Think zinc: Transient nutritional deficiency related to novel maternal SLC30A2 mutation potentially precipitated by antenatal proton pump inhibitor exposure

**Background:** Transient infantile zinc deficiency (TIZD) is a rare condition presenting within the first 6 months of life with periorificial and acral dermatitis. While acrodermatitis enteropathica is caused by recessive loss-of-function variants in SLC39A4, acquired TIZD can result from prematurity, low breastmilk zinc levels, malnutrition, or malabsorptive conditions such as cystic fibrosis. Zinc deficiency is usually rare in breastfed infants due to the enhanced bioavailability of zinc in breastmilk. The SLC30A2 gene encodes the zinc transporter ZnT2, which is responsible for zinc secretion from vesicles in lactating mammary epithelial cells. Homodimer formation between mutant and wild-type ZnT2 causes dysfunction and zinc sequestration in lysosomes of mammary tissue, leading to lower zinc levels in breastmilk. Proton pump inhibitors (PPIs) are known to decrease intestinal zinc absorption by increasing intraluminal pH, but little is known about their effect on transplacental or transmammary zinc transmission.

**Methods:** This is a single case report from a clinical setting. The infant underwent serum zinc measurement, alkaline phosphatase measurement, and maternal breastmilk zinc level assessment. Maternal genetic testing for pathogenic variants in SLC30A2 was performed. The infant was treated with zinc sulfate supplementation at 3 mg/kg/day.

**Key Results:** The 5-month-old male infant presented with a 3-month history of progressively worsening scaly eruption, recurrent infections, lethargy, poor feeding, and hoarse cry. He had been treated for suspected impetigo with multiple oral antibiotics (amoxicillin, flucloxacillin, and co-trimoxazole). Examination revealed dramatic periorifacial, diaper-area, and acral dermatitis with loss of occipital hair and thinning of eyelashes. Serum alkaline phosphatase was 41 U/L (normal range 82–383 U/L) and serum zinc was undetectable at <3 μmol/L (normal range 10–25 μmol/L). Maternal breastmilk zinc levels were low at 3.15 μmol/L (control mean 12.7 μmol/L), while maternal serum zinc was normal. Rapid improvement was noted within days of starting zinc supplementation, with almost complete resolution within 2 weeks. Zinc supplementation was stopped after 3 months with normal follow-up zinc levels following weaning. Maternal genetic testing detected a variant in SLC30A2: c.927G>C, resulting in substitution of tryptophan for cysteine at amino acid position 309. This variant has an allele frequency of <0.01% and in silico tools predict it is pathogenic. The mother had been prescribed omeprazole 20 mg once daily from 30 weeks' gestation to birth for gastro-esophageal reflux. In her previous pregnancy, there was no PPI ingestion and no manifestation of zinc deficiency in the older sibling, who was also exclusively breastfed.

**Clinical Implications:** This case represents the first report of this specific SLC30A2 mutation (c.927G>C) associated with TIZD in a breastfed infant. The authors hypothesize that antenatal PPI ingestion, in the context of a maternal SLC30A2 mutation, reduced zinc levels below a threshold that resulted in manifestations of TIZD. The case raises concerns about potential nutritional complications of PPI use in infants with physiologic gastro-esophageal reflux. Clinicians should consider zinc deficiency in breastfed infants presenting with periorificial and acral dermatitis, particularly when there is maternal PPI use during pregnancy or a family history suggesting possible SLC30A2 mutations.