Molecular analysis of 31 cases with fetal skeletal dysplasia.

OBJECTIVES: The aim of this study was to describe the prenatal ultrasound findings of fetuses with skeletal dysplasia and to evaluate the genetic variations by molecular genetic analysis. METHODS: Between August 1, 2018 and March 1, 2023, we conducted a retrospective case series at a tertiary referral center involving patients with fetal skeletal abnormalities. For cases referred for a possible diagnosis of fetal skeletal dysplasia, an ultrasound database and prenatal genetic counseling records were first searched. Terminated cases diagnosed with skeletal dysplasia by pathologic and radiologic findings and cases with skeletal dysplasia proven by postnatal clinical findings were included in the study. RESULTS: Between 2018 and 2023, a total of 64 cases were diagnosed as skeletal dysplasia based on radiologic findings, pathologic findings, and clinical features. The median week of the first ultrasound performed on patients is 19 0/7 weeks, while the median week of the ultrasound in which skeletal dysplasia is suspected is 21 3/7 weeks. Although micromelia was evaluated as a common feature in all cases, the most common concomitant anomaly was thoracic hypoplasia. Exome sequencing analysis was achieved in 31 (48 %) of cases. In 31 cases, in total of 35 pathogenic single gene mutations and 5 VUS (variants of uncertain significance) variants composing of 23 autosomal dominant, 10 autosomal recessive and 2 X linked recessive mutations were determined. CONCLUSIONS: Prenatal ultrasound findings can lead us to specific diagnoses, and with the appropriate molecular analysis method, a definitive diagnosis can be made without wasting time and money.

Revisiting Atrioventricular Septal Defects: Exploring Chromosomal Abnormalities, Cardiac and Extracardiac Anomalies in a Contemporary Prenatal Cohort.

To estimate if there is an association between partial AVSD with chromosomal abnormalities, cardiac and extracardiac malformations, and to report the outcomes of prenatally diagnosed AVSD in a large, contemporary cohort. This is a retrospective cohort study of 190 prenatally diagnosed fetal AVSD between 2014 and 2023. Type of AVSD (complete vs partial), additional cardiac findings, extracardiac findings, presence of a heterotaxy, results of prenatal karyotype, and pregnancy outcomes were documented and analyzed. A total of 190 cases of fetal AVSD were analyzed. Complete AVSDs comprised 141 (74.2%) of the cohort, while partial AVSDs comprised 49 (25.7%). Karyotype was completed in 131 cases, and in 98 (74.8%) cases chromosomal abnormalities were identified, with trisomy 21 being the most common (53/131, 40.5%). Complete AVSDs were associated with trisomy 21 (45.5%, p = 0.04), Isolated cases of complete AVSDs (p = 0.03). Partial AVSDs were associated with trisomy 18 (53.1%, p < 0.001). In cases of partial AVSDs with aneuploidies, 7 (70%) had an ostium primum defect and 20 (90.9%) of AV canal type VSD. Isolated partial AVSD had no clear association with aneuploidies. There were additional cardiac anomalies in 96 (50.5%) and extracardiac anomalies in 134 (70.5%) of the cohort. There were no differences between partial and complete AVSD in rate of additional cardiac and extracardiac anomalies. AVSD was part of a heterotaxy in 47 (24.7%) of cases, and heterotaxy was associated with complete AVSD in the majority of cases (43/47, 91.4%, p = 0.003). Fetal partial AVSDs are associated with trisomy 18. Fetal complete AVSDs, even isolated, are associated with trisomy 21. There were no differences in association of other aneuploidies, additional cardiac findings, or extracardiac anomalies between prenatally diagnosed complete AVSDs and partial AVSDs.

Aberrant right subclavian artery in the absence of other prenatal ultrasound findings: Should we still be concerned?

