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

The persistent Müllerian duct syndrome (PMDS) is defined 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. We report the first cases of PMDS resulting from a microdeletion of the chromosomal region 12q13.13, the locus of the gene for AMHR2. One case involved a homozygous microdeletion of five exons of the AMHR2 gene. In the second case, the whole AMHR2 gene was deleted from the maternally inherited chromosome. The patient's paternal allele carried a stop mutation, which was initially thought to be homozygous by Sanger sequencing. Diagnostic methods are discussed, with an emphasis on comparative genomic hybridization and targeted massive parallel sequencing.

Hereditary persistence of alpha-fetoprotein (HPAF P): review of the literature.

Alpha-fetoprotein (AFP) serum levels are raised in several clinical conditions, ranging from non-pathological conditions to malignancies. Hereditary persistence of alpha-fetoprotein (HPAFP) is a rare benign disorder with elevated AFP levels. HPAFP is described as a benign autosomal dominantly inherited condition which is not associated with any clinical disability or additional symptoms. In the past 28 years, only 19 families have been described; due to this unfamiliarity with HPAFP, elevated AFP levels are never attributed to HPAFP. However, undiagnosed HPAFP can result in inappropriate and unnecessary treatment decisions. Therefore, HPAFP should be taken into consideration in patients with unexplained elevated AFP levels, and especially in patients with urological disorders.

Variant Klinefelter syndrome 47,X,i(X)(q10),Y and normal 46,XY karyotype in monozygotic adult twins.

Klinefelter syndrome (KS; 47, XXY) is characterized by increased body height, hypergonadotrophic hypogonadism, and infertility. We describe a patient with a variant KS (47,X,i(Xq),Y) who has a twin brother with a 46,XY karyotype. Molecular studies showed that the twins were monozygotic. The presence of an isochromosome Xq in one of two monozygotic twins allows precise investigation of its phenotypic effect. The patient was somewhat shorter (3.5 cm) and had a smaller volume of the testes (8 vs. 18 ml) as compared to his twin brother. Furthermore he had increased gonadotrophin levels and an extreme oligoasthenoteratozoospermia (OAT). These data support the view that genes on Xp cause increased body height and genes on Xq cause infertility in KS. To our knowledge this is the first report on a heterokaryotypic monozygotic twin with a variant KS.

Vesico-ureteral reflux in children with prenatally detected hydronephrosis: a systematic review.

OBJECTIVE: To investigate the value of prenatally detected hydronephrosis (PNH) as a prognostic factor for vesico-ureteral reflux (VUR). METHODS: The MEDLINE database was searched for articles on PNH and VUR published between 1980 and 2004. A total of 18 studies were identified and reviewed for various aspects. Results were separated for primary and/or secondary VUR whenever possible, because of the different underlying pathogenic mechanisms. RESULTS: There was considerable variation between the different studies with respect to methodology and study design. One of the main discrepancies was the way in which postnatal abnormalities were ascertained: by postnatal ultrasound, voiding cystourethrogram (VCUG) alone, or combined or sequential ultrasound and VCUG. Taking these limitations into account, the published data showed there to be a mean prevalence of 15% for postnatal primary VUR after PNH. Of all patients with PNH, 53% had no postnatal anomalies, whereas 29% had other anomalies, such as duplex collecting systems. CONCLUSIONS: Of all infants with PNH, 15% had primary VUR proven postnatally and 53% had no other anomalies detected. We suggest a standardized protocol for future studies, to enable better comparison of follow-up protocols. Published by John Wiley & Sons, Ltd.

An amino-terminal DAX1 (NROB1) missense mutation associated with isolated mineralocorticoid deficiency.

