OBSESSIVE COMPULSIVE DISORDER AND CONSTITUTIONAL DELAY OF GROWTH AND PUBERTY IN WOLFRAM SYNDROME: NEW ASPECTS AND A NOVEL WFS1 MUTATION.

Introduction: Wolfram Syndrome (WS) is a rare autosomal recessively inherited disorder characterized by juvenile-onset diabetes mellitus (DM), diabetes insipidus, optic atrophy (OA), hearing loss and neurodegeneration. This report describes three cases with WS. Case report: The first case was diagnosed with DM and OA at the age of 6 and 11 years, respectively. Second patient was the sibling of the first patient, also had DM and was investigated for WS after his brothers' diagnosis. The third patient was diagnosed with DM at the age of 5 years and developed bilateral sensorineural hearing loss and OA at the ages of 7 and 12 years, respectively. Preliminary diagnoses of all patients were confirmed by Sanger sequencing of the WFS1 gene. Two previously reported and a novel mutation were detected. While our first patient was diagnosed with attention deficit hyperactivity disorder previously described in WS patients, obsessive compulsive disorder observed in case 2, was not previously reported in WS to the best of our knowledge. Puberty delay was detected in our first patient and was diagnosed as constitutional delay of puberty and growth. Conclusion: Early diagnosis of WS can lead to early detection of associated pathologies and to decrease complications, morbidity and mortality.

Genotype-phenotype correlation, gonadal malignancy risk, gender preference, and testosterone/dihydrotestosterone ratio in steroid 5-alpha-reductase type 2 deficiency: a multicenter study from Turkey.

BACKGROUND: Studies regarding genetic and clinical characteristics, gender preference, and gonadal malignancy rates for steroid 5-alpha-reductase type 2 deficiency (5α-RD2) are limited and they were conducted on small number of patients. OBJECTIVE: To present genotype-phenotype correlation, gonadal malignancy risk, gender preference, and diagnostic sensitivity of serum testosterone/dihydrotestosterone (T/DHT) ratio in patients with 5α-RD2. MATERIALS AND METHODS: Patients with variations in the SRD5A2 gene were included in the study. Demographic characteristics, phenotype, gender assignment, hormonal tests, molecular genetic data, and presence of gonadal malignancy were evaluated. RESULTS: A total of 85 patients were included in the study. Abnormality of the external genitalia was the most dominant phenotype (92.9%). Gender assignment was male in 58.8% and female in 29.4% of the patients, while it was uncertain for 11.8%. Fourteen patients underwent bilateral gonadectomy, and no gonadal malignancy was detected. The most frequent pathogenic variants were p.Ala65Pro (30.6%), p.Leu55Gln (16.5%), and p.Gly196Ser (15.3%). The p.Ala65Pro and p.Leu55Gln showed more undervirilization than the p.Gly196Ser. The diagnostic sensitivity of stimulated T/DHT ratio was higher than baseline serum T/DHT ratio, even in pubertal patients. The cut-off values yielding the best sensitivity for stimulated T/DHT ratio were ≥ 8.5 for minipuberty, ≥ 10 for prepuberty, and ≥ 17 for puberty. CONCLUSION: There is no significant genotype-phenotype correlation in 5α-RD2. Gonadal malignancy risk seems to be low. If genetic analysis is not available at the time of diagnosis, stimulated T/DHT ratio can be useful, especially if different cut-off values are utilized in accordance with the pubertal status.

Experiences in microarray-based evaluation of developmental disabilities and congenital anomalies.

BACKGROUND: Chromosomal microarray analysis is the first-tier test for the evaluation of developmental disabilities and congenital anomalies. In this report, we present CMA results of 971 patient and 301 parent samples. MATERIALS AND METHODS: Among 971 patient samples, 133 (13.6%) had pathogenic variants. RESULTS: While analyzing, an "in-house" variant database was also used besides other databases. Owing to this, we have found chance to report the most frequent benign variants in Turkish population. CONCLUSION: With the additional data we acquired in this study, we also emphasized the high potential of CMA in revealing single gene disorders and novel gene-phenotype associations as well as copy number variations.

Long-term evaluation of chromosomal breakages after radioisotope synovectomy for treatment of target joints in patients with haemophilia.

Radioisotope synovectomy (RS) is defined as the intra-articular injection of radioisotopic agents with the aim of fibrosis on hypertrophic synovium in the target joint. The aim of this study was to investigate genotoxic effects on lymphocytes and malign transformation induced by Yttrium(90) (Y(90)) and Rhenium(186) (Re(186)) in children with haemophilia undergone RS. Forty haemophilia patients were enrolled. The mean age was 16.4 +/- 6.2 years (range: 8-40). Y(90) was used for knees, Re(186) was used for other joints. For safety, cytogenetic analysis was performed to determine potential chromosomal changes after RS procedure at three different time points as prior to procedure, 3rd day and 90th day. For the stimulation of chromosomal breakages, diepoxybutane was used (DEB test). Chromosomal breakages (CBs) were found in 23 patients (67.6%) prior to RS. We have found CBs additionally in nine of 11 patients who had no CBs prior to RS after 3 days of radioisotope exposure. At that time, the patients who had CBs were 29 (85.2%). At day 90, only 21 patients revealed (61.7%) CBs. The mean frequency of CBs slightly but not significantly increased in the 3rd day. However, there was a significant decreasing trend between 3rd and 90th days. Radioisotope synovectomy with Y(90) and Re(186) does not seem to induce the genotoxic effects significantly on peripheral blood lymphocytes. However, CBs even after one year in the re-evaluation of four patients, significant decrease in the number of CBs between the 3rd and 90th days and de novo CBs after exposure may be accepted as warning signals for young population. It should also be pointed out that families and patients be informed properly related with historical and potential dangers of radioisotopic agents.