Uncommon adrenal rest tumors and massive adrenal enlargement in adult with congenital adrenal hyperplasia mimicking metastasis from pleomorphic sarcoma.

BACKGROUND: Congenital adrenal hyperplasia (CAH) encompassed a bunch of autosomal recessive disorders characterized by impaired cortisol levels due to an enzymatic deficiency in steroid synthesis. In adult male patients with CAH, a frequent complication related to poor disease control is the development of ectopic adrenocortical tissue in the testes, named testicular adrenal rest tumors (TART). Conversely, ovarian adrenal rest tumors (OART) in females are extremely rare and adrenal rests in sites other than gonads are so uncommon to have been described only few times in literature. CASE PRESENTATION: We report a case of a male patient with untreated CAH and oncologic history of pleomorphic sarcoma who presented with massive bilateral adrenal enlargement and adrenal rest tumors in peri-lumbar and peri-cecal sites, which mimicked metastasis from sarcoma. CONCLUSIONS: The development of massive adrenal enlargement and ectopic adrenal rest tumors in sites other than gonads, even if very uncommon, should be suspected in patients with CAH and prolonged periods of undertreatment.

[Diagnosis and treatment of 21-hydroxylase deficiency with testicular adrenal rest tumors:a report of three cases and literature review].

Objective: To provide insight into the diagnosis for clinicians, the clinical characteristics, diagnosis and treatment history of 3 patients with 21-hydroxylase deficiency (21-OHD) and testicular adrenal rest tumors (TART) were analyzed. Methods: The clinical, laboratory and imaging data of 3 male patients with 21-OHD and TART, confirmed with CYP21 gene sequencing, from May 2010 to May 2021 in the First Medical Center of Chinese PLA General Hospital were analyzed retrospectively. The treatment strategy and clinical outcome were followed up. Results: All the 3 patients were first diagnosed with bilateral adrenal mass at the age of 27-42 years old. They were 145-162 cm tall. The levels of progesterone, 17-hydroxyprogesterone, and adrenocorticotropic hormone (ACTH) of the 3 patients were relatively high, and that of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) of the 3 patients were low. Testosterone level of 1 patient was significantly elevated, and that of the other 2 patients was below the lower limit of normal range. Testicular ultrasound showed heterogeneous hyperechoic masses in both testes. CT of the adrenal glands showed bilateral adrenal enlargement with mass. All 3 patients were treated with dexamethasone. After 4-96 months of follow-up, 17-hydroxyprogesterone level was kept above the median normal level. One of the patients got married and had a baby after treatment. The sizes of adrenal hyperplasia and testicular masses reduced to various degrees with the change of the testicular masses being proportional to that of adrenal hyperplasia. Conclusions: Patients with 21-OHD are prone to have TART, leading to the impaired testicular function. Early glucocorticold therapy is beneficial to the reduction of TART and restoration of testicular function.

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.

Bilateral testicular masses and adrenal insufficiency: is congenital adrenal hyperplasia the only possible diagnosis? First two cases of TARTS described in Addison-only X-linked adrenoleukodystrophy and a brief review of literature.

