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Objective Despite published guidelines no unified approach to hormone replacement in congenital adrenal hyperplasia (CAH) exists. We aimed to explore geographical and temporal variations in the treatment with glucocorticoids and mineralocorticoids in CAH. Design This retrospective multi-center study, including 31 centers (16 countries), analyzed data from the International-CAH Registry. Methods Data were collected from 461 patients aged 0–18 years with classic 21-hydroxylase deficiency (54.9% females) under follow-up between 1982 and 2018. Type, dose and timing of glucocorticoid and mineralocorticoid replacement were analyzed from 4174 patient visits. Results The most frequently used glucocorticoid was hydrocortisone (87.6%). Overall, there were significant differences between age groups with regards to daily hydrocortisone-equivalent dose for body surface, with the lowest dose (median with interquartile range) of 12.0 (10.0–14.5) mg/m2/day at age 1–8 years and the highest dose of 14.0 (11.6–17.4) mg/m2/day at age 12–18 years. Glucocorticoid doses decreased after 2010 in patients 0–8 years (P < 0.001) and remained unchanged in patients aged 8–18 years. Fludrocortisone was used in 92% of patients, with relative doses decreasing with age. A wide variation was observed among countries with regards to all aspects of steroid hormone replacement. Conclusions Data from the I-CAH Registry suggests international variations in hormone replacement therapy, with a tendency to treatment with high doses in children.

Objective Childhood brain tumor survivors (CBTS) are at risk to develop hypothalamic–pituitary (HP) dysfunction (HPD). The risk for HPD may vary between different age groups due to maturation of the brain and differences in oncologic treatment protocols. Specific studies on HPD in infant brain tumor survivors (infant-BTS, 0–1 years at diagnosis) or toddler brain tumor survivors (toddler-BTS, ≥1–3 years) have not been performed. Patients and methods A retrospective nationwide cohort study in CBTS was performed. Prevalence and risk factors for HPD were compared between infant-, toddler-, and older-BTS. Subgroup analysis was performed for all non-irradiated CBTS (n = 460). Results In total, 718 CBTS were included, with a median follow-up time of 7.9 years. Overall, despite the less frequent use of radiotherapy (RT) in infants, no differences in the prevalence of HPD were found between the three groups. RT (OR: 16.44; 95% CI: 8.93–30.27), suprasellar tumor location (OR: 44.76; 95% CI: 19.00–105.49), and younger age (OR: 1.11; 95% CI: 1.05–1.18) were associated with HP dysfunction. Infant-BTS and toddler-BTS showed more weight gain (P < 0.0001) and smaller height SDS (P = 0.001) during follow-up. In non-irradiated CBTS, infant-BTS and toddler-BTS were significantly more frequently diagnosed with TSH-, ACTH-, and ADH deficiency, compared to older-BTS. Conclusion Infant and toddler brain tumor survivors seem to be more vulnerable to develop HP dysfunction than older children. These results emphasize the importance of special infant and toddler brain tumor treatment protocols and the need for endocrine surveillance in children treated for a brain tumor at a young age.

Contains fulltext : 193237.pdf (Publisher’s version ) (Open Access) PURPOSE: Severe fluctuations in plasma sodium concentration and plasma osmolarity, including central diabetes insipidus (CDI), may have significant influence on postoperative morbidity and mortality after pediatric brain tumor surgery.The aim of this study was to describe the frequency, severity and neurological consequences of these fluctuations in pediatric brain tumor survivors. METHODS: A retrospective, multi-institutional chart review was conducted among all children who underwent brain tumor surgery in the sellar or suprasellar region in seven university hospitals in the Netherlands between January 2004 and December 2013. RESULTS: Postoperative CDI was observed in 67.5% of 120 included children. Fluctuations of plasma sodium concentration >/= 10 mmol/L/24 h during the first ten postoperative days were seen in 75.3% of patients with CDI, with a maximum delta of 46 mmol/L/24 h. When compared to patients without CDI, altered mental status occurred more frequently in patients with postoperative CDI (5.1 vs. 23.5% respectively, p = 0.009). Low plasma sodium concentration was related to altered mental status and the occurrence of seizures. Frequency and severity of fluctuations in plasma sodium concentration during the first ten postoperative days were significantly higher in patients with permanent CDI at last follow-up than in patients with transient CDI or without CDI (p = 0.007). CONCLUSION: Postoperative CDI is a common complication after pediatric brain tumor surgery in the sellar or suprasellar region. Extreme plasma sodium concentrations and large intra-day fluctuations still occur and seem to influence the postoperative neurological course. These results illustrate the need for intensive monitoring in a highly experienced center.

