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Summary objective In girls with congenital adrenal hyperplasia (CAH), genital ambiguity usually leads to a rapid neonatal diagnosis. Rarely, CAH causes complete virilization and male sex assignment with a delayed diagnosis. After being confronted with very specific problems in two of such patients, we collected data of patients with CAH and complete virilization in a nationwide study to delineate specific problems of these rare patients in order to improve their management. design and patients Through the German Working Group of Paediatric Endocrinology (Arbeitsgemeinschaft Padiatrische Endokrinologie, APE), questionnaires were sent to all members caring for patients with CAH and complete virilization in their endocrine clinics. Data from 16 patients from 10 paediatric endocrine centres were assessed by questionnaire. results The following problems have been encountered. (1) Sex assignment/gender identity: initially all patients had a male sex assignment. Six patients were diagnosed during the first month of life. Five were reassigned to female sex immediately, one at the age of 19 months. Except in one girl demonstrating some tomboyish behaviour, gender role behaviour in these patients did not differ from unaffected girls. Ten patients were diagnosed late at 3·4–7 years of age. In seven patients with a late diagnosis, male sex assignment was maintained; one of them expressed some concerns about living as a male. In three patients late sex reversal was performed, gender identity is very poor in one and new sex assignment is currently under consideration. (2) Surgery: irrespective of the sex assigned, all patients had between one and three surgical procedures, including clitoris reduction and (repeated) vaginoplasties in patients with female sex assignment. Hysterectomy and ovarectomy were performed in patients with male sex assignment. (3) Short stature: patients with a late diagnosis of CAH had extremely advanced bone ages of +6·3 to +9·5 years, leading to severely reduced final height of 137 to 150 cm in adult patients. Patients tended to follow height percentiles of genetic females. One pubertal patient was suicidal due to short stature. (4) Central precocious puberty (CPP): prolonged exposition to adrenal androgens led to CPP in one patient. He was treated with GnRH analogues until gonadectomy. conclusions Patients with CAH and complete virilization have a high risk of being diagnosed late. There are major problems and uncertainties of the patients’ families and the treating physicians concerning gender assignment. Gender identity is disturbed in some patients. In addition, multiple surgical procedures are necessary and short stature as well as central precocious puberty might be important to avoid late sequelae. While some surgical interventions are probably unavoidable, most of these issues could be resolved with an early diagnosis. Thus, especially for these patients, a neonatal screening programme for CAH would be of paramount importance.

Introduction: Newborn screening for congenital adrenal hyperplasia (CAH) was introduced as a pilot program nationwide in Switzerland (two laboratories) and regionally in Berlin (one laboratory) during 1990. The coverage of all live-births has been >;99%. Methods: A total number of 89 129 newborns were screened by measuring the concentration of 17α-hydroxyprogesterone (17α-OHP) in dried filter paper blood spots taken between the third and fifth day of life. The method used was a sensitive fluoroimmunoassay (DELFIA), which does not require extraction of the samples. Results: Seven cases of CAH were discovered during the pilot study period. Four were females and three were males. Initially, there was a high number of recall examinations, mainly in preterm babies, when a cut-off value of 20 nmol/l blood was used. Subsequently, gestational age adjusted cut-off limits were established for preterm babies using as a limit the 97th percentile of the 17α-OHP concentrations of each group of gestational ages. Using these cut-off limits, the recall rate dropped to 0.2%. Discussion: Introduction of the age adjusted cut-off levels not only increases the cost benefit of screening for CAH by reducing the costs for clinical examinations and overhead expenses for the recall procedure, but also reduces the amount of parental anxiety that is produced by a positive screening result and by requests for an additional specimen.

In a consecutive series of 15 male adolescents and young adults with congenital adrenal hyperplasia (CAH), the size, shape, firmness and echostructure of the testes were assessed. The latter was abnormal in 7 patients under long standing treatment with glucocorticoids (group I). In 8, 5 under and 3 off treatment for several years, ultrasonography (US) was normal (group II). On the basis of the US findings the patients were placed in two groups. In group I, the testes had a heterogeneous ultrasonographic pattern; clinically, most felt hard and irregular, although their volume was normal. Sperm count in 3 patients was 5.0 to 14.4 x 10(6)/ml. Five patients have 21-hydroxylase deficiency that was diagnosed in early infancy and had salt-wasting; two have 11-beta-hydroxylase deficiency that was diagnosed late and had no salt-wasting. In group II, testicular volume, shape, firmness and echostructure were normal. All have 21-hydroxylase deficiency, no history of salt-wasting and were diagnosed late. Sperm counts in 3 patients off treatment were 10.5 to 66.0 x 10(6)/ml. In severe cases with a history of salt loss, TALT with deficient spermiogenesis seems likely despite treatment. In mild cases, TALT is absent and spermiogenesis may be normal even without treatment. US is much more accurate in assessing the testes than palpation.

