Prevalence of Intersex/Differences in Sex Development and Primary Gonadal Insufficiency in a Pediatric Transgender Population

Abstract

Purpose:

This study aims to assess the prevalence of intersex variations/differences in sex development (I/DSDs), associated adrenal conditions, and primary gonadal insufficiency in children with gender dysphoria.

Methods:

We performed a comprehensive review of the medical records for individuals who carried the diagnostic codes for gender dysphoria in addition to intersex and/or other conditions associated with sex steroid variations among patients evaluated by pediatric endocrinologists from 2013 to 2022.

Results:

We found that 9 of 612 (1.5%) transmasculine (TM) and 4 of 215 (1.9%) transfeminine patients had detectable I/DSDs. Although most patients were diagnosed with I/DSDs before evaluation of gender dysphoria, 4 of 13 (30.7%) were diagnosed with I/DSDs after being referred to endocrinology for gender dysphoria. In all cases, diagnoses were made by the endocrinologists evaluating for gender dysphoria. An additional 0.7% of TM patients were diagnosed with distinct hyperandrogenic adrenal conditions, and 1% of TM patients were diagnosed with primary ovarian insufficiency.

Conclusion:

The low, but clinically relevant, prevalence of I/DSDs, distinct adrenal conditions, and primary gonadal insufficiency in this transgender population supports the need for access to individualized expert medical care. Specifically, multidisciplinary clinics with experience in endocrinology may provide specialized support for the transgender community.

Introduction

Numerous studies demonstrate that individuals with intersex variations/differences in sex development (I/DSDs) display a higher rate of gender dysphoria compared with the general population.^1,2 Rates of gender dysphoria can be as high as 54% in certain androgen synthesis defects.³ Recent multicenter studies show that the overall rate of gender dysphoria in patients with I/DSDs is ∼8.5–15%.^1,3 Conversely, the rate of I/DSDs in patients with gender dysphoria is less well studied.

The previous version of the World Professional Association for Transgender Health's Standards of Care states that “adults with a DSD and gender dysphoria have increasingly come to the attention of health professionals.”⁴ Several studies have reported high rate of polycystic ovary syndrome (PCOS) in adult transgender male individuals.^5–7 (Those assigned female at birth but identify as male, masculine, or transgender male are hereafter referred to as transmasculine [TM]. Those who are assigned male at birth and identify as female, feminine, or transgender female are hereafter referred to as trans feminine [TF].) Another study reported a high rate of hyperandrogenism and mild congenital adrenal hyperplasia (CAH) in adult TM individuals.⁸ Beyond these studies, limited to two androgenic conditions, little is known about the prevalence of I/DSDs in transgender patients.

The lack of data on I/DSDs in transgender individuals may relate in part to revisions to the Diagnostic and Statistical Manual of Mental Disorders (DSM) published by the American Psychiatric Association. Before the fifth edition of the DSM in 2013, the diagnosis of “gender identity disorder” specifically excluded those individuals with I/DSDs,⁹ so these individuals would have been characterized separately from the transgender population. Furthermore, the 2017 Endocrine Society Guidelines for Treatment of Gender Dysphoric/Gender Incongruent Persons make no specific recommendations for baseline hormonal testing or for ruling out I/DSDs. They do recommend ruling out conditions that would be exacerbated by gender-affirming therapies.¹⁰

We performed a systematic chart review to determine the prevalence of I/DSDs (including any congenital differences in sex chromosomes, anatomy, and hormone production, such as CAH) and other acquired conditions associated with sex steroid variations (such as PCOS, hypogonadism, and adrenal tumors) in our large pediatric population of transgender patients. Recognition of DSDs, primary ovarian insufficiency (POI), and related endocrine diagnoses in this population is clinically relevant, as certain conditions (e.g., adrenal tumors and CAH) are high risk and their symptoms could be masked by masculinizing therapies. People with I/DSDs and POI have long-term medical, psychological, and reproductive needs and require specialized care as they age.¹¹

Materials and Methods

Participants

This is a single-center retrospective cohort study. Institutional Review Board (IRB) approval (IRB No,. 15080356) was obtained to maintain a data repository for all patients with the diagnosis of gender dysphoria or gender diversity and a separate repository for all patients with I/DSD to be used for secondary retrospective analysis. The study was limited to transgender patients seen in person in our academic medical center between 2013 and 2022 from a referral area of 12 states. Patient consent was waived for this study.

