Transition from Paediatric to Adult Care in CAH: 20 Years of Experience at a Tertiary Referral Center.

Transition medicine aims at the coordinated transfer of young patients with a chronic disease from paediatric to adult care. The present study reflects 20 years of experience in transitioning patients with congenital adrenal hyperplasia (CAH) in a single center setting. Our endocrine transition-clinic was established in 2002 and offers joint paediatric and adult consultations. Data were evaluated retrospectively from 2002 to 2005 and 2008 to present. Fifty-nine patients (29 males) were transferred. Median age was 18.4 years (17.6-23.6). Ninety percent of the patients presented with 21-hydroxlase-deficiency (21-OHD), 38 patients (23 m) with salt-wasting (sw), 7 (1 m) with simple-virilising (sv) and 8 (3 m) with the non-classic (nc) form. Rarer enzyme deficiencies were found in 6 cases: 17α-OHD (2 sisters), P450-oxidoreductase-deficiency (2 siblings), 3ß-hydroxysteroid-dehydrogenase-deficiency (1 m) and 11ß-OHD (1 female). Thirty-four patients (57.6%, 20 m) are presently still attending the adult clinic, 1 patient (1.7%, m) moved away and 24 (40.7%, 8 m) were lost to follow-up (13 sw-21-OHD, 6 sv-21-OHD, 5 nc-21-OHD). Thirty-seven patients (62.7%) attended the adult clinic for >2 years after transfer, 17 (28.8%) for >10 years. In the lost to follow-up group, median time of attendance was 16.3 months (0-195.2). Defining a successful transfer as two or more visits in the adult department after initial consultation in the transition clinic, transfer was efficient in 84.7% of the cases. A seamless transfer to adult care is essential for adolescents with CAH. It requires a continuous joint support during the transition period, remains challenging, and necessitates adequate funding.

Prevalence of osteopathologies in a single center cohort of survivors of childhood primary brain tumor.

Background: Childhood primary brain tumors (CPBT) are the second largest group of childhood malignancies and associated with a high risk for endocrine late effects. Objective: To assess endocrine late effects and their relevance for the development of osteopathologies in survivors. Methods: This single center cross sectional study investigated data from 102 CPBT survivors with a mean age of 13.0 years and a mean age at diagnosis of 8.7 years. Clinical, biochemical, radiographic, and anamnestic data regarding endocrine and bone health were obtained at study visits. In addition, data regarding tumor stage and therapy was obtained by chart review. An expert opinion was applied to define presence of osteopathologies. Results: Impaired bone health, defined by at least one pathological screening parameter, was present in 65% of patients. 27.5% were found to have overt osteopathologies per expert opinion. 37.8% displayed a severe vitamin D deficiency (25-OH vitamin D < 10 ng/ml) and 11% a secondary hyperparathyroidism. Patients with osteopathologies had lower 25-OH vitamin D levels compared to patients without osteopathologies. Multiple endocrine late effects were present: diabetes insipidus in 10.8%, aberrant pubertal development in 13.7%, central hypocortisolism in 14.9%, thyroid dysfunction in 23.8% and growth hormone deficiency in 21.8%. A total of 31.3% of survivors displayed any endocrinopathy. Tumors located near hypothalamic structures and patients who received irradiation had a higher likelihood of endocrine morbidity. Conclusion: This study indicates that endocrine deficiencies are common in pediatric survivors of CPBTs. Osteopathologies are present in this cohort. A prominent effect of hormonal deficiencies on bone health was not detected, possibly because patients were sufficiently treate for their endocrine conditions or indicating resilience of the childhood bone remodeling process. Vitamin D deficiency is frequent and should be treated as recommended.

The adrenal steroid profile in adolescent depression: a valuable bio-readout?

