Detection of an interstitial deletion of 2q21-22 by high resolution comparative genomic hybridization in a child with multiple congenital anomalies and an apparent balanced translocation.

Various molecular cytogenetic techniques are currently available to accurately characterize chromosome rearrangements in patients with multiple congenital anomalies. Among these is comparative genomic hybridization (CGH) whose main advantage is the ability to perform a whole genome scan without prior knowledge of the underlying chromosome abnormality. It has been used mostly in the area of cancer cytogenetics, but its role in clinical genetics is now expanding to even include preimplantation genetic diagnosis. We have used this method to reveal an interstitial deletion in a patient with multiple anomalies, who had for years been thought to have a de novo balanced translocation involving chromosomes 1 and 2. A review of published reports suggests that there is significant phenotypic and genetic heterogeneity in the small group of patients including our own with interstitial deletions of 2q21-q22.

Trisomy 1 in a clinically recognized IVF pregnancy.

Most chromosomal trisomies lead to spontaneous abortion. To date, trisomies of all human chromosomes have been observed. Chromosome 1 has been the most elusive, as trisomy 1 was the last aberration to be identified. To date there has been only one case report of a full trisomy 1 in the literature [1997: Am J Med Genet 68:98]. We have identified a second full trisomy 1 from the chromosome analysis of products of conception. We present a patient who conceived by in vitro fertilization (IVF). The cellular divisions of the fertilized egg were carefully monitored prior to transfer. Hormonal changes (increased hCG) indicated that implantation had occurred. Vaginal ultrasound demonstrated a gestational sac. At 42 days postfertilization no fetal heart beat could be detected. Cytogenetic analysis of the chorionic villi isolated from the products of conception found that all of the cells analyzed contained a 47,XY,+1 chromosomal complement.

Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis.

Molecular analysis of a patient affected by the autosomal recessive skeletal dysplasia, pycnodysostosis (cathepsin K deficiency; MIM 265800), revealed homozygosity for a novel missense mutation (A277V). Since the A277V mutation was carried by the patient's father but not by his mother, who had two normal cathepsin K alleles, paternal uniparental disomy was suspected. Karyotyping of the patient and of both parents was normal, and high-resolution cytogenetic analyses of chromosome 1, to which cathepsin K is mapped, revealed no abnormalities. Evaluation of polymorphic DNA markers spanning chromosome 1 demonstrated that the patient had inherited two paternal chromosome 1 homologues, whereas alleles for markers from other chromosomes were inherited in a Mendelian fashion. The patient was homoallelic for informative markers mapping near the chromosome 1 centromere, but he was heteroallelic for markers near both telomeres, establishing that the paternal uniparental disomy with partial isodisomy was caused by a meiosis II nondisjunction event. Phenotypically, the patient had normal birth height and weight, had normal psychomotor development at age 7 years, and had only the usual features of pycnodysostosis. This patient represents the first case of paternal uniparental disomy of chromosome 1 and provides conclusive evidence that paternally derived genes on human chromosome 1 are not imprinted.

Congenital deficiency of alpha-fetoprotein.

Although alpha-fetoprotein may play a role in fetal immune function or in maintenance of osmotic pressure, its exact function is unknown. We report two infants documented to have congenital deficiency of alpha-fetoprotein. One infant had cord blood levels less than 0.5 ng/ml. The second infant had a neonatal level of 120 ng/ml, which is about 2% of the usual concentration for a term newborn. These infants document the existence of congenital deficiency of serum alpha-fetoprotein. Because it is homologous to albumin, congenital deficiency of alpha-fetoprotein may be analogous to analbuminemia, a benign genetic trait.

Advancing maternal age: the actual risks.

PIP: A growing number of US women are delaying childbirth until their late 30s. Pregnant women 35 years old face various risks including genetic disorders, prenatal medical and obstetric complications, intrapartum complications, and perinatal and neonatal morbidity and mortality. With each passing year, the risk of chromosomal abnormality such as Down's syndrome increases. Physicians perform chorionic villus sampling (CVS) between 9-11 weeks gestation and amniocentesis between 16-18 weeks to detect chromosomal abnormalities. CVS carries the higher risk of spontaneous abortion (1-2%). 35-year old pregnant women are more likely to suffer from hypertension and gestational diabetes than younger women. Yet their incidence remains at an acceptable level. Older pregnant women tend to also be at risk of several antepartum obstetric complications such as gestational bleeding, abruptio placentae, and placenta previa. The likelihood of cesarean section and dysfunctional labor is greater among 35-year old pregnant women. Between 1974 and 1978, older mothers were 4 times more likely to die than young mothers, but by 1982 the overall maternal mortality rate fell by 50%. The main causes of death among older mothers were hemorrhage, embolism, and hypertensive conditions. Positive effects of advanced maternal age were less worry about and better adjustment to pregnancy, cautiousness, and more likely to consult their physicians. Advanced maternal age tends not to effect neonatal outcome other than chromosomal anomalies. Physicians should not allow the pregnancy of 35-year old mothers to go beyond 42 weeks' gestation. Despite the minimal increased risks, 35-year old women should not allow their advanced age to be an absolute barrier to reproductive decisions. Obstetricians should conduct thorough and appropriate antepartum testing and surveillance, however.^ieng

Two sporadic cases of amelia/phocomelia with similar phenotype: rare and unusually symmetrical form of FFU dysostosis or separate entity?

