Early retesting by GHRH + arginine test shows normal GH response in most children with idiopathic GH deficiency.

PURPOSE: Most children with idiopathic isolated GH deficiency (IGHD) normalize GH response to stimulation tests when retested at the completion of growth. The objective of this study was to test the effectiveness of early retesting in challenging the diagnosis of idiopathic IGHD and critically review the diagnostic workup leading to this diagnosis in children with short stature. METHODS: We cross-sectionally retested 38 children with idiopathic IGHD and still on GH treatment. The initial diagnosis of idiopathic IGHD was based on subnormal GH responses to two stimulation tests and normal brain imaging or minor/nonspecific findings at magnetic resonance. The GH response normalization at retesting was considered as the main outcome measure. Clinical features of children who were falsely classified as idiopathic IGHD based on first GH testing were retrospectively analyzed. RESULTS: GH secretion was normal in 36/38 children (95%). Two children showed slightly reduced peak GH responses and normal IGF-I levels. Fourteen children underwent GH retesting before puberty, 24 children during puberty. CONCLUSION: The diagnostic process should be improved to minimize the rate of false positive at GH testing and, in case of unsatisfactory response to GH treatment, the diagnosis of isolated idiopathic GHD should be challenged with early retesting.

Unequal access, low vaccination coverage, growth retardation rates among immigrants children in Italy exacerbated in Roma immigrants.

AIM: Currently children of immigrants are the fastest growing segment of the Italian population under the age of 18. The present study reports the challenges to health services access, the vaccination coverage, the health and nutritional status of a sample of 1310 children of immigrants attended from February 2004 to May 2012 the health center "Medicina Solidale" of the "Policlinico Tor Vergata" in the suburban area of the VIII Municipality of Rome. METHODS: The data were collected using clinical archives of the health center. We analyzed the socio-demographic conditions, health problems and nutritional status on admission to the health center. The anthropometric evaluation was carried out according to international standards of child growth WHO 2006 and the statistical analysis was performed using SPSS version 19, and including risk estimation, Mantel Haentzel statistics and t-test. RESULTS: Sixty-six percent of the children were born in Italy, 62% had never had regular health care and 3.4% of children older than six months had never received any of the immunizations. It has been estimated that being Roma the risk of not been vaccinated is equal to OR=5.4 (IC95%: 2.8-10.1). Seventy-seven percent of unvaccinated children had at least one illiterate parent. This condition was strongly associated with non-immunization (OR=15:36 [IC95%: 6.4-36.4]). Growth retardation was common in Roma children as compared to other ethnicities. CONCLUSION: Significant public health efforts are needed to improve access to health services for immigrant populations and to solve relevant inequalities.

Molecular characterization of 6 unrelated Italian patients with 5alpha-reductase type 2 deficiency.

Steroid 5alpha-reductase (5alphaR) deficiency (OMIM number #264600) is a rare 46,XY disorder of sex differentiation caused by mutations in the 5alphaR type 2 gene (SRD5A2) resulting in dihydrotestosterone deficiency during fetal development. We report on the analysis of the SRD5A2 gene in 6 unrelated 46,XY Italian patients with external genitalia morphology ranging from predominantly female to nearly completely male. Three subjects were seen and assessed at birth, 1 patient was referred to us before puberty, and 2 at postpubertal age. Six different causative mutations (5 missense and 1 nonsense) and a rare polymorphism were identified. Four patients presented homozygous single-base substitutions. These SRD5A2 mutations were located in exon 2 (variant Cys133Gly), exon 4 (Gly196Ser and Ala207Asp) and exon 5 (Tyr235Phe). A fifth subject was a compound heterozygote who carried a nonsense mutation in exon 1 (Trp53X) and a second SRD5A2 alteration in exon 5 (Tyr235Phe). The final patient presented a mutation in only 1 allele (Gly34Trp) together with the Ala49Thr variant. The molecular characterization of these patients made it possible to identify novel mutations and to confirm, before gender assignment or any surgical approach, the suspected 5alphaR deficiency in 2 newborns, 1 of whom had inconclusive hormonal data. 5alphaR deficiency in subjects without parental consanguinity and the presence of compound heterozygotic patients suggest that SRD5A2 mutations carrier frequency may be higher than previously thought.

Isolated precocious pubarche: an approach.

