Heterozygous Variants of the SLC39A4 Gene and Possible Increased Risk for Developing Acrodermatitis Enteropathica with Kaposi’s Varicelliform Eruption

Introduction

Acrodermatitis enteropathica (AE) is a rare, potentially life-threatening autosomal recessive disorder first described by Danbolt and Closs in 1943 [1]. It is characterized by the classic triad of acral or periorificial dermatitis, alopecia, and diarrhea. AE results from pathogenic variants in the solute carrier family 39 member 4 (SLC39A4) gene (chr8q24), which encodes the intestinal zinc transporter ZIP4 [2]. More than 40 pathogenic SLC39A4 variants have been reported worldwide, including missense, frameshift, and splice-site mutations [3]. This transporter mediates dietary zinc absorption, and its dysfunction disrupts systemic zinc homeostasis [4]. Zinc is an essential cofactor for metalloenzymes such as alkaline phosphatase (ALP); it plays a crucial role in growth, immune function, and epithelial integrity [4,5]. Consequently, impaired zinc homeostasis can contribute to the onset and progression of multiple diseases, some of which may be life-threatening [6]. Kaposi first described Kaposi’s varicelliform eruption (KVE) in 1872 [7,8]. KVE represents a disseminated cutaneous infection typically caused by herpes simplex virus (HSV) in patients with compromised epidermal barrier function. Although 94% of cases occur in individuals with eczematous dermatoses [8], its occurrence in AE is exceedingly rare; only 1 case has been documented [9]. This report presents the first known case of KVE complicating AE in a patient with novel compound heterozygous SLC39A4 variants. It underscores 2 major points: the importance of SLC39A4 sequencing over reliance on biochemical screening, and the potential for KVE to arise as an emergent complication in refractory AE.

Case Report

An 8-year-old girl from Eastern China presented with a rash – recurrent since infancy – and a recent exacerbation. The initial perianal rash appeared after weaning and progressively spread centrifugally to the oral and acral regions. Episodic lesions showed transient improvement with zinc supplementation but recurred annually. The condition had entered a refractory phase 6 months prior, with widespread blistering culminating in generalized involvement 20 days before admission (Figure 1A–1H). Physical examination revealed sparse brown hair and characteristic vesiculobullous lesions with crusting in intertriginous and acral regions.

Laboratory investigations demonstrated a normal serum zinc concentration (76.13 μg/dL; reference range: 70–120 μg/dL), but ALP activity was substantially decreased (32 U/L; reference range: 143–406 U/L). Histopathological examination of skin biopsies showed hyperkeratosis, acanthosis with focal spongiosis, intraepidermal vesiculation, and superficial dermal lymphocytic infiltration. Tzanck smear revealed multinucleated giant cells. Serological testing confirmed HSV-1/2 IgG positivity.

Genetic analysis was performed by the Chigene Translational Medicine Research Center using clinically validated protocols. Technical specifications are provided in the Supplementary Materials (S1. Laboratory-Methodology.pdf), with key analysis information summarized in Tables 1 and 2. Parental segregation analysis confirmed maternal inheritance of c.522_523dup and paternal inheritance of c.925T>C, c.1782C>T, and c.1843C>T.

The patient was treated with oral zinc supplementation. The total daily dosage, provided as zinc gluconate and zinc calcium gluconate solution, was calculated to deliver 2.8 mg/kg per day of elemental zinc (approximately 70 mg daily, in total). Partial improvement of scalp and flexural lesions was observed after 1 week, although persistent vesicular eruptions with central umbilication remained on the trunk. Given the serological evidence of HSV exposure and clinical features consistent with KVE, topical crisaborole ointment was added to the treatment regimen. Complete resolution of cutaneous lesions occurred within 14 days of combination therapy.

Discussion

AE results from pathogenic variants in SLC39A4, which encodes the intestinal zinc transporter ZIP4 [10]. Zinc functions as an essential cofactor for metalloenzymes such as ALP and is vital for immune competence, epithelial integrity, and growth [4,5]. Consequently, zinc dysregulation can contribute to the onset and progression of numerous diseases, some of which may be life-threatening [6]. Our patient exhibited classic AE manifestations, including post-weaning onset, acral and periorificial dermatitis, alopecia, and response to zinc supplementation; differential diagnoses included atopic dermatitis, Olmsted syndrome, and biotinidase deficiency [11].

