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.

A Humanized and Viable Animal Model for Congenital Adrenal Hyperplasia-CYP21A2-R484Q Mutant Mouse.

Congenital Adrenal Hyperplasia (CAH) is an autosomal recessive disorder impairing cortisol synthesis due to reduced enzymatic activity. This leads to persistent adrenocortical overstimulation and the accumulation of precursors before the blocked enzymatic step. The predominant form of CAH arises from mutations in CYP21A2, causing 21-hydroxylase deficiency (21-OHD). Despite emerging treatment options for CAH, it is not always possible to physiologically replace cortisol levels and counteract hyperandrogenism. Moreover, there is a notable absence of an effective in vivo model for pre-clinical testing. In this work, we developed an animal model for CAH with the clinically relevant point mutation p.R484Q in the previously humanized CYP21A2 mouse strain. Mutant mice showed hyperplastic adrenals and exhibited reduced levels of corticosterone and 11-deoxycorticosterone and an increase in progesterone. Female mutants presented with higher aldosterone concentrations, but blood pressure remained similar between wildtype and mutant mice in both sexes. Male mutant mice have normal fertility with a typical testicular appearance, whereas female mutants are infertile, exhibit an abnormal ovarian structure, and remain in a consistent diestrus phase. Conclusively, we show that the animal model has the potential to contribute to testing new treatment options and to prevent comorbidities that result from hormone-related derangements and treatment-related side effects in CAH patients.

Risk factors for testicular adrenal rest tumors in pediatric patients with congenital adrenal hyperplasia.

INTRODUCTION: Testicular adrenal rest tumors (TARTs) predominantly occur in patients with congenital adrenal hyperplasia (CAH) and may interfere with the function of the testicles. OBJECTIVE: This study aimed to identify the factors that contribute to the occurrence of TARTs in patients with CAH and influence their volume. STUDY DESIGN: This was a comparative cross-sectional study. Male patients aged 0-16 years with CAH were included. Weight, height, bone age determination, biochemical and androgenic profiles, and testicular ultrasound were performed. Patients were divided into those with and without TARTs and the between-group differences were assessed using the Mann-Whitey U test and Fisher's exact test. A ROC curve was created for serum ACTH levels to identify the cut-off point to diagnose TARTs. Variables that influenced the volume of the TARTs were identified using Spearman's correlation coefficient. RESULTS: TARTs were observed in seven (19.4%) of 36 male children with CAH. Of the patients with TARTs, 85.7% were pubertal. Serum concentrations of adrenocorticotropic hormone (ACTH) levels were significantly higher in patients with TARTs than in those without (309.0 pg/mL vs. 45.2 pg/mL; p = 0.006). ACTH levels >200 pg/mL were found to predict the presence of TARTs (sensitivity 85.7%; specificity 86.2%) (Figure). The factors found to correlate with TARTs volume were ACTH levels (coefficient 0.004; p = 0.009) and the three-year average of serum testosterone levels (coefficient 9.64; p = 0.003).] DISCUSSION: The main limitation of this study was the small sample size. However, an ACTH cut-off point to predict insufficient hormonal treatment and consequently the presence of TART had not been described. CONCLUSIONS: High ACTH (>200 pg/mL) was found to be predictive insufficient hormonal treatment in patients with CAH. The three-year average of serum testosterone levels and ACTH concentrations were correlated with the volume of TARTs.

Patient and Parent Perspectives on Testicular Adrenal Rest Tumors in Congenital Adrenal Hyperplasia.

