Nikki Araguz and an Androgen Insensitivity Syndrome Diagnosis

Although many newspaper accounts have all but completely ignored the fact that Nikki Araguz was likely born with Androgen Insensitivity Syndrome (AIS), whether or not she was born with this genetic intersex condition could become an important, even essential, aspect of her defensive response to the probate lawsuit filed against her by Heather Delgado, her late husband's ex-wife, and Simona Longoria, her late husband's biological mother. Ample supporting and contextual evidence that Nikki Araguz was born with AIS has been presented in the media, with the possibility that historical medical records will follow later, along with DNA analysis to confirm what already seems apparent.

Some news articles have all but accused Nikki Araguz of faking or lying about her claim that she was born with Androgen Insensitivity Syndrome (AIS). Other news articles have simply ignored the topic, and instead contain language that goes out of its way to refer to Nikki Araguz in ways whose apparent intent is to negate and/or dismiss her femaleness, femininity, and womanhood. Such news articles employ specious characterizations such as "ex-man", "born a man", "born a boy", and so on, when such statements may in fact be medically and scientifically misleading, if not patently incorrect. Only during the interview Nikki Araguz gave the Houston PBS television station, was the topic of AIS considered in any detail, or given much legitimacy.

Unfortunately, few people seem to be aware of or understand what Androgen Insensitivity Syndrome is, or the profound implications the existence of such intersex conditions have on the very nature of mammalian sex/gender determination and boundaries. Current genetic science has revealed that sex/gender morphology involves far more than the simple matter of an ostensibly immutable XX or XY sex chromosome pair. Such inaccurate and misinformed notions form the flawed core of general public knowledge all the way from incompetent high school biology lesson plans to scientifically flawed appeals court rulings such as Littleton v. Prange, the appellate court ruling that may be central to the legal dispute against Nikki Araguz. What follows is an examination of Androgen Insensitivity Syndrome (AIS), why most people born with AIS are female for nearly all practical purposes, and how AIS may be important in the lawsuit against Nikki Araguz.

Briefly stated, Androgen Insensitivity Syndrome is a genetic condition in which the people born with it don't respond to testosterone or any other form of androgens. Many females with a 46XX sex chromosome configuration have this congenital condition, but may never notice it because the condition has little consequential impact on them. However, when a person with a 46XY chromosome configuration is born with this genetic immunity to the influence of testosterone and other androgens, the consequences can be profound, biologically and socially. In the most profound instances, such people are born with female genitalia and develop within female norms during puberty, with the exception that they cannot and do not menstruate because they do not possess a uterus or ovaries. They truly are women, females with a 46XY sex chromosome pair, although they are infertile. Until the mid-twentieth century, such women lived generally unremarkable female lives, with the exception that they could not bear children, although medical science did not understand why at the time. Only after twentieth century medical science began to develop sophisticated non-invasive diagnostic technologies, and the ability to analyze the human genome, did geneticists discover that these women have a 46XY sex chromosome pair. The medical literature documents that, historically, very few of these women were ever told of the precise cause for their inability to menstruate and procreate. It has only been a few decades since most such patients have become better informed about the true nature of their condition. In fact, DNA analysis only became sophisticated enough in the late 1980s, to enable genetic researchers to pinpoint the true genetic nature of AIS.

Before human genome analysis revealed the precise cause of AIS, the medical terms used to describe it were extremely unflattering, potentially misleading, downright insensitive, lacking in perspicuity, and are not worth repeating. Even recently however, television portrayals of AIS, have been strikingly insensitive, such as in the February 20, 2006 episode of the FOX television network series  House, MD, in which the insensitive writers had the fictional protagonist Gregory House, MD, an insensitive character anyway, state with completely inconsiderate tactlessness and cruelty that, "the ultimate woman...is a man", in reference to his teenage supermodel patient who they discover was born with AIS, when in fact it is entirely misleading and unrepresentative to refer to women born with complete AIS as "men" or "male". Furthermore, the medical scenario presented in the television program is highly improbable if not entirely unrealistic, perpetuating the myth created decades ago that women with AIS get gonadal cancer, which physicians routinely employed to persuade such patients to have gonad removal surgery. The fictional story was inadequately researched by its writers and the show's producers. The episode also included a sub plot that revealed the patient's father had committed incest with his AIS daughter. Even the wikipedia.org article about this fiction House, MD episode repeats the deprecated, antiquated, and outmoded,  use of the term male pseudohermaphroditism to refer to the general category of intersex conditions that involve people with some form of genetic configuration which includes a Y sex chromosome. The sort of fictional exploration of AIS presented by this television program all too often has significant influence upon the factual impressions the general public develops about such topics.

