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Case Report Infantile Iatrogenic Cushing Syndrome due to Topical Steroids Lulwah Alkhuder and Horia Mawlawi Department of Pediatric Endocrinology, Prince Sultan Medical City, Riyadh, Saudi Arabia Correspondence should be addressed to Lulwah Alkhuder; [email protected] Received 29 April 2019; Revised 27 July 2019; Accepted 21 September 2019; Published 2 December 2019 Academic Editor: Maria Moschovi Copyright © 2019 Lulwah Alkhuder and Horia Mawlawi. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cushing syndrome is an endocrinological disorder characterized by increased free plasma glucocorticoids level. It is either due to an excessive endogenous release of steroids (e.g., pituitary adenoma or adrenal hyperplasia) or exogenous administration of steroids. In children, iatrogenic Cushing syndrome is the most common form of Cushing syndrome occurring in this age group. e vast majority of cases are due to oral or parenteral preparation of steroids, which are commonly prescribed for pulmonary, hematological, renal, or autoimmune pathologies. Topical preparations can rarely cause Cushing syndrome in young children, and only a few cases were reported in the literature, where the patients were older than 5 months of age. In this report, we present a three-month-old girl who developed iatrogenic Cushing syndrome due to prolonged and inappropriate use of topical clobetasol cream for napkin dermatitis. 1.Introduction Cushing syndrome, an endocrinological disorder resulting from abnormally high plasma cortisol levels, is characterized by increased free plasma glucocorticoids level [1]. It can result from either endogenous release of excess steroids (e.g., adrenal gland tumors, adrenal hyperplasia, or pituitary adenoma) or exogenous use of corticosteroid medications such as iatrogenic Cushing syndrome [1]. Clinically, patients with Cushing syndrome present with facial plethora and edema, giving the appearance of “moon face”; accumulation of fat in the supraclavicular area and upper trunk, giving the appearance of “buffalo hump;” accumulation of fat around the waist leading to truncal obesity, which leads to skin fragility resulting in appearance of purple stria, particularly on the abdomen, arms, and upper thighs. Furthermore, it causes hirsutism, skin bruises, ecchymoses, delayed wound healing, proximal muscle wasting, arterial hypertension, hyperglycaemia, and retarded growth [2]. In the pediatric age group, Cushing syndrome is very rare. It is estimated to occur in about 2–5 new cases per million individual per year [2]. e vast majority of these cases are iatrogenic. e most common cause of endogenous Cushing syndrome in preschool children is adrenal pathology such as hyperplasia, adenoma, or carcinoma [2]. Pituitary or ectopic causes are rare in this age group. On the other hand, iatrogenic (or exogenous) Cushing syndrome constitutes the vast majority of cases of Cushing syndrome among young children due to the high prevalence of diseases that require chronic use of corticosteroids such as bronchial asthma, pulmonary diseases, hematological diseases, renal diseases, or dermatological diseases [2, 3]. e diagnostic approach and differential diagnosis as well as the treatment of Cushing syndrome in general and iatrogenic Cushing syndrome, in particular, remain highly challenging in clinical endocrinology. Midnight salivary cortisol test, urine free cortisol (UFC) and low-dose dexa- methasone suppression test (LDDST) have been shown effective as a primary screening for endogenous Cushing syndrome, particularly of the endogenous type, with the confirmation by urine free cortisol (UFC), low-dose dexa- methasone suppression test (LDDST), and dexamethasone/ corticotrophin-releasing hormone (DST-CRH) tests, a de- finitive criteria or a highly sensitive/specific diagnostic test for iatrogenic Cushing syndrome is still lacking in the lit- erature [4]. However, one can diagnose Cushing syndrome of the exogenous type based on the clinical presentation of the Hindawi Case Reports in Pediatrics Volume 2019, Article ID 2652961, 4 pages https://doi.org/10.1155/2019/2652961

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  • Case ReportInfantile Iatrogenic Cushing Syndrome due to Topical Steroids

    Lulwah Alkhuder and Horia Mawlawi

    Department of Pediatric Endocrinology, Prince Sultan Medical City, Riyadh, Saudi Arabia

    Correspondence should be addressed to Lulwah Alkhuder; [email protected]

    Received 29 April 2019; Revised 27 July 2019; Accepted 21 September 2019; Published 2 December 2019

    Academic Editor: Maria Moschovi

    Copyright © 2019 Lulwah Alkhuder and Horia Mawlawi. )is is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in anymedium, provided the original work isproperly cited.

