Early puberty suppression and gender-affirming hormones do not alter final height in transgender adolescents.

BACKGROUND: Early puberty suppression (ePS; Tanner stages 2 and 3) through gonadotropin-releasing hormone agonists (GnRHas) and gender-affirming hormones (GAHs) interferes with growth and may impact final height (FH). AIM: To investigate the impact of ePS and GAH on FH in trans boys and trans girls. METHODS: Retrospective study, including 10 trans boys and 22 trans girls at FH. Bone age (BA) was determined at the start of ePS and at the start of GAH according to Greulich and Pyle; predicted adult height (PAH) was calculated according to Bayley and Pinneau's tables; target height (TH) was calculated as adjusted mean of maternal and paternal height. Target height, PAH, and BA were determined according to sex registered at birth (SRAB) and experienced gender (EG). RESULTS: The age at the start of PS was 12.37 ± 0.74 years in trans boys and 13.10 ± 1.12 years in trans girls. Total height gain since the start of ePS in trans boys was 14.62 ± 4.08 cm, with 70% achieved before the start of GAH. In trans girls, it was 20.68 ± 7.66 cm, with 61% achieved before GAH. Target height for SRAB was the most accurate predictor for FH in both trans boys and girls: the difference with FH was 1.57 cm ± 3.1 (P = .168) and -0.98 cm ± 4.17 (P = .319), respectively. Also the difference between FH and PAH at the start of PS for SRAB was nonsignificant in both trans boys and girls (2.62 cm ± 3.79, P = .056 and -2.35 cm ± 5.2, P = .051, respectively). CONCLUSION: Early puberty suppression and GAH do not impact FH, supporting the safety of the treatment; however, trans adolescents achieve a FH in line with SRAB, rather than EG.

Disproportion and dysmorphism in an adult Belgian population with Turner syndrome: risk factors for chronic diseases?

BACKGROUND: Turner syndrome (TS) is characterized by dysmorphism and body disproportion. TS women are also susceptible to a range of chronic disorders including arterial hypertension (AHT), osteoporosis, sensorineural hearing loss (SNHL), type 2 diabetes mellitus (DM2) and thyroid disease. The association between dysmorphism/body disproportion and chronic disease has never been studied in TS women. The effect of growth hormone treatment on body disproportion is also unclear. Objectives: to analyze dysmorphic features and body disproportion in TS women in relation to the presence of chronic disease and to document the effect of growth hormone therapy on body disproportion. METHOD: 76 adult TS women with a regular follow up at the TS clinic UZ Ghent were invited to participate. Detailed body measurements were performed in 44 volunteering TS women. Scoring systems for overall dysmorphism, craniofacial dysmorphism, thoracic and limb abnormalities and skeletal disproportion were developed. RESULTS: TS women with a higher dysmorphism score were more at risk for AHT (p = 0.04) as well as those with a higher sitting height/standing height ratio (p < 0.05). Prevalence of AHT, osteoporosis and DM 2 was lower in TS women treated with GH during childhood (p < 0.05). CONCLUSIONS: Adult TS women with relatively short legs or with more physical dysmorphic stigmata were more at risk for AHT. GH therapy does not seem to increase the risk of chronic disease on the long term.

Poor growth response during the first year of growth hormone treatment in short prepubertal children with growth hormone deficiency and born small for gestational age: a comparison of different criteria.

