Restoring Normal Anatomy in Female Patients with Atypical Genitalia Laurence S

S EMINARS IN P ERINATOLOGY 41 (2017) 227– 231

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Seminars in Perinatology

www.seminperinat.com

Restoring normal anatomy in female patients with atypical genitalia Laurence S. Baskin, MD

UCSF Benioff Children’s Hospital, 1825 Fourth St, 5th Floor, San Francisco, CA 94143 article info abstract

Keywords: Female patients with congenital adrenal hyperplasia (CAH) have varying degrees of Congenital adrenal hyperplasia atypical genitalia secondary to prenatal and postnatal androgen exposure. Surgical treat- Surgical treatment ment is focused on restoring normal genitalia anatomy by bringing the vagina to the Urogenital sinus normal position on the perineum, separating the distal vagina from the urethra, forming a Genital development normal introitus and preserving sexual function of the clitoris by accepting moderate degrees of hypertrophy as normal and strategically reducing clitoral size only in the most severely virilized patients. There remains a need for continued monitoring of patients as they go through puberty with the possibility of additional surgery for vaginal stenosis. Anatomically based surgery and reﬁnement in surgical techniques with acceptance of moderate degrees of clitoral hypertrophy as normal should improve long-term outcomes. & 2017 Elsevier Inc. All rights reserved.

Babies born with atypical genitalia defined as discordance palpable gonads. Characterizing the controversy with termi- between external genitalia and gonadal and chromosomal nology, many patients and families reject the classification of sex have been classified as having a disorder of sex develop- CAH as a disorder of sex development preferring simple to ment (DSD) although terminology remains controversial.1 use the term congenital adrenal hyperplasia as a diagnostic The incidence of DSD is approximately 1 in 1000–4500 live label once an accurate diagnosis is confirmed.4,5 Rarely, 46,XX births depending on which conditions are included.2 The individuals with CAH present with normal male genitalia birth of an infant with atypical genitalia presents a unique (Prader V virilization) but without palpable gonads.6 In pat- set of challenges. Psychosexual development is influenced by ents without salt-losing forms of CAH, these individuals multiple factors including the genes involved in sexual differ- typically present later in life after being raised as males. This entiation, gender differences in brain structure, prenatal is now a rare occurrence in the United States with mandatory androgen exposure, and cultural and religious influences. screening of newborns allowing for early detection of classi- The most common form of DSD presenting with atypical cal cases of CAH. genitalia is 46,XX congenital adrenal hyperplasia (CAH) due to A unique characteristic of patients with virilization of the 21-hydroxylase deficiency comprising 90–95% of all case.3 external genitalia secondary to endogenous androgens from Rarer forms of CAH include 11β-hydroxylase CAH, 3β-HSD adrenal enzymatic defects is that they have normal female CAH, 17α-hydroxylase CAH and lipoid CAH. Patients with 21- anatomy that has been virilized, i.e., a vagina, uterus, cervix hydroxylase deficiency are a relatively homogenous group of and ovaries, as well as normal female fertility potential. An patients, most of whom present in the newborn period with understanding of normal genital embryology sheds light on atypical genitalia due to endogenous virilization and without how this can occur. Male and female genital development

Funding source: All phases of this study were supported by an NIH Grant, R01DK058105. E-mail address: [email protected] http://dx.doi.org/10.1053/j.semperi.2017.03.011 0146-0005/& 2017 Elsevier Inc. All rights reserved. 228 S EMINARS IN P ERINATOLOGY 41 (2017) 227– 231