Thyroid hormone receptors (TR) mediate the action of thyroid hormones. Genetic studies revealed that the individual TR isoforms possess different functions. In the present paper we studied the expression of the isoforms TRalpha1 and TRbeta1 in the murine pancreatic islet. TRalpha1 and TRbeta1 mRNA transcripts and proteins were detected in islets using reverse transcription-polymerase chain reaction and Western blotting analyses, respectively. In immunohistochemical studies individual cells in the periphery of islets were labelled using an anti-TRalpha1 antibody. No labelled cells were detected in the exocrine pancreas. A similar staining pattern was obtained with an anti-glucagon antibody, but not with an anti-insulin antibody, which suggests that TRalpha1 is mainly expressed in alpha-cells. In order to address a potential function of TRalpha1 in this cell type, the regulation of glucagon gene expression by triiodothyronine was studied in a glucagon-producing cell line by Northern blot analysis and transient transfection assays using glucagon promoter luciferase fusion gene constructs. In these assays, triiodothyronine did not regulate the glucagon mRNA level or the glucagon promoter activity. The predominant localization of TRalpha1 in pancreatic alpha-cells suggests that this receptor isoform mediates a specific, yet unknown, function of thyroid hormones in this cell type.

In 129 children, aged 12.6 +/- 3.8 years, affected by type 1 diabetes mellitus, the levels of dehydroepiandrosterone sulfate (DHEAS), cortisol, T3, fT3, T4, fT4, rT3, TSH, cholesterol, and triglycerides were evaluated and compared with those of a control group of 458 healthy age-matched children. The results were also correlated with hemoglobin HbA1C. The DHEAS-standard deviation score (DHEAS-SDS; -0.36 +/- 0.77) was significantly different from zero in diabetic children, while the cortisol serum level was higher than in control subjects (485 +/- 94 vs 359 +/- 132 nmol/l). Moreover, the DHEAS-SDS and DHEAS-SDS/cortisol ratio correlated negatively with HbA1c. Diabetic patients also showed lower T3 values (2.22 +/- 0.4 vs 2.32 +/- 0.3 nmol/l) and a higher rT3/T3 ratio (0.17 +/- 0.09 vs 0.15 +/- 0.05) than controls. There was a negative correlation between T3 and HbA1C. Cholesterol (4.77 +/- 1.08 vs 4.51 +/- 0.76 mmol/l) and triglycerides (0.82 +/- 0.53 vs 0.63 +/- 0.37 g/L) levels were higher in diabetic children and positively correlated with HbA1c, but not with DHEAS-SDS. We can therefore conclude that diabetes, particularly if poorly controlled, tends to induce a dissociation of cortisol and DHEAS secretion and a low T3 syndrome, similar to that seen in other illnesses.

