Posterior fossa malformations are rare cyst-like pathologies of the central nervous system. Outcomes of patients with these conditions are largely documented in fetal or early childhood studies as most cases are non-compatible with life. Also, different schemes to categorize these occurrences have been proposed. One classification puts forth that the entities are a continuum of pathologies, called the Dandy Walker Complex, wherein Mega Cisterna Magna is the most benign to Dandy Walker Malformation as the most severe form. We report the first case of a patient with a mixed presentation of Mega Cisterna Magna having extracranial manifestations of Dandy Walker Malformation reaching her adult years. The patient is a 26-year-old female who was apparently well until she presented with recurrent headache and seizure episodes of 2-year duration. She had an unremarkable birth and childhood history, apart from learning difficulties in school. In her adult years, she gave birth to an infant with multiple physical anomalies. She has a maternal uncle with abnormal facie and intellectual disability. Physical examination of the patient exhibited a bulging occiput, hypertelorism, down-slanting palpebral fissures, large globular nose, large ear lobules, high arched palate, and clinodactyly. Neurologic examination was unremarkable. Magnetic resonance imaging confirmed Mega Cisterna Magna and was deemed non-surgical. She remained seizure-free during admission as well as on followup, maintained on Phenytoin. The existence of a Dandy-Walker continuum is still debated, as the link among the disease entities are yet to be established using developmental or genetic studies. This case, however, supports the Dandy-Walker Complex classification by demonstrating a rare combination of Mega Cisterna Magna with features of Dandy-Walker Malformation in an adult. This can contribute to disease definition and eventually to the discovery of the pathobiological mechanisms of posterior fossa cysts, and to appropriate diagnosis and management.

We report the case of a 33-week-old female fetus born with craniorachischisis to a gravida 5, para 4 (3104) mother with no previous history of conceiving a child with a neural tube defect. Craniorachischisis is characterized by anencephaly and an open defect extending from the brain to the spine and is the most severe and fatal type of neural tube defect. Although the cause of neural tube defects is hypothesized to be multifactorial and is usually sporadic, the risk is increased in neonates born to mothers with a family history or a previous pregnancy with neural tube defect, both of which are not present in the index case. This case is unique in that only during the fifth pregnancy did the couple conceive a child with a neural tube defect, emphasizing that folic acid supplementation, the sole preventive measure proven to decrease the risk of neural tube defects, remains to be important in the periconceptual period for all women of childbearing age.
Autopsy ; Congenital Abnormalities ; Neural Tube Defects ; Neural Tube Defects

Tuberous sclerosis complex (TSC) is a rare, autosomal dominant multisystem disorder affecting the brain, heart, kidneys, lungs, and skin leading to significant morbidity and mortality. We report a case of TSC and highlight the need for prompt diagnosis and proper surveillance to minimize life‑threatening complications. A 20‑year‑old female presented with facial and ungual papulonodular lesions 4 years after being diagnosed with epilepsy at the age of eight. No family history of genetic diseases was reported. Eight years later, the patient developed recurrent cough, shortness of breath, and blurring of vision. Biopsy of facial and digital nodule showed angiofibroma and ungual fibroma (Koenen tumor), respectively. Chest computed tomography scan revealed extensive cystic lesions diffusely scattered throughout the entire lung parenchyma suggestive of lymphangioleiomyomatosis. Cranial MRI revealed cortical and subependymal tubers, compatible with TSC. The patient had multidisciplinary management. However, her symptoms progressed, and she eventually succumbed to death. Cutaneous lesions such as facial angiofibromas and ungual fibromas along with multisystemic manifestations should alarm the clinician to TSC. Given its highly variable expressivity, awareness of different TSC‑associated signs and symptoms is essential for prompt diagnosis, proper treatment, disease monitoring, and early recognition of TSC complications.
Angiofibroma ; Lymphangioleiomyomatosis ; Tuberous Sclerosis

OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with hereditary spastic paraplegia type 30 (HSP30). METHODS: A proband presented at the Second Hospital of Shanxi Medical University in August 2021 was selected as the study subject. The proband was subjected to whole exome sequencing, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: The proband was found to have harbored a heterozygous c.110T>C variant in exon 3 of the KIF1A gene, which can cause substitution of isoleucine by threonine at position 37 (p.I37T) and alter the function of its protein product. The same variant was not found in his parents, elder brother and elder sister, suggesting that it has a de novo origin. Based on the guidelines of the American College of Medical Genetics and Genomics (ACMG), the variant was rated as likely pathogenic (PM2_Supporting+PP3+PS2). CONCLUSION The c.110T>C variant of the KIF1A gene probably underlay the HSP30 in the proband. Above finding has enable genetic counseling for this family.
Humans ; Male ; East Asian People ; Kinesins/genetics* ; Mutation ; Pedigree ; Spastic Paraplegia, Hereditary/genetics* ; Female

