration of GH in high doses may restore catch-up growth, both in children with CRI and in kidney post-transplant patients. After 12 months of treatment height velocity increased from 4.3 to 6.6 cm/year in 4 children with CRI, and from 2.5 to 7.4 cm/year in 3 patients with kidney transplant. GH therapy alone, but even more in combination with oxandrolone increases the growth rate in Turner syndrome and may increase the final height, but the long-term results of this treatment are awaited. No undesirable collateral effects have been reported.

[Diabetic ketoacidosis: results with two different patterns of insulin administration (author's transl)]. / Cetoacidosis diabética: resultados con dos pautas distintas de terapéutica insulinica.

The response to insulin treatment in 15 children with diabetic ketoacidosis is studied. Insulin continous infusion was administered to nine patients. The other six patients received insulin subcutaneously except one half of the first dose injected by vein as a bolus. Both patterns of insulin administration proved to be equally effective. Anyway the insulin continuous infusion appears as a simple and easier method for a good general control and to prevent hypoglycemic episodes. To prevent a hyperglycemic rebound it is suggested that a dose of subcutaneous insulin must be injected immediately after the insulin infusion is discontinued. A discordance between hyperglycemia correction and the degree of acidosis has been noticed in some patients; this can be corrected decreasing insulin infusion rate.

[Stimulation of growth hormone (HGH) secretion by physical exercise (author's transl)]. / Estimulación de la secreción de hormona de crecimiento (HGH) por medio del ejercicio físico.

Authors study forty eight children with severe lineal growth retardation. The more frequent causes of a stunted growth were ruled out previously (systemic and chronic diseases, metabolic disorders, genetic alterations, etc.). As a screening test, physical exercise was used to detect growth hormone (HGH) deficiency. A normal response was considered when HGH levels rose more than 7,0 ng./ml. after 20 minutes of continuous exercise. In those cases in which this level was not attained. insulin-hypoglycemia alone and followed by insulin plus an arginine infusion were used as stimuli, to confirm the lack of HGH response. A correct response to the exercise was found in 81% of the cases. It is concluded that the physical exercise as HGH stimulus is a good screening test. It presents a high degree of confidence with some other qualities, mainly: little disturbances to the patients, a rapid performance, lack of unpleasant colateral effects, and the possibility that it can be carried out by sanitary non-medical personnel.

[Infantile cushing's disease with paradoxical response to dexamethasona due to a probable periodic hormogenesis (author's transl)]. / Enfermedad de Cushing infantil con respuesta paradójica a la dexametasona por probable hormogénesis periódica.

A case of Cushing's disease in a ten year old girl with bilateral diffuse hyperplasia of the adrenal cortex and postoperative enlargment of the sella turcica is presented. The administration of dexamethasone elicited a paradoxical response with a clear elevation of the already high excretion of 17-hydroxycorticoids. The possible mechanisms for this previously described, but infrequent, response to dexamethasone are discussed. It is concluded that: 1) Interpretation of the classical dexamethasone suppression test can occasionally be misleading; and 2) Periodic hormonogenesis may account for this type of paradoxical response.

[Virilizing adrenal carcinoma (author's transl)]. / Carcinoma córtico-suprarrenal virilizante. Presentación de un caso

A case of virilizing adrenal carcinoma, diagnosed in the first year of age, is presented. The difficulties of differential diagnosis with congenital adrenal hyperplasia are briefly discressed. There is not evidence of metastasis 15 months after complete surgical excision of the tumor and repeated detreminations of 17-CO and 17-OH have remained within normal limits. Finally some considerations are made regarding diagnosis, prognosis and treatment.

[Hereditary acute tyrosinemia. a case report (author's trnasl)]. / Tirosinemia aguda hereditaria. A propósito de una observación

A three month old infant with hepatic cirrhosis of rapid instauration is presented. Diagnosis of acute tyrosinemia was suspected by clinical data and confirmed by the quantitiative determination of plasma amino acids and the peculiar histological characteristics of hepatic cirrhosis. Authors review briefly the pathogenesis, symptoms and treatment of the disease.