The development of animal breeds is accomplished by repeatedly breeding individuals with particular traits of interest. Along with traits of beauty and behavior, most all mammalian species harbor many recessive traits that are deleterious to the species. Two copies of these traits need to be present in order for the "disease" or "defect" to be expressed. Breed development, strong inbreeding and line breeding makes beautiful breeds with highly desired traits, but problem genes can occassionally and accidently become increased in frequency. Unfortunately, an unforeseeable, and undesirable trait has reached a high level in groups of the Burmese and other breeds, which could not be predicted in advance by any breeder. The undesirable trait is known as the "Head Defect".

During the 1970's, a alternative style Burmese cat was established. Phenotypically still within the CFA standard (4), this "strain" of Burmese expresses a more rounded head with a higher frontal prominence, a shorter, broader muzzle, seeming larger and more prominent eyes, and generally a more demarcated nose break. This shorter, broader muzzle form has been referred to as the "Eastern", "new look", "Contemporary", or "more extreme". The longer, narrower muzzle form is referred to as "Traditional" or "less extreme".

The "more extreme" Burmese quickly became popular in the show ring and intensive breeding programs ensued. Shortly after the widespread establishment of the "more extreme" cats, litters involving the "more extreme" cats as both parents began to produce kittens with a severe congenital craniofacial deformity.

The association of the craniofacial deformity with the "more extreme" phenotype of the Burmese has raised a severe dichotomy amongst the Burmese breeders and a rift within fancy cat breeding societies. Conflicting results of the initial investigations, concerns of accuracy, confidentiality, and inaccurate interpretations has posed the question as to whether the "more extreme" phenotype should be propagated, and to whether "more extreme" phenotypes can be maintained without the deformity. As a result, the National Alliance of Burmese Breeders (NABB), a solely "more extreme" Burmese breeding group, initiated a request for proposals through the Winn Feline Health Foundation for the "Study of Craniofacial Malformations Occurring in Burmese Cats". Dr. Lyons responded to this request and is continuing research on the Head Defect, which is also found in other breeds, such as Bombay and American Shorthairs.

An investigation of the defect by Zook et. al (5), provided a detailed clinical description of the defect as well as a suggestion that the deformity may elicit an autosomal recessive mode of inheritance. By 1983, over 90 purebred Burmese from a disperse group of catteries had been afflicted with the deformity. No obvious infections, toxic agents or environmental conditions could be correlated with the deformity. The common genealogy of the cats producing the deformity in their litters revealed cats of common ancestry that had been extremely proliferative, including a line of show-winning cats that had been extensively bred.

A research cooperative was established to investigate causation and the mode of inheritance of the craniofacial deformity (6). The cooperative was known as The Burmese Cooperative Research Project, and a cattery, Searchcore, was established to oversee the test breedings for the project. Under the assumption of a recessive mode of inheritance, Searchcore established matings between known carriers (all "more extreme") and non-carriers and/or cats of unknown status (both of the "less extreme" phenotype). The kittens of the resulting litters were then bred to known carrier cats, which all were of the "more extreme" phenotype. The 33 second generation matings produced 151 kittens of which 20 expressed the craniofacial deformity. The interpretations of the test matings and data collected from 46 questionnaires to breeders were made. Frances O. Smith, D.V.M., of the University of Minnesota, was enlisted by the Searchcore to interpret the pedigree analysis. Dr. Smith suggested an incomplete dominant mode of inheritance and that the deformity was a result of the "more extreme" phenotype (6). Deformed kittens being homozygous and the heterozygous form to be expressed as the "more extreme" phenotypic cats.

The inheritance pattern was informally addressed by Sponenberg and Graf-Webster in 1986 (9). Of 22 litters born to matings between Burmese parents which previously had produced the craniofacial defect, 19 of 88 kittens expressed the deformity. The 69:19 ratio did not deviate significantly from an autosomal recessive mode of inheritance (X2 = 0.545) at the 95% confidence interval. The gene symbol, mc, was suggested by Dr. Roy Robinson to represent the meningoencephalocele syndrome (2,9).