BACKGROUND: Testicular adrenal rest tumors (TARTs) are benign masses deemed to originate from pluripotent testicular steroidogenic cells that grow under chronic ACTH stimulation. These lesions, occasionally misdiagnosed as Leydig cell tumors (LCTs), are typically described in patients with congenital adrenal hyperplasia (CAH). X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder of beta-oxidation with accumulation of very long chain fatty acids (VLCFAs) in various tissues, and a rare cause of primary adrenal insufficiency (PAI). TARTs have never been associated with X-ALD. CASE 1 DESCRIPTION: A 19-year old male, who had previously undergone bilateral enucleation of presumed LCTs, was referred to our unit. Follow-up scans showed persistent bilateral lesions compatible with TARTs. Biochemical exams revealed PAI but excluded CAH. A serum VLCFAs panel was consistent with X-ALD, with gene testing confirming the diagnosis. Histological revision of the previously resected testicular lesions was compatible with TARTs. Start of glucocorticoid replacement therapy was associated with a reduction of testicular masses. CASE 2 DESCRIPTION: A 26-year old X-ALD male was diagnosed with bilateral testicular lesions compatible with TARTs. These lesions increased after ACTH elevation following switch to modified-release hydrocortisone. Clinical and sonographic findings allowed for a "watchful-waiting" approach, avoiding unnecessary surgery. CONCLUSION: These are the first cases reported of TARTs in patients with X-ALD-associated PAI. Testicular lesions in patients with an early onset of ACTH elevation, regardless of the cause, should always be thoughtfully investigated, as they may reveal themselves as TARTs. We suggest that all patients affected from chronic ACTH elevation of a young age of onset should undergo testicular ultrasound in order to evaluate the presence of these lesions. GRT in these patients might also help preserving fertility.

Case Report:clinical experience of bilateral giant pediatric Testicular adrenal rest tumors with 3 Beta-Hydroxysteroid Dehydrogenase-2 family history.

BACKGROUND: We reported a patient with Testicular adrenal rest tumors(TARTs) caused by congenital adrenal hyperplasia(CAH). TARTs occur frequently in CAH population with 21-hydroxylase deficiency(21-OHD). There are few reports of TARTs with 3ß-hydroxysteroid dehydrogenase deficiency-2 (3ß-2HSD).Furthermore,gaint TARTs are rarely mentioned in reported cases involving affected siblings. CASE PRESENTATION: A 14-year-old male patient was admitted by congenital adrenal hyperplasia with progressively increasing bilateral testicular masses.The Patient and his elder brother had been performed mutational and chromosome analysis and biopsy. Hormonal and anthropometric measurements were performed during endocrine treatments. We successfully performed surgery and excised two 83mm×46mm×44mm and 74mm×49mm×31mm tumors. Our pathology and immunochemistry tests have proven TARTs in patient. At first, both siblings received regular doses of hydrocortisone and fludrocortisones and tumor size regressed. During the one-year irregular intake due to Covid-19 pandemic, endocrine treatment became insensitive and tumor size slowly increased. The gene analysis reported two novel mutations C.776 C>T and C.674 T>A. The C.776 C>T is from father and has been reported. The C.674 T>A inherited from mother and cannot found in gene library and may related to TARTs. CONCLUSIONS: This case illustrates inadequate hormone therapy could cause tumor enlargement. It is essential to seek for ultrasound examination once suspected scrotal mass occurred.It is necessary to adjust endocrine medicine or adopt surgery in refractory gaint TARTs. And presence of tunica vaginalis cavity may indicate the severity of TARTs in surgery.

[Clinical characteristics of testicular adrenal rest tumor and factors associated with its occurrence in 21-hydroxylase deficiency patients].

Objective: To analyze the occurrence and clinical characteristics of testicular adrenal rest tumor (TART) in 21-hydroxylase deficiency (21-OHD) patients, and further explore the possible factors related to the occurrence of TART. Methods: Twenty-seven male 21-OHD patients who visited Peking Union Medical College Hospital from January to December 2018 were enrolled and their clinical and biochemical data were collected. The CYP21A2 mutations were identified by Sanger sequencing and multiple ligation probe amplification (MLPA). Patients were divided into different subgroups according to the residual activity of 21-hydroxylase: Null (residual enzymatic activity 0, 3 cases), group A (0-<1%, 9 cases), group B (1%-5%, 7 cases), group C (20%-50%, 2 cases) and group D (6 cases). The ultrasound of testis was used to detect whether there was TART and its morphological characteristics. Results: Among 27 patients with 21-OHD [average age (17.4±9.3) years], 55.6% (15/27) had TART lesions, most of them were adolescents, and the youngest was only 4 years old. The lesions were mostly bilateral and hypoechoic. The levels of 17α-hydroxyprogesterone (17-OHP) and progesterone in patients with TART were higher than those in patients without TART [17-OHP: 199.6 (62.1, 232.7) nmol/L vs 7.4 (3.2, 105.0) nmol/L, P=0.003; progesterone: 97.1 (42.0, 126.8) nmol/L vs 5.4 (0.7, 20.0) nmol/L, P=0.004]. There was a correlation between the occurrence of TART and genotype of CYP21A2. Patients with Null and A genotypes were more likely to have TART than those with B and C genotypes (8/12 vs 4/9, P=0.021). Conclusions: TART is common in 21-OHD male patients, which is related to 17-OHP and CYP21A2 genotype. It is of great significance for the early screening of TART in 21-OHD patients.

