Similar defects appeared in the American Shorthair breed since the 1970s/1980s and may also affect the American Wirehair. Again, they appear to be related to breeding cats for domed heads. The most minor forms of the defect were overlooked as "merely cosmetic" by breeders as the cats generally had superior conformation (wide spaced large eyes, short broad muzzle, concave profile, large boning) and were successful on the showbench. Show success made these desirable breeding animals and caused the spread of the defective gene. The "cosmetic" effects were actually indicators of the more serious defects that would show up when carriers were bred to each other. About 90% of cats with only 1 copy of the mutant gene had a "dot" (longitudinal depression) on their nose that was evident from birth. Others had dermoids (abnormally located patches of skin) and a few had more serious defects such as harelip, severe cleft palate, duplicated canine teeth, duplication of tongue tissue, crooked jaw, coloboma (fissure of the eye) through to lethal athymia (missing or non-functional thymus gland) or seizures (indicating brain abnormalities).
The dermoids were usually pieces of whisker pad, complete with small whiskers, growing in abnormal places on the face e.g. on the side of the nose, below the eye or even on the eye itself. Small dermoids were hard to spot e.g. a whiskery "mole" under a nostril. Breeders often snipped off tiny dermoids, believing them to be cosmetic and not realising they were symptoms of the head defect gene. The nose was often skewed and the jaw crooked, showing that the head had not formed symmetrically. Coloboma (fissure of the eye socket) is caused by the eyelid plate not developing properly; it looked as though the rim of the eye socket (brow) is crooked. These supposedly cosmetic traits were clear indicators that the cat carried the head defect trait.
When a cat with a "dot" on the nose was bred to unaffected cats, about 50% of the offspring inherited the "dot" and about 5% of the offspring inherited lethal defects. The 50% affected offspring also inherited one or more of the defects such as dermoids or harelip . This suggested the gene was an autosomal (not sex-linked) dominant. When 2 cats with dots on the nose were bred together, many more offspring inherited 2 copies of the gene, resulting in gross and lethal head deformities.
See below: (a) "dot" on midline of nose; (b) distortion of brow-line (upper part of eye socket);
c) cheek-pad tissue growing on side of nose, distorting nose shape (Images copyright Carol W Johnson, DVM,PhD,DACVP )
Kittens that inherited 2 copies of the gene were often born alive, but severe head defects meant they survived only a short time. The brain might be covered by skin but the bony skullcap was missing. The skin might cover a fluid filled chamber (hydrocephaly). The brain was grossly abnormal with little or no normal brain tissue; it ranged from holoprosencephaly (malformed forebrain) to anencephaly (no forebrain). Holoprosencephaly is a failure of the forebrain to divide into hemispheres or lobes and is accompanied by under-development of facial features such as the nose, lips, palate and teeth. In milder cases holoprosencephaly causes wide spaced eyes, harelips and cleft palate, but in severe cases it causes cyclopia (the eyes fuse into a single deformed central eye, often with a proboscis above it). Other affected kittens had small rudimentary eyes located on the sides of the head rather than on the face. Some had severe cleft palate, extreme harelip on both sides of the mouth, brachygnathia (short or receding jaw, flat face) and protruding tongue.
Because cats with minor defects such as the nose dot were often superior in other ways, breeders were unknowingly selectively breeding the cranial defect into the breed. The desire to "ultra-type" cats meant that breeders working with extreme types were more likely to breed affected cats together and encounter the head defect than breeders working with the more moderate or traditional types. Some of the affected cats had won high accolades on the showbench and were desirable breeding stock. The gross deformities would only show up a few generations later when cats with the mutation were bred to each other and kittens with lethal head defects were born.
Like the twin-faced kittens, the cranial defect is associated with the sonic hedgehog gene (Shh) which controls facial symmetry. There are 3 known hedgehog proteins: sonic hedgehog (shh), desert hedgehog (dhh) and indian hedgehog (ihh). Sonic hedgehog is the most common and best documented of these. The sonic hedgehog protein is made in the notochord of developing embryos. Different levels of the protein cause different types of cells to be formed in the developing embryo. It is involved in separating the single eye field into two bilateral fields, hence a mutation of sonic hedgehog can cause cyclopia. Too much sonic hedgehog causes duplication of structures. It also affects limb development and orientation, neural tube (brain/spinal cord) development and seems to affect the growth of hair, feathers or scales. The many effects of sonic hedgehog demonstrate that when selectively breeding for one trait, there is a danger that the gene controlling the desired trait also controls undesirable traits.
According to Carol Johnson (correspondence Oct 2006), the defect has not yet been definitively linked to sonic hedgehog. There is no mutation of the shh gene itself and it is speculated that the cranio-facial abnormalities may be due to a mutation in a downstream gene.