[Testicular adrenal rest tumors (TARTs) and adrenogenital syndrome (AGS) - Do not mix up with malignant testicular tumors!] / Testikuläre adrenale Resttumoren beim adrenogenitalen Syndrom.

Testicular adrenal rest tumors and adrenogenital syndrome (AGS) - Do not mix up with malignant testicular tumors! Testicular adrenal residual tumors (TARTs) frequently occur in men with adrenogenital syndrome. Without knowledge of AGS, diagnosis is problematic due to difficult differentiation from other testicular tumors. However, early treatment is crucial for maintaining or regaining fertility, among other aspects. This article provides background knowledge for general practitioners.

[The androgenital syndrome: Don't just think about it in childhood!] / Das adrenogenitale Syndrom: Nicht nur im Kindesalter daran denken!

The androgenital syndrome: Don't just think about it in childhood!In adrenogenital syndrome, the body permanently produces too many male sex hormones. Rare, congenital metabolic diseases are usually discovered in infancy and can be treated at an early stage treated at an early stage, but sometimes they only become apparent in adolescence and adulthood.This article provides background knowledge for GPs.

Genitoplasty in newborn females with adrenogenital syndrome: Focus on the reconstruction technique and its outcomes.

The adrenogenital syndrome is an autosomal recessive disorder in which an enzyme defect in the steroid pathway leads to excessive prenatal exposure of androgens. In the female fetus, masculinization of the external genitalia is observed. Surgery aims for functional and aesthetical reconstruction. Many techniques have been described. A video of our modified pull-through reconstruction technique is hereby presented. A retrospective descriptive database was created with patients who underwent genitoplasty for a CAH-associated genital condition. A video demonstrating the reconstructive technique was recorded while operating on a 9-month-old girl. Prior to surgery a cystoscopy is performed to evaluate the length of the urogenital sinus. Surgery starts with creating a reversed U-flap, after which the urogenital sinus is mobilized. The corpora cavernosa are released and the neurovascular bundle is isolated. To create vaginal space the urogenital sinus is subsequently separated. The vaginal introitus is anchored to the perineal skin flap. Labia minora are created by splitting the preputial skin. Finally excessive skin tissue is resected. Twenty-two female patients underwent reconstructive surgery for the adrenogenital syndrome in a tertiary referral centre over 16 years. Median age at surgery was 3 months (0-190). Median follow-up was 36 months (0-108) after surgery. A good functional and aesthetical outcome was observed. The modified pull-through technique, illustrated by this video, provided satisfactory results with a low complication rate. Follow-up until adulthood is needed to evaluate long-term outcomes.

Reduced steroidogenesis in patients with PCDH19-female limited epilepsy.

Patients affected by protocadherin 19 (PCDH19)-female limited epilepsy (PCDH19-FE) present a remarkable reduction in allopregnanolone blood levels. However, no information is available on other neuroactive steroids and the steroidogenic response to hormonal stimulation. For this reason, we evaluated allopregnanolone, pregnanolone, and pregnenolone sulfate by liquid chromatographic procedures coupled with electrospray tandem mass spectrometry in 12 unrelated patients and 15 age-matched controls. We also tested cortisol, estradiol, progesterone, and 17OH-progesterone using standard immunoassays. Apart from estradiol and progesterone, all the considered hormones were evaluated in basal condition and after stimulation with adrenocorticotropic hormone (ACTH). A generalized decrease in blood levels of almost all measured neuroactive steroids was found. When considering sexual development, cortisol and pregnenolone sulfate basal levels were significantly reduced in postpubertal girls affected by PCDH19-FE. Of interest, ACTH administration did not recover pregnenolone sulfate serum levels but restored cortisol to control levels. In prepubertal girls with PCDH19-FE, by challenging adrenal function with ACTH we disclosed defects in the production of cortisol, pregnenolone sulfate, and 17OH-progesterone, which were not apparent in basal condition. These findings point to multiple defects in peripheral steroidogenesis associated with and potentially relevant to PCDH19-FE. Some of these defects could be addressed by stimulating adrenocortical activity.

Testicular tumors of adrenogenital syndrome: From physiopathology to therapy.

Testicular tumor of adrenogenital syndrome is a rare and benign anomaly usually presenting as bilateral testicular masses. It is the most important cause of infertility in adult male congenital adrenal hyperplasia. Distinction between testicular tumors of adrenogenital syndrome and Leydig cell tumors can be problematic; it is based on clinical, histopathologic, immunohistochemical and endocrine features. Biopsy is advised in cases of longstanding tumors in infertile patients and when surgery is indicated. Fertility preservation is a key management goal in testicular tumor of adrenogenital syndrome. In stages 2 and 3, intensified glucocorticoid treatment is recommended as a first step treatment. Sparing surgical approach is preferred for tumors of stage 4 and steroid unresponsive masses. Magnetic resonance imaging is recommended before surgery. The only indication of surgery in stage 5 is testicular pain.

Leydig cell tumour and giant adrenal myelolipoma associated with adrenogenital syndrome: a case report with a review of the literature.

