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 Table of Contents  
CASE REPORT
Year : 2020  |  Volume : 9  |  Issue : 3  |  Page : 253-256

Persistent Mullerian duct syndrome in two brothers from a Saudi family with a homozygous variant in the AMHR2 gene


King Abdulaziz Medical City, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Jeddah, Saudi Arabia

Date of Submission24-Jul-2020
Date of Decision07-Sep-2020
Date of Acceptance03-Oct-2020
Date of Web Publication07-Nov-2020

Correspondence Address:
Adnan Al Shaikh
King Abdulaziz Medical City, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Jeddah
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjhs.sjhs_169_20

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  Abstract 


Persistent Mullerian duct syndrome (PMDS) is a rare disease characterized by normal virilization and XY genotype including failure of Mullerian duct regression. In this article, we report two cases of PMDS in Saudi patients with a pathogenic homozygous variant in the AMHR2 gene and review the literature. PMDS should be taken into consideration in all cases of bilateral cryptorchidism. Laparoscopy is the elective procedure for the diagnosis of this disease, and laparoscopic surgery for orchidopexy of intra-abdominal testes is the intervention of choice. It remains unclear at present whether the anti-Mullerian hormone is necessary to maintain normal testicular function. Early surgical intervention is important to reduce the risk of malignancy. The patient and his family should be completely informed about the diagnosis, the surgical options, and the need for long-term follow-up. A genetic cause can be strongly suggested in the presence of parental consanguinity.

Keywords: Disorder of sex development, persistent Mullerian duct syndrome, phenotypic male, Saudi Arabia, uterus


How to cite this article:
Al Shaikh A, Shirah B. Persistent Mullerian duct syndrome in two brothers from a Saudi family with a homozygous variant in the AMHR2 gene. Saudi J Health Sci 2020;9:253-6

How to cite this URL:
Al Shaikh A, Shirah B. Persistent Mullerian duct syndrome in two brothers from a Saudi family with a homozygous variant in the AMHR2 gene. Saudi J Health Sci [serial online] 2020 [cited 2021 Jan 20];9:253-6. Available from: https://www.saudijhealthsci.org/text.asp?2020/9/3/253/300288




  Introduction Top


Persistent Mullerian duct syndrome (PMDS) is an uncommon disease, which presents itself with normal virilization and XY genotype with failure of Mullerian duct regression.[1] Nilson first described the condition in 1939 and named it hernia uteri inguinale.[2] From then on, over 250 incidences have been described.[3] The prevalent appearance is in children with a normal phallus, one inguinal, and one scrotal testis. In addition, a presentation of transverse testicular ectopia or bilateral cryptorchidism has been seen.[4] It also has alternative titles such as pseudohermaphroditism, male internal hernia uteri inguinale, persistent oviduct syndrome, and female genital ducts in an otherwise normal male.[4] Testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) appear normal; prepubertal testicular histology also appears normal. Unilateral cryptorchidism is mostly seen, whereas bilateral cryptorchidism accounts for only an estimated 10% ectopic transverse testicular tissue (i.e., both testes migrate through one inguinal canal, usually the left in one hemiscrotum and the opposite inguinal canal and scrotum are empty). In this occurrence, spermatogenesis is damaged, including the descended testicle.[5] In this article, we aim to present two cases of PMDS in Saudi patients and a review of the literature.