BACKGROUND: Testicular adrenal rest tumors (TARTs) increase the risk of infertility in males with classic congenital adrenal hyperplasia (CAH). There is no consensus regarding at what age screening testicular ultrasounds should begin and how often they should be repeated. Furthermore, it is unknown whether patients and parents are aware of the significance of TARTs. OBJECTIVE: The objective of the study was to investigate awareness, concern, and screening rates for TARTs in males with classic CAH. METHODS: Males with CAH and parents completed an online questionnaire from 2019 to 2020. Responses to questions about TARTs were analyzed. Fisher's exact test was used to determine statistical significance. RESULTS: Of 123 responders, 14 were males with CAH (range 16-54 years) and 109 were parents of males with CAH (son's age range infancy to 37 years). Of all responders, 74% were concerned about the possibility of TARTs, 48% had discussions about TARTs with their endocrinologist, and 42% were aware of possible infertility in males with CAH. There was no difference between responses provided by affected males and parents for these topics (p ≥ 0.08). Among male responders with CAH, 93% had at least one testicular ultrasound, and 77% had undergone more than one. Among parent responders, 30% of their sons had at least one testicular ultrasound, and 61% had more than one. The frequency, total number, and age when the first testicular ultrasound was obtained were inconsistent in both groups. Fifty percent of male responders with CAH and 11% of sons were referred to a urologist for evaluation. CONCLUSIONS: Although most responders were concerned about TARTs, less than half recalled discussing this issue with their endocrinologist, and less than half were aware of the possibility of infertility. Although TARTs are most often treated medically, several responders were referred to a urologist. Standardized patient education and consensus guidelines are needed for the surveillance and management of TARTs in males with classic CAH.

Adrenal hyperplasias in childhood: An update.

Pediatric adrenocortical hyperplasias are rare; they usually present with Cushing syndrome (CS); of them, isolated micronodular adrenal disease and its variant, primary pigmented adrenocortical disease are the most commonly encountered. Most cases are due to defects in the cyclic AMP/protein kinase A (cAMP/PKA) pathway, although a few cases remain without an identified genetic defect. Another cause of adrenal hyperplasia in childhood is congenital adrenal hyperplasia, a group of autosomal recessive disorders that affect steroidogenic enzymes in the adrenal cortex. Clinical presentation varies and depends on the extent of the underlying enzymatic defect. The most common form is due to 21-hydroxylase deficiency; it accounts for more than 90% of the cases. In this article, we discuss the genetic etiology of adrenal hyperplasias in childhood.

Corporoplasty: A simplified technique for clitoroplasty.

INTRODUCTION: Clitoroplasty constitutes an important step in feminizing surgery for congenital adrenal hyperplasia (CAH) (1). In this video we present a technique that aims to preserve clitoral sensitivity and engorgement while minimizing the risk of neurovascular lesion. MATERIALS AND METHODS: We present a video of a three-year-old girl with history of CAH classical form, PRADER-III, who underwent clitoroplasty. After an initial endoscopic evaluation of the urogenital sinus, the clitoris was degloved and a rectangular incision was made on the ventral corpora cavernosa 15mm above the corpora bifurcation and 0.5 mm below the coronal sulcus. The cavernous tissue was partially resected. The upper and lower borders of the rectangular gap were closed by a 5-0 PDS running suture similar to the Mikulicz technique. Next, the edge of the glans was deepithelialized to reduce its size. For improved clitoral positioning, the clitoris was sutured to the pubic fat. From that point onward the procedure followed that of a standard vaginoplasty using the en-bloc technique (2-4). Thus far we have performed this technique in 33 patients, with 31 of them being girls with CAH and 2 being women with clitoral hypertrophy. CONCLUSION: Corporoplasty is a simplified technique for clitoroplasty, with the advantage being that is faster and safer than the technique that involves the dissection of the neurovascular bundle. In addition, corporoplasty has the possible benefit of preserving the cavernosal blood flow that permits the engorgement of the clitoris during sexual arousal.

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.

Long-Term Health Outcomes of Korean Adults With Classic Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency.

There is a lack of studies regarding the long-term outcomes of Asian adults with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. We hypothesized that adults with CAH are at higher metabolic risk than their age-, and sex-matched controls. We further investigated the long-term health outcome-related factors in adults with CAH. We compared metabolic risk between adults with CAH (71 men, 93 women) and age-, and sex-matched controls (190 men, 261 women) from the Korean National Health and Nutrition Examination Survey data. The presence of obesity, testicular adrenal rest tumors (TARTs), and menstrual irregularity was assessed. Hormone status and treatment regimens were compared according to the presence of adverse outcomes. The median age was 27.0 y and 28.0 y for men and women, respectively. Adults with CAH had a higher waist circumference (88.0 vs. 82.3 cm in men, and 83.5 vs. 72.3 cm in women), and blood pressure (125.0 vs. 113.0 mmHg in men, and 120.0 vs. 104.0 mmHg in women) than age- and sex-matched controls (P<0.05 for all). The 2.7-fold increased risk for hypertension (men) and 2.0-fold increased risk for obesity (women) was significant in patients with CAH (P<0.05 for both). Obese adults with CAH showed significantly higher adrenal limb thicknesses (men) and 17-hydroxyprogesterone and dehydroepiandrosterone sulfate levels (women) (P<0.05 for both). TARTs occurred in 58.1% of men and did not differ by hormone or treatment regimen. Irregular menstruation was observed in 57.1% of women, with higher dehydroepiandrosterone sulfate levels in those with irregular periods. Adults with CAH had a higher metabolic risk than the general population. Poor disease control may increase their risk of metabolic morbidity and menstrual irregularity.

