Werner Schmid, 1930–2002

Obituary: One of the pioneers of clinical and experimental cytogenetics, Werner Schmid, passed away just shortly prior to his 72nd birthday. Together with Charles Ford, Marco Fraccaro, Harold Klinger, Jérôme Lejeune, Jan Lindsten, Margareta Mikkelsen, Ulrich Wolf, and others he was one of the ‘founding fathers’ of modern-day cytogenetics, and he also was one of the founders of this Journal

Incomplete trisomy 22 III. Mosaic-trisomy 22 and the problem of full trisomy 22

A severely growth-retarded female newborn is described, who died a few hours after birth. About half of the clones and metaphases from an amniotic fluid cell culture (set up at the 3th week of gestation) and only 1/27 of the metaphases from a blood lymphocyte culture contained an additional No. 22 chromosome. Abnormal findings in the patient included a complex congenital heart defect, membranous anal atresia without fistula, distal limb hypoplasia, partial cutaneous syndactyly between second and third toes, and a left preauricular pit. On the basis of this case and other reports from the literature arguments for and againts the existence of full human trisomy 22 are discussed. the conclusion seems likely, that full trisomy 22 usually presents a lethal condition in man, though at present an occasional survival cannot be excluded

Sonstiges - Catalogue of Unbalanced Chromosome Aberrations in Man

This book presents a comprehensive and updated catalogue of the already large, and rapidly growing number of chromosome aberrations in man. A first section introduces the reader to cytogenetic nomenclature, the normal human karyotype, clinical and epidemiologic features and formation of chromosome aberrations. It is followed by chapters on aberrations of chromosomes 1-22, X, Y, triploidy and tetraploidy. Each aberration is presented with its clinical findings, course, mental development, outcome and cytogenetic findings. The more frequent aberrations are presented in illustration sections appended to each chromosome chapter. A consistent structure of the text and references provide for rapid orientation. For further study, the more recent and important literature is given for each aberration, up to the end of 1982. The literature is critically reviewed. The book is completed by three indices: a list of genes mapped to chromosomes or chromosomal segments, an index of malformations and anomalies, and an author index

Incomplete trisomy 22 II. Familial trisomy of the distal segment of chromosome 22q in two brothers from a mother with a translocation, t(6;22)(q27;q13)

Two brothers with duplication of the distal segment of 22q inherited from a t(6;22)(q27;13) translocation carrier mother presented with intraurine growth retardation, congenital hydrocephalus, cleft palate, genital hypoplasia with cryptorchidism and hypospadias, and similar facial features including mongoloid position of eyeaxes, hypertelorism, small nose with prominent bridge, prominent upper lip, and small mandible. In addition the second sib revealed renal hypoplasia, arrhinencephaly and pentalogy of Fallot. The patients died at ages eight days and one day, respectively. The two brothers appear to be the first instances of familial trisomy 22q13→qter

Unequal Interchromosomal Rearrangements May Result in Elastin Gene Deletions Causing the Williams-Beuren syndrome

Williams-Beuren syndrome (WBS) is generally the consequence of an interstitial microdeletion at 7q11.23, which includes the elastin gene, thus causing hemizygosity at the elastin gene locus. The origin of the deletion has been reported by many authors to be maternal in ∼60% and paternal in 40% of cases. Segregation analysis of grandparental markers flanking the microdeletion region in WBS patients and their parents indicated that in the majority of cases a recombination between grandmaternal and grandpaternal chromosomes 7 at the site of the deletion had occurred during meiosis in the parent from whom the deleted chromosome stemmed. Thus, the majority of deletions were considered a consequence of unequal crossing-over between homologous chromosomes 7 (interchromosomal rearrangement) while in the remaining cases an intrachromosomal recombination (between the chromatids of one chromosome 7) may have occurred. These results suggest that the majority of interstitial deletions of the elastin gene region occur during meiosis, due to unbalanced recombination while a minority could occur before or during meiosis probably due to intrachromosomal rearrangements. The recurrence risk of the interchromosomal rearrangements for sibs of a proband with non-affected parents must be negligible, which fits well with the observation of sporadic occurrence of almost all cases of WB

Developmental and behavioural disturbances in 13 boys with fragile X syndrome

Developmental and behavioural aspects were studied in 13 boys aged 2.6–12.5 years from three families with the fragile X syndrome. The following observations were made. (1) Moderate to severe retardation was present in all boys; non-verbal IQs ranged between 25 and 67 (mean 46±14); IQ and age were negatively correlated (P<0.01). (2) Language development was grossly delayed in all boys: most had severe articulation problems. (3) Imitative and symbolic play (e.g. doll play) were strikingly retarded as compared to abstract play (e.g. block design). (4) Autistic features such as no use of eye contact, stereotyped movements and echolalia were found in 9/13 boys; the same number showed aggressive behaviour. (5) General activity was reduced during the 1st year of life; most boys became very hyperactive during the second year; and short attention span and increased distractability were observed in all. (6) Motor development was mildly delayed; all boys were clumsy and moderately hypotonic. The fragile X syndrome ought to be considered in retarded boys with a dissociated developmental pattern, in particular a striking delay in language and play development, and autistic features

