György Kosztolányi

Does "ring syndrome" exist? An analysis of 207 case reports on patients with a ring autosome

SummaryAnalysis of 207 case reports on patients with ring autosome showed that: (1) Forty patients, a fifth of the total, had extreme growth failure together with an otherwise almost-normal appearance, viz. no major malformation, no specific deletion syndrome, no or only a few unspecific minor anomalies. This phenotype may be regarded as the “ring syndrome”, a term proposed by Cote et al. (1981) since it is independent of what chromosome is involved. (2) Severe growth failure, the sole major physical abnormality in the “ring syndrome”, was seen significantly more often among patients with ring of larger chromosomes than among patients with a smaller ring, indicating that the greater the chromosome involved in ring formation, the higher is the probability of severe growth failure. (3) Larger ring chromosomes showed significantly more often instability than smaller rings, suggesting that there may be a correlation between ring instability and the size of the chromosome involved. (4) Growth failure was present in significantly more patients with a “labile” ring than with a “stable” ring, indicating that a correlation may exist between ring instability and growth failure. It is suggested that the “ring syndrome” observed in many cases with ring autosome may result from end-to-end fusion of chromosome ends, an event not involving deletion in the genetic sense. It is also suggested that the “ring syndrome” is caused by a continuous generation of secondary aneuploid cells with increased mortality, i.e. structural ring instability which seems to be a function of the size of the chromosome involved. Thus, formation of a ring chromosome in certain cases might be regarded as a “structural mutation”, i.e. an alteration in the structure of the genetic material per se, rather than a loss or gain of genetic dosages.

Cell formation in the cortical layers of the developing human cerebellum.

Cell proliferation has been studied in the human cerebellar cortex between the 24th gestational week and the 12th postnatal month. Intensive cell formation has been found in the external granular layer (EGL) of the human cerebellum, where the highest cell proliferation rate occurs between the 28th and 34th gestational weeks. This is followed by a gradual decrease that lasts up to the eighth postnatal month. As late in development as the fifth postnatal month, still 30% of cells of the EGL are labeled with the monoclonal antibody Ki‐67, which is specific for dividing cells. The width of the EGL remained unchanged from the 28th gestational week to the end of the first postnatal month, when it starts to decrease and completely disappears by the 11th postnatal month. Large number of Ki‐67 labeled cells occurs in the internal granular layer (IGL) between the 24th and 28th gestational weeks. From the 36th week onwards, the labeling index is less than 1%, although a few labeled cells have always been found in this layer even in the late postnatal period. Labeled cells are distributed in the entire width of the IGL. However, from the 34th gestational week, almost all labeled cells are found among and directly below the Purkinje cells. Their position, the nuclear features, and their occasionally stained cell processes suggest that those are Bergmann glial cells. There are few Ki‐67 labeled cells in the molecular layer (ML) and in the white matter (WM) of the cerebellum throughout the examined period. It is likely that most of these are glial cells. Pyknotic index has been found to be small in all layers of the cerebellum during the examined period.

Inherited ring chromosomes: an analysis of published cases.

SummaryA review of case reports on patients with ring chromosome revealed 30 individuals (plus two fetuses) who inherited the ring from a total of 23 carrier parents (21 mothers and 2 fathers). The proportion of cases with inherited rings, among all patients with a ring, was calculated to be 5.6% as an upper limit. However, because of a propable difference in survival and fertility between individuals with transmitted and de novo rings, and because of the preferential publication of cases involving inherited rings (and thus a publication bias), the proportion of inherited rings should in reality be no more than 1%. Out of 30 transmitted rings, there were 9 where parent and child were both mosaics, suggesting an inherited instability of the chromosome involved leading to de novo re-formation of the ring in the second generation. The relatively mild clinical manifestations of ring chromosomes, in general, was found to be even more striking in familial cases. In half of the offspring the phenotype was very similar to that of the parent. However, in about a third of cases the offspring were more severely (mentally) affected. This fact should be considered in genetic counseling of clinically normal women who carry a ring chromosome.