Precocious pubarche (PP) is most often a benign condition secondary to the early appearance of adrenarche. However, PP may be a manifestation of nonclassical adrenal hyperplasia. The incidence of nonclassical adrenal hyperplasia in patients with PP ranges from about 0-40% of cases. Controversy exists as to whether all children with PP should undergo an ACTH stimulation test. The aim of this study was 1) to determine the frequency of mild adrenal enzyme defects in a very large and ethnically homogeneous group of children with isolated PP (typical pubarche); 2) to determine whether clinical data, in particular bone age, and basal hormonal values can help to distinguish patients who are at risk for having adrenal enzymatic defects and thus should have an ACTH test; and 3) to determine which patients diagnosed as having a mild adrenal enzyme defect might require treatment. We studied 171 subjects (135 girls and 36 boys), aged 7 +/- 1.2 (SD) yr, with isolated PP. Thirty-eight normal subjects (18 age-matched and 20 pubertal) were studied as controls. An ACTH stimulation test (Synacthen, 0.25-mg iv bolus) was performed. Blood samples were drawn at baseline and 1 h postinjection. 17 alpha-Hydroxyprogesterone (17OHP), 17 alpha-hydroxypregnenolone (17PGN), dehydroepiandrosterone, androstenedione, testosterone, 11-deoxycortisol, and cortisol were evaluated. Haplotype (HLA) typing was performed in the patients who were diagnosed with nonclassical 21-hydroxylase deficiency (NC21OHD). Using published nomogram standards for the serum 17OHP response to ACTH, 10 patients (5.8%) were diagnosed as having NC21OHD. Seven of 112 patients (6.2%) were diagnosed as having nonclassical 3 beta-hydroxysteroid dehydrogenase deficiency (NC3HSD) on the basis of the following three criteria: stimulated 17PGN levels and stimulated 17PGN/17OHP and 17PGN/cortisol ratios higher than 2 SD above the mean for pubertal controls. None of the patients had stimulated 11-deoxycortisol values greater than 2 SD above the mean of pubertal controls. Nineteen patients (11%) had a stimulated 17OHP response characteristic of the heterozygotes for 21-hydroxylase deficiency. One hundred and thirty-five of 171 patients with no biochemical evidence of an adrenal biosynthetic defect were diagnosed as having precocious adrenarche. Bone age was advanced (> 2 SD for chronological age) in 80% of the patients with NC21OHD, in 71.4% of the patients with NC3HSD, in 58% of the patients classified as heterozygotes, and in 32.6% of the patients with precocious adrenarche. Basal hormone levels were helpful in detecting NC21OHD, but not NC3HSD. All patients with NC21OHD and only 1 with NC3HSD underwent glucocorticoid suppression treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Growth and insulin-like growth factors (IGFs) in children with insulin-dependent diabetes mellitus at the onset of disease: evidence for normal growth, age dependency of the IGF system alterations, and presence of a small (approximately 18-kilodalton) IGF-binding protein-3 fragment in serum.

Data on growth of children with insulin-dependent diabetes mellitus (IDDM) before the onset of disease are conflicting, and although the insulin-like growth factor (IGF) system has almost invariably been found altered at diagnosis, most of previous studies are affected by the small number of patients investigated. We studied 60 IDDM children at the onset of disease, comparing their stature with target height, normal growth standards, and height of 102 sex- and age-matched controls. Furthermore, we assessed serum IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) levels and IGFBP-3 circulating forms. IDDM children were subdivided into 2 groups according to an age above (n = 26) or below (n = 34) 6 yr. The values of endocrine variables of diabetics older than 6 yr were compared with those of 34 age-matched controls. Although the height of diabetics was higher than growth reference values (mean height +/- SD, 0.64+/-1.4 z-score) and their target height (mean target height +/- SD, 0.1+/-0.84 z-score; P < 0.005), no significant difference in height was found between IDDM children and controls (mean height +/- SD, 0.64+/-0.95 z-score) even analyzing the 2 age groups separately. Overall, IDDM children showed reduced levels of IGF-I (mean +/- SD, -0.65+/-1.9 z-score) and normal levels of IGF-II (mean +/- SD, -0.05+/-1.2 z-score) and IGFBP-3 (mean +/- SD, -0.06+/-1.2 z-score). However, whereas patients younger than 6 yr showed normal values of IGF-I, IGF-II, and IGFBP-3, these peptides were significantly reduced in older subjects compared with either younger IDDM children or controls (P < 0.01). IGFBP-3 immunoblot analysis revealed the presence of an approximately 18-kDa fragment of IGFBP-3 in addition to the major approximately 29-kDa fragment and the intact form (approximately 42-39 kDa) in 46 of 60 IDDM patients, whereas the approximately 18-kDa band was absent in all 34 control sera. No relationship was found between the endocrine variables and stature at diagnosis. In conclusion, our results indicate that IDDM children at the onset of disease are not taller than healthy peers and have increased IGFBP-3 proteolytic activity. Finally, although the IGF system is normal in younger IDDM children, older patients have reduced IGF levels.

