Saethre­Chotzen syndrome with an atypical phenotype: identification of TWIST microdeletion by array CGH.

Saethre­Chotzen syndrome is a very rare autosomal dominant congenital disorder characterized by craniosynostosis and acrocephalosyndactyly. It is caused by a mutation in TWIST1, located on chromosome 7p21. A shortage of functional TWIST1 protein affects the development and maturation of cells in the skull, face, and limbs. The patient described in this report displayed craniofacial features classic for Saethre­Chotzen syndrome, including craniosynostosis, low-set ears, small pinna with prominent crura, a high-arched palate, and a simian crease on the left hand. He did not have the limb anomalies commonly seen in patients with Saethre­Chotzen syndrome, and the results of conventional chromosome analysis were normal. However, results of a microarray-based comparative genomic hybridization (array CGH) study confirmed the karyotype of46,XY.7p21.1p15.3(15,957,375-20,331,837)x1, a region that includes TWIST1. Subsequent fluorescent in situ hybridization analysis confirmed this result. No other chromosome was involved in the rearrangement. This case illustrates the important contribution of array CGH to the identification of TWIST microdeletions, even in a patient not showing the phenotype typical of Saethre­Chotzen syndrome.

Application of array comparative genomic hybridization in Korean children under 6 years old with global developmental delay.

PURPOSE: Recent advancements in molecular techniques have greatly contributed to the discovery of genetic causes of unexplained developmental delay. Here, we describe the results of array comparative genomic hybridization (CGH) and the clinical features of 27 patients with global developmental delay. METHODS: We included 27 children who fulfilled the following criteria: Korean children under 6 years with global developmental delay; children who had at least one or more physical or neurological problem other than global developmental delay; and patients in whom both array CGH and G-banded karyotyping tests were performed. RESULTS: Fifteen male and 12 female patients with a mean age of 29.3±17.6 months were included. The most common physical and neurological abnormalities were facial dysmorphism (n=16), epilepsy (n=7), and hypotonia (n=7). Pathogenic copy number variation results were observed in 4 patients (14.8%): 18.73 Mb dup(2)(p24.2p25.3) and 1.62 Mb del(20p13) (patient 1); 22.31 Mb dup(2) (p22.3p25.1) and 4.01 Mb dup(2)(p21p22.1) (patient 2); 12.08 Mb del(4)(q22.1q24) (patient 3); and 1.19 Mb del(1)(q21.1) (patient 4). One patient (3.7%) displayed a variant of uncertain significance. Four patients (14.8%) displayed discordance between G-banded karyotyping and array CGH results. Among patients with normal array CGH results, 4 (16%) revealed brain anomalies such as schizencephaly and hydranencephaly. One patient was diagnosed with Rett syndrome and one with Möbius syndrome. CONCLUSION: As chromosomal microarray can elucidate the cause of previously unexplained developmental delay, it should be considered as a first-tier cytogenetic diagnostic test for children with unexplained developmental delay.

1p36 deletion syndrome confirmed by fluorescence in situ hybridization and array-comparative genomic hybridization analysis.

Pediatric epilepsy can be caused by various conditions, including specific syndromes. 1p36 deletion syndrome is reported in 1 in 5,000-10,000 newborns, and its characteristic clinical features include developmental delay, mental retardation, hypotonia, congenital heart defects, seizure, and facial dysmorphism. However, detection of the terminal deletion in chromosome 1p by conventional G-banded karyotyping is difficult. Here we present a case of epilepsy with profound developmental delay and characteristic phenotypes. A 7-year- and 6-month-old boy experienced afebrile generalized seizure at the age of 5 years and 3 months. He had recurrent febrile seizures since 12 months of age and showed severe global developmental delay, remarkable hypotonia, short stature, and dysmorphic features such as microcephaly; small, low-set ears; dark, straight eyebrows; deep-set eyes; flat nasal bridge; midface hypoplasia; and a small, pointed chin. Previous diagnostic work-up, including conventional chromosomal analysis, revealed no definite causes. However, array-comparative genomic hybridization analysis revealed 1p36 deletion syndrome with a 9.15-Mb copy loss of the 1p36.33-1p36.22 region, and fluorescence in situ hybridization analysis (FISH) confirmed this diagnosis. This case highlights the need to consider detailed chromosomal study for patients with delayed development and epilepsy. Furthermore, 1p36 deletion syndrome should be considered for patients presenting seizure and moderate-to-severe developmental delay, particularly if the patient exhibits dysmorphic features, short stature, and hypotonia.

A new mosaic der(18)t(1;18)(q32.1;q21.3) with developmental delay and facial dysmorphism.

We report the case of a 22-month-old boy with a new mosaic partial unbalanced translocation of 1q and 18q. The patient was referred to our Pediatric Department for developmental delay. He showed mild facial dysmorphism, physical growth retardation, a hearing disability, and had a history of patent ductus arteriosus. White matter abnormality on brain magnetic resonance images was also noted. His initial routine chromosomal analysis revealed a normal 46,XY karyotype. In a microarray-based comparative genomic hybridization (aCGH) analysis, subtle copy number changes in 1q32.1-q44 (copy gain) and 18q21.33-18q23 (copy loss) suggested an unbalanced translocation of t(1;18). Repeated chromosomal analysis revealed a low-level mosaic translocation karyotype of 46,XY,der(18)t(1;18)(q32.1;q21.3)[12]/46,XY[152]. Because his parents had normal karyotypes, his translocation was considered to be de novo. The abnormalities observed in aCGH were confirmed by metaphase fluorescent in situ hybridization. We report this patient as a new karyotype presenting developmental delay, facial dysmorphism, cerebral dysmyelination, and other abnormalities.

Application of array-based comparative genomic hybridization to pediatric neurologic diseases.

PURPOSE: Array comparative genomic hybridization (array-CGH) is a technique used to analyze quantitative increase or decrease of chromosomes by competitive DNA hybridization of patients and controls. This study aimed to evaluate the benefits and yield of array-CGH in comparison with conventional karyotyping in pediatric neurology patients. MATERIALS AND METHODS: We included 87 patients from the pediatric neurology clinic with at least one of the following features: developmental delay, mental retardation, dysmorphic face, or epilepsy. DNA extracted from patients and controls was hybridized on the Roche NimbleGen 135K oligonucleotide array and compared with G-band karyotyping. The results were analyzed with findings reported in recent publications and internet databases. RESULTS: Chromosome imbalances, including 9 cases detected also by G-band karyotyping, were found in 28 patients (32.2%), and at least 19 of them seemed to be causally related to the abnormal phenotypes. Regarding each clinical symptom, 26.2% of 42 developmental delay patients, 44.4% of 18 mental retardation patients, 42.9% of 28 dysmorphic face patients, and 34.6% of 26 epilepsy patients showed abnormal array results. CONCLUSION: Although there were relatively small number of tests in patients with pediatric neurologic disease, this study demonstrated that array-CGH is a very useful tool for clinical diagnosis of unknown genome abnormalities performed in pediatric neurology clinics.

A de novo centric fission of chromosome 11 in a patient with recurrent miscarriages.

We report on a de novo centric fission of chromosome 11 in a healthy female referred for chromosome analysis due to recurrent miscarriages. Both fission products were mitotically stable. This centric fission of chromosome 11 appears to have no clinical significance for this patient other than recurrent miscarriages.