OBJECTIVE: To explore the clinical characteristics and genetic basis for three children with Congenital chlorine diarrhea (CCD). METHODS: Three children with CCD who attended the Affiliated Children's Hospital of Capital Pediatric Institute from June 2014 to August 2020 were selected as the research subjects. Peripheral blood samples of the three children and their parents were collected for genetic testing. And the results were verified by Sanger sequencing. RESULTS: The clinical manifestations of the three children have included recurrent diarrhea, with various degrees of hypochloremia, hypokalemia and refractory metabolic alkalosis. Genetic testing revealed that the three children have all carried variants of the SLC26A3 gene, including homozygous c.1631T>A (p.I544N) variants, c.2063_1G>T and c.1039G>A (p.A347T) compound heterozygous variants, and c.270_271insAA(p.G91kfs*3) and c.2063_1G>T compound heterozygous variants. Sanger sequencing confirmed that all of the variants were inherited from their parents. CONCLUSION The variants of the SLC26A3 gene probably underlay the CCD in these children. Above finding has enriched the spectrum of SLC26A3 gene variants.
Humans ; Child ; Chlorine ; Genetic Testing ; Hypokalemia/genetics* ; Homozygote ; Diarrhea/genetics* ; Mutation

OBJECTIVE: To explore the clinical features and genetic etiology of a patient with primary distal renal tubular acidosis (dRTA). METHODS: A child who was diagnosed with primary dRTA at the Xi'an Children's Hospital in April 2021 due to poor appetite and persistent crying was selected as the study subject. Clinical data of the patient was collected. Whole exome sequencing (WES) was carried out for the child. Candidate variants were validated by Sanger sequencing of his family members. RESULTS: The child, a 1-month-and-18-day male, had featured poor appetite, persistent crying, poor weight gain and dehydration. Laboratory examination has suggested metabolic acidosis, hyperchloremia, hypokalemia, abnormal alkaline urine and anemia. Ultrasonographic examination of the urinary system revealed calcium deposition in renal medulla. DNA sequencing revealed that he has harbored compound heterozygous variants of the ATP6V0A4 gene, namely c.1363dupA (p.M455NfsX14) and c.2257C>T (p.Q753X), which were respectively inherited from his father and mother. Based on the guidelines from the American College of Medical Genetics and Genomics, both variants were classified as pathogenic (PVS1+PM3+PM2_Supporting). CONCLUSION The compound heterozygous variants of c.1363dupA (p.M455NfsX14) and c.2257C>T (p.Q753X) of the ATP6V0A4 gene probably underlay the pathogenesis of primary dRTA in this patient. Discovery of the c.2257C>T (p.Q753X) variant has also expanded the mutational spectrum of the ATP6V0A4 gene.
Humans ; Male ; Acidosis, Renal Tubular/genetics* ; Family ; Genomics ; Hypokalemia ; Infant

OBJECTIVE: To report the clinical and genetic characteristics of a rare case of Gitelman syndrome with comorbid Graves disease and ACTH-independent adrenocortical adenoma. METHODS: A patient who had presented at the Nanchong Central Hospital on December 21, 2020 was selected as the study subject. Clinical data of the patient was collected. Whole-exome sequencing was carried out on DNA extracted from peripheral venous blood samples from the patient and her family members. RESULTS: The patient, a 45-year-old woman, was found to have Graves disease, ACTH-independent Cushing syndrome, hypokalemia and hypomagnesemia following the discovery of an adrenal incidentaloma. MRI scan had revealed a 3.8 cm × 3.2 cm mass in the left adrenal gland. The mass was removed by surgery and confirmed as adrenocortical adenoma. DNA sequencing revealed that the patient and her sister have both harbored compound heterozygous variants of the SLC12A3 gene, namely c.1444-10(IVS11)G>A and c.179(exon1)C>T (p.T60M), which were respectively inherited from their father and mother. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.1444-10(IVS11)G>A and c.179(exon1)C>T (p.T60M) were respectively classified as a variant of uncertain significance (PM2_Supporting+PP3) and a likely pathogenic variant (PM3_Strong+PM1+PP3). CONCLUSION The conjunction of Gitelman syndrome with Graves disease and adrenal cortex adenoma is rather rare. The newly discovered c.1444-10(IVS11)G>A variant of the SLC12A3 gene, together with the heterozygous variant of c.179(exon1)C>T (p.T60M), probably underlay the pathogenesis in this patient.
Humans ; Female ; Middle Aged ; Gitelman Syndrome/genetics* ; Adrenocortical Adenoma ; Hypokalemia ; Graves Disease/genetics* ; Mothers ; Mutation ; Solute Carrier Family 12, Member 3

