Assignment of an autosomal sex reversal locus (SRA1) and campomelic dysplasia (CMPD1) to 17q24.3-q25.1.

We have mapped the autosomal sex reversal locus, SRA1, associated with campomelic dysplasia (CMPD1) to 17q24.3-q25.1 by three independent apparently balanced de novo reciprocal translocations. Chromosome painting indicates that the translocated segment of 17q involves about 15% of chromosome 17 in all three translocations, corresponding to a breakpoint at the interphase between 17q24-q25. All three 17q breakpoints were localized distal to the growth hormone locus (GH), and proximal to thymidine kinase (TK1). Due to the distal location of the breakpoints, previously mentioned candidate genes, HOX2 and COL1A1, can be excluded as being involved in CMPD1/SRA1. The mouse mutant tail-short (Ts) which maps to the homologous syntenic region on mouse chromosome 11, displays some of the features of CMPD1.

The locus for human adenine phosphoribosyltransferase on chromosome no. 16.

Evidence for assigning the locus determining the structure of adenine phosphoribosyltransferase (APRT) to human chromosome No. 16 is presented. Hybrids of APRT-deficient mouse cells and of human fibroblasts having normal APRT were isolated by fusing the parental cells with Sendai virus, blocking de novo purine nucleotide synthesis with azaserine and selecting for hybrids that could use exogenous adenine. The hybrid clones that were studied had only APRT activity that was indistinguishable from human APRT with regard to electrophoretic migration and reaction with antibodies against the partially purified human enzyme. No. 16 was the only human chromosome consistently present in all of the clones, and in one clone, it was the only human chromosome detected. Selection against hybrid cells with 2,6-diaminopurine (DAP) yielded DAP-resistant survivors that lacked chromosome No. 16. One hybrid that originally had an intact No. 16 yielded adenine-utilizing subclones that lacked No. 16 but had a new submetacentric chromosome. The distribution of centromere-associated heterochromatin and the fluorescence pattern indicated that this chromosome consisted of a mouse telocentric chromosome and the long arm of No. 16. Cells having the submetacentric chromosome had human APRT. Both the enzyme and the chromosome were absent in DAP-resistant derivatives. These results suggest that the structure of APRT is defined by a locus on the long arm of human chromosome No. 16.

Quality assurance in RT-PCR-based BCR/ABL diagnostics--results of an interlaboratory test and a standardization approach.

Here we describe the results of an interlaboratory test for RT-PCR-based BCR/ABL analysis. The test was organized in two parts. The number of participating laboratories in the first and second part was 27 and 20, respectively. In the first part samples containing various concentrations of plasmids with the ela2, b2a2 or b3a2 BCR/ABL transcripts were analyzed by PCR. In the second part of the test, cell samples containing various concentrations of BCR/ABL-positive cells were analyzed by RT-PCR. Overall PCR sensitivity was sufficient in approximately 90% of the tests, but a significant number of false positive results were obtained. There were significant differences in sensitivity in the cell-based analysis between the various participants. The results are discussed, and proposals are made regarding the choice of primers, controls, conditions for RNA extraction and reverse transcription.

Occurrence of cyclopia, myelomeningocele, deafness, and abducens paralysis in siblings.

As holoprosencephaly without chromosome defect may be associated with other CNS-related anomalies such as mental retardation, mental illness, facial paralysis, endocrine disorders, deafness, spina bifida, and myelomeningocele, we present a family in which one girl had a myelomeningocele, a brother had orbital hypotelorism, facial and cerebral asymmetries, cerebral palsy, abducens paralysis, and inner ear deafness. A 3rd pregnancy was terminated at 16 weeks; the fetus had cyclopia. A common cause is discussed in these cases and in those families in which holoprosencephaly and additional malformations occur among different generations.

Clinical pattern and the genetics of the fetal iodine deficiency disorder (endemic cretinism): results of a field study in Highland Ecuador.

