J Pediatr Endocrinol Metab 2015; aop
Patient report Özlem Nalbantoğlu, Korcan Demir*, Hüseyin Anıl Korkmaz, Muammer Büyükinan, Melek Yıldız, Selma Tunç and Behzat Özkan
A novel mutation of AMH in three siblings with persistent Mullerian duct syndrome DOI 10.1515/jpem-2014-0501 Received December 5, 2014; accepted May 14, 2015
Abstract Background: Persistent Mullerian duct syndrome (PMDS) is a rare form of male 46,XY disorder of sex development characterized by the presence of Mullerian duct derivatives in otherwise phenotypically normal males. Aim: To report a novel mutation of the anti-Mullerian hormone (AMH) gene in two of three siblings with PMDS. Cases: A 2-year-old male presented with recurrent leftsided inguinal hernia and absence of right testis. Laparoscopic surgery disclosed Mullerian duct derivates and transverse testicular ectopia. AMH level was found to be low [1.6 ng/mL (normal range 7.4–373.1), 11.42 pmol/L (normal range 52.8–2663.9)]. His 15-year-old and 7-year-old elder brothers were invited, and bilateral undescended testes were noted upon examination. Female reproductive structures were identified during surgery but no transverse testicular ectopia. All cases had 46,XY karyotype. Genetic analyses could be done in two of them and a unique homozygous T to C base substitution was found at position 1591 in the AMH gene. Conclusion: This is the first report of the AMH gene mutation which is referred as p.Y531H (c.1591T > C), which resulted in different phenotypes of PMDS in three siblings. Keywords: anti-Mullerian hormone; persistent Mullerian duct syndrome; 46,XY DSD.
*Corresponding author: Dr. Korcan Demir, Division of Pediatric Endocrinology, Dr. Behçet Uz Children’s Hospital, İzmir, Turkey, Phone: +90 232 4116318, E-mail: [email protected] Özlem Nalbantoğlu, Hüseyin Anıl Korkmaz, Melek Yıldız, Selma Tunç and Behzat Özkan: Division of Pediatric Endocrinology, Dr. Behçet Uz Children’s Hospital, İzmir Muammer Büyükinan: Division of Pediatric Endocrinology, Dr. Behçet Uz Children’s Hospital, İzmir; and Division of Pediatric Endocrinology, Konya Research and Training Hospital, Konya
Introduction Persistent Mullerian duct syndrome (PMDS) is a rare form of 46,XY disorder of sex development (DSD) characterized by the presence of Mullerian duct derivatives in otherwise phenotypically normal males (1). During the first 8 weeks of gestation, both Mullerian and Wollfian ducts are present. Sex differentiation in males is mediated by two hormones produced by the fetal testis. Leydig cells produce testosterone, which ensure the stabilization of the Wolffian ducts and virilization of the external genitalia. Anti-Mullerian hormone (AMH) [also known as Mullerian inhibiting factor (MIF) or substance (MIS)] is a glycoprotein member of the transforming factor β (TGF-β) superfamily. AMH is secreted by Sertoli cells and causes regression of Mullerian ducts, namely fallopian tubes, uterus, and upper vagina (2, 3). AMH is encoded by AMH, located in 19p13.3 and contains 5 exons, while its receptor is a product of AMHR2, which contains 11 exons and is located on chromosome 12q13.13 (4). PMDS is either caused by the deficiency of anti-Mullerian hormone synthesis, an abnormality in AMH receptor or a defect in the timing of the release of AMH (1). Mutations in the gene encoding AMH (AMH, OMIM 600957) or in the AMH receptor gene (AMHR2, OMIM 600956) are referred to as PMDS type I and type II, respectively. Approximately 150 new cases have been reported since Nilson first described PMDS in 1939 (4, 5). Although most of the cases are isolated, some of the cases may be inherited as X-linked, autosomal dominant, or autosomal recessive (6, 7). Here, we report a novel homozygous mutation in the AMH gene in two of three siblings with PMDS.
Case Reports Results of the clinical, surgical, histopathological, laboratory, and genetic analyses are summarized in Table 1.
