Complicated iatrogenic Cushing’s syndrome induced by topical clobetasol propionate in a child with psoriasis: a case report and review of the literature

Abstract

Background

Long-term use of oral or parenteral corticosteroids is the most common cause of hypothalamic–pituitary–adrenal axis suppression and iatrogenic Cushing’s syndrome. Still, iatrogenic Cushing’s syndrome occurs rarely following the administration of topical corticosteroids.

Case presentation

This case study discusses the misuse of a high-potency corticosteroid cream by an Iranian 5-year-old male with plaque-form psoriasis, resulting in Cushingoid symptoms including moon face, buffalo hump, red striae, and weight gain. The child experienced different complications following iatrogenic Cushing’s syndrome, such as frequent vomiting and fever, which led to expiration.

Conclusion

Proper use and monitoring of topical corticosteroids are emphasized, especially among children. This study also underlines the potential side effects of high-potency corticosteroids and the importance of physicians’ and parents’ awareness, highlighting the avoidance of excessive topical corticosteroid prescriptions.

Introduction

Topical corticosteroids (TCS) are widely employed in the treatment of dermatological diseases including psoriasis and atopic dermatitis [1]. TCS are classified by the World Health Organization (WHO) into seven classes, with class 1 having the highest potency and class 7 having the lowest potency [2]. Clobetasol propionate 0.05% cream is classified as an ultra-high-potency TCS according to this classification.

The etiologies of Cushing’s syndrome (CS) can be divided into two categories: adrenocorticotropic hormone (ACTH)-dependent and ACTH-independent. ACTH-independent CS is characterized by low plasma levels of ACTH, which occur either as a result of excessive secretion of endogenous glucocorticoids from the adrenal glands or owing to long-term administration of exogenous glucocorticoids [3]. Long-term use of oral or parenteral corticosteroids is the most common cause of hypothalamic–pituitary–adrenal (HPA) axis suppression and iatrogenic Cushing’s syndrome (ICS), but ICS occurs rarely following the administration of TCS [4, 5].

This manuscript describes the case of a 5-year-old child who suffered from plaque-form psoriasis with ICS as a result of misusing a topical 0.05% clobetasol propionate cream followed by unusual complications that ultimately led to the expiration of the patient. In addition, we review existing reports regarding ICS caused by TCS in children.

Case presentation

An Iranian 5-year-old male with a medical history of plaque-form psoriasis since he was 6 months old was admitted twice owing to Cushingoid symptoms to our hospital. He was the third child and delivered by cesarean section with a birth weight of 3450 g. In the first hospitalization, he was admitted to our hospital (when he was 4 years 10 months old) with Cushingoid symptoms such as excessive weight, abdominal obesity, generalized edema, moon face, buffalo hump, and red striae on the extremities and abdomen. On physical examination, psoriatic lesions were observed as erythematous papules with white scales on the trunk, extremities, and nail folds (Fig. 1). His weight and height were 38 kg (above 95th percentile) and 102 cm (5–10th percentile), respectively. Vital signs indicated blood pressure (BP) of 135/90 mmHg, pulse rate of 170 per minute, respiratory rate of 25 per minute, oxygen saturation measured by pulse oximetry of 93% in room air, and body temperature of 36.5 °C. There were no significant neurological findings noted. The patient had extensive weight gain from 12 kg to 38 kg during the year prior to his admission. One year before hospitalization, the psoriatic lessons were limited, and topical 0.05% clobetasol propionate cream and emollient were prescribed by a physician. The parents were instructed to follow up with the physician, but they did not comply as the lesions had partially disappeared. Upon recurrence of the lesions, the patient’s mother administered the medication arbitrarily. She stated that she was applying approximately 30 g/day of topical 0.05% clobetasol propionate cream to the psoriatic lesions all around his body on a daily basis over the course of a year. The laboratory findings of the first hospitalization are presented in Table 1. Additionally, blood tests conducted 3 months prior showed an ACTH level of 7.98 pg/mL (within the low-normal range) and a cortisol level of 61.95 µg/dL, indicating persistently elevated cortisol despite a suppressed ACTH.

Fig. 1.

A case of iatrogenic Cushing’s syndrome due to the administration of topical clobetasol propionate 0.05%. Psoriatic lesions as erythematous papules with white scales on the extensor surface of the upper limb and nail folds

Table 1.

