Toddler with blistering acrodermal rash

The case

The anxious parents of a previously healthy 19-month-old boy bring the child to the emergency department for evaluation of progressive rash that began 4 months ago. The skin eruption began as small blisters on his knees, which became tense and ruptured, eventually evolving to red-pink scaly plaques. Over the next few months, the boy developed similar lesions on his hands, elbows, neck, perineal area, and face, with sparing of the mucous membranes. 

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History and physical

The child was evaluated at multiple clinics and treated with topical steroids and antifungal creams without improvement. Two weeks prior to this visit, he developed a tactile fever with increased blistering. He was treated with a 7-day course of oral antibiotics without change in the rash. The parents also noted recent thinning of the boy’s hair.

The patient was of appropriate size and meeting his developmental milestones. He travelled to Mexico 3 weeks after onset of the knee rash, at which point he developed mild diarrhea that resolved without treatment. He was exclusively breastfed until aged 2 months, at which time he was transitioned to full formula. He began eating solids at age 4 months, and continued formula feeding through age 14 months. At the time of presentation, he was eating a full and varied diet. His 3 siblings are healthy.

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On examination, the patient appeared alert and well-nourished (Figure 1). He had erythematous, superficially eroded and crusted papules and plaques on the periorbital, perinasal, and perioral skin as well as on his cheeks, ears, posterior scalp, dorsal hands, dorsal feet, elbows, and knees. A few plaques were noted on the antecubital fossae, forearms, and trunk. Confluent, beefy-red eroded plaques with polycyclic borders covered his penis, scrotum, perineum, inguinal folds, medial thighs, and gluteal cleft. Multiple smaller erythematous eroded papules were present at the margin of these lesions. The hair was diffusely thin. No lymphadenopathy was appreciated. Neurologic exam was unremarkable.

Pertinent laboratory data included a hemoglobin of 10.8 gm/d (normal: 10.5-13.5 gm/dL); mean cell volume of 83.5 fL (normal: 70-86 fL); albumin of 4.3 g/dL (normal: 3.4-4.2 g/dL); alkaline phosphatase of 83 U/L (normal: 115-460 U/L); and C-reactive protein of 3.0 mg/dL (normal: 0.0-0.9 mg/dL). Blood cultures returned negative, and a punch biopsy of the thigh was performed by the Dermatology service. Additional testing included a wound culture and herpes simplex virus (HSV) polymerase chain reaction (PCR).

NEXT: Differential diagnosis

Differential diagnosis

The differential diagnosis for this child presenting with chronic, diffuse, eroded, and scaly red papules and plaques is broad and includes infectious etiologies, autoimmune disorders, drug reactions, and nutritional deficiencies (Table).

Infectious etiologies that can cause rash, particularly in the intertriginous areas, include erythrasma, erysipelas, cellulitis, bullous impetigo, staphylococcal scalded skin syndrome (SSSS), and cutaneous candidiasis. Erythrasma, which typically affects adolescents and adults, is a superficial skin infection caused by the skin flora Corynebacterium, and it presents with macerated, scaly plaques in the axillae, groin, and between the toes. Erysipelas is an infection that involves the upper dermis, while cellulitis involves the deeper dermis. In distinguishing between the 2 rashes, erysipelas has a clear line of demarcation with affected tissue and is associated more with systemic symptoms of fever and chills. 

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Exfoliative toxins elaborated by Staphylococcus aureus can cause a range of skin lesions by binding to and disrupting adhesion molecules high in the epidermis. In bullous impetigo, which usually occurs in older children and adults who have antibodies to the toxins and can readily clear them in their kidneys, patients can develop localized lesions. The eruption begins as small red papules that progress to vesicles surrounded by erythema, then into expanding flaccid bullae with clear yellow fluid and central crusts.

In SSSS, which occurs in younger children who lack antibodies and patients with renal failure who cannot clear the antibody-bound toxin, toxins disseminate to the same epidermal adhesion molecules resulting in total body erythema and generalized superficial sloughing of the skin. Patients are usually febrile with diffuse blanching erythema, and flaccid bullae and erosions develop first over areas with the most frictional trauma (feet, hands, buttocks, flexural surfaces) 1 to 2 days later. Gentle pressure to the skin by the examining finger results in a Nikolsky sign or skin sloughing.

NEXT: Other etiologies

Candida infections often occur as a secondary infection in patients with chronic seborrheic dermatitis or contact irritant dermatitis. They tend to manifest as erythematous, macerated plaques/erosions with fine scaling and satellite lesions, which can occur in the inguinal folds, axillae, scrotum, and intergluteal folds. However, given the patient’s lack of response to antifungals, antibiotics, and topical, there was a greater concern for an underlying systemic process triggering his rash.