CONTEXT: Mutations in DAX1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome gene 1; NR0B1) cause X-linked adrenal hypoplasia congenita, a disease characterized by primary adrenal failure, testicular dysgenesis, and gonadotropin deficiency. Most DAX1 mutations are deletions, nonsense, or frameshift mutations that markedly impair its transcriptional activity. Missense mutations have been restricted to the carboxy-terminal domain and are associated with more variable clinical phenotypes. OBJECTIVE: The objective was to identify novel clinical phenotypes associated with DAX1 missense mutations. PATIENTS AND DESIGN: We investigated the genetic basis of isolated mineralocorticoid deficiency in a patient who carries a unique missense mutation (W105C) in the amino-terminal region of DAX1. RESULTS: The W105C DAX1 mutation in the proband was present in three asymptomatic hemizygous males, but it was not detected in the general population. Using in vitro studies of DAX1 expression and function in transfected cells, we demonstrate that the mutant DAX1 protein exhibits mild loss of function, whether studied for genes it represses or for genes it activates. Structure-function studies suggest that the W105C and other mutations in the aminoterminus are compensated by the presence of repeated LXXLL motifs that mediate DAX1 interactions with other proteins. CONCLUSIONS: We describe the first missense mutation in the aminoterminus of DAX1 and conclude that mutations in this region may be partially compensated by redundant functional domains. Mild DAX1 mutations may be a cause of isolated mineralocorticoid deficiency.

Is there an influence of X-chromosomal imprinting on the phenotype in Klinefelter syndrome? A clinical and molecular genetic study of 61 cases.

Studies on Turner syndrome suggested the presence of X-chromosomal-imprinted genes involved in social and verbal cognition. Imprinted genes on autosomes were shown to affect growth. Could imprinting of such genes on the X chromosome also influence psychomotor development and growth in men with Klinefelter syndrome (KS), who have a supernumerary X? We recorded anthropometric and psychomotor development parameters for 61 males with KS (age range 2-56 years). In 54 cases, we were able to assess intelligence quotient (IQ) and found that impaired speech - and motor developmental problems were reported significantly more often in the paternal X - than in the maternal X group (P = 0.02). We found some significant (P < 0.05) increased body size parameters in the paternal X group, which concurs with data reporting a growth promoting influence of paternally derived genes. Our results suggest X-chromosomal imprinting occurs in males with KS.

[From gene to disease; congenital adrenal hypoplasia and the DAX-1 gene]. / Van gen naar ziekte; congenitale bijnierschorshypoplasie en het DAX-1-gen.

Congenital adrenal hypoplasia is an X-linked disorder resulting in adrenocortical deficiency, failure to complete puberty due to hypogonadotrophic hypogonadism, and infertility. The disease is caused by mutations in the DAX-1 gene. The DAX-1 protein is a transcription inhibitor; it represses the transcription of other, as yet mostly unknown, genes. Mutation analysis can confirm a clinical diagnosis of congenital adrenal hypoplasia. An early diagnosis might prevent critical damage due to an adrenal crisis in an undiagnosed patient. Molecular testing can be used for carrier detection and genetic counselling.

Split hand/split foot, iris/choroid coloboma, hypospadias and subfertility: a new developmental malformation syndrome?

This paper presents a patient with the following malformations: split hand and split foot on the left side, a hypoplastic fifth ray of the right hand and a hypoplastic first ray of the right foot with a small cleft between the first and second ray; eye abnormalities which consist of a complete iris coloboma of the left eye in an atypical position (cranio-temporal) and a coloboma of the choroid in the right eye; a glandular hypospadias and terato-zoospermia. Since split hand/split foot can be caused by mutations in the p63 gene, mutation analysis of this gene was performed. However, sequencing analysis did not reveal a mutation. This malformation complex may represent a new syndrome.

Short stature as the only presenting feature in a patient with an isodicentric (Y)(q11.23) and gonadoblastoma. A clinical and molecular cytogenetic study.

A 13-year-old phenotypically female patient presented with short stature (height SDS -2.6), but without any Turner stigmata or other dysmorphic features. Chromosome analysis showed mosaicism for an isodicentric (idic) (Y)(q11.23) containing cell line and a 45,X cell line. Subsequent gonadectomy revealed a left streak ovary and a right ovary of abnormal appearance, which on histological examination appeared to contain a gonadoblastoma. DNA analysis showed that the proposed critical region of the gonadoblastoma locus on the Y chromosome was contained within the patient's idic (Y). Conclusion. The case described here shows that patients with 45,X/46,X, isodicentric (Yp) mosaicism and a female phenotype (1) can lack external virilisation but still have a gonadoblastoma and (2) do not necessarily have Turner stigmata but can present with only short stature. This case also underlines the importance of karyotyping patients with unexplained short stature to enable gonadectomy if Y-derived material is detected.

Analysis of spermatozoa from seven ICSI males with constitutional sex chromosomal abnormalities by fluorescent in situ hybridization.