In girls with congenital adrenal hyperplasia (CAH), genital ambiguity usually leads to a rapid neonatal diagnosis. Rarely, CAH causes complete virilization and male sex assignment with a delayed diagnosis. After being confronted with very specific problems in two of such patients, we collected data of patients with CAH and complete virilization in a nationwide study to delineate specific problems of these rare patients in order to improve their management.Through the German Working Group of Paediatric Endocrinology (Arbeitsgemeinschaft Pädiatrische Endokrinologie, APE), questionnaires were sent to all members caring for patients with CAH and complete virilization in their endocrine clinics. Data from 16 patients from 10 paediatric endocrine centres were assessed by questionnaire.The following problems have been encountered. (1) Sex assignment/gender identity: initially all patients had a male sex assignment. Six patients were diagnosed during the first month of life. Five were reassigned to female sex immediately, one at the age of 19 months. Except in one girl demonstrating some tomboyish behaviour, gender role behaviour in these patients did not differ from unaffected girls. Ten patients were diagnosed late at 3.4--7 years of age. In seven patients with a late diagnosis, male sex assignment was maintained; one of them expressed some concerns about living as a male. In three patients late sex reversal was performed, gender identity is very poor in one and new sex assignment is currently under consideration. (2) SURGERY: irrespective of the sex assigned, all patients had between one and three surgical procedures, including clitoris reduction and (repeated) vaginoplasties in patients with female sex assignment. Hysterectomy and ovarectomy were performed in patients with male sex assignment. (3) Short stature: patients with a late diagnosis of CAH had extremely advanced bone ages of +6.3 to +9.5 years, leading to severely reduced final height of 137 to 150 cm in adult patients. Patients tended to follow height percentiles of genetic females. One pubertal patient was suicidal due to short stature. (4) Central precocious puberty (CPP): prolonged exposition to adrenal androgens led to CPP in one patient. He was treated with GnRH analogues until gonadectomy.Patients with CAH and complete virilization have a high risk of being diagnosed late. There are major problems and uncertainties of the patients' families and the treating physicians concerning gender assignment. Gender identity is disturbed in some patients. In addition, multiple surgical procedures are necessary and short stature as well as central precocious puberty might be important to avoid late sequelae. While some surgical interventions are probably unavoidable, most of these issues could be resolved with an early diagnosis. Thus, especially for these patients, a neonatal screening programme for CAH would be of paramount importance.

CYP17 is a microsomal enzyme embodying two distinct activities, 17alpha-hydroxylase and 17,20-lyase, essential for the synthesis of cortisol and sex hormone precursors, respectively. The two activities are differentially regulated in a tissue and developmental stage-dependent fashion. Leptin might play a role in such differential control. Low dose leptin caused a significant increase in 17,20-lyase activity in adrenal NCI-H295R cells expressing leptin (OB) receptor (OB-R), without significant sustained influence on the 17alpha-hydroxylase activity. To analyze the time dependence of this leptin effect, the impact of long and short-term leptin treatment was studied. To assess the relationship with the OB-R signal transduction pathway, the same experiments were performed in intact cells and in a reconstituted system. The long- and short-term studies in intact cells and in microsomes suggest that the 17alpha-hydroxylase activity of CYP17 can be promptly stimulated by leptin, but that the effect is transient. In contrast, physiological doses of leptin steadily enhance 17,20-lyase activity. This influence is direct, OB-R specific and dependent on the integrity of the signal transduction pathway. The 17,20-lyase activity stimulation relies on phosphate incorporation, as demonstrated by the loss of leptin-dependent 17,20-lyase stimulation after phosphate removal, and by the fact that the DHEA production appears to be related exclusively to the presence of phosphorylated CYP17, independently from novel protein synthesis. The mechanism underlying the observed events seems to involve CYP17 phosphorylation, a feature of the OBR signal transduction pathway, and a process already shown to be crucial for 17,20-lyase activity.

During childhood, the quiescent phase of testicular activity, the hCG stimulation test is widely used to evaluate testicular function. Inhibin B, a gonadal peptide regulating FSH secretion, is an established marker of Sertoli cell function and spermatogenesis in adults. In contrast to the other hormones of the hypothalamo-pituitary-gonadal axis, inhibin B is also secreted in detectable amounts during childhood. The aim of this study was to determine whether basal inhibin B levels are able to predict prepubertal testicular function, so as to avoid a stimulation test. Inhibin B and testosterone before and after hCG stimulation were measured in 54 male children with various testicular disorders by an immunoassay specific for inhibin B. Basal inhibin B was compared to the testosterone increase after hCG. Inhibin B and the hCG-induced testosterone increment correlated strongly (r = 0.84; P0.0001). Patients with anorchia were clearly distinguishable from those with abdominal testes, having undetectable (inhibin B,15 pg/mL) respective normal inhibin B levels for age. Inhibin B and the testosterone response to hCG were low in boys with testicular damage (delayed diagnosis of cryptorchidism; after testicular torsion) and in patients with gonadal dysgenesis, but were normal or increased in children with androgen insensitivity syndrome. We conclude that basal inhibin B predicts the testosterone response to hCG in boys and therefore gives reliable information about both the presence and function of the testes. The diagnostic procedure in cryptorchidism may be reduced to a single inhibin B measurement. Furthermore, inhibin B levels show specific alterations in patients with sexual ambiguity, adding a valuable diagnostic tool to the complex differential diagnosis of male pseudohermaphroditism.

