GENDER ANOMALIES IN CATS
1996 - 2011 Sarah Hartwell

When this article was originally written (1996), I had heard from a breeder who owned a fully fertile tortoiseshell and white stud cat. She wanted to know why he only passed on the gene for red and never for black. Her stud turned out to be a red-and-white bicolor mosaic (meaning a somatic mosaic). Her cat was probably a chimera or had a somatic mutation (like a birthmark or mole). Another cause of tortie tomcats is an additional X chromosome.

Unusual sex chromosome complements (XXY, XYY etc) results in gender anomalies which is a fascinating field in itself. Many of the listed anomalies have not been documented in cats, but their existence in other mammals means there is a probability that they do occur in cats. Gender/fertility problems are only usually investigated in pedigree cats in breeding programs. In the random breeding feline population (60-90% of pet cats, depending on where you live) such anomalies are likely to go unnoticed.

Sex Determination in the Embryo
Genetic Sex
Gonadal Sex
Phenotypic Sex
"Brain-Sex"
Normal and Abnormal Embryos
Chromosome Abnormalities
Hermaphrodites
Gonadal Sex Abnormalities
Phenotype (Outward Appearance) Sex Abnormalities

 

DEFINITIONS

Allele: there are different variants of most genes; these variants are properly known as alleles (for simplicity I use "gene" throughout this article).
Autosome
: any chromosome other than the X or Y "sex" chromosomes.
Genotype: the genetic make-up of an organism.
Phenotype: the outward appearance of an organism (several different genotypes may result in the same phenotype).
Dominant: most genes are inherited in pairs; the dominant gene of a pair is the one which is physically expressed.
Recessive: the recessive gene is only physically expressed if both genes in a pair are the same recessive gene.

Hermaphrodite: having the sex organs of both male and female.
Intersex: Having undifferentiated sex organs, which are neither fully male nor fully female, but intermediate between the two.

Mosaic (1) having a coat with multiple colours e.g. brindle or tortoiseshell; (2) an individual whose cells have different genetic composition e.g. XY/XXY; (3) having somatic mosaicism.
Somatic mosaicism the presence of genetically distinct populations of somatic cells in a given organism due to DNA mutations/damage or chromosome abnormalities.
Germ-line mosaicism a particular mutation early in the development of an embryo means that, later in life, some of the egg or sperm cells will carry the mutated gene which can be passed on to offspring. This will only be detected in offspring which inherit the mutation.
Chimaera an individual which developed from two genetically distinct germ-lines e.g. where two embryos fused in the womb. Scientists have created a deliberate chimaera by mixing sheep and goat embryos; this "geep" had some goatlike body parts and some sheep-like body parts (in fact it looked like a goat's legs had been stitched onto a sheep body!).

A single individual can have more than one form of mosaicism. The fraction of cells having each genotype is quite variable, reflecting how early during embryo development the mosaicism originated. While mosaics and chimeras both have more than one genetically-distinct population of cells and the outward appearance may be identical, there is a clear distinction between mosaicism and chimaerism. In mosaics, the genetically different cell types all arise from a single embryo, whereas chimeras originate from fusing more than one embryo.

Many parts of this text are deliberately simplified so they can be understood by those with no previous genetic knowledge. Readers may also be interested in the book "Cats are Not Peas" which is about George, a male calico.

SEX DETERMINATION & DEVELOPMENT IN THE EMBRYO 

Normal sexual development of mammals is a 3 stage process: establishment of chromosomal (genetic) sex; development of gonadal sex and development of phenotypic sex.

Genetic sex means whether or not the individual has inherited a Y chromosome. In cats (and most mammals), XX = female and XY = male. Other combinations occur and are considered abnormal.

Gonadal sex means whether the embryonic gonad develops as testis or an ovary. Embryo gonads are programmed to become ovaries unless the genes instruct them to become testes. Some of the genes with instructions for making testes are actually on the autosomes not on the X or Y chromosome. In some cases, genetic changes in the embryo's gonadal cells or developmental abnormalities will cause the embryo to develop inappropriate or abnormal gonads for its genetic gender. "Ovotestes" are undifferentiated gonads which have not (or not yet) become ovaries or testes.