Response to a single dose of human chorionic gonadotropin in prepubertal boys.

In normal men a single dose of hCG induces an increase in plasma testosterone (T) and 17 alpha-hydroxyprogesterone (17 alpha-OHP) 2-4 h after the injection; after 24-36 h a maximum increase in plasma 17 beta-estradiol (E2) and 17 alpha-OHP occurs followed by a second surge in T after 48-96 h. The present investigation focuses on the effect of a single dose of hCG (3500 IU/m2 body surface) on testicular steroid production in 12 boys aged 13 months to 12 yr. Plasma hCG, 17 alpha-OHP, androstenedione (A), T, dihydrotestosterone, and E2 were measured basally and 2, 4, 24, 48, 72, and 96 h after hCG administration. Plasma hCG was measured using a double antibody RIA technique and steroids by RIA after celite chromatography. The results show that hCG peaked 2 h after administration of the hormone and high levels persisted for up until 72 h. Plasma T and dihydrotestosterone increased after 48 h and remained significantly high for another 48 h; 17 alpha-OHP, A, and E2 did not change. These findings show that hCG stimulation in prepubertal boys induces significant production of T without affecting the precursors or aromatization product, in contrast to observation in the adult man, where 17 alpha-OHP, A, and E2 increase significantly. A response comparable to that observed in children has been recorded in adult males with hypogonadotropic hypogonadism.

Urinary pyridinium collagen cross-links predict growth performance in children with idiopathic short stature and with growth hormone (GH) deficiency treated with GH. Skeletal metabolism during GH treatment.

GH is able to promote longitudinal growth in children with GH-deficiency (GHD) and in some children with idiopathic short stature (ISS). The objectives of this study were to evaluate the predictive value of bone and collagen markers on the growth response to GH therapy in children with ISS and with GHD, and to characterize the effects of GH treatment on bone and collagen turnover in children with ISS and with GHD. Twenty prepubertal short, slowly growing, children treated with GH, 15 IU/m2 per week, were studied; of them 13 (10 males) had ISS and 7 (5 males) had GHD. An overnight 12-h urinary collection and a fasting morning blood sample were obtained at baseline, 1, 3, 6, and 12 months of treatment. Urinary levels of collagen cross-links, pyridinoline (Pyd) and deoxypyridinoline (Dpd), and circulating levels of osteocalcin, intact PTH, calcitonin, procollagen type III aminoterminal propeptide (PIIINP), insulin-like growth factor-I, and alkaline phosphatase were determined. Urinary collection was also obtained from 127 healthy children (51 males) aged 6-13 yr. In children with ISS, the changes in Dpd over 1 month of GH therapy were related to the changes in height velocity (HV) over 1 yr of therapy (r = 0.67; P < 0.05); the changes in Pyd after 1 month of GH treatment were related to the changes in HV at 6 months of GH treatment (r = 0.57; P < 0.05). All the other markers evaluated were not related to the HV changes in children with ISS. In children with GHD, the changes in Pyd and in Dpd after 1 month of GH treatment were positively related to the changes in HV after 12 months of therapy (r = 0.82; P < 0.05, and r = 0.82; P < 0.05, respectively). The changes in Pyd after 1 month were also related to the HV changes after 6 months of GH (r = 0.77; P < 0.05). Positive relationships between the HV after 6 months of GH and the increases of PIIINP (r = 0.80; P < 0.05) and osteocalcin (r = 0.77; P < 0.05) after 3 months of GH therapy were observed. All patients showed urinary Dpd and Pyd excretions in the normal range. In patients with ISS, Pyd (P < 0.05), Dpd (P < 0.05), osteocalcin (P < 0.01), PIIINP (P < 0.01), and alkaline phosphatase (P < 0.01) increased longitudinally during the GH treatment and the increments reached a maximum after 3-6 months of therapy. Patients with GHD showed an increase of the same markers but the increases occurred earlier, after 1 month of GH therapy. The collagen cross-links, Pyd and Dpd, could be helpful early markers in predicting the responsiveness to GH therapy in children with ISS and with GHD. GH treatment stimulates bone and collagen metabolism.