    Cushing syndrome is an endocrinological disorder characterized by increased free plasma glucocorticoids level. It is either due toan excessive endogenous release of steroids (e.g., pituitary adenoma or adrenal hyperplasia) or exogenous administration ofsteroids. In children, iatrogenic Cushing syndrome is the most common form of Cushing syndrome occurring in this age group.)e vast majority of cases are due to oral or parenteral preparation of steroids, which are commonly prescribed for pulmonary,hematological, renal, or autoimmune pathologies. Topical preparations can rarely cause Cushing syndrome in young children,and only a few cases were reported in the literature, where the patients were older than 5months of age. In this report, we present athree-month-old girl who developed iatrogenic Cushing syndrome due to prolonged and inappropriate use of topical clobetasolcream for napkin dermatitis.

    1. Introduction

    Cushing syndrome, an endocrinological disorder resultingfrom abnormally high plasma cortisol levels, is characterizedby increased free plasma glucocorticoids level [1]. It canresult from either endogenous release of excess steroids (e.g.,adrenal gland tumors, adrenal hyperplasia, or pituitaryadenoma) or exogenous use of corticosteroid medicationssuch as iatrogenic Cushing syndrome [1]. Clinically, patientswith Cushing syndrome present with facial plethora andedema, giving the appearance of “moon face”; accumulationof fat in the supraclavicular area and upper trunk, giving theappearance of “buffalo hump;” accumulation of fat aroundthe waist leading to truncal obesity, which leads to skinfragility resulting in appearance of purple stria, particularlyon the abdomen, arms, and upper thighs. Furthermore, itcauses hirsutism, skin bruises, ecchymoses, delayed woundhealing, proximal muscle wasting, arterial hypertension,hyperglycaemia, and retarded growth [2].

    In the pediatric age group, Cushing syndrome is veryrare. It is estimated to occur in about 2–5 new cases permillion individual per year [2]. )e vast majority of thesecases are iatrogenic.)emost common cause of endogenousCushing syndrome in preschool children is adrenal

    pathology such as hyperplasia, adenoma, or carcinoma [2].Pituitary or ectopic causes are rare in this age group. On theother hand, iatrogenic (or exogenous) Cushing syndromeconstitutes the vast majority of cases of Cushing syndromeamong young children due to the high prevalence of diseasesthat require chronic use of corticosteroids such as bronchialasthma, pulmonary diseases, hematological diseases, renaldiseases, or dermatological diseases [2, 3].

    )e diagnostic approach and differential diagnosis aswell as the treatment of Cushing syndrome in general andiatrogenic Cushing syndrome, in particular, remain highlychallenging in clinical endocrinology. Midnight salivarycortisol test, urine free cortisol (UFC) and low-dose dexa-methasone suppression test (LDDST) have been showneffective as a primary screening for endogenous Cushingsyndrome, particularly of the endogenous type, with theconfirmation by urine free cortisol (UFC), low-dose dexa-methasone suppression test (LDDST), and dexamethasone/corticotrophin-releasing hormone (DST-CRH) tests, a de-finitive criteria or a highly sensitive/specific diagnostic testfor iatrogenic Cushing syndrome is still lacking in the lit-erature [4].

    However, one can diagnose Cushing syndrome of theexogenous type based on the clinical presentation of the

    HindawiCase Reports in PediatricsVolume 2019, Article ID 2652961, 4 pageshttps://doi.org/10.1155/2019/2652961

    mailto:[email protected]://orcid.org/0000-0003-4345-4128https://creativecommons.org/licenses/by/4.0/https://creativecommons.org/licenses/by/4.0/https://creativecommons.org/licenses/by/4.0/https://creativecommons.org/licenses/by/4.0/https://doi.org/10.1155/2019/2652961

  • classic signs of Cushing syndrome with the confirmation of adecreased 8 : 00 am basal cortisol level [5, 6].