Breeders often have litters that have several defective kittens or also notice that a particular mating has many defective kittens. The defect is recessive, thus breeders must realize that over all matings, the defect should be seen about 25%. Some carrier to carrier matings may not produce any defective kittens, and breeders may fail to realize that these kittens should be counted in the overall average. Each kitten has a 25% chance of being defective when both parents are carriers. Each kitten in a litter is independent of its littermates! The chances of getting 4 affected kittens in a litter of four is exactly the same as getting zero kittens affected.

The head deformity originated in Burmese cats in the USA. The defect has been seen in England and Europe due to the importation of the "more extreme" Burmese cats from the USA. Any breed that uses a "more extreme" Burmese has a potential of acquiring the recessive gene. The defect is then likely to reappear when two carriers are bred. Bombay's do have the head defect gene as do some lines of American Shorthairs. Thus, Bombays and some American Shorthairs can now also spread the gene that causes the defect. The introduction of the head defect is accidental and is difficult to predict.

Searchcore also established a collaboration with Cornell University to investigate the developmental mechanism of the deformity (7). Over 40 of the deformed kittens were examined. The defect was originally described as either maxillonasal hypoplasia (5) or incomplete diprosopus (8). The Cornell study initially suggested a mechanism of transformation of the medial nasal part of the frontonasal process, naming the defect: telencephalic meningohydroencephalocele. This defect was also referred to as: Incomplete conjoined twinning, by the Cornell group. This group restated Dr. Smith's interpretation that the "more extreme" phenotype is a less severe expression of the deformity, and some homozygotes cross a threshold which results in the lethal malformation.

The Burmese Head Defect presents at birth. The area of the upper jaw is duplicated and two hard palates and two sets of whisker pads can be easily seen. The head region above the upper jaw does not form properly. Eyes and ears are malformed and there is not complete closure of the skull. The brain appears to be protruding from the skull but it is generally covered by skin that may or may not be covered with fur. Kittens can be born alive and should be humanely euthanized.

Frontal View	Side view
Cranial-Facial Abnormality

Carol W. Johnson, DVM, PhD is a board certified pathologist and has studied many of the deformed cats and the carriers in the American Shorthair breed. The head defect presents as the same condition in the American Shorthairs as in the Burmese. The "more extreme" facial structure is also seen in the American Shorthairs as in Burmese, but clearly defining the carriers remains difficult when just based on nose break and the preferred facial qualities. Other presentations are also common between Burmese and American Shorthairs, particularly dermoids in the nose area. Eyelid colobomas and cleft lips have also been noted in the American Shorthairs. A minor longitudinal depression along the midline of the nose, which may or may not be palpable, has been noticed in nearly 90% of the cats that are carriers in American Shorthairs. This hallmark would be more difficult to identify in Burmese and Bombays since they are solid and darkly colored cats. It should be noted that the midline nose depression may not be a 100% correlation with carriers. Some known carriers do not have the variation, and it is possible that somecats may have this depression and not actually carry the defect. These various indicators of carriers should be combined with pedigree analyses to help determine of cats potentially carrier the defect.

The deformity is not compatible with life thus kittens need to be humanely euthanized if not stillborn. Unfortunately, the only resort for a breeder is to attempt to not breed two carrier cats in a particular mating. To test a cat, a known carrier needs to be bred to theunknown cat. Known carriers are cats that have produced defective kittens. But unfortunately, this defect is recessive, thus only 1 in 4 kittens (on average) will present with the defect. These test crosses need to produce at least 12 non-defect kittens from the same matings to be 95% confident that a unknown cat is not a carrier. And the breeder must be aware that since one parent is a known carrier during a test cross, then each kitten produced from test crosses has at least a 50% chance of being a carrier.