Our endocrinology team runs a multidisciplinary gender clinic for transgender patients (including endocrinology, adolescent medicine, psychology, social work, nursing, and chaplaincy). Patients were referred to gender clinic after receiving the diagnosis of transgender by mental health professionals. We routinely sought histories of genital ambiguity in our transgender clinic. Our team also runs a multidisciplinary clinic for patients with I/DSD (includes gynecology, genetics, urology, psychology, and endocrinology). We screened all patients in I/DSD clinic for gender dysphoria and administered gender identity and gender behavior surveys to patients and parents as part of routine follow-up visits. We identified patients who appeared in both repositories.

In addition, we requested a list from information technology of all patients assigned the diagnosis of gender dysphoria concomitant with I/DSDs, gonadal insufficiency, and adrenal tumors, using the International Classification of Diseases, 10th Revision (ICD-10)¹² and the ICD-9¹³ diagnostic codes listed in Table 1. As an additional screen for gonadal insufficiency of any cause, we requested a list of all transgender patients who had LH/FSH and sex steroid levels drawn.

Table 1.

Diagnostic codes for patient identification

Condition	ICD-9 codes	Diagnoses	ICD-10 codes	Diagnoses
Gender dysphoria	302.5	Transsexualism	F64	Gender identity disorder
	302.6	Gender identity disorder in children	F64.2	Gender identity disorder of childhood
	302.85	Gender identity disorder in adolescents or adults	F64.8	Other gender identity disorder
			F64.9	Gender identity disorder, unspecified
DSD	255.2	Adrenogenital disorders	E25.0–E25.8	Adrenogenital disorders
	259.51–259.52	Androgen insensitivity	E34.51–E34.52	Androgen insensitivity
	752–752.69	Congenital anomalies of genital organs	Q50–Q56	Congenital malformations of genital organs
	752.7	Indeterminate sex pseudohermaphroditism	Q56.4	Indeterminate sex
	752.49	Cervix/vagina/female congenital anomalies	Q51.9	Congenital malformations of uterus/cervix, unspecified
	752.5–752.52	Undescended testicle	Q53.9	Undescended testicle
	752.61	Hypospadias	Q54.9	Hypospadias
	758.81	Sex chromosome abnormalities	Q97.0-Q98.9	Sex chromosome abnormalities
POI	256.3–256.39	Ovarian dysfunction	E28.3	Primary ovarian insufficiency
Adrenal tumors	194.0	Malignant adrenal neoplasm	C74.9	Malignant adrenal neoplasm
	227.0	Benign	D44.1	Neoplasm of adrenal gland
		Adrenal neoplasm	E27.8.	Other disorders of adrenal gland

DSD, difference in sex development; ICD-9 and ICD-10, International Classification of Diseases, versions 9 and 10; POI, primary ovarian insufficiency.

Primary gonadal insufficiency

Gonadotropins were frequently obtained to assess pubertal status or pubertal suppression and rarely in the case of suspected gonadal insufficiency. Primary gonadal insufficiency was diagnosed when gonadotropins were markedly elevated on at least two occasions associated with low sex hormone levels.

Hormonal analysis

Dehydroepiandrosterone (DHEA), 17-hydroxyprogesterone (17-OHP), plasma renin activity (PRA), and testosterone were obtained when the endocrinologist suspected high androgen levels based on examination or history. These levels assist in identifying those with adrenal pathology as the cause of hyperandrogenism. Hormone levels were measured by liquid chromatography tandem mass spectrometry. DHEA sulfate (DHEA-S), LH, and FSH were measured by immunoassay using a Siemens Immulite analyzer (Munich, Germany). The intra-assay and interassay coefficients of variation were <4% and <6%, respectively. As hormone levels vary with age, we compared the numbers of patients above the upper limits of the reference range for each test.

