Familial Translocation t(2;4) (q37.3;p16.3), Resulting in a Partial Trisomy of 2q (or 4p) and a Partial Monosomy of 4p (or 2q), Causes Dysplasia

Background: Wolf-Hirschhorn syndrome, a well-known contiguous microdeletion syndrome, is caused by deletions on chromosome 4p. While the clinical symptoms and the critical region for this disorder have been identified based on genotype-phenotype correlations, duplications in this region have been infrequently reported.Conclusion: Our case report shows that both deletions and duplications of the Wolf-Hirshhorn critical region cause intellectual disability/developmental delay and multiple congenital anomalies.

Allelic and dosage effects of NHS in X-linked cataract and Nance–Horan syndrome: a family study and literature review

Nance–Horan syndrome (NHS) is a rare X-linked dominant disorder caused by mutation in the NHS gene on chromosome Xp22.13. (OMIM 302350). Classic NHS manifested in males is characterized by congenital cataracts, dental anomalies, dysmorphic facial features and occasionally intellectual disability. Females typically have a milder presentation. The majority of reported cases of NHS are the result of nonsense mutations and small deletions. Isolated X-linked congenital cataract is caused by non-recurrent rearrangement-associated aberrant NHS transcription. Classic NHS in females associated with gene disruption by balanced X-autosome translocation has been infrequently reported. We present a familial NHS associated with translocation t(X;19) (Xp22.13;q13.1). The proband, a 28-year-old female, presented with intellectual disability, dysmorphic features, short stature, primary amenorrhea, cleft palate, and horseshoe kidney, but no NHS phenotype. A karyotype and chromosome microarray analysis (CMA) revealed partial monosomy Xp/partial trisomy 19q with the breakpoint at Xp22.13 disrupting the NHS gene. Family history revealed congenital cataracts and glaucoma in the patient’s mother, and congenital cataracts in maternal half-sister and maternal grandmother. The same balanced translocation t(X;19) was subsequently identified in both the mother and maternal half-sister, and further clinical evaluation of the maternal half-sister made a diagnosis of NHS. This study describes the clinical implication of NHS gene disruption due to balanced X-autosome translocations as a unique mechanism causing Nance–Horan syndrome, refines dose effects of NHS on disease presentation and phenotype expressivity, and justifies consideration of karyotype and fluorescence in situ hybridization (FISH) analysis for female patients with familial NHS if single-gene analysis of NHS is negative.

Chromosome 18p deletion syndrome (18p-) in children: the value of cytogenetic and molecular cytogenetic diagnosis

Chromosome 18p deletion syndrome (18p-) is associated with a loss of chromosomal material of the short arm (partial monosomy); however, the whole short arm is lost in the majority of cases. The frequency of 18p- syndrome is 1:60000. The syndrome is cytogenetically and clinically heterogeneous. The clinical manifestations vary extremely from mild forms with congenital anomalies and developmental delays to severe brain malformations. Rare cases demonstrate epilepsy and autism spectrum disorders. The deletion breakpoints are also variable. Accordingly, the syndrome needs the analysis of large groups of diseased children by current genomic technologies. Aim of the study: The evaluation of cytogenetic and molecular- cytogenetic technologies for defining critical breakpoints and possible phenotype- genotype correlations. Results: Here, we describe our observations of 15 patients (9 boys and 6 girls) with 18p deletion syndrome, revealed in a large cohort of patients (n=8536). The mean age was 5.1 years; the sex ratio was in favor of boys (1.5:1) in contrast to the literature data. Critical breakpoints associated with this syndrome within the short arm of chromosome 18 were not revealed. It is possible that the clinical features of the syndrome are associated with many breakpoints in chromosome 18 short arm (p11.1->pter). The frequency of 18p- syndrome in children with intellectual disability, developmental delays, and congenital anomalies was 0.2%. The diagnostic aspects of this pathology and the value of molecular cytogenetic methods in studying the syndrome are discussed. Conclusion: We highlight personalized approach to diagnosis of the syndrome for correct genetic counseling for the improvement the life quality and establishing phenotype-karyotype correlations.

