Don’t judge a book by its cover – A rare case report of 46,XY disorder of sex development

INTRODUCTION

Persistent Müllerian duct syndrome (PMDS), a type of 46,XY disorder of sex development (DSD), is caused by a mutation in the anti-Müllerian hormone (AMH) gene or AMH receptor (AMHR type II) gene. It results in the failure of the regression of Müllerian duct derivatives. Male external genitalia organogenesis is not affected.

CASE REPORT

A 4-year-old developmentally normal firstborn child, reared as a male, born out of a nonconsanguineous marriage, presented with bilateral undescended testis noticed since 2 years of age. The child was born at term by lower segment cesarean section with no ambiguous genitalia noted at birth. Antenatal scans were normal. There was no significant post-natal history such as neonatal hypoglycemia or salt-wasting crisis.

Physical examination revealed no obvious dysmorphisms, and systemic examination was within normal limits. Genital examination revealed bilateral non-palpable gonads, with normal stretched penile length (4.8 cm), with no hypospadias and a small scrotal sac. The external masculinization score was 9.

Ultrasonography (USG) of the abdomen and pelvis showed bilateral hypoechoic structures intraabdominally. Magnetic resonance imaging (MRI) of abdomen and pelvis showed bilateral hyper-intense structures in the lateral pelvic wall—suspected atrophic cystic testicular tissue. Karyotype was 46,XY and the human chorionic gonadotropin (hCG) stimulation test showed a good testosterone response. Basal testosterone (T) was <0.05 ng/mL, stimulated testosterone was 2.92 ng/mL (normal response >1 ng/mL), and dihydrotestosterone (DHT) was 30 pg/mL. Androstenedione was 0.12 ng/mL (0.05–0.5 ng/mL), and the T/DHT ratio was 97 (<10).

The child underwent diagnostic laparoscopy, which showed bilateral gonads in ovarian position with the presence of Müllerian structures: Hypoplastic uterus with bilateral fallopian tubes, as shown in Figures 1 and 2. Bilateral vas deferens were noted running on either side of the uterus.

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Figure 1:

Intraoperative image of gonads and hypoplastic uterus.

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Figure 2:

Intraoperative image of hypoplastic uterus.

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Gonadal biopsy revealed seminiferous tubules suggestive of testicular tissue, as shown in Figure 3. Definitive ovarian parenchyma was not seen. This confirmed female-type PMDS. Bilateral stage 1 Fowler-Stephen orchidopexy was done. Müllerian structures were not removed.

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Figure 3:

Gonadal biopsy image (Hematoxylin and Eosin staining, 10 × magnification) showing seminiferous tubules.

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Serum AMH was 60.97 ng/mL, which was normal suggestive of probable AMH resistance (normal range: 39–213 ng/mL). This was confirmed on clinical exome sequencing which revealed an autosomal recessive homozygous mutation in the AMHR type II gene on chromosome 12: c.1511G>A variant [NM_020547.3:c1511G>A(p Arg504)]. Further plan is to do stage 2 orchidopexy after 6 months, with removal of Müllerian structures and hormonal evaluation and replacement at puberty.

DISCUSSION

PMDS is a rare type of 46,XY DSD due to AMH deficiency or resistance. PMDS patients have normal development of secondary sexual characteristics and external genitalia.^[1] The most common clinical presentations are cryptorchidism (unilateral or bilateral), inguinal hernia, and abdominal mass or testicular tumor.^[2] Normally, both the Wolffian and Müllerian ducts are present in the 7^th week of gestation. At the end of the 7^th week, secretion of AMH by Sertoli cells occurs, which binds to AMHR type II receptors, causing regression of the Müllerian duct.^[1]

PMDS is classified based on anatomy and genetics. There are three types based on anatomical variations:

• Male type, characterized by unilateral undescended testis and contralateral inguinal hernia

• Female type, characterized by bilateral cryptorchidism (testes fixed within the round ligaments, in ovarian position)^[3]

• Transverse testicular ectopia: Both testes are in a single hemiscrotum alongside Müllerian structures.^[4]

Our case fits into the female type of PMDS.

Based on genetics, there are two types:

• Type 1, the most common, occurs due to a mutation of the AMH gene (responsible for AMH synthesis) on chromosome 19

• Type 2 is associated with a mutation of the AMHR gene on chromosome 12 (AMHR gene).^[4]

Our case is type 2 PMDS.

Ren et al. reported a case of a 17-month-old boy who presented with an empty right scrotum and a left inguinal mass and was diagnosed with PMDS. Genetic analysis showed a compound heterozygous nucleotide variation in the AMHR-II gene. He underwent a left transverse testicular ectopia orchidopexy.^[5]

PMDS can occur sporadically, although it is commonly due to autosomal recessive mutations in the AMH gene or AMHR-II gene.^[2]

Differential diagnoses of PMDS include mixed gonadal dysgenesis, congenital hypogonadotropic hypogonadism, and ovotesticular DSD. Congenital hypogonadotropic hypogonadism is characterized by low luteinizing hormone (LH) and follicle-stimulating hormone (FSH), whereas LH and FSH levels are normal in PMDS.^[6] Ovotesticular DSD is characterized by the presence of both ovarian and testicular tissues. The karyotype is almost always 46,XX or rarely 46,XX/46,XY (chimerism) or 46,XX/47,XXY.^[7] Mixed gonadal dysgenesis is characterized by streak gonads, persistent Müllerian duct structures, and ambiguous genitalia.^[8]

Even though in our case, T/DHT was high, suggestive of 5-alpha-reductase deficiency, the clinical picture and laparoscopic findings were not suggestive of the same. This test has limited sensitivity for diagnosing 5-alpha-reductase deficiency, as the testosterone to DHT ratio can fluctuate depending on factors such as the severity of the enzyme deficiency and the child’s age.^[9]

Clinical diagnosis is difficult. PMDS cases are at high risk of testicular malignancies (5–18% risk, up to 33% in some studies), the most common being seminoma. Children with PMDS should be reared as males.^[10] PMDS management is done by a multidisciplinary team of surgeons and endocrinologists. Correct management of PMDS requires early identification of undescended testis, hormonal and chromosomal studies, and confirmation with testicular biopsy. Distinguishing PMDS from other DSDs is important as management is different.^[2] In suspected cases, imaging (USG or MRI) and serum AMH levels help in diagnosis.^[11]

Orchidopexy is performed to relocate the testis into the scrotum, if possible, or to a suprascrotal position to maintain fertility. Orchidectomy is recommended when there is evidence of malignant transformation in the testes or presence of dysgenetic gonads. To preserve virilization capacity, routine orchidectomy should not be done. The current recommendation for PMDS includes bilateral proximal salpingectomy and hysterectomy, leaving intact pedicles of myometrium near the lateral walls of the uterus, as it lies close to the vas deferens. Testicular vasculature should be preserved for the viability of the testes.^[12]