Case 1: Severe acne – not just skin deep

A previously healthy 10-year-old girl presented to a paediatric dermatologist with a three-year history of facial acne resistant to medical therapy. At seven years of age, she developed acne on her face, back and thorax that progressively worsened despite adherence to topical face creams and a trial of minocycline (Minocin, Triax Pharmaceuticals, USA). On further history, she developed pubic hair at seven years of age and axillary hair soon after. Early breast development was noted at nine years of age, but she was pre-menarcheal at the time of consultation. She denied a significant growth spurt, but her parents noted that at 10 years of age, she was the tallest girl in her peer group and the same height as her 15-year-old sister. Her mother’s height was 170.2 cm and her father’s height was 172.7 cm, giving her a midparental height of 165.1 cm (just above the 50th percentile). Her mother and sister both reached menarche at 12 years of age.

On examination, she had acne with open and closed comedones on her face, chest and back. Her height was 145 cm (just above the 75th percentile) and weight was 45.8 kg (at the 90th percentile). Her thyroid was not enlarged. She had Tanner stage 3 breast development, Tanner stage 4 pubic hair growth and a heavy growth of axillary hair. She had normal female genitalia with no clitoromegaly. Further investigations were performed.

CASE DIAGNOSIS: LATE-ONSET CONGENITAL ADRENAL HYPERPLASIA

X-rays revealed that at a chronological age of 10 years and one month, the patient’s bone age was equivalent to that of a 12-year-old child. Her abdominal and pelvic ultrasound were normal, with no evidence of polycystic ovaries. Her thyroid function tests were normal, and estradiol level was normal at 69 pmol/L. The patient’s adrenocorticotropic hormone (ACTH) stimulation test revealed an adequate cortisol response, with an increase from 467 nmol/L to 581 nmol/L at 60 min stimulation. Random luteinizing hormone level was low at 2.0 U/L (normal 3 U/L to 17 U/L) and follicle-stimulating hormone level was 4.8 U/L (normal 0 U/L to 9 U/L). Her testosterone level was also normal at 1.6 nmol/L (lower than 2.1 nmol/L), but her dehydroepiandrosterone (DHEAS) level was elevated at 9.0 μmol/L (normal 0 μmol/L to 7.9 μmol/L). The patient’s baseline 17-hydroxyprogesterone (17-OHP) level was 90.7 nmol/L (normal 0 μmol/L to 5.9 nmol/L) and stimulated to 125.9 nmol/L following a 60 min ACTH stimulation test. With these findings, a diagnosis of late-onset congenital adrenal hyperplasia (CAH) was established.

Late-onset CAH, also known as nonclassic CAH, is an autosomal recessive disorder characterized by virilization, premature adrenarche, advanced bone age and reduced fertility. Late-onset CAH is an allelic variant of classic CAH; however, the presentation is markedly different. Females with classic CAH present with ambiguous genitalia at birth. Males with the classic variant may appear phenotypically normal at birth, but typically present by four weeks of age with failure to thrive, dehydration, hyponatremia and hyper-kalemia if they have the ‘salt-wasting’ form. Despite the significant difference in phenotypic presentation, both classic CAH and late-onset CAH result from 21-hydroxylase deficiency. The resultant deficiency of hormones downstream from 21-hydroxylase decreases the negative feedback on the hypothalamic-pituitary axis. Consequently, ACTH secretion increases, leading to excess stimulation of the adrenal glands to secrete adrenal androgens. The excess androgens result in virilization.

It is generally more challenging to establish a diagnosis of late-onset CAH than of classic CAH. In classic CAH, baseline 17-OHP levels are elevated; however, in late-onset CAH, the baseline 17-OHP levels may be normal. In these patients, an elevated 60 min 17-OHP level on an ACTH stimulation test is required for diagnosis.

The age of onset is quite variable, with signs and symptoms presenting any time from childhood to adulthood. The presentation of late-onset CAH also differs between women and men. Among women, late-onset CAH may present with hirsutism, early growth spurt, menstrual irregularities, male-patterned baldness, short stature secondary to early epiphyseal closure or severe acne. The phenotypic presentation is similar to polycystic ovarian syndrome (PCOS) and, therefore, the two diagnoses are often indistinguishable clinically. Whereas PCOS is estimated to affect 6.5% to 8% of women, late-onset CAH reportedly affects 0.1% to 1% of women, with higher prevalence among certain ethnic groups including members of the Ashkenazi Jewish, Mediterranean and Hispanic populations. However, with increasing recognition of late-onset CAH as a clinical entity and more widespread administration of ACTH stimulation testing among patients with phenotypic hyperandrogenism, current evidence suggests that PCOS and late-onset CAH may be over- and underdiagnosed, respectively.

Among men, acne may be the only phenotypic feature of hyperandrogenism, posing an even greater challenge to the clinician to establish a diagnosis. These patients typically present with acne resistant to topical and systemic treatment. Detailed history may reveal early puberty, and the bone age may be advanced. Similar to females, males with late-onset CAH have an elevated 17-OHP level on ACTH stimulation testing. Because males typically present with acne in isolation, an even higher index of suspicion may be necessary to establish the underlying diagnosis.

Once a diagnosis of late-onset CAH is established, the primary goals of management of the female patient are to minimize androgen production, achieve maximum growth potential and prevent virilization. Late-onset CAH is primarily treated with oral glucocorticoids, which are particularly efficacious in the treatment of associated acne and anovulatory infertility. If, however, the primary concern is hirsutism, antiandrogen therapy is recommended. Among male late-onset CAH patients, glucocorticoid therapy is indicated in the presence of testicular adrenal rest tumours, oligospermia and resistant acne.

On initiation of therapy, close monitoring of clinical parameters including growth, virilization, blood pressure and bone age are essential. Biochemical markers, including 17-OHP, cortisol, ACTH, androstenedione, testosterone, and DHEAS levels, can also be useful to monitor response to treatment. The administration of stress-dose glucocorti-coids to late-onset CAH patients during intercurrent illness perioperatively and during other periods of stress is controversial, but is practiced at some centres.

Finally, it is imperative that clinicians consider rare but concerning causes of hyperandrogenism, early puberty or virilization. Rapidly progressive symptoms of hyperandrogenism should prompt the clinician to investigate for androgen-secreting tumours as an underlying etiology. High total testosterone or DHEAS levels in the presence of normal 17-OHP levels should similarly prompt referral to a specialist for further assessment.

CLINICAL PEARLS

• Consider underlying endocrine disorders in the presence of acne that persists despite medical management. In females, consider PCOS or late-onset CAH, and in males consider late-onset CAH.

• When a child presents with any symptom of early adrenarche, ensure a detailed pubertal history is ascertained and consider testing for baseline and, if necessary, ACTH-stimulated 17-OHP levels.

• PCOS and late-onset CAH are virtually indistinguishable clinically; therefore, female patients with late-onset CAH are often mistakenly diagnosed with PCOS. Baseline and ACTH-stimulated 17-OHP levels are necessary to confirm or exclude the diagnosis of late-onset CAH.