A prospective controlled study of karyotyping for 430 consecutive babies conceived through intracytoplasmic sperm injection.

OBJECTIVE: To compare the karyotype of babies conceived through ICSI with that of naturally conceived babies. DESIGN: Prospective controlled study. SETTING: The Egyptian IVF-ET Center, Cairo, Egypt. PATIENT(S): Four hundred and thirty babies conceived through ICSI and 430 babies conceived naturally. INTERVENTION(S): ICSI and karyotyping. MAIN OUTCOME MEASURE(S): Abnormal karyotype. RESULT(S): Four hundred and thirty consecutive babies conceived through ICSI who were delivered in one hospital had 15 abnormal karyotypes (3.5%). Of the 15 babies, 7 were of female phenotype and 8 of male phenotype. Six babies had sex chromosome anomalies, 8 had autosomal anomalies, and 1 had combined sex chromosome and autosomal anomalies. A control group of 430 consecutive babies conceived naturally who were delivered in one hospital had no abnormal karyotype. The difference between the two groups was significant (P<.001). CONCLUSION(S): ICSI carries a small but significant increased risk of abnormal karyotyping to the offspring. This risk appears to be equally distributed between autosomal and sex chromosome anomalies.

Loss of the Y chromosomal PAR2-region in four familial cases of satellited Y chromosomes (Yqs).

Applying fluorescence in-situ hybridization (FISH) of various Y chromosomal DNA probes to four familial cases of human Yqs, it was possible to demonstrate that the formation of Yqs must have arisen from a reciprocal translocation involving the short arm of an acrocentric autosome and the heterochromatin of the long arm of the Y chromosome (Yqh). Breakpoints map within Yqh and the proximal short arm of an acrocentric autosome resulting in the gain of a nucleolus organizer region (NOR) including the telomere repeat (TTAGGG)n combined with the loss of the pseudoautosomal region 2 (PAR2) at the long arm of the recipient Y chromosome. In no case could the reciprocal product of an acrocentric autosome with loss of the NOR and gain of PAR2 be detected. Using the 15p-specific classical satellite-III probe D15Z1 in two of the four Yqs probands presented here, it could be shown that the satellited material originated from the short arm of chromosome 15. In contrast to the loss of PAR2 in Yqs chromosomes, another Y chromosomal variant (Yqh-) showing deletion of long-arm heterochromatin in Yq12 has retained PAR2 referring to an interstitial deletion of Yq heterochromatin in such deleted Y chromosomes.

Increased incidence of numerical chromosome abnormalities in spermatozoa injected into human oocytes by ICSI.

The potential risk of transmitting chromosomally abnormal spermatozoa from infertile males into oocytes through intracytoplasmic sperm injection (ICSI) has prompted us to investigate the male pronuclei of tripronuclear zygotes (3PN) obtained after ICSI. To specify the type of anomalies, we used triple colour fluorescent in-situ hybridization (FISH) with three specific probes for chromosomes X, Y and 18. From a total of 163 paternal complements of ICSI-3PN zygotes, 90 (55.2%) had Y-chromosome signals. Eighty-three of these were normal, four had the disomy XY and three were diploid. In the remaining 73 ICSI-3PN zygotes without Y-chromosome signals, the origin of paternal pronuclei was extrapolated through chromosome constitution of the first polar body. Five anomalies were found in this group of zygotes, giving a total rate of numerical chromosome aberrations for fertilizing spermatozoa of 7.4%. In contrast to ICSI, only two disomies (1.5%) were found in the control group of IVF-3PN zygotes. Compared with the incidence of chromosome anomalies between paternal-derived pronuclei of ICSI- and IVF-3PN zygotes, the difference was statistically significant (P < 0.025). This study provides the first direct evidence of a higher incidence of numerical chromosome anomalies in sperm-fertilized human oocytes after ICSI.

Current understanding of androgenetic alopecia. Part I: etiopathogenesis.