Pseudohypoparayhyroidism (PHP) is a rare autosomal dominant or recessive genetic disorder characterized by low calcium, high phosphorus, and target organ resistance to parathyroid. The clinical characteristics and genetic features in 4 patients with Type Ib PHP in the Third Xiangya Hospital, Central South University, have been reviewed. All 4 patients had low calcium, high phosphorus, and parathyroid resistance. Among them, 2 patients had slightly elevated thyroid stimulating hormone and mild features of Albright's hereditary osteodystrophy, and one patient had hypokalemia. No guanine nucleotide-binding protein alpha-stimulating activity polypeptide 1 (GNAS) and gene variant associated with hypokalemia were identified using the whole exome sequencing. The results of the methylation-specific multiple ligation-dependent probe amplification showed that there were abnormal methylation of the upstream differentially methylated regions of GNAS in the 4 patients. There were phenotype overlap among the various subtypes of PHP. Detection of GNAS gene methylation in patients with clinical suspicion of Type Ib PHP is helpful for the diagnosis and treatment of PHP.
Humans ; Chromogranins/genetics* ; GTP-Binding Protein alpha Subunits, Gs/genetics* ; Hypokalemia ; Calcium ; Pseudohypoparathyroidism/genetics* ; Phosphorus

OBJECTIVE: To summarize clinical manifestations and results of genetic testing in 12 children with Gitelman syndrome (GS). METHODS: Clinical data of the children was collected. Whole exome sequencing(WES) was carried out to screen potential variants of genomic DNA. Candidate variants were verified by Sanger sequencing. RESULTS: The patients have included 10 boys and 2 girls, whom were diagnosed at between 2.8 to 15.0 year old. Six patients were due to infections, 5 were due to short stature, and 1 was due to lower limb weakness. All patients were found to carry variants of SLC12A3 gene, which included 11 with compound heterozygous variants and 1 with homozygous variant. All of the 19 alleles of the SLC12A3 gene carried by the patients were delineated, which included 15 missense variants, 2 frameshift variants and 2 splice region variants. These variants were unreported previously, which included c.578_582dupCCACC (p.Asn195Profs*109), c.251C>T (p.Pro84Leu) and c.2843G>A (p.Trp948X). CONCLUSION The clinical symptoms of GS in children are atypical and often seen in older children. For children with occasional hypokalemia associated with growth failure, GS should be suspected. The majority of GS children carry two pathogenic variants of the SLC12A3 gene, mainly compound heterozygotes, among which p.Thr60Met is the most common one. The discovery of new variants has enriched the spectrum of SLC12A3 gene variants.
Adolescent ; Child ; Child, Preschool ; DNA ; Female ; Genetic Testing ; Gitelman Syndrome/genetics* ; Humans ; Hypokalemia/genetics* ; Male ; Solute Carrier Family 12, Member 3/genetics*

A boy, aged 1 year and 6 months, was found to have persistent positive urine glucose at the age of 4 months, with polydipsia, polyuria, and growth retardation. Laboratory examinations suggested that the boy had low specific weight urine, anemia, hypokalemia, hyponatremia, hypomagnesemia, metabolic acidosis, glycosuria, acidaminuria, increased fractional excretion of potassium, and decreased tubular reabsorption of phosphate. X-ray examinations of the head, thorax, and right hand showed changes of renal rickets. The slit-lamp examination showed a large number of cystine crystals in the cornea. The genetic testing showed a suspected pathogenic homozygous mutation of the
Amino Acid Transport Systems, Neutral/genetics* ; Cornea ; Cystinosis/genetics* ; Humans ; Hypokalemia ; Infant ; Male ; Mutation ; Rare Diseases

Cystic fibrosis (CF) is a fatal autosomal-recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CF is characterized by recurrent pulmonary infection with obstructive pulmonary disease. CF is common in the Caucasian population but is rare in the Chinese population. The symptoms of early-stage CF are often untypical and may sometimes manifest as Bartter syndrome (BS)-like hypokalemic alkalosis. Therefore, the ability of doctors to differentiate CF from BS-like hypokalemic alkalosis in Chinese infants is a great challenge in the timely and accurate diagnosis of CF. In China, sporadic CF has not been diagnosed in children younger than three years of age to date. Three infants, who were initially admitted to our hospital over the period of June 2013 to September 2014 with BS-like hypokalemic alkalosis, were diagnosed with CF through exome sequencing and sweat chloride measurement. The compound heterozygous mutations of the CFTR gene were detected in two infants, and a homozygous missense mutation was found in one infant. Among the six identified mutations, two are novel point mutations (c.1526G > C and c.3062C > T) that are possibly pathogenic. The three infants are the youngest Chinese patients to have been diagnosed with sporadic CF at a very early stage. Follow-up examination showed that all of the cases remained symptom-free after early intervention, indicating the potential benefit of very early diagnosis and timely intervention in children with CF. Our results demonstrate the necessity of distinguishing CF from BS in Chinese infants with hypokalemic alkalosis and the significant diagnostic value of powerful exome sequencing for rare genetic diseases. Furthermore, our findings expand the CFTR mutation spectrum associated with CF.
Alkalosis ; complications ; Bartter Syndrome ; China ; Cystic Fibrosis ; diagnosis ; genetics ; Cystic Fibrosis Transmembrane Conductance Regulator ; genetics ; Diagnosis, Differential ; Exome ; Female ; Humans ; Hypokalemia ; complications ; Infant ; Male ; Mutation