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2 Nalbantoğlu et al.: AMH mutation and Mullerian duct syndrome Table 1: Clinical and laboratory findings of the cases.
Age, year Clinical summary
Laparoscopic findings
Case 1
2 Recurrent inguinal hernia Undescended right testis Normal penile size Left inguinal hernia Two gonadal structures in left inguinal canal Rudimentary uterus Mature testes without spermatogenetic activity 1.6 ng/mL (7.4–373.1) Homozygous p.Y531H (c.1591T > C)
Histopathological findings of testes AMH Genetic analysis
The Institutional Review Board Committee approved this study.
Case 1 A 2-year-old male (Figure 1, II.4) presented with a recurrent left-sided inguinal hernia and absence of the right testis. He had undergone a previous exploration for left inguinal hernia 4 months ago at another hospital. Swelling on his left inguinal region was present for the last 20 days. Past medical history was unremarkable, except the 2nd degree consanguinity between his parents. Physical examination revealed irreducible left inguinal hernia with undescended right testis. He had a normal-sized penis. Ultrasonography revealed absence of right gonad and left testis located in the left inguinal canal. He was referred to the pediatric surgery department for explorative laparoscopy. At exploration through the left inguinal canal, indirect inguinal hernia containing two testes separated by female reproductive structures (a rudimentary uterus and round ligaments) was
Figure 1: Pedigree of the family.
Case 2
Case 3
7 Bilateral undescended testes Normal penile size Bilateral abdominal testes Rudimentary uterus and tuba uterina Bilateral normal testes
15 Bilateral undescended testes Normal penile size
Not available Homozygous p.Y531H (c.1591T > C)
Not available Not available
Bilateral abdominal testes Rudimentary uterus and tuba uterina Bilateral normal testes
observed and subsequently repaired. After taking wedge biopsies from two gonads, one of the testes was mobilized and placed in the right subdartos pouch through the right inguinal canal, and the other testis was left in its original position. Normal testicular findings were detected on histopathological examination. A low level of AMH was found 11.42 pmol/L (1.6 ng/mL) (normal range, 52.8– 2663.9 pmol/L and 7.4–373 ng/mL). The levels of FSH, LH, and total testosterone comparable with prepubertal levels were 0.2 IU/L, 0.1 IU/L and C) mutation may result in different PMDS phenotypes. Acknowledgments: We would like to thank Dr. S. C eylaner and Dr. K. Karaer (Intergen Genetics Center, Ankara, Turkey) for the molecular analyses.
References 1. Neeraj P, Anuj K, Bhawna N. Persistent Mullerian duct syndrome. Indian J Pathol Microbiol 2009;52:546–8. 2. La Marca A, Broekmans FJ, Volpe A, Fauser BC, Macklon NS. ESHRE Special Interest Group for Reproductive Endocrinology– AMH Round Table: anti-Mullerian hormone (AMH): what do we still need to know? Hum Reproduct 2009;4:2264–75. 3. Rey RA, Grinspon RP. Normal male sexual differentiation and aetiology of disorders of sex development. Best Pract Res Clin Endocrinol Metab 2011;25:221–38.