Salivary testosterone (T) levels in male children and adolescents were measured and compared with plasma T. Salivary concentrations correlated well with plasma total T (r = 0.72) and even better with free plasma T (r = 0.89) in subjects with plasma T levels of pubertal or adult levels (greater than 1.0 nmol/l). In subjects with prepubertal or low plasma T (less than 1.0 nmol/l), there was neither a correlation with plasma total, nor with free T. In hCG tests (responder and nonresponder), salivary T reflected plasma levels faithfully. The results suggest that salivary T, which is suitable for repeated sampling, is a good marker of T secretion in pubertal males.

The acute response to various doses of human growth hormone (hGH) was determined in short patients with thalassaemia and compared to that in patients with classic growth hormone deficiency and Turner's syndrome. Nitrogen balance was analyzed using the stable isotope 15N. While patients with growth hormone deficiency responded with a marked nitrogen retention (+2.9 +/- 0.4 to +6.1 +/- 0.6 mg 15N/kg) to small doses of hGH (2 x 3 IU/m2), those with Turner's syndrome had a higher basal balance, but responded much less (+3.1 +/- 0.7 to +3.7 +/- 1.8 mg 15N/kg). They required a double dose of hGH (2 x 6 IU/m2) to achieve a significant retention (+4.1 +/- 1.0 to +7.1 +/- 0.4 mg 15N/kg). The thalassaemic patients responded still less than the patients with Turner's syndrome to 2 x 6 IU/m2 (+7.7 +/- 0.3 to +8.0 +/- 0.4 mg 15N/kg), and even hGH doses up to 2 x 12 IU/m2 had little effect, indicating a relative resistance to hGH. In conclusion, no or little effect is to be expected from long-term hGH treatment at low doses in thalassaemic patients. When it is decided to treat these patients, the dose should be about 4 times higher than a regular replacement dose in growth hormone deficiency.

This case report presents a thirteen year-old boy who was diagnosed as having Hypomelanosis of Ito. The developmental history includes severe failure to thrive, and moderate atypical autism as well as diverse clinical and neuropsychological symptoms are present. The pattern of neuropsychological functioning, which can be partially related to the neurophysiological findings, is discussed within the context of existing neuropsychological theories about autistic disorders.

The molecular basis of isolated 17,20-lyase deficiency was clarified in a newborn male patient from Israel with micropenis, undescended testes, and hormonal pattern consistent with isolated 17,20-lyase deficiency. Analysis of the CYP17 gene revealed the presence of a compound heterozygosity. One allele carries a single base pair deletion (T at position 198 in exon 1) leading to a frame shift with the introduction of a premature stop codon, TGA, at residue 74 in place of Val. The other allele bears a missense mutation due to a single base change, T to G, which substitutes Phe417 with Cys. The proof of heterozygosity was possible via amplification and direct sequencing of genomic DNA fragments from the parents and the healthy brother of the index case. We could demonstrate that the mother is the carrier of the nonsense mutation and the father of the missense mutation. The brother carries two normal alleles for the CYP17 gene. The nonsense mutation gives no functional product. The missense mutation causes the synthesis of a protein that retains 17 alpha-hydroxylase activity but virtually no 17,20-lyase activity. Experiments based on the use of an electron donor independent from enzyme binding (iodosobenzene) demonstrated that the addition of electrons restores, at least in part, in vitro 17,20-lyase activity, with no significant influence on the 17 alpha-hydroxylase activity. This suggests that the electron transfer system plays a major role in the differential regulation of the two P450c17 activities. This is the first case of mutated CYP17 in which the in vitro model corresponds to the in vivo situation.

We report a 15-year-old boy with hepatocellular carcinoma (HCC) of the fibrolamellar type. He presented with advanced disease and a non-resectable tumor. Clinical features included marked gynecomastia which had been present for 3 years, failure to enter puberty, and failure to thrive. These features might have been due to a high aromatase activity of the tumor. The course of the illness suggested that the tumor had been present for at least 3 years prior to diagnosis. At diagnosis the patient had multiple metastases which included infiltrated ascites. Cytogenetic analysis of the ascites revealed a near triploid karyotype with cell-to-cell variation and an abnormality of chromosome 1 q. This to our knowledge is the first karyotype report of fibrolamellar HCC in a child.