OBJECTIVE: To analyze the value of prenatal diagnostic genetic testing in cases with isolated aberrant right subclavian artery (ARSA). METHODS: This is a retrospective cohort study, conducted between January 2015-January 2022 in a fetal medicine center. Women who had an ultrasound scan and diagnosed with fetal ARSA were included. Ultrasonographic characteristics, genetic, obstetric, and neonatal outcomes were collected and analyzed. RESULTS: A total of 240 fetuses with ARSA were identified and included to the analysis. Eighty-two of the group had isolated ARSA (34.2%, 82/240), 57 had additional soft markers (23.8%, 57/240) and 101 had additional major ultrasonographic abnormalities (42.1%, 101/240). Genetic results were available in 196 cases (81.7%, 196/240). Seventy-four of isolated ARSA cases underwent genetic testing (90.2%, 74/82). A chromosomal abnormality was present in 60 cases; 54 (22.5%, 54/240) aneuploidies and 6 (2.5%, 6/240) copy number variants. Five (6.1%) of the isolated ARSA cases had chromosomal abnormalities. All of these five cases had prenatal genetic testing due to high-risk aneuploidy screening fetuses who had ARSA with at least one additional anomaly had the highest chromosomal abnormality rate (38.6%, 39/101). Seventy-seven of isolated ARSA cases were liveborn (93.9%, 77/82). CONCLUSION: Our results supports the evidence from the literature that isolated ARSA confers a very low-risk for aneuploidy, if the aneuploidy screening tests are low-risk. Also, chromosomal microarray analysis did not yield any extra information in isolated ARSA.

An analysis of factors affecting survival in prenatally diagnosed omphalocele.

OBJECTIVES: To estimate factors affecting survival in prenatally diagnosed omphalocele, factors predicting genetic abnormalities, and association of omphalocele and specific groups of anomalies. METHODS: A retrospective observational study was performed, analyzing data of all omphalocele cases diagnosed prenatally in the perinatology clinic of a referral center. Demographic data, characteristics of the omphalocele (size, content, associated anomalies), results of genetic testing, pregnancy outcomes and postnatal outcomes were analyzed. RESULTS: Sixty-nine fetuses with omphalocele were included. The prevalence of omphalocele in livebirth was 0.007 %. Overall survival during the study period was 73.9 %. Twenty-eight (71.7 %) out of 39 cases with associated anomalies who were born live, survived, whereas survival was 85.7 % in the isolated cases. The most common anomaly associated with omphalocele were cardiac defects with 42 %; followed by placental or umbilical cord anomalies (28.9 %), skeletal defects (27.5), genitourinary anomalies (20.2 %), central nervous system (18.8 %) and facial anomalies (7.2 %), respectively. Eighty-five percent of the fetuses had at least one additional anomaly or ultrasound finding. Skeletal abnormalities and staged surgical repair of omphalocele were associated with survival. Associated skeletal anomalies and staged repair significantly increase the risk of postnatal death (OR: 4.6 95 % CI (1.1-19.5) and (OR: 10.3 95 % CI (1.6-63.9), respectively). CONCLUSIONS: Associated skeletal abnormalities and staged surgical repair are negatively associated with postnatal survival.

Contribution of chromosomal microarray analysis and next-generation sequencing to genetic diagnosis in fetuses with normal karyotype.

AIM: The aim of this study was to investigate the contribution of chromosomal microarray analysis (CMA) and next-generation sequencing (NGS) to genetic diagnosis in fetuses with normal karyotype who underwent invasive testing for different indications. METHODS: The results of invasive genetic testing performed at a tertiary center between September 2020 and March 2022 were retrospectively analyzed. Indications for invasive tests were classified as fetal structural malformation, presence of soft markers, and high risk in screening tests. CMA results were classified as pathogenic or likely pathogenic (pCNVs), benign (bCNVs), and variants of unknown clinical significance (VOUS). RESULTS: A total of 830 invasive tests were performed and aneuploidy was detected in 11.2% of the fetuses. CMA was performed in 465 fetuses with normal karyotype, and pCNVs were detected in 6.9%. pCNVs were detected in 8.2% of fetuses with structural malformations, 6.5% in soft markers, and 4.7% in high risk in screening tests. Pathogenic variants were detected by NGS in 33.8% of fetuses with bCNVs. CONCLUSIONS: pCNVs can be significantly detected not only in fetuses with structural malformations, but also in invasive testing with other indications. NGS significantly contributes to genetic diagnosis in fetuses with structural malformations.

Foetal thoracic hypoplasia: concomitant anomalies and neonatal outcomes.

