The present patient was diagnosed with CAH in the neonatal period after a life-threatening episode, which was suggestive of a severe salt-wasting form of the disease. He was immediately started on daily replacement therapy with glucocorticoids and mineralocorticoids and compliance during childhood must have been acceptable, because normal pubertal development and adult stature were achieved. During adulthood, medical follow-up and self-administered therapy were irregular. He presented to the Emergency department with acute adrenal insufficiency, precipitated by an infectious disease.
Complete baseline endocrine evaluation (before beginning steroid replacement) revealed absolute cortisol deficiency, with elevated ACTH. The concentration of 17-OHP was 60 times the upper limit of normal, whereas 11-deoxycortisol was normal to high, which was unexpected. Renin was slightly elevated and aldosterone was normal. There was increased androgen production; androstenedione was very high. However, the total and free testosterone levels were normal and dehydroepiandrosterone-sulfate (DHEAS) was paradoxically low. This finding may be explained by the chronic stimulation of 3-β-hydroxysteroid dehydrogenase, resembling the physiologic response in chronic stress. We found only two other case reports in the literature which included the hormonal profile of male patients with CAH due to 21-OH deficiency and found low DHEAS, as was the case of our patient [7, 8]. Here, the high to normal 11-deoxycortisol levels, the increased deoxycortisol to cortisol ratio, and the increased androstenedione with low levels of DHEAS indicate abnormal steroidogenesis and were the first clues of an extra-adrenal origin. The gonadotropins were suppressed, probably because of the inhibitory effect of the elevated adrenal sex steroids, suggesting that the circulating testosterone was adrenal in origin.
The cosyntropin stimulation test is the gold standard for determining the severity of disease . It is performed by intravenous injection of a 125μg or 250μg bolus of cosyntropin, an ACTH-analogue, and measuring baseline and stimulated levels of 17-OHP . Patients with the salt-wasting form have the highest post-stimulation 17-OHP levels (over 100,000ng/mL), those with the simple virilizing form have somewhat lower levels and patients with non-classical disease have lower levels (1500 to 10,000ng/mL) [3, 5].
In our case the peak value of 17-OHP was 20,400ng/dL, consistent with CAH due to moderate 21-OH deficiency . A 17-OHP which remains almost unchanged after stimulation has been described in other case reports when values at baseline were already very high [6, 7, 9]. It suggests that the adrenal cells were already maximally stimulated by chronically elevated ACTH and is corroborated by the nearly absent elevation of cortisol. In the present case there was an elevation of delta-4-androstenedione and DHEAS about one and a half times the baseline level. Levels of DHEAS remained below normal. There was a paradoxical increase of 11-deoxycortisol (the peak was almost triple that of the baseline value). Testosterone also increased in response to the ACTH analogue.
The results of the cosyntropin test performed after the adrenalectomy were indicative of a partial contribution of the adrenal cells in the adrenal cortex and testicles compared with the results found in the previous test. Cortisol levels remained nearly unchanged upon stimulation. The pattern of increased 11-deoxycortisol and decreased DHEAS was repeated but 17-OHP was markedly lower, probably indicating that the former two had primarily originated in the testicles and the latter in the adrenal glands. The fact that 17-OHP is still well above the upper limit of normal suggests that the ectopic testicular cells also have 21-OH deficiency.
The adrenal myelolipoma is a rare benign tumor consisting of mature adipose cells and hematopoietic tissue . Prolonged stimulation of the adrenal cortex by ACTH seems to be implicated [6, 8]. A review of the literature by Mermejo et al. in 2010  found reports of 26 cases of myelolipoma associated with CAH. Of these, the majority was secondary to 21-OH deficiency and the patients were either untreated or had medication withdrawn for a long time. Several mechanisms have been proposed to explain the origin of myelolipomas. These include the presence of embryonic bone marrow rests in adrenal tissue or metaplasia of adrenocortical cells [7, 9]. The majority of cases are benign. Surgical excision is advocated in the case of large or growing lesions (above five cm) that have heterogeneity, hemorrhage or other suspicious features, and in cases refractory to medical management [4, 10].
The adrenal glands in the present case are remarkable for their dimension, weight, and heterogeneity, which raised concern about the possibility of malignancy and mass effect over the surrounding abdominal structures. In the review by Mermejo et al.  there were only seven reports in the literature of equally enlarged or larger adrenal glands as a result of CAH due to 21-OH deficiency. Recently, McGeoch et al.  reported a case of giant bilateral adrenal myelolipomas in a man with CAH.
Another curious aspect is the marked asymmetry in size of the tumors. Other recent case reports have described a much larger mass on the left side [6, 9]. We speculate that it is due to restrained growth due to the proximity of the liver.
The testicular masses of the present patient were large, hyperechogenic and markedly heterogeneous. The tumor markers for germinative tumors (CEA, α-FP, β-HCG) were negative. There was massive deposition of collagen inside the seminiferous tubules, which is a general finding in end-stage testicular damage. The diagnosis of nodular bilateral hyperplasia of ectopic adrenal cells was made in the same tissue samples. The immunological stain was positive for actin and vimentin, markers for mesenchymatous tissue, as well as for inhibin, a marker for cells of stroma or sexual cord tumors, which could indicate a Leydig cell tumor. The stain was negative for AE1 and AE3, epithelial tumor markers, PLAP, which excluded the hypothesis of seminoma, CD30, a marker of embrionary carcinoma and also chromogranin or synaptophysin.
Patients with CAH and poorly controlled disease sometimes present with testicular masses representing adrenal rest tissue . In prenatal life, the adrenal glands develop in the vicinity of the gonads. Adrenal cortical tissue may adhere to the gonad and descend along the course of the supplying arteries. Similar testicular lesions can be found in patients with other conditions characterized by elevated levels of ACTH, such as Addison’s disease and Cushing’s syndrome . The estimated prevalence of adrenal rest nodules in patients with CAH is high, ranging from 24% to 95% [12–15]. These lesions are multifocal, bilateral, hypoechoic and well defined . Nodules gradually expand and destroy the surrounding parenchyma and can lead to obstruction of the seminiferous tubules, resulting in deficient spermatogenesis and testosterone synthesis . In addition, spermatogenesis is suppressed because gonadotropin secretion is inhibited by the elevated circulating androgens .
The genetic analysis revealed two different mutations: heterozygous R124H, responsible for a moderate defect and “apparent” homozygous 356W, causing almost undetectable residual enzymatic activity. The geneticist discussed as more probable the possibility of “compound heterozigoty”, the condition of having two heterogeneous recessive alleles in one particular locus causing genetic disease in a heterozygous state. In this case one allele would express the moderate and the other the severe mutation. In this case the phenotype would be defined by the milder mutation, and this agrees with the clinical manifestations of our patient.