We report a 10-year-old boy with familial Wiskott-Aldrich syndrome (WAS) who underwent successful bone marrow transplantation (BMT) at the age of 9 months. With the exception of auto-immune haemolytic anaemia due to warm antibodies lasting 15 months there had not been any complication after BMT. Ten years later the patient presented with diarrhoea, hyperpigmentation of skin and oral mucosa, fatigue and polyuria. Diagnosis of Addison disease was confirmed by typical electrolyte imbalance and absent cortisol response to adrenocorticotrophic hormone. Adrenal antibodies were positive. On therapy with oral gluco- and mineralocorticoids, the symptoms disappeared and electrolytes normalized. To our knowledge auto-immuno endocrinopathy after BMT for WAS has not yet been reported.This is the first report of auto-immune adrenal insufficiency after BMT for WAS. The aetiopathogenesis of this condition remains unknown since auto-immune diseases as toxic side-effects of the ablative treatment before BMT have not yet been reported, and a relapse of WAS and cotransplantation of auto-immune adrenal insufficiency have been ruled out.

Molecular biology has clarified the understanding of steroidogenic enzyme genetics. Nevertheless, there are discrepancies between fundamental and clinical experience. (1) Why do patients with "pure" 17 alpha-hydroxylase or 17,20-desmolase deficiency exist, when one cytochrome regulates both steps? A case of interest is discussed, who had "pure" 17,20-desmolase deficiency until adolescence, but additional 17 alpha-hydroxylase deficiency thereafter. (2) In 11 beta-hydroxylase deficiency, it was puzzling to find 18-hydroxylated compounds, and, in isolated hypoaldosteronism, normal cortisol, since 11 beta- and 18-hydroxylation were thought to be regulated together. This has now been explained by differences in the fasciculata and glomerulosa. The occurrence of 11 beta-hydroxylase deficiency of 17-hydroxylated steroids only, however, remains enigmatic. (3) 3 beta-Hydroxysteroid dehydrogenase deficiency does not only seem to exist in classic (mutations of type II gene), but also in late-onset cases. In them, no molecular basis could be found. (4) Also, in cholesterol side-chain cleavage, there is an inequity: while evidently one cytochrome regulates 20- and 22-hydroxylation, pregnenolone is formed when 20 alpha OH-cholesterol, but not when cholesterol, is added to adrenal tissue of deficient patients. Other factors (promoters, fusion proteins, adrenodoxin, cAMP-dependent expression of genes, and/or proteases), or hormonal replacement in patients may be responsible for these discrepancies.

Statural growth in children with chronic renal failure (CRF) is often delayed. Several studies have shown that one of the main causes is partial resistance to growth hormone (GH), which can be overcome by supraphysiologic doses of recombinant human (rh) GH. Since August 1990 we have been treating 8 boys and 1 girl (ages 1.7-12.7, mean 5.3 yrs) with rhGH (4 IU/m2 s.c. daily). All patients were prepubertal and were 2.4-4.5 (mean 3.2) SDS below the mean normal height for age and sex. 5 patients were on dialysis. Mean growth velocity was -2.0 SDS (5.4 cm/yr) before and +2.6 SDS (9.5 cm/yr) during the first year of therapy with rhGH. Mean height increased from -3.2 to -2.5 SDS at 1 year. Height in the 4 boys treated2 yrs with rhGH improved from -3.3 SDS (before rhGH) to -2.4 (1st yr) and to -2.0 SDS (2nd yr); their height increased by 9.6 cm (1st yr) and 7.8 cm (2nd yr) as compared to 4.6 cm in the year before treatment. The response to rhGH was better in the 4 patients treated conservatively than in those on dialysis. Side effects did not occur. Plasma insulin increased but the oral glucose tolerance test remained normal. We conclude that treatment with rhGH represents an important step forward in selected pediatric patients with CRF. The excellent acceptance reflects the high expectations of the patients and their families.

In a girl aged 5 years with a virilizing adrenal adenoma the urinary and plasma steroid findings suggested the diagnosis of congenital adrenal hyperplasia due to P450c11 (11 beta-hydroxylase) deficiency. After removal of the tumour clinical signs receded and the hormonal values normalized. RNA analysis of the tumour tissue revealed low amounts of P450c11 mRNA which indicates that P450c11 deficiency of the adenoma caused the steroid abnormalities in this girl.