There is preliminary evidence that adrenal steroids other than cortisol may be valuable biomarkers for major depressive disorder (MDD). So far, studies have been conducted in adults only, and conclusions are limited, mainly due to small sample sizes. Therefore, the present study assessed whether adrenal steroids serve as biomarkers for adolescent MDD. In 261 depressed adolescents (170 females) treated at a single psychiatric hospital, serum adrenal steroids (progesterone, 17-hydroxyprogesterone, 21-deoxycortisol, 11-deoxycortisol, cortisol, cortisone, deoxycorticosterone, corticosterone) were determined by liquid chromatography-tandem mass spectrometry. Findings were compared to that of an age- and sex-matched reference cohort (N = 255) by nonparametric analysis of variance. Nonparametric receiver operating characteristics (ROC) analyses were conducted to evaluate the diagnostic performance of single steroids and steroid ratios to classify depression status. Sensitivity analyses considered important confounders of adrenal functioning, and ROC results were verified by cross-validation. Compared to the reference cohort, levels of deoxycorticosterone and 21-deoxycortisol were decreased (P < 0.001). All other glucocorticoid- and mineralocorticoid-related steroids were increased (P < 0.001). The corticosterone to deoxycorticosterone ratio evidenced excellent classification characteristics, especially in females (AUC: 0.957; sensitivity: 0.902; specificity: 0.891). The adrenal steroid metabolome qualifies as a bio-readout reflecting adolescent MDD by a distinct steroid pattern that indicates dysfunction of the hypothalamus-pituitary-adrenal axis. Moreover, the corticosterone to deoxycorticosterone ratio may prospectively qualify to contribute to precision medicine in psychiatry by identifying those patients who might benefit from antiglucocorticoid treatment or those at risk for recurrence when adrenal dysfunction has not resolved.

Rhizomelia and Impaired Linear Growth in a Girl with Juvenile Paget Disease: The Natural History of the Condition.

In ultra-rare bone diseases, information on growth during childhood is sparse. Juvenile Paget disease (JPD) is an ultra-rare disease, characterized by loss of function of osteoprotegerin (OPG). OPG inhibits osteoclast activation via the receptor activator of nuclear factor-κB (RANK) pathway. In JPD, overactive osteoclasts result in inflammatory-like bone disease due to grossly elevated bone resorption. Knowledge on the natural history of JPD, including final height and growth, is limited. Most affected children receive long-term antiresorptive treatment, mostly with bisphosphonates, to contain bone resorption, which may affect growth. In this study, we report the follow-up of height, growth velocity, and skeletal maturation in a 16-year-old female patient with JPD. The patient was treated with cyclic doses of pamidronate starting at 2.5 years of age and with 2 doses of denosumab at the age of 8 years, when pamidronate was paused. In the following years, a sustainable decline in a height z-score and a stunted pubertal growth spurt; despite appropriate maturation of the epiphyseal plates of the left hand, the proximal right humerus and both femora were observed. Whether this reflects the growth pattern in JPD or might be associated to the antiresorptive treatments is unclear, since there is very limited information available on the effect of bisphosphonates and denosumab on growth and the growth plate in pediatric patients. Studies are needed to understand the natural history of an ultra-rare bone disease and to assess the effects of antiresorptive treatment on the growing skeleton.

Semen quality and testicular adrenal rest tumour development in 46,XY congenital adrenal hyperplasia: the importance of optimal hormonal replacement.

OBJECTIVE: To study the impact of the quality of therapeutic control on fertility and on the prevalence of testicular adrenal rest tumours (TART) in young males with congenital adrenal hyperplasia (CAH). DESIGN: Combined cross-sectional and retrospective clinical study. METHODS: Twenty-nine patients and age-matched controls underwent clinical investigation, including semen analysis, testicular and adrenal ultrasound imaging, and serum and hair steroid analysis. The quality of therapeutic control was categorized as 'poor', 'moderate' or 'medium'. Evaluation of current control was based on concentrations of 17-hydroxy-progesterone and androstenedione in serum and 3 cm hair; previous control was categorized based on serum 17-hydroxy-progesterone concentrations during childhood and puberty, anthropometric and puberty data, bone age data and adrenal sizes. RESULTS: Semen quality was similar in males with CAH and controls (P = 0.066), however patients with 'poor' past control and large TART, or with 'poor' current CAH control had low sperm counts. Follicle-stimulating hormone was decreased, if current CAH control was 'poor' (1.8 ± 0.9 U/L; 'good': 3.9 ± 2.2 U/L); P = 0.015); luteinizing hormone was decreased if it was 'poor' (1.8 ± 0.9 U/L; P = 0.041) or 'moderate' (1.9 ± 0.6 U/L; 'good': 3.0 ± 1.3 U/L; P = 0.025). None of the males with 'good' past CAH control, 50% of those with 'moderate' past control and 80% with 'poor past control had bilateral TART. The prevalence of TART in males with severe (class null or A) CYP21A2 mutations was 53% and 25% and 0% in those with milder class B and C mutations, respectively. CONCLUSIONS: TART development is favoured by inadequate long-term hormonal control in CAH. Reduced semen quality may be associated with large TART. Gonadotropin suppression by adrenal androgen excess during the latest spermatogenic cycle may contribute to impairment of spermatogenesis.

