Friday, August 8, 2008

Ambiguous Medicine and Sexist Genetics: A Critique of the DSD Nomenclature

By M. Italiano, M.B.B.S. (A.M.) and Curtis E. Hinkle
© Aug. 8, 2008

Many intersex persons around the world and their allies are concerned about the new nomenclature, DSD or “Disorders of Sex Development”, which has been endorsed by the Chicago Consensus (1) to replace the term “intersex”. We believe that the categories proposed are not only demeaning, but also scientifically flawed.

The age of chromosomes

The DSD nomenclature uses chromosomes, instead of gonads, as the most important classifier of an individual's sex, such as “46,XY DSD” and “46,XX DSD”. This is no more helpful than using male pseudohermaphroditism or female pseudohermaphroditism which was based on gonads. (2) Instead of male pseudohermaphroditism and female pseudohermaphroditism, the new DSD nomenclature proposes “46, XY DSD” and “46, XX DSD” as replacements for the former taxonomy.

Furthermore, what was called true hermaphroditism is now dichotomized to fit more neatly within the binary. True hermaphroditism used to be called “true” because it meant that an individual had both ovarian and testicular tissue and gonads (ovaries and testicles) were considered to be the “true” determiner of one’s sex. Of course the word "true" was problematic because it suggested that all other forms of “hermaphroditism" were not legitimate, only “pseudo conditions”. Also, using the term “hermaphrodite” as a word to describe a person with an intersex variation has often been criticized as insulting and inaccurate. However, by replacing true hermaphroditism with "ovotesticular DSD", we still have another problem. The DSD nomenclature now wishes to divide "ovotesticular DSD" (formerly true hermaphroditism) into “46, XY ovotesticular DSD”, “46, XX ovotesticular DSD”, or “chromosomal DSD” (of “46,XX/46,XY” chimerism or “45, X/46,XY” mosaic types). In effect, it gives an individual in the latter case two types of DSD, an “ovotesticular DSD”, and a “chromosomal DSD”. Also, we see the division based on chromosomes, which again exposes the preeminence of chromosomes as the “true” markers of an individual’s sex. Further, by combining “ovostesticular DSD” with a chimeric or mosaic karyotype, as it does, it also fails to provide a clear classification of so-called “ovotesticular DSD” which has 3 or more cell line types, isochromosomes, inversions, or ring chromosomes in the karyotype.

For individuals who have both 46,XX in some cells and 46,XY in other cells, and who are referred to as having a "chromosomal DSD" of "46,XX/46,XY(chimerism)" type, it is not uncommon for them to have male anatomy only (3) or female anatomy only (4) and they may also be fertile. In this new nomenclature they would be “diagnosed” as having a "chromosomal DSD" despite any practical relevance for them. Furthermore, although the DSD nomenclature is intended to be representative of congenital conditions, there are individuals who have become 46,XX/46,XY because their twin’s cells make up part of their own karyotype (5), or because an individual who is 46,XX received a bone marrow donation from someone who is 46,XY, as well as by many other means (6). In fact, a pregnancy may also lead to "false positives" for a DSD since fetal cells end up in a woman’s bloodstream. (5)

Likewise, individuals with a 45,X/46,XY karyotype are listed as having a “chromosomal DSD”, but with a parenthetical “mixed gonadal dysgenesis” or “ovotesticular” DSD. This is also confusing since many 45,X/46,XY individuals do NOT have mixed gonadal dysgenesis or ovotesticular tissue. Again, some have only typical male or female anatomy (some being fertile as such), and the XO cells are known to disappear during various stages of development. (7) Thus, predicting this type of “chromosomal DSD” in prenatal screening has been demonstrated to be hampered by a high rate of erroneous results, has provided unnecessary cause for alarm (by projecting birth defects which do not exist), has led to unwanted elective abortion, and is considered a serious problem in clinical genetics. (8)

Another problem is that the DSD proponents have misunderstood basic genetics (or intentionally distorted the information) and have assumed that XY chromosomes indicate that testicular tissue is expected. This assumption leads to another error in the new taxonomy because when gonadal dysgenesis is classified as a “46,XY DSD”, (see Table 2 in reference 1) DSD proponents refer to it (parenthetically) as "testicular dysgenesis". This is misleading and ambiguous because many individuals with 46,XY gonadal dysgenesis actually have OVARIAN dysgenesis. (9) It has been known for over 30 years now that in the presence of an unaltered Y chromosome, but in the absence of substances which would cause testicular differentiation and development, that ovaries start to form, not testicles. (reviewed in ref. 9). It is therefore deceptive to classify 46,XY gonadal dysgenesis as 46,XY testicular dysgenesis because testicular dysgenesis is the result on some occasions but at other times the result is ovarian dysgenesis. The type of treatment indications for dysgenetic testicular tissue may differ from that of dysgenetic ovarian tissue, and thus may unnecessarily confuse clinicians. Furthermore, the preeminence of chromosomes in this taxonomy is apparent and the idea that XY chromosomes somehow are the real “male” sex marker is the result of sexist genetics which produces more ambiguous medicine.

