Ambiguous Genitalia in Neonates: a 4-Year Prospective Study in a Localized Area A.N

EMHJ • Vol. 16 No. 2 • 2010 Eastern Mediterranean Health Journal La Revue de Santé de la Médiderranée orientale

Ambiguous genitalia in neonates: a 4-year prospective study in a localized area A.N. Al-Mulhim1 and H.M. Kamal2

األعضاء التناسلية الظاهرة املبهمة املعامل لدى الولدان: دراسة استباقية دامت 4سنوات يف منطقة حمددة عبد املحسن نارص امللحم، حسام مصطفى كامل اخلالصـة:هتدف هذه الدراسة للتعرف عىل اإلمراضية املحتملة لألعضاء التناسلية الظاهرة املبهمة املعامل لدى 41 وليداً حُ وِّ لوا إىل مستشفى يف مدينة اهلفوف، يف اململكة العربية السعودية. وكان أشيع األسباب لألعضاء التناسلية الظاهرة املبهمة املعامل لدى املصابني النمط الصبغي XX 46 )وعددهم 14 مريضاً(، وفرط التنسج الوالدي الكظري، واضطراب عام تشوهي. أما لدى املصابني بالنمط الصبغي XY 46 )وعددهم 18 مريضاً(؛ فقد كان أشيع األسباب عيب التخليق البيولوجي لسبيل التستريون، حتى مع الرتافق باضطراب تشوه معمم. أما املرىض ذوي النمط الصبغي غري السوي، )وعددهم 3 مرىض(، وكان لدى واحد منهم ثالثية الصبغي XX 47( 18(، وقد مات بعد 3شهور من والدته، ولدى اثنني منهم أنامط خمتلفة من متالزمة ترينر الفسيفسائية. ومل يتم حتديد النمط الصبغي لدى 6 مرىض. وقد لوحظت السوابق العائلية اإلجيابية لألعضاء التناسلية الظاهرة املبهمة املعامل لدى 4 مرىض.

ABSTRACT This study aimed to determine the possible etiology of ambiguous genitalia in 41 newborn infants at a referral hospital in Hofuf city, Saudi Arabia. In 46,XX karyotype patients (n = 14), congenital adrenal hyperplasia and general malformation disorder were the most common causes of genital ambiguity, while in 46,XY karyotype patients (n = 18), testosterone pathway biosynthetic defect was the most common cause even in conjunction with a generalized malformation disorder. In patients with abnormal karyotype (n = 3), 1 had trisomy 18 (47,XX) and died after 3 months and 2 had different types of mosaic Turner syndrome. The karyotype was undetermined in 6 patients. Positive family history of ambiguous genitalia was noted in 4 patients.

Ambiguïté sexuelle chez le nouveau-né : une étude prospective de quatre ans dans une zone circonscrite

RÉSUMÉ Le but de cette étude était de déterminer l’étiologie possible de l’ambiguïté sexuelle chez 41 nouveau-nés dans un hôpital de recours de la ville d’Hofuf, en Arabie Saoudite. Chez les nourrissons présentant un caryotype 46,XX (n = 14), l’ambiguïté sexuelle était le plus souvent due à une hyperplasie congénitale des surrénales et à une malformation générale, alors que chez les bébés ayant un caryotype 46,XY (n = 18), la cause la plus fréquente était une anomalie caractérisée par l’absence de biosynthèse de la testostérone, y compris lorsqu’elle était associée à une malformation générale. Parmi les nouveau-nés présentant un caryotype anormal (n = 3), l’un, souffrant de trisomie 18 (47,XX), est décédé à l’âge de trois mois, tandis que les deux autres enfants étaient atteints de différents types de syndrome de Turner en mosaïque. Le caryotype était indéterminé chez six nouveau-nés, et des antécédents familiaux d’ambiguïté sexuelle ont été constatés chez quatre nourrissons.

1Department of Paediatrics, Maternity and Children Hospital, Hofuf, Saudi Arabia. 2Department of Paediatrics, King Fahd Hofuf Hospital, Hofuf, Saudi Arabia (Correspondence to H.M. Kamal: [email protected]). Received: 16/08/07; accepted: 24/10/07

