New cases of recently described Thauvin-Robinet-Faivre syndrome with a novel homozygous FIBP gene variant.

Thauvin-Robinet-Faivre syndrome (#617107) is a rare autosomal recessive overgrowth syndrome characterized by intellectual disability, facial dysmorphism, macrocephaly, and variable congenital malformations. It is caused by homozygous or compound heterozygous FIBP gene mutations. The FIBP gene is located on the 11q13.1 region and codes the acidic fibroblast growth factor intracellular binding protein, which is involved in the fibroblast growth factor (FGF) signaling pathway. FGF signaling is required for neurogenesis and neuronal precursor proliferation. The FGF controls cell proliferation, differentiation, and migration in embryonic development and in adult life. Overgrowth syndromes consist of a wide spectrum disorders characterized by prenatal and postnatal excess growth in weight and length, often associated malformations, intellectual disability, and neoplastic predisposition. Embryonic tumors are especially common in these syndromes. Thauvin-Robinet-Faivre syndrome is a recently described overgrowth syndrome with typical facial dysmorphic and clinical features. To date, only four patients have been reported with this disorder. Herein, two new cases of Thauvin-Robinet-Faivre syndrome are reported with overgrowth, intellectual disability, typical dysmorphic signs in one dysplastic kidney, and a novel homozygous FIBP gene variant. Exome sequencing analysis showed that both affected siblings share the same homozygous c. 412-3_415dupCAGTTTG FIBP gene variant. Reporting two new cases with this rare autosomal recessive overgrowth syndrome with a novel FIBP gene variant will support and expand the clinical spectrum of Thauvin-Robinet-Faivre syndrome. Also discussed will be the function of FIBP in tumorigenesis and the possible renal tumor susceptibility in heterozygous carriers will be emphasized.

SCYL1 deficiency: A rare entity with challenging neurological manifestations after liver transplantation.

BACKGROUND: Pediatric acute liver failure (PALF) with undetermined etiology is associated with higher liver transplantation and lower spontaneous recovery (transplant-free) rates. The diagnostic odyssey in PALF cases hinders appropriate management and follow-up after liver transplantation. Advances in whole exome sequencing analysis have already been successful at identifying new genetic causes of PALF. CASE PRESENTATION: We report a 17-year-old girl who underwent liver transplantation at the age of 7 months due to acute liver failure and presented later with abnormal neurological manifestations, that is, gait disturbances, dysarthria, and mental retardation that led us to the diagnosis of SCYL1 deficiency. CONCLUSION: PALF cases should be screened for possible underlying genetic disorders. Genetic studies and reanalysis of whole-genome sequencing data may help identify new cases and clarify the genotype-phenotype correlation. SCYL1 deficiency should be suspected in PALF patients who develop neurological involvement after LT. Early diagnosis is vital for proper management of ALF crises in SCYL1 deficiency patients. Despite the reported favorable outcomes of ALF crises in SCYL1 deficiency, liver transplantation decision should be discussed on a case-by-case basis.

Bisphosphonate treatment at spondylo-ocular syndrome due to a novel compound heterozygote variant in XYLT2 and review of the literature.

Spondylo-ocular syndrome is a rare autosomal recessive disorder characterized by generalized osteoporosis, hearing loss, visual impairment due to cataract, and platyspondyly. Previous studies have revealed that the syndrome is caused by pathogenic variants in the XYLT2 gene. A patient with spondylo-ocular syndrome and two heterozygous pathogenic variant in the XYLT2 gene in compound state are described here. The patient presented with osteoporosis, platyspondyly, ocular findings, hearing loss, kyphosis, scoliosis, facial findings, intellectual disability, and undescended testicles. Previous reports of bisphosphonate treatment response were variable, whereas a long-term follow-up with bisphosphonate treatment in this case resulted in normalization of vertebral structures. Reporting such cases helps to determine the appropriate genotype-phenotype correlation in patients with XYLT2-related pathogenesis.

De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction.