Adult height in short normal adolescent girls treated with gonadotropin-releasing hormone analog and growth hormone.

GnRH analog associated with GH therapy has potential importance for treatment of short stature in subjects without GH deficiency and with a normal onset of puberty. We treated 10 girls with familial short stature with the GnRH analog leuprolide (3.75 mg, im, every 25 days) and GH (0.1 IU/kg.day, sc, 6 days/week). The combined therapies were started simultaneously, and the patients were treated for 28.1 +/- 5.4 (range, 24-36) months. At the onset of treatment, chronological age was 11.6 +/- 1.4 yr, bone age was 10.6 +/- 0.9 yr, height was -2.7 +/- 0.7 SD, predicted height (PH; Bayley-Pinneau score) was 143.2 +/- 3 cm. Target height was 147.6 +/- 5.6 cm. Tanner stage was II-III for breast and genitalia. During treatment, puberty was completely suppressed in all patients. Statistical analysis was performed using Student's t test for paired data. After 12 months of treatment, we observed a significant (P < 0.02) improvement of predicted height (146.2 +/- 3.4 cm). This improvement remained significant (147.6 +/- 3.5; P < 0.001) when treatment was withdrawn. At that time, chronological age was 13.9 +/- 1.2 yr, and bone age was 12.4 +/- 0.7 yr. At the present time (3 +/- 0.97 yr after discontinuation), all of the girls have reached a final height of 144.6 +/- 3 cm (range, 140-149.3 cm). The final height is not significantly different compared with the PH at the beginning of treatment or with target height. These data show that in our patients, combined treatment with GnRH analog and GH, despite a significant improvement in PH during therapy and upon its withdrawal, does not result in a significant increase in adult stature. Larger and perhaps more prolonged studies in patients of both sexes are required to reach definitive conclusions. Nevertheless, the cost of this treatment in terms of both subject compliance and economic cost should be weighed against the small height gain, if any, that may be achieved.

Characterization of a low molecular mass form of insulin-like growth factor binding protein-3 (17.7 kilodaltons) in urine and serum from healthy children and growth hormone (GH)-deficient patients: relationship with GH therapy.

The insulin-like growth factor binding proteins (IGFBPs) are the carriers for insulin-like growth factor (IGF0-I and IGF-II. IGFBP-3 is GH-dependent and circulates associated with IGFs and an acid-labile subunit to form a 150-kilodalton (kDa) complex. In human serum, two immunoreactive molecular weight forms of IGFBP-3 have been identified. In human urine, radioimmunoassayable levels of IGFBP-3 have been detected. The objectives of this study were to characterize the molecular weight forms of IGFBP-3 in urine and serum of healthy children and adults and in children with GH deficiency (GHD), to quantify the urinary molecular weight forms of IGFBP-3, and to evaluate the relationship of these forms with GH therapy. Urine and serum were obtained from 12 prepubertal children with GHD, before and after 6 months of GH therapy, from 30 prepubertal healthy children, and from 8 healthy adults. Western immunoblotting (WIB) with IGFBP-3 antiserum (alpha IG-FBP-3g1) showed that in urine the most representative IGFBP-3 was a 17.7-kDa form. The 17.7-kDa IGFBP-3 was high in urine of healthy children compared with healthy adults and was low in children with GHD but increased after GH therapy. Urinary IGFBP-3 immunoreactive profile was determined by neutral-size exclusion chromatography, followed by IGFBP-3 RIA analysis of the fractions. Urine showed a major peak of IGFBP-3 immunoreactivity around 17 kDa. The 17-kDa urinary IGFBP-3 chromatographic peak averaged 8461 +/- 367 ng/12 h.m2 of body surface in healthy children, 3415 +/- 739 in adults (P < 0.001), 2294 +/- 354 in children with GHD before GH therapy (P < 0.001), and 7940 +/- 1874 in children with GHD after GH therapy. Urinary IGFBP-3 was also measured by RIA in unfractionated urine; healthy children showed levels significantly higher (14575 +/- 460 ng/12 h.m2) than adults (7823 +/- 1083, P < 0.001) and higher than children with GHD before GH therapy (4710 +/- 703, P < 0.001). Again, however, immunoreactive IGFBP-3 increased after GH treatment (12294 +/- 3394). In the serum of the healthy children we characterized by specific IGFBP-3 WIB analysis, a 17.7-kDa immunoreactive form of IGFBP-3 that was absent in the serum of healthy adults and low in patients with GHD, increased during GH therapy. Serum samples were subjected to neutral-size exclusion chromatography and the fractions were analyzed by WIB.(ABSTRACT TRUNCATED AT 400 WORDS)