BACKGROUND: There is no consensus on the definition of poor growth response after the first year of growth hormone (GH) treatment. We determined the proportion of poor responders identified by different criteria in children with GH deficiency (GHD) and born small for gestational age (SGA). The second aim was to analyze the IGF-1 response in poor growth responders. METHODS: First-year height data of 171 SGA and 122 GHD children who remained prepubertal during the first GH treatment year were retrieved from the BESPEED database and analyzed. Criteria for poor first-year response/responsiveness were: change in height (∆Ht) SDS<0.3 or<0.5, height velocity (HV) SDS<0.5 or <1 based on the population reference, HV SDS<- 1 based on the KIGS expected HV curve (HV Ranke SDS), studentized residual (SR) <- 1 in the KIGS first-year prediction model. RESULTS: ∆Ht SDS<0.5 gave the highest percentage poor responders (37% SGA, 26% GHD). Although % poor responders were comparable for ∆Ht SDS<0.3, HV SDS<+ 0.5, HV SDS<+ 1, SR<- 1, and HV Ranke SDS<- 1, these criteria did not always identify the same patients as poor responders. Among the poor growth responders 24% SGA and 14% GHD patients had an IGF-1 increase < 40%. CONCLUSIONS: The different response criteria yield high but comparable percentages poor responders, but identify different patients. This study does not provide evidence that one criterion is better than another. A limited IGF-1 generation is not the major reason for a poor growth response in the first year of GH treatment in SGA and GHD children. TRIAL REGISTRATION: Retrospectively registered.

Proandrogenic and Antiandrogenic Progestins in Transgender Youth: Differential Effects on Body Composition and Bone Metabolism.

Context: Progestins can be used to attenuate endogenous hormonal effects in late-pubertal transgender (trans) adolescents (Tanner stage B4/5 and G4/5). Currently, no data are available on the effects of progestins on the development of bone mass or body composition in trans youth. Objective: To study prospectively the evolution of body composition and bone mass in late-pubertal trans adolescents using the proandrogenic or antiandrogenic progestins lynestrenol (L) and cyproterone acetate (CA), respectively. Design and Outcome Measurements: Forty-four trans boys (Tanner B4/5) and 21 trans girls (Tanner G4/5) were treated with L or CA for 11.6 (4 to 40) and 10.6 (5 to 31) months, respectively. Anthropometry, grip strength, body composition, and bone mass, size, and density were determined by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography before the start of progestin and before addition of cross-sex hormones. Results: Using L, lean mass [+3.2 kg (8.6%)] and grip strength [+3 kg (10.6%)] significantly increased, which coincided with a more masculine body shape in trans boys. Trans girls showed loss of lean mass [-2.2 kg (4.7%)], gain of fat mass [+1.5 kg (9.4%)], and decreased grip strength Z scores. CA limited normal bone expansion and impeded pubertal bone mass accrual, mostly at the lumbar spine [Z score: -0.765 to -1.145 (P = 0.002)]. L did not affect physiological bone development. Conclusion: Proandrogenic and antiandrogenic progestins induce body composition changes in line with the desired appearance within 1 year of treatment. Bone health, especially at the lumbar spine, is of concern in trans girls, as bone mass accrual is severely affected by androgen suppressive therapy.

Growth, sexual and bone development in a boy with bilateral anorchia under testosterone treatment guided by the development of his monozygotic twin.

BACKGROUND: Sex steroids are essential for sexual maturation, linear growth and bone development. However, there is no consensus on the optimal timing, dosage and dosage interval of testosterone therapy to induce pubertal development and achieve a normal adult height and bone mass in children with hypogonadism. CASE PRESENTATION: A monozygotic monochorial male twin pair, of which one boy was diagnosed with anorchia at birth due to testicular regression syndrome was followed from the age of 3 until the age of 18 years. Low dose testosterone substitution (testosterone esters 25 mg/2 weeks) was initiated in the affected twin based on the start of pubertal development in the healthy twin and then gradually increased accordingly. Both boys were followed until age 18 and were compared as regards to linear growth, sexual maturation, bone maturation and bone development. Before puberty induction both boys had a similar weight and height. During puberty, a slightly faster weight and height gain was observed in the affected twin. Both boys ended up however, with a similar and normal (near) adult height and weight and experienced a normal development of secondary sex characteristics. At the age of 17 and 18 years, bone mineral density, body composition and volumetric bone parameters at the forearm and calf were evaluated in both boys. The affected boy had a higher lean mass and muscle cross-sectional area. The bone mineral density at the lumbar spine and whole body was similar. Trabecular and cortical volumetric bone parameters were comparable. At one cortical site (proximal radius), however, the affected twin had a smaller periosteal and endosteal circumference with a thicker cortex. CONCLUSIONS: In conclusion, a low dose testosterone substitution in bilateral anorchia led to a normal onset of pubertal development and (near) adult height. Furthermore, there was no difference in bone mineral density at the age of 17 and 18 years.