The aim of the current study was to determine the frequency of concomitant anomalies in foetal thoracic hypoplasia and the neonatal outcomes of these pregnancies. This retrospective study included 49 cases of foetal thoracic hypoplasia. All of the cases had skeletal system anomalies. Head and face anomalies (36.7%) were the second most frequent accompanying foetal anomaly, and the least common anomaly was genital system anomalies (4.1%). During the follow-ups, 52.6% (n = 10) of the newborns died in the first 24 h of life, 10.5% (n = 2) in the neonatal period and 36.8% (n = 7) in the infantile period.IMPACT STATEMENTWhat is already known on this subject? Foetal thoracic hypoplasias are lethal anomalies due to inadequate pulmonary development. Data on the other system anomalies that accompany foetuses with thoracic hypoplasia are quite limited in the literature. Moreover, even if the lethal course of thoracic hypoplasia is known, the information on how long newborns will survive is unclear.What do the results of this study add? In this study, most of the cases have additional anomalies, especially skeletal system and head-face anomalies. Approximately half of the newborns with thoracic hypoplasia die within the first 24 h.What are the implications of these findings for clinical practice and/or further research? When we need to consult a family considering the outcome of thoracic hypoplasia, this study can be guiding and helpful. On the other hand, the effects of additional anomalies on the prognosis of foetal and neonatal period are not clear. More studies are needed to better understand the prognosis of thoracic hypoplasias.

Exome sequencing identifies a homozygous C5orf42 variant in a Turkish kindred with oral-facial-digital syndrome type VI.

Oral-facial-digital syndrome type VI (OFDVI) is a rare ciliopathy in the spectrum of Joubert syndrome (JS) and distinguished from other oral-facial-digital syndromes by metacarpal abnormalities with central polydactyly and by a molar tooth sign on cranial MRI. Additional characteristic features include short stature, micrognathia, posteriorly rotated low-set ears, hypertelorism, epicanthal folds, broad nasal tip, tongue hamartoma, upper lip notch, intraoral frenula, cleft lip/palate, and renal anomalies. Recently, novel mutations in C5orf42 were identified in 9 out of 11 OFDVI families. In a subsequent study C5orf42 was found to be mutated in only 2 out of 17 OFDVI probands while 28 patients with a pure JS phenotype also had pathogenic mutations of C5orf42. We report on two affected cousins diagnosed with OFDVI who were born from first degree cousin marriages. Whole exome sequencing (WES) identified a homozygous predicted damaging missense mutation (c.4034A > G; p.Gln1345Arg) in the C5orf42 gene. Our data contribute to the evidence that C5orf42 is one of the causative genes for OFDVI.

Phototherapy causes a transient DNA damage in jaundiced newborns.

In this study, we aimed to clarify the following questions: 1) Does phototherapy (PT) cause genotoxicity in full-term newborn babies undergoing PT as a result of neonatal jaundice?, 2) if genotoxic effect occurs, is there any relationship between the duration of PT and genotoxicity?, and 3) is genotoxic effect temporary or not? The frequency of sister chromatid exchange (SCE) was determined in jaundiced newborns before, during, and after phototherapy, then determined again in childhood (approximately 3.5 years old). Mean frequency of SCE of 22 full-term jaundiced babies significantly increased during the PT procedure and in every single day, compared to the previous day, in comparison to the pre-PT basal value (6.20 ± 0.57;); mean SCE frequencies at 24, 48, 72, and 96 hours were 7.75 ± 0.40, 8.16 ± 0.47, 8.50 ± 0.40, and 9.36 ± 0.55, respectively (all P-values <0.01). In childhood, no significant difference was found between the mean SCE value (4.9 ± 0.9) of 20 of 22 children, who received PT in the neonatal period, and the mean SCE value (4.7 ± 0.6) of 20 coevaluated healthy children (P = 0.40). This study demonstrates that the negative effect of PT on SCE is a temporary effect.

Can FMR1 CGG repeat lengths predict the outcome in ICSI cycles?