A basic problem with the DSD nomenclature is that it divides all the “disorders” into groups based on what are erroneously known as “sex chromosomes”. (10) This sexist interpretation of genetics, typical throughout this new nomenclature, leads to ambiguous medicine because there are individuals who have male anatomy only but have what appears to be XX chromosomes and are diagnosed as having a "46,XX DSD". Likewise, there are individuals who have female anatomy with what appears to be XY chromosomes and are diagnosed as having a "46,XY DSD". If these apparent XY individuals have a piece of the Y chromosome missing, (such as would include the SRY testis determining gene) they are still referred to as having a “46,XY DSD”, which is factually impossible since they are not XY, but X plus only part of the Y. Likewise, someone who is called XY (but in reality has an extra copy of an X chromosomal gene called DAX1) is also put in the category of having a "46,XY DSD", even though this is impossible, since they are not XY, but are instead X (PLUS another piece of an X)+Y. Likewise, individuals who appear to be XX, but are actually XX (PLUS the Y chromosome-specific SRY gene) are listed as having a "46,XX DSD" and a disorder of gonadal (ovarian) development, both of which are technically inaccurate. The fact that the DSD proponents (1) have put a note next to some conditions which indicates whether a deletion or addition of some X or Y chromosomal material exists, further demonstrates the inconsistency of their listing these conditions in the binary categories of “46,XY DSD” or “46, XX DSD” and not that of “chromosomal DSD.” In these regards, the DSD terminology is in violation of the principles and accepted diagnostic nomenclature used by clinical and molecular cytogeneticists. (11) Why didn't the DSD proponents put these in the "chromosomal DSD category"? One apparently needs an entire extra "sex chromosome" or to be lacking one, in order NOT to be put in the binary "EITHER XX or XY" category.

The DSD nomenclature is ambiguous and sexist in its understanding of genetics and it appears that this is necessary in order to preserve an "artificial binary". People who have portions of the X or Y chromosome missing or added are neither XX nor XY. The DSD system again here is flawed. Technically, CAIS individuals do not have a so-called "46,XY DSD" (even though the proponents state that they do) because the androgen receptor gene on the X chromosome is altered so that, in fact, they are only "X"Y. The androgen receptor is certainly involved in sex development. Thus if it is not there or is altered, it is ambiguous and misleading to call these individuals XY. It is equally ambiguous and misleading to call CAIS individuals “genetic males”. Yes, they have the SRY gene and a typical Y chromosome, but the X linked gene sequences for androgen "action" are not something that they "have". The same is true for an XY individual who has a female anatomy only, unaltered X and Y chromosomes, but an alteration on one of the many genes on one of the so-called "non sex chromosomes" (autosomes) which are certainly sex determining.

Sophia Siedlberg, Genetics Advisor to the Organisation Intersex International, came up with a polygenic model which explained the role of genes, not chromosomes, in sex determination. (12) This model has been misappropriated by others who don't know how to interpret it correctly. We can be quite sure, that barring an environmental cause (such as a teratogen), if we have an XY individual who does not appear to be a male, but instead appears female or intersex, that this person CANNOT be a “genetic male”, “chromosomally a male”, “genetically a male” and vice versa for individuals who have XX chromosomes. How do we know this? By the simple rule of basic genetics, that

GENES (+ environment) = PHENOTYPE (observable trait)

Thus, the DSD model based on "sex chromosomal" divisions has failed. By using the umbrella term “development”, it has also misapplied the knowledge base from the field of (sex) “differentiation” and conflated it with that of “development”. (13) It is ambiguous and sexist (in that it prescribes what sex one should be and not what sex one is and it perpetuates gender and sexist stereotypes based on chromosomes). It promotes confusion and oppression. It is NOT scientific. It simply uses scientific terminology in such a way that it confuses those who have little knowledge of genetics and biology. In so doing, it victimizes intersex people while offering “unlimited immunity" to medical and psychological professionals who continue FORCED sex assignments, FORCED sex reassignments, and FORCED gender expression expectations.

DSD makes the central health issue one’s sex

A second big problem with the DSD Consensus is that it largely ignores the health issues of intersexed individuals. With its emphasis on “sex” divisions based on chromosomes, they have persons with non-intersexed conditions like labial adhesions, cloacal exstrophy of the bladder and absent penis in an otherwise typical male, (or absence of a vagina in an otherwise typical female), mixed in with endocrine conditions, such as congenital adrenal hyperplasia, or mixed in with other organ system conditions, such as Smith-Lemli-Opitz Syndrome, and Turner's syndrome. These are then categorized as "sex development disorders", thus taking this "distant commonality" of one symptom, i.e., sex, and placing all of these disparate conditions as a disorder of one’s sex, while the predominant health issues become categorically "secondary" and likely to be ignored by clinicians.