Gorlin-Chaudhry-Moss syndrome (GCMS) is a dysmorphic syndrome characterized by coronal craniosynostosis and severe midface hypoplasia, body and facial hypertrichosis, microphthalmia, short stature, and short distal phalanges. Variable lipoatrophy and cutis laxa are the basis for a progeroid appearance. Using exome and genome sequencing, we identified the recurrent de novo mutations c.650G>A (p.Arg217His) and c.649C>T (p.Arg217Cys) in SLC25A24 in five unrelated girls diagnosed with GCMS. Two of the girls had pronounced neonatal progeroid features and were initially diagnosed with Wiedemann-Rautenstrauch syndrome. SLC25A24 encodes a mitochondrial inner membrane ATP-Mg/Pi carrier. In fibroblasts from affected individuals, the mutated SLC25A24 showed normal stability. In contrast to control cells, the probands' cells showed mitochondrial swelling, which was exacerbated upon treatment with hydrogen peroxide (H2O2). The same effect was observed after overexpression of the mutant cDNA. Under normal culture conditions, the mitochondrial membrane potential of the probands' fibroblasts was intact, whereas ATP content in the mitochondrial matrix was lower than that in control cells. However, upon H2O2 exposure, the membrane potential was significantly elevated in cells harboring the mutated SLC25A24. No reduction of mitochondrial DNA copy number was observed. These findings demonstrate that mitochondrial dysfunction with increased sensitivity to oxidative stress is due to the SLC25A24 mutations. Our results suggest that the SLC25A24 mutations induce a gain of pathological function and link mitochondrial ATP-Mg/Pi transport to the development of skeletal and connective tissue.

Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype Associated with Early-Onset Retinitis Pigmentosa.

Crisponi syndrome (CS)/cold-induced sweating syndrome type 1 (CISS1) is a very rare autosomal-recessive disorder characterized by a complex phenotype with high neonatal lethality, associated with the following main clinical features: hyperthermia and feeding difficulties in the neonatal period, scoliosis, and paradoxical sweating induced by cold since early childhood. CS/CISS1 can be caused by mutations in cytokine receptor-like factor 1 (CRLF1). However, the physiopathological role of CRLF1 is still poorly understood. A subset of CS/CISS1 cases remain yet genetically unexplained after CRLF1 sequencing. In five of them, exome sequencing and targeted Sanger sequencing identified four homozygous disease-causing mutations in kelch-like family member 7 (KLHL7), affecting the Kelch domains of the protein. KLHL7 encodes a BTB-Kelch-related protein involved in the ubiquitination of target proteins for proteasome-mediated degradation. Mono-allelic substitutions in other domains of KLHL7 have been reported in three families affected by a late-onset form of autosomal-dominant retinitis pigmentosa. Retinitis pigmentosa was also present in two surviving children reported here carrying bi-allelic KLHL7 mutations. KLHL7 mutations are thus associated with a more severe phenotype in recessive than in dominant cases. Although these data further support the pathogenic role of KLHL7 mutations in a CS/CISS1-like phenotype, they do not explain all their clinical manifestations and highlight the high phenotypic heterogeneity associated with mutations in KLHL7.

Correction: The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome.

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.

The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome.

PURPOSE: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. METHODS: Clinicians entered clinical data in an extensive web-based survey. RESULTS: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. CONCLUSION: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.

First cardiac manifestation of hypotonia-cystinuria syndrome.

Hypotonia-cystinuria syndrome is a very rare autosomal recessive contiguous gene deletion syndrome of PREPL and SLC3A1 at 2p21 with neuromuscular and neuroendocrinologic presentation. We report a two-year-six-month-old affected female infant and her five-month-old affected brother with a novel homozygous deletion in SLC3A1 and PREPL gene. Both of siblings had mild facial dysmorphism, hypotonia, feeding problems, failure to thrive, developmental delay. She also had dilated cardiomyopathy which differ from other reported patients. Therefore cardiomyopathy may also be considered one of the features of hypotonia-cystinuria syndrome. With this case report, we present cardiac manifestation of hypotonia-cystinuria syndrome for the first time. Because of two siblings had hyperechogenic bowel in prenatal sonography, it might be a prenatal marker for HCS.

Clinical delineation of a subtype of frontonasal dysplasia with creased nasal ridge and upper limb anomalies: Report of six unrelated patients.

