[Show abstract][Hide abstract] ABSTRACT: Objective: We present the 1st case of prepubertal hyperandrogenism because of a defect in the conversion of cortisone (E) to cortisol (F) by hepatic11β-hydroxysteroid dehydrogenase type 1. Methods and Results: Clinical and anthropometric data were obtained. Serum androgens and gonadotropins with luteinizing hormone releasing hormone stimulation test, dexamethasone suppression test, and corticotropin-releasing hormone stimulation test were evaluated. Adrenal imaging and urinary steroid profiling by gas chromatography/mass spectrometry were employed. A 6.9-year-old boy presented with precocious pubarche, height (+2.6 SD), accelerated bone age (11.5 years), and Tanner stage 2 pubic hair and genitalia. Serum androgen levels were elevated and dexamethasone suppressible. Serum F was normal, but the E concentration was increased. Central precocious puberty and congenital adrenal hyperplasia were excluded. The excretion of androgen metabolites was moderately increased, but a highly increased tetrahydrocortisone (THE) and a diminished tetrahydrocortisol (THF + allo-THF) excretion was found with a [THF + allo-THF/ THE] ratio of 0.032 (normal controls 1.05 ± 0.17). The corticotropin-releasing hormone stimulation test showed an exaggerated adrenocorticotropic hormone response, suggesting a relative deficiency of F. Two months of hydrocortisone treatment (17.5 mg daily) failed to suppress androgens adequately. Treatment with dexamethasone (0.375 mg/daily) resulted in androgen suppression. Conclusions: In the case of precocious pubarche and accelerated growth, the diagnosis of 11β-hydroxysteroid dehydrogenase type 1 deficiency (‘apparent cortisone reductase deficiency’) should be considered. The diagnosis is based on determinations of urinary steroid metabolites.
Hormone Research in Paediatrics 03/2003; 59(4):205-210. DOI:10.1159/000069326 · 1.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We present the 1st case of prepubertal hyperandrogenism because of a defect in the conversion of cortisone (E) to cortisol (F) by hepatic 11beta-hydroxysteroid dehydrogenase type 1.
Clinical and anthropometric data were obtained. Serum androgens and gonadotropins with luteinizing hormone releasing hormone stimulation test, dexamethasone suppression test, and corticotropin-releasing hormone stimulation test were evaluated. Adrenal imaging and urinary steroid profiling by gas chromatography/mass spectrometry were employed. A 6.9-year-old boy presented with precocious pubarche, height (+2.6 SD), accelerated bone age (11.5 years), and Tanner stage 2 pubic hair and genitalia. Serum androgen levels were elevated and dexamethasone suppressible. Serum F was normal, but the E concentration was increased. Central precocious puberty and congenital adrenal hyperplasia were excluded. The excretion of androgen metabolites was moderately increased, but a highly increased tetrahydrocortisone (THE) and a diminished tetrahydrocortisol (THF + allo-THF) excretion was found with a [THF + allo-THF/ THE] ratio of 0.032 (normal controls 1.05 +/- 0.17). The corticotropin-releasing hormone stimulation test showed an exaggerated adrenocorticotropic hormone response, suggesting a relative deficiency of F. Two months of hydrocortisone treatment (17.5 mg daily) failed to suppress androgens adequately. Treatment with dexamethasone (0.375 mg/daily) resulted in androgen suppression.
In the case of precocious pubarche and accelerated growth, the diagnosis of 11beta-hydroxysteroid dehydrogenase type 1 deficiency ('apparent cortisone reductase deficiency') should be considered. The diagnosis is based on determinations of urinary steroid metabolites.