PURPOSE: The objective was to estimate the risk for subfertile males with a constitutional sex chromosomal abnormality of transmitting such a chromosome abnormality to their children, conceived by intracytoplasmic sperm injection (ICSI). METHODS: Semen samples were obtained from seven severely oligospermic ICSI candidates. Six of them had a numerical sex chromosomal abnormality, including mosaic 45,X/46,XY, mosaic 46,XY/47, XXY, 47,XXY (Klinefelter's syndrome), and 47,XYY. One male had a structural abnormality, namely, an inversion of the Y chromosome. The semen was studied by three-color fluorescent in situ hybridization (FISH) with probes specific for chromosomes 18,X, and Y. RESULTS: Chromosomal aneuploidy rates of any of the three chromosomes were significantly higher than the aneuploidy rates observed in three control samples but comparable to the rates observed in 10 ICSI candidates with oligoasthenoteratozoospermia (OAT) and a normal constitutional karyotype. CONCLUSIONS: Our data indicate that males with (mosaic) sex chromosomal abnormalities have no higher risk of producing offspring with a sex chromosomal abnormality by ICSI than OAT males with a normal karyotype.

[Genetics in medical practice after 2000]. / Genetica in de medische praktijk na 2000.

Within a few years the 80,000 human genes will be identified which will increase our understanding of the genetic aspects of a large number of diseases, not only the relatively rare monogenic diseases but also the more frequent multifactorial diseases such as atherosclerosis, thrombosis and schizophrenia. Pharmacogenomics will lead to particular medication that is tuned to the genetic variations of the patient. Presently this increase in knowledge in the area of DNA diagnosis and genetic counselling will lead to a continuous increase in requests for assays. The possibilities for application will depend on new technological developments such as the DNA array technology and automation. To meet the increasing number of requests for genetic counselling, genetic nurses will have to play an important role. Moreover, collaboration between clinical geneticists and other specialists will have to be further intensified.

Reproductive decisions of men with microdeletions of the Y chromosome: the role of genetic counselling.

Couples dealing with microdeletions of the Y chromosome have to make decisions about their reproductive future. Do they opt for intracytoplasmic sperm injection (ICSI), artificial insemination with donor insemination (AID) or no treatment? We analysed this decision in 28 couples and investigated the role of the counsellor and the counselling process on the final decision of the couple. Ten counsellors from six fertility clinics in The Netherlands and Belgium were interviewed about their genetic counselling of couples dealing with microdeletions. The answers to the questionnaire were converted to 11 dichotomous variables. Of the 1627 tested men in the six centres, 37 (2.3%) had a microdeletion in the AZFc region, a subregion of the AZF region on the Y chromosome important for normal spermatogenesis. The decisions of 28 of them could be analysed. Most couples chose ICSI (79%). The remaining couples chose donor insemination (7%) or refrained from treatment (14%). Several variables, including the counselling procedure, the counsellor and the available treatments in the fertility centre, influenced the decision of the couple. In conclusion, most couples dealing with microdeletions in the AZF region choose ICSI. Several aspects of the process of genetic counselling appear to be related to the final decision.

Sperm analysis in a subfertile male with a Y;16 translocation, using four-color FISH.

Sperm analysis was performed in a male with oligoasthenoteratozoospermia (OAT) and a reciprocal t(Y;16) (q11. 21;q24), using four-color FISH. Intracytoplasmic sperm injection (ICSI) treatment in this patient had resulted in the birth of one chromosomally balanced and two chromosomally normal children. To assess the risk of having a chromosomally unbalanced conception after ICSI, morphologically normal spermatozoa were studied with a set of probes allowing detection of all segregation variants. There were 51% normal or balanced sperm cells. The fraction of sperm products resulting from alternate and adjacent I segregation was 87%, 12% were products of 3:1 disjunction, and the other 1% had other types of aneuploidy. If morphologically abnormal cells were also included in the FISH analysis, nearly 90% of all the spermatozoa were unbalanced. We conclude that although the majority of males with a Y/autosome translocation are infertile due to azoospermia, our patient produces sufficient morphologically and chromosomally normal spermatozoa to have chromosomally normal or balanced offspring after ICSI. Assuming that ICSI with an unbalanced spermatozoon from this patient would result in a nonviable embryo in many cases, the combination of in vitro and subsequent in vivo selection probably results in a risk of unbalanced offspring of much less than 50%. Hence, FISH studies on the sperm of translocation carriers are useful for estimating the risk of having unbalanced offspring after ICSI and in understanding the mechanisms underlying infertility in such carriers.