Consecutive Cyproterone Acetate and Estradiol Treatment in Late-Pubertal Transgender Female Adolescents.

BACKGROUND: Cyproterone acetate (CA) is an antiandrogenic progestin commonly used in adult transwomen to suppress endogenous androgens, often in combination with estrogens to induce feminization. AIM: To assess the (side) effects and biochemical changes of CA alone and in combination with estrogens in adolescent trans-girls. METHODS: This study was a retrospective analysis of clinical and biochemical data from 27 trans-girls who presented at Tanner stage G4 and were treated with CA monotherapy for at least 6 months (mean = 12 months) and then in combination with incremental doses of estrogens (CA + E; mean = 16 months). Statistical analysis of data included paired or unpaired Student t-test or Wilcoxon signed-ranks or Mann-Whitney U-test as appropriate. OUTCOMES: Anthropometrics, reported beneficial and side effects, safety parameters, and hormone levels. RESULTS: Physical changes included decrease of facial and non-facial hair growth. One third showed breast development under CA (Tanner stages B2-B3), which increased to Tanner stages B3 and B4 in 66.7% and 9.5% respectively, during CA + E. Reported side effects during CA and CA + E were breast tenderness, emotionality, fatigue, and flushes. No relevant weight changes were observed. Main safety parameters showed the following changes. Hemoglobin and hematocrit decreased and liver enzymes transiently and modestly increased during CA. Triglycerides and cholesterol levels slightly decreased during CA but returned to baseline during CA + E; glucose metabolism was unaffected. Relevant hormonal changes included a decrease in gonadotropins during CA + E and in total and free testosterone levels throughout treatment. Prolactin levels increased during CA and were restored during CA + E. CLINICAL IMPLICATIONS: CA produced modest feminizing effects in trans-girls and therefore might be a valuable alternative in situations in which gonadotropin-releasing hormone analogues are not the treatment of choice and/or are not reimbursed. STRENGTHS AND LIMITATIONS: This is the first study to report on the effects of CA in the treatment of trans-girls and one of the few to report on the use of estrogens in this population. Limitations are the modest sample size and the retrospective nature of this study. CONCLUSION: Treatment with CA in late-pubertal trans-girls overall was safe and well tolerated and induced mild clinical and biochemical feminizing changes. Rapid further feminization was observed with incremental doses of E. Tack LJW, Heyse R, Craen M, et al. Consecutive Cyproterone Acetate and Estradiol Treatment in Late-Pubertal Transgender Female Adolescents. J Sex Med 2017;14:747-757.

Developing and evaluating rare disease educational materials co-created by expert clinicians and patients: the paradigm of congenital hypogonadotropic hypogonadism.

BACKGROUND: Patients with rare diseases face health disparities and are often challenged to find accurate information about their condition. We aimed to use the best available evidence and community partnerships to produce patient education materials for congenital hypogonadotropic hypogonadism (CHH) and the olfacto-genital (Kallmann) syndrome (i.e., CHH and defective sense of smell), and to evaluate end-user acceptability. Expert clinicians, researchers and patients co-created the materials in a multi-step process. Six validated algorithms were used to assess reading level of the final product. Comprehensibility and actionability were measured using the Patient Education Materials Assessment Tool via web-based data collection. Descriptive statistics were employed to summarize data and thematic analysis for analyzing open-ended responses. Subsequently, translation and cultural adaption were conducted by clinicians and patients who are native speakers. RESULTS: Co-created patient education materials reached the target 6th grade reading level according to 2/6 (33%) algorithms (range: grade 5.9-9.7). The online survey received 164 hits in 2 months and 63/159 (40%) of eligible patients completed the evaluation. Patients ranged in age from 18 to 66 years (median 36, mean 39 ± 11) and 52/63 (83%), had adequate health literacy. Patients scored understandability at 94.2% and actionability at 90.5%. The patient education materials were culturally adapted and translated into 20 languages (available in Additional file 1). CONCLUSIONS: Partnering with patients enabled us to create patient education materials that met patient- identified needs as evidenced by high end-user acceptability, understandability and actionability. The web-based evaluation was effective for reaching dispersed rare disease patients. Combining dissemination via traditional healthcare professional platforms as well as patient-centric sites can facilitate broad uptake of culturally adapted translations. This process may serve as a roadmap for creating patient education materials for other rare diseases.