Androgenetic alopecia (AGA) is the most common type of hair loss in men and women. This continuous process results in a type of alopecia that follows a definite pattern in those individuals who are genetically predisposed. At present the predisposing genes are unknown but the relatively strong concordance of the degree of baldness in fathers and sons is not consistent with a simple Mendelian trait and a polygenic basis is therefore most likely. AGA can be defined as a DHT-dependent process with continuous miniaturization of sensitive HF. Today we do not understand the molecular steps involved in androgen-dependent beard growth versus androgen-dependent hair loss in AGA. However, recent experimental and clinical advances enable us to explain some pathogenetic steps leading to androgenetic hair loss. Among other steroidogenic isoenzymes such as 17b- and 3b- hydroxysteroid dehydrogenases, the type 2 5a-reductase within the dermal papilla plays a central role by the intrafollicular conversion of T to DHT.

Intracytoplasmic sperm injection: what are the risks?

UNLABELLED: Intracytoplasmic sperm injection, a relatively new technique used at the time of in vitro fertilization to fertilize human oocytes, has provided couples with very severe male factor infertility the ability to conceive their own biologic children. Many men with severe oligospermia or azoospermia can now pass their genes on to their progeny, an event that might not have been possible for them just a few years ago. Recent studies now suggest that there may be genetic and developmental differences in some children conceived through intracytoplasmic sperm injection. It is likely that genetic testing and counseling will be recommended for all couples with male factor infertility in the near future. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader will be able to describe the various indications for the use of ICSI in the treatment of infertility, to identify the potential long-term risks associated with the use of ICSI, and to estimate the rate of chromosomal abnormalities in this population of infertile patients.

Exclusion of PPEF as the gene causing X-linked juvenile retinoschisis.

X-linked juvenile retinoschisis (RS) is a progressive vitreoretinal degeneration localised in Xp22.1-p22.2. A human homologue of the retinal degeneration gene C (rdgC), a gene that in Drosophila melanogaster prevents light-induced retinal degeneration, was localised in the RS obligate gene region. We have tested the gene, designated PPEF in humans, as a candidate gene in RS patients using RT-PCR and the protein truncation test on RNA and SSCP on DNA. No mutations were identified, making it highly unlikely that PPEF is the gene implicated in RS. The data presented facilitate mutation analysis of the PPEF gene in other diseases which have been or will be localised to this region.

Reversión secual 46,XX. Análisis clínico y molecular en tres varones y dos hermafroditas verdaderos / 46,XX sex reversal. Clinical and molecular analysis in three XX males and two true hermaphrodites

La revisión sexual 46, XX es un estado patológico poco frecuente, genéticamente heterogéno, que se caracteriza por la presencia de desarrollo testicular en ausencia de cromosoma Y. Clínicamente, los pacientes pueden ser categorizados en tres tipos: varones XX con genitales normales, varones XX con ambigüedad genital y hermafroditas verdaderos con tejido ovárico y testicular y genitales anormales. En este trabajo se estudiaron cinco pacientes con revisión sexual 46,XX. El diagnóstico clínico, endocrinológico y ultrasonográfico en tres individuos correspondió a varones XX y en los dos restantes a hermafroditismo verdadero. El análisis del gen determinante testicular (SRY) en DNA genómico reveló la presencia de éste en dos varones XX, en cambio el tercero y los dos hermafroditas verdaderos fueron SRY-negativos. Los datos moleculares confirman que el desarrollo testicular en la mayoría de los varones 46,XX se debe a la presencia del gen SRY en el genoma de estos sujetos. Los pacientes SRY-negativos, un varón XX y dos hermafroditas verdaderos, sugieren que en estos casos la diferenciación testicular es consecuencia de mutaciones en genes autosómicos o ligados al X que participan en la cascada que conduce a la diferenciación sexual

Sex chromosomal anomalies in pregnancies conceived through intracytoplasmic sperm injection: a case for genetic counselling.

The prevalence of sex chromosomal anomalies (SCA) is higher after treatment with intracytoplasmic sperm injection (ICSI) than in naturally conceived pregnancies. This finding is not only important in the debate about the genetic safety of ICSI, it also has repercussions on the design of appropriate strategies for prenatal and preimplantation diagnosis in ICSI pregnancies. We discuss here in detail the developmental prognosis of individuals carrying a sex chromosomal anomaly. Major malformations do occur in Turner syndrome, but not so in Klinefelter, the triple X and the XYY syndromes. Infertility represents an almost obligate finding in Klinefelter syndrome, but the latest developments in microassisted reproduction may help to overcome this problem. Importantly, mental retardation does not occur more often in individuals with an SCA than in normal controls. Academic achievement, however, may be somewhat reduced compared with peers. Overall, for most children carrying a sex chromosomal anomaly, a major congenital handicap is not to be expected, and the long-term developmental prognosis is fairly good. Therefore, if an SCA is diagnosed prenatally in an ICSI pregnancy, an unbiased and detailed discussion of the developmental perspectives is warranted. The option of continuing such a pregnancy should be given due consideration.