Small inherited terminal duplication of 7q with hydrocephalus, cleft palate, joint contractures, and severe hypotonia.

We report a 14-month-old girl with submucous cleft palate, resolving mild hydrocephalus, severe hypotonia and joint contractures. The finding of extreme hydrocephalus, cleft palate and club feet in a fetus of the mothers previous pregnancy suggested an inherited defect. Chromosome analysis and FISH studies in the proband revealed an abnormal homolog 13 resulting in a duplication of distal chromosome 7q, 7q35-qter, and a very small associated deletion of distal chromosome 13q, 13q34-qter. The mother showed the balanced translocation. Similar clinical signs have been described with larger distal 7q duplications. Our findings suggest that 7q35-qter, and possibly the gene for sonic hedgehog (SHH) on 7q36, is the critical region for the typical facial features and the profound hypotonia observed in the ‘trisomy of distal 7q’ syndrome.

Phenotypic Variants of the Deafness-Associated Mitochondrial DNA A7445G Mutation

A number of nuclear and mitochondrial mutations have been implicated in non-syndromic hearing loss. Among them, various mutations of mitochondrial Ser(UCN)-tRNA and 12S rRNA genes have been found to be associated with deafness; the A7445G mitochondrial DNA (mtDNA) in this group is unique, simultaneously affecting two different mitochondrial genes, encoding the Ser(UCN)-tRNA and the first subunit of cytochrome oxidase. Besides the hearing loss, it is mainly associated with palmoplantar keratoderma, though; different phenotypic associations have been reported. The current paper reviews the available PubMed reports on the A7445G mtDNA mutation, with special attention to the phenotypic variations. Further, a Hungarian family with the A7445G mutation is reported, in which analysis of both the affected and the non-affected members revealed the mutation in both homo- and heteroplasmic forms, independently of the hearing status of the subjects, a phenomenon previously not reported in other pedigrees. The female lineage represented a rare variant of the U4b haplogroup.

Opitz "C" trigonocephaly-like syndrome in a patient with terminal deletion of 2p and partial duplication of 17q.

A boy with trigonocephaly, cleft palate, multiple minor anomalies, flexion deformities of elbows, cryptorchidism, and severe muscular hypotonia had an unbalanced karyotype with duplication of the distal 17q and deletion of the tip of 2p. This was derived from a reciprocal translocation in the father, 46,XY,t(2;17)(p25;q24). The propositus had some findings observed in patients with distal dup(17q), while trigonocephaly not found in these patients may be associated with the terminal deletion of 2p including the locus of SOX11 gene. It is proposed that the major clinical findings of this patient are consistent with the phenotype characteristic of the Opitz “C” trigonocephaly syndrome.

Investigation of 4q-deletion in two unrelated patients using array CGH

S.S. Kaalund, R.S. Møller, A. Tészás, M. Miranda, G. Kosztolanyi, R. Ullmann, N. Tommerup, and Z. Tümer* Department of Cellular and Molecular Medicine, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark Danish Epilepsy Centre, Dianalund, Dianalund, Denmark Department of Medical Genetics and Child Development, University of Pécs, Pécs, Hungary Max-Planck Institute for Molecular Genetics, Berlin, Germany

Clinical and genetic heterogeneity in frontometaphyseal dysplasia: severe progressive scoliosis in two families.

Frontometaphyseal dysplasia is a rare genetic syndrome affecting the skeletal system and connective tissue. It is believed to be inherited as an X‐linked trait. Features of frontometaphyseal dysplasia overlap with other skeletal dysplasias. Prominent supraorbital ridges, radiologic evidence of cranial hyperostosis, and flared metaphyses are characteristic. Scoliosis, a rare associated finding, is usually mild, and familial progressive scoliosis has not been reported so far. The skeletal dysplasia and the associated clinical findings show significant intra‐ and interfamilial variability. The syndrome has been suggested to be an allelic variant of the Melnick‐Needles osteodysplasty, an X‐linked (dominant) entity. We present two families with frontometaphyseal dysplasia, in which both males and females showed the facial and skeletal features of the syndrome in association with progressive scoliosis. Some of the affected members also had hearing loss and urogenital anomalies, supporting the existence of the recently suggested entity “fronto‐otopalatodigital‐osteodysplasty syndome”.

