Aetiology, Clinical Profile and Management Dilemmas in Transgender Children with Y Containing Chromosomes: The Tip of an Iceberg

Introduction

Intersex disorders are among some of the most distressing problems encountered at birth because of the uncertainty that clouds the newborn’s most basic identity. It is a social emergency requiring rapid determination of a definitive diagnosis to facilitate the development of a suitable treatment plan that will minimize medical, social and psychological complications [1]. Majority of XX DSD will be Congenital adrenal hyperplasia but the difficulty in reaching a diagnosis is more in XY DSD than XX DSD because of the variety of aetiological conditions and limitation of the diagnostic tests available. The management is more miserable due to the inability in constructing a male external genitala. So most often the disparity between genotypic and phenotypic sex is more in XY DSD. Humiliation created at the time of diagnosis will make the parents forget about the Pandora”s box in adolescence. Due to the social stigma attached, the first contact with the physician may also be the last. In this The research protocol of the study was submitted to the Research and Human ethical committee of the institution. The study was started after getting the clearance from both the committees. Children from birth up to 12 years of age, who fulfilled the criteria for DSD (Disorders of sex development) according to the standard literature Table 1 and who came to our paediatric outpatient (OP) clinic and wards, paediatric surgery OP and wards, and endocrinology clinic during one year period (1st January 2010 to 31st December 2010) were analyzed and those with a Y containing chromosome were enrolled. 21 cases were enrolled into the study.

context we tried to analyze the clinical profile of transgender children with a Y containing chromosomes and also tried to formulate a protocol to reach at a reasonable diagnosis in resource limited settings. We also peeped into the follow up issues as well.

Materials and Methods

Table 1: Disorders of Sex Development. A proforma was prepared with personal data including age at first presentation and current age, assigned gender at birth, sex of rearing, gender identity, consanguinity, antenatal history and drugs, family history, initial presenting complaints, description of genitalia at presentation (from old records also), initial investigations - laboratory/ karyotyping/ imaging/ laparoscopy/ biopsy), initial diagnosis and treatment received (medical/ surgical), current appearance of external genitalia (prader staging), reinvestigations done , revised diagnosis , treatment planned, follow up pattern (regular/ irregular) and reason for irregular follow up [2]. The genital ambiguity inclusive of the symmetry of the labioscrotal folds, labial fusion, phallic length, morphology of the phallus, number of urogenital openings, palpable gonads, site of the gonads, position of urethral opening, chordee and anogenital ratio were recorded to describe the stage of virilisation. Laboratory investigations included serum electrolytes, random blood sugar, renal function, hormonal studies like basal concentration of 17– hydroxy progesterone (17-OHP), testosterone, Dihydrotestosterone (DHT), Dehydroepiandrosterone (DHEA), Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH) according to the clinical diagnosis. In cases with a significant testosterone level, hCG stimulation test was done after 3 months of age by giving 1000 units IM on alternate days for 3 doses to study the levels of testosterone and DHT after 3 months of life (this was postponed as a normal gonadotropic surge occurs with a resultant increase in the testosterone level and its precursors in early days). A failure to respond to hCG in combination with elevated LH and FSH levels was consistent with anorchia. A twofold or more increase in levels of testosterone2 or a level more than 300 ng/dl after 24 hours of last dose of hCG suggested the presence of functional testicular tissue [3]. A testosterone to DHT ratio along with androgen precursors before and after hCG stimulation helped to elucidate the 46, XY DSD etiology as shown in Figure 1 and Figure 2.

Karyotyping was done for all patients on peripheral blood lymphocytes. Pelvic and abdominal ultra sonography helped to detect the presence of gonads and mullerian structures. Other investigations included genitogram, laparoscopy and gonadal biopsy. For older cases, previous investigations were analysed, PCR for SRY or mutation analysis for enzyme defects were not available in our settings from the clinical examination and the investigations, and we arrived at the aetiological diagnosis of XY DSD as shown in Figure 1 and 2, which is made with modifications from standard literature. The definitions used for various diagnosis and abbreviations are given in Table 2.

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Diagnosis and Abbreviations Study

Ambiguous genitalia When there is difficulty in assigning sex to an individual from the appearance of external

Discussion

In 2006, the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Pediatric Endocrinology (ESPE) published a consensus statement on management of intersex disorders and proposed the term ‘Disorders of Sex Development (DSD) .The new DSD classification includes three main diagnostic categories: sex chromosome DSD, 46, XY DSD (formerly male Pseudo hermaphrodite) and 46, XX DSD (formerly female Pseudo hermaphrodite) [11, 12, 13]. The category of sex chromosome DSD embraces not only ovotesticular DSD (formerly true hermaphroditism) and 45, X/46, XY mixed gonadal dysgenesis, but also Turner’s syndrome and Klinefelter’ssyndrome. Among 21 cases of DSDs containing Y chromosomes, 17 children were XY DSD, 4 were sex chromosome DSD.