Frontonasal dysplasias are rare congenital malformations of frontonasal process-derived structures, characterized by median cleft, nasal anomalies, widely spaced eyes, and cranium bifidum occultum. Several entities of syndromic frontonasal dysplasia have been described, among which, to date, only a few have identified molecular bases. We clinically ascertained a cohort of 124 individuals referred for frontonasal dysplasia. We identified six individuals with a similar phenotype, including one discordant monozygous twin. Facial features were remarkable by nasal deformity with creased ridge and depressed or absent tip, widely spaced eyes, almond-shaped palpebral fissures, and downturned corners of the mouth. All had apparently normal psychomotor development. In addition, upper limb anomalies, frontonasal encephalocele, corpus callosum agenesis, choanal atresia, and congenital heart defect were observed. We identified five reports in the literature of patients presenting with the same phenotype. Exome sequencing was performed on DNA extracted from blood of two individuals, no candidate gene was identified. In conclusion, we report six novel simplex individuals presenting with a specific frontonasal dysplasia entity associating recognizable facial features, limb and visceral malformations, and apparently normal development. The identification of discordant monozygotic twins supports the hypothesis of a mosaic disorder. Although previous patients have been reported, this is the first series, allowing delineation of a clinical subtype of frontonasal dysplasia, paving the way toward the identification of its molecular etiology.

A patient with mitochondrial disorder due to a novel mutation in MRPS22.

MRPS22 gene defect is a very rare newly discovered mitochondrial disorder. We report a 4-month-old severely affected male infant with MRPS22 mutation. Whole exome sequencing revealed a novel homozygous splicing mutation c.339 + 5 G > A in MRPS22 gene. He has mild dysmorphism, hypotonia, developmental delay but not hypertrophic cardiomyopathy and tubulopathy which differ from other majority of reported patients. Therefore, hypertrophic cardiomyopathy and tubulopathy may not be considered as constant features of MRPS22. With this case report, we also present first symmetrical bilateral brainstem and medial thalamic lesions, and cerebellar and cerebral atrophy on a brain MR imaging follow-up of ten months.

Preparation of electrospun polyurethane nanofiber mats for the release of doxorubicine.

Polyurethane (PU) and doxorubicine loaded-PU nanofiber mats were prepared by the electrospinning technique. The effect of some system and process parameters including flow rate, distance from collector, and concentration of solution on the size and morphology of nanofibers was investigated. The size, morphology and drug content of nanofiber mats were followed by scanning electron microscopy (SEM). FTIR and TGA methods were used for structural and thermal characterization, and DSC was also used for determining the form of drug within nanofiber mat. Doxorubicine release kinetics were studied in two different pHs (4.5 and 7.5) for two drug content and it was observed that there is an inverse correlation between the amounts of drug loaded and released.

Evaluation of Risk Factors for Antibiotic Resistance in Patients with Nosocomial Infections Caused by Pseudomonas aeruginosa.

Background. Pseudomonas aeruginosa (P. aeruginosa) is resistant to various antibiotics and can cause serious nosocomial infections with high morbidity and mortality. In this clinical study, we investigated the risk factors in patients who were diagnosed with P. aeruginosa-related nosocomial infection. Methods. A retrospective case control study including patients with P. aeruginosa-related nosocomial infection. Patients who were resistant to any of the six antibiotics (imipenem, meropenem, piperacillin-tazobactam, ciprofloxacin, amikacin, and ceftazidime) constituted the study group. Results. One hundred and twenty isolates were isolated. Various risk factors were detected for each antibiotic in the univariate analysis. In the multivariate analysis, previous cefazolin use was found as an independent risk factor for the development of imipenem resistance (OR = 3.33; CI 95% [1.11-10.0]; p = 0.03), whereas previous cerebrovascular attack (OR = 3.57; CI 95% [1.31-9.76]; p = 0.01) and previous meropenem use (OR = 4.13; CI 95% [1.21-14.07]; p = 0.02) were independent factors for the development of meropenem resistance. For the development of resistance to ciprofloxacin, hospitalization in the neurology intensive care unit (OR = 4.24; CI 95% [1.5-11.98]; p = 0.006) and mechanical ventilator application (OR = 11.7; CI 95% [2.24-61.45]; p = 0.004) were independent risk factors. Conclusion. The meticulous application of contact measures can decrease the rate of nosocomial infections.

