Muenke syndrome is an autosomal dominant genetic disorder that is typically characterized by unilateral or bilateral coronal synostosis, macrocephaly, midface hypoplasia, and developmental delays. This article reports a case of Muenke syndrome with a soft cleft palate. A heterozygous missense mutation c.749C>G (p.P250A) was identified in the FGFR3 gene through genetic testing. The patient exhibited typical features including coronal synostosis, bilateral hearing loss, right accessory auricle, and developmental delays and underwent surgery to repair the soft cleft palate. Cases of Muenke syndrome with cleft palate in the literature are relatively rare, and common associated symptoms include coronal suture craniosynostosis and hearing impairment. This article reports a differential diagnosis with other craniosynostosis syndromes and provides a reference for clinical diagnosis and treatment.
Humans ; Cleft Palate/surgery* ; Craniosynostoses/diagnosis* ; Mutation, Missense ; Palate, Soft/abnormalities* ; Receptor, Fibroblast Growth Factor, Type 3/genetics*

OBJECTIVE: To explore the genotype-phenotype relationship in a child with Opitz G/BBB syndrome (OS) with mild clinical phenotype. METHODS: A child with motor developmental delay as the initial symptom admitted to Xi'an Children's Hospital on June 10, 2021 was selected for this study. Clinical data were collected, and peripheral blood samples were obtained from the child and his mother. Whole exome sequencing (WES) was performed to identify genetic variant in the child. Candidate variant were verified by Sanger sequencing to assess inheritance patterns and pathogenicity. Real-time fluorescence quantitative PCR (RT-qPCR) and Western blot (WB) analyses were conducted to evaluate the effects of the variant on mRNA and protein expression, respectively, using recombinant expression plasmids generated in vitro. This study was approved by the Medical Ethics Committee of Xi'an Children's Hospital (Ethics No. 20240045). RESULTS: The child, a 9-month-and-7-day-old boy, presented with a low nasal bridge, hypertelorism, and difficulty sitting independently. Echocardiography revealed an atrial septal defect. WES identified a homozygous variant in the MIDI gene, c.1483C>T (p.R495X), which was confirmed by Sanger sequencing and found to be inherited from the mother.Recombinant expression plasmids were successfully constructed. RT-qPCR analysis showed that the variant significantly reduced MIDI gene mRNA expression, while WB results indicated that the variant led to the production of a truncated protein. CONCLUSION The mild clinical phenotype of OS in this child may be attributed to the mRNA degradation escape mechanism induced by the nonsense variant c.1483C>T (p.R495X) in the MIDI gene. These findings provide valuable diagnostic insights for this pedigree and contribute to the understanding of the genotype-phenotype correlation in OS.
Humans ; Male ; Infant ; Transcription Factors/metabolism* ; Microtubule Proteins/genetics* ; Craniosynostoses/genetics* ; Hypospadias/genetics* ; Codon, Nonsense/genetics* ; RNA, Messenger/metabolism* ; Female ; RNA Stability/genetics* ; Phenotype ; Nuclear Proteins/genetics* ; Ubiquitin-Protein Ligases ; Esophagus/abnormalities* ; Hypertelorism

OBJECTIVE: To block the transmission of Cranio-facial-nasal syndrome (CFNS) caused by a large deletion of the EFNB1 gene through preimplantation genetic testing for monogenic disorders (PGT-M). METHODS: A patient with craniofacial deformities and his parents who had visited Shiyan People's Hospital in June 2020 were selected as the study subjects. The child underwent whole exome sequencing (WES) and qPCR validation. After genetic counseling, PGT-M was chosen for the reproductive blockage. This study was approved by the Ethics Committee of the Hospital (Ethics No.: sysrmyy-087). RESULTS: The child was diagnosed with CFNS due to a heterozygous deletion of exons 1-5 of the EFNB1 gene through WES and qPCR, which showed a X-linked dominant inheritance. The mother underwent ovarian stimulation with a modified PPOS protocol, which has yielded 11 oocytes. After ICSI fertilization, 4 blastocysts were formed, and MALBAC whole genome amplification was performed on the trophoblast biopsy cells, and SNP haplotypes of the family members and embryos were analyzed to indirectly determine the presence of maternal pathogenic haplotypes. Chromosomal copy number variation analysis was conducted through next-generation sequencing to screen for euploid embryos, resulting in the identification of two euploid embryos that did not carry the mutation of the EFNB1 gene. The first transfer was unsuccessful, but after adjusting the transfer timing through endometrial receptivity assessment (ERA), clinical pregnancy was achieved. Prenatal diagnosis at 19 weeks excluded the EFNB1 gene exons 1-5 deletion in the fetus. A healthy girl was delivered by Cesarean section at 38⁺⁶ weeks, and Q-PCR confirmed she has no aforementioned EFNB1 gene deletion. CONCLUSION This study has successfully blocked the transmission of CFNS caused by a large deletion of the EFNB1 gene (exons 1-5) using a PGT-M strategy, which may provide reference for the intervention of similar genomic variations that cannot be directly detected.
Humans ; Female ; Male ; Craniofacial Abnormalities/diagnosis* ; Ephrin-B1/genetics* ; Polymorphism, Single Nucleotide/genetics* ; Preimplantation Diagnosis/methods* ; Pedigree ; Asian People/genetics* ; Craniosynostoses/genetics* ; Pregnancy ; Gene Deletion ; Sequence Deletion ; Genetic Testing/methods* ; Adult ; East Asian People