diverges from the indifferent stage at approximately 8 weeks’ gestation under the influence of androgens (Fig. 1).7 In the male, the urethral groove fuses in a proximal to distal fashion to form the tubular urethra. Urethral formation is complete by 17 weeks’ gestation along with fusion of the ventral foreskin and a natural progression from early developmental curvature of the penis to a straight penis. In the both the male and female, an androgen-independent canalization process occurs, opening up the urethral plate to a urethra groove in males and vestibular groove in females (Fig. 1C and E).8 What distinguishes females from males is the absence of the fusion event or formation of the tubular urethra. Interestingly, in females the normal male fusion may occur for example in patients with CAH who are exposed to androgens prenatally. It is accepted that the amount and timing of the prenatal androgen exposure will determine the severity of the male virilization of the normal female fetus. Excessive androgen during the first trimester of fetal life impacts the amount of fusion of the bipotential genitalia externally and the location of the confluence of the urethra, vagina, and common urogenital channel internally. Excess androgen later in fetal life cannot affect genital differentiation but does affect the amount of clitoral hypertrophy. Presumably, patient’s with more severe amounts of prenatal androgen exposure will have a longer common urogenital channel and a higher confluence of the vagina and urethra connection closer to the bladder in contrast to lesser androgen exposure that will result in a lower confluence (Fig. 2). The confluence can be Fig. 1 – Optical projection tomography imaging of human visualized by radiographic imaging by injecting contrast into fetal genital specimens at (A) 8 weeks’ gestation (indifferent the common urogenital channel (genitogram) (Fig. 3). stage) where the male and female genitalia are Virilization of the external genitalia is also dependent on indistinguishable. (B and C) Male and female at 9 weeks’ the amount of prenatal androgen exposure. The more exten- gestation, respectively. (D and E) Male and female at 10.5 sive the androgen exposure the greater the clitoral hyper- weeks’ gestation, respectively. Note that the male trophy or Prader stage (Fig. 4). specimens form a urethral groove (thin light gray arrow Reconstructive treatment of CAH diagnosed at birth to B and D) from fusion of the urethral folds (horizontal gray restore normal anatomy is generally performed in the first arrow in D). Both the male and female specimens undergo year of life. The goal of surgery is to separate the vagina from canalization of the urethral plate (short dark gray arrows the urethra and to restore the continuity of the vagina to a B and D). The female specimens do not undergo fusion normal position on the perineum. This translates into recon- resulting in a vestibular groove (thin light gray arrow C and E). structing the common urogenital sinus single opening into a separate urethra and vaginal opening along with formation of

Fig. 2 – Schematic representation of anatomy of females with virilization secondary to congenital adrenal hyperplasia. (A) High conﬂuence. Note that the urethra and vagina meet close to the bladder neck. (B) Low conﬂuence. Note that the urethra and vagina meet closer to the opening of the common urogenital sinus on the underside of the hypertrophied clitoris. S EMINARS IN P ERINATOLOGY 41 (2017) 227– 231 229

– female neuroanatomy.9 18 The key breakthrough relates to treating the vagina and urethra/bladder as a unit to facilitate separation of the confluence of the urethral and vagina (Fig. 2).17,19,20 The common urogenital channel can be reposi- tioned as the urethra under the clitoris with excess common urogenital sinus used to reconstruct the anterior vagina wall and mucosa-lined introitus.11 If the vagina does not reach out to the perineum, a posterior skin flap (Fortunoff) can facilitate reconstruction of the posterior vagina wall.21 The “virilized” labia can be reduced in size from the effects of the prenatal androgen exposure to resemble labia majora and minora and a clitoral hood fashioned to cover the typically enlarged clitoris. As noted, emphasis is on the preservation of sexual function in contrast to reducing the clitoris to a normal – size.15,22 24 In adult life, patients can always request further reconstructive surgery which, based on personal observation, Fig. 3 – Genitogram of a patient with congenital adrenal does not appear to be a common occurrence. Initial concerns hyperplasia (contrast injected into the common urogenital about long-term urinary continence after urogenital sinus sinus retrograde) showing the high confluence, the vagina, mobilization after potty training have not been reported although long-term follow-up studies are warranted for cervix, uterus, bladder, and urethra. – clinical confirmation.25 27 20 an introitus with the mucosal tissue and formation of a labia The description of total urogenital mobilization by Peña 9–11 fi minora and majora. signaled a signi cant advance in the surgical management 1 The technique of restoring normal female anatomy has of CAH. The basic technique involves a 360 mobilization of evolved over time based on a better understanding of normal the entire urogenital sinus, which is then brought to the

Fig. 4 – Examples of progressively more severe cases of virilization secondary to congenital adrenal hyperplasia. (A) Prader I, (B) Prader II, (C) Prader III, (D) Prader IV, and (E) Prader V (white arrows represent single common urogenital sinus opening). Note the progressively more severe clitoral hypertrophy. 230 S EMINARS IN P ERINATOLOGY 41 (2017) 227– 231