A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling.

Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. De novo dominant mutations in different members of the SWI/SNF chromatin remodeling complex have recently been described in individuals with Coffin-Siris (CSS) and Nicolaides-Baraitser (NCBRS) syndromes. Using a combination of whole-exome sequencing, NGS-based sequencing of 23 SWI/SNF complex genes, and molecular karyotyping in 46 previously undescribed individuals with CSS and NCBRS, we identified a de novo 1-bp deletion (c.677delG, p.Gly226Glufs*53) and a de novo missense mutation (c.914G>T, p.Cys305Phe) in PHF6 in two individuals diagnosed with CSS. PHF6 interacts with the nucleosome remodeling and deacetylation (NuRD) complex implicating dysfunction of a second chromatin remodeling complex in the pathogenesis of CSS-like phenotypes. Altogether, we identified mutations in 60% of the studied individuals (28/46), located in the genes ARID1A, ARID1B, SMARCB1, SMARCE1, SMARCA2, and PHF6. We show that mutations in ARID1B are the main cause of CSS, accounting for 76% of identified mutations. ARID1B and SMARCB1 mutations were also found in individuals with the initial diagnosis of NCBRS. These individuals apparently belong to a small subset who display an intermediate CSS/NCBRS phenotype. Our proposed genotype-phenotype correlations are important for molecular screening strategies.

Expanding the mutational spectrum of CRLF1 in Crisponi/CISS1 syndrome.

Crisponi syndrome (CS) and cold-induced sweating syndrome type 1 (CISS1) share clinical characteristics, such as dysmorphic features, muscle contractions, scoliosis, and cold-induced sweating, with CS patients showing a severe clinical course in infancy involving hyperthermia associated with death in most cases in the first years of life. To date, 24 distinct CRLF1 mutations have been found either in homozygosity or in compound heterozygosity in CS/CISS1 patients, with the highest prevalence in Sardinia, Turkey, and Spain. By reporting 11 novel CRLF1 mutations, here we expand the mutational spectrum of CRLF1 in the CS/CISS1 syndrome to a total of 35 variants and present an overview of the different molecular and clinical features of all of them. To catalog all the 35 mutations, we created a CRLF1 mutations database, based on the Leiden Open (source) Variation Database (LOVD) system (https://grenada.lumc.nl/LOVD2/mendelian_genes/variants). Overall, the available functional and clinical data support the fact that both syndromes actually represent manifestations of the same autosomal-recessive disorder caused by mutations in the CRLF1 gene. Therefore, we propose to rename the two overlapping entities with the broader term of Crisponi/CISS1 syndrome.

Striking hematological abnormalities in patients with microcephalic osteodysplastic primordial dwarfism type II (MOPD II): a potential role of pericentrin in hematopoiesis.

BACKGROUND: Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is a rare primordial dwarfism that is similar to Seckel syndrome. Seckel syndrome is known to be associated with various hematological abnormalities; however, hematological findings in MOPD II patients have not been previously reported. The present study aimed to describe the hematological findings in a series of eight patients with MOPD II from a single center. MATERIALS AND METHODS: The study included eight patients with MOPD II that were analyzed via molecular testing, and physical and laboratory examinations. RESULTS: Molecular testing showed that seven of the eight patients had pericentrin (PCNT) gene mutations. Hematological evaluation showed that 7 (87.5%) patients had thrombocytosis, 6 (75%) had leukocytosis, 5 (62.5%) had both leukocytosis and thrombocytosis, and 2 (25%) had anemia. CONCLUSIONS: We report leukocytosis and thrombocytosis as a common hematologic abnormality in patients with MOPD II. The present findings may improve our understanding of the potential function of the PCNT gene in hematopoietic cell proliferation and differentiation.

A Rare Cause Of Proportional Short Stature and Puberty Precocity: Floating-Harbor Syndrome.

