Iatrogenic Cushing Syndrome from Topical Corticosteroid Use in Infants: A Review of Published Cases

Ekstrom E; Wagner M; Vukovic I

doi:10.5281/zenodo.22279609

Abstract

Background: Topical corticosteroids are widely used in infants, but thin, highly permeable skin and a high

surface-area-to-weight ratio permit systemic absorption sufficient to cause iatrogenic Cushing syndrome. Objective: To review published cases and case series of iatrogenic Cushing syndrome and hypothalamic-pituitary-adrenal (HPA) axis suppression from topical corticosteroid use in infants. Methods: Narrative review of case reports, case series, cohort and meta-analytic data, and management literature. Findings: Most reported infant cases followed unsupervised use of superpotent agents, chiefly clobetasol propionate, applied to the diaper area for 1-7 months; biochemistry uniformly showed secondary adrenal insufficiency (low cortisol with low or inappropriately normal ACTH). A meta-analysis of 522 children found suppression rising from 2.0% with low-potency to 6.6% with high-potency agents. Recovery after physiological hydrocortisone replacement and gradual withdrawal took a median of 2-6

months across series. Conclusions: Clinicians should recognise cushingoid infants promptly, avoid abrupt cessation of potent topical steroids, and taper under hydrocortisone cover to prevent adrenal crisis.

Keywords: Iatrogenic Cushing syndrome; Topical corticosteroids; Infants; Adrenal suppression; Clobetasol propionate

Introduction

Topical corticosteroids are a cornerstone of treatment for diaper dermatitis, atopic dermatitis, and other inflammatory skin conditions in infancy, and their apparent familiarity as an over-the-counter remedy in many countries has made unsupervised, prolonged use common [1,2]. Unlike older children and adults, infants combine a markedly higher body-surface-area-to-body-weight ratio with a thinner, less fully keratinised stratum corneum, and the diaper area itself is frequently occluded, all of which magnify percutaneous absorption of applied steroid [3,4]. When a sufficiently potent agent is applied over a large area for weeks to months, cutaneous absorption can reach systemic concentrations adequate to suppress the hypothalamic-pituitary-adrenal (HPA) axis and to produce the clinical phenotype of Cushing syndrome — a condition that is entirely iatrogenic and, critically, reversible if recognised [5,6]. This review surveys the published individual case reports and case series of iatrogenic Cushing syndrome and HPA-axis suppression attributable to topical corticosteroid use in infants, together with the epidemiological, pathophysiological and management literature that frames those cases.

Epidemiology

Systematic quantification of topical-corticosteroid-induced Cushing syndrome in infants is limited to case reports and small series rather than population-based incidence figures. The best available pooled paediatric estimate comes from a meta-analysis of 12 trials (522 children, drawn from 128 eligible studies) evaluating cutaneous topical corticosteroid use for atopic dermatitis, which found HPA-axis suppression in 3.8% overall (95% CI 2.4-5.8), rising with potency class: 2.0% (3/148) with low-potency agents, 3.1% (7/223, 95% CI 1.5-6.3) with mid-potency agents, and 6.6% (10/151, 95% CI 3.6-11.8) with high-potency agents [7]. Because this pool studied prescribed, monitored dermatitis treatment, it likely under-represents the unsupervised, superpotent exposures — most often clobetasol propionate purchased without prescription for diaper rash or presumed scabies — that produce overt Cushing syndrome in the published infant case literature [8,9,5,10,11,12,13,14,15,16]. A cohort of 14 children with iatrogenic Cushing syndrome from any glucocorticoid route found 85% had adrenal insufficiency at presentation, with 10 of the 14 exposures topical [17]. Case reports of potent topical corticosteroid overuse causing Cushing syndrome are not confined to infants: similar presentations have been described in older children and adults after unsupervised use of potent agents obtained over the counter, underscoring that availability without prescription, not age alone, drives much of this literature [18,19]. Reviews repeat the finding that most reported paediatric cases arise from a single class-I (superpotent) molecule, clobetasol propionate, often within unlabelled fixed-combination antifungal or antibiotic creams sold for diaper dermatitis or scabies [6,15,14]. In adults, a systematic review of 3753 corticosteroid users across all routes found adrenal insufficiency prevalence rising with cumulative dose and duration of exposure (1.4% for treatment under 28 days versus 27.4% for over 1 year), and this literature is frequently, if imperfectly, extrapolated to justify concern about topical paediatric exposure despite the adult-only