OBJECTIVES: The aim of this study was to assess relationship between CGG repeat lengths and ovarian reserve and response to controlled ovarian stimulation (COH). MATERIAL AND METHODS: This prospective cohort study was carried out on patients (n = 49) who were admitted to the in vitro fertilization (IVF) clinic of the Zeynep Kamil Women's and Children's Diseases Training and Research Hospital, University of Health Sciences. Women under 40 years of age with premature ovarian insufficiency underwent genetic analysis to determine CGG repeat lengths. Ovarian reserve was assessed for each participant and participants underwent ovarian hyperstimulation and intracytoplasmic sperm injection (ICSI) cycle. Relationships between ovarian reserve, cycle outcome and CGG repeat lengths were assessed. Variables including fertility assessment including ovarian reserve tests (Follicle stimulating hormone (FSH), Luteinizing hormone (LH), Estradiol (E2), Prolactin (PRL), Thyroid stimulating hormone (TSH), Antimullerian hormone (AMH), antral follicle count (AFC) tests) and some IVF cycle characteristics were assessed in relation to number of CGG repeat numbers. RESULTS: None of the ovarian reserve tests and cycle characteristics was found to be correlated with CGG repeat lengths. Comparison of ovarian reserve tests and cycle characteristics revealed no difference between groups of women with CGG repeat length > 55 and CGG repeat length ≤ 55. Antimullerian hormone (AMH) was a significant predictor for cycle cancellation (AUC = 0.779, P = 0.008). AMH level > 0.035 was found to be the optimal cut off value to predict cycles reaching to embryo transfer with 71% sensitivity and 85% specificity. The rate of cycle cancellation was 71% in cases with AMH ≤ 0.035 whereas it was 20% in cases with AMH > 0.035 (p = 0.001). No difference was determined between groups with and without cycle cancellation in terms of CGG repeat lengths (55.3 vs. 53.9, p = 0.769). Among cycles reaching to embryo transfer stage, 3 (13.6%) pregnancies were achieved. CONCLUSIONS: Our data showed no relationship between CGG repeat lengths and ovarian reserve and response to controlled ovarian stimulation. This data also showed that no clinical difference between FMR gene mutation related POI and other etiologies.

Comet assay and analysis of micronucleus formation in patients with rheumatoid arthritis.

Oxidants play a significant role in causing oxidative stress, which underlies the pathogenesis of rheumatoid arthritis (RA). Genetic factors that predispose individuals to RA are considered to play an important role in the development of the disease. The aim of this study was to determine, by use of the comet assay and the micronucleus (MN) test, whether DNA damage has an effect on the pathogenesis of RA. Furthermore, our aim was to show if there is an association between oxidative stress and DNA damage in RA. This study was conducted between January and June 2010 in the Erzurum Training and Research Hospital. We analyzed lymphocytes from patients with RA (12 in active and 31 in inactive periods) and 30 healthy controls for effects in the comet assay and the MN test. In addition, the levels of malondialdehyde (MDA) and superoxide dismutase (SOD), the activity of glutathione peroxidase (GSH-Px), the erythrocyte sedimentation rate (ESR) and the high-sensitivity C-reactive protein (hs-CRP) rate were determined in all the subjects. The comet-tail length, the MN frequencies and the MDA levels were significantly higher in patients--both in the active and the inactive period--than in the controls. In contrast, the SOD and GSH-Px levels were significantly lower in both patient groups than in the controls. Our results suggest that an increased plasma MDA level and decreased plasma GSH-Px and SOD levels reflect the higher degree of oxidative stress in RA patients, a situation that may impair genetic stability in those patients. Thus, the results suggest that increased DNA damage may play an important role in the pathogenesis of RA.

Orthodontic treatment of an ankylosed maxillary central incisor through osteogenic distraction.

Tooth ankylosis is one of the various problems in dentistry and requires special treatment approaches for satisfactory results. In the orthodontic treatment of an ankylosed tooth, different treatment modalities have been put into practice including both orthodontic and orthodontic-surgical approaches. For favorable results, gingival margin esthetics must be considered as much as leveling the ankylosed tooth in the arch. Distraction osteogenesis accompanied by orthodontic mechanics is a sensible way of achieving this goal. However, devices used in the distraction protocol are high in price and bulky in shape, causing functional and esthetic problems for the patient. This report describes treatment of an infrapositioned ankylosed incisor with continuous distraction forces produced by conventional orthodontic mechanics. In conclusion, the ankylosed tooth was leveled in the upper arch successfully with a harmonic gingival margin.

Sister chromatid exchange and micronucleus studies in patients with Behçet's disease.