OBJECTIVE: To analyze the clinical and genetic characteristics of an infant with craniosynostosis. METHODS: An infant who was admitted to Wuhan Children's Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology in April 2021 due to widening of the lateral ventricles for over a month was selected as the study subject. Clinical data of the patient was collected. Peripheral blood samples were collected from the infant and her parents for chromosomal karyotyping and whole exome sequencing. Candidate variant was verified by Sanger sequencing and bioinformatic analysis. Relevant literature was retrieved from the PubMed, Wanfang and CNKI databases (up to December 2021) by using key words including ERF gene, craniosynostosis, ERF mutation, craniosynostosis and ERF-related craniosynostosis. RESULTS: The infant, a 1-month-and-16-day-old female, was found to have sagittal synostosis by cranial X-ray radiography. Genetic testing revealed that she has harbored a heterozygous c.787C>T (p.Q263*) variant of the ERF gene, which was not found in either parent. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted as pathogenic (PVS1+PS2+PM2_Supporting). In total 63 relevant cases were retrieved from the database, and a total of 64 individuals were analyzed by genetic testing. Most of the cases were sporadic and males. Multiple cranial sutures (including at least two of the sagittal suture, coronal suture, lambdoid suture, and frontal suture) were involved in 45.45% of the cases, and those with sagittal suture closure only have accounted for 20.00%. The main clinical manifestations have included hypertelorism, exophthalmos, development delay, malar dysplasia, etc. Chiari type 1 malformation may present in some patients. Variants of the ERF gene have mainly included splicing and deletional variants, and there was a strong genetic heterogeneity among the infants and their pedigrees. CONCLUSION The c.787C>T (p.Q263*) variant of the ERF gene probably underlay the craniosynostosis of this infant. Above finding has enriched the phenotype ~ genotype spectrum of the ERF gene.
Female ; Humans ; Cranial Sutures/surgery* ; Craniosynostoses/genetics* ; Genetic Testing ; Mutation ; Repressor Proteins/genetics* ; Infant

OBJECTIVE: To conduct clinical and genetic analysis of two male patients with atypical Rett syndrome. METHODS: Collection of clinical data in the two patients and these parents; whole exome sequencing (WES) was used to detect the potential variants, which were verified by Sanger sequencing. X chromosome inactivation (XCI) detection is performed in the Patient 1's mother to detect the allelic expression difference of the MECP2 gene. RESULTS: Patient 1, a 5-year and 10-month-old boy, had mental disorders and mild intellectual disability (ID) (IQ: 54), whose mother had ID. Patient 2 was a 9-month and 18-day-old male presented with recurrent infections, respiratory insufficiency, hypotonia and global developmental delay. WES indentified a hemizygous mutation, c.499C>T (p.R167W), in the MECP2 gene in patient 1, which was inherited from his mother. The inactivation of X chromosome is skewed, and the expression ratio of wild-type and mutant MECP2 is 100%:0. Patient 2 was found a de novo splicing mutation, c.62+2_62+3del in the MECP2 gene. They were both reported pathogenic variant related to Rett syndrome. c.499C>T (p.R167W) was defined as likely pathogenic (PS1+PM2+PP3) and c.62+2_62+3del was pathogenic (PVS1+PM2+PM6) based on American College of Medical Genetics and Genomics standards and guidelines. CONCLUSION Both the two patients were diagnosed with rare male Rett syndrome, which had atypical clinical manifestations and large difference. Above foundings have revealed novel phenotypes in Chinese male patients with Rett syndrome.
Craniosynostoses ; Female ; Genetic Testing ; Humans ; Intellectual Disability/genetics* ; Male ; Methyl-CpG-Binding Protein 2/genetics* ; Mutation ; Phenotype ; Rett Syndrome/genetics*

