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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. [ABSTRACT FROM AUTHOR]

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., (© 2013 S. Karger AG, Basel.)

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., (Copyright © 2010 S. Karger AG, Basel.)

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.

Congenital adrenal hyperplasia (CAH) is a disorder of adrenal steroid synthesis. In more than 90% of cases CAH is caused by CYP21 (21-hydroxylase) deficiency leading to impaired cortisol and aldosterone synthesis and an increase in ACTH secretion. This then leads to stimulation of the adrenal gland and overproduction of androgens with virilisation of female external genitalia. The CYP21 enzyme consists of 495 amino acids and is encoded by the CYP21A2 gene located on chromosome 6p21.3 close to a 98% homologous pseudogene (CYP21p). The pseudogene contains several inactivating mutations that may be transferred to the active CYP21A2 gene by gene conversion (more than 60% of the affected alleles) or gene deletion (30% of the affected alleles). The severity of the disease depends on the degree of CYP21 deficiency. The diagnosis can be made by measuring levels of 17-hydroxyprogesterone and androstenedione in serum.

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

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.