4. 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. 5. di Clemente N, Belville C. Anti-Müllerian hormone receptor defect. Best Pract Res Clin Endocrinol Metab 2006;20:599–610. 6. Berkmen F. Persistent mullerian duct syndrome with or without transverse testicular ectopia and testis tumours. Br J Urol 1997;79:122–6. 7. Shamim M. Persistent Mullerian duct syndrome with transverse testicular ectopia presenting in an irreducible recurrent inguinal hernia. J Pak Med Assoc 2007;57:421–3. 8. El-Gohary MA. Laparoscopic management of persistent müllerian duct syndrome. Pediatr Surg Int 2003;19:533–6. 9. Manjunath BG, Shenoy VG, Raj P. Persistent müllerian duct syndrome: how to deal with the müllerian duct remnants – a review. Indian J Surg 2010;72:16–9. 10. Bergada I, Milani C, Bedecarras P, Andreone L, Ropelato MG, et al. Time course of the serum gonadotropin surge, inhibins, and anti-Mullerian hormone in normal newborn males during the first month of life. J Clin Endocrinol Metab 2006;91:4092–8. 11. Aksglaede L, Sorensen K, Boas M, Mouritsen A, Hagen CP, et al. Changes in anti-Müllerian hormone (AMH) throughout the life span: a population-based study of 1027 healthy males from birth (cord blood) to the age of 69 years. J Clin Endocrinol Metab 2010;95:5357–64. 12. Elchuri SV, Patterson BC, Brown MR, Buchanan I, Mertens AC, et al. Anti-Mullerian hormone levels in American girls by age and race/ethnicity. J Pediatr Endocrinol Metab 2015;28:189–93. 13. Josso N, Rey R, Picard JY. Testicular anti-Mullerian hormone: clinical applications in DSD. Semin Reprod Med 2012;30:364–73. 14. Belville C, Van Vlijmen H, Ehrenfels C, Pepinsky B, Rezaie AR, et al. Mutations of the anti-Mullerian hormone gene in patients with persistent Mullerian duct syndrome: biosynthesis, secretion, and processing of the abnormal proteins and analysis using a three dimensional model. Mol Endocrinol 2004;18:708–21. 15. Telli O, Gökçe MI, Haciyev P, Soygür T, Burgu B. Transverse testicular ectopia: a rare presentation with persistent müllerian duct syndrome. J Clin Res Pediatr Endocrinol 2014;6:180–2. 16. Alp BF, Demirer Z, Gürağaç A, Babacan O, Sarı E, et al. Persistent Mullerian duct syndrome with transverse testicular ectopia and seminoma. Int Urol Nephrol 2014;46:1557–62. 17. Renu D, Rao BG, Ranganath K, Namitha. Persistent Mullerian duct syndrome. Indian J Radiol Imaging 2010;20:72–4. 18. Mazen I, Abdel Hamid M, El-Gammal M, Aref A, Amr K. AMH gene mutations in two Egyptian families with persistent müllerian duct syndrome. Sex Dev 2011;5:277–80.
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Patient report Özlem Nalbantoğlu, Korcan Demir*, Hüseyin Anıl Korkmaz, Muammer Büyükinan, Melek Yıldız, Selma Tunç and Behzat Özkan
A novel mutation of AMH in three siblings with persistent Mullerian duct syndrome DOI 10.1515/jpem-2014-0501 Received December 5, 2014; accepted May 14, 2015
Abstract Background: Persistent Mullerian duct syndrome (PMDS) is a rare form of male 46,XY disorder of sex development characterized by the presence of Mullerian duct derivatives in otherwise phenotypically normal males. Aim: To report a novel mutation of the anti-Mullerian hormone (AMH) gene in two of three siblings with PMDS. Cases: A 2-year-old male presented with recurrent leftsided inguinal hernia and absence of right testis. Laparoscopic surgery disclosed Mullerian duct derivates and transverse testicular ectopia. AMH level was found to be low [1.6 ng/mL (normal range 7.4–373.1), 11.42 pmol/L (normal range 52.8–2663.9)]. His 15-year-old and 7-year-old elder brothers were invited, and bilateral undescended testes were noted upon examination. Female reproductive structures were identified during surgery but no transverse testicular ectopia. All cases had 46,XY karyotype. Genetic analyses could be done in two of them and a unique homozygous T to C base substitution was found at position 1591 in the AMH gene. Conclusion: This is the first report of the AMH gene mutation which is referred as p.Y531H (c.1591T > C), which resulted in different phenotypes of PMDS in three siblings. Keywords: anti-Mullerian hormone; persistent Mullerian duct syndrome; 46,XY DSD.