    )e chronic use of corticosteroids is considered a widelyprescribed medication for a variety of chronic conditions.However, when it is used for a prolonged period, it can resultin the presentation of the systemic effects characteristic ofCushing syndrome. Moreover, this particular group of pa-tients is subjected to develop tertiary adrenal insufficiencyfollowing the decrease or the elimination of corticosteroids.)e mechanism through which this can occur is through thenegative feedback loop on the hypothalamic-pituitary-ad-renal (HPA) axis, which involves mainly corticotropinhormone (CRH) and adrenocorticotropic hormone (ACTH)release. )erefore, the reactivation of CRH is a necessity forthe successful reactivation of the HPA axis after the elim-ination of chronic corticosteroid treatment [7].

    Iatrogenic Cushing syndrome is common with the ex-cessive use of oral and parenteral corticosteroids but rarewith topical preparations [8]. In this article, we present aninfant with iatrogenic Cushing syndrome after a two-monthuse of topical steroids.

    2. Case Report

    A three-and-a-half-month-old girl with an unremarkablepast medical and developmental history presented to theemergency department (ER) with face puffing and gener-alized edema. Her mother stated that the girl’s conditionstarted insidiously two months before the presentation andprogressed over time. )ere were no other associatedsymptoms and no history of recent trauma or insect bite.)emother reported that she has been using topical cortico-steroid cream (clobetasol) for the past two months for thetreatment of napkin dermatitis in a dose of five to eight timesa day. )e rash was subsided in two to three days and thenflared up afterward. In conclusion, she was using a topicalsteroid cream on a continuous basis for two months.

    Reviewing the infant’s prenatal, developmental, past, andfamily history revealed that she was born full term tononconsanguineous parents via caesarian delivery due tobreech presentation. She was not admitted to a neonatalintensive care unit (NICU) after delivery and was dischargedin good condition. She has been given exclusive breast-feeding every one to two hours, and she received all therequired vaccinations at their proper times. She has onehealthy sibling and negative family history of any relevantcondition.

    )e patient’s physical examination revealed facialpuffiness (Figure 1) and generalized body edema (Figure 2).)ere were no abdominal stria, and the cutaneous exami-nation revealed nothing but the napkin rash (Figure 3). )einfant was vitally stable with no dysmorphic features andno skeletal deformities. Her growth parameters werewithin normal limits, and her systemic examination wasunremarkable.

    Upon investigation, the adrenocorticotropic hormone(ACTH) level was very low, 0.7 pg/mL, and the serumcortisol level was 17 μg/dl. )e abdominal ultrasonographicstudy showed normal adrenal glands.

    Physiological doses of hydrocortisone (12mg/m2) wereadministered to the patient for 6 weeks, and then 25% of thedose was tapered weekly. On the fifth week, ACTH stimulationwas performed, where ACTH and cortisol levels were 5.7 pg/mL and 28μg/dl, respectively. Hydrocortisone was stoppedwhile ACTH and cortisol levels were normalized. Clinically,facial puffiness and edema improved significantly over time.

    3. Discussion

    Under normal physiological conditions, the pituitary glandsecretes ACTH that stimulates the adrenal glands to secretecortisol. When corticosteroids are exogenously adminis-tered, suppression of this hypothalamic-pituitary-adrenal(HPA) axis occurs [3]. )ough iatrogenic Cushing syn-drome is common with prolonged administration of oral orparenteral steroids, some cases were reported to developsuch condition upon prolonged use of topical steroids [9–12]. Few of these cases developed severe immunosuppres-sion and fatal secondary infections [13].

    Figure 1:)e patient’s face showing facial puffiness andmoon-faceappearance.

    Figure 2: )e patient’s body showing generalized edema.

