type II hypozincemia of infancy - Dermatologica Sinica

DERMATOLOGICA SINICA 30 (2012) 66e70

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CASE REPORT

Transient zinc deficiency syndrome in a breast-fed infant due to decreased zinc in breast milk (type II hypozincemia of infancy): A case report and review of the literature Wei-Li Yang 1, Chao-Kai Hsu 1, Sheau-Chiou Chao 1, Ching-Yuang Huang 2, Julia Yu-Yun Lee 1, * 1 2

Department of Dermatology, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan Sinlau Christian Hospital, Tainan, Taiwan

a r t i c l e i n f o

a b s t r a c t

Article history: Received: Feb 17, 2011 Revised: Mar 31, 2011 Accepted: Jun 21, 2011

Type II hypozincemia of infancy is a rare, hereditary zinc deficiency occurring in infants while exclusively on breast feeding. It is caused by defective transfer of zinc into breast milk. Only a few dozen cases have been reported. A 6-month-old, full-term, breast-fed female infant presented with a 3-week history of erythematous to dusky red papules and annular plaques over the perioral and diaper area as well as the digits. The eruption was accompanied by poor appetite and irritable crying. Serum zinc was low (4.896 mmol/L, normal ¼ 10.7118.36 mmol/L) in the patient but was normal in the mother. Interestingly, the zinc level in the breast milk was very low (2.142 mmol/L; normal postpartum zinc ¼ 18.36 mmol/L at 6 months). Histopathology of a skin biopsy specimen showed spongiotic psoriasiform dermatitis with pallor of superficial keratinocytes, consistent with deficiency disease. With oral zinc sulfate supplement, her skin lesions improved significantly within 4 days. Type II hypozincemia needs to be differentiated from the classical hereditary acrodermatitis enteropathica, which typically develops symptoms after weaning because of poor intestinal absorption of zinc in the affected infants. Mutations in zinc transporter genes have been detected in SLC39A4 (Zip4) and SLC30A2 (ZnT2), respectively, in classical acrodermatitis enteropathica and type II hypozincemia. No mutation was found in these two genes in the present pedigree. Therefore, the genetic defect in our patient might involve other zinc transporter genes. Copyright Ó 2012, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. All rights reserved.

Keywords: infancy transient zinc deficiency

Introduction Zinc is an important trace nutrient required for proper functions of more than 100 enzymes and plays a crucial role in nucleic acid metabolism.1 Patients with zinc deficiency typically manifest acrodermatitis enteropathica (AE)-like features characterized by erythematous, scaly and crusted lesions with vesicles, pustules and erosions predominantly affecting the extremities as well as the diaper and periorificial areas. Populations at risk of zinc deficiency include patients with intestinal malabsorption syndrome, liver disease, anorexia nervosa or food faddism, extensive cutaneous burns and nephrotic syndrome. In addition, zinc deficiency can be caused by genetic defects in absorption or secretion of zinc in the body.2 There are three types of zinc deficiency in infancy.3 Type I is * Corresponding author. Julia Yu-Yun Lee, Department of Dermatology, National Cheng Kung University Hospital, 138 Sheng-Li Road Tainan, Taiwan. Tel.: þ886 6 235 3535; fax: þ886 6 200 4326. E-mail address: [email protected] (J.Y.-Y. Lee).

characterized by an inherent defect in absorption of zinc from the gut, i.e., the classical AE. The disease onset is typically when weaning from breast milk to formula or cereal, which have lower zinc bioavailability than breast milk.2 Type II is caused by defective transfer of zinc into the mother’s milk. In contrast to the classical AE, the symptoms develop in infants during breast feeding but improve after weaning to formula or table foods. Type III develops in preterm infants who are put on prolonged parenteral alimentation deficient in zinc.3 All three types manifest similar skin lesions clinically. Herein, we report a case of type II hypozincemia in a breast-fed infant, and discuss the genetic defect and mechanism of zinc deficiency. Case presentation A 6-month-old, full-term, breast-fed female infant presented with a 3-week history of multiple erythematous to dusky red, scaly or crusted papules and annular plaques over the perioral and diaper