Laboratory findings of first and second hospitalization

Marker	First hospitalization	Second hospitalization	Normal range
WBCa(/mm3)	13,600	13,500 (lymphocyte: 31.3%, neutrophil: 25.5%)	5000–10,000
Hbb (g/dL)	14.8	13.1	9.5–14
Platelets (/mm3)	315,000	456,000	150,000–450,000
Fasting blood sugar (mg/dL)	70	–	70–100
HbA1C (%)	5.4	–	4–6.5
Serum sodium (mEq/L)	145	137	135–147
Serum potassium (mEq/L)	3.8	3.1	3.4–4.7
Total cholesterol (mg/dL)	296	–	< 170
Triglyceride (mg/dL)	123	–	30–86
HDLc (mg/dL)	96	–	> 45
LDLd (mg/dL)	142	–	< 110
ASTe (U/L)	53	86	14–50
ALTf (U/L)	181	117	4–36
ALPg (U/L)	167	289	130–260
8 a.m. serum cortisol level (µg/dL)	0.2	–	3–21

Bold: the patient exhibited leukocytosis during both hospitalizations. Additionally, thrombocytosis was observed during the second hospitalization. Liver function tests (LFTs) were abnormal in both instances, with total cholesterol, LDL, and triglycerides showing elevated levels

^awhite blood cells

^bhemoglobin

^chigh-density lipoprotein cholesterol

^dlow-density lipoprotein cholesterol

^easpartate transaminase

^falanine transaminase

^galkaline phosphatase

During the first hospitalization, dermatology, endocrinology, and nephrology consultations were performed. Clobetasol propionate 0.05% cream was discontinued gradually. On the basis of the prescription of a pediatric dermatologist, following a test dose of 5 mg methotrexate (MTX), the patient received a weekly oral dose of 5 mg MTX over 6 weeks, along with a topical lotion (containing glycerin, urea, and eucerin) once daily for the treatment of psoriatic lesions. As presented in Table 1, the HPA axis was suppressed, therefore the patient was treated with 15 mg daily oral hydrocortisone to prevent adrenal crisis (Table 1). Owing to the high systolic blood pressure (SBP) (higher than the 95th percentile), the patient was treated with enalapril (3.75 mg per day). Following the treatment, remission of psoriatic lesions was obtained. Finally, the patient was discharged after 9 days of hospital stay, with a prescription for oral methotrexate (MTX) 5 mg weekly, topical emollient, oral hydrocortisone 15 mg daily (10 mg in the morning, 5 mg at night), and enalapril 3.75 mg daily (2.5 mg in the morning, 1.25 mg at night), and recommended for weekly BP monitoring and follow-up.

Two weeks later, he was admitted to the hospital for the second time with activated psoriatic lesions, fever, vomiting (bilious and nonbilious), and diarrhea during the 6 days prior to the hospitalization. Following the initial physical examinations, he was febrile, and his vital signs were the following: BP of 160/100 mmHg, pulse rate of 100 per minute, and respiratory rate of 24 per minute. Laboratory results are presented in Table 1. Abdominal ultrasound indicated a normal upper limit of liver span (115 mm) and increased echogenicity of liver parenchyma. On ultrasound, the adrenal glands were normal. The other workups were normal, which included radiography of the chest, upper gastrointestinal series, Doppler renal study, brain magnetic resonance imaging (MRI), urine analysis, urine culture, blood culture, and stool examination.

During the second hospitalization, the patient was treated with MTX with a dose of 5 mg (given intramuscularly owing to the patient’s intolerability of the oral MTX) per week. In addition, hydrocortisone was started with a dose of 2 mg (given intravenously) every 8 hours. Hypertension was controlled by administrating enalapril 4 mg per day. Regarding complementary tests, nonalcoholic steatohepatitis (NASH) was evident. Based on the clinical and paraclinical data, superior mesenteric artery syndrome (SMA) was considered as a possible diagnosis; however, the normal upper gastrointestinal series eliminated the possibility of SMA. For evaluation of two possible diagnoses as a cause of frequent severe vomiting (peptic ulcer following frequent use of corticosteroids versus pseudotumor cerebri associated with ICS), upper gastrointestinal endoscopy and lumbar puncture (LP) were recommended. Despite explaining the necessity of procedures, the parents of the child did not consent. Thirty days into the second hospitalization, despite our strong recommendations for additional diagnostic investigations, the parents chose to decline further workups and were adamant about discharging the child. Following a thorough evaluation, considering the patient’s precarious state, and acknowledging the unreliability of the parents, the forensic medicine specialist deemed discharge inappropriate. Unfortunately, the patient’s parents removed him from the hospital against medical advice. Upon the next follow-up, the patient had expired.