Case series of testicular adrenal rest tumours in boys with congenital adrenal hyperplasia: A single centre experience.

Testicular adrenal rest tumours (TART) are aberrant adrenal tissue within the testes (1). Although benign, they can lead to obstruction of the seminiferous tubules and infertility in patients with congenital adrenal hyperplasia (CAH). We report six boys who developed TART, a complication of CAH. Diagnosis was confirmed by ultrasound and testicular vein sampling of elevated 17-hydroxyprogesterone (17-OHP) levels. Glucocorticoids dosages were increased 1½-2 folds to suppress size of the aberrant adrenal tissues. Despite reductions in 17-OHP, the lesions remained unchanged. Three patients had testis-sparing surgery to excise the TART and to preserve normal testicular tissues.

Para-ovarian adrenal rest tumors: gynecologic manifestations of untreated congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) is an inherited disorder of adrenal steroidogenesis often diagnosed in infancy. Gynecologists may encounter adult patients with CAH due to the clinical effects of increased androgens, e.g. hirsutism, clitoromegaly, oligomenorrhea, or, rarely, pelvic masses. This case report reviews the association of para-ovarian adrenal rest tumors with CAH, and the role of gynecologists in their evaluation and treatment. A 23-year-old woman with CAH (21-hydroxyase deficiency) untreated for the past 5 years presented with a pelvic mass and elevated serum testosterone (1433 ng/dL) and plasma ACTH (1117 pg/mL). Intraoperative findings revealed multiple retroperitoneal masses. Final pathology demonstrated adrenal rest tissue. Para-ovarian and ovarian adrenal rest tumors may present as a rare gynecologic manifestation in patients with untreated CAH.

Computed tomography findings of testicular adrenal rest tumors resulted from 21-hydroxylase deficiency.

21-hydroxylase deficiency is a rare kind of autosomal recessive disorders, which can result in congenital adrenal hyperplasia and/or testicular adrenal rest tumors. 21-hydroxylase deficiency with TARTs is prone to be misdiagnosed as Leydig cell tumors. Although the sonographic characteristics of TARTs have been summarized in previous reports, its features in computed tomography images were rarely reported. In this study, we presented and summarized the clinical and imaging data of a special case suffering this disease, aiming to improve the imaging diagnosis performance.

Testicular Adrenal Rest Tumors in Boys and Young Adults with Congenital Adrenal Hyperplasia.