  Case Reports Top


Case 1

An 18-month old male was referred to the pediatric surgery clinic with bilateral undescended testis discovered at birth. He was a product of full-term spontaneous vaginal delivery with normal birth parameters. His parents were consanguineous, and he had five sisters and a younger brother with the same problem. There was no family history of any urogenital anomalies, except in his younger brother who was diagnosed later. Full newborn examination was normal including normal male external genitalia apart from the bilateral undescended testis. He had normal growth and development. Genital examination displayed phallus (5 cm) in length with normal urethral opening, empty scrotum, and normal scrotal enlarging sac. The patient was admitted for elective laparoscopic evaluation, followed by orchidopexy. At laparoscopy, there was no vas deference in the usual location neither gonadal vessels. On the right side, there was a tubular structure entering into the internal ring and medially joining what looks like a uterus shape structure with bilateral gonads, initially interpreted as ovarian tissues. To further explore the area, a lower abdominal incision was made. Two fallopian tubes were discovered within the pelvic peritoneum adjacent to the two gonads which receive their blood supply along the Mullerian duct remnants [Figure 1]. Bilateral longitudinal biopsies were taken from gonads and sent for histopathology. This was followed by the primary analysis during surgery. in the event of complete virilization, there is a high androgen level antenatal; the presence of a uterus indicates absent anti-Mullerian hormone (AMH) function. The postoperative course was uneventful. The gonads were found to be testes by histological examination. Further laboratory testing was done. Chromosomal analysis showed 46XY, confirming normal male karyotype. Serum electrolytes were normal, testosterone level <0.4 nmol/l (normal: 0–1.0 nmol/l), dehydroepiandrosterone sulfate 0.4 umol/l (normal 2.2–15.2 umol/l), and 17(OH) P < 0.3 nmol/l (normal: 0.1–2.7 nmol/l). Serum AMH was elevated at 110.40 pmol/L (normal: 15.30–72.10 pmol/L).
Figure 1: Intraoperative images showing normal virilization, uterus, fallopian tubes, and two gonads with no vas deference seen in the normal position

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Whole exome sequencing (WES) identified the homozygous variant c.994C>T p.(Arg332*) in AMHR2 (OMIM: 600956) which leads to a premature stop codon and subsequent mRNA degradation (nonsense-mediated decay) or truncation of the protein. Parallel analysis of the WES data revealed that the affected brother is also homozygous for the detected variant in AMHR2. The variant is found in 0.00092% of the overall population (1 heterozygous, 0 homozygous in gnomAD). Considering the available information, the variant is classified as pathogenic.

The diagnosis was made as PMDS, and further counseling was done to the parent with explanation given regarding the modes of management. The patient underwent another surgical procedure, where the uterus was removed as well as the fallopian tubes were removed bilaterally. Right testis orchidopexy was done, but unfortunately, the left testis atrophied and was removed. The boy continued to follow-up with the pediatric endocrinology clinic and was last seen at 7 years. Genital examination was done in the last clinic visit showed a penile length of 7 cm, palpable right testis, nonpalpable left testis, and a suprapubic scar. Laboratory tests showed low levels of LH, FSH, and testosterone. Testicular ultrasound was done and showed an empty left-sided scrotal sac. The right side demonstrated homogeneous bilobed right testis, which measures 2.4 cm × 0.9 cm with preserved vascularity [Figure 2].
Figure 2: Testicular ultrasound showing homogeneous bilobed right testis, which measures 2.4 cm × 0.9 cm with preserved vascularity

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Case 2

A 10-month-old male was referred to the pediatric surgery clinic with left testicular ectopia and right empty scrotum discovered 1 month after birth. He was a product of full-term spontaneous vaginal delivery with normal birth parameters. His parents were consanguineous, and he had five sisters and an older brother with the same problem. There was no family history of any urogenital anomalies, except in his older brother. Full newborn examination was normal including normal male external genitalia apart from both testes being palpable at the left side in the inguinal canal with empty right scrotum. At the age of 4 months, he had a testicular ultrasound that revealed empty scrotal sacs bilaterally with both testicles seen within the left inguinal canal (left crossed testicular ectopia) [Figure 3]. He had normal growth and development. Genital examination at the age of 10 months displayed a phallus with normal urethral opening, both testes palpable in the left side, right empty scrotum, and normal scrotal enlarging sac. The patient was admitted for left inguinal approach for releasing of both testes and orchidopexy for the left side, followed by laparoscopic exploration and possibly right orchidopexy. At laparoscopy, two bilateral inguinal hernias with bilateral round ligament going through the inguinal canal and connected in the middle to the infantile rudimentary uterus were found. Two lose closely adherent vas deferens were found that attached to the two gonads; the first one was just behind the uterus in the midline with area of patchy change in different color that could be a follicle of an ovary or testis. The other one was just near the left deep inguinal ring. After consent from the family, a laparotomy was performed for total abdominal hysterectomy and bilateral orchidopexy with gonadal biopsy. The postoperative course was uneventful. Histological examination showed the gonads to be testes. In addition, histological examination of the uterus showed endometrial lining with glands, stroma, and myometrium. Further laboratory testing was done. Chromosomal analysis showed 46XY, confirming normal male karyotype. Serum electrolytes were normal, testosterone level <0.3 nmol/l (normal: 0–1.0 nmol/l), and unremarkable 17(OH) P. Serum AMH was >328.40 pmol/L (normal: 15.30–72.10 pmol/L). The remaining blood tests and renal ultrasound were normal. WES identified the same homozygous variant c.994C>T p.(Arg332*) in the AMHR2 gene similar to his older brother. The diagnosis was made as PMDS.
Figure 3: Testicular ultrasound showing empty scrotal sacs bilaterally with both testicles seen within the left inguinal canal (left crossed testicular ectopia)

