Diagnostic Challenges in a Family with Dominant Dystrophic Epidermolysis Bullosa and Isolated Hereditary Nail Disorder: Paternal Gonosomal Mosaicism for COL7A1 Mutation and Maternal RSPO4 Variant.

Dystrophic epidermolysis bullosa (DEB) has long been recognized as a well-known genodermatosis, caused by COL7A1 gene pathogenic variants. Isolated anonychia associated with RSPO4 gene mutation is a recently described non-syndromic autosomal recessive condition. In this family, a 13-year-old girl presented with severe epidermolysis bullosa symptoms. Family history revealed milder but similar complaints in the siblings, and anonychia affecting all nails in the mother and maternal relatives. The father did not have any signs of DEB. Genetic testing revealed heterozygous c.6127G>A (p.Gly2043Arg) variant in the COL7A1 (NM_000094.4) gene, in the proband and her affected siblings. The variant was not detected in the mother or father, prompting investigation into parental mosaicism. Detection of the variant in sperm sample suggested paternal mosaicism. Additionally, RSPO4 gene (NM_001029871.4) was sequenced in the mother and two of her affected sisters for suspected non-syndromic isolated anonychia, revealing homozygous c.79+1G>A variant. Isolated nail disease in the mother was initially thought to be the result of DDEB nails-only subtype and the DEB in the children was inherited from the mother. However, further clinical and genetic investigation showed that the condition in the patient and her siblings arose from gonosomal mosaicism in the father and the nail phenotype in the mother is a separate coincidental condition. This report aims to serve as an example for similar cases and highlight the importance of detailed genetic analysis guided by comprehensive medical history in reaching a diagnosis.

A Paternal "Balanced" Chromosome 2 and 4 Translocation with Chromosome 21q Insertion Leading to Duplication of 2q22.1q24.1 in Two Siblings.

Complex chromosomal rearrangements (CCRs) have been described as alterations between two or more chromosomes with at least 3 breakpoints. CCRs can cause copy number variations (CNVs) resulting in developmental disorders, multiple congenital anomalies, and recurrent miscarriages. Developmental disorders are an important health problem affecting 1-3% of children. The underlying etiology can be explained by CNV analysis in 10-20% of children who have unexplained intellectual disability, developmental delay, and congenital anomalies. Here we report two siblings who were referred to us with intellectual disability, neurodevelopmental delay, happy demeanor, and craniofacial dysmorphism due to chromosome 2q22.1q24.1 duplication. Segregation analysis showed that the duplication originated from meiotic segregation of a paternal translocation between chromosomes 2 and 4 with chromosome 21q insertion. Considering that infertility is seen in many male individuals with CCRs, it is remarkable that the father does not have any fertility problems. Gain of chromosome 2q22.1q24.1 was responsible for the phenotype due to its size and presence of a gene with a probability of being triplosensitive. We corroborate the assumption that the major gene responsible for the phenotype in the 2q23.1 region is methyl-CpG-binding domain 5, MBD5.

Mosaic Small Supernumerary Marker Chromosome Derived from Five Discontinuous Regions of Chromosome 8 in a Patient with Neutropenia and Oral Aphthous Ulcer.

Small supernumerary marker chromosomes (sSMCs) are characterized as additional centric chromosome fragments which are too small to be classified by cytogenetic banding alone and smaller than or equal to the size of chromosome 20 of the same metaphase spread. Here, we report a patient who presented with slight neutropenia and oral aphthous ulcers. A mosaic de novo sSMC, which originated from 5 discontinuous regions of chromosome 8, was detected in the patient. Formation of the sSMC(8) can probably be explained by a multi-step process beginning with maternal meiotic nondisjunction, followed by post-zygotic anaphase lag, and resulting in chromothripsis. Chromothripsis is a chromosomal rearrangement which occurs by breakage of one or more chromosomes leading to a fusion of surviving chromosome pieces. This case is a good example for emphasizing the importance of conventional karyotyping from PHA-induced peripheral blood lymphocytes and examining tissues other than bone marrow in patients with inconsistent genotype and phenotype.

Characteristics and prevalence of non-classical congenital adrenal hyperplasia with a V2811 mutation in patients with premature pubarche.

