Ovarian and paraovarian adrenal rest tumors are not uncommon in gonadectomy materials of historical congenital adrenal hyperplasia cases in childhood.

Objective: The aim of this study was to assess the prevalence of ovarian and paraovarian adrenal rest tumors (ARTs) in gonadectomy materials of a subgroup of congenital adrenal hyperplasia (CAH) patients. Methods: A total of 20 historical cases with clinical/molecular diagnosis of classical CAH were included in the study. All patients had 46,XX karyotype and underwent gonadectomy because of being raised as male. Results: Median age at diagnosis of CAH was 5.7 years and was markedly delayed. All patients revealed severe virilization. Bone age was significantly advanced, and bone age/chronological age ratio was increased with a median ratio of 1.8. Median age at the time of gonadectomy was 9.2 years. Ovarian and paraovarian ARTs were detected during the pathological evaluation of gonadectomy materials in four patients (20%) (two with simple virilizing 21-hydroxylase and two with 11-beta-hydroxylase deficiency) with previously normal pelvic imaging. In three cases with ARTs, paraovarian area was composed of medium-sized polygonal cells, with round or oval monomorphic nuclei and abundant granular eosinophilic cytoplasm which is characteristic of adrenocortical tissue. The fourth case had bilateral ovarian 'steroid cell tumors, not otherwise specified', and the tumor was accepted as benign. Except for the ARTs, heterotopic prostate and bilateral paratubal epididymis tissue were detected in a patient. Conclusions: Ovarian and paraovarian ARTs might be more common than previously described, especially among patients with excessive and prolonged adrenocorticotropic hormone exposure. These tumors could be detected histopathologically even if not detected by classical imaging methods.

Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors.

CONTEXT: Testicular adrenal rest tumors (TART) are a common complication in males with classic 21-hydroxylase deficiency (21OHD). TART are likely to contribute to the androgen excess in 21OHD patients, but a direct quantification of steroidogenesis from these tumors has not been yet done. OBJECTIVE: We aimed to define the production of 11-oxygenated 19-carbon (11oxC19) steroids by TART. METHODS: Using liquid chromatography-tandem mass spectrometry, steroids were measured in left (n = 7) and right (n = 4) spermatic vein and simultaneously drawn peripheral blood (n = 7) samples from 7 men with 21OHD and TART. For comparison, we also measured the peripheral steroid concentrations in 5 adrenalectomized patients and 12 age- and BMI-matched controls. Additionally, steroids were quantified in TART cell- and adrenal cell-conditioned medium, with and without adrenocorticotropic hormone (ACTH) stimulation. RESULTS: Compared with peripheral blood from 21OHD patients with TART, the spermatic vein samples displayed the highest gradient for 11ß-hydroxytestosterone (11OHT; 96-fold) of the 11oxC19 steroids, followed by 11-ketotestosterone (47-fold) and 11ß-hydroxyandrostenedione (11OHA4; 29-fold), suggesting production of these steroids in TART. TART cells produced higher levels of testosterone and lower levels of A4 and 11OHA4 after ACTH stimulation compared with adrenal cells, indicating ACTH-induced production of testosterone in TART. CONCLUSION: In patients with 21OHD, TART produce 11oxC19 steroids, but in different proportions than the adrenals. The very high ratio of 11OHT in spermatic vs peripheral vein blood suggests the 11-hydroxylation of testosterone by TART, and the in vitro results indicate that this metabolism is ACTH-sensitive.

Incidental Finding of Bilateral Ovarian Adrenal Rest Tumor in a Patient With Congenital Adrenal Hyperplasia: A Case Report and Brief Review.

Ovarian adrenal rest tumors (OART) are tumors that develop in females with congenital adrenal hyperplasia (CAH). In contrast to their counterpart in testicles, they are exceptional and few cases have been reported in the literature. In this report, we present clinicopathological findings of a female patient with CAH due to 21-hydroxylase deficiency who was incidentally diagnosed with OART with a review of the literature. The 14-year-old patient, who was raised as a boy, developed a virilizing syndrome with high testosterone levels that were attributed to non adherence to her replacement corticosteroid therapy. She consulted for sex reassignment surgery. Pelvic ultrasound was normal. She underwent hysterectomy and bilateral adnexectomy. No abnormalities were noticed during the operation. Grossly, both ovaries were variegated with well circumscribed and lobulated, brownish-yellow nodules. Histologically, the nodules were composed of nests of large polygonal cells with centrally located nuclei and prominent nucleoli. There was mild atypia and no crystals of Reinke. Thus, the findings of the histopathological examination were consistent with bilateral OART. Histological differential diagnosis of OART can be challenging particularly with leydig cell tumor, stromal luteoma and steroid cell tumors, not otherwise specified. OART must be considered in women with CAH and persistent virilizing symptoms despite negative imaging results.