The clinical manifestations of various degrees of mental retardation, spastic diplegia, and deaf mutism are known as the neurologic type of endemic cretinism (EC), occurring in countries with high goiter endemicity. Maternal iodine deficiency has been established as the major cause in EC, whereas a genetic predisposition has not been well-documented. Genetic data on 70 families with EC from Highland Ecuador are reported. A segregation analysis of 49 fully classified families yielded an estimate of P = 0.245 (var [P] = 0.00167). Half-sibs were all unaffected and no significant birth order effect was observed among 101 probands. The data indicate an autosomal recessive predisposition as a major etiological factor. Because the neurologic type of EC represents a defined section of the spectrum of iodine deficiency disorders (IDD), the term fetal iodine deficiency disorder (FIDD) rather than cretinism is suggested. The clinical findings in 70 patients were used to delineate the minimal diagnostic criteria of FIDD.

Isochromosome Xq in Klinefelter syndrome: report of 7 new cases.

In this collaborative study we report on 2 prenatally and 5 postnatally diagnosed cases with a 47,X,i(Xq),Y chromosomal constitution. Excepting tall stature, the 5 adult patients showed all typical manifestations of Klinefelter syndrome. Taken together with previously reported cases, these data suggest that Klinefelter syndrome with isochromosome Xq has a favorable prognosis with normal mental development, and with normal-to-short stature. The prevalence of this Klinefelter variant is calculated to be between 0.3-0.9% in males with X chromosome polysomies.

[Investigation of a variant form of hypoxanthine-phosphoribosyl transferase in a family (author's transl)]. / Untersuchung einer varianten Form der Hypoxanthin-Phosphoribosyl-Transferase in einer Familie.

In a family study with two patients showing hyperuricaemia, discrete neurological symptoms, as well as gouty arthritis in the older proband, hypoxanthine phosphoribosyl transferase (HPRT) and adenine phosphoribosyl transferase (APRT) were determined in haemolysates and fibroblast extracts. 6 normal subjects and 3 patients with the Lesch-Nyhan syndrome were examined as controls. Reduced HPRT activity by 18% and 12% in the proband and his nephew, respectively, together with an increase to values of 206% and 113% in APRT activity was observed in haemolysates. In fibroblasts the HPRT activity was reduced to 40--43%, but the APRT activity was within the normal range. The studies indicate the presence of a possible variant form of HPRT in these patients.

[Pharmacotherapy during pregnancy. Teratological aspects (author's transl)]. / Pharmakotherapie in der Schwangerschaft. Teratologische Aspekte.

Accidental pharmacotherapy in unrecognized pregnancy gives occasion for human genetic counseling to an increasing extent. In this, it must be clarified to what stage of development a drug was administered, whether a teratogenic effect is to be assumed, how long the effect lasts and whether compensation is possible for the damage which has occurred. Furthermore, genetic and non-genetic induced differences in the uptake, metabolization and excretion of drugs and the extent of the genetically induced sensitivity in special areas of the organ anlage in the embryo must be taken into account in the counseling.

Early genetic amniocentesis--4 years' experience.

Four hundred and thirty early amniocenteses (EAC) from 10 to 14 weeks' gestation were compared with 300 routine amniocenteses (RAC) from 15 weeks' gestation (control A) and 733 routine amniocenteses from 16 to 18 weeks' gestation (control B) with regard to success rates, various growth parameters, and cytogenetic results. Using both in situ and trypsinization techniques, the success rate was 99.8 per cent for EAC versus 100 per cent for RAC. The average turn-around time for establishing a diagnosis was 8.4 days in EAC versus 8.3 days in 15 weeks' specimens (n.s.) and 7.7 days in 16 to 18 weeks' specimens (p < 0.0001) for the last 200 samples. The banding quality of early specimens compared favourably with that of controls (both 500-550 bphs) and was much better than that in long-term cultured chorionic villus sampling (CVS) (350-400 bphs). For level I and level II mosaicism, no statistically significant differences were noted between EAC and control group A. Comparing EAC with control group B, a significant increase in the number of numerical and structural single cell aberrations was observed (p < 0.025 and p << 0.001, respectively), whereas for multiple cell aberrations only the increase in numerical aberrations was statistically significant (p << 0.001) (chi 2-test). Clinical problems arising from the detection of mosaicism were solved in all cases by investigating parallel cultures. It is concluded that early amniocentesis is a reliable procedure which permits prenatal diagnosis of numerical and structural chromosome aberrations to a high standard.