Whereas hereditary AE is typically associated with hypozincemia, our patient demonstrated normal serum zinc levels (76.13 μg/dL), a finding reported in approximately 30% of genetically confirmed cases [12–14]. This phenomenon reflects residual transporter activity in compound heterozygotes. Whole-exome sequencing revealed compound heterozygous variants in SLC39A4: a maternally inherited frameshift variant (c.522_523dup) and 3 paternally inherited missense variants (c.925T>C, c.1782C>T, and c.1843C>T). The maternally inherited c.522_523dup (p.Ala175Glyfs*46) results in truncation of the zinc-binding domain (amino acids 335–430). The paternally inherited c.925T>C (p.Cys309Arg), c.1843C>T (p.Arg615Trp), and c.1782C>T variants collectively impair protein folding and membrane localization [13]. Functional studies have demonstrated that such combinations can reduce zinc uptake by 80–95% despite normal serum concentrations [13,15]. In the present case, substantially decreased ALP activity (32 U/L) served as a critical biomarker of zinc dysregulation [14]. Zhang et al. [15] recently reported similar SLC39A4 variants (c.1462_1474+1del and c.296C>T) in a patient with normal serum zinc levels, reinforcing the importance of genetic testing over biochemical markers alone. Normal serum zinc concentrations do not exclude AE, and zinc supplementation should be initiated when clinical suspicion is high.

Patients with AE exhibit suppressed cellular and humoral immunity, predisposing them to recurrent infections. Variants located in exon 3 are associated with early-onset disease and severe initial manifestations. Multiple systemic complications may occur, requiring heightened clinical vigilance [16]. Secondary infections, such as those caused by Staphylococcus aureus or Candida albicans [17], are common and may show overlapping clinical presentation, potentially leading to misdiagnosis. However, the coexistence of AE with KVE remains exceedingly rare: 1 case has been reported by Satria et al. [9]. The development of KVE in AE reflects immunological collapse induced by zinc deficiency. Although epidermal barrier disruption facilitates HSV entry, the subsequent disseminated infection arises from concurrent defects in innate and adaptive immune responses – both of which depend on zinc homeostasis [18]. This case broadens the recognized spectrum of AE complications and underscores the importance of HSV prophylaxis in patients with refractory AE.

When AE is diagnosed, prompt zinc supplementation is imperative. Oral zinc administration typically produces a rapid and pronounced therapeutic response [19]. Patients require lifelong oral supplementation of elemental zinc at 1–3 mg/kg/day, with low-dose maintenance therapy yielding favorable long-term outcomes [20]. The United States Food and Drug Administration has recognized several zinc formulations, including sulfate, acetate, oxide, chloride, and gluconate, as approved therapeutic agents [21]. Nonetheless, the potential need for dose escalation during infection, physiological stress, or adolescence warrants further investigation [22]. Given the usually self-limiting nature of primary and secondary KVE labialis, conservative treatment with topical alcohol-based tinctures, protective dressings, and antimicrobial ointments represents appropriate first-line management [23]. After confirmation of the diagnosis, our patient was treated with oral zinc supplementation at a dosage of 2.8 mg/kg daily, and crisaborole ointment (a phosphodiesterase 4 [PDE4] inhibitor that reduces interleukin-31) was added. Within 2 weeks, the rash had resolved. During 6 months of follow-up, the lesions did not recur, alopecia was absent. The serum zinc level increased from 76.13 μg/dL before treatment to 110.32 μg/dL after 2 weeks of therapy.

Conclusions

We report a compound heterozygous variant in the SLC39A4 gene that has not been previously documented in major databases. This finding enhances clinical diagnosis by expanding the recognized mutational spectrum and advances genetic counseling by enabling precise carrier risk assessment and prenatal testing strategies. The diagnostic process provides valuable insights: (1) persistent acral dermatitis with hypozincemia warrants prompt SLC39A4 sequencing, and (2) vesiculopustular eruptions in AE require immediate HSV polymerase chain reaction testing to distinguish viral infection from bacterial superinfection. Furthermore, this case underscores the importance of clinician awareness regarding the rare occurrence of KVE in patients with AE and the need for timely adjustment of therapeutic regimens.