Robert Śmigiel

Clinical and molecular-cytogenetic evaluation of a family with partial Jacobsen syndrome without thrombocytopenia caused by an ∼5 Mb deletion del(11)(q24.3)†

Clinical manifestations of Jacobsen syndrome (JBS) depend on the size of the 11qter deletion, which usually varies between ∼7 and 20 Mb. Typical JBS features include developmental delay/mental retardation, short stature, congenital heart defects, thrombocytopenia, and characteristic dysmorphic facial features. We report on a family in which a 4‐year‐old girl as well as her mother and maternal uncle present with subtle features of JBS. Notably, neither thrombocytopenia nor congenital anomalies were detected in this family. Cytogenetic analyses revealed normal karyotypes. Using fluorescence in situ hybridization (FISH) and whole‐genome oligonucleotide array CGH analyses, we identified an ∼5 Mb deletion of the terminal part of chromosome 11q in all the three affected family members. The deletion breakpoint was mapped between 129,511,419 and 129,519,794 bp. This is the smallest deletion reported in a JBS patient. Interestingly, the FLI1 (friend leukemia virus integration 1) hematopoiesis factor gene located ∼6.5 Mb from 11qter and usually deleted in patients with JBS, is intact. Our data support previous hypotheses that FLI1 haploinsufficiency is responsible for thrombocytopenia in patients with JBS.

Bladder agenesis in a male neonate

Bladder agenesis, especially in male, is a rare congenital anomaly. This is a case report of a male patient with several congenital anomalies including penoscrotal transposition, severe kidneys dysplasia, and agenesis of the bladder. The patient lived for 4 months and died because of severe pneumonia.

High-Resolution Array Comparative Genomic Hybridization Utility in Polish Newborns with Isolated Cleft Lip and Palate

Cleft lip with or without cleft palate is one of the most common birth defects of unknown etiology. A fraction of its genetic causes is attributable to copy number variations detected by array comparative genomic hybridization. The value of array comparative genomic hybridization screening as a first-tier test in the newborn population with multiple congenital anomalies has now been accepted. Due to unspecific clinical picture at this age, it can also be applied to neonates with isolated anomalies. Our purpose was to assess utility of array comparative genomic hybridization in the population of newborns with isolated cleft lip and palate. We conducted the study in a group of 52 Polish newborns with apparently isolated cleft lip and palate. In the study group, we found 8 rearrangements. Of these, 2 de novo events have been noted that potentially explain the phenotype. In addition, 2 novel candidate genes for cleft lip and palate, CHN2 and CDH19, are suggested. Given the high number of inherited potentially benign changes, we question the clinical utility of array comparative genomic hybridization in the newborn population with isolated cleft lip and palate, at the same time pointing to the need of skilled professionals clinical assessment at a later age. However, the value of this technology in searching for the cause of isolated anomalies cannot be underestimated.

Single nucleotide polymorphisms in the RET gene and their correlations with Hirschsprung disease phenotype

Hirschsprung disease (HSCR) is a congenital, heterogeneous disorder, characterized by the absence of intestinal ganglion cells. Recent advances show that theRET gene is a major locus involved in the pathogenesis of HSCR. The aim of this study was to analyse if the HSCR phenotype in the Polish population is associated with the presence of polymorphisms in exons 2, 3, 7, 11, 13, 14 and 15 of theRET gene. Molecular results were compared with clinical and long-term follow-up data in 70 Polish patients with HSCR (84.3% with a short segment and 15.7% with a long segment of aganglionic gut). Single-nucleotide polymorphisms were analysed by using the minisequencing SNaPshot multiplex method. The 135G>A polymorphism inRET exon 2 was overrepresented in HSCR patients, compared with a healthy control group. Moreover, the 135G>A variant was shown to be associated with the severe HSCR phenotype. Two other polymorphisms, 2071G>A in exon 11 and 2712C>G in exon 15, were underrepresented in the patients. The results confirm that theseRET polymorphisms play a role in the aetiology of HSCR.

Novel insertion in exon 5 of the TCOF1 gene in twin sisters with Treacher Collins syndrome

Treacher Collins syndrome (TCS) is associated with an abnormal differentiation of the first and second pharyngeal arches during fetal development. This causes mostly craniofacial deformities, which require numerous corrective surgeries. TCS is an autosomal dominant disorder and it occurs in the general population at a frequency of 1 in 50,000 live births. The syndrome is caused by mutations in the TCOF1 gene, which encodes the serine/alanine-rich protein named Treacle. Over 120 mutations of the TCOF1 gene responsible for TCS have been described. About 70% of recognized mutations are deletions, which lead to a frame shift, formation of a termination codon, and shortening of the protein product of the gene. Herewith, a new heterozygotic insertion, c.484_668ins185bp, was described in two monozygotic twin sisters suffering from TCS. This mutation was absent in their father, brother, and uncle, indicating a de novo origin. The insertion causes a shift in the reading frame and premature termination of translation at 167 aa. The novel insertion is the longest ever found in the TCOF1 gene and the only one found among monozygotic twin sisters.

[The role of genetic and environmental factors in the etiology of esophageal atresia and tracheo-esophageal fistula].

Esophageal atresia and tracheo-esophageal fistula are severe congenital malformations, whose etiology is still poorly understood. So far, numerous genetic and environmental factors that may contribute to the occurrence of these defects have been described and the literature is dominated by the view of their common involvement in the etiology and pathogenesis of congenital esophageal atresia. In this review the authors present current knowledge on the embryogenesis of the esophagus and trachea, discuss environmental risk factors, and also list and describe genetic alterations identified so far in patients with congenital esophageal atresia.