CONTEXT: Male patients with congenital adrenal hyperplasia (CAH) may develop bilateral testicular adrenal rest tumours (TARTs). These tumours, in most cases, regress with glucocorticoid therapy and their histological differentiation from Leydig-cell tumors is quite difficult. OBJECTIVE: The aim of this study was to differentiate the histological and clinical features of the TARTs from those of the Leydig-cell tumours. METHODS: The authors report a case of bilateral Leydig-cell tumour associated with giant bilateral adrenal myelolipoma in a male with adrenogenital syndrome who was submitted to a bilateral orchiectomy. RESULTS: Testicular neoplasia continue to grow despite adequate hormonal treatment and a bilateral orchiectomy was performed. The histopathological examination of the specimen ultimately confirmed the diagnosis of bilateral Leydig-cell tumour. CONCLUSIONS: This case shows the importance of all the relevant examinations, blood chemistry analysis, and instrumental tests in the differential diagnosis of TARTs and other testicular tumours.

Bilateral Idiopathic Adrenal Hyperplasia: Genetics and Beyond.

Bilateral adrenal hyperplasia currently accounts for up to 2 thirds of cases of primary aldosteronism. As such, it represents a major opportunity for targeted medical management as opposed to unilateral surgically correctable forms of the disease. Although the majority of cases of primary aldosteronism are sporadic, bilateral adrenal hyperplasia may occur in the context of familial hyperaldosteronism where it is associated with specific germline mutations. Over the past 5 years, impressive progress has been made in our understanding of the genetic basis underlying primary aldosteronism, allowing us to identify and characterize new familial forms of the disease and to understand the mechanisms involved in the formation of aldosterone producing adenoma. In contrast, our knowledge of the genetic contribution to the development of bilateral adrenal hyperplasia, and in a larger context, to renin and aldosterone levels in the general population, is still poor. This review summarizes our current knowledge on the genetics of bilateral adrenal hyperplasia and addresses some open questions to be addressed by future research. In particular, genome-wide association studies in large populations may provide clues to understanding the genetic susceptibility underlying the development of primary aldosteronism.

[Hemiconvulsion-hemiplegia-epilepsy syndrome in a girl with adrenogenital syndrome]. / Hemikonvulsivt hemiplegisk epileptisk syndrom hos pige med adrenogenitalt syndrome.

Hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome is a very rare condition caused by a fever-associated status epilepticus causing various degrees of hemiplegia and secondary epilepsy affecting children under the age of four. The aetiology is not fully understood. We report a case of a two-year-old girl with adrenogenital syndrome presenting with HHE syndrome in the course of a bacterial septicaemia.

Feminizing genitoplasty: a proven technique.

The female child with the adrenogenital syndrome is subject to a variable degree of masculinization. Surgery should be directed to 3 goals: (1) removing the corpora and preserving the glans with its innervation to create a clitoris with normal sensation, (2) creating a normal-appearing introitus by fashioning labia minora from phallic skin and foreskin, and (3) vaginoplasty to provide an adequate opening for the vagina onto the perineum. The entire repair may be completed before the age of 6 months unless the vagina enters the urogenital sinus at the high level, in which case vaginoplasty may be delayed until the child is older. The evolution of this operative approach is described and the details of the operative technique are presented.

Role of a disordered steroid metabolome in the elucidation of sterol and steroid biosynthesis.

In 1937 Butler and Marrian found large amounts of the steroid pregnanetriol in urine from a patient with the adrenogenital syndrome, a virilizing condition known to be caused by compromised adrenal secretion even in this pre-cortisol era. This introduced the concept of the study of altered excretion of metabolites as an in vivo tool for understanding sterol and steroid biosynthesis. This approach is still viable and has experienced renewed significance as the field of metabolomics. From the first cyclized sterol lanosterol to the most downstream product estradiol, there are probably greater than 30 steps. Based on a distinctive metabolome clinical disorders have now been attributed to about seven post-squalene cholesterol (C) biosynthetic steps and around 15 en-route to steroid hormones or needed for further metabolism of such hormones. Forty years ago it was widely perceived that the principal steroid biosynthetic defects were known but interest rekindled as novel metabolomes were documented. In his career this investigator has been involved in the study of many steroid disorders, the two most recent being P450 oxidoreductase deficiency and apparent cortisone reductase deficiency. These are of interest as they are due not to mutations in the primary catalytic enzymes of steroidogenesis but in ancillary enzymes needed for co-factor oxido-reduction A third focus of this researcher is Smith-Lemli-Opitz syndrome (SLOS), a cholesterol synthesis disorder caused by 7-dehydrocholesterol reductase mutations. The late George Schroepfer, in whose honor this article has been written, contributed greatly to defining the sterol metabolome of this condition. Defining the cause of clinically severe disorders can lead to improved treatment options. We are now involved in murine gene therapy studies for SLOS which, if successful could in the future offer an alternative therapy for this severe condition.