*Corresponding author: Dr. Korcan Demir, Division of Pediatric Endocrinology, Dr. Behçet Uz Children’s Hospital, İzmir, Turkey, Phone: +90 232 4116318, E-mail: [email protected] Özlem Nalbantoğlu, Hüseyin Anıl Korkmaz, Melek Yıldız, Selma Tunç and Behzat Özkan: Division of Pediatric Endocrinology, Dr. Behçet Uz Children’s Hospital, İzmir Muammer Büyükinan: Division of Pediatric Endocrinology, Dr. Behçet Uz Children’s Hospital, İzmir; and Division of Pediatric Endocrinology, Konya Research and Training Hospital, Konya
Introduction Persistent Mullerian duct syndrome (PMDS) is a rare form of 46,XY disorder of sex development (DSD) characterized by the presence of Mullerian duct derivatives in otherwise phenotypically normal males (1). During the first 8 weeks of gestation, both Mullerian and Wollfian ducts are present. Sex differentiation in males is mediated by two hormones produced by the fetal testis. Leydig cells produce testosterone, which ensure the stabilization of the Wolffian ducts and virilization of the external genitalia. Anti-Mullerian hormone (AMH) [also known as Mullerian inhibiting factor (MIF) or substance (MIS)] is a glycoprotein member of the transforming factor β (TGF-β) superfamily. AMH is secreted by Sertoli cells and causes regression of Mullerian ducts, namely fallopian tubes, uterus, and upper vagina (2, 3). AMH is encoded by AMH, located in 19p13.3 and contains 5 exons, while its receptor is a product of AMHR2, which contains 11 exons and is located on chromosome 12q13.13 (4). PMDS is either caused by the deficiency of anti-Mullerian hormone synthesis, an abnormality in AMH receptor or a defect in the timing of the release of AMH (1). Mutations in the gene encoding AMH (AMH, OMIM 600957) or in the AMH receptor gene (AMHR2, OMIM 600956) are referred to as PMDS type I and type II, respectively. Approximately 150 new cases have been reported since Nilson first described PMDS in 1939 (4, 5). Although most of the cases are isolated, some of the cases may be inherited as X-linked, autosomal dominant, or autosomal recessive (6, 7). Here, we report a novel homozygous mutation in the AMH gene in two of three siblings with PMDS.
Case Reports Results of the clinical, surgical, histopathological, laboratory, and genetic analyses are summarized in Table 1.
Brought to you by | Stockholms Universitet Authenticated Download Date | 7/24/15 3:06 PM
2 Nalbantoğlu et al.: AMH mutation and Mullerian duct syndrome Table 1: Clinical and laboratory findings of the cases.
Age, year Clinical summary
Laparoscopic findings
Case 1
2 Recurrent inguinal hernia Undescended right testis Normal penile size Left inguinal hernia Two gonadal structures in left inguinal canal Rudimentary uterus Mature testes without spermatogenetic activity 1.6 ng/mL (7.4–373.1) Homozygous p.Y531H (c.1591T > C)
Histopathological findings of testes AMH Genetic analysis
The Institutional Review Board Committee approved this study.
Case 1 A 2-year-old male (Figure 1, II.4) presented with a recurrent left-sided inguinal hernia and absence of the right testis. He had undergone a previous exploration for left inguinal hernia 4 months ago at another hospital. Swelling on his left inguinal region was present for the last 20 days. Past medical history was unremarkable, except the 2nd degree consanguinity between his parents. Physical examination revealed irreducible left inguinal hernia with undescended right testis. He had a normal-sized penis. Ultrasonography revealed absence of right gonad and left testis located in the left inguinal canal. He was referred to the pediatric surgery department for explorative laparoscopy. At exploration through the left inguinal canal, indirect inguinal hernia containing two testes separated by female reproductive structures (a rudimentary uterus and round ligaments) was
Figure 1: Pedigree of the family.
Case 2
Case 3
7 Bilateral undescended testes Normal penile size Bilateral abdominal testes Rudimentary uterus and tuba uterina Bilateral normal testes
15 Bilateral undescended testes Normal penile size
Not available Homozygous p.Y531H (c.1591T > C)
Not available Not available
Bilateral abdominal testes Rudimentary uterus and tuba uterina Bilateral normal testes
observed and subsequently repaired. After taking wedge biopsies from two gonads, one of the testes was mobilized and placed in the right subdartos pouch through the right inguinal canal, and the other testis was left in its original position. Normal testicular findings were detected on histopathological examination. A low level of AMH was found 11.42 pmol/L (1.6 ng/mL) (normal range, 52.8– 2663.9 pmol/L and 7.4–373 ng/mL). The levels of FSH, LH, and total testosterone comparable with prepubertal levels were 0.2 IU/L, 0.1 IU/L and C) mutation may result in different PMDS phenotypes. Acknowledgments: We would like to thank Dr. S. C eylaner and Dr. K. Karaer (Intergen Genetics Center, Ankara, Turkey) for the molecular analyses.