Adrenocorticotrophic hormone stimulation testing

A total of 23 TM patients underwent standard high-dose adrenocorticotropic hormone (ACTH) stimulation testing when CAH was suspected clinically (based on screening labs, advanced bone age, mineralocorticoid deficiency). High-dose ACTH (250 μg) was administered intravenously and a panel of cortisol precursors was measured at 0, 30 and 60 min.

Genetic testing

Cytogenetics and microarray analysis

All I/DSD clinic patients with true I/DSDs (rather than an acquired condition) and a total of 145 transgender patients underwent conventional G-banded chromosome analysis and/or florescent in situ hybridization (FISH) performed by the Children's Mercy Hospital Cytogenetic Laboratory for clinical care purposes. Reasons for genotyping transgender patients included short stature, primary or secondary amenorrhea, genital atypia, or unexplained hyperandrogenism. A minimum of 20 metaphase cells were analyzed. FISH studies used 200 cells and were performed primarily on interphase cells, using DNA probes (Abbott Laboratories, Des Plaines, IL) according to manufacturer protocol. FISH analysis and image capture were performed using Isis FISH Imaging System v5.3 software (MetaSystems, North Royalton, OH).

A total of six patients underwent standard genome-wide oligonucleotide microarray using Agilent 4×180K comparative genomic hybridization (CGH) and CGH + single nucleotide polymorphism designs (Agilent, Inc., Santa Clara, CA) for clinical care purposes. Probes (∼136,000) for the CGH design were evenly distributed across the rest of the genome with an average spacing of one probe per 25 kb. The microarray had an average genomic resolution of 135–200 kb and an enhanced 5–10 kb resolution. Microarray experiments and analyses were performed according to the manufacturer's recommendations.

Targeted gene sequencing for CYP21A2

A total of 16 TM patients underwent genetic testing for the CYP21A2 carrier state on a research basis after previous testing revealed abnormal screening or ACTH stimulation tests for CAH, advanced bone ages, or mineralocorticoid deficiency. DNA was isolated and purified. Genetic analysis for common mutations in the gene encoding the 21-hydroxylase enzyme (CYP21A2) was performed by polymerase chain reaction (PCR). Four different PCRs were performed to analyze the CYP21A2 gene, its pseudogene, and various recombinant forms of those genes. The common CAH mutations tested included c.92C>T, c.293-13C>G, c.332-339del8, c.518T>A, c.710T>A, c.713T>A, c.719T>A, c.884G>T, c.923dupT, c.995C>T, c.1069C>T, and c.1360C>T.

If common variant testing was negative, testing progressed to next-generation gene sequencing of the CYP21A2 gene. In this assay, sheared genomic DNA fragments representing the entire coding region and the splice junction sites of the CYP21A2 gene (NM000700.7) were selectively enriched through exon capture and then subjected to nucleotide sequence analysis of a massively parallel sequence platform to detect the presence of gene duplication, CYP21A2/CYP21A1P gene duplication, 30 kb deletion, and CYP21A2/CYP21A1P gene conversion. Long-range PCR was performed concurrently with the exon capture and included in the sequence analysis.

Whole genome sequencing

One patient's variant was identified by whole genome sequencing under a separate research protocol (IRB No. 11120514), as previously described.¹⁴ The pathogenic variant was clinically confirmed with Sanger sequencing using Clinical Laboratory protocols.

Statistical analysis

Javascript functions were used to calculate 95% confidence intervals (CIs) for the prevalence of I/DSDs in the transgender population.

Results

Racial and ethnic characteristics of the patient populations

Race was reported by adult patients. Children's race and ethnicity were reported by their parents. Race was categorized as White, Black, Asian, Indigenous American, Multiracial, or Other. Ethnicity was reported as Hispanic or non-Hispanic. Results are given in Table 2.

Table 2.