Hormone Research 02/2003; 59(4):205-10. · 2.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Over the past 5 yr several inactivating mutations in the LH receptor gene have been demonstrated to cause Leydig cell hypoplasia, a rare autosomal recessive form of male pseudohermaphroditism. Here, we report the identification of two new LH receptor mutations in a compound heterozygous case of complete Leydig hypoplasia and determine the cause of the signaling deficiency at a molecular level. On the paternal allele of the patient we identified in codon 343 a T to A transversion that changes a conserved cysteine in the hinge region of the receptor to serine (C343S); on the maternal allele a T to C transition causes another conserved cysteine at codon 543 in trans-membrane segment 5 to be altered to arginine (C543R). Both of these mutant receptors are completely devoid of hormone-induced cAMP reporter gene activation. Using Western blotting of expressed LH receptor protein with a hemagglutinin tag, we further show that despite complete absence of total and cell surface hormone binding, protein levels of both mutant LH receptors are only moderately affected. The expression and study of enhanced green fluorescent protein-tagged receptors confirmed this view and further indicated that initial translocation to the endoplasmic reticulum of these mutant receptors is normal. After that, however, translocation is halted or misrouted, and as a result, neither mutant ever reaches the cell surface, and they cannot bind hormone. This lack of processing is also indicated by reduced presence of an 80-kDa protein, the only N-linked glycosylated protein in the LH receptor protein profile. Thus, complete lack of signaling by the identified mutant LH receptors is caused by insufficient processing from the endoplasmic reticulum to the cell surface and results in complete Leydig cell hypoplasia in this patient.
[Show abstract][Hide abstract] ABSTRACT: We searched for nonclassic congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency [NC-CAH(21-OH)] in 272 patients: 123 (92 female, 31male), aged 3.2–12 years (group I) with a history of precocious pubarche (onset 6.2 ±1.3 years) and in 149 adolescent girls aged 11.8–18 years with symptoms developed after normal puberty: 70 with isolated hirsutism, 71 with hirsutism accompanied by menstrual disturbances, 6 with menstrual disturbances only, 1 with clitoromegaly only. We used 24-h urinary steroid profiling by capillary gas chromatography for diagnosis. NC-CAH(21-OH) was diagnosed in 11 patients (7 female, 4 male) in group I (8.4%) and 7 in group II (4.7%). The clinical symptoms of these patients varied in group I from precocious pubic hair only (6 female, 2 male) to precocious growth of pubic hair and mild clitoromegaly in addition (3 female), and in group II from primary amenorrhea (1 patient), to hirsutism and menstrual irregularities (5 patients) and polycystic ovary syndrome in addition (1 patient), and isolated clitoromegaly (1 patient). The frequency of NC-CAH(21-OH) in our patients of Polish origin seems to be in the range of values reported by other authors for different populations.
Annals of Diagnostic Paediatric Pathology 10/1998; 2(1):1-7. DOI:10.1007/s100570050001
[Show abstract][Hide abstract] ABSTRACT: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency suspected in 14 newborns (5 F, 9 M), was treated prenatally with dexamethasone from weeks 7-9 of gestation. The 24 h urinary excretion of selected adrenocortical steroids derived from fetal and definitive adrenal zones was evaluated in these newborns at the age of 3 9 days. Among 11 babies born healthy, in one of six treated until confirmation of male karyotype in gestational weeks 12-17 and in four of five treated until delivery, suppression of fetal adrenal zone steroids was observed, accompanied additionally in three by a diminished excretion of tetrahydrocortisone. In three babies born affected (2 male, 1 female), excretion of 17alpha-hydroxyprogesterone and 21-deoxycortisol metabolites did not differ from 12 affected, age-matched controls, not treated prenatally. However, some influence on suppression of the fetal adrenal zone metabolite 16alpha-hydroxypregnenolone was observed in two newborns treated until delivery. CONCLUSIONS: Heterogeneity in the fetal adrenal response to maternal dexamethasone treatment was confirmed. Suppression of fetal adrenals, especially within the fetal adrenal zone, can be observed in some babies born healthy until at least 1 week after birth.