In a yet more recent fictional television episode, from an NBC television series called Mercy, which aired November 18, 2009, an even greater disservice was done to public education when that program incorrectly portrayed AIS as a condition in which the character involved, a beautiful teenage girl cheerleader hospitalized for a kidney infection, with an outwardly normal female appearance, but with ambiguous genitalia that included a vagina, but with an enlarged penis like clitoris the physicians predicted would become more male over time without surgical intervention. The episode was medically incorrect and misleading because people with AIS don't respond to testosterone. In fact Nikki Araguz exhibits a more classic representation of AIS, in which the opposite occurs. Her genitals could not develop because her body doesn't respond to testosterone. Consequently the rest of her body developed during puberty into an otherwise normal looking female human being by the age of eighteen, except for her undeveloped ambiguous genitalia. Consequently, it isn't likely that the undescended and usually nondescript gonads in a woman with AIS would descend completely to become a scrotum with testes, as the above episode of Mercy incorrectly implied. It is no wonder that the general public has developed hostile and antagonist attitudes toward people with intersex traits, after such television programs use negative social engineering techniques to instill bigotry in the minds of average people. One redeeming aspect of this episode of Mercy, was its portrayal of the AIS patient's ultimate medical treatment, which was to leave her alone, so that she could take her own time to consider the profound implications of her congenital condition, to determine for herself how she wanted to deal with it.

Before getting any more deeply into the practical and sociological consequences of Androgen Insensitivity Syndrome and other intersex conditions, a more detailed explanation of AIS seems in order. As stated previously, people born with AIS don't respond to androgens, such as: testosterone, dihydrotestosterone  (DHT), and other related hormones. In 1989 the precise gene that provides this response, the androgen receptor gene (AR gene), was discovered as part of the broad scientific effort to map and understand the entire human genome. What may surprise the average person is that the ability to respond to androgens is carried on the X chromosome. In fact, a significant amount of the genetic information that supports so called male features exist on the X chromosome, not the Y chromosome. Women with AIS who are born with a 46XX sex chromosome pair, generally don't notice that they have the condition. In such women, the symptoms are often very minor, such as having only sparse pubic hair and sparse axial hair development. However, they are carriers who can pass on this genetic condition to their offspring who have a 46XY sex chromosome pair. When the androgen insensitivity is profound, and occurs in someone with a 46XY sex chromosome pair, the resulting offspring most often appear to be normal females at birth. Their genetic and hormonal condition usually isn't discovered until their late teens, after they have failed to develop a menstrual cycle. Other individuals with AIS may be born with what appear to be underdeveloped male genitalia, but whose genitalia fail to grow and develop during childhood, and who then feminize during puberty, often profoundly, because they have little or no response to androgens. Nikki Araguz appears to be a woman for whom AIS has exhibited this second set of physiological and morphological characteristics. By age nineteen, her outward appearance was that any other female her age, although she apparently possessed rudimentary and underdeveloped male seeming genitals. Specific medical details about the condition of her reproductive organs at the time in here life have not yet been publicly revealed.

androgen receptor gene on X sex chromosome (3)

Meanwhile, the genetic basis for Androgen Insensitivity Syndrome is now well understood. With each passing year, additional details about AIS have been discovered as new AIS patients present themselves to medical professionals, and their genomes have been studied in detail. The root cause of Androgen Insensitivity Syndrome was discovered in 1989, when geneticist Celeste J. Brown, Ph.D., and colleagues, discovered the androgen receptor gene (AR gene) and subsequently described it in various medical journals (2). The AR gene exists at the location Xq11-12 on the X sex chromosome. Its features are encoded on eight exons within the AR gene (see illustration above). Androgen insensitivity appears in various forms from profound to mild, based on whether defects occur in all, or sometimes just one or more, of the exons within the AR gene. The various types of AIS gene defects include: single location mutations involving substitution of the wrong amino acid or insertion of a genetic stop marker in the DNA sequence where the AR gene should be; insertion or deletion of nucleotides  that cause a position shift of one or more genes within the X chromosome; complete or partial deletions of the AR gene; and mutations that involve various forms of gene splices within the X chromosome. More than 400 different AR gene mutations have been discovered thus far, and more are discovered as genomes of newly discovered AIS patients are analyzed (3). What these AR gene defects demonstrate, is that development of a fully functional male phenotype (physical body morphology) requires not just a functional Y chromosome but also a functional AR gene on the X chromosome, other X chromosome linked genetic features, and appropriate hormonal conditions during gestation. When the AR gene on the X chromosome is completely defective, called Complete Androgen Insensitivity Syndrome (cAIS), the person with the AR gene defect is born with a female phenotype (female physical body morphology), despite having a 46XY sex chromosome genotype. Complete Androgen Insensitivity Syndrome is just one of many examples which prove that physical sex/gender determination is far more involved than a mere matter of having an XX or XY sex chromosome pair, one of the faulty notions on which the Littleton v. Prange court ruling, and similar rulings in other jurisdictions, are based.