Testosterone and synthetic androgens were once used somewhat uncritically; on account of the undesired side effects that are now known to occur, however, they should be employed very selectively, in particular in the young patient. Although the main indication is primary hypogonadism, they are also employed in the treatment of gonadotropin deficiency and constitutionally delayed growth and development. While, for the treatment of congenital anorchism a therapeutic scheme could be developed which closely approximated the physiological conditions, no generally applicable treatment schemes could be established for other forms of primary hypogonadism. In the case of constitutional retardation of growth and development, treatment is not indicated, for somatic reasons, although severe psychosomatic disturbances may make treatment necessary in many cases.

Recent discoveries in molecular biology have much clarified the regulation and function of steroid-converting enzymes. Most progress has been made in the area of cytochromes, which regulate the side chain cleavage of cholesterol (P-450 SCC) and the 17 alpha-hydroxylase and 17,20-desmolase (or 17,20-lyase) activities (P-450 17 alpha), as well as in 3 beta-hydroxysteroid dehydrogenase. Nevertheless, there are some discrepancies between fundamental knowledge and clinical experience, which are difficult to understand: why is it for example possible that cases with 'pure' 17 alpha-hydroxylase or 17,20-desmolase deficiency exist, when there is only one cytochrome regulating both steps? After a brief review of clinical and biochemical findings in the various defects of testosterone biosynthesis, a case is discussed, which is of interest in this respect. This XY patient with female external genitalia, who has been shown to have compound heterozygous mutations, had 'pure' 17,20-desmolase deficiency up to adolescence, but additional 17 alpha-hydroxylase deficiency with hypertension developed thereafter. From this observation, it has to be concluded that as yet unknown, possibly age-dependent modulating factors exist, which influence the activity of the cytochrome. Also the estrogen replacement given to the patient might have played a role in this change.

Congenital adrenal hyperplasia (CAH) is the most common cause for female pseudohermaphroditism. In these patients uterus and Fallopian tubes are present and also in severe cases the clitoris cannot function as penis later in life. Therefore, a neonate with ambiguous genitalia due to CAH should be raised as female. To assess the degree of masculinization, a modification of Prader's classification was used. In 23 girls with ambiguous genitalia reduction clitoroplasty preserving the neurovascular bundle and creating a dorsal preputial skin flap and vaginoplasty with a perineal skin flap were performed. The phallic skin was used to create the labia minora and the anterior vaginal wall. The patients were reevaluated 1 to 14 years after the operation. The cosmetic and functional results have been excellent.

In a previous publication, three relatives of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency from two families were considered to be unusual heterozygotes rather than homozygotes with mild clinical manifestations. Their heterozygosity could now be confirmed by HLA tissue typing.

Analysis of urinary steroids excreted by a 7-year old girl with low renin hypertension following ACTH treatment revealed several unknown steroids, which have been analysed by gas chromatography-mass spectrometry. It is proposed that these steroids are monohydroxylated derivatives of cortisol, cortisone, either or both tetrahydro and allo-tetrahydrocortisol and either or both tetrahydro and allo-tetrahydro-11-deoxycortisol. Further analysis indicated that there are two likely positions for the additional hydroxyl group, either on the A or B ring.

For any finite bivariate Markov chain J(t), N(t) on state space for which row-continuity is present, i.e., N(t) changes by at most one at transitions, the ergodic distribution and mean passage times may be found by a simple algorithm. Related structure will be described. The procedure is based on probabilistic insights associated with semi-Markov processes and birth-death processes. The resulting algorithms enable efficient treatment of chains with as many as 5000 = 50 x 100 states or more. Such bivariate chains are of importance to countless applied models in congestion theory, inventory theory, computer design, etc. The algorithm developed is to be used as a basis for calculating the distribution of the maximum of certain stationary meteorological processes over a specified interval.

In a 34-year-old pregnant woman, serum HPL and urinary HCG were normal, but urinary estriol was repeatedly low. A normal boy was delivered after 38 week gestation. During the neonatal period, he had hypoglycemia, muscular hypotonia and transient hyperbilirubinemia. The ACTH-test was normal, but the THS-response to metyrapone was low. Serum ACTH did not respond to insulin and metyrapone. Growth hormone, TSH and gonadotropin responses to stimuli were normal. Treatment with hydrocortisone resulted in disappearance of the symptoms. It is concluded that fetal ACTH-deficiency is one of the specific endocrine causes of low maternal estriol.