BACKGROUND: Genetic factors that predispose individuals to Behçet's disease (BD) are considered to play important roles in the development of the disease. The aim of this study was to determine, by counting sister chromatid exchange (SCE) and micronucleus (MN) frequencies, whether DNA damage have an effect on the pathogenesis of BD. Furthermore, our aim was to show if there is an association between oxidative stress and chromosome instability in BD. METHODS: We analyzed lymphocytes from patients with BD (16 in active and 14 in inactive periods) and 20 healthy controls for SCE and MN frequencies. In addition, malondialdehyde (MDA) level, superoxide dismutase (SOD) level, glutathione peroxidase (GSH-Px) activity, erythrocyte sedimentation rate (ESR) and polymorphonuclear leukocyte (PMNL) count were determined in the all subjects. RESULTS: The SCE and MN frequencies were significantly higher in both the active and inactive period patients than in the controls (p < 0.00001, p < 0.0001, p < 0.01 and p < 0.05, respectively), and the MDA level was significantly higher in both the active and inactive period patients than in the controls (p < 0.01 and p < 0.05, respectively). In contrast, the SOD and GSH-Px levels were significantly lower in both the active and inactive period patients than in the controls (p < 0.01, p < 0.05, p < 0.01 and p < 0.05, respectively). CONCLUSIONS: Our results suggest that increased plasma MDA level and decreased plasma GSH-Px and SOD levels reflect the increased levels of oxidative stress in BD patients, and this situation may impair genetic stability in BD patients.

Sister chromatid exchange analysis in patients with psoriasis.

Psoriasis is a common, chronic inflammatory skin disease with unknown aetiology. An increased reactive oxygen species (ROS) and insufficient antioxidant activity have been determined in psoriatic lesions. The analysis of sister chromatid exchange (SCE) is a cytogenetic technique used to show DNA damage caused by an exchange of DNA fragments between sister chromatids. The study aimed to determine the rates of SCE in psoriatic patients (17 female and 19 male) and healthy controls (15 female and 15 male) as well as superoxide dismutase (SOD), glutathione peroxidase (GP) and catalase (CAT) activity in both groups. We found significantly higher SCE rates in the patients (P < 0.00001). In addition, statistically significant decreased levels of erythrocyte SOD and CAT activities were noted in the patients(P < 0.001 and P < 0.05 respectively). Furthermore, a statistically significant increased erythrocyte GP activity was found in the psoriasis group (P < 0.05). Our results indicate that chromosomal instability may play an important part in the aetiology of psoriasis. In addition, the results support the hypothesis of an imbalance in the oxidant-antioxidant system in psoriasis.

Micronucleus analysis in patients with colorectal adenocarcinoma and colorectal polyps.

AIM: To determine, by counting micronucleus (MN) frequencies, whether chromosomal or DNA damage have an effect on the pathogenesis of early colorectal adenocarcinoma (CRC). METHODS: We analyzed MN frequencies in 21 patients with CRC, 24 patients with colon polyps [10 neoplastic polyps (NP) and 14 non-neoplastic polyps (NNP)] and 20 normal controls. RESULTS: MN frequency was significantly increased in CRC patients and in NP patients compared with controls (3.72 +/- 1.34, 3.58 +/- 1.21 vs 1.97 +/- 0.81, P < 0.001). However, there was no difference in the MN frequency between CRC patients and NP patients (P > 0.05). Similarly, there was no difference in the MN frequency between NNP patients (2.06 +/- 0.85) and controls (P > 0.05). CONCLUSION: Our results suggest increased chromosome/DNA instabilities may be associated with the pathogenesis of early CRC.

Intraperitoneal dedifferentiated liposarcoma: a case report.

Dedifferentiated liposarcoma is a variant of liposarcoma with a more aggressive course. Mutations of the p53 gene have been found in different types of soft tissue sarcoma. It is generally accepted that p53 mutations in human malignant tumors are often related to a poor prognosis. In our case, analysis of p53 gene mutation in tumor samples was performed. p53 gene mutation was observed in dedifferentiated tumor tissue samples but not in well-differentiated tumor tissue samples. It has been reported that p53 gene mutation occurs most commonly in the retroperitoneum and rarely in other anatomic locations. Herein we report a case of dedifferentiated liposarcoma located at intraperitoneum.

Double aneuploidy in a Turkish child: Down-Klinefelter syndrome.

