Cytogenetic, Molecular, and Phenotypic Characterization of a Patient with de novo Derivative Chromosome 18 and Review of the Literature.

We present a patient with a de novo derivative chromosome 18 which includes a terminal deletion of 18p and a terminal duplication of 18q accompanied by a cryptic duplication of 18p. The girl had mild dysmorphic features such as micro-retrognathia, upslanted palpebral fissures, bilateral epicanthus, high palate, low-set ears, short neck, and full cheeks. She also had an H-type tracheoesophageal fistula which required surgery. Her cognitive and motor skills were delayed. Karyotype analysis showed an additional segment on the short arm of chromosome 18. Chromosomal microarray revealed a 7.3-Mb terminal loss from 18p11.32 to 18p11.23, a 22.2-Mb terminal gain from 18q21.31 to 18q23, and a 3.9-Mb interstitial gain from 18p11.22 to 18p11.21. We hypothesize that the mother has gonadal mosaicism for normal chromosome 18, der(18)dup(p11.22p11.21), and der(18)dup(p11. 22p11.21)inv(18)(p11.22q21.31), or both the terminal del/dup and the interstitial duplication occurred simultaneously.

Primary Hypertrophic Osteoarthropathy Mimicking Juvenile Idiopathic Arthritis: A Novel SLCO2A1 Mutation and Imaging Findings.

Primary hypertrophic osteoarthropathy (PHO), also known as pachydermoperiostosis, is a rare, multisystemic, autosomal recessive condition typically presenting with digital clubbing, osteoarthropathy, and various skin manifestations. Radiographs show distinctive periosteal reaction and thickening along the long bones. PHO is caused by homozygous mutations in the HPGD gene in chromosome 4q34.1 or the SLCO2A1 gene in 3q22.1q22.2. Here, we report on a 20-year-old male with enlarged and swollen joints with arthralgia, palmoplantar hyperhidrosis, and large hands and feet with marked digital clubbing. We also present radiographic, MRI, and ultrasonographic features of the case. These clinical and imaging findings were compatible with the diagnosis of PHO, and a novel homozygous mutation, c.576C>G, p.Ile192Met, was found in SLCO2A1.

A Novel PORCN Frameshift Mutation Leading to Focal Dermal Hypoplasia: A Case Report.

Focal dermal hypoplasia (FDH), also known as Goltz-Gorlin syndrome, is a rare, multisystemic, X-linked dominant genodermatosis characterized by defective development of mesodermal and ectodermal tissues. Major clinical features of the disorder are skin manifestations, skeletal defects, and developmental eye abnormalities. FDH is caused by heterozygous mutations in the PORCN gene located at Xp11.23, and 90% of individuals with FDH are females. Here, we report a female patient with cutaneous changes, multiple eye anomalies, short stature, and ectrodactyly of the right foot. These clinical findings were compatible with the diagnosis of FDH, and a novel mutation, NM_022825.3:c.488delG was found in the PORCN gene causing a premature stop codon.

Autosomal Recessive Oculodentodigital Dysplasia: A Case Report and Review of the Literature.

Oculodentodigital dysplasia (ODDD) is a rare condition characterized by a typical facial appearance and variable findings of the eyes, teeth, and fingers. ODDD is caused by mutations in the GJA1 gene in chromosome 6q22 and inherited in an autosomal dominant manner in the majority of the patients. However, in recent clinical reports, autosomal recessive ODDD cases due to by GJA1 mutations were also described. Here, we report on a 14-year-old boy with microphthalmia, microcornea, narrow nasal bridge, hypoplastic alae nasi, prominent columnella, hypodontia, dental caries, and partial syndactyly of the 2nd and 3rd toes. These clinical findings were concordant with the diagnosis of ODDD, and a novel homozygous mutation (c.442C>T, p.Arg148Ter) was determined in the GJA1 gene leading to a premature stop codon. His phenotypically normal parents were found to be carriers of the same mutation. This is the third family in the literature in which ODDD segregates in an autosomal recessive manner.

Skin-Dominant Phenotype in a Patient with H Syndrome: Identification of a Novel Mutation in the SLC29A3 Gene.

H syndrome (OMIM 602782) is a very rare autosomal recessive genodermatosis with multisystem involvement. Hallmarks of this disorder are juvenile onset and progressive, hyperpigmented, hypertrichotic lesions with histiocytic infiltration. Associated systemic manifestations form a long list, and there is high variability between patients. In some patients, dysmorphic and other systemic features may be so subtle that the disorder may readily be mistaken as an acquired skin disease and treated as such. Herein, we report a novel homozygous c.1339G>A (p.Glu447Lys) mutation in the SLC29A3 gene in a patient with skin-dominant presentation of H syndrome. Additionally, due to the present case, double superior vena cava can be added to the list of possible cardiovascular manifestations of H syndrome.

TBX1 gene mutation screening in patients with non-syndromic Fallot tetralogy.

Fallot tetralogy (FT) is the most frequently observed conotruncal heart defect (CTHD) and accompanies 15% of the 22q11 deletion syndromes, DiGeorge/ velocardiofacial (DGS/VCFS) syndromes. TBX1 is a gene located in the 22q11 region and has a role in neural crest migration and conotruncal development. The mouse Tbx1 locus shows 98% homology with TBX1. DGS/VCFS-like aortic arch abnormalities in the mouse were attributed to deletions in this locus. The T-box region, common to both mice and humans, is part of TBX1 with proven effects on heart outflow track anomalies. The role of TBX1 in non-syndromic CTHDs is still unclear. In this study, we screened the TBX1 gene T-box region exons in 50 FT patients without 22q11 deletion and in 50 healthy volunteers. Our study did not show any disease causing mutations, but one polymorphic change. These results do not support a major role of the T-box region in the etiology of isolated FT. Furthermore, this study also confirms that mouse cardiac-development study models do not always provide an explanation for human phenotype-genotype correlations.