References 1. Neeraj P, Anuj K, Bhawna N. Persistent Mullerian duct syndrome. Indian J Pathol Microbiol 2009;52:546–8. 2. La Marca A, Broekmans FJ, Volpe A, Fauser BC, Macklon NS. ESHRE Special Interest Group for Reproductive Endocrinology– AMH Round Table: anti-Mullerian hormone (AMH): what do we still need to know? Hum Reproduct 2009;4:2264–75. 3. Rey RA, Grinspon RP. Normal male sexual differentiation and aetiology of disorders of sex development. Best Pract Res Clin Endocrinol Metab 2011;25:221–38.
4. 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. 5. di Clemente N, Belville C. Anti-Müllerian hormone receptor defect. Best Pract Res Clin Endocrinol Metab 2006;20:599–610. 6. Berkmen F. Persistent mullerian duct syndrome with or without transverse testicular ectopia and testis tumours. Br J Urol 1997;79:122–6. 7. Shamim M. Persistent Mullerian duct syndrome with transverse testicular ectopia presenting in an irreducible recurrent inguinal hernia. J Pak Med Assoc 2007;57:421–3. 8. El-Gohary MA. Laparoscopic management of persistent müllerian duct syndrome. Pediatr Surg Int 2003;19:533–6. 9. Manjunath BG, Shenoy VG, Raj P. Persistent müllerian duct syndrome: how to deal with the müllerian duct remnants – a review. Indian J Surg 2010;72:16–9. 10. Bergada I, Milani C, Bedecarras P, Andreone L, Ropelato MG, et al. Time course of the serum gonadotropin surge, inhibins, and anti-Mullerian hormone in normal newborn males during the first month of life. J Clin Endocrinol Metab 2006;91:4092–8. 11. Aksglaede L, Sorensen K, Boas M, Mouritsen A, Hagen CP, et al. Changes in anti-Müllerian hormone (AMH) throughout the life span: a population-based study of 1027 healthy males from birth (cord blood) to the age of 69 years. J Clin Endocrinol Metab 2010;95:5357–64. 12. Elchuri SV, Patterson BC, Brown MR, Buchanan I, Mertens AC, et al. Anti-Mullerian hormone levels in American girls by age and race/ethnicity. J Pediatr Endocrinol Metab 2015;28:189–93. 13. Josso N, Rey R, Picard JY. Testicular anti-Mullerian hormone: clinical applications in DSD. Semin Reprod Med 2012;30:364–73. 14. Belville C, Van Vlijmen H, Ehrenfels C, Pepinsky B, Rezaie AR, et al. Mutations of the anti-Mullerian hormone gene in patients with persistent Mullerian duct syndrome: biosynthesis, secretion, and processing of the abnormal proteins and analysis using a three dimensional model. Mol Endocrinol 2004;18:708–21. 15. Telli O, Gökçe MI, Haciyev P, Soygür T, Burgu B. Transverse testicular ectopia: a rare presentation with persistent müllerian duct syndrome. J Clin Res Pediatr Endocrinol 2014;6:180–2. 16. Alp BF, Demirer Z, Gürağaç A, Babacan O, Sarı E, et al. Persistent Mullerian duct syndrome with transverse testicular ectopia and seminoma. Int Urol Nephrol 2014;46:1557–62. 17. Renu D, Rao BG, Ranganath K, Namitha. Persistent Mullerian duct syndrome. Indian J Radiol Imaging 2010;20:72–4. 18. Mazen I, Abdel Hamid M, El-Gammal M, Aref A, Amr K. AMH gene mutations in two Egyptian families with persistent müllerian duct syndrome. Sex Dev 2011;5:277–80.
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