Assisted Reproduction and Infertility
Patients with PMDS are 46 XY genetic males, as there are no chromosomal abnormalities. Males are symptomatic, whereas female relatives are fertile and phenotypically normal.65
Usually, examination
of the neonate reveals uni- or bi-lateral cryptorchidism, and during surgery the Müllerian derivatives, tightly attached to the testes, are discovered. In the majority of cases, one testis has descended and dragged the fallopian tube.65
normal and contain germ cells,65
Usually, both testes are histologically but the fertility of the patient
depends on replacing the testes in the scrotum during orchidopexy.65 This is not always possible, as testes are often not properly connected to the male excretory ducts as a result of aplasia of the epididymis and the upper vas deferens region.
Josso et al.65 studied 82 families with PMDS in 2005 and found that 38
(46%) had a mutation in the AMH gene and 33 (40%) in the MIRSII gene. In the remaining 11 families, both genes were normal. In these cases it is supposed that the syndrome is due to complex malformations of the urogenital tract or to mutations after the activation of AMH/MIRSII. The AMH gene mutations were detected along the whole length of the gene except for exon 4, frequently in exon 1 and the 3’ end of exon 5 encoding the C-terminus, a region of recurrent mutations. The majority of mutant proteins failed to be secreted, whereas those with a deletion at the C-terminus secreted faster.77
Of the MIRSII mutations, the most common is a deletion of 27bp on exon 10 (del6331–6357).78
In 2010, this deletion was detected in a
seven-month-old male infant and his seven-year-old brother.79 Mutations in the intracellular domain (i.e. R406Q) result in a binding- site defect in the kinase domain and failure to transduce the signal.80 On the other hand, mutations in the extracellular domain usually impair the secretory phase by preventing migration of the receptor to the cell surface.81
Menabò et al.82 reported three novel AMH gene
mutations: p.A405P in the paternal allele and p.G326V and p.V508A in the maternal allele.
Two anatomical variants of PMDS have been recognised:83 the male
type and the female type. The most common form (80–90%) is the male type, which is characterised by unilateral cryptorchidism with a contralateral inguinal hernia (hernia uteri inguinalis). When there is herniation of both testes, the entire uterus and both oviducts, it is called transverse testicular ectopia.84–86
the syndrome (10–20%) is known as bilateral cryptorchidism.87 The uterus is placed in the pelvis and the two testes are located in an ‘ovarian’ position. Co-existence of PMDS, transverse testicular ectopia and mosaic Klinefelter’s syndrome (46XY/47XXY) has recently been reported.88
There are also two biological forms of Kleinfelter’s syndrome,89 depending on the serum levels of circulating AMH. AMH-positive males, as MIRSII mutants, have normal-for-age AMH levels, whereas AMH-negative patients have low or undetectable levels of the protein as the mutation is located on the AMH gene.
Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is also subdivided into two types: type I (isolated) or Rokitansky sequence, and type II or Müllerian renal cervical somite (MURCS) association. Female patients, who usually present at adolescence with primary amenorrhoea but no signs of androgen excess, have a normal 46XX karyotype, normal development of secondary sexual characteristics and normal external
10
genitalia and normal ovaries, but there is aplasia of the uterus and upper two-thirds of the vagina. The lower third of the vagina is normal because of the different embryonic origin. The incidence of the syndrome is approximately 1:4,500 female births.90,91 cases are sporadic.90
The majority of
However, cases of MURCS and azoospermia, renal anomalies, cervicothoracic spine dysplasia (ARCS), the corresponding term for males, have been found in the same family, proving that familial occurrence has been underestimated.92
Evidence indicates that MRKH is transmitted in an autosomal dominant manner with an incomplete degree of penetrance and variable expressivity of a single mutant gene.90,93
Chromosome
abnormalities in association with Müllerian agenesis are rare and involve the X chromosome.94–96
The type I form of the syndrome is
characterised by complete uterus aplasia and two rudimentary horns linked by a peritoneal fold and normal oviducts. MURCS,97
which is
more common, is characterised by symmetrical or asymmetrical uterine hypoplasia, aplasia or dysplasia of one of the two horns, with or without defects of the oviducts.98
Although the aetiology of the syndrome remains unclear, it has been hypothesised that there is a defect in the fourth week of gestation in the intermediate mesoderm, leading to malformations of the blastema, cervicothoracic somites and pronephric ducts.99 phosphate uridyl-transferase,100,101
the cystic fibrosis transmembrane conductance regulator gene102 and the AMH/MISRII gene have not been
proved to be responsible for the syndrome. The TCF2 (Hnf1b) gene,103 Hox genes (Hox7–Hox13 and PBX1)104
and beta-catenin gene105 also examined, but no involvement was detected.
A loss-of-function mutation of the Wnt4a gene in an 18-year-old girl has been documented.106
A defect in the gene results in The girl had a hyperandogenic phenotype in
association with the absence of Müllerian duct derivatives. It is known that the Wnt4a protein suppresses genes encoding the steroidogenic enzymes CYP17A1 and HSB3132.107
masculinisation of the foetal gonad and the production of androgens. In 2006, a similar case of Wnt4 deficiency was reported,108
the existence of a new syndrome, separate from MRKH,109
indicating given the
fact that the Wnt4a gene was not found to be mutated in 19 cases of females with MRKH syndrome without androgen excess.110,111
The female form of In 28
DNA samples from adolescent girls with MRKH syndrome, a new L12P mutation in exon 1 of the Wnt4a gene was identified that induces the enzymes involved in androgen biosynthesis.112
It has not been proved
that mutations in the coding sequence of Wnt5a, Wnt7a and Wnt9b are responsible for MRKH.113
Recently, research has supported a polygenic aetiology of MRKH syndrome due to the detection of interstitial and terminal deletions of many genes in chromosomes 22,114
4115 Conclusion
Expression profiling and functional analysis of many genes have illuminated the molecular basis of genetic defects of the female reproductive tract. Several questions of major importance remain unanswered, however. Furthermore, the role and implication of these genes in the pathology of cancer and infertility in adult women remain to be clarified. More experiments are needed to shed light on the genetic pathways of congenital anomalies of the female genital tract. n
EUROPEAN OBSTETRICS & GYNAECOLOGY and 17q12.116 were
The galactose-1-
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