No Effect of Thyroid Dysfunction and Autoimmunity on Health-Related Quality of Life and Mental Health in Children and Adolescents: Results From a Nationwide Cross-Sectional Study.

Background: In adults, a significant impact of thyroid dysfunction and autoimmunity on health-related quality of life (HRQoL) and mental health is described. However, studies in children and adolescents are sparse, underpowered, and findings are ambiguous. Methods: Data from 759 German children and adolescents affected by thyroid disease [subclinical hypothyroidism: 331; subclinical hyperthyroidism: 276; overt hypothyroidism: 20; overt hyperthyroidism: 28; Hashimoto's thyroiditis (HT): 68; thyroid-peroxidase antibody (TPO)-AB positivity without apparent thyroid dysfunction: 61] and 7,293 healthy controls from a nationwide cross-sectional study ("The German Health Interview and Examination Survey for Children and Adolescents") were available. Self-assessed HRQoL (KINDL-R) and mental health (SDQ) were compared for each subgroup with healthy controls by analysis of covariance considering questionnaire-specific confounding factors. Thyroid parameters (TSH, fT4, fT3, TPO-AB levels, thyroid volume as well as urinary iodine excretion) were correlated with KINDL-R and SDQ scores employing multiple regression, likewise accounting for confounding factors. Results: The subsample of participants affected by overt hypothyroidism evidenced impaired mental health in comparison to healthy controls, but SDQ scores were within the normal range of normative data. Moreover, in no other subgroup, HRQoL or mental health were affected by thyroid disorders. Also, there was neither a significant relationship between any single biochemical parameter of thyroid function and HRQoL or mental health, nor did the combined thyroid parameters account for a significant proportion of variance in either outcome measure. Importantly, the present study was sufficiently powered to identify even small effects in children and adolescents affected by HT, subclinical hypothyroidism, and hyperthyroidism. Conclusions: In contrast to findings in adults, and especially in HT, there was no significant impairment of HRQoL or mental health in children and adolescents from the general pediatric population affected by thyroid disease. Moreover, mechanisms proposed to explain impaired mental health in thyroid dysfunction in adults do not pertain to children and adolescents in the present study.

Prevalence of Osteopathologies in Children and Adolescents After Diagnosis of Acute Lymphoblastic Leukemia.

Background: Impaired bone health is a late effect of childhood malignancies which can be difficult to detect in juvenile survivors. It may, however, lead to compromised quality of life, or even permanent disability later in life due to osteoporosis, pain or fractures if left untreated. Acute lymphoblastic leukemia (ALL) is the most frequent childhood malignancy with an over 85% five-year survival. ALL and its treatment cause bone alterations in adults, but little information on the bone health status in juvenile survivors is available. Objective: To report data on skeletal late effects in juvenile survivors of childhood ALL based on a comprehensive assessment of bone health and to assess the influence of a vitamin D deficiency on bone health in this cohort. Methods: In a single center cross sectional study 128 pediatric patients (11.9 ± 4.76 years) with a mean follow up of 5.88 ± 3.75 years after diagnosis of ALL were recruited. The bone health status of the survivors was assessed based on clinical examination, review of medical records, biochemical and radiographic analyses, by clinical experts. A score which utilized 8 different parameters was formed and used to assess the effect of a vitamin D deficiency on bone health. Results: In this cohort, 18% of survivors displayed overt osteopathologies as defined by clinical expert assessment. Impaired bone health, defined by at least one pathological screening parameter, was detected in 77%. Despite recommendations for adequate vitamin D supplementation, 15% displayed a vitamin D deficiency associated with hyperparathyroidism. The applied score identified survivors with osteopathologies with high sensitivity and specificity. The median score did not differ between patients without and with severe vitamin D deficiency. Conclusion: Our findings suggest that impaired bone health and osteopathologies are common skeletal late effects following treatment of childhood ALL. Major contributing factors are BMT, irradiation and older age at diagnosis. Vitamin D deficiency likely accounts for hyperparathyroidism in some patients but does not seem to further affect bone health in this cohort. Survivors of ALL need thorough surveillance to investigate bone health, since bone morbidity is common and still poorly understood. Early detection and appropriate intervention may improve bone health.

