Under-reported aspects of diagnosis and treatment addressed in the Dutch-Flemish guideline for comprehensive diagnostics in disorders/differences of sex development

We present key points from the updated Dutch-Flemish guideline on comprehensive diagnostics in disorders/differences of sex development (DSD) that have not been widely addressed in the current (inter)national literature. These points are of interest to physicians working in DSD (expert) centres and to professionals who come across persons with a DSD but have no (or limited) experience in this area. The Dutch-Flemish guideline is based on internationally accepted principles. Recent initiatives striving for uniform high-quality care across Europe, and beyond, such as the completed COST action 1303 and the European Reference Network for rare endocrine conditions (EndoERN), have generated several excellent papers covering nearly all aspects of DSD. The Dutch-Flemish guideline follows these international consensus papers and covers a number of other topics relevant to daily practice. For instance, although next-generation sequencing (NGS)-based molecular diagnostics are becoming the gold standard for genetic evaluation, it can be difficult to prove variant causality or relate the genotype to the clinical presentation. Network formation and centralisation are essential to promote functional studies that assess the effects of genetic variants and to the correct histological assessment of gonadal material from DSD patients, as well as allowing for maximisation of expertise and possible cost reductions. The Dutch-Flemish guidelines uniquely address three aspects of DSD. First, we propose an algorithm for counselling and diagnostic evaluation when a DSD is suspected prenatally, a clinical situation that is becoming more common. Referral to ultrasound sonographers and obstetricians who are part of a DSD team is increasingly important here. Second, we pay special attention to healthcare professionals not working within a DSD centre as they are often the first to diagnose or suspect a DSD, but are not regularly exposed to DSDs and may have limited experience. Their thoughtful communication to patients, carers and colleagues, and the accessibility of protocols for first-line management and efficient referral are essential. Careful communication in the prenatal to neonatal period and the adolescent to adult transition are equally important and relatively under-reported in the literature. Third, we discuss the timing of (NGS-based) molecular diagnostics in the initial workup of new patients and in people with a diagnosis made solely on clinical grounds or those who had earlier genetic testing that is not compatible with current state-of-the-art diagnostics

Ovarian adrenal rest tissue in congenital adrenal hyperplasia--a patient report.

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

Prevalence of testicular adrenal rest tissue in neonates.

Item does not contain fulltextBACKGROUND: 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.1 februari 201

Perinatal rupture of the uropoietic system.

Item does not contain fulltextAIMS: 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

Increased Prevalence of Testicular Adrenal Rest Tumours during Adolescence in Congenital Adrenal Hyperplasia

Item does not contain fulltextTesticular adrenal rest tumours (TART) are one of the most important causes of infertility in adult male patients with congenital adrenal hyperplasia (CAH). These benign tumours are already detected in children, but screening of TART is not routinely performed.To define retrospectively the prevalence of TART in 41 paediatric male CAH patients aged 0-19 years regularly followed by high-frequency (Fcentral 12-MHz) ultrasound techniques.Above the age of 10 years, there was a clear increase in the prevalence of TART: 10-12 years, 28\% (2 of 7 patients), 13-14 years, 50\% (4/8), and 15-16 years, 75\% (3/4). Above the age of 16 years, TART were detected in 100\% of the patients (7/7). The tumours were not detectable by palpation.TART is already present in childhood with an increasing prevalence after onset of puberty. We recommend regular ultrasound from the onset of puberty in all boys with classic CAH. © 2014 S. Karger AG, Basel

Testicular adrenal rest tumors in patients with congenital adrenal hyperplasia can cause severe testicular damage.

Contains fulltext : 70873.pdf (publisher's version ) (Closed access)OBJECTIVE: To evaluate the histological features of testicular tumors and residual testicular parenchyma in male patients with congenital adrenal hyperplasia (CAH) and longstanding bilateral testicular adrenal rest tumors (TART). DESIGN: Descriptive study. SETTING: University medical center in the Netherlands. PATIENT(S): Seven male patients who had CAH with longstanding bilateral TART and who were treated with testis-sparing surgery. INTERVENTION(S): Enucleation of TART and taking biopsies of the surrounding testicular parenchyma. MAIN OUTCOME MEASURE(S): Description of the histological features of TART and residual testicular parenchyma. RESULT(S): All tumors had a similar histological appearance, with sheets of polygonal cells separated by dense fibrous tissue with focal lymphocytic infiltrates and without Reinke crystals. All biopsies showed a decrease in tubular diameter with peritubular fibrosis and, in four patients, tubular hyalinization. The germinative layer showed decreased spermatogenesis and reduced Johnsen scores. CONCLUSION(S): Testicular adrenal rest tumors can lead to end-stage damage of testicular parenchyma, most probably as a result of longstanding obstruction of the seminiferous tubules. Therefore, treatment at an early stage is advised

