Test Detail

Genodermatosis of the Great Dane due to a mutation in SLC27A4, which encodes fatty acid transport protein 4 (FATP4), involved in epidermal lipid metabolism and in the formation of the skin barrier. Affected puppies are born with thickened, wrinkled and scaly skin (hence the German name "Faltendoggen" = wrinkled Great Danes), with periocular and peribuccal predominance, sometimes with palpebral edema that prevents the eyes from opening. It is a congenital lamellar ichthyosis, autosomal recessive, and constitutes the canine model of human ichthyosis prematurity syndrome due to SLC27A4.

Affected breed: Great Dane. All 15 published cases were black or harlequin coated. No large series with carrier frequency have been published; consider "limited data". The variant has not been found in other breeds or in wolves.

- Thickened and very wrinkled skin from birth, with periocular and peribuccal predominance\n- Generalized whitish-yellowish scales and lamellar plates\n- Marked palpebral edema that may prevent eye opening\n- Hairless skin (axillae, groin) dry and of leathery texture\n- Increased risk of secondary skin superinfections\n- All published cases were black or harlequin coated\n- Histologically: epidermal and follicular orthokeratotic hyperkeratosis, enlarged keratohyalin granules, vacuolated keratinocytes, eosinophilic and alcianophilic lipid material in follicles and sebocytes

The disease has been recognized clinically in Great Danes for years by the characteristic phenotype of wrinkled and scaly skin of neonatal onset. In 2015, Metzger and colleagues performed a GWAS in 9 affected and 13 control dogs of the breed, mapped the locus to chromosome 9, the SLC27A4 gene region, and, by resequencing, identified the causal variant: a missense substitution c.1250G>A in exon 8 (p.Arg417Gln). The variant not only changes the amino acid but, above all, creates a new splice acceptor site within exon 8 that gives rise to an aberrant transcript with an in-frame loss of 54 base pairs and to a marked reduction or absence of functional SLC27A4 protein in the skin of affected dogs. The variant segregated perfectly in 15 affected dogs and was not found in 413 dogs of 35 different breeds or in 7 wolves.

- Test Great Dane breeding animals with the SLC27A4 c.1250G>A test before mating, especially in black and harlequin coat lines\n- Do not mate two carriers: 25% risk of affected homozygotes in each litter\n- A carrier can be mated to a clear animal; offspring intended for breeding should be tested and the clear ones preferably selected\n- Exclude affected homozygous animals from breeding\n- In a Great Dane puppy with wrinkled and scaly skin at birth, especially if black/harlequin coated, suspect "Faltendoggen" and confirm with a genetic test before any mating of the parents\n- Remember the poor prognosis of the form (most published cases were euthanized) and communicate it clearly to the buyer

Differential diagnosis with other canine congenital ichthyoses (PNPLA1 of the Golden Retriever, NIPAL4 of the American Bulldog, KRT10 of the Norfolk Terrier, TGM1 of the Jack Russell Terrier) and with nonspecific neonatal dermatopathies, congenital demodicosis and, in puppies with tight and wrinkled skin, with restrictive dermatopathy. Electron microscopy shows alterations in lamellar bodies and in the lipid barrier. The prognosis is guarded: due to the risk of superinfections and the cosmetic/functional severity, many puppies are euthanized. Management is palliative (emollients, control of superinfections, ocular care if there is palpebral edema). Pre-breeding genetic testing is the essential preventive tool.

1. Metzger J, Wöhlke A, Mischke R, Hoffmann A, Hewicker-Trautwein M, Küch EM, Naim HY, Distl O. 2015. A novel SLC27A4 splice acceptor site mutation in Great Danes with ichthyosis. PLoS One 10:e0141514. PMID: 26506231
2. OMIA:001973-9615. Ichthyosis, SLC27A4-related, perro.