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  Discussion Top


Sexual differentiation is implemented by the action of the testicular hormones, testosterone, and AMH, on the undifferentiated bipotential fetal reproductive tract. The initial phase of phenotypical sexual development ceases at an estimated 8 weeks of gestation; during this phase, both the Mullerian and Wolffian ducts are present.[6] Beyond 8 weeks in the male, local Mullerian-inhibiting substance production by the testicular Sertoli cells of 46 XY individuals initiates, which results in ipsilateral Mullerian duct regression.[7] In the absence of AMH, Mullerian ducts form into the uterus, fallopian tubes, and the upper vagina, and inversely, the shortage of testosterone synthesis or action allows the external genitalia and urogenital sinus to take on the constitutive female form.[6] On the other hand, if the testosterone production and function is normal, and there was only a lack of production or action of AMH, the opposite effect will happen; external virilization is achieved normally, and by definition, it is never linked to hypospadias, but the uterus and fallopian tubes fail to regress, defining the so-called PMDS.[6]

AMH, a glycoprotein, belongs to the transforming growth factor B family. The AMH gene has been mapped to chromosome 19 and AMH-R to chromosome 12, which is consistent with an autosomal mode of transmission. AMH interacts with the AMH receptor complex, constituted by two serine/threonine kinases.[8] AMH mutation occurs predominantly in the population of Arab or Mediterranean countries, distinguished with a high rate of consanguinity; 81% of patients are homozygous. Inversely, patients with AMH-R mutations predominantly originate in Northern Europe, and only 45% are homozygous.[9] The parents of homozygote and compound heterozygote for AMH or AMH-R mutations are normal. PMDS can occur by a mutation in the gene encoding AMH or by a mutation in the AMH receptor, which is described as Type I and Type II, respectively.[9] Approximately 45% of PMDS patients have a mutation of the Mullerian-inhibiting substance gene, whereas 39% have a mutation in the Mullerian-inhibiting substance receptor. Finally, in 16%, no mutation for either the Mullerian-inhibiting substance gene or receptor can be found.[10] The AMH levels in patients with PMDS have an important role in indicating the type of mutation. Low or undetectable AMH level is suggestive of AMH mutation, whereas high AMH levels are more indicative of mutations in the AMHR2 gene.[7]

It is crucial to distinguish PMDS from other intersex disorders. It should be distinguished from mixed gonadal dysgenesis, which is characterized by indistinct genitalia with unilateral testis and streak gonad contralaterally, with persistent Mullerian duct structures on the side of the streak.[11] Patients usually present chromosome mosaicism of XO/XY. A karyotype and assessment of testicular tissue response to chorionic gonadotropin stimulation are needed to ascertain both genetic sexes and the presence of functional testicular tissue.[12] We believe that testicular biopsy has to be performed for comprehensive evaluation, and the detection of Mullerian inhibitory factor using bioassay techniques, particularly in patients with bilateral cryptorchidism and in those with an inguinal hernia associated with a suspicious mass.

Although virilization is generally unaffected in patients with PMDS, fertility has rarely been reported. Infertility is common in those patients, and the prognosis for fertility remains uncertain with the absence of spermatozoa seen at semen analysis. Generally speaking, paternity is not well documented in the literature. Yet, there have been a few known incidences of fertility, although evidence of paternity was not established.[13]

Laparoscopy is a trusted procedure for bilateral cryptorchidism; furthermore, laparoscopic treatment in the setting of PMDS has been described.[14] Abdominal magnetic resonance imaging would help establish the varying structures in such patients on the basis of signal intensity characteristics and morphologic features. Abdominal magnetic resonance imaging was a beneficial instrument for visualization of the complex pelvic anatomy.[15]

