Here, we report the clinical observations of two Chinese fraternal twins who presented with severe dehydration, poor feeding, and absence of stimuli responses within a few days of birth. Trio clinical exome sequencing of the family identified compound heterozygous intronic variants (c.1439+1G>C and c.875+1G>A) in SCNN1A gene in these two patients. Sanger sequencing results showed that the c.1439+1G>C variant was inherited from the mother, and c.875+1G>A from the father, rarely reported in pseudohypoaldosteronism type 1 with sodium epithelial channel destruction (PHA1b) patients. Case 2 received timely symptomatic treatment and management after obtaining these results, which improved the clinical crisis. Our results suggest that the compound heterozygous splicing variants in SCNN1A were responsible for PHA1b in these Chinese fraternal twins. This finding extends the knowledge of the variant spectrum in PHA1b patients and highlights the application of exome sequencing in critically ill newborns. Finally, we discuss supportive case management, particularly in maintaining blood potassium concentration.
Case Report • Arch. Endocrinol. Metab. 67
(4)
• 2023 • https://doi.org/10.20945/2359-3997000000620 linkcopy
Pseudohypoaldosteronism type 1b in fraternal twins of a Chinese family: report of two cases and literature review
Authorship
person Zhen Gao
interpreted the data and wrote the manuscript
schoolDepartment of Neonatology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaShanghai Jiao Tong UniversityChinaShanghai, ChinaDepartment of Neonatology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
person Jingjing Sun
collected clinical information and provided genetic counseling · provided patient samples and determined the phenotype based on the clinical presentation
schoolDepartment of Neonatology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaShanghai Jiao Tong UniversityChinaShanghai, ChinaDepartment of Neonatology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaschoolNHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai, ChinaShanghai Key Laboratory of Embryo and Reproduction EngineeringChinaShanghai, ChinaNHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai, China
person Cheng Cai
collected clinical information and provided genetic counseling
schoolDepartment of Neonatology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaShanghai Jiao Tong UniversityChinaShanghai, ChinaDepartment of Neonatology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaschoolNHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai, ChinaShanghai Key Laboratory of Embryo and Reproduction EngineeringChinaShanghai, ChinaNHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai, China
person Xiaohui Gong
designed the study and revised the manuscript
schoolDepartment of Neonatology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaShanghai Jiao Tong UniversityChinaShanghai, ChinaDepartment of Neonatology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaschoolNHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai, ChinaShanghai Key Laboratory of Embryo and Reproduction EngineeringChinaShanghai, ChinaNHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai, China
provided patient samples and determined the phenotype based on the clinical presentation · designed the study and revised the manuscript
schoolDepartment of Neonatology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaShanghai Jiao Tong UniversityChinaShanghai, ChinaDepartment of Neonatology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaschoolNHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai, ChinaShanghai Key Laboratory of Embryo and Reproduction EngineeringChinaShanghai, ChinaNHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai, China
Disclosure: no potential conflict of interest relevant to this article was reported.
