Objective: To investigate the clinical presentation and genetic characteristics of malignant infantile osteopetrosis. Methods: This was a retrospective case study. Thirty-seven children with malignant infantile osteopetrosis admitted into Beijing Children's Hospital from January 2013 to September 2022 were enrolled in this study. According to the gene mutations, the patients were divided into the CLCN7 group and the TCIRG1 group. Clinical characteristics, laboratory tests, and prognosis were compared between two groups. Wilcoxon test or Fisher exact test were used in inter-group comparison. The survival rate was estimated with the Kaplan-Meier method and the Log-Rank test was used to compare the difference in survival between groups. Results: Among the 37 cases, there were 22 males and 15 females. The age of diagnosis was 0.5 (0.2, 1.0) year. There were 13 patients (35%) and 24 patients (65%) with mutations in CLCN7 and TCIRGI gene respectively. Patients in the CLCN7 group had an older age of diagnosis than those in the TCIRGI group (1.2 (0.4, 3.6) vs. 0.4 (0.2, 0.6) years, Z=-2.60, P=0.008). The levels of serum phosphorus (1.7 (1.3, 1.8) vs. 1.1 (0.8, 1.6) mmol/L, Z=-2.59, P=0.010), creatine kinase isoenzyme (CK-MB) (457 (143, 610) vs. 56 (37, 82) U/L, Z=-3.38, P=0.001) and the level of neutrophils (14.0 (9.9, 18.1) vs. 9.2 (6.7, 11.1) ×10⁹/L, Z=-2.07, P=0.039) at diagnosis were higher in the CLCN7 group than that in the TCIRG1 group. However, the level of D-dimer in the CLCN7 group was lower than that in the TCIRGI group (2.7 (1.0, 3.1) vs. 6.3 (2.5, 9.7) μg/L, Z=2.83, P=0.005). After hematopoietic stem cell transplantation, there was no significant difference in 5-year overall survival rate between the two groups (92.3%±7.4% vs. 83.3%±7.6%, χ²=0.56, P=0.456). Conclusions: TCIRGI gene mutations are more common in children with osteopetrosis. Children with TCIRGI gene mutations have younger age, lower levels of phosphorus, CK-MB, and neutrophils and higher level of D-dimer at the onset. After hematopoietic stem cell transplantation, patients with CLCN7 or TCIRGI gene mutations have similar prognosis.
Child ; Male ; Female ; Humans ; Osteopetrosis/therapy* ; Retrospective Studies ; Prognosis ; Genes, Recessive ; Phosphorus ; Chloride Channels/genetics* ; Vacuolar Proton-Translocating ATPases/genetics*

OBJECTIVE: To explore the clinical and genetic characteristics of a pediatric patient suspected for Autosomal Recessive Congenital Ichthyosis (ARCI). METHODS: Clinical data of the patient was analyzed. Peripheral blood samples were collected from the patient and his parents for the extraction of genomic DNA. Next-generation sequencing (NGS) was then carried out. Candidate variants were confirmed by Sanger sequencing. A variety of bioinformatic tools including Mutation Taster, PROVEAN, and PolyPhen2 were used to predict the pathogenicity of the variants based on guidelines from the American College of Medical Genetics and Genomics (ACMG). RESULTS: The patient, a 1-month-and-7-day-old male, had presented with cutaneous erythema and fine scaling of the whole body. NGS revealed that he has harbored compound heterozygous variants c.1579G>A (p.Val527Met) (paternal) and c.923T>C (p.Leu308Pro) (maternal) of the ALOX12B gene. The former was known to be likely pathogenic, while the latter was unreported previously and categorized as "likely pathogenic" based on the ACMG guidelines. Based on the clinical and genetic findings, the patient was diagnosed with ARCI. CONCLUSION The c.1579G>A and c.923T>C variants of the ALOX12B genes probably underlay the ARCI in this patient. Above finding has enriched the spectrum of ALOX12B mutations and enabled molecular diagnosis of the patient, based on which genetic counseling and prenatal diagnosis may be provided.
Arachidonate 12-Lipoxygenase/genetics* ; Child ; Female ; Genes, Recessive ; Genetic Testing ; High-Throughput Nucleotide Sequencing ; Humans ; Ichthyosis, Lamellar/genetics* ; Male ; Mutation ; Pregnancy