The Muenke syndrome (MS) is characterized by unicoronal or bicoronal craniosynostosis, midfacial hypoplasia, ocular hypertelorism, and a variety of minor abnormalities associated with a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. The birth prevalence is approximately one in 10,000 live births, accounting for 8-10% of patients with coronal synostosis. Although MS is a relatively common diagnosis in patients with craniosynostosis syndromes, with autosomal dominant inheritance, there has been no report of MS, in an affected Korean family with typical cephalo-facial morphology that has been confirmed by molecular studies. Here, we report a familial case of MS in a female patient with a Pro250Arg mutation in exon 7 (IgII-IGIII linker domain) of the FGFR3 gene. This patient had mild midfacial hypoplasia, hypertelorism, downslanting palpebral fissures, a beak shaped nose, plagio-brachycephaly, and mild neurodevelopmental delay. The same mutation was confirmed in the patient's mother, two of the mother's sisters and the maternal grandfather. The severity of the cephalo-facial anomalies was variable among these family members.
Adult ; Asian Continental Ancestry Group/*genetics ; Child, Preschool ; Craniosynostoses/*genetics/surgery ; DNA Mutational Analysis ; Female ; Humans ; Hypertelorism/genetics ; Korea ; Male ; *Mutation ; Pedigree ; Phenotype ; Receptor, Fibroblast Growth Factor, Type 3/*genetics ; Skull/*abnormalities/surgery ; Syndrome ; Treatment Outcome

Here we report the first case of a Korean infant with a cloverleaf-shaped craniosynostosis, in which the diagnosis of Beare-Stevenson syndrome was suspected upon observation of the typical morphological features. This infant exhibited craniofacial anomalies, ocular proptosis, cutis gyrata, acanthosis nigricans, prominent umbilical stump, furrowed palms and soles, hypospadia, and sacral skin tag coupled with dermal sinus tract. Brain magnetic resonance imaging revealed that the patient also had non-communicating hydrocephalus with Chiari malformation. This is the 8th report of Beare-Stevenson syndrome in the literature, which was confirmed by the detection of a Tyr375Cys mutation in the fibroblast growth factor receptor 2 (FGFR2) gene.
Syndrome ; Receptor, Fibroblast Growth Factor, Type 2/*genetics ; Polymorphism, Single Nucleotide/genetics ; Mutation ; Male ; Korea ; Infant, Newborn ; Humans ; Genetic Predisposition to Disease/genetics ; DNA Mutational Analysis ; Craniosynostoses/diagnosis/*genetics ; Craniofacial Abnormalities/diagnosis/genetics ; Abnormalities, Multiple/diagnosis/*genetics

Craniosynostosis occurs in approximately 1:2000 live births. It may affect the coronal, sagittal, metopic and lambdoid sutures in isolation or in combination. Although non-syndromic synostoses are more common, over 150 genetic syndromes have been identified. Recent advances in genetic mapping have linked chromosomal mutations with craniosynostotic syndromes. Despite the identification of these genetic mutations, the fundamental biomolecular mechanisms mediating cranial suture biology remain unknown. Today, many laboratories are investigating murine cranial suture biology as a model for human cranial suture development and fusion. Normal murine cranial suture biology is very complex, but evidence suggests that the dura mater provides the biomolecular blueprints (e.g. the soluble growth factors), which guide the fate of the pleuripotent osteogenic fronts. While our knowledge of these dura-derived signals has increased dramatically in the last decade, we have barely begun to understand the fundamental mechanisms that mediate cranial suture fusion or patency. Interestingly, recent advances in both premature human and programmed murine suture fusion have revealed unexpected results, and have generated more questions than answers.
Animal ; Craniosynostoses/*etiology/genetics/surgery ; Fetal Development ; Fetus/*physiology ; Human ; Mutation