[Medical care of young women with Turner syndrome in Germany]. / Medizinische Betreuung von jungen Frauen mit Ullrich-Turner-Syndrom in Deutschland.

BACKGROUND: Many recommendations for medical care for women with Turner syndrome (TS) have been published in the past. There are no studies that analyse the care situation of the women in Germany until now. METHODS: The study was performed in 2015 based on a questionnaire that was completed by TS women (aged ≥ 18 years; median: 25 years). The questionnaire was devised by a French team and used with their permission. All women had received growth hormone treatment during childhood. The women were identified and addressed in writing through eleven cooperating centers and the support group. In all, 130 questionnaires were evaluated. RESULTS: 79 of the 130 women (61 %) stated that they had health problems. 38 % of the women were under medical care by only one physician and 42 % by two physicians. The gynecologist was mentioned most often (by 80.3 %), followed by the family physician (53.8 %). ENT was mentioned as a problem system by 35 %, but only 3 % of the women attended an ENT physician. The question as to whether at least one of the following examinations (measurements of blood pressure, blood sugar, blood fats, liver function and/or thyroid hormones, echocardiographic and/or audiogram examination) had been performed during a period of 4 years was answered as follows: blood pressure (85 %), blood sugar (47 %), blood fats (41 %), liver function (46 %), thyroid hormones (44 %), echocardiography (57 %) and audiogram (35 %). A comprehensive examination was performed in 9.8 % of the women. 103 women (80.5 %) received sexual hormone replacement therapy. 76 women were on further drugs; thyroid hormones (44 %) and antihypertensive drugs (11 %) were stated most often. CONCLUSIONS: This is the first study which analyses the current situation of medical care of TS women in Germany. Our data show that medical care of young adult TS women is not optimal. The study cannot clarify the reasons. Due to the numerous and different comorbidities, the medical care of TS women is complex and should therefore be provided multidisciplinarily by different specialists under the direction of one physician.

GHD Diagnostics in Europe and the US: An Audit of National Guidelines and Practice.

INTRODUCTION: Almost 20 years after the first international guidelines on the diagnosis and treatment of GHD have been published, clinical practice varies significantly. The low accuracy of endocrine tests for GHD and the burden caused by ineffective treatment of individual patients were strong motives for national endocrine societies to set up national guidelines regarding how to diagnose GHD in childhood. This audit aims to review the current state and identify common changes, which may improve the diagnostic procedure. METHODS: A group of eight German pediatric endocrinologists contacted eight pediatric endocrinologists from Spain, France, Poland, the UK, the Netherlands, Denmark, Italy, and the US. Each colleague responded as a representative for the own country to a detailed questionnaire containing 22 open questions about national rules, guidelines, and practice with respect to GHD diagnostics and GH prescription. The results were presented and discussed in a workshop and then documented in this study which was reviewed by all participants. RESULTS: National guidelines are available in 7 of 9 countries. GH is prescribed by pediatric endocrinologists in most countries. Some countries have established boards that review and monitor prescriptions. Preferred GH stimulation tests and chosen cutoffs vary substantially. Overall, a trend to lowering the GH cutoff was identified. Priming is becoming more popular and now recommended in 5 out of 9 countries; however, with different protocols. The definition of pretest-conditions that qualify the patient to undergo GH testing varies substantially in content and strictness. The most frequently used clinical sign is low height velocity, but definition varies. Height, IGF-1, and bone age are additional parameters recommended in some countries. CONCLUSIONS: GHD diagnostics varies substantially in eight European countries and in the US. It seems appropriate to undertake further efforts to harmonize endocrine diagnostics in Europe and the US based on available scientific evidence.