Immune etiologies that can present with diffuse red scaly rash include atopic dermatitis, psoriasis, and seborrheic dermatitis. The infantile form of atopic dermatitis presents with pruritic, red scaly lesions on the extensor surfaces of the arms, legs, face, and scalp, with sparing of the diaper area, which makes it unlikely in this patient. Psoriasis presents with symmetrically distributed cutaneous plaques with sharply defined margins and a silver scale, while seborrheic dermatitis is characterized by well-demarcated erythematous papules and greasy yellow scales, usually around the scalp, ear, midface, and intertriginous areas, particularly the diaper. Both processes are not consistent with the patient’s presentation. 

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Other etiologies to consider include junctional disorders that disrupt the integrity of the dermal keratinocytes such as epidermolysis bullosa, or drug reactions causing toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome (SJS). In epidermolysis bullosa, genetically mediated defects in cell adhesion molecules in the epidermis, epidermal-dermal junction, or in the dermis result in blistering and erosions/ulcerations in areas of friction-induced trauma. In some variants, the mucous membranes are also involved in these chronic disorders. Although the patient did have drug exposure with antibiotics, there was no mucosal involvement, which excludes SJS and TEN.

Finally, various nutritional deficiencies that can result in skin fragility, rash, hair loss, impaired immune function, and delayed developmental growth should be considered, including deficiencies in essential fatty acids, biotin, niacin, or zinc. Biotin is essential in carbohydrate and fatty acid metabolism. Symptoms of deficiency may include mental status changes, myalgias, anorexia, nausea, and red scaly dermatitis of the extremities. Both the rashes seen in biotin and essential fatty acid deficiency can result in skin changes similar to that of zinc deficiency. The patient’s varied diet made this an unlikely cause. Niacin deficiency can result in pellagra, a triad of photosensitive dermatitis in sun-exposed areas, diarrhea, and dementia. Given the patient’s rash in the perineal area, this also was unlikely.

The rash associated with zinc deficiency, secondary to a zinc-deficient diet, chronic zinc loss in the gastrointestinal tract, or acrodermatitis enteropathica (AE), presents with erythematous scaly plaques and/or erosions on the extensor surfaces of the extremities and periorificial areas, and hair loss, which occurred in this patient. In time, children with zinc deficiency also stop gaining weight and become fussy. Any gastrointestinal disorder resulting in malabsorption (eg, cystic fibrosis [CF]) and secondary zinc deficiency can result in similar symptoms, and needs to be distinguished from AE.

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Diagnosis

The patient’s zinc level returned low at 26 ug/dL. The punch biopsy showed epidermal hyperplasia, spongiosis, keratinocyte vacuolization, upper epidermal necrosis, and significant neutrophilic exocytosis with occasional clusters of gram-positive cocci in the stratum corneum consistent with necrolytic migratory erythema seen in nutritional deficiency and superimposed bacterial infection. The HSV PCR remained negative, and wound culture returned positive for methicillin-sensitive S aureus and Corynebacterium sp. 

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Patient outcome

The patient was discharged home on oral clindamycin and topical mupirocin, and he was initiated on zinc acetate supplementation at 1.7 mg/kg/day. One month later, his rash had improved, but he continued to develop intermittent new vesicles. His zinc level was rechecked and remained low at less than 16 ug/dL. Zinc supplementation was increased to 4 mg/kg/day, which resulted in resolution of the rash and a normal serum zinc level after 1 month. With follow-up over the succeeding months, his alopecia began to resolve and no further lesions were noted (Figure 2).

Conclusion and discussion

Acrodermatitis enteropathica is a rare inherited form of zinc deficiency, characterized by diarrhea, alopecia, acral dermatitis, and “dementia” (irritability). It is caused by an autosomal recessive defect in the SLC39A4 gene, which impairs intestinal zinc absorption.¹ Studies have shown that human breast milk compared with formula has a relatively high concentration of zinc because of greater bioavailability from the high-citrate, lactoferrin, and low-phosphorus environment, as well as the presence of a zinc transporter protein that facilitates absorption. These factors often compensate for an affected child’s poor absorption. Breast milk zinc levels start declining around age 6 months and no longer compensate adequately.² In patients who develop these characteristic symptoms upon weaning from breast milk, it is best to consider a diagnosis of AE. It is atypical in this patient that his symptoms developed over a year from weaning off breast milk. Rarely breast milk is low in zinc, and full-term babies of affected mothers will present with zinc-deficiency symptoms at 1 month of age. Because zinc is not concentrated in babies until the last month of gestation, symptoms will develop sooner in premature infants. In patients who develop symptoms while on breast milk, it is important to consider more common malabsorption syndromes in the differential, such as CF.

