Zinc deficiency-associated dermatitis in a prematurely born infant

A 6-month-old male infant presented with his mother to our dermatology outpatient clinic with patchy, scaly, and crusted erythema on his cheeks and neck, accompanied by oral erosions. At the age of 3.5 months, the infant had developed first skin lesions around the earlobes followed by general weakness due to restricted oral intake caused by mucosal lesions at 5.5 months. Using local antiseptics and antimycotics as well as systemic antibiotics, no sufficient and persistent improvement of the symptoms could be achieved. The presentation to our hospital was due to a progressive deterioration of his dermatological findings as well as his general condition.

Following premature amnion rupture in the 30th week of pregnancy, the boy was born naturally 7 weeks before the due date (33rd week of pregnancy) after an otherwise uneventful pregnancy and treated prophylactically with ampicillin and gentamicin for 7 days. Diarrhea, other previous diseases, or allergies were absent, and no permanent medications had been administered. Both parents were healthy with atopic dermatitis and rhinoconjunctivitis allergica in the uncle. There were no pets in the household nor any history of travel abroad. The mother had been on a vegetarian diet before pregnancy, but reintroduced meat and a balanced diet upon the onset of her pregnancy. At presentation, the mother was still fully breastfeeding the boy.

Clinically, lightning figure-like, sharply demarcated and partially confluent erythema on both cheeks and the neck with marginal, mid-lamellar scaling and whitish-yellowish crusting (Figure 1a) were found. The upper lip and forehead were spared, whereas small, spotted erosions on the hard palate were observed enorally (Figure 1b). No other abnormal physical findings were noted including pre-auricular, retroauricular or cervical lymph nodes. The infant's earlier development appeared regular.

Neither bacterial nor mycological pathogens could be detected in skin swabs. Clinical chemistry laboratory examination showed a markedly decreased serum zinc level of 0.11 mg/l (reference range: 0.70–1.10 mg/l). All other evaluated laboratory parameters, including electrolytes, liver and kidney values, C-reactive protein (CRP), and differential blood count, were within normal ranges.

As part of further investigations, at 0.77 mg/l the mother's serum zinc level was found to be within normal limits, similar to the zinc level in the mother's milk at different time points during lactation (1st time point of mother's milk zinc level measurement at infant's age of 5.5 months: 354 µg/l, 2nd time point of mother's milk zinc level measurement at infant's age of 12 months: 288 µg/l; normal range: 170–3,020 µg/l).

Initially, an improvement of the skin findings could be achieved by local therapy starting with fusidic acid once a day, intensified after 1 week with the overlapping use of a class II steroid (prednicarbate) for 2 weeks in a tapered dosage (2 x daily for 3 days, 1 x daily for 5 days, every 2nd day for 6 days). When the diagnosis of zinc deficiency dermatitis was made, oral substitution with elemental zinc 5 mg once daily was initiated.

After only 2 weeks of oral zinc substitution, erythema, scaling, and crusting on the cheeks and nuchal areas clearly faded (Figure 2a,b). With continuous oral zinc substitution there was no recurrence over 7 months of follow-up.

Zinc is an essential trace element found primarily in seafood, meat products, nuts, dairy and cereal products and is generally better absorbed from animal than from plant foods.¹

As an essential component of a large number (> 300) of enzymes including metalloenzymes (e.g., lactate dehydrogenase, alkaline phosphatase), DNA and RNA polymerases and transcription factors (zinc finger domain) with catalytic, structural and regulatory functions, zinc plays a key role in growth, physical development, and metabolism.^{2, 3} In addition, zinc contributes to maintaining the integrity of cells and organs as well as the immune system by stabilizing cellular components and membranes.⁴

Since there is no long-term storage system for zinc in the human body, daily intake of zinc-containing food is indispensable for the maintenance of physical and mental health.

Infancy is a particularly vulnerable phase. With the ongoing development of numerous bodily functions, rapid body growth, and increased demand for zinc intake, zinc levels have to be maintained by an adequate exogenous supply. Normally, this requirement can be completely covered by breast milk up to the age of 6 months. However, several causes in both mother and child may result in critically decreased zinc levels.

