A novel variant in FOXC1 associated with atypical Axenfeld-Rieger syndrome

Mutations in the Forkhead Box C1 (FOXC1) are known to cause autosomal dominant hereditary Axenfeld-Rieger syndrome, which is a genetic disorder characterized by ocular and systemic features including glaucoma, variable dental defects, craniofacial dysmorphism and hearing loss. Due to late-onset of ocular disorders and lack of typical presentation, clinical diagnosis presents a huge challenge. In this study, we described a pathogenic in-frame variant in FOXC1 in one 5-year-old boy who is presented with hypertelorism, pupil deformation in both eyes, conductive hearing loss, and dental defects. By whole exome sequencing, we identified a 3 bp deletion in FOXC1, c.516_518delGCG (p.Arg173del) as the disease-causing variant, which was de novo and not detected in the parents, and could be classified as a “pathogenic variant” according to the American College of Medical Genetics and Genomics guidelines. After confirmation of this FOXC1 variant, clinical data on Axenfeld-Rieger syndrome-associated clinical features were collected and analyzed. Furthermore, Although the affected individual present hearing loss, however, the hearing loss is conductive and is reversible during the follow-up, which might not linke to the FOXC1 variant and is coincidental. Routine examination of FOXC1 is necessary for the genetic diagnosis of hypertelorism-associated syndrome. These findings may assist clinicians in reaching correct clinical and molecular diagnoses, and providing appropriate genetic counseling.

KCNG1-Related Syndromic Form of Congenital Neuromuscular Channelopathy in a Crossbred Calf

Inherited channelopathies are a clinically and heritably heterogeneous group of disorders that result from ion channel dysfunction. The aim of this study was to characterize the clinicopathologic features of a Belgian Blue x Holstein crossbred calf with paradoxical myotonia congenita, craniofacial dysmorphism, and myelodysplasia, and to identify the most likely genetic etiology. The calf displayed episodes of exercise-induced generalized myotonic muscle stiffness accompanied by increase in serum potassium. It also showed slight flattening of the splanchnocranium with deviation to the right side. On gross pathology, myelodysplasia (hydrosyringomielia and segmental hypoplasia) in the lumbosacral intumescence region was noticed. Histopathology of the muscle profile revealed loss of the main shape in 5.3% of muscle fibers. Whole-genome sequencing revealed a heterozygous missense variant in KCNG1 affecting an evolutionary conserved residue (p.Trp416Cys). The mutation was predicted to be deleterious and to alter the pore helix of the ion transport domain of the transmembrane protein. The identified variant was present only in the affected calf and not seen in more than 5200 other sequenced bovine genomes. We speculate that the mutation occurred either as a parental germline mutation or post-zygotically in the developing embryo. This study implicates an important role for KCNG1 as a member of the potassium voltage-gated channel group in neurodegeneration. Providing the first possible KCNG1-related disease model, we have, therefore, identified a new potential candidate for related conditions both in animals and in humans. This study illustrates the enormous potential of phenotypically well-studied spontaneous mutants in domestic animals to provide new insights into the function of individual genes.

Case Report: Potocki-Lupski Syndrome in Five Siblings

Potocki-Lupski syndrome (PTLS) is a rare developmental disorder resulting from the partial duplication of the short arm of chromosome 17. Affected children may have hypotonia, facial dysmorphism, or neurological abnormalities. PTLS is also frequently associated with failure to thrive due to swallowing difficulties or growth hormone deficiency. We report the first Romanian family (a mother and her five children) diagnosed with PTLS (17p11.2 microduplication). Fortunately, they present a less severe form of the disease. The neurological manifestations (speech delay, mild intellectual disability) are associated with craniofacial dysmorphism (microcephaly, micrognathia, triangular face, broad forehead, long chin, prominent ears, dolichocephaly, down slanting palpebral fissures). The diagnostic was established using a multiplex ligation-dependent probe amplification technique (MLPA) test, which detected the duplication of three regions of the 17p11.2 chromosome (RAI1, DRC3-6, LLGL1-4RA). Children with PTLS have specific phenotypes (craniofacial dysmorphism or neurological manifestations), which must draw the pediatrician's attention to a possible genetic condition. However, every child with this disease is unique and may have a different clinical presentation. A multi-disciplinary team is needed for the management of these patients. The parent's counseling and genetic advice are essential for a family with children with PTLS.