Long-term outcome of partial P450 side-chain cleavage enzyme deficiency in three brothers: the importance of early diagnosis.

OBJECTIVE: CYP11A1 mutations cause P450 side-chain cleavage (scc) deficiency, a rare form of congenital adrenal hyperplasia with a wide clinical spectrum. We detail the phenotype and evolution in a male sibship identified by HaloPlex targeted capture array. FAMILY STUDY: The youngest of three brothers from a non-consanguineous Scottish family presented with hyperpigmentation at 3.7 years. Investigation showed grossly impaired glucocorticoid function with ACTH elevation, moderately impaired mineralocorticoid function, and normal external genitalia. The older brothers were found to be pigmented also, with glucocorticoid impairment but normal electrolytes. Linkage studies in 2002 showed that all three brothers had inherited the same critical regions of the maternal X chromosome suggesting an X-linked disorder, but analysis of NR0B1 (DAX-1, adrenal hypoplasia) and ABCD1 (adrenoleukodystrophy) were negative. In 2016, next-generation sequencing revealed compound heterozygosity for the rs6161 variant in CYP11A1 (c.940G>A, p.Glu314Lys), together with a severely disruptive frameshift mutation (c.790_802del, K264Lfs*5). The brothers were stable on hydrocortisone and fludrocortisone replacement, testicular volumes (15-20 mL), and serum testosterone levels (24.7, 33.3, and 27.2 nmol/L) were normal, but FSH (41.2 µ/L) was elevated in the proband. The latter had undergone left orchidectomy for suspected malignancy at the age of 25 years and was attending a fertility clinic for oligospermia. Initial histology was reported as showing nodular Leydig cell hyperplasia. However, histological review using CD56 staining confirmed testicular adrenal rest cell tumour (TART). CONCLUSION: This kinship with partial P450scc deficiency demonstrates the importance of precise diagnosis in primary adrenal insufficiency to ensure appropriate counselling and management, particularly of TART.

Testicular Adrenal Rest Tumor (TART) in congenital adrenal hyperplasia.

Congenital adrenal hyperplasia is one of the most common autosomal recessive genetic disorders. Testicular adrenal tumors are significant complications of congenital adrenal hyperplasia. We would like to present two patients of testicular adrenal rest tumors. Patient 1 24 year-old male, he was diagnosed with congenital adrenal hyperplasia at the age of 8 due to precocious puberty. He received hydro-cortisone treatment until the age of 18. Testicular mass had been detected and right radical orchiectomy had been applied 6 months ago and reported as testicular adrenal rest tumor. In scrotal ultrasound, a mixed type mass lesion (6 × 4x3 cm) covering a large part of left testis was observed. The imaging findings were consistent with adrenal rest tumor. The patient took adrenocorticotropic hormone supressive therapy with dexamethasone 0.75 mg once a day. Patient 2, 38 year-old male, he had been followed-up as adrenal insufficiency for 35 years. He underwent right orchiectomy operation due to the testicular mass in 2010 and the pathological examination revealed Leydig cell tumor. In scrotal ultrasound, small multifocal lesions were detected on the left testis and resection was done. It was reported as testicular adrenal rest tumor. He is being followed-up with glucocorticoid treatment according to androgen and adrenocorticotropic hormone levels. Early diagnosis of testicular adrenal rest tumor is significant in preventing irreversible testicular damage and infertility. In the differential diagnosis, we should keep in mind that testicular adrenal rest tumor can mimic other testicular tumors such as primary germ cell tumors.

Ovarian Adrenal Rest Tumors Undetected by Imaging Studies and Identified at Surgery in Three Females with Congenital Adrenal Hyperplasia Unresponsive to Increased Hormone Therapy Dosage.