European Journal of Pediatrics 08/1998; 157(7):539-43. DOI:10.1007/s004310050873 · 1.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A simplified urinary marker analysis for diagnosis of congenital adrenal hyperplasia (CAH) and 5alpha-reductase deficiency in infancy by GC/MS-SIM is introduced. The analysis was performed in 161 patients aged 3-90 days, 99 females and 62 males. CAH due to 21-hydroxylase deficiency was diagnosed in 61 patients (42 females and 19 males; in 10 cases simple virilizing form and in 51 patients salt-wasting form) and CAH induced by 3beta-hydroxysteroid dehydrogenase deficiency without salt loss in 1 female patient. In 2 full-term newborns and 6 preterm infants, a false-positive diagnosis of CAH, which had been based on serum steroid evaluation, was made. In these cases, increased excretion of fetal adrenal zone steroids was confirmed as a possible source of false-positive serum 11-deoxycortisol and 17alpha-hydroxyprogesterone values. Lack of fetal adrenal zone steroid metabolites in 2 male newborns with salt loss symptoms led to the diagnosis of adrenal insufficiency due to X-linked adrenal hypoplasia and adrenal hemorrhage. A single analysis of urinary CAH markers by the very sensitive and selective GC/MS-SIM method can replace numerous assays of various steroids that must be carried out for positive diagnosis of abnormal steroidogenesis in infancy.
Hormone Research 02/1997; 48(6):243-51. DOI:10.1159/000185529 · 2.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The molecular basis of 5 alpha-reductase (5 alpha R) deficiency was investigated in four patients from three European families. In the French family, the first patient was raised as a female, and gonadectomy was performed before puberty. The second sibling, also raised as female, differed in that gonadal removal was performed after the onset of pubertal masculinization. The other two patients, both from Polish families, developed masculinization of external genitalia during puberty. All patients developed a female sexual identity. In all cases, no known consanguinity or family history of 5 alpha R deficiency was reported. The genomic DNAs of the patients were sequenced after polymerase chain reaction amplification of the five exons of the 5 alpha R type 2 gene. We found two homozygous mutations responsible for glutamine to arginine and histidine to arginine substitution in families 1 and 3, respectively. In family 2, we found a heterozygous mutation responsible for an asparagine to serine substitution at position 193. The glutamine/arginine 126 mutation in the French family was previously reported in a Creole ethnic group, and the Polish histidine/arginine 231 mutation was previously reported in a patient from Chicago. Moreover, all of the mutations created new restriction sites, which were used to determine the kindred carrier status in the three families. Because 5 alpha R deficiency is known to be a heterogenous disease in terms of clinical and biochemical expression, our data suggest that molecular biology analysis of the type 2 gene could be an essential step in diagnosing 5 alpha R deficiency.
[Show abstract][Hide abstract] ABSTRACT: The excretory patterns of urinary steroids determined by capillary gas chromatography in 11 children (aged 0.8-16.5 years) with adrenocortical tumors were established. In 8 patients the predominant clinical feature was virilization, in 3 others, Cushing's syndrome. In 5 patients (3 carcinoma, 2 adenoma) very high excretion of 3 beta-hydroxy-5-ene steroids was observed. In 2 others (adenomas) only moderately elevated excretion of 11 beta-hydroxyandrosterone was found. In 1 patient (adenoma) pregnanediol dominated in the steroid profile, accompanied by moderately elevated 3 beta-hydroxy-5-ene steroids. Out of 3 Cushingoid patients (1 carcinoma, 2 adenomas), 1 presented an atypical urinary steroid pattern for hypercortisolemia, without 5 alpha-reductase and 11 beta-hydroxysteroid dehydrogenase deficiencies. Neither the urinary steroid pattern nor tumor size alone were reliable indicators of tumor malignancy, as evaluated by a pathological examination and subsequent metastasis-free survival.
Hormone Research 02/1995; 44(4):182-8. DOI:10.1159/000184622 · 2.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Adrenocortical tumors in children are rare but inportant causes of virilization and/or Cushing's syndrome. Other symptoms, including feminization and hyperaldosteronism, are less frequent. We present steroid urine profiles in 8 girls with adrenocortical tumors.