Mapping of breakpoints in balanced chromosomal translocations by shallow whole-genome sequencing points to EFNA5, BAHD1 and PPP2R5E as novel candidates for genes causing human Mendelian disorders

Background Mapping the breakpoints in de novo balanced chromosomal translocations (BCT) in symptomatic individuals provides a unique opportunity to identify in an unbiased way the likely causative genetic defect and thus find novel human disease candidate genes. Our aim was to fine-map breakpoints of de novo BCTs in a case series of nine patients. Methods Shallow whole-genome mate pair sequencing (SGMPS) together with long-range PCR and Sanger sequencing. In one case (BCT disrupting BAHD1 and RET) cDNA analysis was used to verify expression of a fusion transcript in cultured fibroblasts. Results In all nine probands 11 disrupted genes were found, that is, EFNA5, EBF3, LARGE, PPP2R5E, TXNDC5, ZNF423, NIPBL, BAHD1, RET, TRPS1 and SLC4A10. Five subjects had translocations that disrupted genes with so far unknown (EFNA5, BAHD1, PPP2R5E, TXNDC5) or poorly delineated impact on the phenotype (SLC4A10, two previous reports of BCT disrupting the gene). The four genes with no previous disease associations (EFNA5, BAHD1, PPP2R5E, TXNDC5), when compared with all human genes by a bootstrap test, had significantly higher pLI (p<0.017) and DOMINO (p<0.02) scores indicating enrichment in genes likely to be intolerant to single copy damage. Inspection of individual pLI and DOMINO scores, and local topologically associating domain structure suggested that EFNA5, BAHD1 and PPP2R5E were particularly good candidates for novel disease loci. The pathomechanism for BAHD1 may involve deregulation of expression due to fusion with RET promoter. Conclusion SGMPS in symptomatic carriers of BCTs is a powerful approach to delineate novel human gene–disease associations.

A novel IGF2/H19 domain triplication in the 11p15.5 imprinting region causing either Beckwith-Wiedemann or Silver-Russell syndrome in a single family.

Defects of 11p15.5 imprinting result in two growth disorders with opposite phenotypes: Beckwith–Wiedemann syndrome (BWS) characterized by overgrowth and Silver–Russell syndrome (SRS) associated with growth retardation. In a small group of patients with BWS and SRS, copy number variations (CNVs) involving the 11p15.5 region are observed; and their effects depend on the localization, size, and the parental mode of transmission. We report a novel IGF2/H19 domain cis‐triplication in the 11p15.5 region identified in a girl with BWS and her father with symptoms of SRS. To the best of our knowledge, this is the first report of IGF2/H19 domain triplication associated with BWS or SRS and the second report of an additional copy of this region in an individual with clinical features of SRS. This study shows that paternal IGF2/H19 domain triplication results in BWS, gives additional support to the hypothesis that the maternal amplification of IGF2/H19 domain may lead to the manifestation of SRS and underlines difficulties of genetic counseling in patients with CNVs involving the 11p15.5 region.

Pielęgnacja noworodka z zarośnięciem przełyku

Nursing care of a newborn with Congenital Esophageal Atresia is extremely demanding, and its quality is important in the recovery process of the baby. Appropriate pre and postoperative treatment can help to improve the outcome of the surgery. This is the stage when the child is most susceptible to all sorts of complications and problems. Nursing requires assiduous attention, vigilance and careful analysis of clinical parameters of the newborn. Understanding the nature and significance of the defect and proper care can remarkably improve the outcome of the treatment. The aim of the study is to describe the standards of nursing care of a newborn with Congenital Esophageal Atresia before and after surgery. Nursing Topics 2015; 23 (2): 251–258

Znaczenie kliniczne wczesnej diagnostyki zespołu Pradera-Williego – historia trzech chorych

Streszczenie Zespol Pradera-Williego (Prader-Willi Syndrome – PWS) jest zespolem dysmorficznym o zlozonym podlozu genetycznym i zroznicowanym obrazie klinicznym. Zdecydowana wiekszośc przypadkow PWS powstaje de novo jako wynik delecji fragmentu ramienia krotkiego chromosomu 15 pochodzącego od ojca (75% przypadkow). Zakres objawow klinicznych w PWS jest szeroki. Opisuje sie glownie cechy dysmorficzne twarzy, takie jak: wąskie czolo, oczy w ksztalcie migdalow, wąskie szpary powiekowe, kąciki ust skierowane ku dolowi, wąska warga gorna zachodząca na dolną – tzw. rybi pyszczek, a takze male dlonie i stopy, niski wzrost, obnizenie napiecia mieśniowego, hipogonadyzm, hiperfagie i otylośc, zaburzenia rozwoju psychoruchowego oraz zaburzenia zachowania. W pracy przedstawiono odmienny przebieg kliniczny trzech przypadkow zespolu Pradera-Williego: 1) wcześnie rozpoznanego i prawidlowo leczonego (pacjenci 1 oraz 2) poźno rozpoznanego i nieleczonego (pacjenci 2 i 3). Dodatkowo przedstawiono przegląd piśmiennictwa dotyczącego kryteriow rozpoznawania zespolu Pradera-Williego, jego przebiegu klinicznego oraz mozliwości leczenia oraz rehabilitacji.