Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder of unknown aetiology that affects numerous body systems including skin, brain and kidneys. Some TSC has been linked to chromosome 9, additional TSC genes on chromosomes 11 and 12 have been proposed, but the majority of TSC families remain unlinked. Using TSC families in which data had excluded linkage to chromosome 9, we failed to detect linkage with loci on chromosomes 11, 12 and others. One marker examined was D16S283, the closest locus on the proximal side of the polycystic kidney disease type 1 (PKD1) gene. Linkage between TSC and D16S283 demonstrated a lod score of 9.50 at theta = 0.02 with one family independently presenting a lod score of 4.44 at theta = 0.05. These data reveal an important TSC locus near the region of PKD1 on chromosome 16p13.

Duplication of distal 11q and 22p occurrence in two unrelated families.

We report chromosome rearrangements and/or duplication of chromosomes 11 and/or 22. This investigation was prompted by propositi with multiple congenital anomalies and an apparently identical chromosome abnormality - ie, 47, +der(22)t(11;22)(q23;q11.2)mat in two unrelated families. The propositi had failure to thrive, development delay, cleft palate, congenital heart disease, meningomyelocele, and hydrocephaly. The breakage points identified on chromosomes 11 and 22 are site-specific and occur in a nonrandom fashion. Band 11q23 corresponds to the gap produced in some individuals by special treatment of the chromosome preparation with mercaptoethanol and may provide a method to identify individuals at risk for chromosome breakage and rearrangements during gametogenesis.

Familial t(4;13) with abnormal offspring in three generations.

A newborn infant girl died at 1 day and was found to have severe intrauterine growth retardation, microcephaly, cleft lip and palate, single umbilical artery, absent thumbs, bicuspid pulmonic valve, pulmonary hypoplasia, malrotation of large and small bowel, and a 46,XX,13q+ chromosome constitution derived from a paternal t(4;13)(q25;q32) with resulting del(13q) and dup(4q). The paternal grandmother and great-grandmother also carried the balanced translocation. Each had had a child with multiple congenital anomalies including "duplex" thumbs. However, a chromosome analysis was not performed on these abnormal infants. Our patient's clinical and cytogenetic manifestations are discussed in relation to the Niebuhr map of chromosome 13.

Achalasia and microcephaly.

The authors report the combination of achalasia, microcephaly, and mental retardation in three surviving sisters and similar manifestations in a brother who died after recurrent vomiting and respiratory infections. The achalasia in the females was relieved with an operation. There was no demonstrable chromosomal abnormality. In this family achalasia, microcephaly, and mental retardation occurred together as an apparent autosomal recessive syndrome.

Association of terminal chromosome 1 deletion with sertoli cell-only syndrome.

We report on del(1)(q44), developmental delay, cryptorchidism, and seizure disorder in a 19-year-old man. Endocrinologic evaluation showed delayed puberty and elevated gonadotropins. Testicular biopsy was consistent with Sertoli cell-only syndrome. The case illustrates a previously an unreported manifestation in males with del(1)(q44), and suggests a link between the development of germinal epithelium and genes in the 1q44 area.

Practical guide to the diagnosis of thalassemia. Council of Regional Networks for Genetic Services (CORN).

Thalassemias occur in individuals of all ethnic backgrounds and are among the most common genetic diseases worldwide. The diagnosis of thalassemia can easily be part of primary medical practice. Here we outline a practical approach to the detection of thalassemias in three common clinical settings. The first involves any patient with a low mean corpuscular volume (MCV) with or without anemia. The second is a neonatal screening result indicating possible presence of thalassemia. Finally, evaluation for thalassemia should be considered in the context of family planning or pregnancy in patients whose ethnicity indicates origin from high risk geographic areas. We also review the various types of the thalassemia syndromes and provide an overview of general therapeutic considerations.

The dup(3q) syndrome: report of eight cases and review of the literature.

Clinical and cytogenetic examinations were performed on eight unrelated infants with duplication of part of the long arm of chromosome 3. A review of published cases shows a clinical syndrome characterized by statomotoric retardation, shortened life span, and a multiple congenital anomalies (MCA) syndrome of abnormal head configuration, hypertrichosis, hypertelorism, ocular anomalies, anteverted nostrils, long philtrum, maxillary prognathia, down-turned corners of the mouth, highly arched or cleft plate, micrognathia, malformed auricles, short, webbed neck, clinodactyly, simian crease, talipes, and congenital heart disease. The dup(3q) syndrome is a clinically easily recognizable entity.

Prenatal diagnosis of chromosomal and enzymatic defects.

Second trimester amniocentesis is a valuable procedure to detect chromosomal and enzymatic defects. A brief review of the current literature and the author's experience is presented.

Near-haploid cell line in the blastic crisis of chronic myelogenous leukemia: a possible marker for lymphoid malignancy.