A 16-year-old phenotypic female with XY genotype presented an unusual form of nonfamilial male pseudohermaphroditism. Seemingly a normal girl during childhood, the patient failed to undergo pubertal changes presenting with scant pubic hair, absent axillary hair, lack of breast development, retarded bone age and primary amenorrhea. Neither uterus nor adnexa were palpable above the blind-ending vagina. Serum testosterone and estradiol were barely detectable by radio-immunoassay, while LH and FSH reached castrate levels. Two small testes were removed from the pelvic sidewalls which, on biopsy, showed atrophy and hyalinization of seminiferous tubules, but clusters of Leydig cells without signs of hypertrophy or hyperplasia. Administration of testosterone resulted in urinary nitrogen retention and a decrease in serum LH and FSH. Radioimmunoassay of various serum or plasma steroids and gas chromatographic determination of urinary steroids prior to and following ACTH stimulation yielded results which permitted to rule out 20,22-desmolase, 3Β-hydroxysteroid dehydrogenase, 17-hydroxylase and 17Β-hydroxysteroid dehydrogenase deficiency. Low plasma dehydroepiandrosterone sulfate (DHEA-S) and an-drostenedione (Δ4A) concentrations, low urinary 17-ketosteroid and particularly low dehydroepiandrosterone (DHEA) excretion and the minimal rise of plasma DHEA-S and Δ4A and of urinary DHEA in response to ACTH in conjunction with a normal response of other serum and urinary C-21 steroids are consistent with 17,20-desmolase deficiency. Direct confirmation of this defect, however, seems impossible in the absence of in vitro studies of testicular steroidogenesis.

Follow-up data on a girl with 3 beta-hydroxysteroid dehydrogenase deficiency at a pubertal bone age are presented. On examination at age 14.7 years (bone age 12 years), there was no spontaneous breast development. On treatment with hydrocortisone and fludrocortisone, most steroids with the exception of increased 17OH-pregnenolone in plasma and delta 5-pregnenetriol and pregnanetriol in urine, were normal. After 1 week off hydrocortisone, plasma 17OH-pregnenolone, DHA and delta5-androstenediol and urinary delta 5-pregnenetriol and pregnanetriol increased markedly, while plasma 17OH-progesterone increased only slightly. On increased hydrocortisone medication, there was no response of plasma estradiol to HMG. This first observation of a pubertal girl with 3 beta-hydroxysteroid dehydrogenase deficiency indicates that in this patient, the defect persists at a pubertal bone age and that it is not limited to the adrenals, but also affects the ovaries. Girls with this type of defect thus require estrogen replacement at a bone age of about 12 years. The large quantities of pregnanetriol in the urine are not due to an incomplete defect or an additional 21-hydroxylase deficiency, but most likely to the peripheral or hepatic conversion of 17OH-pregnenolone or delta 5-pregnenetriol.

The matrix-geometric results of M. Neuts are extended to ergodic row-continuous bivariate Markov processes [J(t), N(t)] on state space B = {(j, n)} for which: (a) there is a boundary level N for N(t) associated with finite buffer capacity; (b) transition rates to adjacent rows and columns are independent of row level n in the interior of B. Such processes are of interest in the modelling of queue-length for voice-data transmission in communication systems. One finds that the ergodic distribution consists of two decaying components of matrix-geometric form, the second induced by the finite buffer capacity. The results are obtained via Green's function methods and compensation. Passage-time distributions for the two boundary problems are also made available algorithmically. MATRIX-GEOMETRIC; GREEN'S FUNCTION; COMPENSATION In a previous paper [10] a theoretical treatment of finite row-continuous bivariate Markov chains B(t)= [J(t), N(t)] was developed, providing an algorithmic basis for finding their ergodic distributions and associated passagetime moments. The continuous-time chain B(t) with state space = {(j, n):'0 j J, 0 n N} was described as row-continuous in the sense that the marginal process N(t), indexed by row coordinate n, changed at transition epochs by at most 1. In the present paper we restrict our discussion to those row-continuous chains for which the transition rate matrices, v°, vn, v, describing rates local to row n, are independent of n for each 1 _ n 5 N 1. For n = 0, one has vo = 0, and for n = N, v = 0. Such processes may be described as row-homogeneous, row-continuous processes modified by two retaining boundaries, as for earlier similar univariate contexts [4]. This research was conducted at the MIT Laboratory for Information and Decision Systems with partial support provided by the USAF OSR Grant Number AFOSR-79-0043, U.S. Air Force Geophysics Laboratory Grant Number F19628-80-C-0003, and the National Science Foundation Grant Number NSF/ECS 79-19880. © Applied Probability Trust 1988