Resistance to GHRH but Not to PTH in a 15-Year-Old Boy With Pseudohypoparathyroidism 1A.

Pseudohypoparathyroidism 1A (PHP1A) consists of signs of Albright hereditary osteodystrophy (AHO) and multiple, variable hormonal resistances. Elevated PTH levels are the biochemical hallmark of the disease. Short stature in PHP1A may be caused by a form of accelerated chondrocyte differentiation leading to premature growth plate closure, possibly in combination with GH deficiency in some patients. Treatment of short stature with recombinant growth hormone (rhGH) in pediatric patients may improve final height if started during childhood. The 10 11/12-year-old boy with clinical signs of AHO presented for evaluation of short stature [height standard deviation score (SDS) -2.72]. Clinically his mother was affected by AHO as well. A heterozygous mutation c.505G>A (p.E169K) in exon 6 of the GNAS gene confirmed a diagnosis of PHP1A in the boy. However, hormonal assessment was unremarkable except for low serum IGF-1 (SDS -2.67). On follow-up, GH deficiency due to GHRH resistance was suspected and confirmed by clonidine and arginine stimulation tests. Treatment with rhGH (0.035 mg/kg) for 2 years resulted in catch-up growth (height SDS -1.52). At age 15 years the PTH levels and bone age of the patient remain within the normal range. In patients with PHP1A, short stature is caused by the effects of Gs-α deficiency on the growth plate. However, resistance to GHRH and the resulting GH deficiency might also contribute. Recombinant GH treatment increases growth in these patients. Diagnostic workup for GH deficiency as a factor contributing to short stature is recommended even in the absence of other hormonal resistances.

[Life Situation of Young women with Turner Syndrome: Results of a Questionnaire-based Study in Germany]. / Lebenssituation von jungen Frauen mit Ullrich-Turner-Syndrom nach dem Ende der Wachstumshormontherapie: Ergebnisse einer Umfrage in Deutschland.

INTRODUCTION: Psychosocial problems such as anxious personality, low self-esteem, late separation from home and/or late sexual experience have been described in girls and women with Turner syndrome (TS). METHODS: The study was performed in 2015 based on a questionnaire that was sent out to 779 women with TS aged 25 years (median). The questionnaire was devised by a French team and used with their permission. In all, 130 questionnaires (16.7 %) could be evaluated. The questions from the individual topics were not always completely answered. RESULTS: (mean ± SD).: 116 women (89.9 %) were not married; 52 women (40 %) lived in their parents' home. 47.6 % had a high-school/technical diploma or university degree. 60 women (46 %) had a job; 51 women (39 %) had not completed vocational training. Puberty was induced at the age of 14.2 ± 2.1 years in 78 % of the women. 80 % of the women received hormone replacement therapy at the time of the questionnaire survey. 66 of 93 women (71 %) found that the disease had a negative influence on emotional life. "Love life and sexual relationship" was the topic mentioned most frequently by 44 women (66.6 %). 116 women answered questions on sexuality. Here, 77 % had the first French kiss at the age of 16.4 ± 3.6 years and 62.4 % had sexual intercourse for the first time at the age of 19.0 ±â€Š3.4 years. 81 % of the women stated that they had a partner relationship for more than 6 months (94 women had a male partner and 5 had a female partner). The question as to the wish to have children was answered in the affirmative by 89 of 124 women (71.8 %); 38.2 % desired spontaneous pregnancy and 44.9 % had considered in vitro fertilization or adoption. DISCUSSION: The women's answers show that care needs to be improved. There are deficits in the topics of family, emotional life, relationships, sexuality, fertility and pregnancy. Therefore, the medical team should also include psychologists and social workers.

