Persistent Müllerian duct syndrome due to anti-Müllerian hormone receptor 2 microdeletions: a diagnostic challenge

Tosca, Lucie; Giltay, Jacques C.; Bouvattier, Claire; Klijn, Aart J.; Bouligand, Jérôme; Lambert, Alain; Lecerf, Laure; Josso, Nathalie; Tachdjian, Gérard; Picard, Jean‐Yves

doi:10.1093/humrep/deaa014

Cited by 6 publications

(4 citation statements)

References 20 publications

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“…Adding with our patients in China, there were 93 families with 78 different variants in AMH ( Supplementary Table 2 ) and 94 families with 80 different variants in AMHR2 have been reported ( Supplementary Table 3 ). 6 8 9 10 11 12 13 14 15 16 The relationship between the phenotypes and genotype of all patients was analyzed statistically ( ). There was no significant difference in anatomy between patients with either AMH or AMHR2 variants.…”

Section: Resultsmentioning

confidence: 99%

“…In our literature review, variants of AMH and AMHR2 were reported in 87.9% of all patients and were approximately equally distributed among the genes coding AMH and its type II receptor, AMHR2 . 6 8 9 10 11 12 13 14 15 16 Statistics indicated that AMH presented 78 different variants in 93 families, and 80 different alleles of AMHR2 were discovered in 94 families. In our Chinese patients, mutational analyses revealed possible causative variants in all patients.…”

Section: Discussionmentioning

confidence: 99%

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Surgical management and molecular diagnosis of persistent Müllerian duct syndrome in Chinese patients

Tian

et al. 2022

Asian Journal of Andrology

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Persistent Müllerian duct syndrome (PMDS) is a rare clinically and genetically overlapping disorder caused by mutations in the anti-Müllerian hormone ( AMH ) gene or the anti-Müllerian hormone receptor type 2 ( AMHR2 ) gene. Affected individuals present uterus and tubes in normally virilized males and are discovered unexpectedly during other surgeries. Since it is rare and complex, a definitive clinical diagnosis can be missed, and there are no guidelines regarding how to deal with the uterus. In the present study, exome sequencing and Sanger verification were performed for causal variants in 12 PMDS patients. Preoperative diagnoses were made by positive exome sequencing in 8 patients. Of them, 7 patients evoked on the basis of ultrasound indicating bilateral testes on the same side of the body. Twelve different AMH variants (2 frameshift/nonsense, 1 deletion, 8 missense, and 1 in-frame) in 9 patients and 6 different AMHR2 variants (5 missense and 1 splicing) in 3 patients were identified. Seven variants were classified as “pathogenic” or “likely pathogenic”, and 4 of them were novel. All but two patients with AMH defects showed low serum AMH concentrations, but all patients with AMHR2 defects showed elevated AMH levels. During surgery, an abnormal vas deferens was observed in half of the patients. Eight patients underwent orchidopexy with uterine preservation. Of them, 2 patients presented complications including irreducible cryptorchidism, and 3 patients developed Müllerian remnant cysts. Three patients underwent subtotal hysterectomy. Of them, one patient had complication of injury to the vas deferens, and one had hemorrhage after operation. This is the first report of PMDS involving a large Chinese population. The present study not only expands the variation spectrum but also provides clinical experience about the management of the uterus.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Surgical management and molecular diagnosis of persistent Müllerian duct syndrome in Chinese patients

Tian

et al. 2022

Asian Journal of Andrology

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“…Although all types of variants have been described in exons 1-11 and in introns 2, 5, 7, and 8, a 27-bp deletion in exon 10, c.1332_1358del, has been reported in 32 families, representing by far the most frequent variant found in patients with PMDS. Recently, the first cases resulting from microdeletions of 12q13.13, where AMHR2 maps, were identified using high-resolution array CGH [Tosca et al, 2020]. In 1 case, a homozygous microdeletion of 11.39 kb removed exons 7-11 and extended beyond the AMHR2 gene, while in the second case, the whole AMHR2 gene was deleted.…”

Section: Amhr2 Gene Variantsmentioning

confidence: 99%

AMH and AMHR2 Involvement in Congenital Disorders of Sex Development

Brunello¹,

Rey²

2021

Sex Dev

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Anti-müllerian hormone (AMH) is 1 of the 2 testicular hormones involved in male development of the genitalia during fetal life. When the testes differentiate, AMH is secreted by Sertoli cells and binds to its specific receptor type II (AMHR2) on the müllerian ducts, inducing their regression. In the female fetus, the lack of AMH allows the müllerian ducts to form the fallopian tubes, the uterus, and the upper part of the vagina. The human AMH gene maps to 19p13.3 and consists of 5 exons and 4 introns spanning 2,764 bp. The AMHR2 gene maps to 12q13.13, consists of 11 exons, and is 7,817 bp long. Defects in the AMH pathway are the underlying etiology of a subgroup of disorders of sex development (DSD) in 46,XY patients. The condition is known as the persistent müllerian duct syndrome (PMDS), characterized by the existence of a uterus and fallopian tubes in a boy with normally virilized external genitalia. Approximately 200 cases of patients with PMDS have been reported to date with clinical, biochemical, and molecular genetic characterization. An updated review is provided in this paper. With highly sensitive techniques, AMH and AMHR2 expression has also been detected in other tissues, and massive sequencing technologies have unveiled variants in AMH and AMHR2 genes in hitherto unsuspected conditions.

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“…The persistent Müllerian duct syndrome (PMDS) is a rare disorder characterized by the persistence of Müllerian derivatives in an otherwise normally virilized 46, XY male. It is usually caused by mutations in either the anti-Müllerian hormone (AMH) or AMH receptor type 2 (AMHR2) genes [14].…”

Section: Abnormal Sexual Developmentmentioning

confidence: 99%

Genetic Explanations for Fertility Disorders

Geraedts¹

2020

OBM Genetics

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This article reviews the genetic testing of infertility disorders. Genetic abnormalities can lead to disturbances of sexual development and hamper reproduction by influencing gamete production and maturation, fertilization, and embryonic development. Until now, the vast majority of detectable genetic abnormalities causing infertility were chromosomal abnormalities in both males and females. However, the number of monogenetic disorders, which play a role in disturbing fertility, such as single gene defects or complex disorders involving multiple genes in combination with environmental factors, is increasing. The common genetic causes of infertility in males are sex chromosomal abnormalities, Robertsonian translocations, cystic fibrosis transmembrane conductance regulator (CFTR) mutations, and Y chromosome microdeletions. In females, Turner syndrome, genetic causes of premature ovarian failure, such as fra(X) and complex disorders like polycystic ovary syndrome (PCOS), and endometriosis are the most prevailing. However, insight into the total impact of genetic abnormalities is increasing. This is because a growing number of mutations are detected among subfertile patients with an unknown etiology. Genetics is one of the most important yet under-emphasized causes of subfertility. Improved understanding of the genetics of infertility holds promise to define the etiology and counsel cases that were previously diagnosed with idiopathic infertility.

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Persistent Müllerian duct syndrome due to anti-Müllerian hormone receptor 2 microdeletions: a diagnostic challenge

Cited by 6 publications

References 20 publications

Surgical management and molecular diagnosis of persistent Müllerian duct syndrome in Chinese patients

Surgical management and molecular diagnosis of persistent Müllerian duct syndrome in Chinese patients

AMH and AMHR2 Involvement in Congenital Disorders of Sex Development

Genetic Explanations for Fertility Disorders

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