Chromosomal map of human brain malformations

The etiology of most central nervous system (CNS) malformations remains unknown. We have utilized the fact that autosomal chromosome aberrations are commonly associated with CNS malformations to identify new causative gene loci. The human cytogenetic database, a computerized catalog of the clinical phenotypes associated with cytogenetically detectable human chromosome aberrations, was used to identify patients with 14 selected brain malformations including 541 with deletions, and 290 carrying duplications. These cases were used to develop an autosomal deletion and duplication map consisting of 67 different deleted malformation associated bands (MABs) in 55 regions and 88 different duplicated MABs in 36 regions; 31 of the deleted and 8 duplicated MABs were highly significantly associated (P<0.001). All holoprosencephaly MABs found in the database contained a known HPE gene providing some level of validation for the approach. Significantly associated MABs are discussed for each malformation together with the published data about known disease-causing genes and reported malformation-associated loci, as well as the limitations of the proposed approac

Skeletal muscular changes in Pena-Shokeir Sequence

In 1974, PENA and SHOKEIR first described alethal syndrome consisting of facial anomalies(flat and depressed nasal tip, micro- and retro-gnathia, malformed and low-set ears, hypertelo-rism), multiple ankyloses, pulmonary hypoplasiaand camptodactyly. Since then more than 60patients with the Pena-Shokeir sequence havebeen described.In addition to the lesions mentioned above, thefollowing signs were present in most cases: Still-birth or death during delivery or within a fewdays after birth, intrauterine growth retardation,cryptorchidism, polyhydramnios, abnormal pla-centa and short umbilical cord. Familial caseshave been reported.Major congenital malformations of inner organs,however, have been diagnosed in only a fewcases.Pena-Shokeir sequence is now regarded as a he-terogeneous sequence, in which different neuro-muscular lesions may play an important patho-genetic role.In our eight patients with the characteristic find-ings of the Pena-Shokeir sequence an attemptwas made to define more clearly the nature ofskeletal muscular changes observed

Impact of prenatal diganosis on the prevalence of live births with Down sysndrome in the eastern half of Switzerland 1980-1996

Objectives and methods: To investigate the impact of prenatal diagnosis on trisomy 21 live births, we collected all prenatal and postnatal trisomy 21 cases (n = 1096) in the eastern half of Switzerland for the years 1980-1996. Results: Despite increasing prenatal detection rates of trisomy 21 foetuses (an increase of 169% in the last 5 versus the first 5 years of the study period) and subsequent termination of pregnancies, the number of liveborn Down syndrome children remained constant. The reason is a shift towards a higher mean maternal age from 28 to 30 years between 1980 and 1996. If mean maternal age at delivery was considered, the observed increase of trisomy 21 conceptions matched well with the calculated figures. Conclusion: If the tendency to have pregnancies at a more advanced age continues and if the use of prenatal diagnosis does not increase, an increase in incidence of Down syndrome liveborns may be expected in the first decades of the 21st century

Fortschritte der klinischen Zytogenetik

Zu Beginn der 70er Jahre gelang mit der Entwicklung der differenzierten Chromosomenbänderungstechniken ein Durchbruch in der klinischen Zytogenetik. Mit diesen neuen Methoden konnte das Auflösungsvermögen der Chromosomenstruktur erheblich verbessert werden. Somit lassen sich wesentlich mehr und vor allem strukturelle Chromosomenaberrationen überhaupt feststellen, und die bereits vorher nachweisbaren können nunmehr besser definiert werden. Obschon Träger von Chromosomenaberrationen natürlich nicht von ihrem rundleiden «geheilt» werden können, ist die Bedeutung einer verfeinerten zytogenetischen Diagnostik doch beachtlich: Erstens kann den Familienmitgliedern eines Patienten das Wiederholungsrisiko für die vorliegende Chromosomenstörung genau angegeben werden, und bei erhöhtem Risiko kann mit Hilfe der pränatalen zytogenetischen Diagnostik einem Elternpaar zu Nachkommen verholfen werden, die mit Gewissheit die in der Familie aufgetretene Chromosomenaberration nicht aufweisen und auch keine andere. Zweitens wird man aufgrund der Erfahrungen mit zytogenetisch ähnlichen oder gleichen Fällen einigermassen sichere Prognosen über körperliche und geistige Entwicklung, allfällige Komplikationen im Verlauf, auf die man im voraus achten sollte, und über die idealen Förderungsmöglichkeiten stellen können, und zwar desto besser, je genauer eine Aberration auch zytogenetisch definiert ist. Ferner erspart eine zytogenetische Diagnose in der Regel dem Patienten und seinen Eltern weitere langwierige und belastende diagnostische Untersuchungen. At the beginning of the 1970s, a breakthrough in clinical cytogenetics was achieved with the development of differentiated chromosome banding techniques. These new methods considerably improved the resolution of chromosome structure. This means that considerably more chromosomal aberrations, and above all structural chromosomal aberrations, can be detected, and those that were previously detectable can now be better defined. Although carriers of chromosomal aberrations cannot, of course, be "cured" of their condition, the significance of refined cytogenetic diagnostics is nevertheless considerable: firstly, the risk of recurrence of the chromosomal disorder in question can be precisely indicated to a patient's family members, and in the case of increased risk, prenatal cytogenetic diagnostics can help a parent couple to have offspring who are certain not to have the chromosomal aberration that has occurred in the family, or any other. Secondly, on the basis of experience with cytogenetically similar or identical cases, it will be possible to make reasonably reliable predictions about physical and mental development, any complications in the course of the disease, which should be taken into account in advance, and about the ideal support options, and the more precisely an aberration is defined cytogenetically, the better. Furthermore, a cytogenetic diagnosis generally spares the patient and his parents further lengthy and stressful diagnostic examinations