Phenotypic sex means making the outward appearance of the embryo male. Unless instructed otherwise, the embryo will be female in appearance. If a Y chromosome is present, this causes production of hormones which cause the embryo to build male internal and external structures. Hormonal abnormalities at this stage can mean a male embryo fails to respond to these hormones and appears to be female or that a female embryo can turn out appearing male (and various intermediate stages).

Chimeras are individuals composed of cells which come from different embryos. Mosaics are also composed of two or more cell populations, but the cells all originate within the same individual. In both cases, the different cells can contain different mixes of X and Y chromosomes. The gonadal sex of chimeras and mosaics depends upon the proportion of XX cells and XY cells present in the indifferent gonad at the time when gonadal sex determination happens. It also depends on whether those cells are able to form a functional testis or ovary. The type of gonad formed then determines the phenotypic sex i.e. whether the individual looks male, female, neither or both.

"Brain-Sex": In a mosaic or chimaera, the brain might be masculine or feminine depending on which cells it arose from (there is evidence that male and female brains are wired differently). If the brain and the gonads developed from different cell populations, the brain-sex of an individual might not match its apparent gender. For example, an individual which looks male might have female behaviour because its brain is mostly female. If there have been developmental abnormalities a genetic female might outwardly appear to be male or vice versa. Some tortoiseshell male cats might behave like females because genetically they are females or because the cells which formed the majority of their brain are XX while the cells which formed their gonads are XXY or XY.

Normal and Abnormal Embryos

A normal sperm cell carries either an X chromosome or a Y chromosome. A normal egg cell only has one X chromosome. These meet up to form either an XX (female) or XY (male) embryo.

Sometimes an egg is abnormal and contains either XX or no X chromosome. When fertilized by a normal sperm it becomes XXY, XXX or XO (YO will not develop). It might also be fertilized by an abnormal sperm (see below).

Abnormal sperm can be XX, XY, YY or O (O means no X or Y at all). If one of these sperm fertilizes a normal egg it can produce XXY, XYY, XXX or XO. If it fertilizes an abnormal egg it will produce XXXX. XXXY, XXYY etc. In humans, mental retardation is often found when there are 4, 5 or 6 X chromosomes present.

The frequency of these abnormal conditions in cats is not known.

 

CHROMOSOME ABNORMALITIES

Chromo-somes

Name

Details

Identified in Cats?

XO

Turner's Syndrome (monosomy)

Majority of "pure" Turner's indviduals die before birth. Surviving Turner's individuals usually XX/XO mosaics with a substantial fraction of normal XX cells.

Infertile. Underdeveloped genitalia. Small stature.

 ?
Might account for some infertile females.

XX

Normal Female

Female unless affected by developmental abnormality.

Yes

XXX

Triplo-X

Varies. Some are normal appearing female, fertile. Others are sterile females. Often larger than normal stature.

 

XXY

Klinefelter Syndrome

Male. Sterile, underdeveloped genitalia, may develop some female appearance. Tend to be large and may have mild retardation.

 In mosaic form.

XYY

Jacob's Syndrome

Rare in the "pure" condition (mostly XY/XYY mosaics). Tall, fertile and apparently normal.

 

XY

Normal Male

Male unless affected by developmental abnormality.

 Yes

XX/XO

Turner mosaic

Surviving Turner's individuals are frequently XX/XO mosaics.

 

XX/XXY

Klinefelter mosaic

Appearance depends on which structures are XX and which are XXY.

Yes

XY/XYY

Jacob mosaic

Apparently normal male. Seen in cattle: XY/XYY chimaeric bull (fusion of normal XY embryo and abnormal XYY embryo).

 

XY/XO

XY-Turners
Mixed Gonadal Dysgenesis

Appearance and behaviour depends on which parts are XO and which parts are XY. Phenotypically male, female or ambiguous genitalia.

 

YO 

Lethal

YO eggs do not develop because many essential genes are carried on the X chromosome.