Racial and ethnic characteristics of the patient populations

Number of patients
TM	612
TF	215
Total	827
Age range, years	3.8–24
Race
White	767
Black	19
Asian	14
Indigenous American	3
Multiracial	19
Other	5
Ethnicity
Hispanic	37
Non-Hispanic	790

TF, transfeminine; TM, transmasculine.

We identified 827 individual patients who underwent evaluation in our pediatric endocrinology clinics between 2013 and 2022. Ages ranged from 3.6 to 21 years at the initial visit. Of those, 612 were TM and 215 were TF.

Intersex variations/difference in sex development

Thirteen of 827 (1.6%) (patients 1–13; Table 3) of all transgender patients had evidence for I/DSDs (95% CI, 0.8–2.7; Table 3). By gender, 9 of 612 TM (1.6%; 95% CI, 0.7–2.8) and 4 of 215 TF (1.9%; 95% CI 0.5–4.7) had I/DSDs.

Table 3.

Transgender patients with differences of sex development

Pt No.	Age presenting with gender dysphoria, years	Gender	Ethnicity	DSD	Presenting signs of DSD	Age of identification of DSD	DSD definitive diagnostic method
1	19.1	TM	C	MRKH	Primary amenorrhea	19.1 years	Gynecologic exam
2	14.5	TM	C	Swyer syndrome	Edema of dorsum of feet	2 weeks of age	Karyotype and microarray
3	17.2	TM	C	Sex chromosome mosaicism	Nuchal thickness on prenatal ultrasound	Birth	Karyotype
4	16.8	TM	C	Turner syndrome	Coarctation of the aorta	Birth	Karyotype
5	12.1	TM	C	CAH (CYP21A2 mutation) c.290-13C>G (Intron 2 G variant) homozygous or deletion on second allele	Ambiguous genitalia	Birth	Hormonal testing
6	20.5	TM	C	CAH testing before EMR	Ambiguous genitalia	Birth	Hormonal testing
7	9.3	TM		PPP1R12A variant c.2152C>T	Ambiguous genitalia	Birth	Whole genome sequencing
8	15.8	TM	C	Clitoromegaly Adrenal carcinoma and CAH ruled out	Clitoromegaly	15.8 years	Physical exam
9	17.8	TM	C	Clitoromegaly Adrenal carcinoma and CAH ruled out	Clitoromegaly, recurrent dehydration	17.8 years	Physical exam
10	8.2	TF	C	VACTERL	Ambiguous genitalia	Birth	Physical exam
11	9.2	TF	C	Duplication 6q16.2q16.3 380,615	Ambiguous genitalia Undescended testes Hypospadias	Birth	Physical exam karyotype and microarray
12	9.1	TF	C	BUDT	BUDT	9.1 years	Physical exam
13	10.5	TF	C	BUDT	BUDT	Birth	Physical exam

BUDT, bilateral undescended testes; C, Caucasian; CAH, congenital adrenal hyperplasia; DHEA, dehydroepiandrosterone; EMR, electronic medical record; MRKH, Mayer–Rokitansky–Küster–Hauser syndrome; VACTERL, vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, limb anomalies.

As for the timing of diagnosis, 8 of 13 (47%) were identified as having I/DSDs based on genital atypia at birth. An additional patient (patient 2; Table 3) was diagnosed with Swyer syndrome in the neonatal period. The remaining four patients (30.7%) were not known to have I/DSDs until undergoing endocrine evaluation for gender dysphoria (Table 3). Their mean age of diagnosis was 16.3 years. One patient (patient 1) was diagnosed at 19 years with Mayer–Rokitansky-Küster–Hauser (MRKH) syndrome after being referred from endocrinology to gynecology. Two patients (patients 8 and 9) were noted to have clitoromegaly, and one patient (patient 12) was noted to have bilateral undescended testes by physical examination at the initial endocrine visit.

Sex chromosome variants

Three of 145 (2%) patients who underwent karyotypes had sex chromosome variants: one had Swyer syndrome, one Turner syndrome mosaicism, and one Turner syndrome (patients 2, 3, and 4, respectively; Table 3).