A loss-of-function mutation (H54R) in the ZnT-2 zinc transporter (SLC30A2) of mammary epithelial cells will result in a reduction in zinc secretion into the tubular lumen and consequently a decrease in zinc concentration in breast milk. Reports in four cases confirm the development of transient zinc deficiency in exclusively breastfed infants from mothers with low breast-milk zinc concentrations but normal maternal serum zinc levels. Maternal zinc supplementation cannot correct this condition, confirming the genetic background of this disorder.^{5, 6}

Another genetic disorder, which is present in the affected infant itself, is a mutation in the zinc transporter gene SLC39A4 (solute carrier family 39 member A4), which leads to impaired enteric zinc absorption and acrodermatitis enteropathica. In 1936, T. Brandt first described this very rare autosomal recessive disease of infancy with a global incidence rate of 1 : 500,000 newborns. Since human breast milk contains zinc-binding proteins to facilitate zinc absorption by the child, the disease manifests in breast milk-fed infants only after weaning or earlier in formula-fed infants.⁷

In addition to hereditary factors there is a pivotal effect of prematurity on the newborn's zinc status. Premature infants have a negative zinc balance, which is mainly due to insufficient zinc stores, marginal intake and a high requirement during rapid growth.⁸ As elucidated in our case, fully breastfed premature infants are particularly susceptible to this condition even with a normal zinc concentration in breast milk and normal intestinal absorption by the child.

The clinical symptoms of zinc deficiency are not specific for any of these causes – a distinction between transient, acquired zinc deficiency and hereditary acrodermatitis enteropathica is not possible based on the clinical picture. However, the following symptoms in combination with the findings are indicative of the diagnosis.

One of the earliest symptoms of acute zinc deficiency is an increased susceptibility to infection due to suppression of various factors of cell-mediated immunity.⁹ Especially acute diarrhea and respiratory infections are linked to lower zinc status in children and incidence and severity are reduced by an adequate supply of zinc.¹⁰

Acute zinc deficiency primarily presents as dermatitis with perioral-facial and perianal erosions, scrotal eczema, flat blisters in the flexural folds of the fingers and palms and episodic papulo-vesicular, sharply demarcated eczema.¹¹

The symptom combination of dermatitis, diarrhea and alopecia is characteristic of chronic zinc deficiency but not decisive for the criterion of chronicity. Dermatitis manifests with eczematous to psoriasiform skin lesions characteristically on the distal extremities and orifices. Other symptoms include growth retardation, reduced mental performance, neurological symptoms such as irritability or photophobia and general susceptibility to infection.^{11, 12} Our patient presented with none of the latter symptoms but with long-standing dermatitis due to zinc deficiency that presumably developed shortly after birth. As with many chronic diseases, a duration of 6 months was reached. Therefore, the zinc deficiency was classified as chronic.

Despite clinically threatening symptoms, zinc deficiency dermatitis can be cured quickly and completely by exogenous zinc supplementation. The dosage and duration of zinc supplementation depends on the cause. Genetic acrodermatitis enteropathica requires lifelong oral zinc supplementation. Starting at 3 mg/kg body weight (BW)/day of elemental zinc, the dose can be adjusted over time, depending on individual needs. In acquired, transient zinc deficiency dermatitis, lower doses of 0.5–1 mg/kg BW/day of elemental zinc are sufficient. In all dermatitis due to zinc deficiency, exogenous zinc supplementation can be expected to result in a rapid clinical response within days, while serum zinc levels rise only slowly. During zinc supplementation, serum zinc levels and zinc-dependent enzymes such as alkaline phosphatase should be monitored every 3–6 months. As zinc and copper are absorbed via a shared cation transporter, zinc overdose can inhibit the absorption of copper, another essential trace element. Therefore, serum copper needs to be monitored regularly during lifelong zinc supplementation to avoid copper deficiency.¹³

Considering the upcoming introduction of complementary food and the recommendation for a balanced diet for mother and child, our patient – with a body weight of almost 7 kg – was started on a dose of 5 mg elemental zinc per day, which corresponds to an average substitution dose for transient zinc deficiency dermatitis. Within 2 weeks after starting oral zinc supplementation the boy showed almost healed skin findings. At the age of 7 months, complementary food (balanced whole food with meat and fish) was introduced, supplemented by occasional breastfeeding of the now one-year-old boy. With regard to a recent increase in zinc in the serum to 1.96 mg/l, zinc supplementation was discontinued. Diurnal fluctuation in serum zinc concentration, zinc supplementation and/or food ingestion shortly before blood sampling as well as individual absorption and distribution rates can explain the serum zinc level above the upper reference limit.¹⁴

The boy's zinc deficiency is most likely due to prematurity and the accompanying increased zinc requirement with rapid thriving. Routine measurement of serum zinc in fully breastfed preterm infants will allow diagnosis and adequate therapy of zinc deficiency avoiding the use of local steroids and local and/or systemic antibiotics and the associated unwanted effects.¹⁵

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