A five-year-four-month-old Caucasian boy of nonconsanguineous parents presented with a one-year history of papules over the cheeks, glabella and ears. His mother noted that he experienced several episodes of body odour that resolved spontaneously. He also experiences occasional headaches.
He had no history of salt-craving, axillary or pubic hair, or change in phallus size. Rapid growth was noted by the mother in the past six months.
His medical history was unremarkable, and the family history only revealed that the paternal grandmother’s first child died shortly after birth. No autopsy results were available.
On examination, the patient was in no distress. His blood pressure was 94/53 mmHg, and his pulse was 87 beats/min. His height was 120.7 cm and his weight was 21.3 kg, at the 97th and 80th percentiles, respectively. He had no body odour, his penile length was 7 cm (>2 SD) and his testes were descended and 3 mL in volume. His cutaneous examination revealed multiple keratotic papules on his cheeks, as well as open comedones around the inner and outer ears and nose. He exhibited no cutaneous hyperpigmentation. Partial initial laboratory results demonstrated a normal complete blood count, electrolyte levels, and normal tests of liver and renal function. Follicle-stimulating and luteinizing hormone levels were also within normal limits. His bone age was nine years. Additional investigations revealed the diagnosis.
CASE 2 DIAGNOSIS: PERIPHERAL PRECOCIOUS PUBERTY FROM CONGENITAL ADRENAL HYPERPLASIA DUE TO 11β-HYDROXYLASE DEFICIENCY
Random testosterone and dehydroepiandrosterone sulphate levels were in the high-to-normal range, and his 17-hydroxyprogesterone (17-OHP) level was moderately elevated at 14.2 nmol/L (normal <3.0 nmol/L). An expedited endocrinology referral was made, and a 250 μg adrenocorticotropic hormone stimulation test demonstrated an inadequate cortisol response and elevated levels of 11-deoxycortisol, testosterone, androstenedione and 17-OHP. These laboratory results confirmed congenital adrenal hyperplasia due to 11β-hydroxylase deficiency (11OHD).
Congenital adrenal hyperplasia (CAH) refers to a family of inherited disorders caused by a severe or partial impairment of adrenal steroidogenesis. Greater than 90% of cases of CAH are caused by a defect in the enzyme 21-hydroxylase and can present with salt wasting, adrenal crisis and virilization. A less common cause of CAH is 11OHD, which occurs in approximately 1:100,000 to 1:200,000 live births. 11β-hydroxylase converts 11-deoxycortisol and deoxycorticosterone to cortisol and corticosterone, respectively. 11OHD results in an accumulation of the precursor steroids, which are shunted into the adrenal androgen synthesis pathway. In girls, this results in virilization of female external genitalia. In boys, the excess androgens lead to precocious pseudopuberty, with growth of the penis and thinning of scrotal skin, but no testicular enlargement. In both sexes, rapid somatic growth, pubic hair growth, body odour and accelerated bone maturation are characteristic. Unlike 21-hydroxylase deficiency, 11OHD does not present with salt wasting. Rather, a state of mineralocorticoid excess is often apparent in 11OHD due to elevated levels of deoxycorticosterone; which leads to hypernatremia, hypokalemia, metabolic alkalosis and hypertension.
While 11OHD does not usually cause an adrenal crisis, early diagnosis is important to prevent virilization and the onset of a growth spurt. Without treatment, the early growth spurt and advanced bone age lead to early closure of the growth plates and short adult stature.
In the present case, the facial papules were initially diagnosed as keratosis pilaris. Facial comedones may be mistaken for other entities, and the differential diagnosis includes keratosis pilaris rubra faceii, facial angiofibromas, periorifical dermatitis and molluscum contagiosum. Keratosis pilaris rubra faceii lesions consist of asymptomatic hyperkeratotic follicular papules overlying the cheeks, which may have an underlying erythematous telangiectatic background. It is often seen in combination with keratosis pilaris in the extensor aspects of the upper arms and anterior aspects of the thighs. Angiofibromas are benign dermal neoplasms that consist of dermal fibroplasia and dilated blood vessels. Multiple angiofibromas are seen in tuberous sclerosis, multiple endocrine neoplasia type 1 and Birt-Hogg-Dubé syndrome. Periorificial dermatitis presents as an erythematous eruption composed of tiny papules and papulopustules distributed around the mouth, eyes and nose. Molluscum contagiosum lesions present as pearly, flesh-coloured to pink papules that often appear translucent. The lesions can present anywhere on the body, including the face.
In distinction, comedones represent plugs of cornified cells, sebum and microorganisms in a dilated infundibulum of a pilosebaceous follicle. The orifice may be ‘open’ as in a blackhead or ‘closed’ as in a whitehead. Comedones are important to recognize because their presence in the prepubertal age group is never normal and is a sign of virilization necessitating further investigation.
The differential diagnosis of precocious puberty includes central and peripheral (gonadal and/or adrenal steroid-dependent) causes. In a patient with suspected virilization from CAH (an adrenal steroid-dependent cause), important initial laboratory evaluations include a random determination of the level of glucose, electrolytes, liver enzymes, cortisol, adrenocorticotropic hormone, renin and 17-OHP.
Our patient was treated with hydrocortisone 2.5 mg orally three times per day (8.8 mg/m2/day) with counselling to double the dose in times of mild illness and to triple it for moderate-to-severe illness. Hydrocortisone therapy suppresses the adrenocorticotropic hormone-driven adrenal hyperplasia and subsequent mineralocorticoid and androgen excess. He is currently doing well but needs to be monitored for central precocious puberty. As a result of the early exposure to excess androgens and the rapid decrease in androgens once treated, the patient’s hypothalamic-pituitary axis is subject to early maturation. Genetic testing for the CYP11B1 (11β-hydroxylase) gene will be scheduled for the patient.
CLINICAL PEARLS
Comedones in the prepubertal age group are a sign of early virilization and warrant clinical and laboratory investigations for precocious puberty.
11OHD is an uncommon form of congenital adrenal hyperplasia that can present with early virilization.
Early diagnosis of 11OHD is important to prevent virilization, hypertension and short stature in adulthood.
RECOMMENDED READING
Antal Z, Zhou P. Congenital adrenal hyperplasia: Diagnosis, evaluation, and management. Pediatr Rev 2009;30:e49–57.
Muir A. Precocious puberty. Pediatr Rev 2006;27:373–81.
Ninkarm S, New MI. Steroid 11 beta-hydroxylase deficiency congenital adrenal hyperplasia. Trends Endocrinol Metab 2008;19:96–9.