Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes.

BACKGROUND: Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders characterised by susceptibility to fractures, primarily due to defects in type 1 collagen. The aim of this study is to present a novel OI phenotype and its causative candidate gene. METHODS: Whole-exome sequencing and clinical evaluation were performed in five patients from two unrelated families. PHLDB1 mRNA expression in blood and fibroblasts was investigated by real-time PCR, and western blot analysis was further performed on skin fibroblasts. RESULTS: The common findings among the five affected children were recurrent fractures and/or osteopaenia, platyspondyly, short and bowed long bones, and widened metaphyses. Metaphyseal and vertebral changes regressed after early childhood, and no fractures occurred under bisphosphonate treatment. We identified biallelic NM_001144758.3:c.2392dup and NM_001144758.3:c.2690_2693del pathogenic variants in PHLDB1 in the affected patients, respectively, in the families; parents were heterozygous for these variants. PHLDB1 encodes pleckstrin homology-like domain family B member-1 (PHLDB1) protein, which has a role in insulin-dependent Akt phosphorylation. Compared with controls, a decrease in the expression levels of PHLDB1 in the blood and skin fibroblast samples was detected. Western blot analysis of cultured fibroblasts further confirmed the loss of PHLDB1. CONCLUSION: Two biallelic frameshift variants in the candidate gene PHLDB1 were identified in independent families with a novel, mild-type, autosomal recessive OI. The demonstration of decreased PHLDB1 mRNA expression levels in blood and fibroblast samples supports the hypothesis that PHLDB1 pathogenic variants are causative for the observed phenotype.

The presence of virulence factor genes downregulates uterine AQP3 and alters glutathione peroxidase activity and uterine histopathology in canine pyometra.

Present study was designed to evaluate the role of virulence factor genes (papG, cnf1 and hylA) in the pathogenesis of canine pyometra. Antimicrobial susceptibility test and detection of virulence genes were performed Escherichia coli (E. coli) detected in uterine swab samples. Animals were divided into two groups based on the presence (VF+, n:14) or absence (VF-, n:7) of the virulence factor genes papG, cnf1 and hylA. Blood and tissue glutathione peroxidase activity, uterine histopathologic analysis and AQP3, ESR1, PGR, OXTR gene expressions were determined in both groups. Statistical analyses were performed using Stata version 15.1. All E. coli isolates were susceptible to amikacin, whereas resistant to ampicillin, amoxicillin/clavulanic acid and lincomycin. None of the isolates were susceptible to cefotaxime. E. coli isolates had at least one virulence gene. The most prevalent gene was fimH (100%), followed by fyuA (95.8%), usp (83.3%), sfa (75%), cnf1 and hlyA (70.8%) genes. Blood GPx activity was greater in VF+ animals. On the other hand, uterine tissue GPx activity was lower in VF+ group compared to the control group. Expression levels of AQP3 were upregulated more than fivefold in VF-dogs compared to the control group. In addition, AQP3 expression levels were found approximately threefold higher in VF (-) than VF (+) group (p < .05). Varying degree of inflammation noted for all animals with pyometra, but the presence of bacteria noted only in VF+ animals. In conclusion, the presence of virulence factor genes does not play a role in the histopathological degree of inflammation, the presence of bacteria was found to vary. Serum GPx activity increased in VF+ animals. While the hormone receptor expressions were similar, AQP expression was upregulated in the absence of virulence factor genes.

An investigation of the etiology and follow-up findings in 35 children with overgrowth syndromes, including biallelic SUZ12 variant.

Overgrowth-intellectual disability (OGID) syndromes are clinically and genetically heterogeneous group of disorders. The aim of this study was to examine the molecular etiology and long-term follow-up findings of Turkish OGID cohort. Thirty-five children with OGID were included in the study. Single gene sequencing, clinical exome analysis, chromosomal microarray analysis and whole exome sequencing were performed. Five pathogenic copy number variants were detected in the patients; three of them located on chromosome 5q35.2 (encompassing NSD1), others on 9q22.3 and 22q13.31. In 19 of 35 patients; we identified pathogenic variants in OGID genes associated with epigenetic regulation, NSD1 (n = 15), HIST1H1E (n = 1), SETD1B (n = 1), and SUZ12 (n = 2). The pathogenic variants in PIK3CA (n = 2), ABCC9 (n = 1), GPC4 (n = 2), FIBP (n = 1), and TMEM94 (n = 1) which had a role in other growth pathways were detected in seven patients. The diagnostic yield was 31/35(88%). Twelve pathogenic variants were novel. The common facial feature of the patients was prominent forehead. The patients with Sotos syndrome were observed to have milder intellectual disability than patients with other OGID syndromes. In conclusion, this study showed, for the first time, that biallelic variants of SUZ12 caused Imagawa-Matsumoto syndrome, monoallelic variants in SETDIB resulted in OGID. Besides expanded the phenotypes of very rare OGID syndromes caused by FIBP and TMEM94.

Cervical ectopic pregnancy - the first case of live birth and uterus-conserving management.