[a] Untreated adult woman with pAIS
and ambiguous genitalia

People born with what is characterized as complete Androgen Insensitivity Syndrome (cAIS), have one of various genetic defect types that affect the entire AR gene, rendering them profoundly incapable of processing androgens. The cells throughout their bodies simply do not contain working androgen receptors. For all practical purposes, these people are females, with female body types, except for the absence of functional ovaries and a uterus. They are invariably declared female at birth and are given female birth certificates. If they have a 46XY sex chromosome pair, that is usually only discovered during puberty, and only because of recent advances in medical diagnostic technology. It has only been possible for scientists to make such genetic determinations since the advent of DNA analysis. People born with less profound forms of AIS, called partial Androgen Insensitivity Syndrome (pAIS), usually have one or more working exons within the AR gene. Because there are multiple ways in which a gene can become defective, and because the various ways in which the defects are caused and may effect only some if not all of the exons, the correlation between specific AR gene defects and their morphological consequences in the people with them are still being cataloged by geneticists, although many have already been enumerated. The clinical photo [a] just above, illustrates an example of a woman born with pAIS, an overall female body type, and ambiguous genitalia.

[b] newborn with
ambiguous genitalia

It should be clarified that a direct correlation between defects in all eight exons within the AR gene and development of female genitalia does not appear to have been established. Nor has the reverse condition, where someone with a completely defective AR gene may have developed rudimentary male genitalia during gestation, despite having a complete inability to respond to androgens. However, most people with partial AIS and a 46XY sex chromosome pair appear to develop male genitalia at least to some degree, while most people with complete AIS seem to develop female genitalia in nearly all cases. In other words, it is possible that Nikki Araguz could have a completely inoperable AR gene, where none of the eight exons are functional, and yet she still developed some level of male genitalia during gestation. Such a combination seems likely to also account for her profound level of secondary female development during puberty, with regard to pelvic widening and breast development during puberty, lack of facial bone bossing, lack of body hair other than head hair, and so on. There is every possibility that by the time Nikki Araguz reached adulthood, her body looked similar to the example in the clinical photograph [a] above.

It should also be noted that the scientific, social, and political, dynamics that AIS and similar genetic conditions represent have been largely kept underground by the medical and scientific professions until recent decades. It has taken significant pressure from people born with intersex conditions, including AIS, to change the practices, behaviors, and apparent beliefs, of many medical professionals about how to manage intersex patients. A significant portion of the medical profession continues to be resistant to fully informing and involving many intersex patients in their own treatment. The medical profession also continues to under report the prevalence of intersex conditions, including AIS, while independent sources have developed prevalence statistics that may be as high as 1:5,000 (5). The history of the medical profession's treatment of intersex patients has been dominated by their lying to such patients, performing surgeries on them without any reasonable level of informed consent, treating them and studying them like lab rats, and making profound decisions about the lives of intersex infants, many of whom experience extreme indignation and humiliation when they discover the truth later in their lives. Throughout the 1960s, 1970s, and 1980s, there are hundreds of documented cases in which surgeons lied to their AIS patients, telling them that their gonads could become cancerous, in order to persuade them that they should be removed, with the physician's hope that doing so would help such patients confirm their female identities. The perpetuation of this mythology has become so prevalent that many recent generation physicians continue to believe it, without any reasonable statistics to support the incidence of such malignancies! These are cases of what may have seemed like good intentions many decades ago, but intentions many people now believe had gone extremely ethically and medically wrong. Such surgeries are the intersex equivalent of prophylactic mastectomy for women who have the BRCA1 breast cancer gene, although performed without informed consent or adequate evidence of actual risk.

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If Nikki Araguz and her attorneys believe it helps their case to prove that she was born with AIS, they can have a medical specialist perform appropriate DNA analysis, including a detailed mapping of her X sex chromosomes(s) and specifically the AR gene within it or them. Such DNA analysis can irrefutably determine what mutations if any exist within Nikki's AR gene, and the likely physiological and morphological consequences associated with those genetic mutations. Such a diagnostic confirmation would clearly differentiate the nature of her case from the arguments made by justice Phil Hardberger in his Littleon v. Prange ruling. The attorneys representing Nikki Araguz would have a strong basis for claiming that Nikki's original birth certificate was a medical error, and that there is a reasonable medical basis for both the mistake and for changing it to provide a female classification on her birth certificate, notwithstanding California law regarding provision of a new, changed, birth certificate after genital reconstruction surgery.