Contains fulltext : 172188.pdf (Publisher’s version ) (Closed access) 3 p.

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Item does not contain fulltext STUDY QUESTION: Should fertility preservation be offered to children with Klinefelter syndrome (KS)? SUMMARY ANSWER: Current evidence shows that fertility preservation should not be offered to adolescents with KS younger than 16 years because of lower retrieval rates for germ cells by testicular sperm extraction (TESE) compared with retrieval rates for adolescents and adults between 16 and 30 years. WHAT IS KNOWN ALREADY: KS, the most common chromosomal disorder in men leading to non-obstructive azoospermia, is caused by the presence of at least one additional X chromosome. The onset of puberty in adolescents with KS leads to progressive degeneration of the testicular environment. The impact of the subsequent tissue degeneration on fertility potential of patients with KS is unknown, but in previous literature it has been suggested that fertility preservation should be started in adolescents as early as possible. However spermatozoa can be found by TESE in about 50% of adults with KS despite severe testicular degeneration. This review discusses the current evidence for fertility preservation in children and adolescents and possible prognostic markers for fertility treatment in KS. STUDY DESIGN, SIZE, DURATION: An extensive literature search was conducted, searching Pubmed, Embase, Cinahl and Web of Science from origin until April 2016 for 'Klinefelter syndrome' and 'fertility' and various synonyms. Titles and abstracts have been scanned manually by the authors for eligibility. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total 76 studies were found to be eligible for inclusion in this review. Information from the papers was extracted separately by two authors. MAIN RESULTS AND THE ROLE OF CHANCE: Various studies have shown that pre-pubertal children with KS already have a reduced number of germ cells despite a normal hormonal profile during childhood. The presence of spermatozoa in the ejaculate of adolescents with KS is extremely rare. Using TESE, the retrieval rates of spermatozoa for adolescents younger than 16 years old are much lower (0-20%) compared with those for adolescents and young adults between 16 and 30 years old (40-70%). Although spermatogonia can be found by TESE in about half of the peri-pubertal adolescents, there are currently no clinically functional techniques for their future use. Children and adolescents need to be informed that early fertility preservation before the age of 16 cannot guarantee fertility later in life and may even reduce the chances for offspring by removing functional immature germ cells which may possibly develop into spermatozoa after puberty. Furthermore, except for the age of patients with KS, there are no identified factors that can reliably be used as a predictive marker for fertility preservation. LIMITATIONS, REASONS FOR CAUTION: Most of the evidence presented in this review is based on studies including a small number of adolescents with KS. Therefore, the studies may have been underpowered to detect clinically significant differences for their various outcomes, especially for potential predictive factors for fertility preservation, such as hormone levels. Furthermore, the population of patients with KS diagnosed during childhood might be different from the adult population with KS where the diagnosis is based on infertility. Results based on comparisons between the two groups must be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: Despite the limitations, this review summarizes the current evidence for managing fertility preservation in patients with KS to provide optimal health care. STUDY FUNDING/COMPETING INTERESTS: There was no funding for this study. S.F., Y.H., K.D., W.L.M.N., D.S., H.L.C.-v.d.G. and L.R. declare to have no conflicts of interests. D.D.M.B. reports grants from Merck Serono, grants from Ferring and grants from MSD, outside the submitted work. K.F. reports personal fees from MSD (commercial sponsor), personal fees from Ferring (commercial sponsor), grants from Merck-Serono (commercial sponsor), grants from Ferring (commercial sponsor) and grants from MSD (commercial sponsor), outside the submitted work. 8 p.

Item does not contain fulltext Congenital adrenal hyperplasia (CAH) is one of the most common inherited autosomal recessive disorders, caused by deficiency of one of the enzymes involved in steroid synthesis. The clinical picture of the most prevalent form, i.e. 21-hydroxylase deficiency, is characterized by cortisol and mostly aldosterone deficiency and androgen excess (leading to congenital virilization in girls). Treatment consists of glucocorticoids, aimed at substitution of cortisol deficiency and, decrease of androgen excess. Usually supraphysiological doses of glucocorticoids are required to effectively suppress adrenal androgens. Furthermore, with the currently available glucocorticoid preparations, it is not possible to simulate a normal circadian rhythm in CAH patients. Therefore, it is a difficult task for (pediatric) endocrinologists to find the best balance between under- and overtreatment thereby avoiding important long term complications. In this review we will discuss the current pharmacologic treatment options. We give age dependent dose recommendations and describe the limitations of current treatment strategies. We discuss effects on fertility, bone density and cardiovascular risks. Recommendations about the use of glucocorticoids in case of fever or stress situations are given. The principles of treatment of non classic (mild) CAH are discussed in a separate section. Also prenatal therapy, to prevent congenital virilization of a female CAH newborn, is discussed. Furthermore, an overview of alternative pharmacological treatment options in the future is given.