Hypoparathyroidism as the major manifestation in two patients with 22q11 deletions.

We report on two adolescents with 22q11 deletion. Their main clinical manifestation was chronic symptomatic hypocalcemia secondary to hypoparathyroidism, together with seizures and cerebral calcifications. Neither congenital cardiac abnormality nor T cell deficiency were detected. The phenotypic manifestations of the observed patients were consistent with velo-cardio-facial syndrome (VCFS). A microdeletion of chromosome region 22q11 has been demonstrated in approximately 90% of DiGeorge syndrome (DGS) patients and in 75% of VCFS patients; the association of the deletion with a wide spectrum of clinical findings suggests the existence of a contiguous gene syndrome. The presence of certain traits of DGS/VCFS should lead to investigations of the parathyroid function and molecular analysis of the 22q11 region hybridization studies.

Clinical and roentgenographic findings in a patient with primordial microcephalic dwarfism type Caroline Crachami.

We describe a patient with primordial microcephalic dwarfism with severe intrauterine growth retardation and severe and progressive postnatal deficit in length, weight and head circumference. The patient was extroverted and sociable but mildly mentally retarded. He had marked delay of bone maturation and an enlargement of the sella turcica. This child and two previously reported patients [Boscherini et al., Eur J Pediatr 137:237-242, 1981] have many characteristics in common with Caroline Crachami, the famous "Sicilian dwarf". We think that these patients belong to a separate category of microcephalic primordial dwarfism.

Long-term treatment with growth hormone improves final height in a patient with Pallister-Hall syndrome.

Pallister-Hall syndrome is a disorder of development consisting of hypothalamic hamartoma, pituitary dysfunction, central polydactyly and visceral malformations. This disorder is inherited as an autosomal dominant trait and is caused by mutations of the GLI3 gene encoding a zinc finger transcription factor. We describe a case of Pallister-Hall syndrome with growth hormone neurosecretory dysfunction, successfully treated with growth hormone until attainment of final height. We conclude that children with Pallister-Hall syndrome and short stature be evaluated carefully for spontaneous somatotropic function and, if necessary, treated with growth hormone.

Bone turnover and bone mineral density in young adult patients with panhypopituitarism before and after long-term growth hormone therapy.

We examined the effects of biosynthetic growth hormone (GH) on biochemical indices of bone turnover and on bone mineral density in a group of GH-deficient adults. Thirteen patients (eight males and five females) aged 24 +/- 5 years (range 16-35) were studied before and 12 and 24 months after GH treatment (0.1 IU.kg-1 day-1, 6 days a week). Serum levels of insulin-like growth factor I (IGF-I), calcitonin, parathyroid hormone, alkaline phosphatase, intact osteocalcin, fasting urinary hydroxyproline/creatinine ratio and bone mineral density (BMD), measured at the lumbar spine by dual-photon absorptiometry, were evaluated. After 12 months of treatment, IGF-I, alkaline phosphatase, osteocalcin and the fasting urinary hydroxyproline/creatinine ratio increased significantly. However, after 24 months of therapy, serum levels of osteocalcin decreased to pretreatment values while IGF-I, fasting urinary hydroxyproline/creatinine ratio and alkaline phosphatase remained elevated significantly. No changes were found in parathyroid hormone and calcitonin plasma levels or in BMD either after 12 or 24 months of treatment. These data demonstrate that GH, at the dosage that we used, activates bone turnover during 24 months of therapy in adults with panhypopituitarism, even if a downward trend for osteocalcin became apparent at 24 months. However, this activation in bone turnover was not accompanied by an increase in BMD. We can hypothesize that GH, at the relatively high dosage used, may stimulate osteoclastic activity to a greater extent than osteoblastic activity. It is probable that the dose of GH replacement therapy in adults plays a key role.

