CNS malformation in a child with Kabuki (Niikawa-Kuroki) syndrome: report and review.

Kabuki (Niikawa-Kuroki) syndrome (KS) comprises characteristic facial changes, developmental delay, skeletal anomalies, mental retardation, and abnormal dermatoglyphics. We report on a 5-year-old Caucasian boy with KS who required surgery for a giant left temporoparietal subarachnoid cyst at age 5 1/2 years. Review of the 143 published cases shows that while malformations may be found in the endocrine, cardiac, genitourinary and skeletal systems, this is the first case of Kabuki syndrome with a major central nervous system malformation.

Chromosome 18q paracentric inversion in a family with mental retardation and hearing loss.

We report on a mother and child with a paracentric inversion of the long arm of chromosome 18: 46,XX,inv(18)(q21.1q23). The child had findings in common with those seen in 18q- syndrome including: microcephaly, epicanthal folds, midface hypoplasia, and abnormally modeled ears, dermatoglyphic whorls on fingertips, clubfeet, hearing loss, and developmental delay. The mother and several maternal relatives had mild mental retardation and hearing loss. Magnetic resonance imaging of the child's brain showed abnormal myelination. Molecular studies including PCR-based markers for the MBP locus and fluorescent in situ hybridization with a P1 genomic clone on mother and child demonstrated only one copy of the MBP locus (18q23) with the deletion extending beyond the MBP locus. Therefore, the deletion in the MBP region may account for the abnormal myelination seen in the patient. The other clinical findings, including mental retardation and hearing loss in this family, may reflect disruption of distal or proximal genes within the deleted MBP region or at the more proximal breakpoint 18q21.1, and may represent a contiguous gene syndrome. Further study of this family may help define those genes functioning in the MBP region that contribute to the phenotype of 18q- syndrome.

Tetraploidy: a report of three live-born infants.

We present three live-born infants with tetraploidy and compare them with two previously reported live-born infants with the same genetic defect. Common anomalies noted included microcephaly; a prominent, narrow forehead; microphthalmia/anophthalmia; cleft palate; orthopedic anomalies; genital ambiguity; and abnormalities of the central nervous system, including pituitary hypoplasia. Together these constitute a rather characteristic phenotype. An error in cytoplasmic cleavage is theorized to be a mechanism for the chromosome anomaly and is supported by the presence of parental polymorphisms in one of our cases; however, the presence of a small percentage of tetraploid cells in the leukocytes and skin fibroblasts of this patient's mother does not exclude maternal mosaicism as the basis for polyploidy in certain instances.

Prenatal detection of the 47, XYY karyotype.

The ethical decisions involved before and after the prenatal diagnosis of a 47, XYY karyotype in the fetus of a 32-year-old woman are discussed. It was decided that the parents should be presented with all the known facts about XYY-associated abnormalities and allowed to choose whether pregnancy should continue; the physician's role would be to support them in their decision and help them carry it out.

The diagnosis of genetic disorders before birth.

Genetic disorders account for a significant number of the health care problems in our society. Advances in therapy and educational opportunities for the handicapped have increased both the life span and quality of life for many of those affected by genetic disorders. Recent developments in clinical and laboratory genetics have made possible the better delineation of certain malformation and/or mental retardation syndromes, so that their mode of inheritance can be understood. This information enables the genetic counselor to predict the risk for occurrence of a large number of genetic disorders. Most genetic counseling is done, however, only after the birth of at least one affected individual has alerted the family to their predilection for having children with a genetic disorder. The carrier state of a certain number of genetic disorders can now be detected, so that even before the birth of their first child, a family can be forewarned that they are at increased risk. Previously this knowledge often influenced couples to decide against having any children. The advent of prenatal diagnosis of genetic disease, however, which was pioneered in the 1960s, allows specific diagnoses of inherited disorders in the fetus; parents no longer have only a mathematical risk figure for guidance. The technics which permit a preview of the genotype of the fetus with respect to a certain disorder constitute an exciting new field or medicine. They are not now available for use in routine pregnancies, but in high-risk situations the collaboration of the primary care physician and the medical geneticist can contribute significantly to the prevention of certain severely handicapping genetic disorders. The field is new and promises to offer much more in the future as more of the inherited disorders are biochemically characterized and become subject to prenatal detection.

An additional case of Smith-Lemli-Opitz syndrome in a 46,XY infant with female external genitalia.

Ambiguity of the external genitalia has been frequently documented in male patients classified as the Smith-Lemli-Opitz (SLO) syndrome. Four previous case reports suggest that in extreme cases of the SLO syndrome there may be complete lack of development of the male external genitalia even in the presence of a normal male 46,XY karyotype. We present an additional case of a phenotypically female infant with dysmorphic features compatible with SLO syndrome and a 46,XY chromosome complement.

Fetal loss and familial chromosome 1 translocations.

A structural abnormality of chromosome No. 1 was found in two families who had a history of repeated abortions. The propositus in Family H was a low birth weight, malformed infant who had a partial trisomy of 1g. His mother and a sibling were balanced carriers of a t(1;4) (q25;135). In family B, the 29-year-old phenotypically normal propositus and his mother were found to be balanced carriers of a t(1;12) (p12;q24). It is suggested that the fetal wastage in both families was related to the abnormal karyotypes of the parents. These two families also provide an opportunity to further understand the effect of an abnormality of chromosome number 1 on phenotype.