Patients with congenital adrenal hyperplasia have a predisposition for developing adrenal rest tumors. In contrast to testicular adrenal rest tumors, ovarian adrenal rest tumors are less common, and only a few cases have been reported in the literature. This report presents three Chinese female congenital adrenal hyperplasia patients (9 to 15 years of age) with small ectopic adrenal cortical nodules that were not detected by imaging but were diagnosed at surgery. All three patients developed virilization with elevation of 17- hydroxyprogesterone, androstenedione, and androgen levels despite receiving maximum adrenal hormone replacement therapy. Ultrasound and magnetic resonance imaging of the abdomen and pelvis suggested bilateral expansion of the adrenal glands, but no lesions of the ovaries were observed. Laparoscopy and/or laparotomy revealed small nodular lesions surrounding the pelvic gonad in all three cases. Histopathological examination of the resected tissue in all cases revealed hyperplasic nodules of cells surrounded by fibrous tissue. The cells were arranged as nests with abundant cytoplasm, which were partially lightly stained with a small centered nucleus. Immunohistochemistry staining revealed the cells to be synaptophysin positive, melan-A positive, and chromogranin A negative, indicating the cells were adrenocortical tissue and not adrenal medullary cells. Thus, the findings of the histopathological examination were consistent with ovarian adrenal rest tumors. Female congenital adrenal hyperplasia patients with virilization who showed an inadequate response to hormone therapy and had negative imaging results may benefit from laparoscopic examination or laparotomy in order to confirm the diagnosis of ovarian adrenal rest tumors while receiving unilateral subtotal adrenalectomy or subtotal bilateral adrenalectomy.

[Characterization of ovarian adrenal rest tumors in children and adolescent females with congenital adrenal hyperplasia due to 21-hydroxylase deficiency].

OBJECTIVE: To summarize the characterization of ovarian adrenal rest tumors (OART) in children and adolescent females with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD). METHOD: We have diagnosed 4 cases of CAH 21-OHD with OART in the recent 5 years in pediatric endocrinology unit of the first affiliated hospital of Sun Yat-Sen University. Clinical characterizations were summarized, including symptoms, growth patterns and bone age advancements, serum steroid concentrations, imaging results and the follow-up data. RESULT: The 4 cases of OART accounted for 2.5 % of the CAH 21-OHD girls, which was much lower than the detection rate, 29.5%, of testicular ART in our patient group during the same period. The 4 cases included 3 salt wasters and 1 with simple virilizm. OART were diagnosed at the age of 8.9 years, 15.8 years, 21.4 years and 9.3 years, respectively. Before the diagnosis of OART, their daily hydrocortisone doses reached 16 mg/(m(2)·d)to 24 mg/(m(2)·d). The patients presented with deteriorated acne, deepened voice, amenorrhea (2 cases), accelerated growth and advanced bone age, ΔBA/ΔCA reached 1.2(during GnRHa treatment)and 2.0. Their serum adrenal steroids increased significantly and hyperplasia of adrenal glands were found in all patients. The diagnosis could be confirmed before the operation in only 1 case. The diagnosis could not be made until the planned sub-total adrenalectomy in the other 3 cases. The follow-up periods of OART were 4.8, 4.7, 3.8 and 2.7 years, respectively. Removal of OART resulted in symptoms relief at least partialy and lowered daily hydrocortisone doses, 14 to 19 mg/(m(2)·d). CONCLUSION: The detection rate of OART was much lower than testicular ART. Before the diagnosis of OART, the patients presented with deteriorated virilescence, accelerated growth and advanced bone age, elevated serum adrenal steroids and hyperplasia of adrenal glands. Removal of the OART resulted in symptoms relief at least partialy.

Ectopic virilising adrenocortical tumour in the spinal region in an 8 year-old boy: a case report and review of the literature.

INTRODUCTION: The adrenocortical rest tumours are the very rare entity in the pediatric population. They are usually found along the gonadal descent paths (celiac axis, the broad ligamen, the adnexa of the testes or the spermatic cord). They have been also described to occur at rare ectopic sites like intracranial locations, placenta, kidney, pancreas and liver. CLINICAL CASE: Here we present a unusual case of an ectopic, virilising, primary adrenocortical tumour localized in the spinal region in a 8 years-old-boy. DISCUSSION: This is the first case of functional ectopic, adrenocortical tumour localized in the spinal region in a pediatric population. We discuss here the clinical presentation and the diagnostic challenges and provide the review of the literature.

[Diagnostic benefits of adrenocortical scintigraphy in hepatic adrenal rest tumor].