Expression and down-regulation by retinoic acid of IGF binding protein-2 and -4 in medium from human neuroblastoma cells.

Insulin-like growth factors (IGFs) regulate the autocrine/paracrine growth of neuroblastomas. The IGFs bind to specific binding proteins (IGFBPs) which modulate their biological activity. We investigated, by Western ligand blotting (WLB), the presence of IGFBPs and their possible modulation by retinoic acid (RA), IGF-I, IGF-II and truncated Des(1-3)IGF-I in conditioned medium (CM) of the human neuroblastoma SK-N-BE(2) cell line. We demonstrated the presence of two IGFBPs, with MW 37 kDa and 25 kDa. Following immunoprecipitation, they turned out to be IGFBP-2 and -4, respectively. The RA-induced differentiation in SK-N-BE(2) cells was accompanied by a marked reduction of the intensity of both IGFBP bands after 48 h (32% and 24% of control, respectively) and 72 h (2% and 0% of control, respectively) incubation. The addition of exogenous IGFs, which did not induce cell differentiation, did not change the IGFBP pattern significantly, except for the truncated form of IGF-I, which induced a marked decrease in both the 37 kDa and 25 kDa bands after 72 h incubation (45% and 18% of control, respectively). These findings suggest that IGFBPs have a role in RA-induced differentiation in human neuroblastoma cells.

Is obesity-related insulin status the cause of blunted growth hormone secretion in Turner's syndrome?

Growth hormone (GH) secretion is reduced in girls with Turner's syndrome (TS) at pubertal age. We have recently proposed that the impairment of GH release in TS girls might be secondary to obesity. In the present study, we assessed the influence of overweight-related insulin status on spontaneous GH secretion in a group of 15 TS girls. Eighteen age-matched short normal subjects and six short obese prepubertal children were chosen as controls. Anthropometry, spontaneous GH secretion, insulin-like growth factor-I (IGF-I) serum levels, basal fasting insulin, and glucose concentrations were determined. The percentage of ideal body weight (IBW) was used as an index of nutritional status. Baseline fasting glucose (milligrams per deciliter) to insulin (milliunits per liter) ratio (G/I) was chosen as an index of insulin resistance. GH secretion was significantly lower in TS girls than in non-obese children (P < .005), whereas no significant difference was seen between TS and obese subjects. IGF-I levels were not statistically different in all groups. GH secretion was confirmed to be related to the degree of overweight (r = -.52, P < .05 in TS girls and r = -.74, P < .0001 in control group). G/I was closely related to both the percentage of IBW (r = -.59, P = .02) and GH level (r = .57, P = .03) in TS patients. These results confirm that the blunted GH secretion in TS patients is dependent on nutritional status, and suggest that insulin resistance secondary to overweight might represent the pathophysiologic link between the obesity-related metabolic status and impaired GH secretion.

A clinician looks at androgen resistance.

Androgen resistance in genetic males occurs when gonadotropins and testosterone are normal, but the physiological androgen response in androgen target organs is absent or decreased. In androgen-dependent target tissues two main defects may be found: 1) defective testosterone metabolism (5 alpha-reductase type 2 deficiency) and 2) anomalies in androgen receptors (androgen insensitivity syndrome (AIS)). The clinical manifestations of these defects vary from subjects with female external genitalia to subjects with mild forms of impaired masculinization. In particular, in the complete form of AIS (CAIS) the phenotype is feminine, and in the partial form (PAIS) the external genitalia are ambiguous with an extremely variable phenotype. The diagnosis requires clinical, hormonal, genetic, and molecular investigation for appropriate gender assignation and treatment. In AIS, cloning of androgen receptor cDNA using the polymerase chain reaction, denaturing gradient gel electrophoresis, and nucleotide sequencing have enabled a variety of molecular defects in the androgen receptor to be identified. The complexity of phenotypic presentation of AIS probably reflects the heterogeneity of androgen receptor gene mutations, but to date a relationship between genotype/phenotype has been difficult to establish, with the same point mutation reported to be associated with different phenotypic expressions. Other factors must therefore also contribute to the clinical presentation of AIS, although none have yet been identified. Establishing the functional consequences of androgen receptor mutations in vitro systems and correlating them with clinical presentation may ultimately provide an explanation for the variable clinical presentation of AIS and perhaps enable prediction of the response to androgen therapy in infants with PAIS.