Adrenal myelolipomas.

Adrenal myelolipomas are benign, lipomatous tumours with elements of myeloid cells, most of which present as adrenal incidentalomas and comprise 3·3-6·5% of all adrenal masses. Adrenal myelolipomas are usually unilateral (in 95% of cases), variable in size, most often found during midlife, and affect both sexes almost equally. On imaging, adrenal myelolipomas show pathognomonic imaging features consistent with the presence of macroscopic fat. Large adrenal myelolipomas can cause symptoms of mass effect, and can occasionally be complicated by haemorrhage. In the event of a concomitant adrenal cortical adenoma or hyperplasia, adrenal hormone excess might be detected in patients with adrenal myelolipoma. Patients with congenital adrenal hyperplasia exhibit a higher prevalence of adrenal myelolipomas than other patient groups, and are at risk of developing large and bilateral lesions. This Review discusses the pathogenesis, clinical presentation, and management of adrenal myelolipomas.

Effects of mitotane on testicular adrenal rest tumors in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: a retrospective series of five patients.

We conducted a retrospective study on the long-term effect of mitotane treatment on testicular adrenal rest tumors (TARTs) in five adult patients with classic 21-hydroxylase deficiency. After 60 months of mitotane treatment, a decrease in adrenal steroids was observed in four patients. Testicular ultrasonography showed complete disappearance of TART in two patients, stabilization in two patients and a halving of TART volume in the remaining patient. Sperm count improved notably in two patients who had normal baseline inhibin B levels and small inclusions, thus enabling cryopreservation of the subjects' semen. Four years of follow-up of these two patients after the withdrawal of mitotane showed no recurrence of TART and persistent normal testicular function. In conclusion, mitotane could be used as a last resort in CAH patients in the cases of azoospermia associated with TARTs but normal inhibin B levels, as it can improve long-term endocrine and exocrine testicular function.

Adrenal Tumor Mimicking Non-Classic Congenital Adrenal Hyperplasia.

Elevated 17-hydroxyprogesterone may be caused by congenital adrenal hyperplasia, ovarian or adrenal tumors. A positive cosyntropin stimulation test result for 17-hydroxyprogesterone may be found in functional or non-functional tumors and be related to tumor size. Here, we present a case of a 36-year-old woman with a 4-year history of infertility. Laboratory test results revealed elevated progesterone and 17-hydroxyprogesterone, with normal luteinizing hormone, follicle-stimulating hormone, estrogen, testosterone, and anti-Mullerian hormone levels. The 250-µg cosyntropin stimulation test revealed a 17-hydroxyprogesterone level of 11.3 ng/ml (34.3 nmol/L) and 31.8 ng/ml (96.2 nmol/L) at 0 and 60 min, respectively. Non-classic congenital adrenal hyperplasia was diagnosed initially; however, genetic testing revealed no 21-hydroxylase deficiency. She received dexamethasone but progesterone and 17-hydroxyprogesterone levels remained high. Abdominal computed tomography found a 4.5 × 4.8-cm left adrenal tumor. Subsequent pathological report was compatible with an adrenal cortical adenoma. Progesterone and 17-hydroxyprogesterone levels returned to the normal range postoperatively and the 250-µg cosyntropin stimulation test of 17-hydroxyprogesterone showed a normal response. When biochemically diagnosed NCCAH demonstrate no typical features and show poor response to steroid, the patient should undergo gene mutation analysis and receive adrenal or ovarian imaging. For women suffering from infertility, adrenalectomy of 17-OHP secreting adrenal tumor may improve fertility outcome.

11-Keto-testosterone and other androgens of adrenal origin.