    2 Case Reports in Pediatrics

  • )e infant presented in this article developed iatrogenicCushing syndrome after inappropriate and prolonged use ofa highly potent topical steroid, i.e., clobetasol propionate fornapkin dermatitis [14]. )e mother used high doses ofcorticosteroid for two months consistently causing clobe-tasol to be absorbed through the skin, reaching the systemiccirculation and resulting in the development of iatrogenicCushing syndrome [15]. )e clinical presentation of thechild was typical for a case of Cushing syndrome includingthe signs of moon face, generalized edema, and weight gain,while her laboratory profile confirmed the diagnosis. ACTHwas suppressed by the exogenously administered steroids,but cortisol levels were still within normal limits. Fortu-nately, our case was not complicated by the life-threateningadrenal insufficiency. Lately, the risk of developing life-threatening adrenal insufficiency has been evident in pa-tients being administered almost any form of glucocorti-coids, including topical creams. It has been known thatglucocorticoid creams can lead to adrenal insufficiency evenwithin the prescribed doses [16].

    Unluckily, most of the symptoms of iatrogenic adrenalinsufficiency are not specific and therefore are difficult todifferentiate from other underlying disease pathology.Consequently, many clinicians and healthcare practitionersmight not recognize such conditions and forget to include itin their differentials. )erefore, it is advisable to always keepiatrogenic adrenal insufficiency in mind in patients treatedwith all forms of steroids and presenting with iatrogenicCushing syndrome [16].

    )e girl’s height, blood pressure, skin, immune system,and blood glucose levels were not affected. Similar to ourcase, Siklar et al. [15], Sahip et al. [11], Güven et al. [13], andTempark et al. [12] reported similar cases of iatrogenicCushing syndrome after prolonged use of clobetasol for thetreatment of napkin dermatitis. However, our case repre-sents an early diagnosed case, where only facial puffiness and

    generalized edema developed with the suppression of ACTHlevel. )e cases reported in the literature are rather advancedcases where the full-blown picture of the Cushing syndromeoccurred.

    In our case, clobetasol is not the topical steroid of choicefor the management of the napkin rash. As shown in Fig-ure 3, the rash is extensive, and the skin was inflamed anddamaged. )is allows more permeation and penetration ofthe topical medication. )us, it was better to choose a lowpotency topical steroid, e.g., hydrocortisone than to choose avery potent agent such as clobetasol [17]. Furthermore,screening methods such as midnight salivary cortisol couldprove to be helpful in early detection of potential iatrogenicCushing syndrome while using topical steroids [18]. Man-agement of iatrogenic Cushing syndrome includes thestoppage of the causative medication, administration ofexogenous physiological doses of steroids, and taperingthem slowly over time [2].

    )e presented case, along with the previously publishedcases in the literature, should warrant the importance ofadequate health education of the mothers and parents aboutthe appropriate instructions of using any topical steroidpreparation. Physicians should instruct them to apply thinlayers of the topical preparation and not to exceed the dailydose of treatment, while these preparations should only befor the short-term use.

    Ethical Approval

    )e authors have received consent from the parents of thechild to use the data and the clinical picture for publicationpurposes if it remains anonymous.

    Conflicts of Interest

    )e authors declare no conflicts of interest.

    Acknowledgments

    )e authors would like to thank the parents of the child forgiving us the permission to use this case for educationalpurposes as well as publish it as a case report.

    References

    [1] R. R. Lonser, L. Nieman, and E. H. Oldfield, “Cushing’sdisease: pathobiology, diagnosis, and management,” Journalof Neurosurgery, vol. 126, no. 2, pp. 404–417, 2017.

    [2] C. A. Stratakis, “Cushing syndrome in pediatrics,” Endocri-nology andMetabolism Clinics of North America, vol. 41, no. 4,pp. 793–803, 2012.

    [3] C. A. Stratakis, “Diagnosis and clinical genetics of Cushingsyndrome in pediatrics,” Endocrinology and MetabolismClinics of North America, vol. 45, no. 2, pp. 311–328, 2016.