Cognitive, Emotional, and Psychosocial Functioning of Girls Treated with Pharmacological Puberty Blockage for Idiopathic Central Precocious Puberty.

Central precocious puberty (CPP) develops due to premature activation of the hypothalamic-pituitary-gonadal (HPG) axis, resulting in early pubertal changes and rapid bone maturation. CPP is associated with lower adult height and increased risk for development of psychological problems. Standard treatment of CPP is based on postponement of pubertal development by blockade of the HPG axis with gonadotropin releasing hormone analogs (GnRHa) leading to abolition of gonadal sex hormones synthesis. Whereas the hormonal and auxological effects of GnRHa are well-researched, there is a lack of knowledge whether GnRHa treatment influences psychological functioning of treated children, despite the fact that prevention of psychological problems is used as one of the main reasons for treatment initiation. In the present study we seek to address this issue by exploring differences in cognitive function, behavior, emotional reactivity, and psychosocial problems between GnRHa treated CPP girls and age-matched controls. Fifteen girls with idiopathic CPP; median age 10.4 years, treated with slow-release GnRHa (triptorelin acetate-Decapeptyl SR® 11.25) and 15 age-matched controls, were assessed with a comprehensive test battery consisting of paper and pencil tests, computerized tasks, behavioral paradigms, heart rate variability, and questionnaires filled in by the children's parents. Both groups showed very similar scores with regard to cognitive performance, behavioral and psychosocial problems. Compared to controls, treated girls displayed significantly higher emotional reactivity (p = 0.016; Cohen's d = 1.04) on one of the two emotional reactivity task conditions. Unexpectedly, the CPP group showed significantly lower resting heart rates than the controls (p = 0.004; Cohen's d = 1.03); lower heart rate was associated with longer treatment duration (r = -0.582, p = 0.037). The results suggest that GnRHa treated CPP girls do not differ in their cognitive or psychosocial functioning from age matched controls. However, they might process emotional stimuli differently. The unexpected finding of lower heart rate that was associated with longer duration of the treatment should be further explored by methods appropriate for assessment of cardiac health.

Consecutive lynestrenol and cross-sex hormone treatment in biological female adolescents with gender dysphoria: a retrospective analysis.