Discussion

In this report, we describe a 5-year-old boy with early-onset psoriasis who was admitted for Cushingoid symptoms associated with prolonged use of topical 0.05% clobetasol without a dermatologist’s prescription. The initial presentation included skin changes and excessive weight gain, alongside abnormal blood pressure and liver enzyme levels. Upon the second admission with activated psoriatic lesions and severe systemic symptoms, the patient expired. In our case, we were unable to conduct LP and endoscopic examinations owing to the lack of parental consent, which led to ambiguity regarding the cause of frequent vomiting. However, this constraint does not undermine the significance of this report, given the rare occurrence of ICS following the administration of TCS.

Medical practitioners encounter two significant challenges in the prescription of TCS (overuse versus steroid phobia). Firstly, the potential for TCS misuse or overuse, as illustrated in our case, can give rise to adverse effects such as ICS, skin atrophy, and telangiectasia [6]. As mentioned in similar case reports, in developing countries, TCS is available over the counter or illegally, which incites the misuse of TCS [7, 8]. Secondly, the phenomenon of steroid phobia, encompassing caregivers’ concerns regarding corticosteroid side effects, leads to insufficient application of TCS and consequently yields unfavorable treatment outcomes for the underlying condition [9].

Negative feedback from cortisol on the hypothalamus and pituitary completes the control loop of the HPA axis. Prolonged administration of TCS in children can induce negative feedback inhibition, leading to suppression of the HPA axis and ultimately causing CS [8, 10]. Several factors contribute to the development of side effects associated with TCS, including age, epithelial integrity, lesion size and location, TCS potency, and duration of therapy [5]. High-potency TCS should be applied for a limited period of time, especially on areas such as palms and soles, and for chronic or hyperkeratotic lesions [11]. Inflammatory conditions on the face and intertriginous regions can be effectively treated with low- to medium-potency TCS for prolonged periods. It is crucial to consider the skin surface area when choosing TCS since excessive skin surface treatment can cause systemic adverse effects, as observed in our patient [11]. The degree of skin absorption also varies depending on disease conditions [12]. Similar to our case, skin inflammation caused by psoriatic lesions increases drug absorption [12]. Moreover, children are more likely to suffer from negative systemic side effects of TCS owing to their greater surface-area-to-weight ratio and slower drug metabolism [5, 13]. In contrast to adults, TCS are easily absorbed through the epidermis and dermis and passes into the systemic blood circulation of children. This increased absorption can lead to a higher risk of adverse systemic effects including HPA axis suppression, hypertension, hyperglycemia, osteoporosis, and ICS [14]. To minimize the side effects of TCS, it is highly advised to adopt treatment regimens that minimize side effects, combine corticosteroids with other topical agents, follow package insert recommendations, and use caution when applying TCS on vulnerable areas, as well as on infants and children [15].

As summarized in Table 2, we conducted a literature review to identify similar cases of psoriasis patients experiencing side effects of TCS administration (Table 2). The first reported case in 1982 involved a patient who used 7900 g of betamethasone cream 0.1% (125 g daily), which is less potent than clobetasol propionate, for 9 weeks and developed Cushingoid symptoms. The widespread distribution and inflammatory nature of the lesions facilitated steroid absorption, leading to suppression of the HPA axis [16]. Another study by Kim et al. reported a case of suspected ICS in a patient with annular pustular psoriasis. Similar to our case, the patient applied 15–30 g of clobetasol propionate cream daily without a dermatologist’s prescription. After 4 months, the patient developed Cushingoid symptoms and had low basal blood-cortisol levels, possibly due to secondary suppression of the HPA axis [17]. In another reported case in 2020, an 11-year-old girl with a history of psoriasis for 2 years presented with acute generalized pustular psoriasis. Additional TCS was added to her treatment, and despite the initial relief in redness, the patient’s mother started using the cream in increasing amounts (10 g per day). As a result, the patient developed Cushingoid symptoms, septicemia, hypertension, and osteopenia [5].

Table 2.