[Genetically determinded deafness; 5 cases of Pendred's syndrome (author's transl)]. / Zur Abklärung genetisch bedingter Schwerhörigkeit. 5 Fälle von Pendred-Syndrom.

In our experience, Pendred's Syndrome is the most frequent one clinically seen of 124 syndromes with genetically determined deafness. It is defined as a triad: congenital perceptive hearing loss, goiter, and an abnormal perchlorate test. Inheritance is by an autosomal-recessive pattern. In 5 patients seen by us--one of whom had experienced multiple episodes of sudden deafness--the difficulty of diagnosis is shown. We also emphasize the need for genetic counselling in families with the known syndrome.

Athelia in a female infant - heterozygous for anhidrotic ectodermal dysplasia.

The case of a female infant with athelia is reported. Her mother, maternal aunt and grandmother show hypodontia, sparse hair and small breasts associated with mammillary hypoplasia. The clinical features and the results of MINOR's sweat test suggest a heterozygous state of anhidrotic ectodermal dysplasia as the most likely explanation.

Chromosomal mosaicism in prenatal diagnosis: a problem still unsolved.

The problems in differentiating chromosomal mosaicism from pseudomosaicism after amniocentesis and CVS are demonstrated in 6 cases. Two cases of true mosaicism (45, X/46, XX and 46, XY/47, XXY) were of clinical relevance. In both cases the aberrant cell line was less expressed in amniotic fluid cells than in fetal blood and cultivated fibroblasts. Two cases of pseudomosaicism (chromosome 2 and chromosome 10 trisomy) originated either from preexisting mutants or from in vitro mutations whereas a case of true chromosome 20 mosaicism indicated the possibility of a mosaic confined to a single fetal tissue. The problems of interpreting mosaicism after CVS is illustrated in a 45, X/46, XY case, in which the abnormal cell line was detectable only in extrembryonic tissue.

The effect of oxygen tension on colony formation and cell proliferation of amniotic fluid cells in vitro.

The effects of reduced oxygen concentrations in the gas phase over the culture medium on colony formation and cell proliferation were investigated in high and low cell density primary and secondary cultures of amniotic fluid cells. Using two standard culture methods (25 cm2 plastic flasks and Leighton type tubes) a significantly reduced culture time was observed at high cell density for mass cultures by incubation within a low oxygen tension gas phase (2.5 per cent to 7.5 per cent O2) instead of conventional air (18 per cent O2). At low cell density colony formation was significantly enhanced in cultures grown at reduced oxygen tension. Using gas permeable membranes as support, lowering the oxygen tension from 7.5 per cent to 2.5 per cent yielded an increase in plating efficiency of cells from approximately 5 per cent to 25 per cent, whereas plating efficiency was less than 2 per cent for cells grown at ambient 18 per cent O2. It is suggested that low oxygen tension in the gas phase is an effective means of enhancing clonal growth in amniotic fluid cell cultures, thereby reducing both culture time and risk of culture failure.

[Growth and nutrition: long term follow-up in early treated phenylketonuric and hyperphenylalaninemic children (author's transl)]. / Wachstum und Ernährung: Langzeitbeobachtungen bei frühbehandelten Kindern mit Phenylketonurie- und Hyperphenylalaninämie-Varianten.

In a retrospective longitudinal study physical growth was related to nutritional data in 35 (23 male, 12 female) early treated patients with phenylketonuria and hyperphenylalaninemic variants. In males growth was slightly retarded only in the first year of life, weight gain was normal in both sexes as was growth in females. Bone changes were noted in 10/33 patients. Protein was prescribed as phenylalanine free protein hydrolysate or phenylalanine free aminoacid mixture and as natural protein according to individual phenylalanine tolerance. In 34/35 patients total serum protein was normal whereas hemoglobin was near the lower normal limit. Serum phenylalanine increased continuously with age.