BACKGROUND: Prior to the start of cross-sex hormone therapy (CSH), androgenic progestins are often used to induce amenorrhea in female to male (FtM) pubertal adolescents with gender dysphoria (GD). The aim of this single-center study is to report changes in anthropometry, side effects, safety parameters, and hormone levels in a relatively large cohort of FtM adolescents with a diagnosis of GD at Tanner stage B4 or further, who were treated with lynestrenol (Orgametril®) monotherapy and in combination with testosterone esters (Sustanon®). METHODS: A retrospective analysis of clinical and biochemical data obtained during at least 6 months of hormonal treatment in FtM adolescents followed at our adolescent gender clinic since 2010 (n = 45) was conducted. McNemar's test to analyze reported side effects over time was performed. A paired Student's t test or a Wilcoxon signed-ranks test was performed, as appropriate, on anthropometric and biochemical data. For biochemical analyses, all statistical tests were done in comparison with baseline parameters. Patients who were using oral contraceptives (OC) at intake were excluded if a Mann-Whitney U test indicated influence of OC. RESULTS: Metrorrhagia and acne were most pronounced during the first months of monotherapy and combination therapy respectively and decreased thereafter. Headaches, hot flushes, and fatigue were the most reported side effects. Over the course of treatment, an increase in musculature, hemoglobin, hematocrit, creatinine, and liver enzymes was seen, progressively sliding into male reference ranges. Lipid metabolism shifted to an unfavorable high-density lipoprotein (HDL)/low-density lipoprotein (LDL) ratio; glucose metabolism was not affected. Sex hormone-binding globulin (SHBG), total testosterone, and estradiol levels decreased, and free testosterone slightly increased during monotherapy; total and free testosterone increased significantly during combination therapy. Gonadotropins were only fully suppressed during combination therapy. Anti-Müllerian hormone (AMH) remained stable throughout the treatment. Changes occurred in the first 6 months of treatment and remained mostly stable thereafter. CONCLUSIONS: Treatment of FtM gender dysphoric adolescents with lynestrenol monotherapy and in combination with testosterone esters is effective, safe, and inexpensive; however, suppression of gonadotropins is incomplete. Regular blood controls allow screening for unphysiological changes in safety parameters or hormonal levels and for medication abuse.

Delayed Adrenarche may be an Additional Feature of Immunoglobulin Super Family Member 1 Deficiency Syndrome.

Immunoglobulin super family member 1 (IGSF1) deficiency syndrome is characterized by central hypothyroidism, delayed surge in testosterone during puberty, macro-orchidism, and in some cases, hypoprolactinemia and/or transient growth hormone (GH) deficiency. Our patient was a 19-year-old male adolescent who had been treated since the age of 9 years with GH and thyroxine for an idiopathic combined GH, thyroid-stimulating hormone (TSH), and prolactin (PRL) deficiency. His GH deficiency proved to be transient, but deficiencies of TSH and PRL persisted, and he had developed macro-orchidism since the end of puberty. Brain magnetic resonance imaging and PROP1 and POU1F1 sequencing were normal. A disharmonious puberty (delayed genital and pubic hair development, bone maturation, and pubertal growth spurt, despite normal testicular growth) was observed as well as a delayed adrenarche, as reflected by very low dehydroepiandrosterone sulfate and delayed pubarche. Direct sequencing of the IGSF1 gene revealed a novel hemizygous mutation, c.3127T>C, p.Cys1043Arg. Pathogenicity of the mutation was demonstrated in vitro. Male children with an idiopathic combined GH, PRL, and TSH deficiency, showing persistent central hypothyroidism but transient GH deficiency upon retesting at adult height, should be screened for mutations in the IGSF1 gene, especially when macro-orchidism and/or hypoprolactinemia are present. We suspect that delayed adrenarche, as a consequence of PRL deficiency, might be part of the clinical phenotype of patients with IGSF1 deficiency.

Cardiovascular pathology in males and females with 45,X/46,XY mosaicism.

CONTEXT: The phenotype of 45,X/46,XY mosaicism is heterogeneous ranging from females with Turner syndrome (TS) to apparently normal males. Males with 45,X/46,XY frequently show stigmata typically associated with TS. We hypothesised that males with 45,X/46,XY have similar cardiovascular pathology as females with 45,X/46,XY. OBJECTIVE: To investigate cardiovascular abnormalities in 45,X/46,XY males and to compare them with 45,X/46,XY females. DESIGN: Patients with 45,X/46,XY mosaicism were selected from the Belgian Registry for Growth and Puberty problems and via the multidisciplinary clinic for disorders of sexual development. PATIENTS: EIGHTEEN PATIENTS WERE INCLUDED: 8 raised as females (F) and 10 as males (M). INTERVENTION: Complete cardiac examination with blood pressure measurement, ECG, echocardiography and MRI. MAIN OUTCOME MEASUREMENT: Cardiac parameters were registered for both groups. In a second phase, clinical features and external masculinisation score (EMS) were retrospectively collected from the medical files. RESULTS: A structural heart defect was diagnosed before inclusion in 1 F with coarctation and 1 M with spontaneously closed VSD. A bicuspid aortic valve was found in 8 (3 F, 5 M). Dilation of the ascending aorta was present in 4 M and was severe in 2 young boys. QTc was prolonged in 3 F and 2 M. CONCLUSION: Males with 45,X/46,XY mosaicism have similar cardiovascular pathology as 45,X/46,XY females. Dilation of the ascending aorta can be important, also in males. We advise cardiac screening and life-long monitoring in all males with 45,X/46,XY mosaicism according to the existing guidelines for Turner syndrome.