Pediatric Research 05/1993; 33. DOI:10.1203/00006450-199305001-00066 · 2.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Head trauma can damage the hypothalamus as well as pituitary gland, which can in effect lead to disorders in secretion of tropic hormones or to disfunction of the pituitary itself. The aim of the study was evaluate the frequency and types of hormonal disorders after head injury in children. The study was conducted on 77 patients 10.8-8 yr.) with collection of auxological data and hormonal stimulation tests the insulin-hypoglicemia, the GRF 1-29, the TRH and GnRH test and serum and urine osmolality) which were carried out from 1 month to 7 yr. after the injury was sustained. Results are presented on tables.
Pediatric Research 05/1993; 33. DOI:10.1203/00006450-199305001-00147 · 2.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Twenty severely GH-deficient prepubertal children aged 10.7 +/- 2.1 yr (mean +/- SD) and with a height SD of -4.92 +/- 1.02 were treated with sc injections of GHRH 1-44 (10 micrograms/kg BW) for 6 months either daily (11 patients) or 3 times/week (nine patients). An acute iv GHRH test (2 micrograms/kg BW) was performed before and after 2 and 6 months of treatment. Mean (+/- SD) peak GH responses to these tests were 2.92 +/- 3.01, 4.57 +/- 4.91, and 7.56 +/- 8.14 micrograms/L, respectively (P less than 0.05, pretreatment vs. 6 months). The mean growth velocity (GV) during treatment was only 2.99 +/- 1.67 cm/yr and only two patients increased their GV by more than 2 cm/yr. A correlation was found between GV during treatment and the peak serum GH response to GHRH acute test before treatment (r = 0.68, P less than 0.005) as well as between GH response to the acute test and patient's bone age (r = -0.46, P less than 0.05). The results indicate that in some severely GHD patients with no response to GHRH even after a 2-month priming period, 6 months of treatment with GHRH can evoke pituitary responsiveness. We speculate that the duration of the GHRH deficiency and its severity plays a role in the ability of somatotrophs to respond to this stimulus.
[Show abstract][Hide abstract] ABSTRACT: The availability for clinical use of somatocrinine growth hormone releasing hormone (GRF) brings about the possibility of treatment of growth hormone deficient children (GHD) of hypothalamic origin. We present the results of the first 6 months of treatment of GRF in 20 GHD children. Ten boys and 10 girls with mean chronological age of 10.7 ± 2.7 yr, bone age 6.1 ± 2.5 “yr” and with a mean growth retardation of 4.7 ± 0.6 SD were treated with GRF 1 - 44 SANOFI by daily (N = 11) or thrice weekly (N = 9) subcutaneous injection in doses of 10 ug/kg body weight. All of the children were in prepubertal stage and in all the peak GH response to clonidine and I'dopa provocative tests was below 5 ng/ml. Nine patients had TSH deficiency and were parallely treated with I'thyroxine. The GRF i.v. bolus test was performed before treatment and 2 and 6 months after initiation of treatment. In 9 out of 20 patients acceleration of growth velocity was found. Three patients reached a growth velocity of more than 4.4 cm per yr. Growth velocity during the treatment was significantly correlated with peak GH response to GRF i.v. bolus before (r = 0.6786) and during the treatment (r = 0.4863 and r = 0.5947, respectively). The growth velocity was greater in younger children and in those with less advanced bone age. Acute response to GRF was significantly greater after 6 months of treatment than before the treatment (mean peak GH response 2.9 ± 3.0 and 7.6 ± 8.1 ng/ml respectively, p < 0.05). No side effects of the treatment were observed and immunological tolerance was good. We concluded that chronic administration of GRF is well tolerated and resulted in enhanced growth in some of the GHD children and evoked better response of somatotrophs to GRF i.v. bolus. The GH response to a single i.v. GRF bolus may have a prognostic value for growth response to GRF therapy.
Pediatric Research 01/1988; 23(1). DOI:10.1203/00006450-198801000-00118 · 2.31 Impact Factor