We aimed to determine the prevalence and clinical characteristics of non-classical congenital adrenal hyperplasia (NCCAH) with V281L mutation in patients with premature pubarche. An adrenocorticotrophic hormone (ACTH) stimulation test was performed in 14 of the 159 patients with premature pubarche (PP). Patients whose stimulated 17alpha-hydroxyprogesterone (17-OHP) level on the ACTH test was > or =10 ng/mL underwent a mutational analysis of the CYP21 gene. NCCAH was defined in nine (5.7%) patients, all of whom had the V281L mutation. Four of the NCCAH patients were homozygote and four of them were heterozygote. One other patient was compound heterozygote for V281L mutation and the I2 splice mutation. One of the patients with V281L heterozygous mutation developed true precocious puberty and the other one had rapid progressive early puberty and developed polycystic ovary syndrome. ACTH stimulated 17-OHP > or = 10 ng/mL in PP patients is load star to mutation analysis and heterozygote patients should be followed for clinical and biological hyperandrogenism up to completion of the whole 'genome sequence'.

The association between telomere length and ischemic stroke risk and phenotype.

The chronological age of a person is a key determinant of etiology and prognosis in the setting of ischemic stroke. Telomere length, an indicator of biological aging, progressively shortens with every cell cycle. Herein, we determined telomere length from peripheral blood leukocytes by Southern blot analyses in a prospective cohort of ischemic stroke patients (n = 163) and equal number of non-stroke controls and evaluated its association with various ischemic stroke features including etiology, severity, and outcome. A shorter telomere length (i.e. lowest quartile; ≤ 5.5 kb) was significantly associated with ischemic stroke (OR 2.95, 95% CI 1.70-5.13). This significant relationship persisted for all stroke etiologies, except for other rare causes of stroke. No significant association was present between admission lesion volume and telomere length; however, patients with shorter telomeres had higher admission National Institutes of Health Stroke Scale scores when adjusted for chronological age, risk factors, etiology, and infarct volume (p = 0.046). On the other hand, chronological age, but not telomere length, was associated with unfavorable outcome (modified Rankin scale > 2) and mortality at 90 days follow-up. The association between shorter telomere length and more severe clinical phenotype at the time of admission, might reflect reduced resilience of cerebral tissue to ischemia as part of biological aging.

A child with myelodysplastic syndrome with hypocellular fibrosis.

A 9-year-old girl with intractable anemia, rare mucocutaneous bleeding, and pallor was presented. Hemoglobin was 49 g/L; reticulocyte 0.79%, mean corpuscular volume 81 fL, platelet 37×109/L; white blood cell count 3.2×109/L with dysmorphic cells in peripheric blood. Further evaluation revealed 10% cellularity with grade IV reticulin fibrosis, immature, and/or dysplastic hematopoietic cells without sideroblasts, or blast increase in biopsy, Monosomy 8 was found in bone marrow aspiration material using FISH. Vitamin B12, folic acid, hemoglobin electrophoresis, immunoglobulin levels, CD55, CD59, complement 3, 4, abdominal ultrasonography, chest x-ray were normal; diepoxybutane, acid ham, sucrose lysis tests, viral serologies, antinuclear antibody, anti DNA were negative. On diagnosis of "Myelodysplastic Syndrome-refractory cytopenia with hypocellular fibrosis," she received a successful allogeneic BM transplantation from her full matched sibling.

Importance of patient selection criteria in determining diagnostic copy number variations in patients with multiple congenital anomaly/mental retardation.

BACKGROUND: Etiology of developmental delay/intellectual disability is very heterogeneous. In recent years, genetic causes have been defined through the use of chromosomal microarray analysis as a first step genetic test. RESULTS: Samples from 30 patients with multiple congenital anomaly and/or mental retardation were analyzed with array comparative genomic hybridization in the context of this study. Before this analysis, karyotyping, subtelomeric fluorescence in situ hybridization and additionally fragment analysis for fragile X in males, had been routinely made all of which were reported to be normal. The purpose of our study was to determine the copy number variations as well as to investigate methods to increase diagnostic yield of array comparative genomic hybridization and forming a suitable flow chart decision pipeline for test indication especially for developing countries. Genomic changes were identified at a rate of about 27% in our series. Although this ratio is higher than the literature data, it could be due to the patient selection criteria. CONCLUSION: Chromosomal microarray analysis is not easily utilized for all patients because of its high-cost. Thus, for increasing cost-effectiveness, it may be used step by step for defined targets. Along with discussing the patients with copy number variations relevant with the phenotype, we suggest a flow chart for selection of diagnostic test with the highest diagnostic rate and the lowest expenditure which is quite important for developing countries.

