Stroke in Young Heralding the Diagnosis of Congenital Adrenal Hyperplasia
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.289002
Source of Support: None, Conflict of Interest: None
Liza Das and Nimisha Jain contributed equally
Stroke in young, by definition, affects individuals under the age of 50 years. The contribution of hypertension to the occurrence of stroke is seen in about 50% cases. It is imperative to note that hypertension is a common attribute in older patients with stroke whereas non-hypertensive causes (including aneurysms, Moyamoya disease, vasculitis, migraine and thrombophilias) predominate in the younger population. Nevertheless, stroke in young due to hypertension has been reported and of all the causes of young onset hypertension, endocrine causes are important and potentially treatable. Endocrine disorders associated with hypertension can be classified as glucocorticoid-responsive or unresponsive [Table 1]. Herein, we depict the case of a rare and missed cause of hypertension manifesting as hemorrhagic stroke in a young adult male.
A 24-year-old male presented with acute onset headache followed by weakness of the right side of his body. He was diagnosed with hypertension leading to intracranial hemorrhage. He was fourth in order of birth with normal perinatal and developmental history till the age of 5 years when his parents had noticed accelerated growth followed by appearance of secondary sexual characteristics (facial, axillary, pubic hair and increased phallic length), suggestive of precocious puberty. He continued to grow for the next 3 years. Later, at a routine medical camp, he was found to have short stature with hypertension at the age of 14 years. He had no history of salt crises, periodic weakness of limbs with hypokalemia, paroxysms, loss of consciousness, visual disturbances or seizures. There was significant relevant family history in the form of neonatal losses reported by both mother and maternal aunt.
Examination revealed a severely stunted individual (−5.7SDS), with disproportionate upper and lower segments for his age (ratio 1.1, normal being 0.9) [Figure 1]a. He had a hairy body habitus and fused epiphyses. Sexual maturation status was: axillary hair +, pubic hair P5, testicular volume bilateral 8 ml and stretched penile length of 12 cm. There was documented hypertension with normal heart rate. Patient also had right sided spastic hemiparesis with extensor plantar, exaggerated deep tendon reflexes and circumduction gait. Rest of his systemic examination including fundus was normal. On investigations, he was found to have hypokalemia (K +− 3.2 mEq/l) with rest of the biochemical profile being normal. Hormonal profile was suggestive of hypocortisolism (non-stimulable on short synacthen stimulation test), normal dehydroepiandrosterone sulphate (DHEAS) and testosterone. 17α-OH progesterone (17α-OHP) was mildly increased and 11- deoxycortisol was enormously high (>10,000 ng/dl). Plasma aldosterone and renin were appropriately suppressed. Urinary metanephrines and normetanephrines were significantly low. Electrocardiogram and echocardiography revealed left ventricular hypertrophy. Brain MR imaging showed a lenticular left-sided gangliocapsular bleed and microbleeds in right basal ganglia [Figure 1]b. CECT adrenals were suggestive of bilateral asymmetric enlarged adrenals with formation of myelolipomas [Figure 1]c. USG scrotum showed the presence of bilateral suspicious heterogeneously hypoechoic lesions suggestive of testicular adrenal rest tumors (TARTs). However, this was confirmed on MR imaging [Figure 1]d. A diagnosis of congenital adrenal hyperplasia (CAH) due to 11β-hydroxylase deficiency was contemplated. Patient was initiated on hydrocortisone at 15 mg/m2 and antihypertensives were gradually tapered over a period of two weeks. Blood pressure and serum potassium levels improved but did not normalize with 80 mg telmisartan and 10 mg amlodipine. Later, spironolactone was added which led to remarkable improvement in both parameters. Genetic analysis confirmed homozygous deletion in exon 3 of the CYP11B1 gene (chr 8: 143958613G>A; Depth: 55x) variant c.421C>T (p. Arg141Ter) on whole exome sequence analysis. His hormonal profile at baseline and at follow-up (3 months) is summarized in [Table 2]. This case illustrates the long term untoward consequences due to delayed diagnosis and treatment of CAH including precocious puberty, short stature and young onset stroke, the latter being the most detrimental. Stroke in affected individuals, like in ours, is due to uncontrolled hypertension and adverse effects of excess mineralocorticoid on the systemic vasculature.