The adrenal glands produce significant amounts of steroid hormones and their metabolites, with various levels of androgenic activities. Until recently, the androgenic potency of these adrenal-derived compounds were not well known, but some recent studies have shown that the production of 11-oxo- and 11beta-hydroxy-derived testosterone and dihydrotestosterone evidently have high androgenic activity. This fact has clinical importance, for instance, in various types of congenital adrenal hyperplasia with androgenization or polycystic ovarian syndrome, and laboratory determinations of these substances could help to better evaluate the total androgen pressure in patients with these disorders. Another area of concern is the treatment of prostate cancer with androgen deprivation, which loses effectiveness after a certain time. The concurrent blocking of the secretion of adrenal C(19)-steroids, whether using corticoids or adrenostatics, could increase the effectiveness of androgen-deprivation therapy.

A Rare Case of Congenital Adrenal Hyperplasia with Giant Adrenal Myelolipoma.

Adrenal incidentalomas are tumors located in the adrenal glands and found on imaging done for purposes not related to adrenal disease. In other cases adrenal mases can be radiologically found when an adrenal hormone secreting tumor is suspected, such as a pheochromocytoma or Cushing's diseases. Adrenal incidentalomas may be classified as functional or non-functional based on whether they produce hormones, such as aldosterone, cortisol, and androgens, or catecholamines. Studies indicate that around 8% of adrenal incidentalomas are adrenal gland myelolipomas (AGMs). AGMs are non-malignant masses that can cause the compression of vital organs and vessels if said masses become large enough. In patients with congenital adrenal hyperplasia (CAH), adrenocorticotropic hormone (ACTH) levels tend to be elevated due to the lack of adrenal-hormone production. Patients with CAHs are treated with steroids that suppress ACTH levels and prevent adrenal gland hyperplasia. Around 10% of AGMs are found in untreated CAHs. Our patient was a 36-year-old male who was on steroids due to CAH and intermittent abdominal pain; a CT scan revealed a large left adrenal mass that was displacing organs towards the right. Pathological analysis revealed an AGM exceeding 30 x 23.6 x 16.7 cm. This AGM is one of the largest ever to be reported in the literature.

Beta-Catenin Causes Adrenal Hyperplasia by Blocking Zonal Transdifferentiation.

Activating mutations in the canonical Wnt/ß-catenin pathway are key drivers of hyperplasia, the gateway for tumor development. In a wide range of tissues, this occurs primarily through enhanced effects on cellular proliferation. Whether additional mechanisms contribute to ß-catenin-driven hyperplasia remains unknown. The adrenal cortex is an ideal system in which to explore this question, as it undergoes hyperplasia following somatic ß-catenin gain-of-function (ßcat-GOF) mutations. Targeting ßcat-GOF to zona Glomerulosa (zG) cells leads to a progressive hyperplastic expansion in the absence of increased proliferation. Instead, we find that hyperplasia results from a functional block in the ability of zG cells to transdifferentiate into zona Fasciculata (zF) cells. Mechanistically, zG cells demonstrate an upregulation of Pde2a, an inhibitor of zF-specific cAMP/PKA signaling. Hyperplasia is further exacerbated by trophic factor stimulation leading to organomegaly. Together, these data indicate that ß-catenin drives adrenal hyperplasia through both proliferation-dependent and -independent mechanisms.

Congenital adrenal hyperplasia presenting as pelvic inflammatory disease in a phenotypic male: A case report.

RATIONALE: Congenital adrenal hyperplasia (CAH) is caused by various enzyme deficiencies, among which 21-hydroxylase (21-OH) deficiency accounts for more than 90% of cases. Neonatal screening became mandatory only a few decades ago. Many patients who were born before this went undiagnosed and some of the severely virilized females were raised as men. PATIENT CONCERNS: A 58-year old man with a history of excisional surgery in the external genitalia when he was a toddler presented with three days of dysuria and low abdominal pain. DIAGNOSIS: The patient's laboratory results showed leukocytosis and elevated C-reactive protein (CRP); thus, the physicians decided to perform a computed tomography (CT) scan. The CT demonstrated pelvic inflammatory disease (PID), left adrenal gland myelolipoma, and a mesenteric mass. Meanwhile, we suspected CAH based on the clinical history and assessed the patient's hormone levels. Seventeen-hydroxyprogesterone (17-OH-PG) was markedly elevated and the patient was diagnosed with classic simple virilizing CAH. INTERVENTIONS: Intravenous antibiotics were administered, and positron emission tomography-CT (PET-CT) was performed to evaluate any metastases. OUTCOMES: After 2 weeks of antibiotic treatment, CRP decreased to 0.12 mg/dL and PID was resolved. The patient opted for resection of the female genitalia along with the mesenteric and adrenal gland tumors in the near future, and was safely discharged. LESSONS: The adrenal gland myelolipoma was thought to have developed as a result of a longstanding exposure to adrenocorticotropic hormone. There are controversies regarding the management of female genitalia in CAH patients who identify themselves as men. In this case, the physician and patient decided to remove the female genitalia because the surgery for the mesenteric mass was inevitable and there was a possibility of recurrent PID. To our knowledge, this is the first article to report primary mesenteric tumor in a CAH patient to date. In conclusion, patients who were born before neonatal screening for CAH became the mainstay, who are suspected to have CAH from their history, and present with abdominal pain must be diagnosed by performing an imaging study, testing levels of serum 17-OH-PG, and screening for female genitalia and adrenal gland myelolipoma.