OBJECTIVE: To explore the genetic etiology for a fetus with Walker-Warburg syndrome(WWS). METHODS: A fetus with WWS diagnosed at Gansu Provincial Maternity and Child Health Care Hospital in June 9, 2021 was selected as the study subject. Genomic DNA was extracted from amniotic fluid sample of the fetus and peripheral blood samples from its parents. Trio-Whole exome sequencing (trio-WES) was carried out. Candidate variants were verified by Sanger sequencing. RESULTS: The fetus was found to harbor compound heterozygous variants of the POMT2 gene, namely c.471delC (p.F158Lfs*42) and c.1975C>T (p.R659W), which were respectively inherited from its father and mother. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), they were respectively rated as pathogenic (PVS1+PM2_Supporting+PP4) and likely pathogenic (PM2_Supporting+PM3+PP3_Moderate+PP4). CONCLUSION Trio-WES may be used for the prenatal diagnosis of WWS. The compound heterozygous variants of the POMT2 gene probably underlay the disorder in this fetus. Above finding has expanded the mutational spectrum of the POMT2 gene and enabled definite diagnosis and genetic counseling for the family.
Pregnancy ; Child ; Female ; Humans ; Walker-Warburg Syndrome ; Prenatal Diagnosis ; Fetus ; Genetic Counseling ; Genomics ; Mutation

OBJECTIVE: To analyze the clinical phenotype and genetic characteristics of a child with Hereditary spastic paraplegia (HSP). METHODS: A child with HSP who was admitted to the Third Affiliated Hospital of Zhengzhou University on August 10, 2020 due to discovery of tiptoeing for 2 years was selected as the study subject, and relevant clinical data was collected. Peripheral blood samples of the child and her parents were collected for the extraction of genomic DNA. And trio-whole exome sequencing (trio-WES) was carried out. Candidate variants were verified by Sanger sequencing. Bioinformatic software was used to analyze the conservation of variant sites. RESULTS: The child was a 2-year-and-10-month-old female with clinical manifestations including increased muscle tone of lower limbs, pointed feet, and cognitive language delay. Trio-WES results showed that she had harbored compound heterozygous variants of c.865C>T (p.Gln289*) and c.1126G>A (p.Glu376Lys) of the CYP2U1 gene. And the corresponding amino acid for c.1126G>A (p.Glu376Lys) is highly conserved among various species. Based on guidelines from the American College of Medical Genetics and Genomics, the c.865C>T was predicted as a pathogenic variant (PVS1+PM2_Supporting), and c.1126G>A was rated as a variant of uncertain significance (PM2_Supporting+PM3+PP3). CONCLUSION The child was diagnosed with HSP type 56 due to compound variants of the CYP2U1 gene. Above findings have enriched the mutation spectrum of the CYP2U1 gene.
Female ; Humans ; Cytochrome P450 Family 2/genetics* ; Mutation ; Pedigree ; Phenotype ; Spastic Paraplegia, Hereditary/genetics* ; Infant

OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with recurrent fetal hydrocephalus. METHODS: A couple who had presented at the Affiliated Hospital of Putian College on March 3, 2021 was selected as the study subject. Following elective abortion, fetal tissue and peripheral blood samples were respectively obtained from the abortus and the couple, and were subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing. RESULTS: The fetus was found to harbor compound heterozygous variants of the B3GALNT2 gene, namely c.261-2A>G and c.536T>C (p.Leu179Pro), which were inherited from its father and mother, respectively.According to the guidelines of American College of Medical Genetics and Genomics, both variants were classified as pathogenic (PVS1+PM2_Supporting; PM3+PM2_Supporting+PP3+PP4). CONCLUSION The compound heterozygous variants of the B3GALNT2 gene probably underlay the α-dystroglycanopathy in this fetus. Above results have provided a basis for genetic counseling of this pedigree.
Female ; Humans ; Pregnancy ; Aborted Fetus ; Asian People/genetics* ; East Asian People ; Fetus ; Genetic Counseling ; Mutation ; N-Acetylgalactosaminyltransferases ; Pedigree ; Walker-Warburg Syndrome/genetics*

Humans ; Infant ; Female ; Dandy-Walker Syndrome/diagnosis* ; Tomography, X-Ray Computed ; Craniocerebral Trauma/complications*

Humans ; Microcephaly ; Pedigree ; Nervous System Malformations ; Glucose

OBJECTIVE: To explore the clinical characteristics and genetic etiology of a child with Aicardi-Goutières syndrome 3 (AGS3). METHODS: Trio whole exome sequencing was carried out for the child and his parents, and candidate variants were verified by Sanger sequencing. To further clarify their pathogenicity, the crystal structure of the variants was simulated and analyzed, and the plasmid of variants was expressed in vitro. A literature search was also carried out to summarize the phenotypic and genetic characteristics of AGS3. RESULTS: The child was found to harbor novel compound heterozygous variants of the RNASEH2C gene, namely c.434G>T (p.Arg145Leu) and c.494G>C (p.Ter165Ser), which were inherited from his mother and father, respectively. Analysis of protein crystal structure suggested that the c.434G>T (p.Arg145Leu) variant may affect the stability of local structure, and in vitro experiments showed that this variant can lead to protein degradation. The c.494G>C (p.Ter165Ser) variant has destroyed the stop codon, resulting in prolonged variant. CONCLUSION The novel compound heterozygous variants of the RNASEH2C gene probably underlay the AGS3 in this child, which has enriched the phenotypic and mutational spectrum of this disorder.
Humans ; Child ; Mutation ; Autoimmune Diseases of the Nervous System/genetics* ; Nervous System Malformations/genetics*