In the literature, definite cause is identified only in 50% cases of XY, DSD. In our study causes were identified in 82.3% of cases with a reasonable accuracy. But some of the patients were not labeled a diagnosis before enrolling into the study. They were counseled several times to complete the investigations and to arrive at a definite diagnosis. The commonest cause of XY, DSD in our study was AIS (53% of cases (35.29% CAIS, 17.6% PAIS)) followed by 5- α reductase deficiency (17.67%). 5.9% (n=1) cases were there each in Pure gonadal dysgenesis (PGD) and persistent mullerian duct syndrome (PMDS). In the study by Joshi et al, also 28% of cases were Androgen insensitivity syndrome (19.2% PAIS, 8.7% CAIS), 22.8% were 5- α reductase deficiency, 3.5% had PGD, 1.8% had PMDS, and 15.8% cases had incomplete workup [14]. Other studies by Morel et al and Saage et al also showed 90% and 88% cases with AIS [15, 16]. Among AIS, CAIS constituted the majority (35.29%). We had 6 cases of CAIS. All were presented with complete female phenotype with inguinal swelling. 2 were evaluated and diagnosed early as their siblings presented with PAIS. There were 3 cases of Partial androgen insensitivity syndrome. 2 cases presented with clitoromegaly and inguinal swelling .One case with hypospadias and indeterminate sex. Karyotyping revealed 46, XY and investigations revealed elevated testosterone but normal T/DHT ratio even after hCG stimulation. Another 3 cases who presented with ambiguous genitalia /cryptorchidism and hypospadias were found to have low DHT values and high T/DHT ratio and diagnosed to have 5- α reductase deficiency. Differentiating PAIS from 5- α reductase deficiency is important as the latter group will masculinize at puberty presumably due to direct action of testosterone of the phallus [17]. One case of pure gonadal dysgenesis was a phenotypic female for whom there was ambiguity of genitals due to clitoromegaly and right inguinal swelling, who presented at the age of 3 months. Karyotype was 46, XY and ultrasound and laparoscopy revealed rudimentary uterus with bilateral fallopian tubes. Testicular biopsy revealed bilateral hyalinised testes. Gonadectomy and feminizing genitoplasty were done and now the child is being reared as female. There was one case of Persistent mullerian duct syndrome who was a phenotypic boy who had bilateral cryptorchidism from birth. But lost to follow up and later came back at 51/2 years of age with testis at the root of scrotum. Ultrasound revealed mullerian structures and inguinal area exploration revealed mullerian structures. The same was removed. The gonads were testes. The child is being reared as male only. Work up was incomplete in 3 cases (17.7%).One case was a newborn who presented with cryptorchidism and ambiguous genitals. Karyotyping was 46, XY. But the parents did not turned up for review later on. The other 2 cases were having cryptorchidism and hypospadias at birth, for which multiple surgeries were done. Investigations done could not point towards a definite aetiology. They were12 years of age on review and started undergoing testosterone therapy to increase the phallic size. Sex Chromosome DSD are rare in most of the studies. The Ovotesticular DSD is the rarest variant making only up to 10% of intersex disorders. About 70% have a 46,XX karyotype, fewer than 10% have 46, XY and about 20% have 46,XX/46,XY mosaicism the karyotypes were 46 XY and 46 XX/46 XY [18]. The 46 XY ovotesticular DSD baby presented with ambiguous genitalia at birth. On examination, the gonads were at the root of scrotum and biopsy revealed bilateral ovotestes. For the second case, the karyotype was 46 XX/46 XY. This is called Chimerism. 46 XX/46 XY chimer is an individual in whom some cells have the male chromosome complement and some have female. When more than one set of cell line with different sets of chromosomes make up the body, it is called Chimerism. It occurs when two non identical zygotes combine at a very early stage of development to form a single foetus. It is different from Mosaicism where the individual originates from single foetus [19]. In our study this case was a phenotypic girl who presented at the age of 4 years with left inguinal swelling. Gonadal biopsy revealed ovotestis with fibro muscular changes on the right side and testes on the left side. The abnormal karyotype of two patients was 47 XXY and 49 XXXXY (50) / 48 XXXY (30) / 46 XY (20). 47 XXY (Klinefelter Syndrome) presented with bilateral cryptorchidism, microphallus, developmental delay and abnormal facies in infancy. 49 XXXXY (50) / 48 XXXY (30) / 46 XY (20) is a rare karyotype and is considered to be a mosaic variant of klinefelter syndrome. In the literature we have not found any case reports of such a mosaicism. Our baby presented with ambiguous genitalia at birth. Had bifid scrotum with cryptorchidism and microphallus. He was a low birth weight baby with facial dysmorphism, cleft palate, clinodactyly, developmental delay, failure to thrive and congenital heart disease. Mosaic forms are due to mitotic non dysjunction after fertilization of the zygote. These forms can arise from a 46XY zygote or a 47 XXY zygote. Severity of somatic malformations is proportional to the number of additional X chromosomes. The classical triad of 49XXXXY syndrome consists of mental retardation, radio ulnar synostosis and hypogonadism. Other features included LBW, slow growth, cranial anomalies, abnormal genitals, multiple skeletal deformities with joint laxity and cardiac defects. When analyzing the presenting features, All of them had either inguinal swelling or cryptorchidism except 2 cases of 5 alfa reductase deficiency.

Conclusion

It’s difficult to reach at a definite diagnosis in XY DSD as it is time consuming, unavailability of all investigations at ease, cost, need of perseverance from the part of parents. More difficult to follow them up due to different reasons. Thorough and apathetic counseling is essential from the first visit with detailed discussion with parents based on karyotype, endocrine function, genital anatomy, expected pubertal change and fertility issues to assign a sex for rearing. Androgen insensitivity syndrome is the most common XY DSD in our study. Majority of the DSDs containing Y chromosomes are being reared as female.