214 املجلة الصحية لرشق املتوسط املجلد السادس عرش العدد الثاين

Introduction concern were: clitoromegaly, vaginal without time to carry out karyotyping absence or hypoplasia, urogenital si- or other tests. The diagnosis of ambiguous genitalia in nus, significant micropenis, hypospa- a newborn infant is an emergency that dias, labioscrotal fusion, in addition to can be difficult to manage, not only be- palpable/impalpable gonads or un- Results cause salt-wasting entities must be ruled descended testis/testes (if palpable). out, but also due to the importance of Apparent males with simple hypo- A total of 41 cases were reported to have gender assignment before psychological spadias or undescended testes (but with ambiguous genitalia during the study period. gender is established [1]. Particularly in normal phallus) or borderline micro- less-developed areas of the Arab world penis (but with palpable descended tes- These included 14 patients with with a legacy of tribalism, the situation is tes) were not considered ambiguous. 46,XX karyotype, of whom 13 (92.9%) more complex socially and psychologi- A detailed history was taken and had enlarged clitoris and 1 (7.1%) had cally. Although hormonal, genetic, mo- physical examination and screening for hypoplastic clitoris and vagina (Fraser lecular and radiographic investigations pituitary hormones (thyroid stimulat- syndrome); 6 patients had labial fusion are needed to determine the etiology, ing hormone, adrenocorticotropic hor- (42.9%) (Table 1). No gonads were physical examination remains a key for mone (ACTH) and gonadotropins) palpable in any of them. Congenital diagnosis [2], particularly careful palpa- were conducted. Diagnostic evalu- adrenal hyperplasia (CAH) was diag- tion to locate gonads at the genital folds ation included serum biochemistry, nosed in 5 patients as 21-hydroxylase or in the inguinal region. In most cases it other hormonal profile, chromosomal deficiency (35.7%); 3 of these were is impossible to correlate the etiology of study and imaging studies. Hormonal salt-losers. Extragenital anomalies (al- the disorder with the appearance of the profile included basal concentrations ways multiple) were reported in 4 cases external genitalia [3]. of 17-hydroxyprogesterone, cortisol, (28.8%). These included cloacal exstro- In this study, we aimed to determine dehydroepiandrosterone, testosterone phy, imperforate anus, congenital heart the possible etiologies of ambiguous and dihydrotestosterone and, when disease, omphalocele, renal agenesis, genitalia in newborn infants attending necessary, stimulation tests by human skeletal anomalies and dysmorphism. the main referral centre for Al-Ahsaa area chorionic gonadotropin (hCG) and A positive family history was reported in the Eastern Province of Saudi Arabia. ACTH. Chromosomal analysis was in 3 patients, 2 of whom were sisters done on cultured lymphocytes, includ- with congenital adrenal hyperplasia, ing sex-determining region Y (SRY) while the third had a similarly affected Methods gene signalling by polymerase chain cousin with isolated clitoromegaly. All reaction. In addition, radiological im- patients were raised as females. Death The study group comprised all recently aging included abdominal and pelvic was reported in 1 patient because of born infants (in the first 4 weeks of age) ultrasonography and, when necessary, multiple congenital anomalies. who presented for endocrinologist genitogram and/or magnetic resonance Eighteen (18) patients had 46,XY evaluation in the Maternity and Chil- imaging for anatomical localization and karyotype (Table 2). Micropenis was dren Hospital, Hofuf, over the period identification of gonads and internal seen in 16 cases (88.9%); 9 of these had January 2003–December 2006. The genitalia. These investigations were both testes undescended (50.0%) and hospital is the main referral centre for done in the laboratories of King Faisal 2 had undescended left testis (11.1%). Al-Ahsaa area in the Eastern Province, Specialist and Research Center, King Hypospadias was found in 4 patients which is one of the most populated Fahad Hofuf Hospital and the Mater- (16.7%), 3 with penile type and 1 had areas in Saudi Arabia, and so the data nity and Children Hospital. Intramus- penoscrotal type. Positive family history may represent a profile of the problem cular testosterone was tried in 7 patients of undescended testes in several family of ambiguous genitalia in the whole assigned as males with 46,XY karyotype members was reported in 1 patient. The country. to assess phallic growth response. hCG test was negative in 11 patients A neonate was considered to have According to the karyotyping, our (61.1%). Extragenital anomalies were genital ambiguity when there was dif- cases were classified into 4 groups: reported in 7 cases (38.9%). These in- ficulty in determining the sex on initial 46,XY karyotype, 46,XX karyotype, cluded skeletal anomalies (congenital view or when the external genitalia ambiguous karyotype and undeter- hip dysplasia and club foot), congenital showed significant structural deviation mined karyotype. Sex assignment was lobar emphysema, renal anomalies, im- from normal in an apparent male or matching with the karyotype, except in perforate anus and dysmorphism. Three female. The clinical genital features of those patients who died soon after birth (3) syndromic cases were reported