Longitudinal linear growth and final height is impaired in childhood acute lymphoblastic leukemia survivors after treatment without cranial irradiation.

OBJECTIVE: To evaluate long-term growth and final height (FH) in survivors of childhood acute lymphoblastic leukemia (ALL) who were treated without cranial radiation therapy and underwent evaluation of growth hormone (GH) status at the end of treatment. STUDY DESIGN: Data on longitudinal growth (collected at the start of treatment, end of treatment, and 1 year thereafter) and FH of 67 adult survivors of childhood ALL who had been treated according to European Organisation for Research and Treatment of Cancer 58831/2 protocols with chemotherapy as the only treatment modality were reviewed retrospectively. Height data were expressed as SDS for national references. The relative role of sex, age at diagnosis, intensity of chemotherapeutic regimen, and GH status at the end of treatment as contributing factors were analyzed. RESULTS: A modest but significant loss in FH (change in SDS [ΔSDS] = -0.59 ± 0.86; P < .001) was found. Two-thirds of the height deficit observed from diagnosis until FH occurred during treatment. The height deficit was more severe in the male patients (P = .036). The ΔSDS for height from diagnosis to FH was not correlated with age at diagnosis or intensity of treatment. No correlation was found between the results of the GH stimulation test and ΔSDS for height from diagnosis or the end of treatment to FH. CONCLUSION: Adult survivors of childhood ALL treated with chemotherapeutic regimens of moderate intensity without cranial radiation therapy exhibit a modest loss in SDS for height at FH irrespective of GH status at the cessation of treatment.

Improved molecular diagnostics of idiopathic short stature and allied disorders: quantitative polymerase chain reaction-based copy number profiling of SHOX and pseudoautosomal region 1.

CONTEXT: Short stature has an incidence of three in 100 in children. Reliable molecular genetic testing may be crucial in the context of beneficial disease management. Deletions spanning or surrounding the SHOX gene account for a significant proportion of patients with idiopathic short stature (ISS) and allied disorders, such as Leri-Weill dyschondrosteosis. OBJECTIVE: Several shortcomings of current strategies for copy number profiling of the SHOX region prompted us to develop an improved test for molecular diagnostics of the SHOX region. DESIGN AND RESULTS: We introduced a quantitative PCR (qPCR)-based copy number profiling test, consisting of 11 amplicons targeting clinically relevant regions, i.e. the SHOX gene and regulatory regions. To ensure an optimal sensitivity and specificity, this test was validated in 32 controls and 18 probands with previously identified copy number changes. In addition, 152 probands with SHOX-associated phenotypes were screened, revealing 10 novel copy number changes. CONCLUSION: This highly validated qPCR test supersedes other approaches for copy number screening of the SHOX region in terms of reliability, accuracy, and cost efficiency. In addition, another strong point is the fact that it can be easily implemented in any standard equipped molecular laboratory. Our qPCR-based test is highly recommended for molecular diagnostics of idiopathic short stature and allied disorders.

Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations.