Anaesthesia and orphan disease: management of a case of Nicolaides-Baraitser syndrome undergoing cleft palate surgery

Background Nicolaides-Baraitser syndrome (NCBRS) is a rare disease caused by mutations in the SMRCA2 gene, which affects chromatin remodelling and leads to a wide range of symptoms including microcephaly, distinct facial features, recurrent seizures, and severe mental retardation. Until now, less than 100 cases have been reported. Case presentation A 22-month old male infant with NCBRS underwent elective cleft palate surgery. The anaesthetists were challenged by the physiological condition of the patient: narrow face, very small mouth, mild tachypnea, slight sternal retractions, physical signs of partial monosomy 9p, and plagiocephalus, midface hypoplasia, V-shaped cleft palate, enhanced muscular hypotension, dysplastic kidneys (bilateral, estimated GFR: approx. 40 ml/m2), nocturnal oxygen demand, and combined apnea. In addition, little information was available about interaction of the NCBRS displayed by the patient and anaesthesia medications. Conclusions The cleft palate was successfully closed using the bridge flap technique. Overall, we recommend to perform a trial video assisted laryngoscopy in the setting of spontaneous breathing with deep inhalative anaesthesia before administration of muscle relaxation to detect any airway difficulties while remaining spontaneoues breathing and protective reflexes.

Multicolor-FISH Characterization of a Prenatal Mosaicism for a Chromosomal Rearrangement Undetected by Molecular Cytogenetics

Fetal mosaicism for chromosomal rearrangements remains a challenge to diagnose, even in the era of whole-genome sequencing. We present here a case of fetal mosaicism for a chromosomal rearrangement explored in amniocytes and fetal muscle, consisting of a major cell population (95%) with partial monosomy 4q and a minor population (5%) with additional material replacing the 4qter deleted segment. Molecular techniques (MLPA, array-CGH) failed to assess the origin of this material. Only multicolor-FISH identified the additional segment on chromosome 4 as derived from chromosome 17. Due to the poor prognosis, the couple chose to terminate the pregnancy. Because of low-level mosaicism, chromosomal microarray analysis (CMA), now considered as first-tier prenatal genetic analysis, did not allow the identification of the minor cell line. In case of large CNVs (>5 Mb) detected by CMA, karyotyping may be considered to elucidate the mechanism of the underlying rearrangement and eliminate mosaicism.

A Case of Partial Trisomy of 10q and Partial Monosomy of 6p Resulting from Maternal t(6;10) (p23;q24)

Chromosomal analysis is practiced routinely since long time in congenital malformations to find out structural and or numerical chromosomal aberrations. Translocation is one of the structural chromosomal aberrations where exchange of genetic material between the chromosomes is seen because of two breakpoints. On the basis of involvement of type of chromosome, two different types of translocation are defined. A case of two-year-old girl child with the history of developmental delay, generalised hypotonia and recurrent infections was reported whose cytogenetic analysis showed additional genetic material on ‘p’ arm of one chromosome 6. To find out the additional genetic material, parental chromosomal study was done which revealed balanced translocation between ‘q’ arm of chromosome 10 and ‘p’ arm of chromosome 6 and normal chromosomal pattern in father. Balanced translocation in mother gave rise to formation of derivative chromosome 6 which was transmitted to daughter causing partial trisomy of 10q and partial monosomy of 6p. This gain and loss of genetic material could be the cause of phenotypic features. In the current case, karyotyping was an investigation of choice and offering genetic counselling regarding prenatal diagnosis in future pregnancy was a thoughtful step.

Fetal cystic hygroma associated with terminal 2p25.1 duplication and terminal 3p25.3 deletion: Cytogenetic, fluorescent in situ hybridization and microarray familial characterization of two different chromosomal structural rearrangements

We report a prenatally diagnosed case of partial trisomy 2p and partial monosomy 3p, resulting from unbalanced translocation (2;3)(p25.1;p25.3) of paternal origin. Parents were non consanguineous Caucasians, with familial history of recurrent miscarriages on the father’s side. Detailed sonographic examination of the fetus showed a septated cystic hygroma measuring 6 mm at 13 weeks’ gestation. Karyotyping and fluorescent in situ hybridization (FISH) analysis of cultured amniotic fluid cells revealed an unbalanced translocation der(3)t(2;3)(p25.1; p25.3) and apparently balanced inv(3)(p13p25.3) in a fetus. Parental cytogenetic evaluation using karyotyping and FISH analysis showed the presence of both a balanced translocation and a paracentric inversion in father t(2;3) (p25.1;p25.3) inv(3)(p13p25.3). Microarray analysis showed a 11.6 Mb deletion at 3p26.3-p25.3 and duplication of 10.5 Mb at the 2p25.3-p25 region. The duplicated region at 2p25.1p25.3 contains 45 different genes, where 12 are reported as OMIM morbid genes with different phenotypical implications. The deleted region at 3p26.3-p25.3 contains 65 genes, out of which 27 are OMIM genes. Three of these (CNTN4, SETD5 and VHL) were curated by Clingene Dosage Gene Map and were given a high haplo-insufficiency score. Genes affected by the unbalanced translocation could have contributed to some specific phenotypic changes of the fetus in late pregnancy. The application of different cytogenetic methods was essential in our case, allowing the detection of different types of structural chromosomal aberrations and more thorough genetic counseling for future pregnancies.