Restoration of Height after 11 Years of Letrozole Treatment in 11ß-Hydroxylase Deficiency.

11ß-hydroxylase deficiency (11ß-OHD) is the second most common form of congenital adrenal hyperplasia (CAH). Males with 11ß-OHD CAH are often diagnosed late with a significantly advanced bone age leading to a poor height prognosis due to early closure of epiphysis. Delaying epiphyseal fusion by treatment of aromatase inhibitors (AIs) might be a useful strategy in patients with very advanced bone ages. However, there are limited data regarding the effect on final height and long-term safety of this approach. We report our experience with 11 years of letrozole treatment and 17 years of follow-up in a boy with 11ß-OHD. He presented at 2 years and 11 months of age with a bone age of 13 years (predicted adult height, PAH, 129.5 cm). Letrozole was added after 1 year of glucocorticoid treatment due to no improvement in height prognosis (130 cm), and continued until the age of 14 years and 11 months. He also received GnRH analog treatment at 10 years and 3 months of age for 2.5 years due to central activation of puberty. He reached a final height of 165.2 cm (35.2 cm above his PAH). This long-term treatment with letrozole was associated with changes in vertebral morphology such as vertebral body end-plate changes, Schmorl nodes, and mild protrusions in the intervertebral discs. Testicular volumes, gonadotropins, testosterone, and anti-Müllerian hormone were normal at age 20 years. A spermiogram showed a normal count but impaired sperm motility and morphology. This unique case represents the longest duration of AI treatment reported in CAH and the first case in which letrozole was started before puberty with the final height reported. We conclude that AIs may restore height in selected patients with CAH with very advanced bone age and severely compromised height prognosis.

Testicular adrenal rest tumors in patients with congenital adrenal hyperplasia: 6 years of follow-up.

Background Testicular adrenal rest tumors (TARTs) leading to primary gonadal failure are the main etiology of infertility in congenital adrenal hyperplasia (CAH). We aimed at identifying the evolution of TART and related findings in young CAH patients. Methods Twelve male patients (3-23 years old) with 21-hydroxilase deficiency (11 with classic salt-wasting form) were included. Testicular ultrasonography (US) was performed in two moments, by a single blinded specialist in pediatric diagnostic imaging. Tumor progression was classified according to the Response Evaluation Criteria in Solid Tumors (RECIST). The clinical and laboratory data were retrieved from medical records. Serum 17-OH-progesterone (17OHP) and androstenedione concentrations were evaluated during the whole period of follow-up, from the CAH diagnosis. A logistic regression model with repeated measures was developed for the analysis. Results The prevalence of TART was 41.6% (n = 5) in the initial US evaluation and 66.6% (n = 8) after 6 years of follow-up. Tumor progression was detected in 4 of the 5 patients, and 1 presented with a stable tumor. Three patients presented with new tumors in the second evaluation. Most of the patients (n = 11) were pubertal, including a 7-year-old child with TART who presented with central precocious puberty. At regression analysis, it was observed that an inadequate hormonal control led to a 16 times greater chance of a patient to present with TART (OR = 16.08; confidence interval [CI] 95% = 2.38-108.81; p = 0.004). Conclusions We found a high prevalence of progressive TART in young pubertal subjects. US testicular screening should help in improving therapeutic optimization in CAH patients to reduce future impairment in fertility.