OBJECTIVE: To carry out genetic testing and prenatal diagnosis for a family affected with recessive dystrophic epidermolysis bullosa (RDEB). METHODS: All exons of the COL7A1 gene and their flanking regions were subjected to PCR and Sanger sequencing. Suspected variant was validated in family members, based on which prenatal diagnosis was provided. RESULTS: Sanger sequencing found that the proband has carried two variants of the COL7A1 gene, namely c.7289delC (p.Pro2430Glnfs*36) and c.7474C>T (p.Arg2492*), which were respectively derived from his mother and father. The same variants were not found among 100 healthy controls. By prenatal diagnosis, the fetus was found to have inherited the c.7474C>T (p.Arg2492*) variant from its father. CONCLUSION The pathogenic variants of the COL7A1 gene of the RDEB family were clarified, based on which prenatal diagnosis was provided.
Child ; Collagen Type VII ; genetics ; Epidermolysis Bullosa Dystrophica ; genetics ; Exons ; Female ; Genes, Recessive ; Genetic Testing ; Humans ; Male ; Mutation ; Pregnancy ; Prenatal Diagnosis ; Sequence Analysis, DNA

Wilson disease a rare autosomal recessive inherited disorder of copper metabolism, is characterized by excessive deposition of copper in the liver, brain, and other tissues. Wilson disease is often fatal if it is not recognized early and treated when it is symptomatic. Gitelman syndrome is also an autosomal recessive kidney disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. Hereditary sensory autonomic neuropathy type IV (HSAN-IV), a very rare condition that presents in infancy, is characterized by anhidrosis, absence of pain sensation, and self-mutilation. It is usually accompanied by developmental delay and mental retardation. We report a case of Wilson disease manifested as fulminant hepatitis, acute pancreatitis, and acute kidney injury in a 15-year-old boy comorbid with HSAN-IV and Gitelman syndrome. Such concurrence of three genetic diseases is an extremely rare case.
Acute Kidney Injury ; Adolescent ; Brain ; Calcium ; Copper ; Genes, Recessive ; Gitelman Syndrome ; Hepatitis ; Hepatolenticular Degeneration ; Humans ; Hydrogen-Ion Concentration ; Hypohidrosis ; Intellectual Disability ; Kidney ; Liver ; Magnesium ; Male ; Metabolism ; Pancreatitis ; Potassium ; Sensation

OBJECTIVE: To carry out mutation analysis for a Chinese family affected with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). METHODS: Whole exome sequencing (WES) was used to screen potential mutations within genomic DNA extracted from the proband. Suspected mutation was validated by combining clinical data and results of Sanger sequencing. RESULTS: A homozygous deletional mutation c.3665_3675delGTGCTGTCTTA (p.S1222fs) was found in the proband, for which her parents were both heterozygous carriers. CONCLUSION WES is capable of detecting mutation underlying this disorder and facilitating genetic counseling and prenatal diagnosis for the affected family. A novel pathogenic mutation of the SACS gene was discovered.
Female ; Genes, Recessive ; Heat-Shock Proteins ; genetics ; Humans ; Muscle Spasticity ; Mutation ; Spinocerebellar Ataxias ; congenital

Genes, Recessive ; Humans ; Nephritis, Hereditary ; diagnosis ; Nephrotic Syndrome ; diagnosis

Ellis-van Creveld (EvC) syndrome is a rare autosomal recessive malformation disorder. Cardiac defects are observed in about 50% of EvC cases. Surgical data is lacking on the prognosis and life expectancy of EvC patients. Herein, we report the case of a 38-year-old man with EvC syndrome who underwent two surgical corrections for cardiac anomalies. This report supplements the available information on the clinical course of EvC syndrome in older patients.
Adult ; Ellis-Van Creveld Syndrome ; diagnosis ; genetics ; surgery ; Genes, Recessive ; Hand Deformities ; complications ; Humans ; Life Expectancy ; Male ; Mitral Valve Insufficiency ; surgery ; Prognosis ; Quality of Life ; Tooth Abnormalities ; complications

OBJECTIVETo analyze the clinical features and gene mutation of Chinese children with Alport syndrome(AS).

METHODFrom May 2011 to May 2014, clinical and pathological information gathered from 25 patients was retrospectively analyzed. COL4A5, COL4A4 and COL4A3 genes were analyzed using next-generation sequencing in these patients, and gene mutations of related family members were identified by Sanger method.

RESULTOf these 25 cases, 19(76%) had X-linked Alport syndromes (XL-AS), 6 had autosomal recessive Alport syndromes (AR-AS). Twenty five patients had an onset of hematuria and proteinuria and in 8 cases the disease was induced by upper respiratory tract infections. Hearing loss was present in 2 of 25 (8%) cases and ocular lesions in 1 of 25 (4%). Renal pathology showed that 16 of them had minimal change disease (MCD), 8 mesangial proliferative glomerulonephritis (MsPNG), 1 focal segmental glomerulo-sclerosis (FSGS). Extensive lamination and split of glomerular basement membrane (GBM) dense layers were found in 2 (8%) of 25 patients. Twenty one of 25 patients (84%) showed abnormal renal α-chain distribution. COL4A5, COL4A4 and COL4A3 genes of 25 patients (23 families) were analyzed and 24 pathogenic mutations were identified: 18 in COL4A5, 1 in COL4A3 and 5 in COL4A4. It was observed that 13 patients inherited the mutation from the mother, 3 patients inherited from the father, 2 patients inherited 1 mutation from the mother and another mutation from the father, and 7 patients carried the novel mutations.