Although genetic analysis can irrefutably determine whether or not Nikki Araguz was born with Androgen Insensitivity Syndrome, secondary evidence has already appeared in media reports that support her claim. As a first example, Nikki's mother, Sheri Bockelman, has reported that two of her five sisters were born with a genetic abnormality that causes uterus didelphys. According to Sheri Bockelman, her sisters who have uterus didelphys, were each born with a double uterus and only one kidney (6). This could be evidence of a correlation between the X chromosome gene defect that causes uterus didelphys, and the X chromosome gene defect that damages the X sex chromosome and causes Androgen Insensitivity Syndrome. If such a correlation exists, Sheri Bockelman may also be an AIS carrier and not know it, which would be further supporting evidence that could be confirmed with DNA analysis of Sheri Bockelman's sex chromosomes to determine if she is an AIS carrier.

Nikki Araguz - at age nineteen

A second example of evidence supporting Nikki Araguz's claim that she has AIS, is the video documentary made of Nikki Araguz when she was about age nineteen, during her college years. The video provides dramatic evidence that her body had already developed into an outwardly normal appearing female one by then, apparently without exogenous hormonal intervention. In support of the AIS diagnosis, Nikki Araguz's facial features then, and now, do not show any evidence of being affected by testosterone. When working androgen receptors in the facial bones are stimulated with testosterone, they produce the classic square male jaw, taller chin, forehead bossing, nasal cartilage growth, and other features associated with male faces, featured that are the product primarily of hormonal stimulation, rather than purely genetic encoding. Since androgen receptors in the cells throughout the bodies of people with AIS do not respond to androgens, they can never develop such male facial characteristics. Parenthetically, such hormonal responses are not dependent on the existence of a Y sex chromosome. In all humans with a normal AR gene, cells throughout the human body are capable of responding to both estrogens and androgens, which is what makes hormone therapy for transsexual people possible, causing masculinization in transsexual men and feminization in transsexual women.

Medical records should certainly provide a third source of evidence to support Nikki Araguz's claim of being born with AIS. Even if historical medical records from Nikki Araguz's childhood have long since been lost, it seems likely that the surgeon who performed genital reconstruction surgery on Nikki Araguz, Marci Bowers, MD, took photographs of Nikki's external genitalia before surgery, and documented the contents of Nikki's abdominal cavity in her surgical notes. In addition, if Nikki's congenital genitalia were indeed underdeveloped, she would likely have needed a full-thickness skin graft as part of the vaginoplasty surgery she received, which is usually taken from the location where a tummy tuck procedure would be performed, would have been documented by Dr. Bowers in her surgery notes, and Nikki Araguz would have the resulting horizontal scar across her lower abdomen left behind as proof. It seems likely that Dr. Bowers might be called upon to testify, about her direct observations during her surgery on Nikki Araguz, and as an expert witness about intersex conditions and surgery for them.

Nikki Araguz
when the lawsuit began

It seems predictable that both sides of the lawsuit against Nikki Araguz will seek to obtain DNA evidence to confirm whether or not Nikki has Androgen Insensitivity Syndrome and to determine the configuration of her sex chromosomes generally. There is a small chance that Nikki Araguz may have a sex chromosome configuration other than 46XY. It is even possible that she could have some form of sex chromosome mosaic, such as 47XXY. It would seem irresponsible for a competent Texas court of law to make a ruling based on Littleton v. Prange, without having DNA evidence about the sex chromosome configuration of both Thomas and Nikki Araguz before it. If the attorneys representing Nikki Araguz obtain DNA evidence that confirms her Androgen Insensitivity Syndrome diagnosis, observers should expect Nikki's attorneys to try to also obtain expert testimony from a geneticist like Celeste J. Brown, Ph.D, who is surely an expert in Androgen Insensitivity Syndrome, to testify about the condition, about its manifestation in Nikki Araguz, and about its implications with regard to a pragmatic sex designation for Nikki Araguz. Armed with appropriate evidence, the attorneys representing Nikki Araguz should be expected to argue that issuance of a second, female, California birth certificate to Nikki Araguz was correction of a genetically supported medical sex designation error at the time of her birth, rather than a modification as a consequence of the surgical gender reassignment of a transsexual woman. Such an argument would differentiate it from the conclusions reached in the Littleton v. Prange case, and possibly render Littleton v. Prange irrelevant to Nikki's case.