Amino acids in the plasma and urine of 6 hypopituitary dwarfs before and after 3–5 days of human growth hormone (HGH) administration (2 mg/m2 daily) were studied. As reported previously, the concentrations of several amino acids in the plasma of untreated hypopituitary dwarfs are low. After administration of HGH certain amino acids in the plasma increased regularly (threonine, serine, glycine, methionine and others) and the overall amino acid pattern in the plasma became normal. Other amino acids did not show consistent changes. The changes in the plasma concentrations do not seem to be related to renal mechanisms, since urinary amino acids and amino acid clearances varied only little. The HGH induced increase of plasma amino acids affects different amino acids than those involved in the increase of plasma amino acids induced by puberty in the male. This suggests that HGH and testosterone have different effects on the amino acid metabolism.

Besides the well-known side effects, long term corticosteroid treatment in pharmacological doses causes inhibition of statural growth in children. This is of special importance in asthmatic children, since their growth may be impaired by the disease itself. The degree of inhibition of growth depends on the type of corticosteroids used (the inhibition by synthetic derivatives is stronger than that by hydrocortisone), on the dosage, and on the duration of treatment. The mechanisms leading to an inhibition of growth are not fully understood: possibly the corticosteroids inhibit the release of growth hormone from the pituitary, or they antagonize the metabolic action of growth hormone peripherally. In an effort to avoid the growth-inhibiting effect of corticosteroids, different approaches have been tried: Replacement of corticosteroids by ACTH seems to have normalized the growth rate in some cases, but failed to do so in others. A final evaluation of the value of ACTH with respect to growth can therefore not yet be made. At the present time, therapy with corticosteroids at an alternate day schedule seems to be promising: the daily dosage is doubled, but the corticosteroids are given only every other day. Treated in this way, the patients observed so far, have been able to maintain a normal growth rate.

Eight cases of males with persistent Müllerian structures are reported in four pairs of unrelated siblings. A genetically inherited failure to produce or to respond to the Müllerian-inhibiting substance elaborated by the fetal testis is postulated.

The methods of estimation of bone maturation (GreulichPyle. Tanner et al.) and the possibilities for the calculation of future adult height (BayleyPinneau, Roche et al., Tanner et al.) are briefly described and their advantages and disadvantages in normal children and in children with growth disorders are discussed. In normal children, all methods provide valuable results, but there are small differences of precision depending on whether the pubertal development is early, average, or late. In pathological conditions, however, as e.g. in precocious puberty or in girls with Turner syndrome, the methods of Roche et al. and of Tanner et al. may overestimate adult height considerably, while that BayleyPinneau remains reasonably accurate. A computerized system, which facilitates the complicated and time-consuming calculations is briefly presented.

By reporting a further case attention is drawn to the autosomal recessive inherited DIDMOAD-syndrome. While diabetes mellitus and optic atrophy are easy to recognize, one often has specifically to look for deafness, diabetes insipidus and the frequently associated dilatation of the urinary tract. Awareness of this condition is important for genetic counselling and vocational guidance, and allows to avoid invasive neuroradiological investigations.

Three otherwise healthy relatives of patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency and salt-wasting presented with clinical and/or biochemical findings, which exceeded those usually seen in heterozygotes: Two females (1 mother and 1 prepubertal sister of a patient with CAH) had marked hypertrichosis and hirsutism and excreted pregnanetriolone in their urine. The mother had increased basal plasma 17α-OH-progesterone (296 ng/100 ml), which increased to 7170 ng/100 ml after ACTH as in homozygotes of CAH. One adult male (brother of a patient with CAH) was clinically normal, but also excreted pregnanetriolone and had a high plasma 17α-OH-progesterone (1905 ng/100 ml), which increased further to 6352 ng/100 ml after ACTH. It is concluded that these subjects represent unusually marked heterozygotes of CAH rather than mild homozygotes. In females, this condition should be included in the differential diagnosis of idiopathic hirsutism, in males, it will pass unnoticed, unless relatives of patients with CAH are systematically tested.