The treatment of PMDS has no known professional or academic uniformity in terms of surgical intervention, due to the literature being inconsistent in the matter of risk of malignant transformation. Although the malignant transformation of gonads in PMDS has been documented previously, these were, in our opinion, presumably dysgenetic gonads.[16] The chance of testicular neoplasia in PMDS estimates the risk of neoplasia in other intra-abdominal gonads. Surgical excision of the infantile uterus and fallopian tubes risks impairment to vasa deferentia and the deferential blood supply of the testis.[17] As there is no consensus, numerous surgical techniques for Mullerian remnant removal have been posited, these include transabdominal, transvesical, and posterior with rectal retraction.[18]

In our opinion, which is shared by many, early orchidopexy is preferred, in which testicular malignancy is not changed, but is benefited from the possibility of palpation during follow-up. Compared with normally descended testis, the cryptorchid testis increases the chance of malignant tumor manifestation by 7%–35%, especially seminoma. Almost all reported tumors in PMDS occurred postpubertal. If malignancy is associated with this syndrome, the staging and treatment policy should be similar to that for other testicular tumors.[19]


  Conclusion Top


In cases of bilateral cryptorchidism, it is our view that PMDS ought to be taken into serious consideration. Imaging of the pelvis should be done to locate the testis and evaluate internal genitalia. Laparoscopy is still the popular choice for the diagnosis of this condition, and laparoscopic surgery for orchidopexy of intra-abdominal testes is the preferred mode of intervention. It remains unclear whether AMH is necessary to preserve normal testicular function. Early surgical intervention is important to reduce the risk of malignancy. It is upon our advice that the patient be well informed about the diagnosis, the laparoscopic surgical procedures, and the need for long-term follow-up. A genetic cause may be strongly suggested in the presence of parental consanguinity.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Josso N, Belville C, Di Clemente N, Picard JY. AMH and AMH receptor defects in persistent Müllerian duct syndrome. Hum Reprod Update 2005;11:351-6.  Back to cited text no. 6
    
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Josso N, Rey R, Picard JY. Testicular anti-Müllerian hormone: Clinical applications in DSD. Semin Reprod Med 2012;30:364-73.  Back to cited text no. 7
    
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Nishi MY, Domenice S, Maciel-Guerra AT, Zaba Neto A, Silva MA, Costa EM, et al. Analysis of anti-Müllerian hormone (AMH) and its receptor (AMHR2) genes in patients with persistent Müllerian duct syndrome. Arq Bras Endocrinol Metabol 2012;56:473-8. doi: 10.1590/s0004-27302012000800002. PMID: 23295284.  Back to cited text no. 9
    
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Hoshiya M, Christian BP, Cromie WJ, Kim H, Zhan Y, MacLaughlin DT, et al. Persistent Mullerian duct syndrome caused by both a 27-bp deletion and a novel splice mutation in the MIS type II receptor gene. Birth Defects Res A Clin Mol Teratol 2003;67:868-74.  Back to cited text no. 10
    
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Ocal G, Berberoğlu M, Sıklar Z, Ruhi HI, Tükün A, Camtosun E, et al. The clinical and genetic heterogeneity of mixed gonadal dysgenesis: Does “disorders of sexual development (DSD)” classification based on new Chicago consensus cover all sex chromosome DSD? Eur J Pediatr 2012;171:1497-502.  Back to cited text no. 12
    
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Saleem M, Ather U, Mirza B, Iqbal S, Sheikh A, Shaukat M, et al. Persistent Mullerian duct syndrome: A 24-year experience. J Pediatr Surg 2016;51:1721-4.  Back to cited text no. 13
    
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Alharbi KN, Khushaim AO, Alrasheed M, Akhtar M, Neimatallah M. Radiological findings in persistent Müllerian duct syndrome: Case report and review of literature. J Radiol Case Rep 2017;11:7-14.  Back to cited text no. 15
    
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Farikullah J, Ehtisham S, Nappo S, Patel L, Hennayake S. Persistent Müllerian duct syndrome: Lessons learned from managing a series of eight patients over a 10-year period and review of literature regarding malignant risk from the Müllerian remnants. BJU Int 2012;110 (11 Pt C):E1084-9.  Back to cited text no. 17
    
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[PUBMED]  [Full text]  


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