[Prenatal sex determination via GBN saliva test. A comparison with the results of prenatal chromosomal analysis]. / Pränatale Geschlechts-bestimmung durch den GBN-Speicheltest. Ein Vergleich mit den Ergebnissen der pränatalen Chromosomendiagnostik.

In 114 pregnant women the results of the GBN saliva test were compared with the results of sex determination by prenatal chromosomal analysis. GBN test results predicting boys corresponded in 40,7% of the cases with male karyotypes, whereas test results predicting girls corresponded in 56,5% with female karyotypes. Mean age of the women tested was 35,9 +/- 3,6 years. The test results in women aged 35 or younger did not show a better correlation with the chromosomal sexing than in older women (46,5% and 48,4%). Saliva tests performed in the 16th to 20th week of gestation corresponded to the same extent with the chromosomal sex of the fetuses as those performed in the 21st to 32nd week of gestation (48,5% and 46,2%). The mode of ascertainment of the pregnant women and other factors possibly influencing the results are discussed. It is concluded that the GBN saliva test is not suitable for prenatal sex prediction in women of the age group investigated.

Ullrich-Turner syndrome is not caused by haploinsufficiency of RPS4X.

Ullrich-Turner syndrome (UTS) is frequently associated with monosomy X but may also occur with structural aberrations of the X and the Y chromosomes. It has been hypothesized that the ribosomal protein genes RPS4X and RPS4Y play a critical role in the prevention of UTS. Individual patients with a 46,X,i(Xq) karyotype cannot be differentiated phenotypically from 45,X UTS patients and carry three gene copies of RPS4X. Since haploinsufficiency of one or several gene(s) is thought to cause the UTS phenotype, direct assessment of RPS4X expression levels in these patients should establish whether RPS4X is involved in UTS. We have investigated fibroblasts of four 46,X,i(Xq) UTS patients with typical symptoms and a non-mosaic chromosome complement, and have found significantly increased RPS4X mRNA levels in all patients. Based on our results, we conclude that haploinsufficiency of RPS4X is not the cause of UTS.

Mesomelic dysplasia with short ulna, long fibula, brachymetacarpy, and micrognathia. Clinical and radiological differential diagnostic features.

A girl with a "new" variant of mesomelic dysplasia is reported. The disorder is characterized by mesomelic brachymely, especially of the arms, a short ulna, relatively long fibula, brachymetacarpy, minor symmetrical changes at the hands, developmental arrest of the spine, contractures, and micrognathia. The clinical and radiological differential diagnostic features are discussed.

[XX-male syndrome from the andrologic viewpoint]. / Das XX-male Syndrom aus andrologischer Sicht.

Three cases of XX-male Syndrome which have been evaluated at the Department for Andrology of the University-Hospital Hamburg are reported. The clinical, cytogenetical, histological and endocrinological features of this syndrome are described from an andrological point of view, including the evaluation of the spermatogram. As there are no typical clinical features for the XX-male syndrome, and the sex-chromatin is positive in Klinefelter's Syndrome also, it is necessary to use the chromosome-analysis for the diagnosis of this rare gonosomal aberration.

Bilateral femoral dysgenesis with micrognathia, cleft palate, anomalies of the spine and pelvis, and foot deformities. Clinical and radiological findings.

Two girls afflicted with bilateral femoral hypoplasia, micrognathia, cleft palate, anomalies of the spine and pelvis, and foot deformities are reported. Based on 10 cases reported in the literature the following points are emphasized: 1. Femoral hypoplasia may be bilateral or unilateral. 2. Many patients show asymmetrical changes. 3. To our knowledge, the complete syndrome including a cleft palate has been reported only in females. 4. Femoral hypoplasia without a cleft palate may represent a different entity, of possibly autosomal dominant inheritance, or may occur in children of diabetic mothers.