Expanding the clinical spectrum of MYCN-related feingold syndrome

Feingold syndrome (OMIM#164280) is an autosomal dominant disorder characterized by variable combinations of microcephaly, limb malformations, esophageal and duodenal atresias, and learning disability/mental retardation. Hand and foot abnormalities may include hypoplastic thumbs, clinodactyly of second and fifth fingers, syndactyly (characteristically between second and third and fourth and fifth toes), and shortened or absent middle phalanges [Feingold et al., 1997]. Cardiac and renal malformations, vertebral anomalies, and deafness have also been described in a minority of patients [Kellermayer et al., 2005]. As a result of the versatile clinical picture, this entity has also been reported as oculo-duodeno-esophageal-digital (ODED) syndrome, microcephaly-oculo-digitoesophageal-duodenal syndrome, and microcephalymesobrachyphalangy-tracheoesophageal-fistula (MMT) syndrome. However, some of the variable features of Feingold syndrome are included in ‘‘microcephalydigital abnormalities-normal intelligence’’ (MIM#602585), described as an independent, distinct condition [Kawame et al., 1997]. The critical region of Feingold syndrome was mapped to chromosome 2p23-p24 [Celli et al., 2003] and a recent article revealed MYCN (2p24.1), as a causative gene in this genetic entity [van Bokhoven et al., 2005]. These findings indicated that MYCN dosage is an important factor in early embryonic development andpostnatal brain growth. Indeed, studies in human fetal brain and mice suggest that MYCN is involved in embryonic limb, visceral organ, and nervous system development [Hirvonen et al., 1990; Moens et al., 1992; Stanton et al., 1992]. Here, we report on a family—expressing variable features of Feingold syndrome—who carry a novel mutation of MYCN. The boy with classical features of the syndrome and his mother and maternal grandmother, only possessing the clinical phenotype of ‘‘microcephaly-digital abnormalitiesnormal intelligence’’ disorder also carry the same pathogenic mutation. The 4-year-old boy was born as a first child from non-consanguineous parents. The pregnancy was complicated by maternal nephropathy. He was deliveredvaginally at 39weekswithApgars 4 and8 at 1 and 5 min, birth weight 3,300 g. Esophageal atresia (Vogt III/B type) was detected shortly after birth and was repaired surgically. Cranial ultrasound showed subependymal hemorrhage. He developed seizures and has been treated with anti-epileptics since the age of 10 months. At the age of 4 he could not walk independently and his developmental quotient was 59 (Budapest-Binet). On physical examination his length was 98 cm (10–25 pc), weight 13.5 kg (5 pc), and OFC 46 cm (< 2 SD). Microcephaly and scaphocephaly, epicanthal folds, down-slanting palpebral fissures, relatively large ears, bulbous nasal tip, and dental malocclusion could be observed (Fig. 1). He also had clinodactyly of the fifth finger of the hands, small distal phalanges of the thumbs, mild brachydactyly on the feet, contractures of the wrist, elbow, ankle, and knee, and increased muscle tone. Bullet-shaped distal phalanges of the first finger, middle phalanx hypoplasia of the fifth finger, and

De novo complex chromosomal rearrangement in a woman with recurrent spontaneous abortion and one healthy daughter

SummaryAlthough rare, complex chromosomal rearrangements have been reported in the literature. The result is multiple congenital malformations in the offspring and recurrent spontaneous abortion. Chromosome 7 is usually involved, but in our patient chromosome 18 was involved.