    [4] J. W. Findling and H. Raff, “Cushing’s syndrome: importantissues in diagnosis and management,” !e Journal of ClinicalEndocrinology & Metabolism, vol. 91, no. 10, pp. 3746–3753,2006.

    [5] L. K. Nieman, “Recent updates on the diagnosis and man-agement of Cushing’s syndrome,” Endocrinology and Meta-bolism, vol. 33, no. 2, pp. 139–146, 2018.

    Figure 3: )e patient’s genitalia showing the napkin rash.

    Case Reports in Pediatrics 3

  • [6] K. J. Shetty and R. Spurgeon, Cushing’s Syndrome: Challengesin Diagnosis and Management. Chapter 65, )e Association ofPhysicians of India, Mumbai, India, 2013.

    [7] R. M. Paragliola, G. Papi, A. Pontecorvi, and S. M. Corsello,“Treatment with synthetic glucocorticoids and the hypo-thalamus-pituitary-adrenal axis,” International Journal ofMolecular Sciences, vol. 18, no. 10, 2017.

    [8] S. Semiz, Y. I. Balcı, Ş. Ergin, M. Candemir, and A. Polat, “Twocases of Cushing’s syndrome due to overuse of topical steroidin the diaper area1,” Pediatric Dermatology, vol. 25, no. 5,pp. 544–547, 2008.

    [9] E. M. Abma, R. Blanken, and L. J. De Heide, “Cushing’ssyndrome caused by topical steroid therapy for psoriasis,”!eNetherlands Journal of Medicine, vol. 60, no. 3, pp. 148–150,2002.

    [10] S. Decani, V. Federighi, E. Baruzzi, A. Sardella, and G. Lodi,“Iatrogenic Cushing’s syndrome and topical steroid therapy:case series and review of the literature,” Journal of Derma-tological Treatment, vol. 25, no. 6, pp. 495–500, 2014.

    [11] B. Sahip, M. Celik, S. Ayturk et al., “Iatrogenic Cushing’ssyndrome after topical steroid therapy for psoriasis,” IndianJournal of Dermatology, vol. 61, no. 1, p. 120, 2016.

    [12] T. Tempark, V. Phatarakijnirund, S. Chatproedprai,S. Watcharasindhu, V. Supornsilchai, and S. Wananukul,“Exogenous Cushing’s syndrome due to topical corticosteroidapplication: case report and review literature,” Endocrine,vol. 38, no. 3, pp. 328–334, 2010.

    [13] A. Güven, S. Karadeniz, O. Aydin, M. Akbalik, and M. Aydin,“Fatal disseminated cytomegalovirus infection in an infantwith Cushing’s syndrome caused by topical steroid,”HormoneResearch in Paediatrics, vol. 64, no. 1, pp. 35–38, 2005.

    [14] J. D. Ference and A. R. Last, “Choosing topical corticoste-roids,” American Family Physician, vol. 79, no. 2, pp. 135–40,2009.

    [15] Z. Siklar, I. Bostanci, O. Atli, and Y. Dallar, “An infantileCushing syndrome due to misuse of topical steroid,” PediatricDermatology, vol. 21, no. 5, pp. 561–563, 2004.

    [16] S. Borresen, M. Klose, A. Rasmussen, and U. Feldt-Ras-mussen, “Adrenal insufficiency caused by locally appliedglucocorticoids-myth or fact?,” Current Medicinal Chemistry,vol. 22, no. 23, pp. 2801–2809, 2015.

    [17] M. Turpeinen, O. P. Salo, and S. Leisti, “Effect of percutaneousabsorption of hydrocortisone on adrenocortical re-sponsiveness in infants with severe skin disease,” BritishJournal of Dermatology, vol. 115, no. 4, pp. 475–484, 1986.

    [18] C. Carrozza, S. M. Corsello, R. M. Paragliola et al., “Clinicalaccuracy of midnight salivary cortisol measured by automatedelectrochemiluminescence immunoassay method in Cush-ing’s syndrome,” Annals of Clinical Biochemistry, vol. 47,no. 3, pp. 228–232, 2010.

    4 Case Reports in Pediatrics

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