Fertility Preservation for Patients with Malignant Disease. Guideline of the DGGG, DGU and DGRM (S2k-Level, AWMF Registry No. 015/082, November 2017) - Recommendations and Statements for Girls and Women.

AIM: The aim of this official guideline published by the German Society of Gynecology and Obstetrics (DGGG) and coordinated with the German Society of Urology (DGU) and the German Society of Reproductive Medicine (DGRM) is to provide consensus-based recommendations, obtained by evaluating the relevant literature, on counseling and fertility preservation for prepubertal girls and boys as well as patients of reproductive age. Statements and recommendations for girls and women are presented below. Statements or recommendations for boys and men are not the focus of this guideline. METHODS: This S2k guideline was developed at the suggestion of the guideline commission of the DGGG, DGU and DGRM and represents the structured consensus of representative members from various professional associations (n = 40). RECOMMENDATIONS: The guideline provides recommendations on counseling and fertility preservation for women and girls which take account of the patient's personal circumstances, the planned oncologic therapy and the individual risk profile as well as the preferred approach for selected tumor entities.

Mortality in children with classic congenital adrenal hyperplasia and 21-hydroxylase deficiency (CAH) in Germany.

BACKGROUND: Adrenal crises in children with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) are life-threatening and have the potential to death. METHODS: A survey was performed among Paediatric Endocrinologists in Germany to report on deceased children with CAH. Our survey covered the whole of Germany. RESULTS: The participating centres reported 14 cases of death (9 female, 5 male) from 1973 until 2004, but no deaths thereafter. 11 children had the SW form and 3 the simple virilizing (SV) form. All patients were on glucocorticoid replacement, and the SW forms additionally on mineralocorticoid replacement. The age at death varied between 6 weeks and 16.5 years. Seven children died before introduction of general neonatal screening, and 7 children thereafter. Before death, the clinical signs of impending crisis were nonspecific. Five patients developed hypoglycaemia and convulsions with cerebral oedema. Half of the deceased patients died at home. The hydrocortisone dosage was only doubled in two of the 14 cases. CONCLUSIONS: According to the assessments by the attending centres, almost all deaths could be related to an inadequate administration of stress doses of hydrocortisone. Since no deceased CAH children were reported in Germany from 2005 on, we assume the effectiveness of educational programs over the past years.

Correction: Hyperleptinemia in children with autosomal recessive spinal muscular atrophy type I-III.

[This corrects the article DOI: 10.1371/journal.pone.0173144.].

Hyperleptinemia in children with autosomal recessive spinal muscular atrophy type I-III.

BACKGROUND: Autosomal-recessive proximal spinal muscular atrophies (SMA) are disorders characterized by a ubiquitous deficiency of the survival of motor neuron protein that leads to a multisystemic disorder, which mostly affects alpha motor neurons. Disease progression is clinically associated with failure to thrive or weight loss, mainly caused by chewing and swallowing difficulties. Although pancreatic involvement has been described in animal models, systematic endocrinological evaluation of the energy metabolism in humans is lacking. METHODS: In 43 patients with SMA type I-III (8 type I; 22 type II; 13 type III), aged 0.6-21.8 years, auxological parameters, pubertal stage, motor function (Motor Function Measurement 32 -MFM32) as well as levels of leptin, insulin glucose, hemoglobin A1c, Homeostasis Model Assessment index and an urinary steroid profile were determined. RESULTS: Hyperleptinemia was found in 15/35 (43%) of our patients; 9/15 (60%) of the hyperleptinemic patients were underweight, whereas 1/15 (7%) was obese. Hyperleptinemia was associated with SMA type (p = 0.018). There was a significant association with decreased motor function (MFM32 total score in hyperleptinemia 28.5%, in normoleptinemia 54.7% p = 0.008, OR 0.969; 95%-CI: 0.946-0.992). In addition, a higher occurrence of hirsutism, premature pubarche and a higher variability of the urinary steroid pattern were found. CONCLUSION: Hyperleptinemia is highly prevalent in underweight children with SMA and is associated with disease severity and decreased motor function. Neuronal degradation of hypothalamic cells or an increase in fat content by muscle remodeling could be the cause of hyperleptinemia.