We report on two infants born at term with amelia/phocomelia and a striking appearance with facial hemangiomas and micrognathia. The upper limbs were absent and the lower limbs were extremely short, containing only a tibia; the phocomelic feet lacked one to four lateral rays. There was no known teratogen exposure and the infants were born in different regions of the USA. This may be considered an unusually symmetrical and rare form of FFU dysostosis, or a separate entity.

Use of the ultrasound aspiration transducer in midtrimester amniocentesis.

Midtrimester amniocentesis was performed on 2,100 consecutive patients over a four-year period. A specially designed ultrasonic aspiration transducer was used to guide the needle into the amniotic cavity under direct vision by following the path of the needle tip ultrasonically as it entered the fluid. This technique has made the aspiration of amniotic fluid relatively simple and safe. We obtained an adequate amount of amniotic fluid in 99.2% of the patients at their initial visits. The incidence of grossly bloody taps was 0.8%, and the total number of bloody amniotic fluid specimens was 2.37%. The rate of primary culture failure was 0.53%. The total fetal loss within eight weeks after amniocentesis was 0.9% as compared with 0.52% in a control population composed of pregnant women between 16 and 24 weeks of gestation. The estimated amniocentesis-related fetal loss was 0.38%.

De novo duplication of the 7q11 leads to q22 region.

A patient with de novo partial trisomy for the 7q11 leads to 7q22 region as defined by methotrexate high resolution banding is described. he presented with delayed growth and development and characteristic physical features. These consisted of frontal bossing, prominent metopic suture, almond shaped eyes, enophthalmos, large, low set, posteriorly rotated ears, long philtrum, narrow upper lip, high arched palate, and a short neck. Specific genitourinary anomalies were noted.

Childhood acute lymphoblastic leukemia associated with an unusual 8;14 translocation.

An 8;14 chromosome translocation with the break points t(8;14(q11;q32) is described in bone marrow cells of a patient with null cell terminal deoxynucleotidyl transferase (TdT)-positive acute lymphoblastic leukemia. The patient, who is dysmorphic and mentally retarded, ha a normal 46,XY constitutional chromosome karyotype. A review of the more usual cytogenetic findings in this type of leukemia and a comparison of B-cell lymphoproliferative cytogenetic associations are presented.

A liveborn case of 49,XXXY, + 18.

The first case of a liveborn male infant trisomic for both the X and the No 18 chromosome is presented. The patient had multiple congenital anomalies many of which were similar in appearance to patients with trisomy 18. The proband died after 2 days. Both maternal and paternal karyotypes were normal.

Incidence of chromosomal rearrangements in couples with reproductive loss.

We report on 50 couples with reproductive loss did not have any detectable chromosome abnormality. A history of a previous child with multiple congenital abnormalities may be significant in identifying couples with a structural rearrangement. Only by studying more families can this hypothesis be tested. Studies of abortus tissue reveal a high percentage of chromosome abnormalities but a very low incidence of unbalanced translocations. Cytogenetic studies are indicated in a couple which has a past history of spontaneous abortions and a previous child with multiple congenital anomalies.

Prenatal diagnosis of trisomy 20 mosaicism.

Three cases of trisomy 20 mosaicism in amniotic fluid cell cultures are described. Two of the pregnancies resulted in normal full-term infants. The third pregnancy was terminated and revealed a phenotypically normal fetus. A review of five previously reported cases is presented. Explanations of these findings include in vitro nondisjunction, culture of extraembryonic tissue, and true fetal mosaicism. The diagnostic dilemma this presents is discussed.

De novo trisomy 9pter leads to q13.

A case of de novo trisomy 9p was observed. Cytogenetic analysis of G-, R-, Q-, and C-banded preparations revealed a karyotypic description of 47,XY,+del(9)(pter leads to q13). In addition to the principal characteristics of the 9p trisomy syndrome, the child presented with skeletal and urogenital abnormalities. It appears that certain clinical abnormalities are due to trisomy of 9q1.

A case of 46,XY,t(1;13) (q24;q32) with mental retardation.

A 14-year-old mentally retarded boy with congenital malformations of unknown etiology was found to have a de novo apparently balanced reciprocal translocation between chromosomal arms 1q and 13q. There is only one other case where a similar translocation was observed but the breakpoints could be localized only by regions and the individual was not mentally retarded.