In adult patients with congenital adrenal hyperplasia (CAH) the presence of testicular adrenal rest tumours (TART) is an important cause of gonadal dysfunction and infertility. In the last decade several papers have focused on the origin and pathogenesis of these tumours. In this paper we review the embryological, histological, biochemical and clinical features of TART and discuss the treatment options. Furthermore, we propose a new five-stage classification of TART, based on sonographic, clinical and biochemical parameters, that may lead to a better follow up and treatment of patients with TART.

Een stoornis van de geslachtelijke ontwikkeling met onduidelijk geslacht na de geboorte is een ingrijpende situatie en eist multidisciplinaire behandeling door een gespecialiseerd team. Aan de hand van de karyotypering kan een eerste onderscheid gemaakt worden tussen virilisatie van een genotypisch meisje en ondervirilisatie van een genotypische jongen. Belangrijk in het diagnostische traject is de hormonale evaluatie op het juiste tijdstip. Echografisch onderzoek van de genitalia interna helpt bij verdere evaluatie van de genitalia interna en de positie van de gonaden. Geslachtstoewijzing wordt uitgesteld totdat een definitieve diagnose is gesteld. Naast snelle diagnostiek naar de onderliggende oorzaak is psychologische begeleiding van de ouders een belangrijk doel.

Bijnier en gonaden maken gebruik van dezelfde enzymsystemen voor productie van steroiden. Stoornissen in een van de enzymen zal leiden tot onvoldoende secretie van specifieke bijniersteroiden zoals cortisol (en aldosteron), maar zal daarnaast, afhankelijk van de lokalisatie van het enzymdefect in de steroidsynthese, leiden tot ofwel een overproductie van (bijnier)androgenen (bij 46,XX DSD), dan wel een deficientie van zowel bijniersteroiden alsook gonadale steroiden (bij 46,XY DSD). De verschillende vormen van de synthesestoornissen worden besproken. Patienten met de meest voorkomende vormen van bijnierhyperplasie, zoals de 21- en 11-hydroxylasedeficientie en de 3b-HSD, vormen binnen de groep met DSD een speciale subgroep met betrekking tot de langetermijnconsequenties. Immers, de overproductie van androgenen interfereert niet alleen met groei en puberteitsontwikkeling, maar op volwassen leeftijd ook met fertiliteit. Indien echter adequaat wordt behandeld, is fertiliteit bij deze beelden in tegenstelling tot bij vele andere vormen van DSD wel degelijk mogelijk. Suppressie van de pathologische activiteit van de bijnier is daartoe echter een absolute voorwaarde.

Item does not contain fulltext Patients with congenital adrenal hyperplasia (CAH) are often clinically less severely affected by cortisol deficiency than anticipated from their enzymatic defect. We hypothesize that adrenal steroid hormone precursors that accumulate in untreated or poorly controlled CAH have glucocorticoid activity and partially compensate for cortisol deficiency. We studied the in vitro effects of 17-hydroxyprogesterone (17OHP), progesterone (P), 21-deoxycortisol (21DF), and androstenedione (Delta4) on the human glucocorticoid receptor (hGR). Competitive binding assays were performed in HeLa cells. Nuclear translocation of the hGR was studied by transfection of COS-7 cells with a GFP-tagged hGR and fluorescence microscopy. Transactivation assays were performed in COS-7 cells and in HEK 293 cells after cotransfection with hGR and luciferase reporter vectors using a dual luciferase assay. 17OHP, P, and 21DF are able to bind to the hGR with binding affinities of 24-43% compared with cortisol. Delta4 has a low binding affinity. Incubation with 21DF led to complete nuclear translocation of the hGR, whereas treatment with 17OHP or P resulted in partial nuclear translocation. 21DF transactivated the hGR with an EC50 approximately 6 times the EC50 of cortisol. 17OHP and P transactivated the hGR with EC50s of more than 100 times the EC50 of cortisol. No hGR transactivation was detected after incubation with Delta4. 21DF, 17OHP, and P are able to bind, translocate, and transactivate the hGR in vitro and thus may have glucocorticoid activity. 21DF might have a clinically relevant agonistic effect on the hGR and could potentially partially compensate the cortisol deficiency in CAH patients. 7 p.