Testicular growth and spermatogenesis: new goals for pubertal hormone replacement in boys with hypogonadotropic hypogonadism? -a multicentre prospective study of hCG/rFSH treatment outcomes during adolescence.

CONTEXT/OBJECTIVE: Testosterone treatment for pubertal induction in boys with hypogonadotropic hypogonadism (HH) provides virilization, but does not induce testicular growth or fertility. Larger studies evaluating the outcomes of gonadotropin replacement during adolescence have not been reported to date; whether previous testosterone substitution affects testicular responses is unresolved. We aimed to assess the effects of human chorionic gonadotropin (hCG) and recombinant FSH (rFSH) in boys and adolescents with HH with respect to a) testicular growth, b) spermatogenesis, c) quality of life (QoL) and to identify factors influencing therapeutic success. DESIGN/SETTING: A prospective case study was conducted in 26 paediatric endocrine centres PATIENTS/INTERVENTIONS: HCG and rFSH were administered until cessation of testicular growth and plateauing of spermatogenesis to (1) prepubertal HH boys with absent or early arrested puberty (group A) and to (2) HH adolescents who had previously received full testosterone replacement (group B). OUTCOME MEASURES: Bi-testicular volumes (BTVs), sperm concentrations and QoL. RESULTS: Sixty (34 A/26 B) HH patients aged 14-22 years were enrolled. BTVs rose from 5 ± 5 to 34 ± 3 ml in group A vs 5 ± 3 to 32 ± 3 ml in group B, with normal final BTVs (≥24 ml) attained in 74%/70% after 25/23 months in A/B, respectively. Sperm in the ejaculate were found in 21/23(91%)/18/19(95%), with plateauing concentrations after 31/30 months of hCG and 25/25 months of combined treatment in A/B. Sperm concentrations were normal (≥15 mill/ml) in 61%/32%, with mean concentrations of 40 ± 73 vs 19 ± 38 mill/ml in A/B (n.s.). Outcomes were better in patients without bilateral cryptorchidism, with non-congenital HH causes, higher baseline BTVs, and higher baseline inhibin B and AMH levels. QoL increased in both groups. CONCLUSIONS: HCG/rFSH replacement during adolescence successfully induces testicular growth and spermatogenesis, irrespective of previous testosterone replacement, and enhances QoL.

Managing Transition in Patients Treated with Growth Hormone.

Growth hormone (GH) promotes growth in children, but is also essential for bone strength, body composition, metabolic factors, such as lipid profile, and maintenance of quality of life. The Merck KGaA (Germany) funded "360° GH in Europe" meeting, held in Lisbon, Portugal, in June 2016, comprised three sessions entitled "Short Stature Diagnosis and Referral," "Optimizing Patient Management and Adherence," and "Managing Transition." The scientific program covered all stages of pediatric GH treatment, and reported here are the outcomes of the third session of the meeting, which considered transition from pediatric GH treatment to teenage and young adult GH therapy. A large number of patients with chronic diseases, including GH deficiency, drop out of therapy during the transition period. Multiple factors are associated with this, such as lack of understanding of the disease process, insufficient knowledge of treatment options, the patient becoming more independent, and requirement for interaction with a new set of health-care workers. Education regarding disease management and treatment options should be provided from an early age and right through the transition period. However, endocrine specialists will view the transition period differently, depending on whether they are pediatric endocrinologists who mainly deal with congenital diseases, in which auxology is important, or adult endocrinologists who are more concerned with body composition and metabolic factors. View points of both a pediatric and an adult endocrine specialist are presented, together with a case study outlining practical aspects of transition. It was noted in the meeting discussion that having one person to guide a patient through transition from an early age is important, but may be constrained by various factors such as finances, and options will differ by country.

Plasma concentrations of osteocalcin are associated with the timing of pubertal progress in boys.