Adrenal hyperandrogenism

Four additional patients were found to have discrete conditions associated with adrenal androgen excess. One patient (patient 14; Table 4) was found to have an adrenal tumor of uncertain etiology after being found to have a high level of DHEA-S during endocrine evaluation. Pheochromocytoma and neuroblastoma have been ruled out. He is being monitored with serial imaging studies.

Table 4.

Transgender patients with conditions of androgen excess

Pt No.	Age presenting with gender dysphoria, years	Gender	Ethnicity	Androgen excess condition	Presenting signs of androgen excess	Age of identification of androgen excess	Androgen excess definitive diagnostic method
14	16.7	TM	Multi	Adrenal nodule	DHEA-S >600	18.3	Adrenal imaging
15	16.8	TM	C	CAH CYP21A2 Exon 6 cluster variants c.710T>A c.713T>A c.719T>A and c.844G>T	Facial acne, irregular menses, salt cravings Elevated PRA	16.8 years	Hormonal testing
16	15.8	TM	C	CAH Carrier with salt loss c.1069C>T (R356W variant)	DHEA >1000 ng/dL and elevated PRA Prolonged QT syndrome	15.8 years	Hormonal testing Targeted gene sequencing
17	13.8	TM	C	CAH carrier c.293-13 C>G (Intron 2G variant)	DHEA >1000 Elevated PRA	18.1	Hormonal testing Targeted gene sequencing

DHEA-S, dehydroepiandrosterone sulfate; PRA, plasma renin activity.

One patient (patient 15; Table 4) was diagnosed with CAH secondary to 21-hydroxylase deficiency after being found to have an elevated 17-OHP and PRA in endocrine clinic. ACTH stimulation testing confirmed the diagnosis of CAH, and genetic testing for variants in the CYP21A2 gene demonstrated three variants known as cluster 6 variant on one allele and a known disease-causing variant on the second allele. Two patients (patients 16 and 17; Table 4) were identified as CAH carriers for pathogenic variants in the CYP21A2 gene; one had hyperkalemia, hyperreninemia, and prolonged QT syndrome and was found to have a severe salt-wasting mutation on gene sequencing. The other carrier was identified based on unusual adrenal hormone levels and PRA, which also prompted gene sequencing.

Primary gonadal insufficiency

An unexpectedly large number of patients displayed primary gonadal insufficiency (Table 5). Seven TM patients had POI and one TF had testicular failure. Nearly 1% of TM patients (7/827) had POI. The etiology of the gonadal failure was investigated. Four TM and one TF had undergone chemotherapy for oncologic reasons (patients 18, 19, 20, 21, and 25; Table 5), and one (patient 22; Table 5) had received methotrexate for juvenile idiopathic arthritis. The remaining two TM patients were suspected to have autoimmune POI (patients 23 and 24).

Table 5.

Patients with primary gonadal insufficiency

Pt No.	Gender	Ethnicity	Underlying condition	Age of gonadal toxin exposure	Gonadal toxin	Presenting signs of ovarian insufficiency	Age of diagnosis of POI, years	Age of referral for gender dysphoria
18	TM	C	Ewing's sarcoma	11.3	Cyclophosphamide Doxorubicin Vincristine Radiation	Secondary amenorrhea	13.3	17.6
19	TM	C	CML	17.0	Busulfan Cyclophosphamide Radiation	Hypergonadotropic hypogonadism	18.2	18.1
20	TM	C	Osteosarcoma	16.7	Cyclophosphamide Cisplatin	Secondary amenorrhea, hypergonadotropic hypogonadism	19.5	19.5
21	TM	C	ALL	5.9	Cyclophosphamide Radiation	Hypergonadotropic hypogonadism	14.3	14.2
22	TM	C	JIA	14	Methotrexate versus autoimmune	Hypergonadotropic hypogonadism	13.9	13.9
23	TM	C	Mixed connective tissue disorder	NA	NA Presumed autoimmune	Hypergonadotropic hypogonadism	17.25	17.25
24	TM	C	Unknown	NA	NA Presumed autoimmune	Secondary amenorrhea, hypergonadotropic hypogonadism	18.2	14.25
25	TF	C	Aplastic anemia	15.75	Melphalan Radiation	Hypergonadotropic hypogonadism	17.25	17.25

ALL, acute lymphocytic/lymphoblastic leukemia; CML, chronic myeloid leukemia; JIA, juvenile idiopathic arthritis; NA, not applicable.