Contains fulltext : 51189.pdf (Publisher’s version ) (Closed access) We report a young girl who died in an Addisonian crisis due to previously undiagnosed congenital adrenal hyperplasia (CAH), in whom ovarian adrenal rest tissue was detected at postmortem histopathological examination. This is a very rare complication in female patients with CAH with only two previously reported cases.

Background: Patients with classic congenital adrenal hyperplasia (CAH) due to CYP21 deficiency are treated with supraphysiological doses of glucocorticoids to suppress elevated androgen production. This implies also side effects of high-dose glucocorticoids, possibly leading to iatrogenic Cushing's syndrome. Bilateral adrenalectomy has been suggested as the ultimate therapy in severe cases, when insufficient androgen suppression was obtained despite high glucocorticoid doses. Usually, ACTH levels rise after bilateral adrenalectomy, and this could imply an increased risk for the development of ectopic adrenal rests. In female CAH patients ovarian adrenal rests are not commonly detected by conventional radiological techniques. Methods: We report the case of an adult female CAH patient who underwent bilateral adrenalectomy in early puberty because of poorly controlled CAH. Results and Conclusions: Several years after surgery, she developed secondary amenorrhea and hair loss as a result of androgen overproduction in ovarian adrenal rests that appeared to be detectable only by pelvic venous sampling. After unilateral oophorectomy androgen levels normalized.

Background: Infertility is a serious complication among male congenital adrenal hyperplasia (CAH) patients which is often caused by testicular adrenal rest tumors (TART). TART are already present in childhood and early infancy in CAH patients. The incidence of TART in neonates without CAH has not yet been described in detail before. Objective: To study the prevalence of testicular adrenal rests in non-CAH neonates. Design: Descriptive study. Setting: Radboud University Nijmegen Medical Centre, The Netherlands. Patients and Methods: 115 testis samples of 89 male infants without CAH who died within the neonatal period were histologically examined. Main Outcome Measures: Prevalence of adrenal rest tissue in the neonatal testes. Results: Adrenal rests were found in 4 samples (3.5%). These adrenal nodules were all located within the epididymis; only in 1 sample a nodule was found close to the rete testis but still within the caput of the epididymis. No nodules were found within the testes. Of the 4 children with adrenal rests, 3 had urological malformations. Conclusion: The incidence of testicular adrenal rests in non-CAH neonates is low. Further studies are necessary to study the incidence of TART in CAH infants and detect typical risk factors in this patient group.

Contains fulltext : 80605.pdf (Publisher’s version ) (Closed access) Kallmann syndrome (KS) is the combination of hypogonadotropic hypogonadism and anosmia or hyposmia, two features that are also frequently present in CHARGE syndrome. CHARGE syndrome is caused by mutations in the CHD7 gene. We performed analysis of CHD7 in 36 patients with KS and 20 patients with normosmic idiopathic hypogonadotropic hypogonadism (nIHH) in whom mutations in KAL1, FGFR1, PROK2 and PROKR2 genes were excluded. Three of 56 KS/nIHH patients had de novo mutations in CHD7. In retrospect, these three CHD7-positive patients showed additional features that are seen in CHARGE syndrome. CHD7 mutations can be present in KS patients who have additional features that are part of the CHARGE syndrome phenotype. We did not find mutations in patients with isolated KS. These findings imply that patients diagnosed with hypogonadotropic hypogonadism and anosmia should be screened for clinical features consistent with CHARGE syndrome. If such features are present, particularly deafness, dysmorphic ears and/or hypoplasia or aplasia of the semicircular canals, CHD7 sequencing is recommended.