Gitelman's syndrome (GS) is caused by loss-of-function mutations in SLC12A3 and characterized by hypokalemic metabolic alkalosis, hypocalciuria, and hypomagnesemia. Long-term prognosis and the role of gene diagnosis in GS are still unclear. To investigate genotype-phenotype correlation in GS and Gitelman-like syndrome, we enrolled 34 patients who showed hypokalemic metabolic alkalosis without secondary causes. Mutation analysis of SLC12A3 and CLCNKB was performed. Thirty-one patients had mutations in SLC12A3, 5 patients in CLCNKB, and 2 patients in both genes. There was no significant difference between male and female in clinical manifestations at the time of presentation, except for early onset of symptoms in males and more profound hypokalemia in females. We identified 10 novel mutations in SLC12A3 and 4 in CLCNKB. Compared with those with CLCNKB mutations, patients with SLC12A3 mutations were characterized by more consistent hypocalciuria and hypomagnesemia. Patients with 2 mutant SLC12A3 alleles, compared with those with 1 mutant allele, did not have more severe clinical and laboratory findings except for lower plasma magnesium concentrations. Male and female patients did not differ in their requirement for electrolyte replacements. Two patients with concomitant SLC12A3 and CLCNKB mutations had early-onset severe symptoms and showed different response to treatment. Hypocalciuria and hypomagnesemia are useful markers in differentiation of GS and classical Bartter's syndrome. Gender, genotypes or the number of SLC12A3 mutant alleles cannot predict the severity of disease or response to treatment.
Adolescent ; Adult ; Alleles ; Bartter Syndrome/genetics/pathology ; Chloride Channels/*genetics ; DNA Mutational Analysis ; Female ; Genetic Association Studies ; Genotype ; Gitelman Syndrome/*genetics/pathology ; Humans ; Hypokalemia/etiology ; Male ; Middle Aged ; Phenotype ; Polymorphism, Genetic ; Solute Carrier Family 12, Member 3/genetics ; Young Adult

Congenital adrenal hyperplasia is an uncommon diagnosis in routine clinical practice. 21-hydroxylase deficiency, which is its most common subtype, may be diagnosed at birth in a female infant by virilisation or by features of salt wasting in both genders. However, other uncommon subtypes of this condition such as 17-alpha-hydroxylase deficiency, 11-beta-hydroxylase deficiency may present much later in adolescence or adulthood. A high index of suspicion is necessary when evaluating children with hypertension, hypokalaemia, metabolic alkalosis or sexual infantilism.
Adolescent ; Adrenal Hyperplasia, Congenital ; diagnosis ; genetics ; Alkalosis ; diagnosis ; Diagnosis, Differential ; Female ; Humans ; Hypertension ; diagnosis ; Hypokalemia ; diagnosis ; Models, Biological ; Paralysis ; diagnosis ; Sexual Infantilism ; diagnosis ; Steroid 21-Hydroxylase ; metabolism

OBJECTIVETo investigate the clinical and genetic characteristics of 7 patients from 5 families with 17a-hydroxylase/17,20 lyase deficiency (17OHD) and the CYP17A1 mutation in Chinese.

METHODSClinical features and laboratory data were collected from 5 families with 17OHD. PCR direct sequencing was performed to screen the mutation of CYP17A1 gene of the patients. Polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) and sequencing were performed to screen the mutations of CYP17A1 gene in 288 healthy individuals from Shandong province.

RESULTSSeven patients (5 of them were 46,XX; 2 were 46,XY) had typical clinical presentation of sexual infantilism, hypertension and hypokalemia. Hormone profile indicated decreased plasma cortisol and sex hormones, and elevated blood adrenocorticotrophic hormone (ACTH). TAC329AA and H373L in exon 6 and D487_F489del in exon 8 were identified from the patients. One heterozygote for D487_F489del was identified in 288 healthy controls.

CONCLUSIONThe TAC329AA and D487_F489del of the CYP17A1 gene were the most frequent mutations in Chinese with 17OHD.There might be certain frequency of heterozygotes for D487_F489del in Chinese population.

Adolescent ; Adult ; Asian Continental Ancestry Group ; genetics ; Exons ; Female ; Gene Frequency ; Humans ; Hypertension ; genetics ; Hypokalemia ; genetics ; Male ; Middle Aged ; Molecular Sequence Data ; Mutation ; Pedigree ; Polymerase Chain Reaction ; Sequence Analysis, DNA ; Sexual Infantilism ; genetics ; metabolism ; Steroid 17-alpha-Hydroxylase ; genetics ; metabolism ; Steroid 21-Hydroxylase ; genetics ; metabolism ; Young Adult