 N/A

TURNER'S SYNDROME

Turner's Syndrome is a chromosome anomaly where a cat inherits a single X chromosome, but no other sex chromosome. It is usually lethal and the kitten will have several physical abnormalities due to lacking part of the necessary genetic information. In October 2010 I heard of a cream female kitten born to a black silver mother and a cream father (cream is genetically red with the addition of "dilute"). The parents were Maine Coons so their colour genetics were known over several generations. The mother's pedigree showed she could not have inherited a red gene and has never produced red/cream kittens on previous matings to a cream male (i.e. she wasn't a "hidden tortie"). The only way to have a cream female kitten is in the absence of a black gene. This meant the kitten was XO (Turner's syndrome) and had inherited her X gene, with the red gene, from the father. The kitten also had a severely underdeveloped lower jaw, twisted front legs and a kinked shortened tail. She had the neck webbing that is also characteristic of Turner's in humans. She also had a cleft palate and a shortened tongue which prevented her suckling so she was put to sleep soon after birth.

HERMAPHRODITES

in 2005, Carol Gravley emailed about her marmalade hermaphrodite cat. Early on, the cat appeared physically male with developing testicles and was neutered in a timely fashion. A few weeks later, s/he started displaying signs of being in heat and was taken back to the vet where s/he was spayed. The cat seems to have been functionally female and now has the appearance of an abnormal female. There are various possible causes of a female cat also having testicles, but without tissue testing it isn't possible to know whether it is chimerism or a chromosome abnormality.

 

GONADAL SEX ABNORMALITIES

Name

Cause

External Appearance

Identified in Cats?

XX Male (Sex reversal, de la Chapelle syndrome)

Either an autosomal trait or due to a Y-chromosome gene turning up on an autosome instead of on the Y-chromosome.

Genetically female, phenotypically male. Some testicular tissue in one or both gonads.

Generally have male external genitalia (but abnormal in form) and are cryptorchid.

Internal genitalia: uterus, but other male or female internal structures may be absent.

 

XX True Hermaphrodite (Sex Reversal)

Inerited as an autosomal trait or due to a Y-chromosome gene turning up on an autosome instead of on the Y-chromosome.

Genetically female, appear intersex. Some testicular tissue in one or both gonads.

At least one ovotestis. The degree of outward masculinization is related to the amount of testicular tissue present.

Normal or abnormal female external genitalia e.g. enlarged clitoris (pseudophallus) or any phenotype in between these extremes.

Possible. Hermaphrodite Burmese taken into cat shelter in Chelmsford, Essex (1996?) but no follow up. Not known if this was true or pseudo- hermaphrodite.

XY Female (Sex reversal, Swyer syndrome)

Genetically female, phenotypically female.

Generally have female external genitalia.

 

PHENOTYPE (OUTWARD APPEARANCE) SEX ABNORMALITIES

Name

Cause

External Appearance

Identified in Cats?

Pseudo-hermaphroditism

Chromosome constitution and gonads match up, but internal or external genitalia are ambiguous. See details below.

 See below.

Possible. Hermaphrodite Burmese taken into cat shelter in Chelmsford, Essex (1996?) but no follow up. Not known if this was true or pseudo- hermaphrodite.

Female (XX) Pseudo-hermaphrodite

Have ovaries but appear externally male or intersex due to masculinization of external genitalia.

Excess androgen while embryo developing.

Has ovaries, uterus and vagina. Masculinization ranges from enlarged clitoris through to full external male genitalia with internal prostate.

 

Male (XY) Pseudo- hermaphrodite

(Failure of Mullerian duct regression )

Persistent Mullerian Duct Syndrome (PMDS) . Known to be autosomal recessive in some dog breeds.

Female internal sex organs, external male appearance. May be fertile. May be monorchid or cryptorchid.

An intersex condition that may be PMDS has also been reported in a Persian cat

Male (XY) Pseudo-hermaphrodite

(Failure of androgen-dependent masculinization)

Androgen Insensitivity Syndrome (AIS). Androgen resistance and androgen insensitivity (developing embryo fails to respond properly to male hormones)

May be partial (PAIS) or complete (CAIS).

No female internal structures, but male structures fail to form properly. Failure of masculinization ranges from mild (some masculinization occurs), to complete (no masculinization occurs).

 

Progestin-induced virilisation

XX. Occurs if progestin is administered during pregnancy.

The individuals are anatomically and functionally female, but may develop some male secondary characteristics. Severely affected individuals may be misidentified as male.