The Comparative Genetics Laboratory of Dr. Leslie Lyons at the School of Veterinary Medicine at UCDavis is currently searching for a marker and the gene causing the Head Defect. Dr. Lyons has interacted with the Burmese and Bombay breeding communities for many years to collected the necessary samples for the project and is now working with American Shorthair breeders also. Additionally, Dr. Lyons laboratory also develops feline genetic tools and resources that will assist the project. These tools include genetic maps and DNA libraries for the cat.

History of Dr. Lyons' Research

The first proposal by Dr. Lyons was in response to the request of the NABB. The project proposed a combination of a prospective and retrospective study to investigate the genetics of the craniofacial deformity expressed in a portion of Burmese cats. After reviewing the previous studies and the limited available data, and determining that a single gene was highly likely to be responsible for the defect, it was decided that a beneficial study could be initiated. The project had four goals: 1) formally verify the mode of inheritance of the craniofacial defect and formally address the mode of inheritance of the Burmese facial morphology, 2) establish genetic linkage or non-linkage between the craniofacial defect and facial morphology in formal pedigree analysis of existing and proposed pedigrees, 3) test a panel of high resolution polymorphic genomic markers, feline microsatellite loci, for linkage to the craniofacial deformity and Burmese facial morphology, 4) provide suggestions for the eradication of the deformity from the Burmese breed.

Results from this study suggested:

1) The defect is caused by two copies of the mutated gene and is autosomal recessive. Pedigree analyses from cats that were imported into France were very helpful with clarifying the confusion.

2) The "more extreme" facial structure is strongly associated with the defect, but no strict "threshold" could be determined. Breeders should realize that not all short facial structures are due to this gene. For example, Persians have very short facial structures, but do not have a problem with this defect. In addition, many "Traditional" Burmese breeders have successfully produced cats that have shorter facial structures that are not a result of contemporary breedings but due to selection of cats with the preferred type. The cats were both from Traditional breedings and crosses with imported cats from Thailand. Although a longer process, good selection can produce competitive show cats.

3) Genetic markers were tested in the Burmese cats and they were found to have sufficient genetic variation for gene mapping studies. Many breeds of animals have problems with inbreeding and low genetic variaiton. Low genetic variation also makes it difficult to find markers for genes of interest. Hence, the analysis of different breeds of cats, Burmese, Bombays and American Shorthairs, is actually very beneficial for identifying genetic markers.

4)Counselling for breeders is very important for this problem. Breeders need to slowly eliminate the known carriers from their programs. Importantly, breeders must realize that although a cat may carry this defect, any given cat may have many other attributes that are important to the breed and a cattery. Thus, although some breeders have the ability to eliminate the questionable lines, other breeders may not have the luxury to be as aggressive. Breeders should be tolerant and cooperative with the decisions that need to be made for a particular cattery. Without a definitive test, like a genetic marker, carriers will go undetected, even with the most aggressive culling.

Read the original Winn Foundation proposal
This project was for 2 years, $30,000.00

Report to the Winn Foundation and second year of project

UCDavis Winn Foundation Proposal (Feb. 2002 - Jan. 2004)
2 years, $30,000.00 with $20,000.00 match from UCD Center for Companion Animal Health and $20,000.00 match from Dr. Lyons research program.

Grant Proposal to National Institute for Dental and Craniofacial Research (NIDCR) (Jan. 2003 - Dec. 2004)
2 years, $100,000.00

NIDCR Program Announcement 1
NIDCR Program Announcement 2

There are many ways for breeders to participate. If you have a litter with a defective kitten, the project can use that individual kitten. Additionally, samples from the relatives are very helpful. Thus, a breeder can help by providing a sample from a cat that is a relative, but they have never had a defective kitten. Breeders can also help to spread the information and encourage other breeders to participate. The project will be more successful with greater enthusiasm from the breeders.