Pathophysiology

Percutaneous absorption of corticosteroid depends on the molecule's lipophilicity and potency, the integrity and thickness of the stratum corneum, the surface area treated relative to body mass, and occlusion. Infant skin at birth and through the first year is thinner than adult skin, and the diaper itself functions as an occlusive dressing that markedly increases penetration compared with exposed skin [3,4]. Classic physiological studies documented measurable suppression of adrenocortical responsiveness in infants treated with hydrocortisone for severe skin disease, and showed that absorption varies with age and with the severity of the underlying dermatitis, with more inflamed, barrier-disrupted skin absorbing more drug [3,4]. Earlier work using potent topical steroids similarly demonstrated measurable falls in plasma cortisol in infants and children with eczema, establishing decades ago that cutaneous corticosteroid is not pharmacologically inert once applied to compromised or occluded infant skin [21]. Absorbed corticosteroid suppresses hypothalamic corticotrophin-releasing hormone and pituitary ACTH secretion through negative feedback; with sustained suppression the adrenal cortex itself becomes atrophic and unresponsive to ACTH stimulation, producing the biochemical signature seen uniformly across the published infant cases — low basal cortisol together with low or inappropriately normal ACTH, i.e. secondary (central) rather than primary adrenal insufficiency [15,10,12,9]. Children with atopic dermatitis may also have intrinsically altered glucocorticoid sensitivity independent of exogenous exposure, a variable that complicates interpretation of HPA testing in this population [22]. Once the exogenous steroid is stopped, the child is left, at least transiently, without adequate endogenous cortisol production, which is the physiological basis for the risk of adrenal crisis on abrupt withdrawal [23,6].

Clinical Presentation

Reported infant cases share a strikingly consistent phenotype: progressive facial rounding and puffiness ("moon facies"), generalised or truncal adiposity with prominent cheeks, hirsutism or hypertrichosis (often most visible on the forehead and back), cutaneous striae, telangiectasia, and localised skin changes (atrophy, hypopigmentation, or acneiform change) at the site of application [5,10,11,13,14]. Hypertension for age has been documented repeatedly [12,11,24]. A distinctive and diagnostically important pattern is growth failure that can occur with or without weight gain: one infant showed frank linear growth arrest (height -3.6 SD) despite normal weight after seven months of superpotent clobetasol to the groin, illustrating that failure to thrive is not incompatible with iatrogenic Cushing syndrome [12]. Cardiac involvement has been reported in a young infant with clobetasol-induced Cushing syndrome, who presented with left ventricular hypertrophy and pericardial effusion [8]. Two further infant cases from overuse of topical steroid confined to the diaper area were reported together as a paired case series, reinforcing the diaper region as the single most common site of exposure in this literature [25]. Several clusters arose from misdiagnosis: eight infants developed cushingoid features after a fixed-combination betamethasone/clotrimazole/gentamicin cream was applied for undiagnosed scabies over one to eight months, underscoring that inappropriate use for an unrecognised primary dermatosis is a recurring precipitant [14,11]. No verified paediatric case in the reviewed literature documented hyperglycaemia as a presenting feature, and glucose was explicitly normal where reported; hypertension, not dysglycaemia, is the more consistently documented cardiovascular sign in infants [15,11].

Report Age at Preparation / Site / Outcome after presen potency duration withdrawal

tation

Matejek 6 mo, Clobetasol Whole Not recovered 2022, case 1 M propionate body, 2 at 3 wk; lost to 0.05%, very g/day, >=4 follow-up potent wk Tempark 8 mo, F Clobetasol, very Diaper Hydrocortisone 2010 potent area, not 3 mo, then stated stopped once normal Jevalikar 8 mo, F Clobetasol Diaper/but Hydrocortisone; 2016 propionate tocks, 3 mo facies and 0.05% cortisol combination, recovered by 3 superpotent mo Kuikel 2022 15 mo Clobetasol Widespread Prednisolone 0.05%, very , not stated taper 45 d; potent resolved by 3 mo Razavi 2014 17 mo, Clobetasol Groin, ~28 Hydrocortisone M propionate g/wk, 7 mo taper 2 mo; 0.05%, catch-up superpotent growth by 22 mo Almansour 18 mo, Clobetasol Diaper Monitoring 2026 F propionate, area, only; partial high potency prolonged recovery Estrada-Ch 3 Betamethasone Affected Antiscabetic avez 2018, mo-1.5 combination, areas, 1-8 treatment; n=8 y potent mo limited follow-up Kilci 2025, 3-60 Clobetasol Not stated, Hydrocortisone; n=7 mo propionate, very median 2 median potent mo recovery 6 mo