1027-8117/$ e see front matter Copyright Ó 2012, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.dsi.2011.09.013

W.-L. Yang et al. / Dermatologica Sinica 30 (2012) 66e70

areas, and the digits (Figure 1). The development of the rash was accompanied by poor appetite and irritable crying, but no diarrhea. The patient was the first born to the unrelated, healthy parents and there was no family history of zinc deficiency. Histopathological examination of a skin biopsy specimen from the diaper area revealed spongiotic psoriasiform hyperplasia of the epidermis with pallor of the superficial keratinocytes (Figure 2). The papillary dermis was slightly edematous with a moderately dense perivascular infiltrate of small lymphocytes. The pathological findings were consistent with deficiency disease. Blood from the patient and her mother and a fresh breast milk sample were obtained in zinc-free vacutainer tubes and sent to our Hospital Lab immediately. All samples were diluted with deionized water (1:5 dilution) and then centrifuged. Zinc content from the supernatant was measured by atomic absorption spectroscopy (Perkin-Elmer 5100, Waltham, Massachusetts, USA). Decreased serum zinc level (4.896 mmol/L, normal ¼ 10.7118.36 mmol/L) was detected. Alkaline phosphatase level was also decreased (104 U/L, normal ¼ 150e420 U/L in infants). The zinc level in the maternal serum was normal (12.85 mmol/L), but in the breast milk was very low (2.142 mmol/L; normal postpartum zinc ¼ 61.2 mmol/L at 2 weeks, 18.36 mmol/L at 6 months).4 For comparison, a sample of breast milk from a mother with a healthy, full-term 3-month-old infant was checked and the zinc level was 24.94 mmol/L (serum zinc of that mother was not checked). With oral zinc sulfate supplement (element zinc 3 mg/kg/day), the patient’s skin lesions improved significantly in 4 days, and resolved completely in 25 days (Figure 3). At that time the serum zinc was found to be 21.42 mmol/L and alkaline phosphatase level was 320 U/L. The zinc supplement was discontinued and there was no recurrence afterwards. We did mutation analysis of SLC39A4 and SLC30A2 genes by direct DNA sequencing using the genomic DNA extracted from the peripheral blood of the patient and her mother. No mutation was detected.

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One year later, the parents brought in their second baby, a 5month-old boy, with erythematous and focally scaly lesions with desquamation over the perioral and diaper areas. The baby boy was fed with breast milk exclusively. Because of the earlier experience, the parents sought our attention within days after onset of the skin lesions. The boy’s serum zinc was very low (3.06 mmol/L), and the zinc in the breast milk collected at the same time was also very low (1.07 mmol/L). The skin lesions responded quickly to zinc supplement. We advised the parents to start other food supplements additionally instead of feeding the baby only with breast milk. Discussion Zinc deficiency in humans is mostly caused by dietary deficiency. However, transient, symptomatic zinc deficiency caused by inadequate zinc contents in breast milk has been reported in breast-fed babies.3,5e21 Sharma et al22 described this condition in an Indian pedigree with 10 affected children in three interrelated families (Families 1, 2 and 3), in which the three fathers were brothers from family A and the three mothers (two sisters and the third one was an aunt to the two sisters) were from family B. The disease had its onset before weaning and disappeared when the affected children started a normal solid diet. Eleven babies of these three couples survived the age of 3 months, which was the age of onset of symptoms, and 10 of them had been afflicted with the disease. One girl escaped the disease because she was fed cow’s milk after 3 months of age. For other members of Families A and B without consanguineous marriage, there was no affected offspring. The pedigree and consanguinity suggested an autosomal recessive inheritance.22 Type II hypozincemia appears to be rare, but the incidence in the general population is unknown. In the previously reported cases where more detailed information was available, 21 of 37 patients were preterm and 11 of 37 patients were term infants (Table 1).