DSD lacks clinical relevance

Even without considering the fact that the DSD Consensus largely ignores health issues, its taxonomy is in many cases irrelevant for the purposes of clinicians, especially those with subspecialties. An XX male with testes, a penis, and no female reproductive organs, who finds out at the age of 30 that his chromosomes are atypical after an infertility check, is in the same category as an otherwise typical female with ovaries and a uterus who has vaginal atresia. Both have a “46,XX DSD”. The same holds true for a male, typical in every way but with isolated hypospadias (classified as having a “46,XY DSD”), whose clinician finds that they have given their prior patient, an XY female with streak ovaries, uterus, and vagina who has given birth after embryo donation the same diagnostic classification of “46,XY DSD”. Again, ambiguous diagnoses lead to ambiguous treatment implications and vice versa. This is ambiguous medicine.

Gender conformity based on sexist genetics

With disorders of sex development, which sounds like “sexual development” (and can be confused with psychosexual development or psychosexual disorders), we now see a pathologizing of gender, gender identity, gender role, sexual orientation, and its ties to (re)assignment. People with a so-called DSD, especially in the binary XX or XY categories, are expected to conform in the above categories according to a binary gender expression, as indicated by the expectations of the DSD category, as well as the whim of the person who enforces the assignment or re-assignment. Those who reject such enforcement can be labeled mentally disordered, and treatment can be instituted or re-instituted at the whim of professionals, and this can be enforced legally.

DSD is about ambiguous medicine, sexist genetics, body control, and mind control. It certainly is not a client centered consensus statement. The fact that almost no intersex people had input into this consensus is glaringly evident.

In effect, we have moved from the “age of gonads” to the “age of chromosomes” even though it has been established that "sex chromosomes" as portrayed do not determine one’s sex. (10) This is based on prescriptive notions about genetics, not a descriptive understanding of the role of chromosomes in sex determination. Genes, not "sex chromosomes", determine sex, and most of the genes involved are not on the X and Y chromosomes. They are on the autosomes.

It appears to the authors of this article that the DSD nomenclature misinterprets genetics based on a sexist, binary male/female model and in so doing, it has erroneously pathologized and stigmatized intersex people in order to try to preserve the heterosexist male/female hierarchies that justify the oppression of many classes of people, not just those who are intersexed.

REFERENCES
1) Hughes, I.A. et al. Consensus statement on management of intersex disorders. J. Ped. Urol., 2006, 3:148-162.
2) DamianiI, D. & Guerra-Júnior, G. As novas definições e classificações dos estados intersexuais: o que o Consenso de Chicago contribui para o estado da arte? Arq Bras Endocrinol Metabol. 2007, 51: 013-7.
3) Gencik, A. et al. Chimerism 46,XX/46,XY in a phenotypic female. Hum. Genet., 1980, 55: 407-408.
4) Sudik, R. et al. Chimerism in a fertile woman with a 46,XY karyotype and female phenotype: Case Report. Hum. Rep., 2001, 16: 56-58.
5) Schoenle, E. et al. 46,XX/46,XY Chimerism in a Phenotypically Normal Man. Hum. Genet., 1983, 64: 86-89.
6) Ford, C.E. Mosaics and Chimaeras. British Med. Bull, 1969, 25:104-109.
7) Chang, H.J. et al. The phenotype of 45,X/46,XY mosaicism: an analysis of 92 prenatally diagnosed cases. Amer. J. Hum. Genet., 1990, 46: 156-167.
8) Robinson, A. et al. Prognosis of prenatally diagnosed children with sex chromosome aneuploidy. Am J. Med. Genet., 1992, 44: 365-368.
9) Wachtel S.S. & Simpson J.L. Sex Reversal in the Human. In Wachtel S.S. (Ed.) Molecular Genetics of Sex Determination., 1994, 287-309. Academic Press, Inc.
10) Italiano, M The Scientific Abuse of Genetics and Sex Classifications. Manuscript published July 17, 2008 © Organisation Intersex International.
11) Schaffer, L.G. & Tommerup, N. ISCN 2005: An International System for Human Cytogenetic Nomenclature (2005): Recommendations of the International Standing Committee on Human Cytogenetic Nomenclature., 2005. Karger, S.C. Publ.
12) Siedlberg, S. The Gender Genital Gene Genie. Manuscript published 2001.
13) Italiano, M. Some problems with the new terminology for intersex. Manuscript published July 13, 2008 © Organisation Intersex International.