The blast cells of a 14-year-old patient in the blastic phase of chronic myelogenous leukemia (CML) were studied. Cellular morphology, presence of the enzyme terminal deoxynucleotidyl transferase (TdT), and reactivity to the common acute lymphoblastic leukemia antiserum (CALLA) substantiated a lymphoid blast cell line. Immunologic surface markers were nonreactive for E-rosette (T) cells and immunoglobulin-bearing (B) cells. Cytogenetic, studies revealed persistance of the Philadelphia chromosome and a near-haploid cell line, i.e., 28,XY,t(9;22), +14, +15, +21, +22(GTG). The patient responded to chemotherapy with vincristine, prednisone, and L-asparaginase, first line drugs used for remission-induction of acute lymphoblastic leukemia in childhood. We suggest that severe hypodiploidy or near-haploidy, along with TdT and CALLA, may provide more accurate prognostic information in patients with CML and the lymphoid blastic crisis.

Prevention of developmental disabilities: a model for organizing clinical activities.

Prevention of developmental disabilities receives widespread support, however, a comprehensive approach involving federal and local governments, major professional groups, and the general public has yet to be defined and implemented. Three major issues appear to impede a coordinated approach: (a) prevention's image problem; (b) the complexity surrounding prevention efforts; and (c) the absence of consistent evaluation methods. The University of California, Irvine-University Affiliated Program has developed a model for prevention activities in response to these issues. This model is interdisciplinary, promotes reasoned cooperative efforts, and provides a basis for evaluation and research. This paradigm can be helpful to policy makers in prioritizing prevention activities. The model is composed of five major and functional approaches to prevention with a central core devoted to ethical considerations. The model emphasizes the variety, scope and interdisciplinary nature of prevention/intervention activities, as well as the necessity for a longitudinal approach.

Minimizing the risk of amniocentesis for prenatal diagnosis.

Although the risk of amniocentesis in the second trimester of pregnancy is small, untoward sequelae can be further reduced. One hundred twenty amniocenteses were attempted during a two-year period. In eight instances, the patient had to return for a second tap because of bacterial contamination, inadequate number of fetal cells, or inability to obtain amniotic fluid. These eight patients all underwent repated amniocentesis and successful karyotyping. There were no major complications and one minor complication. Two spontaneous abortions were not apparently related to the procedure. In both these cases, fluid could not be obtained because one patient had a blighted ovum with a small sac and the other had large uterine fibromyomas.

X-autosome translocation with a 47,XXXY qs,t(9p-;Xq+) karyotype.

A male with a karyotype 47,XXXY qs,t(9p-;Xq+) was ascertained utilizing ASG-banding. The karyotype was repeated because the original diagnosis of Klinefelter syndrome (47,XXY) was inconsistent with many of the stigmata present. It is suggested that many karyotypes completed prior to the advent of banding techniques will be repeated in an attempt to provide more accurate diagnosis, describe more aberrations, and possibly establish new syndromes.

E trisomy phenotype associated with small metacentric chromosome and a familial Y-22 translocation.

As a result of this case report, several entities are postulated due to an extra metacentric D or E chromosome: 1) infants presenting with a phenotype similar to the E 18 trisomy; however, the karyotype can be interpreted as either a deleted E or D chromosome; 2) another group of children all presenting with mental retardation, facial asymmetry, scoliosis and cerebral palsy, postulated due to a partial trisomy of E 16 or E 17; 3) individuals with a normal phenotype, but chromosomally presented with an additional satellited metacentric chromosome consistent with centric fusion of a D or G chromosome and 4) children presenting with an inconsistent phenotype and chromosomally presenting with an extra chromosome manifesting satellites or satellite association; the same chromosome abnormality often is found in unaffected parents and/or sibs.

Prenatal diagnosis and genetic counseling.

Since the early 1960's knowledge regarding human genetics has increased at an exponential rate. Because genetics was not commonly taught in medical schools before the late 1960's, this review article is intended to acquaint physicians or refresh their knowledge regarding chromosomal, mendelian and multifactorial inheritance and the indications for prenatal diagnosis. Establishing an accurate diagnosis and mode of inheritance is essential in identifying and selecting those families at risk for genetic disease in their offspring. Medical genetics is evolving as a specialty in order to provide consultation and, if needed, management of those families who would benefit by genetic services. Families who would benefit from genetic counseling include, for example, those in whom any of the following conditions is present: known chromosomal disorders, known disorders due to mendelian inheritance, mental retardation of unknown origin, failure of sexual maturation or failure of sexual development, congenital malformations, floppy infant syndrome or leukemia.A list of more than 70 disorders now detectable in a fetus by means of amniocentesis provides a beginning in the prevention of genetic disease. Knowledge regarding these diseases allows a physician to provide families with accurate risk figures so that they may make informed decisions about having children. Also, a compassionate and nonjudgmental approach to counseling is essential. Decisions, in the final analysis, must be made by the family but aided and supported by the physician.