CONCLUSIONXL is the main inherited type in AS. Most of patients showed MCD and MsPNG in renal biopsy. This research examined 24 mutations and 16 mutations were not reported previously.

Child ; Deafness ; Genes, Recessive ; Genotype ; Hematuria ; Humans ; Kidney ; Mutation ; Nephritis, Hereditary ; genetics ; pathology ; Pedigree ; Phenotype

PURPOSE: Spinal and bulbar muscular atrophy (SBMA) is an X-linked motor neuron disease characterized by proximal muscle weakness, muscle atrophy, and fasciculation. Although SBMA is not uncommon in Korea, there is only one study reporting clinical characteristics and genotype-phenotype correlation in Korean patients. MATERIALS AND METHODS: In this study, age at the onset of symptoms, the score of severity assessed by impairment of activities of daily living milestones, and rate of disease progression, and their correlations with the number of CAG repeats in the androgen receptor (AR) gene, as well as possible correlations among clinical characteristics, were analyzed in 40 SBMA patients. RESULTS: The median ages at onset and at diagnosis were 44.5 and 52.5 years, respectively, and median interval between onset and diagnosis and median rate of disease progression were 5.0 years and 0.23 score/year, respectively. The median number of CAG repeats in the AR gene was 44 and the number of CAG repeats showed a significant inverse correlation with the age at onset of symptoms (r=-0.407, p=0.009). In addition, patients with early symptom onset had slower rate of disease progression. CONCLUSION: As a report with the largest and recent Korean cohort, this study demonstrates clinical features of Korean patients with SBMA and reaffirms the inverse correlation between the age at disease onset and the number of CAG repeats. Interestingly, this study shows a possibility that the rate of disease progression may be influenced by the age at onset of symptoms.
Activities of Daily Living ; Adult ; Age of Onset ; Asian Continental Ancestry Group/*genetics ; Bulbo-Spinal Atrophy, X-Linked/genetics/*physiopathology ; Disease Progression ; Female ; Genes, Recessive ; Genetic Association Studies ; Genotype ; Humans ; Male ; Middle Aged ; Muscle Weakness/*physiopathology ; Muscular Atrophy, Spinal ; Muscular Disorders, Atrophic/*genetics ; Phenotype ; Receptors, Androgen/*genetics ; Republic of Korea ; Trinucleotide Repeats/genetics

OBJECTIVETo analyze mutations in a pedigree of familial hemophagocytic lymphohistiocytosis (FHLH) from Sichuan and provide genetic counseling for the family.

METHODSClinical data of a case with FHLH diagnosed at West China Second Hospital was retrospectively analyzed. Genomic DNA was extracted from peripheral blood samples of the proband and his family members. Eight candidate genes for primary HLH were amplified with PCR and analyzed by direct sequencing.

RESULTSThe proband was diagnosed as HLH based on clinical manifestations of recurrent fever for 2 months, hepatosplenomegaly, lymphadenopathy, pancytopenia, hyperferritinemia, and decreased fibrinogen and hemophagocytosis in bone marrow. Genetic testing for primary HLH was carried out considering the relapse of illness after hormone therapy for 8 weeks and the family history. The results of gene sequencing showed that the proband has carried compound heterozygous mutations in PRF1 gene (c.1349C> T in exon 3 and c.445G> A in exon 2). His father has carried a heterozygous mutation (c.445G> A in exon 2) and nonsense mutation (c.900C> T in exon 3), and his mother carried a heterozygous mutation (c.1349C> T in exon 3). Both c.1349C> T and c.445G> A have been previously reported as pathogenic mutations.

CONCLUSIONThe family has been diagnosed as familial HLH type 2 based on clinical and laboratory examinations and molecular genetic testing. Gene sequencing has indicated that is was a recessive type familial HLH.

Base Sequence ; DNA Mutational Analysis ; Exons ; genetics ; Family Health ; Female ; Genes, Recessive ; genetics ; Genetic Predisposition to Disease ; genetics ; Heterozygote ; Humans ; Lymphohistiocytosis, Hemophagocytic ; diagnosis ; genetics ; Male ; Mutation ; Pedigree ; Perforin ; genetics ; Phenotype ; Polymerase Chain Reaction ; Retrospective Studies