An 81-year-old female was referred to our hospital for the examination of an S7 liver tumor. The tumor was suspected to be a hepatic adrenal rest tumor (HART) based on ultrasonography, dynamic CT, Gd-EOB-DTPA-enhanced MRI, and CT during abdominal angiography. After various hormonal tests, the tumor was confirmed as hormonally non-functional. The diagnosis of HART was confirmed based on (131)I-adosterol accumulation in the tumor by adrenocortical scintigraphy. The resected tumor was histologically compatible with HART, and it may have been able to produce cortisol based on the immunohistochemical findings of various adrenocortical hormone metabolic enzymes. Adrenocortical scintigraphy may thus be useful in diagnosing HART.

Restoration of fertility by gonadotropin replacement in a man with hypogonadotropic azoospermia and testicular adrenal rest tumors due to untreated simple virilizing congenital adrenal hyperplasia.

CONTEXT: Classical congenital adrenal hyperplasia (CAH), a genetic disorder characterized by 21-hydroxylase deficiency, impairs male fertility, if insufficiently treated. PATIENT: A 30-year-old male was referred to our clinic for endocrine and fertility assessment after undergoing unilateral orchiectomy for a suspected testicular tumor. Histopathological evaluation of the removed testis revealed atrophy and testicular adrenal rest tumors (TARTs) and raised the suspicion of underlying CAH. The remaining testis was also atrophic (5 ml) with minor TARTs. Serum 17-hydroxyprogesterone levels were elevated, cortisol levels were at the lower limit of normal range, and gonadotropins at prepubertal levels, but serum testosterone levels were within the normal adult range. Semen analysis revealed azoospermia. CAH was confirmed by a homozygous mutation g.655A/C>G (IVS2-13A/C>G) in CYP21A2. Hydrocortisone (24 mg/m(2)) administered to suppress ACTH and adrenal androgen overproduction unmasked deficient testicular testosterone production. As azoospermia persisted due to sustained hypogonadotropic hypogonadism, a combined s.c. gonadotropin replacement with human chorionic gonadotropin (hCG) (1500 IU twice weekly) and FSH (human menopausal gondadotropin (hMG) 150 IU three times weekly) was initiated. RESULTS: Normalization of testosterone levels and a stable low sperm concentration (0.5 mill/ml) with good sperm motility (85% A+B progressive) were achieved within 21 months of treatment. Despite persisting TARTs, while receiving treatment, the patient successfully impregnated his wife twice, the latter impregnation leading to the birth of a healthy girl. CONCLUSIONS: TARTs in unrecognized (simple virilizing) CAH may lead to unnecessary orchiectomy. In hypogonadotropic, azoospermic CAH, a combined treatment with oral corticosteroids and subcutaneously administered hCG and FSH can successfully restore testicular testosterone production and fertility, even if only one hypoplastic and atrophic testis with adrenal rest tumors is present.

Hyperandrogenism of ovarian etiology: utilizing differential venous sampling for diagnosis.

BACKGROUND: We report the diagnosis and management of testosterone hypersecretion in the presence of an adrenal mass and no initially discernible ovarian mass. CASE: A 64-year-old woman with severe hyperandrogenism, including serum testosterone 392 ng/dL, male-pattern baldness, and hirsutism, required bilateral ovarian and adrenal venous sampling to determine the source of the testosterone. Once an ovarian origin was confirmed, total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed for definitive treatment. The adrenal adenoma was left in situ. There was a dramatic decrease in subjective symptomatology and normalization of testosterone postoperatively. CONCLUSION: Preoperative differential venous sampling determined the correct source of testosterone. Subsequent removal of the ovary and steroid cell tumor correctly treated the hyperandrogenism and avoided an unnecessary surgical procedure for the adrenal adenoma.

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

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.

Unilateral testicular tumour associated to congenital adrenal hyperplasia: Failure of specific tumoral molecular markers to discriminate between adrenal rest and leydigioma.