Noonan syndrome (NS) is an autosomal dominant disorder caused by mutations in PTPN11, KRAS, SOS1, and RAF1. We performed SOS1, RAF1, BRAF, MEK1, and MEK2 mutation analysis in a cohort of 102 PTPN11- and KRAS-negative NS patients and found pathogenic SOS1 mutations in 10, RAF1 mutations in 4, and BRAF mutations in 2 patients. Three novel SOS1 mutations were found. One was classified as a rare benign variant and the other remains unclassified. We confirm a high prevalence of pulmonic stenosis and ectodermal abnormalities in SOS1-positive patients. Three patients with SOS1 mutations presented with tumors (embryonal rhabdomyosarcoma, Sertoli cell testis tumor, and granular cell tumors of the skin). One patient with a RAF1 mutation had a lesion suggestive for a giant cell tumor. This is the first report describing different tumor types in NS patients with germ line SOS1 mutations.

Molecular characterization of iodotyrosine dehalogenase deficiency in patients with hypothyroidism.

CONTEXT: The recent cloning of the human iodotyrosine deiodinase (IYD) gene enables the investigation of iodotyrosine dehalogenase deficiency, a form a primary hypothyroidism resulting from iodine wasting, at the molecular level. OBJECTIVE: In the current study, we identify the genetic basis of dehalogenase deficiency in a consanguineous family. RESULTS: Using HPLC tandem mass spectrometry, we developed a rapid, selective, and sensitive assay to detect 3-monoiodo-l-tyrosine and 3,5-diodo-l-tyrosine in urine and cell culture medium. Two subjects from a presumed dehalogenase-deficient family showed elevated urinary 3-monoiodo-l-tyrosine and 3,5-diodo-l-tyrosine levels compared with 57 normal subjects without thyroid disease. Subsequent analysis of IYD revealed a homozygous missense mutation in exon 4 (c.658G>A p.Ala220Thr) that co-segregates with the clinical phenotype in the family. Functional characterization of the mutant iodotyrosine dehalogenase protein showed that the mutation completely abolishes dehalogenase enzymatic activity. One of the heterozygous carriers for the inactivating mutation recently presented with overt hypothyroidism indicating dominant inheritance with incomplete penetration. Screening of 100 control alleles identified one allele positive for this mutation, suggesting that the c.658G>A nucleotide substitution might be a functional single nucleotide polymorphism. CONCLUSIONS: This study describes a functional mutation within IYD, demonstrating the molecular basis of the iodine wasting form of congenital hypothyroidism. This familial genetic defect shows a dominant pattern of inheritance with incomplete penetration.

Growth hormone treatment and fat redistribution in children born small for gestational age.

OBJECTIVE: To determine whether in children born small for gestational age (SGA) high-dose growth hormone (GH) treatment is not only associated with catch-up of growth and with gain of lean mass, but also with a more central fat distribution. STUDY DESIGN: Short children who were SGA (n = 25; age [mean +/- SD], 5.3 +/- 1.5 years) were randomly assigned to remain untreated (n = 14) or to receive GH (n = 11; sc 66 mug/Kg/d). Growth status and body composition were assessed at the study's start, after 1 year, and after 2 years with anthropometry and absorptiometry. RESULTS: Children who were treated with GH gained more height and weight than children who were untreated and developed a less adipose body composition (all P < .0001), as expected. However, these changes were also accompanied by a relatively more centripetal distribution of fat mass (0-2 year change in ratio of trunk fat to limb fat; 0.26 +/- 0.23 versus 0.02 +/- 0.15; P < .0001). CONCLUSION: In children who are SGA, catch-up growth induced by exogenous GH in high doses is accompanied by a less adipose body composition and a more central fat distribution.

Renal hemodynamic changes and renal functional reserve in children with type I diabetes mellitus.