Urinary excretion of pyridinium crosslinks in short children treated with growth hormone.

The aim of this study was to evaluate the effect of growth hormone (GH) treatment on bone resorption in children with GH deficiency and those with idiopathic short stature. The study population included seven children with subnormal spontaneous GH secretion and 13 children with idiopathic short stature, all of them pre-pubertal. Anthropometric measurements, free, protein-bound and total urinary pyridinoline (Pyd) and deoxypyridinoline (Dpd), serum GH, and serum immunoreactive PTH were measured at baseline and months 1, 3, 6 and 12 of GH treatment. The urinary excretion of total Pyd and Dpd, standardized by the cube of height (m3) in overnight, 24-hour urine collections was not different from age-matched healthy controls at baseline in either group of patients. During treatment with human recombinant GH, both pyridinium crosslinks increased above normal values, reaching a peak after one month in children with GH deficiency and later (after 3-6 months) in children with short stature. Free and total crosslink forms were correlated, and GH treatment did not affect the proportion of free to bound crosslinks. Serum concentrations of iPTH showed a moderate but not statistically significant increase. This study provides no evidence of reduced bone resorption in untreated GH deficiency or in idiopathic short stature. GH treatment induced a marked, but temporary, increase of bone resorption in both groups of patients.

Feminizing Sertoli cell tumor associated with Peutz-Jeghers syndrome (histologic and ultrastructural study).

A case of Peutz-Jeghers syndrome associated with Sertoli cell tumor of the testis and bilateral gynecomasty in an 8-year-old boy is described. The authors emphasize the unusual histologic and ultrastructural features of the tumor and discuss the physiopathologic aspects of the present case.

Twelve-hour spontaneous nocturnal growth hormone secretion in growth retarded patients.

Twelve-hour nocturnal GH secretion was studied in 30 children with familial short stature (FSS), constitutional growth delay (CGD), total growth hormone deficiency (TGHD), partial growth hormone deficiency (PGHD), or idiopathic short stature (ISS). No difference was observed between subjects with FSS and children with CGD. The mean 12-hour serum GH concentration was significantly lower in patients with TGHD (p less than 0.001), children with PGHD (p less than 0.01), and subjects with ISS (p less than 0.01) than in subjects with FSS and CGD. No overlap was observed between the range of mean concentration values of children with TGHD and that of subjects with FSS. A significant correlation was found between growth velocity expressed as SD from the mean for bone age and GH concentration (p less than 0.001). All patients with a growth velocity less than 3rd percentile for bone age showed a mean nocturnal concentration less than 4 ng/ml. These data suggest that evaluation of 12-hour spontaneous nocturnal GH secretion with GH sampling every 30 minutes can be usefully employed in the diagnosis of GH deficiency.

Preliminary validation of a prediction model for the short-term growth response to growth hormone therapy in children with idiopathic short stature.

A discriminant scoring system, using multivariate analysis, has been developed for pretreatment prediction of responsiveness to a 6-month trial of growth hormone (GH) treatment in short children with subnormal growth velocity, but without GH deficiency. Inclusion criteria included a birth weight above 2.5 kg, height below the 3rd centile for chronological age, height velocity below the 25th centile for bone age, no signs of puberty, a maximal GH response to pharmacological stimulation of above 10 micrograms/l and treatment with GH at a dose of 12-16 IU/m2/week. Children with an increase in height velocity greater than 2.5 cm/year after therapy were considered to be responders. Pretreatment clinical data from 67 patients were employed in a discriminant analysis in order to establish the model. The scoring system developed was as follows: score = -0.4 + 0.92X1 - 0.87X2, where X1 is the height velocity SD score (SDS) for chronological age, and X2 is the bone age SDS for chronological age. This model had a specificity of 96.3% and a sensitivity of 92.5% in predicting the responsiveness to GH. The model has subsequently been applied to a group of 14 patients in order to establish its validity; in this group its sensitivity was 83.3% and its specificity 100%. These preliminary data suggest that the model can be used as a guideline for selecting short, slowly growing, non-GH-deficient children who will respond to short-term GH therapy.