For Debate: Personalized Health Care: As Exemplified by Home Sodium Measurements in a Child with Central Diabetes Insipidus and Impaired Thirst Perception

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An adrenal rest tumour in the perirenal region in a patient with congenital adrenal hyperplasia due to congenital 3beta-hydroxysteroid dehydrogenase deficiency.

Contains fulltext : 69730.pdf (publisher's version ) (Closed access)BACKGROUND: In contrast to the high incidence of testicular adrenal rest tumours (TART) in adult male patients with congenital adrenal hyperplasia (CAH), ovarian adrenal rest tumours in female CAH patients are very rare and other locations of adrenal rest tumours have never been reported. Here, we report on an adult patient with CAH due to 3beta-hydroxysteroid dehydrogenase (HSD) deficiency with bilateral TART and additionally a large perirenal adrenal rest tumour. CASE REPORT: The patient was known with CAH due to 3beta-HSD deficiency and treated with hydrocortisone and fludrocortisone since the neonatal period. In puberty, there was lack of compliance with consequently high POMC concentrations. At the age of 16 years, bilateral TART were detected by scrotal ultrasound. Intensifying glucocorticoid medication did not result in decrease in POMC concentrations and shrinkage of size of the tumours. At the age of 23 years, abdominal ultrasound was performed because of abdominal complaints, showing a round inhomogeneous structure with a diameter of 4 cm near the left renal hilus. A computer tomography scan showed a multinodular lesion in the retroperitoneal region beside the left kidney. Histological investigation after removal of the tumour showed sheets of large polygonal cells with abundant eosinophilic cytoplasm, separated by dense fibrous tissue strands. The histological and immunohistochemical profile resulted in a diagnosis of an adrenal rest tumour. CONCLUSION: In adult CAH patients, ectopic adrenal rest tumours can be present outside the testicular region. Further investigations are necessary to determine whether regularly screening for these tumours is useful

Cardiovascular and metabolic risk in pediatric patients with congenital adrenal hyperplasia due to 21 hydroxylase deficiency

Item does not contain fulltextBACKGROUND: The aim of the study was to evaluate the cardiovascular and metabolic risk profile in pediatric patients with congenital adrenal hyperplasia (CAH). METHODS: A cross-sectional study was performed in 27 CAH patients (8-16 years). Blood samples were taken to evaluate circulating cardiovascular risk (CVR) markers. Insulin resistance (IR) was evaluated by homeostatic model assessment (HOMA)-IR. Blood pressure (BP) was evaluated by office BP measurements and 24-h ambulatory BP measurements (24-h ABPM). Dual energy X-ray absorptiometry (DXA) scans were performed in patients >12 years. RESULTS: Body mass index (BMI) standard deviation score (SDS) was elevated (0.67), with seven patients being overweight and four obese. DXA scans showed percentage body fat SDS of 1.59. Office BP levels were higher than reference values. Twenty-four hour ABPM showed systolic hypertension (n=5), while 11 patients had a non-dipping BP profile. HOMA-IR was >75th percentile in 12 patients. CONCLUSIONS: CAH patients develop an unfavorable CVR profile already in childhood with increased BMI, increased fat mass, elevated BP levels, a non-dipping BP profile and IR compared to population reference values

Monochorionic dizygous twins presenting with blood chimerism and discordant sex

Item does not contain fulltextMonochorionic dizygous twins are probably more frequent than considered previously as many cases remain unrecognized, especially when the children have the same sex. Here we present a pair of dizygous, sex-discordant monochorionic twins who were conceived after artificial insemination. Histological examination of the placenta and extensive genetic studies of the healthy boy and girl clearly proved that they indeed were monochorionic dizygous twins with a fully joined blood circulation. We conclude that when counseling parents expecting monochorionic twins of discordant sex, not only a disorder of sexual differentiation in one of the twins should be addressed but also the possibility of dizygosity with a completely normal (sexual) development of both children