Descriptions and comparison of cases

Study	Patient age/sex	TCS	Duration of use	Clinical manifestations of Cushing’s syndrome	Complications and outcomes	ACTH (pg/mL)a
Ref. [16]	13 years/female	Betamethasone	9 weeks	Cushingoid face, developed buttocks and thighs striae	Six weeks after discontinuing TCS, the daily fluctuations in plasma cortisol levels returned to normal	< 1
Ref. [17]	NA	Clobetasol propionate	4 months	Moon face, facial flushing, hypertrichosis, central obesity, purple striae, and multiple erythematous scaly annular patches	NA	NA
Ref. [5]	11 years/female	NA	2 years	Weight gain of 20 kg in the last 2 years, flushed and typical moon facies, erythroderma, truncal obesity with striae, and hypertrichosis with a neck hump	Gradual resolution of lesions and 75% reduction in psoriasis area and severity index at 4 weeks of treatment	10.3
Ref. [18]	8 month/female	Clobetasol propionate	2 months	Excessive weight gain, truncal obesity, moon face, hirsutism, buffalo hump, erythematous papules at the skin fold areas, monomorphic erythematous pustules at the upper back without comedone	Her weight was decreasing, while her height was increasing to her normal percentile. Serum morning cortisol and ACTH returned to normal ranges	< 10
Ref [19]	19 months/male	Aristobet-N (betamethasone–neomycin) nasal drop	2 months	Obesity, moon-like face, excessive hair on the forehead, back and pubis. No axillary hair. Weight was 17.5 kg (95th percentile) and within 1 week increased to 18.0 kg	3 months after weaning off, the steroid was within normal limits	NA
Ref. [19]	9 months/male	Aristobed-N (betamethasone-neomycin) nasal drop	7 weeks	Round face, a height of 62 cm (below the 5th percentile), and a body mass index of 36.7 kg/m2 (above the 95th percentile)	Initially had a low serum cortisol level of 1.69 nmol/L, which increased to 128 nmol/L one month after starting steroid withdrawal. Bone age assessment was consistent with the child’s chronological age	NA
Ref. [20]	9 years/female	Betamethasone sodium phosphate eye drops (0.1% solution)	6 months	Weight gain, truncal obesity, buffalo hump, moon face, femoral skin striae	After 6 months of methotrexate treatment, morning serum cortisol and plasma ACTH levels were 10.1 µg/dL and 42.6 pg/mL, respectively	< 2
Ref. [21]	6 years/female	Clobetasol propionate	8 weeks	Moon facies and mild facial plethora, Tanner stage 1 for breast and pubic hair development, 1.6 kg weight gain	The patient’s facial appearance returned to normal after the topical steroid taper	NA
Ref. [22]	3.5 months/female	Clobetasol propionate	2 months	Face puffing and generalized edema	ACTH and cortisol levels were normalized. Facial puffiness and edema improved	0.7
Ref [7]	6 months/male	Clobetasol propionate	4 weeks	Dystrophy presented with a Cushingoid face and scratch marks on the abdomen	NA	1.3
Ref. [7]	2 years/female	Dexamethasone eye drop	Few weeks	Short stature, dystrophy, low body mass index, growth hormone deficiency, bone mineralization deficiency, nephropathy, hepatopathy, anemia, and chronic inflammation	8 weeks later the patient showed catch-up growth	< 7
Ref. [8]	6 months/male	Betamethasone	2–3 months	ICS symptoms, hirsutism, a Cushingoid face, and a buffalo hump. Hyperpigmentation around the diaper region	Full recovery	NA
This case report	5 years/male	Clobetasol propionate	1 year	Excess weight, abdominal obesity, generalized edema, moon face, and red striae on the abdominal area	Complications included frequent vomiting, activated psoriatic lesions, and fever. Treatment led to improvement in Cushingoid symptoms and psoriatic lesions	NA

^aACTH normal range: 10 to 50 (pg/mL)

NA, not available

Conclusion

Regulating the safe dose of TCS in pediatric patients can be challenging. Physicians should avoid excessive TCS prescriptions, especially highly potent TCS for children, and seek alternatives or combination therapy whenever possible. Furthermore, parents should be warned and educated regarding TCS side effects and the necessity of using TCS in the appropriate quantity and treatment duration.

Author contributions

B.N.: conceptualization, investigation, project administration, supervision, validation, reviewing and editing. P.N.: conceptualization, investigation, validation, reviewing and editing. K.A.: data curation, investigation, writing original draft, reviewing and editing. N.N.: data curation, investigation, writing original draft, reviewing and editing.

Funding

Financial funding for this study was provided by Isfahan University of Medical Sciences.

Data availability

Data from this case report are available upon request to the corresponding authors.

Materials availability

Not applicable.

Code availability

Not applicable.

Declarations

Ethics approval and consent to participate

This case report has been approved by the ethics committee of Isfahan University of Medical Sciences based on the ethical standards in the Declaration of Helsinki. A written informed consent was obtained from the patient’s legal guardian.

Consent for publication

Written informed consent was obtained from the patient’s legal guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare no competing interests.