Figure 1 A 6-month-old, breast-fed full-term Taiwanese female infant presents with multiple erythematous to dusky red, scaly or crusted papules and annular plaques over the perioral area (A), diaper area (B) and digits (C) for a 3-week duration.

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Figure 2 (A) Histopathological examination of a skin lesion reveals spongiotic psoriasiform hyperplasia with pallor of the superficial keratinocytes, covered by a thick confluent layer of parakeratosis containing plasma globules. The papillary dermis is slightly edematous with a moderately dense perivascular infiltrate of small lymphocytes. (B) A close-up view of the confluent parakeratosis and hypogranulosis.

These patients presented with skin lesions and some also with diarrhea or irritability. Clinical symptoms or signs improved dramatically after days to weeks of zinc supplement. Our patient was a full-term baby and had disease onset while on breast feeding. The clinical and pathological findings as well as low to very low zinc levels in the patient’s serum and the mother’s breast milk supported the diagnosis of type II hypozincemia of infancy in our patient. Type II hypozincemia differs from the classical AE in several aspects.23 The differences are summarized in Table 2. The functions of zinc have been grouped into three categories: catalytic, structural and regulatory.4 Zinc is an essential component of the catalytic site of hundreds of different metalloenzymes, including carbonic anhydrase, alkaline phosphatase, RNA polymerases, etc. Zinc is also an important structural component of gene regulatory proteins and facilitates appropriate protein folding. The third function of zinc is regulation. For example, zinc acts as an ionic signal in cells moving through gated membrane channels. “Gluzinergic” means zinc selectively stored in and released from neurons in the cerebral cortex that also release glutamate.4 Adequate zinc levels are crucial for wound healing, immune response and neurological function.2 Patients with zinc deficiency present with eczematous scaly plaques which can become vesicular, bullous, pustular or desquamative. The lesions typically affect the extremities, and diaper and periorificial areas.4 Patients are also predisposed to systemic infections and superinfection with Candida albicans and bacteria, usually Staphylococcus aureus. Diarrhea may be prominent but is not seen in all cases. More prolonged deficiency may result in growth impairment and neuropsychological changes

such as emotional instability, irritability and depression.23 If untreated, the disease is fatal.2 Zinc supplement should be started and clinical improvement is seen very rapidly, within days to weeks. In zinc-deficiency states such as classical AE or transient infantile zinc deficiency, zinc supplement should be started at 2e3 mg/kg/day of elemental zinc.4,5 In patients with zinc deficiency caused by low dietary zinc, treatment with elemental zinc supplementation, 0.5e1 mg/kg/day is recommended.4 In malnourished patients, a multinutrient replacement approach is warranted. Zinc homeostasis depends on adequate zinc absorption and maintenance of appropriate intracellular and extracellular zinc levels. Dietary sources of zinc include meat, fish, shellfish, eggs and dairy products. Most vegetables, fruits and refined carbohydrates contain very little zinc. Moreover, phytates (found in cereal grains, legumes and nuts) and fibers interfere with intestinal zinc absorption.2 Human breast milk contains very high levels of zinc during the first 1 to 2 months of lactation.2 The mammary gland can secret an extraordinary amount of zinc into milk during lactation. The zinc concentration in the breast milk is maintained over a wide range of dietary zinc intake, which suggests that the import and export of zinc by the mammary gland are tightly regulated. Impairments in this process can result in severe zinc deficiency in breast-fed infants.24 It has been shown that oral supplementation of zinc to human mothers with low zinc content of their milk did not lead to an increase of zinc in the milk.25,26 Zinc transporters are transmembrane proteins. There are two families of mammalian zinc transporters. The first is the ZnT family

Figure 3 After the supplement with oral zinc sulfate for 25 days, her skin lesions including perioral area (A) and diaper area (B) resolve completely.