Psychiatric disturbances in a 6-year-old boy with Klinefelter's syndrome.

A 6-year-old boy with severe psychiatric problems was found to have Klinefelter's syndrome. He had a mixed emotional and behavioral clinical picture similar to and difficult to distinguish from that of other child psychiatric disorders. Klinefelter's syndrome should be considered in the differential diagnosis of a prepubertal boy with multiple emotional, behavioral, academic, social, and developmental problems.

Partial trisomy 6p and partial trisomy 22 resulting from 3:1 meiotic disjunction of maternal (6p;22q) translocation.

A male infant, partially trisomic for a small segment of chromosomes 6 and 22 resulting from a maternal translocation, is described. Comparison of the phenotypic features of the proband with those noted in partial 6p and partial 22 trisomies revealed some common features found in both chromosome anomalies but especially reinforced those features thought to be characteristic of 6p trisomy syndrome.

High resolution cytogenetic evaluation of couples with recurring fetal wastage.

Both high resolution and routine chromosome analyses were used to study couples with a history of two or more spontaneous abortions in early pregnancy. In the 20 couples studied, two of the women were found to have an inversion. One paracentric inversion, (13)(q13.1q22.3), was apparent on routine analysis. The small pericentric inversion (11)(p11.12q12.3), was only detected by high resolution techniques. Given the low yield and increased cost and effort involved, we do not believe that high resolution studies are justified for screening couples with repeated abortions.

Participants' reaction to amniocentesis and prenatal genetic studies.

Little is known about the effect of amniocentesis and prenatal diagnosis of genetic disease on couples undergoing such studies. A questionnaire was composed to evaluate, among other things, the reason for referral, attitudes and concerns of the pregnant woman and her husband toward prenatal study, and suggestions for improving the experience. Of 315 women referred to this unit for this purpose, 196 have had time to complete their pregnancy and were mailed the questionnaire; 157 (80%) of the latter responded. The majority of the women found the experience reassuring, would recommend it to others, and would seek it again themselves with a subsequent pregnancy.

Ring 4 chromosome with terminal p and q deletions.

A ring 4 chromosome was found in a boy with low birth weight, microcephaly, micrognathia, rounded broad nose, malformed ears, cleft soft palate, and retardation in growth and development. The ring 4 is formed by union of the ends after breakage and loss of the terminal parts of the short (p) arm and the long (q) arm. G-banded chromosome studies showed our patient to have a union at p16q35. Clinical findings in our patient were compared with those in others with the union at p16q35, p15q35, and p16q33. The patients with p15q35 had a deletion of more p-arm genetic material than those with the p16q35 union, and the patient with p16q33 had a greater loss of q-arm material. The loss of only a small part of the p16 band is associated with low birth weight, microcephaly, and retardation in growth and development.

Paternal Robertsonian translocation t(13q;14q) and maternal reciprocal translocation t(7p;13q) in a couple with repeated fetal loss.

Marriages involving partners both of whom have abnormal karyotypes are rare and are usually ascertained because of a history of infertility, repeated abortions, or the birth of a balanced translocation carrier or chromosomally abnormal offspring. Abnormalities which have been noted include sex chromosome aberrations in both parents or a sex chromosome abnormality in one parent and an autosomal abnormality in the other. Four papers have reported balanced reciprocal autosomal translocations in both parents, two couples representing a first cousin marriage. We present a case of a paternal 13;14 Robertsonian translocation and a maternal (7p;13q) reciprocal translocation in a couple with repeated fetal loss.

An unbalanced (6q;13q) translocation in a male with clinical features of Ehlers-Danlos type II syndrome.

Ehlers-Danlos syndrome has been divided into several different types according to the variety and severity of clinical manifestations, and may follow autosomal dominant, autosomal recessive, or X linked patterns of inheritance. Only rarely have chromosome anomalies been seen in patients manifesting phenotypic features of the syndrome and most are considered insignificant. However, one case report involved a balanced t(9;17)(q34;q11) in a female with the clinical features of Ehlers-Danlos type I and IV syndromes and, as noted by McKusick: "It is possible, furthermore, that certain very rare syndromes that are transmitted in a Mendelian manner are the result of small chromosome aberrations, such as deletion or inversion, affecting the action of several genes". We present a 14 year old male with features of Ehlers-Danlos type II syndrome and an unbalanced (6q;13q) translocation.

Congenital heart disease in infants with Down's syndrome.

Medical records of 118 newborn infants with Down's syndrome were reviewed to document the types of congenital heart disease (CHD) in those having echocardiography. Of 102 infants having echocardiography, 49 (48%) had heart defects; 47 of these had trisomy 21 and 2 had unbalanced translocation karyotypes. Of the 53 (52%) who did not have heart defects, all had trisomy except 1 with a mosaic karyotype and 1 with a translocation karyotype. The most common heart malformation was an atrioventricular canal, followed in frequency by ventricular septal defect, atrial septal defect, patent ductus arteriosus, and tetralogy of Fallot. Benefits of echocardiography in such infants are early detection of CHD, with aggressive management to prevent future complications, and reassurance to parents if the infant does not have CHD.