Topical glucocorticoid application causing iatrogenic Cushing’s syndrome followed by secondary adrenal insufficiency in infants: two case reports

Chronic exposure to inappropriate high levels of exogenous glucocorticoids results in Cushing's syndrome (CS) [1]. CS may be characterized by growth failure and weight gain. These children present with “moon face,” truncal obesity, “buffalo hump,” skin bruises, arterial hypertension, hyperglycemia, and proximal muscle wasting [2]. CS in the pediatric age group is very rare, and the vast majority of cases are iatrogenic owing to oral or parenteral administered glucocorticoid hormones. An iatrogenic CS is associated with the systemic daily dosage of 10–12 mg/m² hydrocortisone (corresponding to 0.3 mg dexamethasone) or higher for more than 7 days [2, 3]. Immediate withdrawal from exogenous steroids can lead to life-threatening adrenal insufficiency [3]. However, iatrogenic CS in childhood owing to topical glucocorticoid administration may occur and is probably underreported [4, 5]. Dermal application is used in inflammatory skin diseases [6] or inhalation in obstructive lung diseases [7]. Further, topical glucocorticoids are frequently used as rectal application in inflammatory bowel disease [8], as nose spray in obstructive rhinitis [9], or as eye drops in postoperative ocular inflammations [10]. Systemic side effects of topical glucocorticoid depend on the substance used and are subject to individual resorption conditions [11, 12]. Parents must be fully informed about potential side effects. Herein, we present a case of iatrogenic CS in a 2-year-old infant induced by dexamethasone-containing eye drops and a second case of a 6-month-old infant in whom CS was induced by dermal application of clobetasol.

Cushing’s syndrome due to topical administration of glucocorticoids is a rare condition in infants and children, but probably underreported [12]. Exogenous glucocorticoids lead to suppression of hypothalamic–pituitary–adrenal (HPA) axis, and life-threatening addisonian crisis can occur [11]. The first case we presented developed iatrogenic CS after inappropriate and prolonged use of highly potent topical glucocorticoid, that is, clobetasol propionate for treatment of scabies. At least 43 cases with iatrogenic CS from very potent topical steroid usage (clobetasol) in children and adults have been published over the last 35 years. particularly in developing countries [5]. Most patients were infants with diaper dermatitis and were treated for a median duration of 2.75 months (1–17 months) [5]. In all cases, CS was clinically obvious and suppressed cortisol and ACTH levels were detected. After discontinuation of topical steroids, HPA axis recovered after 3.49 ± 2.92 months (1–12 months) [5]. The effect of topical glucocorticosteroids depends on type of corticosteroid and its bioavailability, the vehicle, the integrity of the skin, the use of occlusive dressings, surface area, frequency and duration of treatment, presence of inflammation, and anatomic region [13]. Anatomic regions with a thin epidermis are significantly more permeable to topical steroids than thick-skinned areas [14]. Occlusive dressings will enhance drug resorption, often by a factor up to ten [15, 16]. Our patient received a daily dosage of 2 g/day of 0.05% clobetasol (corresponding to 0.1 g clobetasol per day). The potency of clobetasol is estimated to be 600 times higher compared with hydrocortisone, therefore 1 mg clobetasol corresponds to 600 mg hydrocortisone. It is known that the use of 2 g/day of 0.05% clobetasol propionate can decrease morning cortisol levels after only a few days [17] and use over 100 g/week can lead to the development of features of CS and symptoms of adrenal insufficiency [18]. The patient here (case 1) presumably received this amount. Furthermore, the boy presented with abdominal scratch marks and was malnourished. Presumably these factors and the stressful journey facilitated the development of CS in his case. The reported family has refugee status and only limited Greek, German, or English knowledge, contributing to communication problems. Professional interpreters should be introduced to explain medical details [19].

There are several ophthalmologic indications for topical ocular steroid treatment in children, one being postoperative treatment [10]. Often, an intensive therapy scheme is necessary over several weeks [10]. The systemic resorption of glucocorticoid-containing eye drops depends on the frequency, concentration, and duration of application. In general, the conjunctiva, but also the nasal mucosa via the lacrimal drainage system, is highly resorptive [20]. Therefore, it is advisable to apply finger pressure to the lacrimal sac for 1–2 minutes after instillation of dexamethasone eye drops to decrease the risk of resorption and systemic effects [21]. Our patient initially received 0.3 mg dexamethasone daily. Even after reducing the dexamethasone dosage to 50% of the initial dose, the measured serum dexamethasone concentration was 1.02 nmol/L, indicating systemic resorption. This corresponds to 30-fold potency of hydrocortisone. Interestingly, when dexamethasone eye drops were reduced to 0.15 mg daily, catch-up growth occurred and endogenous cortisol secretion normalized. It is known that a decrease in growth velocity is observed as soon as daily dosages exceed a cortisol equivalent of 10–12 mg/m² body surface/24 hour [22]. Caution is necessary if additional medications are administered. Glucocorticoids are mainly metabolized in the liver via CYP3A4 into inactive compounds and are further eliminated as urinary metabolites. Therefore, comedication of CYP3A4 inhibitors, that is, protease inhibitors, itraconazole, macrolides, and diltiazem can increase the risk of the development of CS from using topical corticosteroids [5]. For evaluation, the adrenal axis ACTH-and CRH-stimulation test, as we have undertaken in case 2, were performed. Ach et al. proposed the glucagon stimulation test as a safe alternative test for the assessment of the hypothalamic pituitary adrenal axis [23, 24]. If CS is obvious and iatrogenic adrenal insufficiency is induced, abrupt discontinuation of long-standing glucocorticoid treatment should be avoided [3, 25]. A reduction scheme should be provided and explained in detail to the parents [26]. If a language barrier is obvious, the education should be given with the help of an interpreter. Further compliance should be checked at a follow-up visit to avoid life-threatening complications. The duration of recovery of the HPA axis suppression varies [25]. Therefore, the patient must be educated to increase the hydrocortisone dose as indicated in the personalized emergency pass in case of acute illness or any symptoms resembling addisonian crisis, including vomiting. Patients should immediately go to the hospital to potentially receive parenteral corticosteroids and, if necessary, hemodynamic support.

Both cases reveal that young infants are at high risk of Cushing’s syndrome from topically applied highly potent glucocorticoids. Therefore, physicians prescribing topical steroids should be aware of such complications and closely follow these patients. A precise application recommendation including dosage, duration, and frequency must be explained to the parents, and if necessary, with the help of an interpreter. Further, physicians should avoid abrupt withdrawal from long-term treatment with glucocorticoids, which can cause adrenal crisis if adrenal insufficiency is present. Instead, careful weaning of topical corticosteroids is indicated as treatment with hydrocortisone should be considered.