Floating-Harbor syndrome is a sporadic autosomal dominantly inherited malformation syndrome characterized by typical craniofacial findings, proportional short stature, significantly delayed bone age, delayed expressive language, delayed speech, and normal head circumference. It is caused by heterozygous mutations in the SNF2-associated CBP activator protein gene (SRCAP) located on chromosome 16. Here, we report 9 years and 4 months old male patient who presented to the pediatric genetics outpatient clinic with retardation in early developmental stages, dysmorphic facial features, and short stature. The patient was diagnosed with Floating-Harbor syndrome with typical facial features and clinical findings. A triangular face, short filtrum, posteriorly rotated ear, deep-set eyes, bulbous nose, prominent columella, and low hairline are unique facial features in the syndrome. He also has short stature, significant retardation in bone age, and retardation in expressive language. Floating-Harbor syndrome should be remembered in the differential diagnosis of patients evaluated for short stature and learning disability with its unique facial features. By reporting a new case of Floating-Harbor syndrome we aimed to expand the clinical and molecular spectrum in this rare syndrome and increase diagnostic awareness for pediatric endocrinology practitioners.

A Recurrent c.416C>T Variant in the B3GAT3 Gene in the Turkish Population: Report of Two Siblings and Expanding the Clinical Spectrum.

Introduction: Linkeropathies are a group of rare multi-systemic genetic disorders primarily affecting the skeletal and cardiac systems due to defects in the enzymes responsible for proteoglycan synthesis. Case Presentation: We present a case of two siblings with the B3GAT3 variant. The 14-year-old boy exhibited short stature, severe kyphoscoliosis, splenomegaly, and aortic root dilatation, along with several physical abnormalities including bifid uvula, blue sclera, limited elbow extension, and pectus carinatum. His 6-year-old sister also exhibited comparable yet less pronounced physical features. Clinical exome sequencing analysis revealed a homozygous c.416C>T variant in the B3GAT3 gene for the sister; the same variant was also present in the boy patient. The boy underwent preoperative halo-gravity traction for severe kyphoscoliosis, followed by posterior instrumentation and fusion surgery without complications. Discussion/Conclusion: B3GAT3-related linkeropathy syndrome is a rare disorder and we further expand the clinical spectrum with novel findings.

Bacterial and fungal communities in chronic rhinosinusitis with nasal polyps.

OBJECTIVE: Multiple inflammatory mechanisms dynamically interact in the development of chronic rhinosinusitis with nasal polyps (CRSwNP). Disruption of the relationship between host and environmental factors on the mucosal surface leads to the development of inflammation. Microorganisms constitute the most important part of environmental factors. METHODS: 28 volunteers (18 CRSwNP patients and 10 healthy individuals) were included in the study. Eight patients were recurrent nasal polyposis cases, and the remaining were primary cases. Swab samples were taken from the middle meatus under endoscopic examination from all participants. After DNA extraction, a library was created with the Swift Amplicon 16S + ITS kit and sequenced with Illumina Miseq. Sequence analysis was performed using QIIME, UNITE v8.2 database for ITS and Silva v138 for 16S rRNA. RESULTS: The predominant bacteria in all groups were Firmicutes, Proteobacteria, Actinobacteria as phyla and Staphylococcus, Corynebacterium, Sphingomonas as genera. Comparison of bacterial communities of CRSwNP patients and control group highlighted Corynebacterium, as the differentiating taxa for control group and Streptococcus, Moraxella, Rothia, Micrococcus, Gemella, and Prevotella for CRSwNP patients. The predominant fungal genus in all groups was Malassezia. Staphylococcus; showed a statistically significant negative correlation with Dolosigranulum. Corynebacterium had a positive correlation with Anaerococcus, and a negative correlation with Neisseria, Prevotella, Fusobacterium and Peptostreptococcus. CONCLUSION: Nasal microbiome of CRSwNP patients shows greater inter-individual variation than the control group. Corynebacterium is less abundant in patients with CRSwNP compared to the control group. Malassezia is the predominant fungus in the nasal cavity and paranasal sinuses and correlates positively with the abundance of Corynebacterium.