BACKGROUND: Animal models have shown that the skeletal hormone osteocalcin stimulates testicular testosterone synthesis. To assess whether osteocalcin might be a useful marker to detect pubertal development disorders, we examined osteocalcin plasma concentrations in children and adolescents with and without disorders of pubertal development. METHODS: Osteocalcin concentrations were investigated in a total of 244 patients with endocrine disorders (122 males, mean age: 11.87+3.77 years), including patients with precocious puberty and constitutional delay of puberty. RESULTS: Osteocalcin concentrations were highest among adolescents with precocious puberty and advanced pubertal development (120.60±45.22 ng/mL), while the concentrations were lowest among patients with constitutional delay of puberty (102.20±37.13 ng/mL). Overall, osteocalcin concentrations were strongly correlated with markers of bone metabolism. CONCLUSIONS: Although plasma osteocalcin concentrations are associated with pubertal development in boys, it does not appear to be a useful diagnostic marker for altered pubertal development.

Loss of Functional Osteoprotegerin: More Than a Skeletal Problem.

Introduction: Juvenile Paget's disease (JPD), an ultra-rare, debilitating bone disease due to loss of functional osteoprotegerin (OPG), is caused by recessive mutations in TNFRFSF11B. A genotype-phenotype correlation spanning from mild to very severe forms is described. Aim: This study aimed to describe the complexity of the human phenotype of OPG deficiency in more detail and to investigate heterozygous mutation carriers for clinical signs of JPD. Patients: We investigated 3 children with JPD from families of Turkish, German, and Pakistani descent and 19 family members (14 heterozygous). Results: A new disease-causing 4 bp-duplication in exon 1 was detected in the German patient, and a microdeletion including TNFRFSF11B in the Pakistani patient. Skeletal abnormalities in all affected children included bowing deformities and fractures, contractures, short stature and skull involvement. Complex malformation of the inner ear and vestibular structures (2 patients) resulted in early deafness. Patients were found to be growth hormone deficient (2), displayed nephrocalcinosis (1), and gross motor (3) and mental (1) retardation. Heterozygous family members displayed low OPG levels (12), elevated bone turnover markers (7), and osteopenia (6). Short stature (1), visual impairment (2), and hearing impairment (1) were also present. Conclusion: Diminished OPG levels cause complex changes affecting multiple organ systems, including pituitary function, in children with JPD and may cause osteopenia in heterozygous family members. Diagnostic and therapeutic measures should aim to address the complex phenotype.

A Piece of the Puzzle: The Bone Health Index of the BoneXpert Software Reflects Cortical Bone Mineral Density in Pediatric and Adolescent Patients.

INTRODUCTION: Suspected osteopathology in chronically ill children often necessitates the assessment of bone mineral density. The most frequently used methods are dual-energy X-ray-absorption (DXA) and peripheral quantitative computed tomography (pQCT). The BoneXpert software provides an automated radiogrammatic method to assess skeletal age from digitalized X-rays of the left hand. Furthermore, the program calculates the Bone Health Index (BHI), a measure of cortical thickness and mineralization, which is obtained from indices of three metacarpal bones. In our study, we analyzed the manner in which BHI information provided by BoneXpert compares with DXA or pQCT measurements in youths. STUDY DESIGN: The BHI was retrospectively obtained using digitalized X-rays of the left hand and compared with the results of 203 corresponding DXA readings (Lunar Prodigy, GE Healthcare) of the lumbar vertebrae and femur as well as 117 pQCT readings (XCT 900, Stratec) of the distal radius. RESULTS: The BHI values showed a strong positive correlation with the DXA readings at each and all lumbar vertebrae (L1 -L4: r = 0.73; P < 0.0001). The age-adjusted Z-score of L1 -L4 and the height-adjusted score showed a positive correlation with the BHI-SDS (standard deviation score, r = 0.23; P < 0.002 and r = 0.27; P < 0.001, respectively). Total bone mineral density, as assessed via pQCT, also positively correlated with the BHI (r = 0.39; P < 0.0001), but the trabecular values displayed only a weak correlation. CONCLUSIONS: The BHI obtained using BoneXpert can be a useful parameter in the assessment of bone health in children in most cases. This technique provides observer-independent information on cortical thickness and mineralization based on X-ray imaging of the hands.