Surgical Evaluation of Using the Prepuce in Feminizing Genitoplasty

• Background and Rationale: Disorders of sex development(DSD) are medical conditions in which the development of chromosomal, gonadal, or anatomic sex varies from normal and may be incongruent with each other. Five main groups of DSD patients may be identified, submitted to the gender assignment process, and may be considered for a surgical genital reconstruction. (Lee Pa et al, 2006) Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive disorders resulting from deficiency of one of the five enzymes required for synthesis of cortisol in the adrenal cortex. CAH is the most common cause of genital ambiguity. (van der Zwan, 2013) About 90-95% of individuals with CAH have a mutation in CYP21A2 gene, encoding 21-hydroxylase enzyme. The worldwide incidence of classical 21 OHD is 1:15,000 to 1:16,000 live births of which approximately 75% are salt wasters. That leads to a block of normal production of cortisone and results in overproduction of steroid metabolism by-products through pituitary feedback. These androgenic steroids lead to a variable degree of masculinization of normal female fetus.

The goal of therapy in CAH is to both correct the deficiency in cortisol secretion and suppresses adrenocorticotropic hormone (ACTH) overproduction. Proper treatment with glucocorticoid reduces stimulation of the androgen pathway, thus preventing further virilization and allowing normal growth and development. In addition to hormonal therapy, feminizing reconstructive surgery targets the correction of anatomical disturbance. The feminizing genitoplasty operation consists of reducing the size of the phallus (clitoroplasty), creating labia minora and vaginoplasty.

• Sample size: Sample size calculation: n = 2(Za+Z1-β)2σ2/Δ2 n sample size Za = 1.65 ( p<0.05 as acceptable and a study with 80% power; using the below table, we get the following values: Zα, is 1.65 a error 5% 1% .1% 2 sided 1.96 2.5758 3.2905

1 sided 1.65 2.33 Z1-,β= 0.8416 power 80% 85% 90% 95% value 0.8416 1.0364 1.2816 1.6449 σ standard deviation =0 .5 Δ effect size 36% =0.36 Effect of using the prepuce in minimizing vaginal stenosis is 100% - effect of using other techniques 64%

N =2(1.65+0.8416)2 0.52 / 0.362 = 24 patients.

• Study Design: non-controlled prospective clinical trial with all patients included in single group.

- Ethical committee approval : approved (N-100-2018)

- Study Methods

Population of study & disease condition:

24 patients suffering from congenital adrenal hyperplasia (CAH) presenting with virilized external genitalia to outpatient clinic of diabetes Endocrine And Metabolism Pediatric Unit (DEMPU) of Cairo University Specialized Pediatric Hospital will be considered.

Methodology in details :

Patient recruitment females with congenital adrenal hyperplasia presenting with persistent urogenital sinus and virilized external genitalia to the outpatient clinic of Diabetes Endocrine And Metabolism Pediatric Unit (DEMPU) of Cairo University Specialized Pediatric Hospital

Pre-operative management History taking laying stress on age at diagnosis, family history of similar conditions and consanguinity in addition to any salt losing events.

Reviewing the patients charts for the investigations (basal adrenal precursors, karyotype, pelvic ultrasound) Complete genital examination to detect the degree of virilization (number and types of openings, the presence of rugae or pigmentation, phallus size and Prader scale).

Routine pre-operative blood tests will be done .

Perioperative hormonal therapy in the form of hydrocortisone and/or fludrocortisone in conjunction with pediatric anesthesia and pediatric endocrinology teams including dose adjustment and electrolytes follow up.

Genitography: Patient is generally anesthetized either in same setting of surgery or pre-operatively in different setting, The depth of confluence from perineal marker is measured in ratio to perineal marker dimensions whatever the scale of genitography picture is, then measurements are taken in millimeters. Other measurements of proximal urethra and vagina to the confluence are taken.

Operative technique Cystoscopy will be done promptly before proceeding to surgery in the same setting.

Confluence depth more than 20 mm is considered high anomaly with consequent difficult and lengthy procedure with high probability of need to use vaginal pullthrough in combination with the use of inner layer of the prepuce.

feminizing genitoplasty will be done as a one-stage procedure. The patient is placed in the lithotomy position for the best exposure of the perineum. A Foley catheter French 6 is placed in the vagina to facilitate identification of structures during dissection, The clitoroplasty will be attempted in all Cases.

The dissection of the flap from the inner surface of the prepuce with its pedicle will be done after measuring the distance between the native vagina and perineum. and then tubularized onto a rectal stent (French 12 or 14).

The proximal edge of the preputial flap will be sutured to upper vagina and its distal edge to outer edge. The rectal drain will be left in the vagina for 5 days postoperatively, by this technique the vaginoplasty can be achieved without further mobilization of the vagina which may affect the continence of the patient if we divide pubourethral ligament, labia this procedure will be followed by clitoroplasty and labioplasty.

In cases of low urogenital sinus (less than 2 cm), the use of preputial flap alone is often sufficient.

in case of high confluence additional procedure will be done in the form of laparoscopic vaginal pull-through

Postoperative management:

Wound will be closed by x-shaped bandage for 24 hours.

Vitamin K, ethamsylate (dicynone) and tranexamic acid (cyklokapron) will be given to help in hemostasis.

After dressing removal the wound will be left exposed and flushed with sterile -saline every 4-6 hours

Urinary catheter and vaginal stent will be removed on 5th to 7th day post operatively.

Parenteral broad spectrum antibiotics and antianaerobes will be given for one week. Stress doses of steroids will be continued for 2-3 days after surgery at double usual oral dose followed by tapering and returning to the original dose

postoperative management: One month after operation, examination under anaesthesia will be done with calibration of vagina using Hegar dilators and making decision for further need for repeated vaginal dilatation.

Urodynamics will be applied for patients older than 3 years old to asses the continence in cases with high confluence.

Primary outcome:

To calibrate the vagina and asses the degree of vaginal stenosis if present and need for further vaginal dilatation.

Secondary outcome:

To asses other outcomes specially the continence in patients older than 3 years old and the prescence of urethrovaginal fistula.

Short term complications:

- Infection at vestibule and incision lines

- accidental removal of the catheter

- haematoma

- secondary haemorrage

Intermediate and long term complications:

- urethrovaginal fistula

- recurrent persistant urogenital sinus (UGS)

- Vaginal stenosis

- Urinary incontinence