Increased glomerular filtration rate (GFR) has been implicated in the development of diabetic nephropathy. Large normal interindividual variations of GFR hamper the diagnosis of renal hemodynamic alterations. We examined renal functional reserve (RFR) in children with type 1 diabetes mellitus to assess whether hyperfiltration occurs. The renal hemodynamic response following dopamine infusion was examined in 51 normoalbuminuric diabetic children (7.7 +/- 3.6 years) with a mean duration of diabetes of 6.2 years and compared them with 34 controls. Mean baseline GFR in diabetic children did not differ from the control population (130.7 +/- 22.9 vs. 124.8 +/- 25 ml/min per 1.73 m(2)), whereas renal plasma flow was significantly lower (463.7 +/- 103.9 vs. 587.2 +/- 105 ml/min per 1.73 m(2), p < 0.001), and filtration fraction was increased (29 +/- 8 vs. 21 +/- 2%, p < 0.001), compared with controls. The mean RFR was lower (p < 0.001) than in control subjects (-0.77 +/- 23 vs. 21 +/- 8 ml/min per 1.73 m(2)). This study documents an increased filtration fraction and reduced or absent RFR in children with type 1 diabetes mellitus in the stage before apparent nephropathy. GFR values were within normal range. Although the reduced RFR and increased filtration fraction indicate the presence of hemodynamic changes, their relevance to the development of hyperfiltration and subsequent diabetic nephropathy remains unknown.

Lack of evidence of hypervolemia in children with insulin-dependent diabetes mellitus.

Hypervolemia is considered to play a major role in the pathogenesis of diabetic vasculo- and nephropathy. The aim of our study is to determine whether children and adolescents with insulin-dependent diabetes mellitus (IDDM) experience alterations in blood volume (BV) before onset of apparent nephropathy. BV (calculated as the sum of measured plasma volume (PV) and red cell volume (RCV)) was determined in 31 children (9-16 yr) with a mean duration of IDDM of 6.6 yr and without microalbuminuria. Due to dependence of these values on age, size and sex, all data were normalised for body size parameters. While no statistical difference for BV normalised for lean body mass (LBM) (86.98+/-9.5 ml/kg) was found in diabetic children compared with our control population (84.91+/-12.08 ml/kg), a difference could be shown when normalised for body surface area (BSA) (diabetic children 2.37+/-0.3 L/m(2); control population 2.15+/-0.38 L/m(2), p=0.002). Increased BV is only present when normalising for BSA and not for the theoretical superior LBM-index. Because the study population exhibited a poor glycemic control (HbA1c 10.2+/-2.4 %), an influence of glucosuria-induced polyuria on BV cannot be excluded. Taking into account these limitations our data do not confirm the presence of hypervolemia before onset of diabetic nephropathy.

A reference frame for blood volume in children and adolescents.

BACKGROUND: Our primary purpose was to determine the normal range and variability of blood volume (BV) in healthy children, in order to provide reference values during childhood and adolescence. Our secondary aim was to correlate these vascular volumes to body size parameters and pubertal stages, in order to determine the best normalisation parameter. METHODS: Plasma volume (PV) and red cell volume (RCV) were measured and F-cell ratio was calculated in 77 children with idiopathic nephrotic syndrome in drug-free remission (mean age, 9.8 +/- 4.6 y). BV was calculated as the sum of PV and RCV. Due to the dependence of these values on age, size and sex, all data were normalised for body size parameters. RESULTS: BV normalised for lean body mass (LBM) did not differ significantly by sex (p < 0.376) or pubertal stage (p < 0.180), in contrast to normalisation for the other anthropometric parameters. There was no significant difference between reference values for children and adults. CONCLUSION: LBM was the anthropometric index most closely correlated to vascular fluid volumes, independent of age, gender and pubertal stage.

Transplacental passage of a nonionic contrast agent.

UNLABELLED: We report the presence of iopromide in the bowel and urine of a preterm infant, born 10 days after intravenous administration of the nonionic monomer to his mother. Excessive urinary iodine excretion and borderline hyperthyrotropinaemia were observed in the infant. Moreover, crossing of the fetal blood-brain barrier was demonstrated by detection of the angiographic material in CSF and thus direct fetal neurotoxic effects cannot be excluded. CONCLUSION: These widely used contrast media may cross the placenta and accumulate in various fetal tissues in significant amounts causing possible neonatal toxicity. Therefore the perinatal safety of these diagnostic agents should at least be questioned.