A 37-old III gravida II para with two previous cesarean sections (CS) presented in 7 + 3 weeks of pregnancy with cervical ectopic pregnancy (CEP). At 12th week of pregnancy, a cerclage was performed to avoid cervical distention by the expanding placenta. Due to missing experience in CEP management and to avoid emergency operation, we recommended CS in 30th week of pregnancy due to unspecific pain of the patient. Vaginal bleeding never occured.After transverse laparotomy, the urinary bladder was sharply dissected from the anterior uterine and cervical wall. The baby was delivered by transverse cervicotomy caudally of the placenta. The placenta was left in situ. The patient then got prophylactic embolization of the uterine arteries to prevent further severe hemorrhage. 48 h later, ultrasound showed a floating, avascular placenta within a poor echogenic fluid-filled cervical space as well as macrohematuria. After re-laparotomy and cervicotomy at the same day, the placenta was completely and easily evacuated. A bladder injury was recognized and closed. We performed a cervical internal os plasty by inverting the cervical lips and suturing their distal ends on the proximal cervical tissue, resulting in complete bleeding cessation. Although, the patient got 8 erythrocyte concentrates at all, she was always in a stable condition without hemorrhagic shock.This case demonstrates for the first time a live-birth with uterus-conserving management in CEP.

Investigation of (epi)genotype causes and follow-up manifestations in the patients with classical and atypical phenotype of Beckwith-Wiedemann spectrum.

Beckwith-Wiedemann syndrome (BWS) is a genomic imprinting disorder, characterized by macroglossia, abdominal wall defects, lateralized overgrowth, and predisposition to embryonal tumors. It is caused by the defect of imprinted genes on chromosome 11p15.5, regulated by imprinting control (IC) domains, IC1, and IC2. Rarely, CDKN1C and chromosomal changes can be detected. The aim of this study is to retrospectively evaluate 55 patients with BWS using the new diagnostic criteria developed by the BWS consensus, and to investigate (epi)genetic changes and follow-up findings in classic and atypical phenotypes. Loss of methylation in IC2 region (IC2-LoM), 11p15.5 paternal uniparental disomy (pUPD11), and methylation gain in IC1 region (IC1-GoM) are detected in 31, eight, and five patients, respectively. Eleven patients have had no molecular defects. Thirty-five patients are classified as classical and 20 as atypical phenotype. Patients with classical phenotype are more frequent in the IC2-LoM (25/31), while patients with atypical phenotype are common in the pUPD11 group (5/8). Malignant tumors have developed in six patients (10.9%); three of these patients have IC1-GoM, two pUPD11, one IC2-LoM genotype, and four an atypical phenotype. We observed that the face was round in the infantile period and elongated as the child grew-up, developing prognathism and becoming asymmetrical if hemi-macroglossia was present in the classical phenotype. These findings were mild in the atypical phenotype. These results support the importance of using the new diagnostic criteria to facilitate the diagnosis of patients with atypical phenotype who have higher tumors risk. This study also provides important information about facial gestalt.

The factors associated with transient hypothyroxinemia of prematurity.

BACKGROUND: Hypothyroxinemia is defined by low levels of thyroxine (T4) despite low or normal levels of thyroid-stimulating hormone (TSH). This study aimed to evaluate the factors associated with transient hypothyroxinemia of prematurity (THOP) in newborns admitted to the neonatal intensive care unit (NICU). METHOD: This is a single center, retrospective, case-control study. Premature newborns, between 24 and 34 weeks of gestation, hospitalised between January 2014-December 2019 in Istanbul University-Cerrahpasa Faculty of Medicine NICU were analyzed through their medical records. Thyroid function tests were routinely performed between the 10th and 20th days of postnatal life and were evaluated according to the gestational age references. Thirty six possible associated factors (prenatal and postnatal parameters, medical treatments, clinical diagnoses and applications in NICU) were searched in the patient group with THOP (n = 71) and the control group with euthyroid prematures (n = 73). The factors for THOP were identified by univariate analysis, followed by multivariate analysis. RESULTS: Mean gestational ages of the study and the control groups were 29.7 ± 2.48 and 30.5 ± 2.30 weeks, respectively (p = 0.606). The birth weight, small for gestational age (SGA), intraventricular hemorrhage (IVH), congenital heart disease (CHD) were found to be the possible associated factors for THOP in the univariate analysis and CHD (p = 0.007, odds ratio [OR]:4.9, 95% confidence interval [CI]: 1.5-15.8), BW (p = 0.004, OR:0.999, 95% CI: 0.9-1.0) and SGA (p = 0.010, OR:4.6, 95% CI: 1.4-14.7) were found to be factors associated with THOP determined by univariate logistic regression analysis. CONCLUSiONS: Although some treatment practices might have had direct effects on pituitary-thyroid axis, related with the severity of the newborn clinical conditions, non of them was found to be a associated factor for THOP. However, CHD and SGA may be considered as associated factors with THOP detected in preterm infants.