Márta Czakó

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.

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.

Isodicentric Y chromosome in an Ullrich‐Turner patient without virilization

We report on a 17-year-old young woman with Ullrich-Turner syndrome (UTS), who was found to have a karyotype 45,X/46,X,idic(Y)(q11). She had age-appropriate genitalia without virilization in spite of the presence of the Y-derived marker chromosome and SRY locus in 70% of her lymphocytes. Having reviewed the literature, we conclude that a possible explanation for the lack of virilization in these mosaic patients is most likely an uneven distribution of tissue mosaicism (gonadal mosaicism).

Influence of genetic polymorphisms on bone disease of preterm infants

Bone disease is an important complication among very low birth weight (VLBW, <1500 g) infants. In adults, osteoporosis is associated with polymorphisms of vitamin D receptor (VDR), estrogen receptor (ER), and collagen Iα1 (COLIA1) genes. However, limited information is available regarding the role of these polymorphisms in bone disease in premature infants. We have investigated the possible association between bone disease and the allelic polymorphisms of these three genes in 65 VLBW infants. Twenty infants (30.8%) were diagnosed with bone disease based on high activity of bone formation (serum alkaline phosphatase and osteocalcin), bone resorption (urinary excretion of calcium and pyridinium crosslink) markers, and positive radiologic signs. Statistically significant correlation between thymine-adenine repeat [(TA)n] allelic variant of ER gene and bone disease was observed. Infants without bone disorder more often carried a high number of repeats [(TA)n >18] [odds ratio (OR): 0.17, 95% confidence interval (CI): 0.05–0.55]. A low number of repeats [(TA)n <19] was found more frequently in infants suffering from bone disease (OR: 6.00, 95% CI: 1.77–20.31). Significant interaction (p = 0.009) between VDR and COLIA1 genotypes was observed. In a logistic regression model, bone disorder of preterms significantly correlated with male gender (p = 0.002), lower gestational age (p = 0.015), homozygous allelic variants of high number of (TA)n repeats (p = 0.006), and interaction between VDR and COLIA1 genotype (p = 0.009).

A novel frame shift mutation in the HMG box of the SRY gene in a patient with complete 46,XY pure gonadal dysgenesis

Pure gonadal dysgenesis or Swyer syndrome is a sex-reversal disorder resulting from embryonic testicular regression sequences especially during the first few weeks of fetal life and is induced by mutations in the SRY gene. In the present report, we describe a nonmosaic XY sex-reversed female with pure gonadal dysgenesis. Molecular analysis using sequential PCR to detect Y chromosomal microdeletions showed the presence of SRY, ZFY and AZFa, b and c regions. Automated sequencing of the SRY region revealed a new mutation (deletion of A (adenine) in codon 82 at position +244), leading to a frame shift mutation within the helix I of the HMG-box domain. This mutation generates a truncated protein and is very likely to produce an impairment of SRY DNA binding activity. The present findings further support the functional importance of the putative DNA binding activity of the SRY HMG-box domain.

α-Thalassemia/mental retardation syndrome in a 45,X male

An unbalanced Y;autosome translocation leading to a male with a 45,X karyotype is rare with about 30 published cases. A male with a 45,X karyotype as a result of a unique, submicroscopic, unbalanced Y;16 translocation is presented with α‐thalassemia/mental retardation syndrome.

Kleefstra syndrome in Hungarian patients: additional symptoms besides the classic phenotype

BackgroundKleefstra syndrome is a rare genetic disorder, with core phenotypic features encompassing developmental delay/intellectual disability, characteristic facial features – brachy(micro)cephaly, unusual shaped eyebrows, flat face with hypertelorism, short nose with anteverted nostrils, thickened lower lip, carpmouth with macroglossia - and childhood hypotonia. Some additional symptoms are observed in different percentage of the patients. Epilepsy is common symptom as well. The underlying cause of the syndrome is a submicroscopic deletion in the chromosomal region 9q34.3 or disruption of the euchromatin histone methyl transferase 1.Case presentationWe describe two Hungarian Kleefstra syndrome patients, one with the classic phenotype of the syndrome, the diagnosis was confirmed by subtelomeric FISH. Meanwhile in our second patient beside the classic phenotype a new symptom – abnormal antiepileptic drug metabolic response – could be observed. Subtelomere FISH confirmed the 9q34.3 terminal deletion. Because of the abnormal drug metabolism in our second patient, we performed array CGH analysis as well searching for other rearrangements. Array CGH analysis indicated a large – 1.211 Mb -, deletion only in the 9q subtelomeric region with breakpoints ch9:139,641,471-140,852,911.ConclusionsThis is the first report on Kleefstra syndrome in patients describing a classical and a complex phenotype involving altered drug metabolism.