Zinc acts like a metal component of an activating cofactor for many enzymatic systems in the body, including alkaline phosphatase, carbonic anhydrase, or dehydrogenases.³ Accordingly, this patient’s relatively low level of alkaline phosphatase was an important early clue to his diagnosis of zinc deficiency. Zinc also plays a vital role in wound healing and growth, and it is involved in immune responses to infection.⁴ Ten percent to 40% of dietary zinc is absorbed in the small bowel, but absorption can be inhibited by other factors in the bowel such as the presence of fiber, iron, or other heavy metals. Sixty percent of zinc is loosely bound to albumin, while 30% is bound tightly to macroglobulins. Normal zinc levels range from 70 mcg/dL to 120 mcg/dL. Zinc is mostly bound intracellularly to metalloproteins, with primary stores in the liver and kidney.⁵

NEXT: Clinical signs of zinc deficiency

Clinical manifestations of zinc deficiency commonly include an erythematous and vesiculobullous dermatitis; alopecia; ophthalmic disorders including photophobia; anorexia; diarrhea; growth retardation; delayed sexual maturation; impaired taste or smell; hypogonadism; neuropsychiatric manifestations; anemia; and frequent infections with poor wound healing.³ The rash associated with low zinc levels typically presents with erythematous scaly plaques, which can develop into vesicular, bullous, or pustular lesions with subsequent desquamation, particularly in areas where the skin turns over most quickly (intertriginous and periorificial areas). Characteristic locations include the extensor extremities, the anogenital skin, and the periorificial area of the face. Other cutaneous stigmata include angular cheilitis, paronychia, and generalized alopecia.   Skin lesions often become secondarily infected with bacterial or fungal infections.³

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Symptomatic low levels of zinc also may be associated with a variety of other conditions. These include diseases with impaired intestinal absorption (Crohn disease, CF), increased urinary excretion (renal tubular defect in sickle cell disease, nephrotic syndrome), decreased binding capacity (hypoalbuminemia secondary to liver disease), or iatrogenic causes (inadequate supplementation in total parenteral nutrition [TPN]-dependent patients; those with decreased intake; or premature infants whose nutritional demands are greater than maternal supply).^6,7 For zinc deficiency related to dietary intake, supplementation with 1-2 mg/kg/day of elemental zinc is generally sufficient; for deficits related to impaired zinc absorption, higher replacement doses (around 3mg/kg/day of elemental zinc) are generally required.⁸ Symptoms should resolve within 1 month of appropriate supplementation, as was seen in this patient. In patients whose symptoms do not respond within 1 month of initiation of therapy, it is important to consider the therapeutic level of treatment versus another underlying cause, such as malabsorption syndromes (eg, CF). These syndromes will only partially improve with supplementation, and will require addressing the primary defect, such as the utility of pancreatic enzyme replacement in CF.

The classic symptoms of AE consist of diarrhea, alopecia, periorificial and acral dermatitis, and irritability, typically presenting around weaning of high zinc dietary sources such as breast milk. The child in this case demonstrated classic symptoms of alopecia with a perioral and acral distribution of rash, as well as lab data supporting the zinc deficiency. His zinc deficiency was determined to be of unknown etiology because symptoms developed almost 1 year after weaning off breast milk. The patient additionally lacked other typically seen clinical symptoms such as failure to thrive or frequent infections. Although the etiology of the patient’s zinc deficiency continues to be evaluated at this time, he had substantial clinical improvement once his zinc level returned to normal.

REFERENCES

1.    Küry S, Dréno B, Bézieau S, et al. Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nat Genet. 2002;31(3):239-240.

2.    Lönnerdal B. Dietary factors influencing zinc absorption. J Nutr, 2000;130(5S suppl):1378S-1383S.

3.    Maverakis E, Fung MA, Lynch PJ, et al. Acrodermatitis enteropathica and an overview of zinc metabolism. J Am Acad Dermatol. 2007;56(1):116-124.

4.    Shankar AH, Prasad AS. Zinc and the immune function: the biological basis of altered resistance to infection. Am J Clin Nutr. 1998;68(2 suppl):447S-463S.

5.    Krebs NF, Westcott JE, Butler N, et al. Meat as a first complementary food for breastfed infants: feasibility and impact on zinc intake and status. J Pediatr Gastroenterol Nutr. 2006;42(2):207-214.

6.    McClain C, Soutor C, Zieve L. Zinc deficiency: a complication of Crohn's disease. Gastroenterology. 1980;78(2):272-279.

7.    Phebus CK, Maciak BJ, Gloninger MF, Paul HS. Zinc status of children with sickle cell disease: relationship to poor growth. Am J Hematol. 1988;29(2):67-73.

8.    Neldner KH, Hambidge KM. Zinc therapy of acrodermatitis enteropathica. N Engl J Med. 1975;292(17):879-882.

Dr Cindy Luu is a third-year pediatric resident and rising pediatric emergency medicine fellow, Department of General Pediatrics, Children’s Hospital of Los Angeles, California. Dr Oh is assistant professor of clinical pediatrics, Department of General Pediatrics, Children’s Hospital Los Angeles, California. Dr Minnelly Luu is an assistant professor of Dermatology, Children’s Hospital Los Angeles, California, and Department of Dermatology and Pathology, Keck School of Medicine, University of Southern California, Los Angeles. Dr DeClerck is an assistant professor, Department of Dermatology and Pathology, Keck School of Medicine, University of Southern California, Los Angeles. The authors have nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article.