Contains fulltext : 49346.pdf (Publisher’s version ) (Open Access) Congenital adrenal hyperplasia (CAH) is generally regarded as a paediatric endocrine disease, but nowadays nearly all patients reach adulthood as a result of improved diagnosis and treatment. It is now increasingly recognised that treatment goals shift during life: one of the major treatment goals in childhood and puberty, i.e. normal growth and development, is no longer relevant after childhood, whereas other aspects, such as fertility and side effects of long-term glucocorticoid treatment, become more important in adulthood. This paper focuses on fertility in male and female adult patients with CAH. In males with CAH the fertility rate is reduced compared with the normal population, the most frequent cause being testicular adrenal rest tumours. Development and growth of these tumours is assumed to be ACTH dependent and undertreatment may play an important role. If intensifying glucocorticoid treatment does not lead to tumour decrease, surgical intervention may be considered, but the effect on fertility is not yet known. In females with CAH the degree of fertility depends on the phenotype of the CAH. Most fertility problems are seen in the classic salt-wasting type. Age of menarche and regularity of the menstrual cycle depends on the degree of adrenal suppression. Not only adrenal androgens have to be normalised but also the levels of adrenal progestins (progesterone and 17-OH-progesterone) that interfere with normal ovulatory cycles. The regularity of menstrual cycles can be considered as an important measure of therapeutic control in adolescent females with CAH and therefore as a therapeutic goal from (peri)pubertal years on. Other factors that contribute to impaired fertility in females with CAH are ovarian hyperandrogenism (polycystic ovary syndrome), ovarian adrenal rest tumours, genital surgery and psychological factors. Subfertility in CAH can have its origin already in the peripubertal years and is therefore of interest to the paediatric endocrinologist.

Congenital adrenal hyperplasia (CAH) is a disorder of adrenal steroid synthesis. The symptoms and signs of CAH depend on the degree of enzyme deficiency; severe salt-wasting (SW) form, less severe simple virilizing (SV) form and mild nonclassic (NC) form. In this paper, puberty and fertility in CAH are discussed. The time of onset of puberty and progress of pubertal development is quite normal, except in NC patients (earlier). Also the age of menarche in CAH girls is normal, but it can depend on the level of therapeutic control. In prepuberty, bone age is advanced. In puberty, peak height velocity is normal but occurs at a younger age and can therefore be considered to be low (compared to healthy early maturers). In puberty there seems to be an increased sensitivity for glucocorticoids leading to growth inhibition. All three above factors can play a role in reducing adult height. Subfertility is frequently found in both female and male CAH patients. In females, the pregnancy rate depends on the severity of 21-hydroxylase deficiency (SW

Item does not contain fulltext AIMS: Ruptures of the uropoietic system resulting in either urinary ascites or urinoma are rare complications in the neonate. Although ruptures without clear predisposing factors are described, in most cases they are associated with obstructive uropathy. The diagnosis is often delayed and the prognosis is related to the degree of renal damage. There is discussion about possible protective mechanisms of the rupture for renal function in patients with obstructive uropathy. METHODS: We retrospectively analyzed the clinical presentation, predisposing factors and the renal function before and after treatment of 10 neonates with a rupture of the pyelum or urinary bladder in our hospital. RESULTS: The group consisted of 9 boys and 1 girl. The average birth weight was 3,880 g. The patients presented with distended abdomen (n = 10), abdominal mass (n = 2), ascites (n = 5), oligohydramnion (n = 2), hypertension (n = 1) and anuria (n = 1). Underlying diagnosis included obstruction of the ureteropelvic junction (UPJ obstruction) in 3 children and posterior urethral valves in 7 children. Five children presented with urinoma, 3 children had a urinoma in combination with ascites and 2 children had isolated ascites. All children had reduced renal function at the time of diagnosis. In all 10 cases, the serum creatinine decreased after treatment. Scintigraphic investigation with mercapto-acetyltriglycerine (MAG III) demonstrated diminished function and perfusion of all 3 kidneys with UPJ obstruction and isolated urinoma even after treatment. Children with posterior urethral valves and urinoma revealed better function of the ruptured kidney and diminished function of the kidney which was not ruptured. One child with a rupture of the urinary bladder and urinary ascites showed good function and perfusion of both kidneys. CONCLUSION: Perinatal ruptures of the uropoietic system are rare. The clinical presentation is aspecific. One should consider a rupture of the urinary bladder or pyelum in a neonate with a distended abdomen, hydronephrosis and ascites. The long-term prognosis depends on the underlying diagnosis and the location of the rupture. Probably, a UPJ obstruction with an isolated urinoma is associated with irreversible renal damage of the ruptured kidney. A rupture resulting in urinary ascites apparently provides better decompression with better function of the ruptured kidney. Scintigraphic investigation is necessary for a separate evaluation of the single kidney function.