Congenital chylothorax in Opitz G/BBB syndrome†

Chylothorax is defined as a collection of lymph in the pleural space. It may be primary or secondary. Primary chylothorax is due to lymphatic duct abnormalities and may occur in isolation or in association with clinical conditions (polyhydramnios, hydrops, intrathoracic mass) or certain genetic syndromes (i.e., Noonan, Turner and Fryns syndromes [Van Straaten et al., 1993], Down syndrome [Ho et al., 1989], inversion of chromosome 2 and Kabuki syndrome [Maayan-Metzger et al., 2005]). Primary or congenital chylothorax is relatively uncommon: 1:10,000–15,000 live births. Secondary chylothorax occurs more often and is mostly associated with trauma or thoracic surgery. Opitz G/BBB syndrome is a heterogeneous disorder characterized by malformations of the ventral midline (OS; MIM 145410 and 300000). It was originally described as two distinct entities: the G syndrome characterized by hypospadias, hypertelorism, laryngo-tracheo-esophageal (LTE) abnormalities and central nervous system (CNS) midline defects [Opitz et al., 1969a] and the BBB syndrome with hypertelorism, hypospadias, cleft lip and/or palate, and anal anomalies [Opitz et al., 1969b]. The two syndromes were later merged and reclassified as G/BBB syndrome, comprising most prominently hypertelorism, hypospadias, and midline closure defects [Robin et al., 1996]. The autosomal dominant form maps to 22q11.2, the X-linked one maps to Xp22.3 [Robin et al., 1995]. No specific phenotypic findings have yet been shown to differentiate between the autosomal and X-linked genetic forms of OS. Mutations in the MID1 gene have been detected in 36–75% of the familial X-linked OS cases [Gaudenz et al., 1998, Cox et al., 2000] and in 6–36% of sporadic cases. A recent cohort reported a MID1 mutation detection rate of 22% for familial cases and 6% for sporadic cases [So et al., 2005]. Mutations in MID1 lead to a marked accumulation of protein phosphatase 2A (PP2A), a central cellular regulator. Elevated PP2A causes hypophosphorylation of microtubule-associated proteins, consistent with the OS phenotype [Trockenbacher et al., 2002]. Furthermore, it has been suggested that MID1 forms a large complex that is associated with microtubules and regulates microtubule dynamics [Schweiger and Schneider, 2003]. Interestingly, MID1 and its homolog MID2 share functional redundancy that may contribute to the wide variability of the MID1 associated OS phenotype [Granata et al., 2005]. Nonetheless, the low frequency of MID1 mutations and the high variability of the phenotype in general suggest the involvement of other genes in the pathogenesis of OS [De Falco et al., 2003]. Indeed, partial duplication of 5p [Leichtmann et al., 1991), and a terminal deletion of chromosome 13 (q32.3qter) in children with OS have also been described [Urioste et al., 1995]. These observations highlight the benefit of any report on unusual findings in OS patients that may improve our understanding of the genetically unresolved cases. Here we present a clinical case of Opitz G/BBB syndrome complicated by congenital chylothorax. Our patient, a 3.2 kg male, was delivered at 37 weeks of gestation by Cesarean following induction in a 27-year-old primigravid mother. The mother was noted tohavemarkedhypertelorism; theparents were healthy and the family history was otherwise

Jumping translocation of 15q24-qter resulting in partial trisomy: A case report

We report on a jumping translocation with five different cell lines detected in four tissues in a 2-year-old patient. This rare type of chromosomal abnormality (not more than 30 cases published so far) proved to be a series of non-reciprocal translocations of the 15q24-qter donor chromosome segment to the telomeric region of chromosomes 5q, 10q, 16q and 19p, respectively. The process, in addition to a few cells without translocation, resulted in partial trisomy of 15q24-qter which was associated with somatic overdevelopment in the patient, with hemihypertrophy and minor anomalies. The phenotype of our patient was different from that of the other two patients found in the literature having the same donor chromosome segment involved in a similar rearrangement. Possibly, the difference in the phenotype lies in the various ratios of somatic mosaicism with five cell lines, in particular the presence of normal one which is extremely rare in patients with jumping translocation. Here we discuss the various ways on how the rearrangement could arise.

Infant with MCA and severe cutis laxa due to a de novo duplication 11p of paternal origin

Infant With MCA and Severe Cutis Laxa Due to a De Novo Duplication 11p of Paternal Origin T. Gardeitchik, N. de Leeuw, L. Nijtmans, P. Jira, T. Kozicz, M. Czako, I. van de Burgt, and E. Morava* Department of Pediatrics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Institute for Genetic and Metabolic Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Jeroen Bosch Hospital, s’ Hertogenbosch, The Netherlands Department of Cellular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands Department of Medical Genetics, University of Pecs, Pecs, Hungary