Congenital adrenal hyperplasia (CAH) is a group of inherited (autosomal recessive) disorders due to enzymatic blocks at various levels of cortisol biosynthesis. This ultimately results in glucocorticoid deficiency, increased ACTH levels due to impaired feedback inhibition by the low glucocorticoid levels, accumulation of precursor metabolites and hyperplastic adrenal glands. CAH due to 21α-hydroxylase deficiency accounts for over 90% cases while 11β-hydroxylase deficiency ranks second with a prevalence of around 5–8% in most series  followed by 17α-hydroxylase deficiency. The latter two (11β-hydroxylase deficiency and 17α-hydroxylase deficiency) are the only two types of CAH that are associated with hypertension, else salt crises are more common. The distinction between 17α-hydroxylase deficiency and 11β-hydroxylase deficiency lies in the level of circulating androgens. While the former is associated with hypoandrogenemia, leading to complete female phenotype in 46XY patients, the latter manifests with hyperandrogenemia (ambiguity in 46XX and isosexual gonadotropin- independent precocity in 46XY individuals). A combined picture of hypertension and precocious puberty in a patient with CAH thus implies 11β-hydroxylase deficiency, as was noted in our patient and later confirmed on genetic analysis.
11β- hydroxylase deficiency is characterized by a genetic defect on chromosome 8q. The condition is relatively rare, with only about a 100 cases described in the literature and only a handful confirmed by genetic analysis. Hypertension is seen in 59–67% cases of 11β- hydroxylase deficiency. Deficiency of this enzyme impairs conversion of DOCA (deoxycorticosterone acetate) to corticosterone in the zona glomerulosa and 11-deoxycortisol to cortisol in the zona fasciculata layers of the adrenal cortex, thereby causing accumulation of both DOCA and 11-deoxycortisol. However, 11-deoxycortisol is the more robust marker that is validated for diagnosis of this condition  and it was unequivocally high in our patient. Low levels of catecholamines were expected due to decreased serum cortisol leading to a lack of stimulation of the phenylethanolamine-N-methyltransferase (PNMT) enzyme which is required for catecholamine biosynthesis. DOCA is the chief metabolite mediating the hypertension that acts by directly stimulating the mineralocorticoid receptor, thereby suppressing the renin–angiotensin–aldosterone system (RAAS) leading to low levels of both renin and aldosterone as was noted in our patient. However, DOCA is a weak mineralocorticoid unlike aldosterone, causing only mild blood pressure elevation. Hence, the severity of hypertension, target organ damage and hemorrhagic stroke at a young age manifested by our patient is uncommon features of this condition.
Our patient had normal levels of circulating androgens. However, the unequivocal presence of precocity in him is in line with prior hyperandrogenemia which led to early pubertal changes and ultimate short stature. Current normal levels of androgens in our patient despite being treatment naïve could be explained by myelolipomatous transformation of functional adrenal tissue due to intense ACTH drive. Myelolipomas are benign adrenal tumors containing both lipoid (mature adipose tissue) and myeloid (hematopoietic cells) components, believed to be of metaplastic origin. They are uncommonly described in patients with 11β-hydroxylase deficiency, probably because of early identification of patients with this condition. Further, a finding of bilateral myelolipomas in our patient was another unusual finding.
Patient was initiated on hydrocortisone and successful lowering of adrenal androgens led to unmasking of an underlying primary testicular failure with increased gonadotropins and modestly lowered testosterone [Table 1]. MR imaging confirmed the presence of TARTs which was the cause of the testicular failure due to their development at an early age. TARTs resemble adrenocortical tissue histologically and cause obstructive azoospermia. Definitive management (medical in early stages and surgery later) can be rewarding even in partially treated tumors.
Management of CAH due to 11β-hydroxylase deficiency includes glucocorticoid replacement and addition of fludrocortisone may be required later in some patients if they develop salt crises. Bilateral adrenalectomy is rarely required in refractory cases which include uncontrolled hypertension, non-resolving dyselectrolytemia, large myelolipomas and difficult-to-treat androgen excess.
This case aptly depicts the importance of early identification and treatment of cases of CAH due to 11β-hydroxylase deficiency. Any short child with history of precocity and hypertension should be a strong clinical suspect of this near fatal condition. Management involves the use of hydrocortisone which serves to supplement glucocorticoids, suppress ACTH and prevent the rise in mineralocorticoid precursors, thereby averting secondary hypertension. It is thus gratifying to identify and treat such patients early in their disease.
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[Table 1], [Table 2]