Testicular adrenal rest tumours are frequently associated with congenital adrenal hyperplasia (CAH). These ACTH-dependent tumours cannot be easily distinguished histologically from Leydig-cell tumours. We report the case of a 30-year-old man who was explored for infertility, azoospermia and unilateral testicular tumour. High levels of 17-OH progesterone and ACTH, low cortisol and undetectable gonadotropins levels, associated to bilateral adrenal hyperplasia, led to the diagnosis of CAH by 21-OH deficiency with a composite heterozygoty. The testicular tumour was first considered as adrenal rest. However, histological analysis of this unilateral painful tumour showed a steroid-hormone-secreting cell proliferation with atypical and frequent mitosis. To discriminate between a benign adrenal rest tumour and a possible malignant leydigioma, tumoral expression of specific gene products was analyzed by RT-PCR. No 11-beta-hydroxylase nor ACTH receptor mRNAs could be found in the tumour, which did not behave like usual adrenal rest cells. For this unilateral testicular tumour, the lack of adrenal-specific markers associated with a high rate of mitosis and pleiomorphism supported a leydigian origin with malignant potential. However, lack of tumoral LH-R mRNA expression and a tumour-free 3-year follow-up led us to retain the diagnosis of adrenal rest tumour with loss of adrenal gene expression and progressive autonomous behaviour.

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

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.

Testicular adrenal rest tumors in adult males with congenital adrenal hyperplasia: evaluation of pituitary-gonadal function before and after successful testis-sparing surgery in eight patients.

CONTEXT: In male patients with congenital adrenal hyperplasia (CAH), testicular adrenal rest tumors (TART) are frequently present. These tumors can interfere with testicular function. Intensifying glucocorticoid therapy does not always lead to tumor regression and improvement of testicular function. Recently, testis-sparing surgery was introduced for treatment of TART. OBJECTIVE: The aim of this study was to evaluate tumor volume, symptoms, and pituitary-gonadal function in male patients with CAH caused by 21-hydroxylase deficiency and bilateral TART before and after testis-sparing surgery. SETTING: This study was conducted at Radboud University Nijmegen Medical Centre in The Netherlands. PATIENTS: Eight adult male CAH patients with bilateral TART and infertility were included. INTERVENTIONS: Evaluation of testicular magnetic resonance imaging, symptoms, fasting serum concentrations of ACTH, LH, FSH, inhibin B, 17-OH progesterone, androstenedione, testosterone, and estrone, and semen analysis (six of eight patients) was performed before and 6 and 22 months after testis-sparing surgery. MAIN OUTCOME MEASURES: The main outcome measures were absence of residual tumor and improvement of symptoms and pituitary-gonadal function. RESULTS: Residual tumors were not found on any of the patients' magnetic resonance imaging after surgery. Two patients reported testicular pain and discomfort that disappeared after surgery. Parameters of pituitary-gonadal function did not improve after surgery: semen analysis showed azoospermia (five patients) or oligospermia (one patient) without improvement, and all patients had persistently low inhibin B concentrations. CONCLUSION: Testis-sparing surgery did not improve pituitary-gonadal function despite successful removal of the tumors. Further studies are needed to investigate whether surgery at an earlier stage in the natural history of TART can prevent permanent testicular damage.

Testicular adrenal rest hyperplasia due to 21-hydroxylase deficiency: a case report.

Bilateral testicular tumors are a rare complication of congenital adrenal hyperplasia. It can be extremely difficult to distinguish histologically between Leydig cell tumors and adrenocortical rest hyperplasia, which may lead in some cases to unnecessary orchidectomy. A 7-yr-old boy was admitted because of precocious puberty and enlargement of testicles. Hormonal studies established the diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Testicular biopsy revealed interlacing strands, cords, and rests of cells resembling interstitial (Leydig) cells but with no Reinke crystalloids. Here we report a case of testicular adrenal rest hyperplasia in congenital adrenal hyperplasia and discuss the pathological and clinical features and origin of this rare lesion by using immunohistochemical evaluation.

Testis sparing surgery for steroid unresponsive testicular tumors of the congenital adrenal hyperplasia.

The association between testicular tumors/nodules and congenital adrenal hyperplasia (CAH) has been recognized for many years. Tumors are considered to be an aberrant adrenal tissue that has descended with the testes and has become hyperplastic due to ACTH stimulation. The recommended treatment consists of increasing the glucocorticoid dose to suppress ACTH secretions. If the testicular size is not reduced after suppression therapy or a side effect of glucocorticoid dose is noted, surgical intervention should be considered. We diagnosed steroid unresponsive testicular tumors of the CAH in two patients who were treated by testicular sparing tumor enucleation. We believe that testis sparing surgery is the procedure of choice for all patients with testicular adrenal rest tumor, since it maximizes future fertility potential.