Dental disorders in patients recovered from malignant neoplasms in childhood

During the development of the bodyʼs homeostatic systems, anticancer drugs and radiation affect both tumor cells and healthy tissues. Damage to tissues with low potential for restorative functions, such as teeth, leads to a high probability of irreversible changes. The purpose of this literature review is to provide information on dental defects resulting from anticancer treatment. The most common anomalies in the development of teeth include a violation of the number, size, shape, mineralization of teeth, defects of dentin and enamel. The effect of a number of chemotherapeutic drugs has been studied in animal models and include a deficiency and thinning of the roots of the teeth. Irradiation leads to a wider spectrum of dental pathology: the integritation of the teeth changes, craniofacial dysmorphism, post-radiation mandibular hypomobility, damage to the salivary glands, the risk of developing osteoradionecrosis. The extent and severity of these effects depends from the child's age type of tumor and the radiation dose. The stage of tooth development is critical. Patients who received hematopoietic stem cell transplantation (HSCT) before the age of 3 have a higher risk of dental disorders and anomalies in the development and growth of the face. Radiation therapy plays a leading role in the formation of caries. The study of the long-term effects of radiation therapy, chemotherapy, HSCT on the development of dental complications is of interest to identify the most vulnerable groups of patients in order to ensure the possibility of early intervention and improve the quality of life.

Case Report: Neuroblastoma Breakpoint Family Genes Associate With 1q21 Copy Number Variation Disorders

Microduplications and reciprocal microdeletions of chromosome 1q21. 1 and/or 1q21.2 have been linked to variable clinical features, but the underlying pathogenic gene(s) remain unclear. Here we report that distinct microduplications were detected on chromosome 1q21.2 (GRCh37/hg19) in a mother (255 kb in size) and her newborn daughter (443 kb in size), while the same paternal locus was wild-type. Although the two microduplications largely overlap in genomic sequence (183 kb overlapping), the mother showed no clinical phenotype while the daughter presented with several features that are commonly observed on 1q21 microduplication or microdeletion patients, including developmental delay, craniofacial dysmorphism, congenital heart disease and sensorineural hearing loss. NBPF15 and NBPF16, two involved genes that are exclusively duplicated in the proband, may be the cause of the clinical manifestations. This study supports an association between NBPF genes and 1q21 copy number variation disorders.

A Novel Variant in FOXC1 Associated With Atypical Axenfeld-Rieger Syndrome

Background Mutations in the Forkhead Box C1 (FOXC1) are known to cause autosomal dominant hereditary Axenfeld-Rieger syndrome, which is a genetic disorder characterized by ocular and systemic features including glaucoma, variable dental defects, craniofacial dysmorphism and hearing loss. Due to late-onset of ocular disorders and lack of typical presentation, therefore, clinical diagnosis present a huge challenge. Results In this study, we described a pathogenic variant in FOXC1 in one 5 year-old boy who is presented with hypertelorism, pupil deformation in both eyes, conductive hearing loss, and dental defects. By whole exome sequencing, we identified a 3bp deletion in FOXC1, c.516_518delGCG (p.Arg173del) as the disease-causing variant, which was de novo and not detected in the parents, and could be classified as a “pathogenic variant” according to the American College of Medical Genetics and Genomics guidelines. After confirmation of this FOXC1 variant, clinical data on Axenfeld-Rieger syndrome-associated clinical features were collected and analyzed. Although the affected individual present hearing loss, however, the hearing loss is conductive and is reversible during the follow-up, which might not linked to the FOXC1 variant and is coincidental. Conclusions Routine examination of FOXC1 is necessary for the genetic diagnosis of hypertelorism-associated syndrome. These findings may assist clinicians in reaching correct clinical and molecular diagnoses, and providing appropriate genetic counseling.