Discussion

In this study, we identified a low but clinically relevant percentage (1.6%) of transgender individuals with I/DSDs, in nearly one-third of whom the I/DSDs were diagnosed after endocrine evaluation for gender dysphoria. To our knowledge, our prevalence estimates are the first for a transgender population and are ∼16- to 72-times higher than in the general population Estimates of the prevalence of I/DSDs in the general population range from 1 in 1000 to 4500 live-births.^15–17

The 2017 Endocrine Society Guidelines state that “studies have failed to find differences in circulating levels of sex steroids between transgender and non-transgender individuals.”¹⁰ Several studies from around the world have shown that up to 83% of TMs display androgen excess and/or PCOS before beginning masculinizing hormone therapy.^5–8,18,19 One previous study from Germany reported that half of TMs had ACTH stimulation tests consistent with mild CAH.⁸ However, genetic testing was not carried out in these individuals. There were four additional TM individuals in our cohort without I/DSDs having conditions associated with adrenal androgen excess. Utilizing individualized genetic testing, we identified one individual with 21-hydroxylase deficiency, and two carriers of 21-hydroxylase deficiency.

Whether CYP21A2 heterozygotes have symptoms of hyperandrogenism has been a subject of debate, with some calling symptomatic carriers “manifesting heterozygotes.”²⁰ Very high rates of the CAH carrier state (28–33%) have been found in premature adrenarche, in PCOS, and in hirsutism in several countries, suggesting that these individuals can be symptomatic.^20–26 This may necessitate the use of glucocorticoids for stress dosing in the event of major surgery or trauma depending on results of stimulation testing, and may change an individual's desire to pursue fertility preservation following genetic counseling.²⁷

The prevalence of POI in the general adolescent population is 1 in 10,000,²⁸ whereas we found 1.1% of TM patients carries a diagnosis of POI, that is, a 100-fold increased risk of gonadal insufficiency. As with other adolescent patients with POI, most of the patients had undergone chemotherapy for oncologic or hematologic reasons. This unusual association between primary gonadal insufficiency and gender dysphoria warrants ongoing evaluation, as it carries clinical implications. These patients will need to remain on a hormone replacement therapy long-term for bone health, even if they choose not to continue gender affirming hormone therapy for their affirmed gender. Discussions about fertility need to be undertaken in the context of potential infertility. In addition, treatment paths may be impacted, as these individuals do not need treatment with gonadotropin-releasing hormone (GnRH) analogs or other forms of menstrual or testosterone suppression.

A previous report showed sex chromosome variants present at a rate of 2.6% in TM and 0.6% in TF patients for an overall rate of 1.5%,²⁹ consistent with the 2% we observed in this study. In our study, all patients with sex chromosome variants were known to be affected before being evaluated for gender dysphoria. Our results and those of others²⁹ suggest that routine karyotyping for sex chromosome variants in the absence of other features of Klinefelter syndrome or Turner syndrome would be low yield.

The 2017 Endocrine Society Guidelines recommendation is to evaluate and address any conditions that could be exacerbated by gender-affirming hormone therapy.¹⁰ Our data lend support to that recommendation and also support additional evaluations. Select patients should undergo baseline laboratory evaluation for high-risk conditions such as CAH or adrenal tumors. A substantial number of patients had conditions that could be masked by masculinizing therapy (such as CAH, adrenal tumors, MRKH, and Swyer syndrome, where signs of androgen excess and menstrual irregularity/amenorrhea would not trigger further evaluation).