Association Between N363S and BclI Polymorphisms of the Glucocorticoid Receptor Gene (NR3C1) and Glucocorticoid Side Effects During Childhood Acute Lymphoblastic Leukemia Treatment.

OBJECTIVE: Glucocorticoids (GCs) are the key drugs for the treatment of pediatric acute lymphoblastic leukemia (ALL). Herein, investigation of the relationship between the N363S and BclI polymorphisms of the GC receptor gene (NR3C1) and the side effects of GCs during pediatric ALL therapy was aimed. MATERIALS AND METHODS: N363S and BclI polymorphisms were analyzed in 49 patients with ALL treated between 2000 and 2012. The control group consisted of 46 patients with benign disorders. The side effects of GCs noted during the induction and reinduction periods were evaluated retrospectively according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: The BclI allele and genotype frequencies were found similar in the two groups. No N363S polymorphism was detected in either of the groups. During induction, dyspepsia was found more frequently in the CG than in the CC (wild-type) genotype (36.4% vs. 5.3%, p=0.018) and depression symptoms more frequent in patients with the G allele (CG+GG) than the CC genotype (39.3% vs. 10.5%, p=0.031). During reinduction, Cushingoid changes, dyspepsia, and depression symptoms were more frequent in patients with the G allele (CG+GG) than in patients with the CC genotype (48.1% vs. 17.6%, p=0.041; 29.6% vs. 0.0%, p=0.016; 40.7% vs. 11.8%, p=0.040, respectively). CONCLUSION: In our study, patients with the BclI polymorphism were found to have developed more frequent side effects. We think that the BclI polymorphism should be considered while designing individualized therapies in childhood ALL.

Translocation (13;17)(q14;q25) as a novel chromosomal abnormality in acute myeloid leukemia-M4.

We report a case of AML-M4 in which G-band karyotyping revealed a previously unreported t(13;17)(q14;q25) in metaphase preparations. The breakpoints at 13q14 and 17q25 are associated with poor prognosis. The MSF and FKHR genes are located on 17q25 and 13q14, respectively. This report of AML-M4 harboring t(13;17)(q14;q25) as a unique cytogenetic abnormality provides more data on the leukomogenesis with rearrangements related with 13q14 and 17q25.

The role of genetic counseling on decisions of pregnant women aged 35 years or over regarding amniocentesis in Turkey.

We investigated the effects of genetic counseling given before amniocentesis that is given based on maternal serum screening (using the cut-off value of 1/250) and genetic sonogram results (+/- abnormal ultrasound marker) on pregnant women who are 35 years and older age. Their attitudes towards amniocentesis after genetic counseling were evaluated. Among 340 women, 223 (65.6%) were in the high-risk group and 117 (34.4%) were in the low-risk group according to non-invasive test results. After counseling, 216 pregnant women (167 cases have high-risk, 49 cases who had low-risk) decided to have amniocentesis while 124 women (56 with high-risk and 68 with low-risk) declined it. Fourteen abnormal karyotypes were detected. All pregnant women who had fetuses with chromosomal aberrations were in high-risk group. Our study shows that screening by non-invasive prenatal diagnostic tool has an effect on families' choice of amniocentesis. The use of these test results during counseling decreased the number of amniocentesis in a ratio of 36.5%.

Congenital bilateral parotid gland agenesis in Klinefelter syndrome.

Bilateral parotid gland agenesis is a rare clinical entity and it's an etiopathogenesis remains obscure. The literature contains no reports of the co-existence of bilateral parotid gland agenesis and Klinefelter syndrome. The condition is usually asymptomatic and causes asymmetry in the head and neck areas. Its diagnosis is generally made in the light of accompanying developmental anomalies. Herein we report the clinical and radiological findings of a 17-year-old male with Klinefelter syndrome accompanied by unilateral peripheral facial nerve paralysis and isolated congenital bilateral parotid gland agenesis.