CLINGEN PEDIATRIC ACTIONABILITY

Stage II: Summary Report Secondary Findings in Pediatric Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening Update History Stage 2 Status (Pediatric):Complete (Actionability curation complete.)

GENE/GENE PANEL: SLC39A4
Condition: Acrodermatitis enteropathica, zinc-deficiency type
GENEDISEASE PAIRS: SLC39A4201100
Topic
Narrative Description of Evidence
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The only data available suggests an incidence of 1:500,000 births in Denmark. The condition appears to be more common in the North-West of Tunisia, sub-Saharan Africa, and South East Asia.
1 2 3
Clinical Features
(Signs / symptoms)
Acrodermatitis enteropathica (AEZ) is characterized by zinc malabsorption due to pathogenic variants in SLC39A4, a gene encoding a zinc transporter. Patients have low plasma zinc concentrations, and low levels of serum alkaline phosphatase. AEZ initially manifests as skin lesions. These typically are eczematous pink scaly plaques that can become pustular, vesiculobullous, psoriasisform, or crusted, appearing in the acral, periorificial, and anogenital areas. If treatment is not initiated, they may evolve into erosions and are susceptible to secondary infection. Other observed manifestations include diarrhea, generalized alopecia, Beau-Reil nail lines, paronychia, conjunctivitis, blepharitis, and erythematous oral mucous membranes. Prolonged zinc deficiency leads to failure to thrive, mental slowness, photophobia, hypogeusia, anemia, poor wound healing, hypogonadism (males), and delayed puberty.
1 2 3 4 5
Natural History
(Important subgroups & survival / recovery)
AEZ usually presents in the first 4-10 weeks of life in infants that are not breast-fed, and around the time of weaning in breast-fed infants. However, there are case reports of breast-fed infants with earlier onset due to the heterozygous status of the mother and thus likely reduced zinc content in the breast milk. Left untreated, AEZ results in generalized organic failure and death prior to adulthood, with most reported deaths occurring before age 12.
1 2 3 4 5
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
AEZ patients require lifelong oral zinc supplementation. Any interruption of the therapy will inevitably induce a relapse. However, with adherence to lifelong zinc supplementation, prognosis is good with resolution of symptoms in days or weeks. (Tier 3)
1
In a case series of 29 AEZ patients diagnosed based on clinical criteria (mean age of onset 6.9 months; genotypic confirmation in 13 patients), 26 were treated with zinc sulfate and 3 with zinc gluconate at a dose of 5-10 mg/kg/d. In all cases, the changes were quick and positive with complete healing of the cutaneous lesions within three weeks. The monitoring period ranged from 7 to 24 years for 26 of these patients. No patients experienced any growth failure or intellectual delay. The other three patients were lost to follow-up (n = 2) or died after irregular treatment and onset of infection (n = 1). No growth failure or intellectual delay was observed after treatment. In one patient where treatment was repeatedly interrupted, 5 separate relapses were induced. Three patients had relapses during adolescence, despite regular treatment, and required higher doses. In a large historical review of case reports (n = 179) of AEZ, most of which were not confirmed to meet clinical criteria for hereditary disease on the basis of zinc therapy withdrawal, 34 out of 51 untreated patients experienced a lethal outcome, whereas only 2 of 128 patients who were treated with zinc therapy experienced a lethal outcome. (Tier 5)
3 5
Surveillance
Zinc and copper levels should be monitored regularly. Regular clinical and biological follow-up of the patients enables adaptation of the dose of zinc supplement to possible physiological (e.g., adolescence, pregnancy), or pathological (e.g., inflammatory states) variations in zinc levels. (Tier 4)
1 2
Circumstances to Avoid
No circumstances-to-avoid recommendations have been provided.
 
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Recessive
1 2 3
Prevalence of Genetic Mutations
No information on prevalence of pathogenic variants in SLC39A4 was identified.
 
Penetrance
OR
Relative Risk
(Include any high risk racial or ethnic subgroups)
The risk to develop AEZ is 100% in homozygotes or compound heterozygotes, though it may be masked by breast milk consumption. (Tier 4)
1
In a large historical review of case reports (n = 179) of AEZ, most of which were not confirmed to meet clinical criteria for hereditary disease on the basis of zinc therapy withdrawal, 34 out of 51 untreated patients experienced a lethal outcome. (Tier 3)
1
In a case series of 29 patients meeting clinical criteria (relapse after withdrawal of zinc) for hereditary AEZ, the following clinical signs were reported at initial consult:
 
-Mucosal signs: 19/29 (66%)
 
-Phanere affections (complete alopecia of the scalp, eyelashes, and eyebrows): 15/29 (52%)
 
-Diarrhea: 15/29 (52%)
 
-Neuropsychiatric disorders: 13/29 (45%) (Tier 3)
1
Information on relative risk was not available.
 
 
Expressivity
No genotype-phenotype correlations have been observed. (Tier 3)
4
4. What is the Nature of the Intervention?
Nature of Intervention
Treatment includes oral zinc supplementation. In a case series following 26 AEZ patients from 7 to 24 years (13 patients followed more than 10 years), treatment with zinc sulfate or zinc gluconate was well-tolerated with no reported side effects.
3
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Establishing a diagnosis of AEZ is not very easy because of the rarity of the disease, which often leads to a long diagnostic delay. Clinical and biochemical diagnostic methods are rarely sufficient to establish a definitive diagnosis, because acquired zinc deficiency causes are varied and not always obvious to determine. (Tier 4)
1

 
Final Consensus Scores
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
Morbidity and mortality associated with zinc deficiency / Zinc supplementation
2
3C
3C
3
11CC
To see the scoring key, please go to: https://clinicalgenome.org/working-groups/actionability/projects-initiatives/actionability-evidence-based-summaries/
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. Kury S, Kharfi M, Blouin E, Schmitt S, Bezieau S. Clinical utility gene card for: acrodermatitis enteropathica - update 2015. Eur J Hum Genet. (2016) 24(5).
2. Acrodermatitis enteropathica. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=37
3. Kharfi M, El Fekih N, Aounallah-Skhiri H, Schmitt S, Fazaa B, Kury S, Kamoun MR. Acrodermatitis enteropathica: a review of 29 tunisian cases. Int J Dermatol. (2010) 49(9):1038-44.
4. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Acrodermatitis enteropathica, zinc-deficiency type; aez. MIM: 201100: 2016 May 02. World Wide Web URL: http://omim.org.
5. Van Wouwe JP. Clinical and laboratory diagnosis of acrodermatitis enteropathica. Eur J Pediatr. (1989) 149(1):2-8.
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