Test Detail

Genodermatosis of the American Bulldog caused by a mutation in the NIPAL4 gene (also called ichthyin), which encodes a transmembrane protein with a role in epidermal lipid metabolism and the formation of the skin barrier. Homozygous dogs present non-epidermolytic ichthyosis with generalised scales and erythema, especially on hairless skin, from the first weeks of life. It is the canine model of human autosomal recessive congenital ichthyosis due to NIPAL4.

Affected breed: American Bulldog. Among 800 American Bulldogs analysed, 34 % of the clinically healthy ones were heterozygous (Casal et al. 2017); the allele frequency derived from that figure is approximately 22 % (estimate, not a published figure). The same variant has since been described in an American Bully (Briand et al. 2019).

- Generalised scales from the first weeks of life, with a dishevelled coat\n- Adherent scales and erythema on hairless skin (abdomen, axillae, groins)\n- Brownish adherent scales over erythematous skin\n- Histologically: orthokeratotic laminated/compact hyperkeratosis with hypergranulosis and mild acanthosis\n- Abnormal lamellar lipid bodies on electron microscopy\n- Frequent Malassezia overgrowth in the stratum corneum (without concomitant inflammatory response)

Mauldin and colleagues described the disease in 2015 in an extended family of American Bulldogs, with clinical, histopathological and electron microscopy studies showing a moderate non-epidermolytic ichthyosis with absence of NIPAL4 (ichthyin) immunolabelling in the epidermis; linkage analysis identified an association with NIPAL4 and a SINE element inserted upstream of the gene as an associated marker, without identifying the causal variant at that time. In 2017, Casal and colleagues completed the molecular study: they sequenced NIPAL4 and identified a homozygous single-base deletion (cytosine) in exon 6 (c.744delC) that produces a frameshift and a premature stop codon (p.Ile249*) with a truncated protein of 248 amino acids instead of 404. The variant segregated perfectly in the family and was detected in 34 % of clinically healthy American Bulldogs analysed (derived allele frequency ~22 %), which justifies genetic screening in the breed.

- Test American Bulldog breeding animals with the NIPAL4 c.744delC test before mating; given the high carrier frequency, it is essential even in lines with no history\n- Do not mate two carriers: 25 % risk of affected homozygotes in each litter\n- A valuable carrier may be mated to a clear animal; the offspring intended for breeding should be tested and, ideally, the carrier progressively replaced by clear offspring without narrowing the gene pool (important in a breed with limited genetic diversity)\n- Exclude affected homozygous animals from breeding\n- In a puppy with generalised scales and erythema from the suckling period, suspect ARCI and confirm with the NIPAL4 genetic test\n- Communicate the status to the buyer and record the result in the pedigree

Differential diagnosis with other congenital ichthyoses of the dog (PNPLA1 in the Golden Retriever, SLC27A4 in the Great Dane, KRT10 in the Norfolk Terrier, TGM1 in the Jack Russell Terrier), with atopic dermatitis and with Malassezia or bacterial overgrowth. Biopsy with electron microscopy (when available) shows abnormal lamellar bodies, which supports the diagnosis. Management is palliative: emollients, keratolytic baths (salicylic acid, urea), control of secondary infections. Molecular testing is decisive for breeding advice in a breed with a high carrier frequency.

1. Mauldin EA et al. 2015. Autosomal recessive congenital ichthyosis in American Bulldogs is associated with NIPAL4 (ICHTHYIN) deficiency. Vet Pathol 52:654-662. PMID: 25322746
2. Casal ML et al. 2017. A defect in NIPAL4 is associated with autosomal recessive congenital ichthyosis in American Bulldogs. PLoS One 12:e0170708. PMID: 28122049
3. Briand A et al. 2019. NIPAL4 deletion identified in an American Bully with autosomal recessive congenital ichthyosis and response to topical therapy. Vet Med Sci 5:112-117. PMID: 30741495
4. OMIA:001980-9615 - Ichthyosis, NIPAL4-related. https://omia.org/OMIA001980/9615/