Breeders need to supply samples:

a. defective kitten cadavers

See instructions for sending tissues and cadavers.

b. blood samples from siblings

See instructions for sending blood samples

c. blood samples from parents

See instructions for sending blood samples

d. blood samples from grandparents

See instructions for sending blood samples

Ideally, all these samples can be obtained from each litter that has a defective kitten, but some missing samples can be tolerated.

Is the defect recessive or incompletely dominant?

Confusion results from which trait is being discussed. In order to produce defective kittens, 2 copies of the mutated gene are required. The defect is recessive. But, the "more extreme" presentation of the face is more complex. Most genes that affect structure are influenced by environment and other "background" genes. When breeders use a "more extreme" Burmese, the shorter face is more dominant, but variation is seen. Thus, the inheritance of the "more extreme" facial structure is incompletely dominant. So far, we can not predict which of the "more extreme" cats carrier the head defect. Other mild defects and abnormalities provide some clues, such as the dermoids and the color variation on the midline of the nose, but they are not 100% accurate or 100% predictive. Once the gene is identified, perhaps we will be able to make facial measurements that will help identify these cats, but a DNA test will be far more accurate.

How can the disease be recessive when I had all my kittens affected?

Breeders do not immediately know which cats are carriers. When 2 carrier cats are bred, 25% (1 in 4) of the kittens should have the defect. But this is an overall average. Breeders will not recognize that cats are carriers if they have a litter that has no affected kittens, hence breeders often miss this litters amd they are not counted to create the overall average. Cats will not "throw" the defect more or less often, it is all a game of luck and averages.

How can we get rid of the problem?

At this time, the only thing breeders can do is learn about the defect and the lines that potential carry the defect. Two carriers should not be bred together if possible. If a cat is identified as a carrier, is could be eliminated from a breeding program if there are options to not use that cat. Breeders want to be careful to not destroy complete breeding programs and reducing the numbers of Burmese used to quickly. This could cause other inbreeding problems! There are lots of other good qualities in these cats!

What cat caused this problem?

This question is likely to very quickly cause animosity amongst the breeding community and will quickly stop a project in its tracts. Although pedigree examinations can generally identify an individual cat, this process tends to cause fractionation amongst breeders. Breeders need to realize that it is no longer important which cat may have been the originator of the problem. Every offspring produced from the initial cat has a 50% chance of being a carrier. Without a carrier test, each cat produced and the subsequent offspring have a chance of propagating the problem. The elimination of all these cats would cause a big lose of cats in the breed, and may cause more inbreeding problems. The defect is caused by one problem gene, but the same Burmese cats may have many excellent qualities that are needed within a breed. Additionally, the elimination of all suspect cats could greatly damage some breeding programs, which is NOT the goal of the research and hopefully not the goal of the cat community. Breeders should focus on presently known carriers and either not breeding these cats to other carriers, or not breeding the carriers at all.

1. Thompson J et al: Genetics of the Burmese cat. Heredity 34, 1943

2. Robinson R: Genetics for Cat Breeders. 3rd Ed. Pergamon Press, Oxford, 1991.

4. Show Standards: The Cat Fanciers' Association, Inc. May 1,1993-April 30, 1994.

5. Zook BC et al:Encephalocele and other congenital craniofacial anomalies in Burmese cats. Vet Med/Small Anim Clin 78:695-701, 1983.

6. Searchcore: Report of the Burmese Research Group. June 14, 1984.

7. Noden DM and Evans HE: Inherited homeotic midfacial malformations in Burmese cats. J Craniofacial Genet Devel Bio (Suppl) 2:249-266, 1986.

8. Sekeles, E: Craniofacial and skeletal malformaitons in a cat. Feline Prac 11:28-31, 1981.

9. Sponenberg DP and Graf-Webster E: Heredity meningoencephalocele in Burmese cats. J Hered 77:60, 1986.