215 EMHJ • Vol. 16 No. 2 • 2010 Eastern Mediterranean Health Journal La Revue de Santé de la Médiderranée orientale

Table 1 Clinical data and likely causes of ambiguous genitalia in 46,XX karyotype anomalies (congenital cyanotic heart children (n = 14) lesions, brain malformations, renal and/ Clinical data and causes No. % or respiratory anomalies) and death Clinical data ensued soon after birth. Clitoromegaly 13 92.9 Labial fusion 6 42.9 Treatment strategies were planned Extragenital anomaly 4 28.6 according to the sex of raising and Extremely ambiguous genitalia 1 7.1 genital morphology and associ- Death 1 7.1 Positive family history 3 21.4 ated clinical features. These included Causes repeated courses of hCG injections and Congenital adrenal hyperplasia orchidopexy for undescended testes, (21-hydroxylase deficiency) 5 35.7 reconstructive surgery for hypospadias, 4 28.6 Generalized developmental malformation clitoromegaly and vaginal hypoplasia Fraser syndrome 1 7.1 Congenital local genital defect 4 28.6 and hormonal replacement in patients with congenital adrenal hyperplasia.

(Goldenhar syndrome, VATER as- features of the chromosomal aberra- Discussion sociation and Potter syndrome). tion; 1 patient had trisomy 18 (47XX) Surprisingly, 1 patient proved to have and the other 2 patients had different Approximately 1 in 2000 children glo- pseudohypoaldosteronism supported types of mosaic Turner (1 with SRY bally is born with an intersex condition by refractory electrolyte disturbances gene, 1 with no SRY signal detected). [4]. Great care should be always taken with normal corticosteroid pathway and All were raised as females. The patient in the declaration of sex, which is guided high aldosterone. Death was reported in with trisomy 18 died after 3 months by the etiology, the anatomic condition 2 patients because of Potter syndrome because of complex congenital heart and family considerations. The last is a and hydrops fetalis. All cases were disease. reflection of the cultural background. raised as males. The undetermined karyotype group Once the appropriate sex assignment Three (3) patients had abnormal included 6 patients who presented has been made, the next critical step is karyotype: all had ambiguous genitalia with severe ambiguous genitalia in as- treatment and, if needed, reconstructive in addition to the relevant characteristic sociation with severe lethal congenital surgery in a timely fashion [5]. In Saudi Arabia, literature on ambiguous genitalia is scarce [ ], creating a Table 2 Clinical data and likely causes of ambiguous genitalia in 46,XY karyotype 6,7 children (n = 18) need for further exploration of the prob- Clinical data and causes No. % lem in this community. In our study, in Clinical data spite of detailed diagnostic workup, a Micropenis 16 88.9 definitive etiologic diagnosis was made Undescended testes (both) 9 50.0 in less than one-third of the cases, in- Extragenital anomaly 7 38.9 cluding females with congenital adrenal Hypospadias 4 22.2 hyperplasia, syndromic patients and Undescended testis (single) 2 11.1 Death 2 11.1 patients with abnormal karyotype. Oth- Causes erwise, causes of ambiguity in patients Generalized developmental malformation, with with 46,XY karyotype were, in order of testosterone biosynthetic defect 4 22.2 frequency: testosterone biosynthetic Generalized developmental malformation, with defect (negative hCGT stimulation test normal testosterone synthetic pathway 2 11.1 Syndromic: response), part of generalized develop- Goldenhar syndrome 1 5.6 mental malformation, congenital local VATER association 1 5.6 genital defect or peripheral androgen Potter syndrome 1 5.6 insensitivity (suggested by high testo- Congenital local genital defect, with testosterone 5 27.8 sterone and dihydrotestosterone lev- biosynthetic defect Congenital local genital defects, with intact els); however, there was a high degree testosterone synthetic pathway 5 27.8 of overlap between testosterone biosyn- Androgen insensitivity syndrome 1 5.6 thetic defect and other causes in half of