Testicular Feminization Syndromes (Tfm)

XY. Androgen receptor gene mutation. Normal embryo testosterone levels, but target organs fail to respond appropriately. Ranges from complete to partial failure of androgen-dependent masculinization.

When the androgen receptor is completely nonfunctional, males appear entirely female, but sterile and do not have oestrus. Internal female structures absent. Complete Tfm.

When the androgen receptor has partial function (incomplete Tfm) it gives ambiguous genitalia through to phenotypic males that are infertile.

Domestic shorthaired cat (1989). Bilateral abdominal testes were present, but no epididymides, vasa deferentia, or uterus. External genitalia were female.

XX Congenital adrenal hyperplasia (CAH)

XX. An endocrine disorder in which the adrenal glands produce abnormally high levels of virilizing hormones and masculinises XX individuals (to varying degrees).

XX individuals with 17 alpha-hydroxylase deficiency are anatomically female, but do not produce sex-hormones at puberty.

 

XY Congenital adrenal hyperplasia (CAH)

In XY individuals (17 alpha-hydroxylase deficiency) inhibits virilization of male embryos.

XY. Appear female.

 

XY 5-alpha-reductase deficiency (5-ARD)

Affects XY individuals, making them unable to metabolise testosterone into dihydrotestosterone which is required for male development in utero.

XY. It ranges from female-appearing or ambiguous genitalia at birth to normal-appearing but infertile males.

 

XX Freemartin

XX. Found in cattle where male and female twins are carried and the placentae fuse.

The male hormones produced by the bull embryo masculinise the female embryo. Although she appears externally female, she is infertile and may behave like a castrated male (bullock).

It has not been identified in other species.

Hypospadias

Associated with XX Sex Reversal and other conditions giving ambiguous genitalia.

Urethra located on underside of penis due to incomplete masculinization. Ranges from mild through to urethra exiting near base of penis.

 

Cyptorchidism & Monorchidism

May occur as separate from conditions listed previously and cause not known. May be genetic, may be developmental.

Delayed descent may be a variant of cryptorchidism.

Undescended testes. May be unilateral (monorchid, may be fertile) or bilateral (crytporchid, sterile).

Yes. Affected monorchid cats should not be used for breeding as trait may be hereditary.

Delayed descent noted in some male cats.

TERMS: Hermaphrodite, Intersex and Gynandromorph

A hermaphrodite has both male and female reproductive organs. In some invertebrates this is normal and both sets of reproductive organs are functional. Some hermaphrodites begin life as one sex, but change sex during their lifetime. In mammals, the term hermaphrodite is also used to describe ambiguous genitalia although the term "intersex" is now preferred.

Pseudohermaphrodites outwardly resemble hermaphrodites but have normal sex chromosomes (either XX or XY), for example female hyenas have an external birth canal that outwardly resembles a penis. In some species, it is a form of mimicry.

True hermaphrodite mammals tend to be mosaics of XX and XY tissues and may be chimeras (two fertilised eggs fuse in the womb) or one egg being fertilised by two sperm (one X sperm and one Y sperm).

A gynandromorph visually has both male and female characteristics. It is noticeable in butterflies and birds where the 2 sexes are visually very different. A gynandromorph may have bilateral asymmetry (one side visually female and the side visually male) or can be mosaic (intermixed male and female tissues). A bilateral gynandromorph tends to occur at the 8 - 64 cell stage of the embryo. If it occurs later, the result is usually a mosaic. Gynandromorphs are usually infertile due abnormal sexual organs.

Intersex refers to individuals that have ambiguous external genitalia or their sex chromosomes do not match their external appearance. The condition is variable in appearance and can be caused by hormonal, developmental or chromosomal abnormalities. Some intersex individuals appear externally male but are internally female/chromosomally female and vice versa. Because domestic pets are routinely castrated or spayed before puberty, the issue is less emotive than in humans although owners may be aware of behavioural differences in an intersex pet. Sometimes surgery is needed to allow normal urination.

MESSYBEAST : BASIC GENETICS FOR BREEDERS & CAT LOVERS