Only detailed DNA analysis can determine whether some or any of the eight exons within Nikki Araguz's AR gene are functional. However, both Nikki Araguz and her mother, Sheri Bockelman, have described the genitalia she had at birth as underdeveloped. Both of them have also reported that her genitalia failed to develop further, as male genitalia would during childhood and puberty, in response to endogenous, systemic androgens. In addition, Nikki Araguz's apparent inability to respond to androgens seems readily apparent in both historical and contemporaneous photographs and video of her. During the late 1970s and early 1980s, despite her persistence, Sheri Bockelman was unable to get the attention of medical professionals in Texas about her child's congenital condition.

Even if DNA tests confirm that Nikki Araguz was born with Androgen Insensitivity Syndrome, her attorneys seem likely to have an uphill legal battle, especially because of the judicial composition of Texas courts. Nikki Araguz's attorneys also seem likely to have an uphill battle because the fact pattern supporting Nikki's defense case includes facts which her adversaries seem likely to argue against as vulnerabilities pursuant to Littleton v. Prange. However, the attorneys representing Nikki Araguz could argue that her case should be distinguished from the Littleton v. Prange ruling if the diagnosis that she was born with AIS is confirmed. It also seems likely that the attorneys who represent Nikki Araguz will need to attack various aspects of Littleton v. Prange directly anyway, using scientific expert witness testimony and supporting medical evidence to make a case that the Littleton ruling should not and does not apply to Nikki, even if it might apply to other people. Surely, having a woman with a medical history of AIS before the courts in Texas presents cogent and convincing evidence that Littleton v. Prange is an unworkable and illogical ruling. If successful though, such an approach could also lead to a judicial ruling that might possibly make the result of the case inapplicable to the Texas transsexual population generally as well.

In addition, if the courts in Texas are asked by Nikki Araguz's attorneys to consider the 2009 statutory change to Texas marriage law (6) in order to make a determination about her case, even when considered in a most favorable light, that statutory change may be considered ambiguous by the court, and open to multiple interpretations. Given the language of the 2009 Texas marriage statute modification, it isn't clear how a diagnosis of AIS might help Nikki Araguz in any regard, since the statutory change regards court documentation of  "change of sex" as valid identification for a marriage license, while an AIS diagnosis would provide the basis for an argument that Nikki Araguz was not "changing sex", but was instead being surgically assigned a sex from a state of congenital, genetic, and morphological sex/gender ambiguity. It doesn't seem likely that a court of law would accept such contradictory arguments. Despite this, attorney Darrell Steidley, who represents Nikki Araguz, has filed a Motion to Dismiss, on the basis that the 2009 marriage statute renders Nikki's marriage to Thomas Araguz legal and valid as of September 2, 2009, as an informal marriage. Given the foregoing, if DNA analysis confirms Nikki Araguz's Androgen Insensitivity Syndrome diagnosis, such a diagnosis adds complexities to her case that may enable she and her attorneys to succeed, but which could also make the related sociopolitical crusade desired by some segments of the transsexual and intersex populations less then relevant to it.

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references

(1) Dihydrotestosterone
http://en.wikipedia.org/wiki/Dihydrotestosterone

(2) Brown CJ, Goss SJ, Lubahn DB, et al, 1989 Androgen receptor locus on the human X chromosome: regional localization to Xq11-12 and description of a DNA polymorphism. Am J Hum Genet 44: 264-269.

(3) Androgen insensitivity syndrome: clinical features and molecular defects; Angeliki Galani, Sophia Kitsiou-Tzeli, Christalena Sofokleous, Emmanuel Kanavakis, Ariadni Kalpini-Mavrou

http://hormones.gr/preview.php?c_id=227

An additional article about Androgen Insensitivity Syndrome but with extremely low prevalence statistics:

http://www.naspag.org/articles/JPediatrAdolescGynecolv21p305-310.pdf

(4) An extended survey of numerous intersex conditions involving people with a 46XY sex chromosome pair

http://www.endotext.org/pediatrics/pediatrics11/pediatricsframe11.htm

(5)  ... data suggest an androgen insensitivity syndrome incidence of approximately 1 case per 20,400. This statistic is based on analysis of a Danish patient registry that included only hospitalized cases; thus, the true incidence of androgen insensitivity syndrome may be higher.

http://emedicine.medscape.com/article/924996-overview

(6) Texas Family Law Code: Title 1, Subtitle A, Chapter 2, Subchapter A, Section 2.005, Paragraph (b)(8)

Texas Family Law Code: Title 1, Subtitle A, Chapter 2, Subchapter A, Section 2.005, Paragraph (b)(8)