FEMORAL-FACIAL SYNDROME - A RARE CASE REPORT

Femoral-facial syndrome (FFS) is an extremely rare fetal malformation. It comprises bilateral femoral hypoplasia and craniofacial dysmorphism. Maternal diabetes is associated with approximately 40% of cases of FFS. We present the case of Femoral-Facial syndrome of Newborn female child. She was delivered by vaginal route at 36th week of gestation. Mother had a history of type 2 diabetes mellitus. She was having markedly shortened bilateral lower limbs, deformed hip joint and mild talipes equino-varus deformity of left foot. There was prominent forehead, short nose with broad tip, long philthrum, thin upper lip, micrognathism and malformed low set external ears. Skeletal radiograph shows complete absence of right femur and marked hypoplasia of left femur.

Wolf-Hirschhorn Syndrome: Clinical and Genetic Study of 7 New Cases, and Mini Review

Wolf–Hirschhorn syndrome (WHS), a rare disorder determined by distal 4p deletion, is characterized by a pre and postnatal growth retardation, hypotonia, intellectual disability, epilepsy, craniofacial dysmorphism, and congenital fusion anomalies. The clinical aspects are dependent on the deletion’ size. Our aim was to identify rare specific characteristics in a cohort of seven cases with 4p deletion and to assess the utility of Multiplex ligation-dependent probe amplification (MLPA) (cheap and sensitive test)—combined kits—as a diagnostic test and selection tool for cases that require other investigations (chromosomal microarray analysis—CMA, karyotype). For all cases we conducted a clinical examination with the main features identified: facial dysmorphism, intellectual disability, postnatal development delay, cardiac defects and hypotonia. In some cases, we observed seizures, structural brain abnormalities, immunodeficiencies, and renal anomalies. Prenatal growth retardation was detected in a relatively small number of cases, but postnatal growth failure was a constant feature. In all cases, the clinical diagnosis was confirmed by genetic analyses: karyotype and/or MLPA. In conclusion, renal and brain defects, as well as immunodeficiency are rare manifestations and should be looked for. Although CMA is the standard test, in our experience, MLPA is also a reliable screening method as the identified cases were either confirmed by MLPA or selected for further investigations.

Oro-Dental Manifestations in a Pediatric Patient Affected by Helsmoortel-Van der Aa Syndrome

Aim: Aim of this case report is to describe oro-facial abnormalities in a patient affected by Helsmoortel-Van der Aa syndrome, a rare autism syndrome, with not well described dental and cranial malformations. Case Report: Helsmoortel-Van der Aa Syndrome is a rare autosomal genetic syndrome causing mental impairment and autism, craniofacial dysmorphism, chest deformity and multiple organs dysfunction. Oro-facial involvement in Helsmoortel-Van der Aa syndrome has not been thoroughly described yet. The present article reports a case of a 9 years old male patient affected by Helsmoortel-Van der Aa Syndrome, presenting with oral breathing typical facies, high arched palate, II class and dental crowding. The patient teething was adequate to his age. The enamel of incisors and molars showed demineralization areas and dark spots, a clinical picture consistent with molar incisor hypomineralization syndrome. These hypo-mineralized areas are more susceptible to cavities, in fact the patient’s 4.6 tooth was decayed. The child was brought to our attention due to a mucocele on the lower lip, confirmed by histopathologic examination. Available data on oro-dental manifestation of this syndrome are rather poor and inconsistent, also due to the rarity of the disease. The finding of enamel abnormalities in the presented case could suggest a potential genetic etiopathogenesis linked to the same genes causing Helsmoortel-Van der Aa syndrome.

Tripod-shaped Syndactyly in Apert Syndrome with FGFR2 p.P253R Mutation

Apert syndrome is a rare acrocephalosyndactyly (craniosynostosis) syndrome characterized by craniofacial dysmorphism and syndactyly of the hands and feet. It is caused by FGFR2 mutations and inherited in an autosomal dominant manner. This article describes a novel clinical variant of Apert syndrome having bilateral symmetrical tripod-shaped syndactyly in hands with milder craniofacial features in a sporadic case, along with a mutation in the fibroblast growth factor receptor 2 (FGFR2) gene. The patient had shown craniosynostosis, dysmorphic face, ocular hypertelorism, marked depression of the nasal bridge, long philtrum, and low set ears. Direct resequencing of the FGFR2 gene through Sanger’s method identified a heterozygous missense mutation; FGFR2c.758C>G (FGFR2p.P253R) in the exon-7 of the gene.