POI and primary testicular failure could be persistently masked by treatment with GnRH analogs and by either masculinizing or feminizing hormones that would lower gonadotropins and endogenous sex steroid levels. Any of these conditions may impact the risk/benefit discussion related to gender-affirming therapy, as these conditions may have impacts on long-term fertility and risks for other health conditions. Evaluation for I/DSDs in certain cases had the added advantage of improving insurance coverage for surgery, as procedures for those diagnosis codes were sometimes more likely to be covered under insurance policies.

Limitations

Our study is limited in that our prevalence estimates are likely underestimates. This was a retrospective study in which many patients underwent baseline laboratory assessments in accordance with the 2009 and 2017 Endocrine Society Guidelines for Treatment of Gender Dysphoric/Gender Incongruent Persons, which make no recommendations for routine baseline hormonal testing.^10,30 Numbers may be further underestimated by the fact that some TM patients, for example, are not bothered by and do not complain about symptoms that could be associated with I/DSDs or POI, such as hair growth and menstrual irregularity and even primary amenorrhea.

Another reason for potential underestimation is the complexity of coding. Patients with mild hypospadias and/or unilateral undescended testes may not necessarily receive diagnostic codes in the electronic medical record and would not be consistently referred to urology or I/DSD clinic for further evaluation. There are also conditions that include genital atypia as part of a larger syndrome, not all of which were included in the electronic search (e.g., cloacal anomalies), as many of these patients receive care outside the I/DSD clinic at our institution.

Conclusions

Our study demonstrated a clinically relevant percentage of transgender individuals with I/DSDs and a higher-than-expected prevalence of POI. In addition, four TM individuals with conditions associated with adrenal androgen excess, which may be masked with testosterone therapy, were identified. These findings point to the need for a prospective, multicenter data repository identifying conditions that could be undiagnosed or masked by hormonal treatments in this at-risk population. They also point to the need for transgender and gender diverse youth to have access to individualized care and to multidisciplinary clinics that include subspecialists such as endocrinologists.

Abbreviations Used

17-OHP

17-hydroxyprogesterone

ACTH

adrenocorticotropic hormone

ALL

acute lymphocytic/lymphoblastic leukemia

BUDT

ilateral undescended testes

C

Caucasian

CAH

congenital adrenal hyperplasia

CGH

comparative genomic hybridization

CI

confidence interval

CML

chronic myeloid leukemia

CYP21A2

21-hydroxylase gene

DHEA

dehydroepiandrosterone

DHEA-S

dehydroepiandrosterone sulfate

DSM

Diagnostic and Statistical Manual of Mental Disorders

EMR

electronic medical record

FISH

florescent in situ hybridization

GnRH

gonadotropin-releasing hormone

I/DSD

intersex/difference in sex development

ICD

International Classification of Diseases

IRB

Institutional Review Board

JIA

juvenile idiopathic arthritis

MRKH

Mayer–Rokitansky–Küster–Hauser syndrome

NA

not applicable

PCOS

polycystic ovary syndrome

PCR

polymerase chain reaction

POI

primary ovarian insufficiency

PRA

plasma renin activity

TF

transfeminine

TM

transmasculine

VACTERL

vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, limb anomalies

Authors' Contributions

H.R.—Investigation (lead), writing—Original draft (lead). M.M.K.—Investigation (supporting), writing—review and editing (equal). M.M.—Investigation (equal), writing—review and editing (equal). K.D.—Resources (equal), writing—review and editing (equal). R.M.—Resources (equal), writing—review and editing (equal). A.T.—Resources (equal), writing—review and editing (equal). J.D.J.—Conceptualization, methodology, investigation, writing—original draft (supporting), writing—review and editing (lead), visualization, supervision.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

Sequencing of the CYP21A2 gene was performed on a research basis and funded by Quest Diagnostics, Nichols Institute, San Juan Capistrano, CA.

Cite this article as: Randhawa H, Knoll MM, McPhaul M, Dileepan K, McDonough R, Turpin A, Jacobson JD (2023) Prevalence of intersex/differences in sex development and primary gonadal insufficiency in a pediatric transgender population, Transgender Health 9:6, 544–552, DOI: 10.1089/trgh.2023.0033.