Unilateral asymptomatic testis enlargement in children and adolescents.

In literature a well codified definition of unilateral asymptomatic testis enlargement does not exist. Therefore in these cases the pediatrician or adolescentologist will have to make a clinical and diagnostic evaluation in order to exclude: a) an enlarged testis secondary to tumors, surgery, or endocrinological diseases; b) a small testis due to a previous (ex. cryptorchidism) or current disease (e.g. varicocele).The presence of a mild difference in testis volumes during puberty is not at all rare. This situation may be due to the technique used for evaluation of testis volume or secondary to a varicocele. The identification of variants of testis enlargement is important, because, while on one hand there are conditions without clinical relevance, on the other hand, there are diseases that require early diagnosis and immediate treatment. The Authors report a brief review of the literature and their own clinical experience. 14 patients with unilateral testis enlargement were observed. At the first examination, mean age was 12.3±1.2 years and the volume of the enlarged testis varied between 4 ml and 20 ml (mean volume 10±4 ml) versus 1.5 ml and 10 ml (mean volume 5±2 ml) of the contralateral testis. In 75% of cases the right testis was affected. During the ten year follow-up, the volume of the enlarged testis never exceeded 25 ml and progressive reduction of the difference between the two testes was demonstrated. Therefore, they propose another clinical condition defined as transitory unilateral testis enlargement of puberty.

Rete testis-associated nodular steroid cell nests: description of putative pluripotential testicular hilus steroid cells.

A putative hilus interstitial cell has been proposed as the cell of origin for testicular tumors of adrenogenital syndrome, but its normal histology is not documented. We present hitherto undescribed nodular steroid cell nests associated with the rete testis that are distinctive in their morphology and immunohistochemical profile from Leydig cells and do not have the morphology of typical extra-adrenal cortical rests. These nodules measured 1, 1, 1.8, 2, and 2.5 mm in size with a distinct sinusoidal vasculature. Individual cells were rounded to polygonal with evenly distributed moderate-to-abundant eosinophilic cytoplasm. The nuclei were homogenous and round, with fine chromatin and ocasionally with prominent nucleoli. The differential diagnosis included adrenocortical rests, testicular adnexal Leydig cells, carcinoid tumorlets, paraganglionic rests, and adenomatoid mesothelial proliferation. Immunohistochemistry showed positivity for melan A (5/5), inhibin (3/5), and calretinin (2/4), although the immunoreactivity was distinctively different from the concurrent intratesticular Leydig cells and testicular adnexal Leydig cells in all cases. The unique morphology, immunophenotype, and distinctive location of these cells in the testicular mediastinum raises the possibility that these cells represent testicular hilus steroid cells, the putative histogenetic cell implicated for testicular tumors of adrenogenital syndrome. We propose to name these proliferations rete testis-associated nodular steroid cell nests.

Vaginal replacement in the pediatric age group: a 34-year experience of intestinal vaginoplasty in children and young girls.

BACKGROUND/PURPOSE: The absence of vagina is rare in the pediatric population. It can occur as a result of congenital malformations such as an aplasia of mullerian ducts (46,XX Mayer-Rokitansky-Küster-Hauser syndrome) or a complete androgen insensitivity syndrome (46,XY testicular feminizing syndrome). Intersex patients, who underwent reassessment of a female sex, need a genital reconstruction toward a feminine phenotype. Patients with congenital adrenogenital syndrome with high urogenital sinus could have a severe hypoplastic vagina. In all these cases, a vaginal replacement is required. We reviewed our experience of vaginal replacement using a sigmoid conduit. METHODS: In 34 years, we evaluated 47 patients. The observation period was from 1 to 34 years (mean: 12 years). The preoperative diagnosis was Mayer-Rokitansky-Küster-Hauser syndrome in 17 cases, androgen insensitivity syndrome in 24 cases, adrenogenital syndrome with high urogenital sinus in 5 and 1 patient was affected by penile agenesis. Forty-six patients were treated with vaginal reconstruction by interposition of sigmoid colon. Only in 1 case we performed a vaginal construction with an ileal loop: in this case, the sigmoid colon was extremely dilated by a chronic constipation secondary to a high anorectal malformation corrected at birth. RESULTS: The outcome for 47 patients is excellent: 18 are sexually active and 4 are married. Only 1 patient with adrenogenital syndrome died of endocrine problems. Complications occurred in 17 cases: in 1 patient a necrosis of the replaced vagina occurred, thus requiring vaginal exeresis; now she is waiting for a second operation. Another patient had an abdominal abscess, which was surgically treated. In 12 cases a second procedure was required: 6 had stenotic new-vaginal introitus, 4 had new-vaginal prolapse, and 2 had intestinal obstruction. CONCLUSIONS: We believe that the preferable technique for vaginal replacement is the use of intestinal conduit. The sigmoid colon is the best intestinal tract to be used owing to its size, location and preserved blood supply. Our experience leads us to believe that the sigmoid segment is the segment of choice, although we consider ileal loop as a good alternative when the sigmoid colon is not available.