PURPOSE: Testicular adrenal rest tumors are a well-known complication in males who have congenital adrenal hyperplasia with potential infertility in adulthood. We assessed the prevalence of testicular adrenal rest tumors in infants to young men presenting to a congenital adrenal hyperplasia Comprehensive Care Center. MATERIALS AND METHODS: A total of 35 males with congenital adrenal hyperplasia due to 21-hydroxylase deficiency underwent scrotal ultrasonography, including 7 younger than 5 years, 9 who were 5 to 12 years old and 19 who were older than 12 years. Three and 35 patients had classic and nonclassic congenital adrenal hyperplasia, respectively. Bone age x-ray or advanced bone age x-ray history, glucocorticoid dose, fludrocortisone dose, and serum 17-hydroxyprogesterone, testosterone and androstenedione levels within 3 months of ultrasound were also recorded. RESULTS: Testicular adrenal rest tumors were detected in 5 of 35 patients (14%), including 1 of 9 (11%) who were 5 to 12 years old and 4 of 19 (21%) who were older than 12 years. The tumors were not detected in any patients younger than 5 years, including 1 infant with poor hormonal control. The youngest patient with positive findings was 6.6 years old. All patients with positive findings had bilateral disease and only 1 had suspicious physical findings. The glucocorticoid dose and 17-hydroxyprogesterone did not differ between patients with vs without a testicular adrenal rest tumor. Those with a tumor were more likely to have advanced bone age x-ray results (100% vs 42%, p = 0.04) and higher fludrocortisone dose (p <0.01). All males with nonclassic congenital adrenal hyperplasia had negative tumor findings. CONCLUSIONS: Testicular adrenal rest tumors were present in young males with classic congenital adrenal hyperplasia but not in infants or toddlers. These tumors were associated with higher fludrocortisone requirements and a history of advanced bone age x-ray results. However, the tumors did not develop in all poorly controlled males. Longitudinal studies are needed to understand the individual predisposition to testicular adrenal rest tumors and the age at which to begin screening patients with congenital adrenal hyperplasia.

Testicular adrenal rest tumors in congenital adrenal hyperplasia-cross-sectional study of 51 Croatian male patients.

Testicular adrenal rest tumors (TARTs) are common cause of infertility in males with congenital adrenal hyperplasia (CAH). We studied the role of genotype and disease regulation on TART development, their impact on gonadal function, and frequency in 47 21-hydroxylase deficiency (21-OHD) and four 11-hydroxylase deficiency (11-OHD) male patients. Testicular ultrasound (TU), genotype, hormonal measurement in 51, and spermiogram in five patients were performed. TARTs were detected in 14 SW21-OHD and one 11-OHD patient: 1/8 patients aged <7 years (1.8 years old is the youngest), 1/8 patients aged <12 years, 5/17 patients aged <18 years, and in 8/18 adults. All 21-OHD TART patients had exclusively severe mutations of CYP21A2 gene. Poor hormonal control in 8/15 patients with and 12/36 patients without TART indicates correlation of tumor development with poor disease control. None of the TART patients fathered a child. Low inhibin-B was found in 7/15 TART patients. Azoospermia was found in four and oligoasthenozoospermia in one patient. CONCLUSION: TART was detected exclusively in patients with severe CYP21A2 mutations. Disease regulation plays a role in development of TART that impairs testicular function and increases the risk of infertility. Screening for TART by TU is indicated from early childhood. What is Known: • Due to improved diagnostic and therapeutic possibilities, majority of the male patients with congenital adrenal hyperplasia nowadays reach adulthood and screening for long-term complications is becoming more important. • Testicular adrenal rest tumors (TARTs) are common cause of infertility and impaired gonadal function in males with CAH. What is New: • A 1.8-year-old boy described in this paper is the youngest reported patient with TART. • Screening for TART by testicular ultrasound from early childhood, especially in patients with severe CYP21A mutations, is recommended.

Congenital Adrenal Hyperplasia with 11-Beta Hydroxylase Deficiency with Testicular Adrenal Rest Tumour.

Congenital adrenal hyperplasia refers to the non-malignant enlargement of adrenal gland tissue as a result of deficiency of one of several enzymes involved in adrenal hormone synthesis, secondary to a genetic mutation. 11 - Beta hydroxylase is one such enzyme, and its deficiency is a rare cause of Congenital Adrenal Hyperplasia. We describe the case of an 18-year old man who presented to us with an acute right ganglio-capsular bleed, hypertension and bilateral scrotal swelling. Investigations revealed hypokalemia, and normal renal and cardiac functions. Furthermore, sex hormone levels were found to be markedly raised, and Renin to Aldosterone ratio was also deranged. CT imaging of the adrenals confirmed hyperplasia, and ultrasound of the testes confirmed Testicular Adrenal Rest tumour, a rare finding. His condition improved significantly with treatment, and he is currently undergoing physical and occupational rehabilitation. Our case highlights the importance of evaluation of hypertension in young patients and a high degree of suspicion for rarer causes.