New domains of neural cell-adhesion molecule L1 implicated in X-linked hydrocephalus and MASA syndrome.

The neural cell-adhesion molecule L1 is involved in intercellular recognition and neuronal migration in the CNS. Recently, we have shown that mutations in the gene encoding L1 are responsible for three related disorders; X-linked hydrocephalus, MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs) syndrome, and spastic paraplegia type I (SPG1). These three disorders represent a clinical spectrum that varies not only between families but sometimes also within families. To date, 14 independent L1 mutations have been reported and shown to be disease causing. Here we report nine novel L1 mutations in X-linked hydrocephalus and MASA-syndrome families, including the first examples of mutations affecting the fibronectin type III domains of the molecule. They are discussed in relation both to phenotypes and to the insights that they provide into L1 function.

Investigation of the activation state of the X chromosome in non-Hodgkin's lymphomas.

Cytogenetic analysis of non-Hodgkin's lymphomas (NHLs) has previously revealed a high incidence of numerical abnormalities involving the X chromosome. We have now used a combination of fluorescence in situ hybridization (FISH) and Southern blot analysis of methylation to examine the activation state of additional X chromosomes in NHL. Although FISH analysis of X chromosome centromeres in interphase nuclei was complicated by a number of factors, such as cell-cycle position, there was evidence that more than one X chromosome was present in the active state in 4/9 NHL. Methylation studies were carried out using the M27 beta probe, which also suggested that more than one activated X chromosome was present in at least 2/7 NHL cases. The two approaches therefore provided evidence that in some cases of NHL, unlike sex-chromosome-syndrome individuals, additional X chromosomes may be present in the active state. These data support the suggestion that NHL-associated oncogenes might be located on the X chromosome.

Sex chromosomal abnormalities. Etiology, phenotypic expression, and the role of lyonization.

Individuals with sex chromosomal abnormalities have significantly better chances of leading normal lives than individuals with autosomal abnormalities. This is due, in part, to the role of lyonization in the genetic inactivation of X chromosomes. In contrast to earlier studies contaminated with subject ascertainment bias, prospective studies of individuals with SCA generally indicate a relatively normal profile with respect to overall intellectual capacity and psychopathology. Although some SCAs affect neuromotor, speech, language, cognitive and emotional development to some degree, it is noteworthy that none of the effects necessarily occurs and that some of the deficits are amenable to corrective intervention. Results from prospective studies also indicate significant genotype-environment interactions that can have important implications for intervention.

Higroma quístico del cuello: correlación ultrasonográfica y hallazgos morfológicos en 15 casos / Cervical cystic hygroma: ultrasonographic correlation and morphologic findings in 15 cases

Se estudió una serie de 15 casos con diagnóstico necrópsico de higroma quístico del cuello. El diagnóstico ultrasonográfico fue correcto en 11 y en 5 había signos de óbito fetal en el momento del diagnóstico; sin embargo, se encontró maceración en 14 fetos. Entre las malformaciones asociadas el primer lugar lo ocupó el hydrops, presente en 14 casos. El fenotipo fue femenino en el 86,7 % y sólo 2 casos tenían fenotipo masculino y testículos. Se discute la patogenia de la entidad y su relación con el síndrome de Turner

Higroma quístico del cuello: correlación ultrasonográfica y hallazgos morfológicos en 15 casos / Cervical cystic hygroa: ultrasonographic correlation and morphologic findings in 15 cases

Se estudió una serie de 15 casos con diagnóstico necrópsico de higroma quístico del cuello. El diagnóstico ultrasonográfico fue correcto en 11 y en 5 había signos de óbito fetal en el momento del diagnóstico; sin embargo, se encontró maceración en 14 fetos. Entre las malformaciones asociadas el primer lugar lo ocupó el hydrops, presente en 14 casos. El fenotipo fue femenino en el 86,7

y sólo 2 casos tenían fenotipo masculino y testículos. Se discute la patogenia de la entidad y su relación con el síndrome de Turner