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Table 1 Summary of reports cases of transient infantile zinc deficiency. Ref.

Case no.

Birth history

Clinical

Feeding

Infant zinca

ALKP

Maternal zinca

Breast milk zinca

2

1 1 1 10

d Preterm Preterm 9 preterm 1 term 2 term Preterm Preterm d Preterm Preterm 1 term Preterm Preterm Term 1 preterm 1 term 1 term 1d 2 term Term Preterm Preterm Preterm Term

D, GI, Irritable D D, GI, Hair D

BF BF BF BF (fortifier)

Y(6.89) Y(6.12) Y(2.49) Y(2.49w8.68)

Y d Y(128) d

d Normal Normal 6.36e11.78

Y Y(3.06) Y(2.10) Y(2.49w4.97)

D, Hair D, GI, Irritable D, GI D D D

BF BF BF BF BF BF

Y; d Y(2.98) Y(5.66) Y Y Y

d d d d d d

Normal d d Normal Normal d

Y(3.98; 3.52) d d Y Y Y

D, D, D, D,

BF BF BF BF

Y Y(2.29) Y Y(2.45; 3.06)

d Y d d

d d d Normal

Y Y(5.66) Y Borderline low;Y

D

BF

Y

d

d

Y

D D D D D D, Irritable

BF BF BF BF BF BF

Y Y Y Y Y(3.58; 4.77) Y(4.90)

d d d d d Y(104)

SlightlyY d d d d 12.85

Y Y Y Y Y(2.29; 3.18) Y(2.14)

5 6 7

8 9 10 11 12 13

14 15 16 17

2 1 1 1 2 2 1 1 1 2

18

2

19

2 1 1 1 2 1

20 21 30 31

Our case

GI, Irritable Hair, Irritable GI GI

a mmol/L, serum zinc normal range ¼ 10.7118.36 mmol/L. ALKP ¼ alkaline phosphatase; BF ¼ breast feeding; case no. ¼ case number; D ¼ dermatologic symptoms; GI ¼ gastrointestinal symptoms; Hair ¼ alopecia; Ref. ¼ reference; d ¼ no data.

(encoded by SLC30), which acts to decrease the intracellular zinc level by transporting zinc from the cytoplasm to the lumen of organelles or the extracellular space. The second is the ZIP family (encoded by SLC39), which increases intracellular zinc levels by promoting zinc influx into cells or zinc release from intracellular vesicles.4 Human zinc transporters are designated SLC30A or SLC39A. Ten ZnT transporters and 14 Zip transporters have been identified thus far.4,27 Mutations have been detected in SLC39A4 (encoding Zip4) in some of the pedigrees with AE.25,28,29 In type II hypozincemia, a missense mutation has been identified in SLC30A2 (encoding ZnT2) in two infants from two mothers with low milk zinc concentration resulting in transient neonatal zinc deficiency in a pedigree.8 In our patient, mutation analysis of both SLC30A2 and SLC39A4 genes was performed but no mutation was found. Thus, the genetic defect in our patient may involve other zinc transporter genes and needs to be further investigated. In summary, we presented a Taiwanese infant with type II hypozincemia, which should be differentiated from classical AE because of the difference in treatment and prognosis. As breast feeding and delayed weaning are becoming more common in Taiwan and other parts of the world, it is important to be aware of this type of infantile hypozincemia so that early diagnosis can be

Table 2 Comparison of type I and type II hypozincemia of infancy. Type I hypozincemia (acrodermatitis enteropathica) Incidence Onset

Rare, 1/500,000 During weaning from breast milk to formula or cereal. Mother milk has protective role Mechanism Defect of zinc absorption in the gut Mutations SLC39A4, encoding Zip4 found Treatment Life-long zinc supplement

Type II hypozincemia Unknown During breast feeding and improves after weaning to formula or table food Defect of zinc secretion into the breast milk SLC30A2, encoding ZnT2 Short-term zinc supplement

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