Neurological complications of iatrogenic Cushing syndrome in a child by Maria Francesca Messina in Journal of Clinical Case Reports Medical Images and Health Sciences

 Neurological complications of iatrogenic Cushing syndrome in a child by Maria Francesca Messina in Journal of Clinical Case Reports Medical Images and Health Sciences

Abstract 

A female infant, aged 6 months presented to our Unit of Paediatric Endocrinology of the University of Messina for evaluation of microcephaly and failure to thrive. A clinical examination showed: length 59.5 cm (-1.9 SDS), target height 170.4 cm (+ 1.2 SDS), weight 5.8 kg (-1.5 SDS), head circumference 39.5 cm (-2.1 SDS), cushingoid appearance with marked facial puffiness and moon-face appearance and a severe burn-like injury in the napkin area. The mother reported that she has been using topical corticosteroid products because a diagnosis of neonatal psoriasis was made. In particular, for the past three months she applied hydrocortisone cream in the napkin area (five to eight times/day), a betamethasone 0.5% ointment on the scalp, eyelids and eyebrows (two times/ day) and a betamethasone 0.5% foam diluted in the bath water (once/day). Laboratory investigations revealed low levels of ACTH (10.4 pg/ml) and cortisol (6.3 mcg/dl) and, undetectable levels of adrenal steroids, i.e. testosterone < 2.5 ng/ml, DHEAS < 0.2 mcg/dl, delta-4-androstenedione < 0.05 ng/ml. The abrupt withdrawal of topic steroids determined a striking statural growth and head circumference gain and in a few months these auxological parameters reached the 50th percentile and the baby achieved the full genetic potential, confirming 

Introduction

 Glucocorticoid are one of the most important drugs and since their introduction in 1948 they have never been given up or replaced (1).They are widely used in routine clinical practice because of their important antiinflammatory and immunosuppressive effects but unfortunately their pleiotropic effects can cause several adverse reactions (2). Side effects are more common when glucocorticoid are administered by systemic route (oral, intravenous or intramuscular) but every route of administration (dermal, ocular, nasal) may determine a systemic absorption, especially when applied for long time and at high doses (3, 4). Cushing syndrome (CS) is a systemic endocrine disorder resulting from abnormally high plasma cortisol levels but in the pediatric population the most common etiology is iatrogenic, secondary to excessive exogenous administration of glucocorticoids (5). Iatrogenic CS is a rare complication from the use of topical glucocorticoids but has been reported in the previous literature (6-8). The use of topical glucocorticoids is a very important tool in dermatological therapy due to their anti-inflammatory and anti-proliferative effects. These topical dermatological medications are widely used in children but it is underestimated that the penetration of drug in inflamed and damaged skin may be remarkable with a massive absorption and high risk of systemic side effects (9- 11). We discuss about a female infants, aged 6 months, who came to our observation due to a microcrania and failure to thrive as the clinical manifestations of a severe iatrogenic CS secondary to dermatological steroid

Case presentation 

We describe the case of a female infant, aged 6 months who presented to our Unit of Paediatric Endocrinology of the University of Messina for evaluation of microcephaly and failure to thrive. She was born at term (39 gestational weeks) by non- consanguineous parents. Her birth weight was 3020 gr (-0.4 SDS) and birth length was 49 cm (-0.2 SDS). A clinical examination showed: length 59.5 cm (-1.9 SDS), target height 170.4 cm (+ 1.2 SDS), weight 5.8 kg (-1.5 SDS), body mass index (BMI) 16.3, ideal weight/ height 101%, head circumference 39.5 cm (-2.1 SDS), blood pressure over the 97° centile for age, cushingoid appearance with marked facial puffiness and moon-face appearance but no other classical features of CS (Figure 1). The cutaneous examination revealed a mild unspecified dermatitis in the scalp and a severe burn-like injury in the napkin area (Figure 2). Neurological examination was negative, reflexes were normal and psychomotor development was age appropriate. The mother reported that she has been using topical corticosteroid products because of neonatal psoriasis diagnosed by a dermatologist, according to the skin lesions and a family history positive for psoriasis (mother). For the past three months she applied hydrocortisone cream in the napkin area in a dose of five to eight times a day, a betamethasone 0.5% ointment on the scalp, eyelids and eyebrows two times a day and a betamethasone 0.5% foam diluted in the bath water once a day. The clinical appearance and the pharmacological history suggested the hypothesis of iatrogenic CS and endocrinological work up was started. Laboratory investigations revealed low levels of moring both ACTH (10.4 pg/ml, normal values 10-50) and cortisol (6.3 mcg/dl, normal values 5-23) and, undetectable levels of adrenal steroids, i.e. testosterone < 2.5 ng/ml, DHEAS < 0.2 mcg/dl, delta-4-androstenedione < 0.05 ng/ml; electrolytes, glucose, urea and creatinine were normal. The use of topical corticosteroids was immediately stopped. The clinical course was striking in term of normalization of phenotypic appearance, statural growth and head circumference gain (Fig. 3). In eight months these auxological parameters normalized (reaching the 50th percentile) and the baby achieved her full genetic potential 