perineum. In partial urogenital mobilization, dissection is and associated issues such as urinary tract infections and/or avoided superior to the urethra under the pubic bone, a urinary continence, fertility, and childbirth. nerve-rich zone that contains the sphincteric musculature necessary for urinary continence.16 Long-term follow-up is – references now being reported confirming normal continence.9 11,28 The hypertrophied clitoris, except in the most severe cases (i.e., when the appearance is that of a penis) can be often be left with moderate amounts of hypertrophy and covered with 1. Lee PA, Houk CP, Ahmed SF, Hughes IA, International Con- a reconstructed clitoral hood. In severe cases of clitoral sensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society, the European Society hypertrophy, nerve-sparring reduction on the ventral aspect for Paediatric E. Consensus statement on management of can be performed with an understanding of the neuroanat- intersex disorders. International Consensus Conference on omy and hence preservation of future sexual function and Intersex. Pediatrics. 2006;118(2):e488–e500. reducing clitoral size.22,24 These surgical recommendations 2. Hughes IA, Nihoul-Fekete C, Thomas B, Cohen-Kettenis PT. are consistent with the consensus statement on 21- Consequences of the ESPE/LWPES guidelines for diagnosis hydroxylase deficiency from the Pediatric Endocrine Society and treatment of disorders of sex development. Best Pract Res – and the European Society for Pediatric Endocrinology.3 Clin Endocrinol Metab. 2007;21(3):351 365. 3. Speiser PW, Azziz R, Baskin LS, et al. Congenital adrenal Systematic long-term evaluation is lacking for reconstruc- hyperplasia due to steroid 21-hydroxylase deficiency: an tion for patients with CAH. Nevertheless, women with CAH Endocrine Society clinical practice guideline. J Clin Endocrinol who have had surgical restoration of normal female anatomy Metab. 2010;95(9):4133–4160. in childhood are generally in agreement that they are pleased 4. Lin-Su K, Lekarev O, Poppas DP, Vogiatzi MG. Congenital adrenal that they had surgical reconstruction early in life as opposed hyperplasia patient perception of disorders of sex development’ to later in life when they could personally assent or consent nomenclature. Int J Pediatr Endocrinol. 2015;2015(1):9. 5. Gonzalez R, Ludwikowski BM. Should CAH in females be to the operation.28,29 A cohort of women with CAH surgically classified as DSD? Front Pediatr. 2016;4:48. treated later in life (or treated without surgical reconstruc- 6. Mouriquand PD, Gorduza DB, Gay CL, et al. Surgery in tion) does not presently exist as a comparison group. disorders of sex development (DSD) with a gender issue: if Thus based on expert opinion, the overwhelming majority (why), when, and how? J Pediatr Urol. 2016;12(3):139–149. of surgical specialists continue to recommend restoration of 7. Li Y, Sinclair A, Cao M, et al. Canalization of the urethral plate normal anatomy in female patients in early childhood. precedes fusion of the urethral folds during male penile Factors that influence this decision include the smaller urethral development: the double zipper hypothesis. J Urol. 2015;193(4):1353–1359. distance between the perineum and normal vagina in child- 8. Overland M, Li Y, Cao M, et al. Canalization of the vestibular hood as opposed to after puberty, the better healing prospects plate in the absence of urethral fusion characterizes develop- in young children and the possible facilitating effects of ment of the human clitoris: the single zipper hypothesis. maternal estrogen on reconstruction in young infants. J Urol. 2016;195(4 Pt 2):1275–1283. Special considerations with surgery include the need for 9. Ludwikowski BM, Gonzalez R. The surgical correction of uro- long-term follow-up and the likelihood that patients will genital sinus in patients with DSD: 15 years after description of need additional procedures at the time of sexually maturity total urogenital mobilization in children. Front Pediatr. 2013;1:41, http://dx.doi.org/10.3389/fped.2013.00041, Review. PMID: 24400287. specifically to ensure that the vagina is of adequate caliber for 10. Salle JL, Lorenzo AJ, Jesus LE, et al. Surgical treatment of high 26 satisfactory sexual intercourse. This may simply involve an urogenital sinuses using the anterior sagittal transrectal exam under anesthesia and/or revision of the distal vagina approach: a useful strategy to optimize exposure and out- for inadequate caliber (vaginal stenosis). At this time in life, comes. J Urol. 2012;187(3):1024–1031. the surgery is typically elective facilitating post-operative 11. Rink RC. Genitoplasty/vaginoplasty. Adv Exp Med Biol. 2011; – participation of the patient if temporary vaginal dilation is 707:51 54. 12. HoubenCH,TsuiSY,MouJW,ChanKW,TamYH,LeeKH. necessary after correction of vaginal stenosis. Retrospective Reconstructive surgery for females with congenital adrenal studies have documented a decrease in clitoral sensitivity hyperplasia due to 21-hydroxylase deficiency: a review from 30 after clitoral surgery. The majority of long-term studies, thePrinceofWalesHospital.Hong Kong Med J. 2014;20(6):481–485. however, have not shown a significant change in sexual 13. YankovicF,CherianA,StevenL,MathurA,CuckowP.Current function or satisfaction in patients undergoing corrective practice in feminizing surgery for congenital adrenal hyper- surgery for virilization secondary to congenital adrenal plasia; a specialist survey. JPediatrUrol. 2013;9(6 Pt B):1103–1107. – hyperplasia.12 14,28,29,31 Patients that have had clitoral surgery 14. van der Zwan YG, Janssen EH, Callens N, et al. 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