Diagnostic Approach

Suspicion should be raised by the combination of cushingoid facies or body-habitus change in an infant with a history, sometimes only elicited on direct questioning, of regular application of a potent topical corticosteroid, frequently obtained without prescription or used within a combination antifungal/antibacterial cream whose steroid component the caregiver did not recognise [6,10,11]. Biochemical confirmation follows the same principles used for endogenous Cushing syndrome, adapted to the fact that the driving process is exogenous and typically causes HPA-axis suppression rather than autonomous cortisol excess [23]. Reported infants have shown low or undetectable basal (morning) serum cortisol together with low or inappropriately normal ACTH — for example, cortisol 0.22 μg/dL with ACTH 5.9 pg/mL in one napkin-area case, and cortisol <0.3 ng/mL with an ACTH-stimulated peak of only 0.4 ng/mL in another [10,12]. Dynamic ACTH stimulation testing has been used to confirm the degree and reversibility of suppression and to guide the timing of steroid withdrawal [9,15]. Because the population most often affected is preverbal and the exposure history depends entirely on caregiver recall, a deliberately structured medication and product history — including topical antifungal, antibacterial, and "diaper cream" products that may contain unlabelled corticosteroid — is an essential diagnostic step [14,26].

The unifying management principle across the published cases is that the causative topical corticosteroid must be discontinued, but not abruptly, because the child's endogenous HPA axis is typically already suppressed and cannot immediately compensate; abrupt cessation risks acute adrenal insufficiency (adrenal crisis) [6,23]. Most reported infants were therefore covered with physiological-dose hydrocortisone replacement during withdrawal, commonly in the range of 6-12 mg/m/day in individual case reports and a median of 10 mg/m/day (range 7.5-50) across a seven-patient series, with gradual tapering guided by clinical and biochemical recovery [10,9,12,16]. Concurrent treatment of the underlying dermatological indication — for example antiscabetic therapy where scabies had been misdiagnosed and mistreated with steroid — is required alongside steroid withdrawal [11,14]. Broader paediatric dermatology guidance similarly emphasises using the lowest effective potency, limiting duration and surface area, and avoiding occlusion or combination products of unclear composition in infants, particularly in the diaper area [1,27,28]. Where topical corticosteroid is used therapeutically under monitored conditions, such as structured wet-wrap protocols for atopic dermatitis, dosing and duration are deliberately constrained specifically to avoid the exposures seen in the unsupervised case literature [28]. Families and prescribers should be counselled explicitly that visible efficacy does not indicate systemic safety, and that any once-daily, low-potency regimen is preferable to frequent (five-to-eight-times-daily) application of superpotent agents, a pattern present in several of the most severe reported infant cases [9,5].

Outcomes/Prognosis

Where documented, HPA-axis recovery and resolution of cushingoid features after appropriate withdrawal and hydrocortisone cover has generally been favourable. In a cohort of 14 children with iatrogenic Cushing syndrome (10 topical exposures), median time to HPA-axis recovery was 60 days (range 30-780) [17]. Pooled literature spanning 22 paediatric and 21 adult cases over 35 years reported a mean recovery time of 3.49 ± 2.92 months in children, similar to adults (3.84 ± 2.51 months); a subsequent case-report series drawing on the same broader literature pool of 43 clobetasol-associated cases cited an equivalent 3.49-month mean (range 1-12 months), representing the same underlying dataset rather than an independent replication [6,15]. A more recent series of seven children reported a longer median recovery of six months [16]. Individual reports document full clinical and biochemical normalisation: catch-up linear growth and normalised cortisol by 22 months in the infant with growth arrest [12], resolution of facial and pigmentary changes with cortisol recovery to 10.9 μg/dL by three months in a napkin-area case [10], and normalisation of the steroid axis within weeks after dose reduction in a toddler exposed to potent dexamethasone eye drops [15]. No verified case of adrenal crisis following abrupt topical-corticosteroid cessation in an infant was identified in the reviewed literature, though several authors explicitly state that replacement hydrocortisone was given specifically to prevent this complication, reflecting recognised theoretical risk rather than a documented paediatric event in this dataset [6,23].

(range 1-12) from a 43-case pooled series [15]; median 6.0 months

Conclusion

Iatrogenic Cushing syndrome from topical corticosteroids in infants is a preventable, reversible condition that arises almost exclusively from unsupervised, prolonged application of superpotent agents — most often clobetasol propionate — to the diaper area, frequently within unlabelled combination products. The consistent biochemical picture of secondary adrenal insufficiency means that the central management risk is not the Cushing syndrome itself but abrupt withdrawal of the child's only circulating glucocorticoid; recognition, careful biochemical confirmation, and a physiological hydrocortisone taper over weeks to months are the mainstays of safe recovery. Clinicians should maintain a low threshold to ask about topical steroid and combination-cream use in any infant presenting with unexplained cushingoid features, growth arrest, or hypertension, and should counsel caregivers explicitly on potency, duration, and site limits when prescribing or dispensing topical corticosteroids for infants.