216 املجلة الصحية لرشق املتوسط املجلد السادس عرش العدد الثاين

these patients. Lack of gonadal biopsy ambiguity. However, it is important to with ambiguous genitalia secondary to in our patients, mostly due to parental remember that our study was hospital- the presence of SRY genes [13,14]. In refusal, prevented our reaching certain based and age-limited, which might our study, we reported 2 cases of mosaic specific possible diagnoses such as contribute to differences. Nimkarn et Turner genotype, 1 of them had the SRY gonadal dysgenesis or Leydig cell apla- al. found that all female pseudoher- gene while in the other case no SRY sia/hypoplasia. In patients with 46,XX maphrodites in their study had CAH, signal was detected; this last case was karyotype, CAH was the most common and the most frequent cause of male considered as a unique variety and, to cause; other causes were considered as pseudohermaphroditism was andro- our knowledge, this is the first report of either a part of generalized developmen- gen insensitivity or 5-alpha reductase ambiguous genitalia in mosaic Turner tal malformation or congenital local deficiency (46.8%) followed by gonadal genotype with no Y chromosome (mo- genital defect. dysgenesis (19.1%) [11]. In another saic 45,X[11]/46,X,idic(X)(q11)[9]). Ambiguity in patients with unde- study, which included true and pseu- termined karyotype was suspected to dohermaphrodites, sex chromosome be secondary to severe malformation abnormalities represented the majority Conclusion disorder or unknown chromosomal of causes of intersex ,followed by CAH disorder. Genetic predisposition, which and androgen insensitivity disorders [8]. In 46,XX karyotype patients, CAH was suspected in 3 cases with 46,XX On the other hand, Forest et el. agreed followed by general malformation dis- karyotype and 1 with 46,XY karyotype, with our study when they reported that order were the most common causes was not, however, a contributing factor 50% of pseudohermaphrodites had no of ambiguous genitalia in more than despite the high incidence of consan- etiological diagnosis [12]. In a Saudi two-thirds of patients while in XY guinity in the patients’ parents (29.3% study done in the 1990s (1989–99), karyotype patients, testosterone path- first degree and 36.6% second degree). congenital developmental defects were way biosynthetic defects was the most Our data may differ from other the most common etiology for ambigu- common cause even in conjunction studies in different parts of the world ous genitalia followed by CAH (mostly with a generalized malformation dis- [3,8–10], at least in the absence of true 21-hydroxylase deficiency) [6]. order. Mosaic Turner syndrome was a hermaphroditism and in the differing There are several literature reports not uncommon cause for ambiguous order of the top causes of genital of mosaic Turner patients associated genitalia.

References

1. Tapia Ceballos L et al. Seudohermafroditismo masculino [Male experience at the Unit of Medical Genetics of the Univer- pseudohermaphroditism]. Anales de pediatrÍa (Barcelona, sity of Zulia, Maracaibo, Venezuela. Investigación clínica, 1998, Spain), 2007, 67(1):57–60. 39(4):273–92. 2. Sultan C et al. Ambiguous genitalia in the newborn. Seminars in 9. Ammini AC et al. Etiology, clinical profile, gender identity and reproductive medicine, 2002, 20(3):181–8. long-term follow up of patients with ambiguous genitalia in 3. Zdravković D et al. Uzroci dvopolnog izgleda spoljasnjih India. Journal of pediatric endocrinology & metabolism, 2002, genitalija kod novoredjencadi [Causes of ambiguous external 15(4):423–30. genitalia in neonates]. Srpski arhiv za celokupno lekarstvo, 2001, 10. Al-Agha AE, Thomsett MJ, Batch JA. The child of uncertain sex: 129(3–4):57–60. 17 years of experience. Journal of paediatrics and child health, 4. Maharaj NR et al. Intersex conditions in children and adoles- 2001, 37(4):348–51. cents: surgical, ethical, and legal considerations. Journal of 11. Nimkarn S et al. Ambiguous genitalia: an overview of 22 years pediatric and adolescent gynecology, 2005, 18(6):399–402. experience and the diagnostic approach in the Pediatric De- 5. Coran AG, Polley TZ Jr. Surgical management of ambiguous partment, Siriraj Hospital. Journal of the Medical Association of genitalia in the infant and child. Journal of pediatric surgery, Thailand, 2002, 85(Suppl. 2):S496–505. 1991, 26(7):812–20. 12. Forest MG et al. Disorders of sexual differentiation in infants and 6. Al-Alwan I et al. Clinical utility of adrenal ultrasonography in children. Physiopathological studies. Annales d’endocrinologie, the diagnosis of congenital adrenal hyperplasia. Journal of 1980, 41(6):545–53. pediatrics, 1999, 135(1):71–5. 13. Papadimas J et al. Ambiguous genitalia, 45,X/46,XY mosaic 7. Al-Mutair A et al. Cytogenetics and etiology of ambiguous karyotype, and Y chromosome microdeletions in a 17-year-old genitalia in 120 pediatric patients. Annals of Saudi medicine, man. Fertility and sterility, 2001, 76(6):1261–3. 2004, 24(5):368–72. 14. Dundar M et al. A case of ambiguous genitalia presenting with 8. Alvarez-Nava F, Gonzalez-Ferrer S, Soto M. Diagnosis and a 45,X/46,Xr(Y)(p11.2;q11.23)/47,X,idic(Y)(p11.2),idic(Y)(p11.2) management of patients with sex differentiation disorders: karyotype. Annales de génétique, 2001, 44(1):5–8.

217