Experience in optimizing fertility outcomes in men with congenital adrenal hyperplasia due to 21 hydroxylase deficiency.

OBJECTIVE: Men with congenital adrenal hyperplasia (CAH) have impaired fertility. We aimed to assess fertility outcomes and the importance of hypogonadotropic hypogonadism, testicular failure and the presence of testicular adrenal rest tumours (TART). DESIGN: Retrospective analysis of men attending an adult CAH clinic in a tertiary centre. PATIENTS: Fifty men with CAH due to 21 hydroxylase deficiency were identified of whom 35 were salt wasting and 15 were non-salt-wasting. MEASUREMENTS: Review of fertility history and parameters including luteinizing hormone (LH), follicle-stimulating hormone (FSH), androstenedione, 17-hydroxyprogesterone (17-OHP), semen analysis and the presence of testicular adrenal rest tissue (TART) on ultrasound. RESULTS: TART were detected by ultrasound in 21 (47%), and their presence was associated with an elevated FSH (P = 0·01). Severe oligospermia was present in 11 of 23 (48%), and this was associated with an elevated FSH (P = 0·02), suppressed LH (P < 0·01) and TART (P = 0·03) when compared to those with a sperm count >5 × 10(6) per ml. Of those that desired fertility, 10 of 17 (59%) required treatment intensification and four underwent in vitro fertilization. Intensification resulted in a rise in median LH (0·6-4·3 IU/l; P = 0·01). Live birth rate was 15 of 17 (88%) with a median (range) time to conception of 8 (0-38) months. CONCLUSIONS: Suppressed LH is a marker for subfertility and is often reversible. Testicular failure is closely associated with TART formation. If TART are detected, sperm cryopreservation should be offered given the risk of progression to irreversible testicular failure. Male fertility in CAH can be improved by intensified treatment and assisted reproductive technology.

Chemical Shift MR Imaging of the Adrenal Gland: Principles, Pitfalls, and Applications.

Adrenal lesions are a common imaging finding. The vast majority of adrenal lesions are adenomas, which contain intracytoplasmic (microscopic) fat. It is important to distinguish between adenomas and malignant tumors, and chemical shift magnetic resonance (MR) imaging can be used to accomplish this distinction by depicting the fat in adenomas. Chemical shift imaging is based on the difference in precession frequencies of water and fat molecules, which causes them to be in different relative phases during the acquisition sequence and allows in-phase and opposed-phase images to be obtained. It is important to acquire these images by using the earliest possible echo times, with the opposed-phase echo before the in-phase echo, and by using a single breath hold to preserve diagnostic accuracy. Intracytoplasmic fat is depicted as signal drop on opposed-phase images when compared with in-phase images. Both qualitative and quantitative methods for assessing signal drop are detailed. The appearances of adrenal adenomas and other adrenal tumors on chemical shift MR images are described, and discriminatory ability at chemical shift MR imaging compared with that at adrenal computed tomography (CT) is explained. Other adrenal-related conditions in which chemical shift MR imaging is helpful are also discussed. Chemical shift MR imaging is a robust tool for evaluating adrenal lesions that are indeterminate at nonenhanced CT. However, it is important to know the advantages and disadvantages, including several potential imaging pitfalls. The characterization of adrenal lesions by using chemical shift MR imaging and adrenal CT should always occur in the appropriate clinical setting.

Testicular adrenal rest tumours in young adult males with congenital adrenal hyperplasia: prevalence and impact on testicular function.