The impact of vitamin D receptor genotype on the management of anemia in hemodialysis patients.

BACKGROUND: Both in vitro and in vivo studies have shown that calcitriol, the active form of vitamin D, is involved in hematopoiesis. We hypothesized that the vitamin D receptor (VDR) genotype, which may differentiate response to endogenous or exogenous active vitamin D, has a role in the management of anemia in hemodialysis (HD) patients. METHODS: The VDR BsmI gene polymorphism was determined in 91 HD patients and 85 healthy controls. In addition to well-known factors responsible for both anemia and inadequate response to erythropoietin (EPO), we examined the contribution of the VDR genotype to hematocrit (Hct), hemoglobin (Hb) level, total weekly dose of EPO, and EPO-Hb ratio as an index of patient EPO need. RESULTS: Genotype distributions for the VDR gene were under the Hardy-Weinberg equilibrium and similar in patients and controls (genotypes BB, Bb, and bb: 22.0%, 38.5%, and 39.5% in patients versus 24.7%, 48.2%, and 27.1% in controls). There were statistically significant differences in Hct, Hb level, EPO dose, and EPO-Hb ratio in patients with the three BsmI genotypes, whereas the other parameters were the same. Comparison of patients with an Hb level less than versus greater than 11 g/dL showed that the former patients had lower albumin levels (P = 0.001), higher C-reactive protein levels (P = 0.014), and a greater frequency of BB genotype (P < 0.001). Similarly, comparison of patients with an EPO-Hb ratio in the highest quartile versus those in the lowest quartile showed that the former patients had lower albumin and transferrin levels (P = 0.013 for both) and greater frequencies of BB genotype (P = 0.016). In logistic regression analysis, both BB genotype and low serum albumin level were found to be the only independent predictors for an Hb level less than 11 g/dL (P < 0.001 and P = 0.046, respectively). Both parameters also predicted being in the highest quartile of EPO-Hb ratio (P = 0.004 for both). CONCLUSION: The VDR BsmI gene polymorphism may predict both Hb level and EPO need in HD patients. However, because the underlying mechanisms have not been clarified in the present study, further research on this issue is needed.

Relationship between antimetabolite toxicity and pharmacogenetics in Turkish cancer patients.

INTRODUCTION: Antimetabolites may cause severe toxicity and even toxic death in cancer patients. Our aim was to evaluate the relationship between antimetabolite toxicity and pharmacogenetics in patients with severe clinical toxicity or alanine transaminase (ALT) elevation after fluorouracil (5FU), capecitabine or methotrexate administration. PATIENTS AND METHODS: Cancer patients with severe antimetabolite toxicity were evaluated for methylenetetrahydrofolate reductase (MTHFR) gene C667T, thymidilate synthase (TS) gene 5' UTR variable number of tandem repeats (VNTR), dihydroprymidine dehydrogenase (DPYD) gene IVS14+1G/A, Xeroderma pigmentosum (XPD) gene Lys751Gln and X-ray repair cross-complementing group 1 (XRCC1) gene Arg399Gln polymorphisms. RESULTS: Eighteen patients were enrolled, with a male/female ratio of 0.8. They had osteosarcoma in methotrexate group (n=7), gastrointestinal malignancies in 5FU group (n=9) and breast cancer in the capecitabine group (n=2). Mucositis and dermatitis occurred in all groups, together with ALT elevation in the methotrexate group and 2 toxic deaths were encountered. DPYD, TS, MTHFR, XPD and XRCC1 gene polymorphism rare allele frequencies were observed to be higher than in the general population. CONCLUSION: Pharmacogenetics might contribute to tailored therapy.

Endothelial nitric oxide synthase gene polymorphism in gastric cancer.

BACKGROUND/AIMS: Nitric oxide, a labile compound synthesized by nitric oxide synthase, is a major regulator not only of physiological vascular tonus but also of the abnormal vascularity associated with tumors. Endothelial production of nitric oxide regulates blood flow and angiogenesis and reduces tumor cell adhesion to the endothelium. A high concentration of nitric oxide and its metabolites causes DNA damage during nitration, nitrosation and deamination. Both positive and negative effects on carcinogenesis and tumor growth, apoptosis, and cytotoxic mechanisms may be explained by differential susceptibility of tumor cells to nitric oxide-mediated reactions. METHODS: In this study, three major polymorphisms (786T>C, the 27 base pair variable number of tandem repeats in intron 4, and 894G>T) of the endothelial nitric oxide synthase gene were investigated in gastric cancer and normal tissues of 50 patients with gastric cancer and in the peripheral blood of 98 healthy subjects. RESULTS: We found no significant differences in intron 4a/b and 894G>T (Glu298Asp) allele and genotype frequencies between control and patient specimens. Nevertheless, the genotype and allele frequencies of 786T>C polymorphism were found to be significantly different between the healthy controls and tumor tissues. CONCLUSIONS: The results suggest that endothelial nitric oxide synthase 786T>C polymorphism may play a role in the development of gastric cancer.