The occurrence of double aneuploidy in the one person is a relatively rare phenomenon. A 5-year-old child, the second-born of non-consanguineous parents, possessed an extra X chromosome in addition to trisomy 21. The proband's parents and his brother showed normal karyotype. The phenotypic characteristics of the child have been discussed in light of the published reports on double aneuploidies of XXY and trisomy 21.

Oculocutaneous albinism type 1A: a case report.

The term, oculocutaneous albinism (OCA), describes a group of inherited disorders of melanin biosynthesis that exhibits congenital hypopigmentation of ocular and cutaneous tissues. The clinical spectrum of OCA ranges from a complete lack of melanin pigmentation to mildly hypopigmented forms. OCA1A is the most severe type with a complete lack of melanin production throughout life; the milder forms OCA1B, OCA2, OCA3 and OCA4 show some pigment accumulation over time. Clinical manifestations include various degrees of congenital nystagmus, iris hypopigmentation and translucency, reduced pigmentation of the retinal pigment epithelium, foveal hypoplasia, reduced visual acuity and refractive errors, color vision impairment, and prominent photophobia. All four types of OCA are inherited as autosomal recessive disorders. At least four genes are responsible for the different types of the disease (TYR, OCA2, TYRP1, and MATP). Diagnosis is based on clinical findings of hypopigmentation of the skin and hair in addition to the characteristic ocular symptoms. Herein we present a case with OCA1A.

Bardet-Biedl syndrome: a case report.

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous autosomal recessive disorder characterized by progressive retinal dystrophy, polydactyly, obesity, hypogonadism, mental retardation, and renal dysfunction. Other manifestations include diabetes mellitus, heart disease, hepatic fibrosis, neurological features, and multiple pigmented nevi. To date, twelve BBS genes have been cloned (BBS1-BBS12). Herein we discussed a patient with BBS who had multiple pigmented nevi.

Primary skeletal muscle lymphoma: A case report.

Primary lymphomas of the bone or skeletal muscle are rare. Three mechanisms of lymphomatous involvement of the muscle have been described, namely direct invasion from adjacent involved lymph nodes or bone, metastatic spread and, least commonly, primary muscle lymphoma. We herein present a rare case of primary mucle non-Hodgkin lymphoma with a description if the associated clinicopathological findings and a review of the relevant literature. A 41-year-old female patient was referred to our hospital with a painful mass in the right lower extremity. Following resection and histopathological examination, a diffuse large B-cell lymphoma originating from the muscle with cutaneous and subcutanenous infiltration was diagnosed. The patient received chemotherapy with six cycles of cyclophosphamide, hydroxydaunomycin, oncovin and prednisone (CHOP regimen) and a complete radiological response was achieved after six cycles of treatment.

Comparison of 2 distalization systems supported by intraosseous screws.

INTRODUCTION: The aim of this study was to compare the effects of 2 distalization systems supported by intraosseous screws for maxillary molar distalization. METHODS: Forty subjects with skeletal Class I dental Class II malocclusion were divided into group 1 (8 girls, 12 boys) and group 2 (11 girls, 9 boys). An anchorage unit was prepared by placing an intraosseous screw in the premaxillary area of each subject. To increase the anchorage in group 2, we used an acrylic plate resembling the Nance button around the screw. The screws were placed and immediately loaded to distalize the maxillary first molars or second molars when they were present. Skeletal and dental changes were measured on cephalograms, and dental casts were obtained before and after distalization. RESULTS: The average distalization times were 4.6 months for group 1 and 5.4 months for group 2. On the cephalograms, the maxillary first molars were tipped 9.05 degrees in group 1 and 0.75 degrees in group 2. The mean distal movements were 3.95 mm in group 1 and 3.88 mm in group 2. On the dental casts, the mean distalization amounts were 4.85 mm for group 1 and 3.70 mm for group 2. In group 1, the maxillary molars were rotated distopalatally to a moderate degree, but this was not significant in group 2. Mild protrusion of the maxillary central incisors was also recorded for group 1 but not for group 2. However, there were no changes in overjet, overbite, and mandibular plane angle measurements for either group. CONCLUSIONS: Immediately loaded intraosseous screw-supported anchorage units were successful for molar distalization in both groups. In group 2, side effects such as molar tipping and rotation were smaller, but distalization times were longer and hygiene was poorer.