Subfertile men with constitutive chromosome abnormalities do not necessarily refrain from intracytoplasmic sperm injection treatment: a follow-up study on 75 Dutch patients.

A follow-up study was performed to investigate the impact of the detection of a chromosome abnormality in infertile men who are candidates for intracytoplasmic sperm injection (ICSI) treatment. In this collaborative study between clinical genetics centres and fertility clinics in the Netherlands, 75 ICSI couples of which the male partners had a chromosome abnormality were included. All couples were extensively counselled on the risk of having a chromosomally unbalanced child. Forty-two out of 75 couples chose to proceed with the ICSI treatment. So far, treatment has resulted in a pregnancy in 11 cases. Four of them opted to have invasive prenatal diagnosis. Despite the genetic risks related to a chromosome abnormality in infertile men, a small majority (56%) of the couples did not refrain from the ICSI treatment.

One normal child and a chromosomally balanced/normal twin after intracytoplasmic sperm injection in a male with a de-novo t(Y;16) translocation.

A balanced translocation t(Y;16)(q11.21;q24) is described in a male with severe oligoasthenoteratozoospermia (OAT). Before having a chromosome investigation, the patient and his partner had undergone intracytoplasmic sperm injection (ICSI) treatment resulting in the birth of a healthy 46,XX child. After detection of the t(Y;16) translocation, the couple opted for further ICSI treatment, although they were extensively counselled on the risk of having chromosomally unbalanced offspring. This treatment resulted in a twin pregnancy, one with a 46,XX karyotype and the other a 46,X,t(Y;16) (q11.21;q24) karyotype, the same as the father. After an uncomplicated pregnancy two healthy children were born. We conclude that patients with a Y/autosome translocation as a cause of OAT can have chromosomally normal children after ICSI treatment.

Polymorphic detection of a parthenogenetic maternal and double paternal contribution to a 46,XX/46,XY hermaphrodite.

True hermaphroditism in humans usually is associated with a 46,XX karyotype or with mosaicism in which admixtures of cells with an XX and an XY karyotype are seen. However, the mechanisms that cause such mosaicisms are poorly understood. To date, with rare exceptions, analyses of hermaphrodites have been limited mostly to cytogenetic investigations. In this report, we describe a 5-year-old patient with true hermaphroditism and a 46,XX/46,XY karyotype (ratio 38:12) in lymphocytes, suggesting involvement of two fertilization events. Microsatellite DNA polymorphisms distributed throughout the genome were analyzed, to investigate the origin of the cell lines concerned. The results are consistent with double paternal and single maternal genetic contributions. Possible mechanisms that would explain these findings are discussed. The most likely mechanism involves a single haploid ovum dividing parthenogenetically into two haploid ova, followed by double fertilization and fusion of the two zygotes into a single individual, at the early embryonic stage.

VSD, hypospadias and normal psychomotor development in a patient with inv dup 8(q13-q21.2).

This paper describes a patient with a de novo inverted duplication of chromosome 8(q13-q21.2). He was born with a ventricular septum defect, glandular hypospadias and protruding ears. At the age of 5 1/2 years he had normal psychomotor development. Review of the literature on partial duplications of 8q reveals that the associated phenotype may be mild. Normal psychomotor development, as in our patient, however appears to be uncommon.

A case of de novo interstitial deletion of chromosome 5(q33q34).

The present paper describes a girl with a small de novo deletion of chromosome 5(q33q34). Fluorescence in situ hybridisation with locus specific probes was used to define the extent of this deletion. Clinical features in this patient are microcephaly, dysmorphic facial features such as epicanthus, small biparietal distance and retrognathia, four-finger lines on both hands and mild mental retardation.

Unbalanced karyotype, dup 14(q13-q22), in a mother and her two children.

A duplication of chromosome 14(q13-q22) caused mild mental retardation and some dysmorphic features in two children and their mother. The unbalanced karyotype did not affect the fertility of the mother. Fluorescent in situ hybridization, with a chromosome 14 specific paint, was used to confirm that the inserted material was from chromosome 14.