Discussion 

CS is very rare in pediatric age. It is estimated to occur in about 2-5 new cases per million individual per year and the vast majority of these cases is iatrogenic (5). Synthetic glucocorticoid are one of the most important and widely used drugs in both children and adults. They have potent anti-inflammatory and immunosuppressive effects and are the best drugs to treat a large variety of diseases, such as inflammatory, allergic, dermatological and, autoimmune disorders (4, 12). Since their introduction in 1948, they have never been replaced with other drugs and new preparations have been synthetized over the years in order to strengthen the therapeutical power and minimize the side effects (1, 13). Most clinicians are aware that a prolonged use of high potency glucocorticoid can induce iatrogenic CS, a welldefined clinically entity, easily recognized when high-dose, long-term glucocorticoid are administered by systemic route; but iatrogenic CS might develop in other therapeutical setting such as local delivery of steroids, i.e. dermatological, intraarticular, inhaled and, ocular (8, 14-18). Erroneously, most clinicians believe that the action of topical steroid is limited to the site of application while every topical preparation may be systemically absorbed and cause important side effects. Topical steroids are widely used in the pediatric population for the management of various dermatological conditions and, they are graded in terms of potency as either low, medium, high, and very high. While low potency steroids are well-tolerated and relatively safe, the absorption of high-potency steroids can cause severe side effects (9 -11, 18). Children are more exposed to the risk of developing CS than adults because they have higher ratio of body surface area to body weight and thinner skin barrier so the absorption of topical drugs is greater. In particular betametasone dipropionato in optimized vehicle is particular superpotent and the absorption is sufficient, in a few weeks, to produce a total suppression of plasma cortisol and ACTH levels by inhibiting the pituitary-adrenal axis. Classical CS, both endogenous and iatrogenic, is characterized by a suggestive clinical picture, and obesity represent the distinctive hallmark. Weight gain without a corresponding gain in height is one of the first features of CS in pediatric population and, short stature has been reported in 40% of patients with subnormal growth velocity in all the cases. One of the most striking feature is the contrast between height SDS values, which were almost below the mean and weight or BMI values which are consistently above it; so, the typical growth pattern is characterized by short stature and obesity (12). In our case we noticed that both the parameters, weight and length, were below the mean. The ponderal and statural growth charts showed a parallel deceleration that is very unusual in iatrogenic CS, and when steroids were abruptly taken off, we observed a rapid increase of both length and weight. This auxological trend, confirmed the suspicion that a systemic absorption of glucocorticoid was the etiology of the failure to thrive in our infant. Another very interesting and undoubtedly side effect of this inappropriate treatment was microcephaly. This is a very unusual finding and, microcephaly has never been listed among the signs and symptoms that characterize the classical full-blown picture of CS. Only few authors pointed out a neurological damage in iatrogenic CS and in one report brain atrophy and hypomielination has been documented by MRI in a 5th month-old female who has been exposed to unprescribed topical steroid (Clobetasol-17-propionato) for diaper dermatitis for two months (19- 21). Although neurological complications are not classically reported among the clinical signs and symptoms of CS, it is well-known that glucocorticoid receptors are widely distributed through-out the brain. They are mainly located in the hippocampus and many reports documented a significant volume reduction of this area after chronic glucocorticoid exposure (22- 24). Most adults with CS manifest cognitive impairment and psychiatric disturbances (depression and anxiety), while children should have compulsive behaviors,hyperactivity and significant changes in mood; all these symptoms confirm the potential glucocorticoid-related hippocampus damage (25- 27). But the effects of glucocorticoid on nervous system are not limited to this specific area, in fact a reduction of total brain weight and, atrophy of the prefrontal cortex and increase of dendritic growth in the amygdala have been documented (21- 23). It is also well-known that the glucocorticoid therapy is indicated in the management of acute multiple sclerosis, an autoimmune demyelinating disease of the central nervous system (28). The mechanisms by which glucocorticoids induce morphological changes in the brain are largely unknown but four pathways have been demonstrated and in particular: decreased glucose utilization, increased action of excitatory amino acids neurotransmitters, decrease of both neurotropic factors and neurogenesis. All these mechanisms can significantly affect the integrity of the brain, determining brain atrophy but, at present, this anatomic alteration has been shown to be reversible in adult patients with CS (29, 30). Data on the evolution of brain atrophy are very limited in pediatric age and some authors reported a long-lasting decline in cognitive function after a return to eucortisolism and despite almost complete reversal of the cerebral atrophy (31). In our child, we assisted to a rapid reversal of microcephaly after stopping glucocorticoid treatment that is an unquestionable evidence that neurological damage was a side effect of this treatment and, probably reflected a transitory brain atrophy. We also demonstrated a prompt normalization of antropometric parameters, both length and weight after the withdrawal of topical steroids medications. In conclusion, we present this case to increase awareness of the severe side effects of topical steroid and alert the physicians that iatrogenic CS may also produce neurological complications, especially in young infants.

Acknowledgments:

 We would like to thank the patient’s family for cooperation and inducement to report the clinical history in order to prevent other children from having the same inappropriate treatment and severe side effects 

Financial disclosure:

 The authors have no financial  relationship relevant to this article to disclose

Funding source: 

No funding was secured for this study

Conflict of interest statement: 

The authors have not conflicts of interest relevant to this article to disclose.

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