Testicular adrenal rest tumours (TARTs) have been described in patients with congenital adrenal hyperplasia (CAH). The aim of the study was to determine the prevalence of TARTs in patients with CAH, the associated factors and their impact on gonadal function. It is a prospective study concerning six young adult men with CAH, four cases with 21-hydroxylase deficiency and two cases with 11-hydroxylase deficiency. All patients were under glucocorticoid therapy. The mean age was 25 years (range: 20-31). All patients underwent a physical examination with testicular palpation, scrotal ultrasonography, a blood sample for serum testosterone, FSH, LH, inhibin B, ∆4-androstenedione and 17-OH-progesterone measurements and a semen analysis. Ultrasound revealed TARTs in four patients; three were bilateral. The mean tumour size was 6.3 ml (range: 0.02-14.1). The tumours were palpable in two cases. 17-OH-progesterone was <10 ng/ml in all cases. Decreased testosterone level was found in one case. The semen analysis revealed azoospermia in one case and poor semen quality in four patients. TARTs were common and associated with impaired spermatogenesis.

Hepatic adrenal rest tumor: Diagnostic pitfall and proposed algorithms to prevent misdiagnosis as lipid-rich hepatocellular carcinoma.

We present a case of adrenal rest tumor of the liver in which differential diagnosis from lipid rich-hepatocellular carcinoma (HCC) was challenging. The patient was a 50-year-old woman in whom a 3-cm tumorous mass was discovered in segment 7 of the liver during computed tomography evaluation of a uterine leiomyoma. The preoperative diagnosis was HCC, and subsegmental liver resection was performed. The tumor appeared as a well-demarcated golden yellow nodule consisting of clear or partially eosinophilic cells arranged in a trabecular pattern. The initial impression of this lesion was that of clear cell type or lipid-rich type HCC because it stained positive for Hep Par1, but negative for arginase-1 and positive for CD56 which is one of the neuroendocrine markers. The lesion also stained positive for SF-1 and 3ß-HSD, both of which are markers of adrenocortical tissue. The final diagnosis was hepatic adrenal rest tumor. Hepatic adrenal rest tumor should be considered in the differential diagnosis of segment 7 tumor. A diagnostic algorithm that includes immunohistochemical staining for CD56 and arginase-1 is to rule out the possibility of lipid-rich HCC.

Testicular adrenal rest tumors in congenital adrenal hyperplasia: a case report and literature overview.

OBJECTIVE: In this paper, the etiology, differential diagnosis, and therapy of testicular adrenal rest tumors (TARTs) is presented based on a patient presentation and an overview of the most recent literature concerning this subject. METHODS: Retrospective analysis of the clinical and biochemical data of an 18-year-old male patient diagnosed at the age of 2 weeks with the classic salt-wasting form of congenital adrenal hyperplasia that has been monitored in the pediatric and adolescent outpatient department since the age of 4 years. RESULTS: The results of adrenal hormone tests (17-hydroxyprogesterone, 17-ketosteroids, and pregnanes) had been unsatisfactory, particularly over the previous 5 years. Scrotal ultrasound detected TARTs bilaterally. After increasing the dose of hydrocortisone and introducing dexamethasone, considerable regression of the tumors was noted. CONCLUSION: Lack of complete regression of the lesions is caused by fibrosis and is probably due to decreased sensitivity of adrenocorticotropic hormone and angiotensin II receptors in this tissue.

[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.

Testicular tumours in adrenogenital syndrome.

Congenital adrenal hyperplasia (CAH) arises from genetic enzyme defects, often in CYP21A2, causing primary adrenal insufficiency. In this case report, a man in his late 20s with lifelong CAH faced challenges in adhering to medication. Suboptimal treatment led to the development of testicular adrenal rest tumours, diagnosed by ultrasound, and hypogonadism. Enhanced adherence restored hormone levels, promoting eugonadism. Adherence plays a crucial role in diminishing tumour size and preventing complications, potentially necessitating orchiectomy in severe cases.