SCIMAGO INSTITUTIONS RANKINGS
Department of Neonatology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaShanghai Jiao Tong UniversityChinaShanghai, ChinaDepartment of Neonatology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
NHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai, ChinaShanghai Key Laboratory of Embryo and Reproduction EngineeringChinaShanghai, ChinaNHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai, China
Figures | Tables
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imageFigure 1 Serum potassium levels of case 2 during the first hospitalization. open_in_new
imageFigure S1 Timeline of case 2. open_in_new
imageFigure 2 Genetic findings. ( A ) Pedigree of the family with segregation of the identified SCNN1A variants. The squares represent males, and circles represent females. The filled symbols indicate the affected individuals. ( B ) Sanger sequencing verification results. Black arrows indicate the point variants. open_in_new
imageFigure 3 Distribution of variants by location and type. ( A ) Schematic diagrams showing the structure of SCNN1A A schematic view of the location of PHA1b-related variants in the SCNN1A gene. The underlined variants are the variants reported in this study. red: pathogenic and likely pathogenic variants; black: VUS (variants of uncertain significance); green: likely benign and benign variants. ( B ) Classification of SCNN1A variants associated with PHA1b open_in_new
table_chartTable 1
Clinical, biochemical, and endocrine profiles of Chinese twins with a systemic form of PHA1
| Patients | Case 1 | Case 2 | Reference range |
|---|---|---|---|
| Sex | Female | Male | |
| Birth | Term | Term | |
| Birth weight (g) | 2.800 | 3.100 | |
| Consanguinity of family history | No | No | |
| Day of onset | 8 | 9 | |
| Primary symptoms | Poor response, refusing milk Heterozygous intronic missense mutations in SCNN1A c.1439+1G>C and c.875+1G>A | Poor response, refusing milk Heterozygous intronic missense mutations in SCNN1A c.1439+1G>C and c.875+1G>A | |
| Serum HCO3 (mmol/L) | 12.9 | 11.3 | 18-23 |
| Serum Creatine (μmol/L) | 67 | 87 | 27-66 |
| Serum Sodium (mmol/L) | 117 | 127 | 136-145 |
| Serum Potassium (mmol/L) | 10.4 | 10.1 | 3.5-5.2 |
| PH | 7.09 | 7.06 | 7.33-7.49 |
| BE (mmol/L) | -15.8 | -26.7 | -3-3 |
| Lactose (mmol/L) | 11.4 | 9.7 | 0.5-2.2 |
| Aldosterone (ng/L) | >2000 | 1337.18 | 59.5-173.9 |
| Plasma renin activity (μg/dL/h) | N/A | 9.47 | 0-15 |
| ACTH (pmol/L) 8am | 3.75 | 8.5 | 1.59-14 |
| Cortisol (nmol/L) | 671.86 | 348.03 | 185.00-624.00 |
| Renal ultrasound | Normal | Normal | |
| Testosterone (nmol/L) | 3.87 | 4.82 | |
| 17-OHP(ng/mL) | 7.8 | 9.27 | 0-11 |
| Management | When discharged from hospital, he was intake with 10% NaCl at 10 mEq/kg/d and ionexchange resins at 1 g/kg/d | ||
| Complication | Died on day 2 of admitted in hospital due to cardiac arrest | Died at 5 months after birth due to cardiac arrest |
table_chartTable S1
The list of all reported mutants in SCNN1A related to PHA1 systemic type
| Variant | AA change | Classification | Exon/intron | |
|---|---|---|---|---|
| 1 | c.-55+2T>C | p.? | VUS | 1st Intron |
| 2 | c.107C>T | p.(Ala36Val) | likely benign | 2nd Exon |
| 3 | c.166C>T | p.(Arg56*) | pathogenic | 2nd Exon |
| 4 | c.189C>A | p.(Cys63*) | pathogenic | 2nd Exon |
| 5 | c.203_204del | p.(Ile68Thrfs*76) | pathogenic | 2nd Exon |
| 6 | c.206A>G | p.(His69Arg) | pathogenic | 2nd Exon |
| 7 | c.217C>T | p.(Arg73Cys) | pathogenic | 2nd Exon |
| 8 | c.301C>A | p.(Gln101Lys) | pathogenic | 2nd Exon |
| 9 | c.416G>A | p.(Arg139Lys) | pathogenic | 2nd Exon |
| 10 | c.505_506del | p.(Thr169Serfs*36) | pathogenic | 3rd Exon |
| 11 | c.540G>T | p.(Leu180=) | benign | 3rd Exon |
| 12 | c.587dup | p.(Pro197Alafs*9) | pathogenic | 3rd Exon |
| 13 | c.598dup | p.(Ala200Glyfs*6) | pathogenic | 3rd Exon |
| 14 | c.684+2T>A | p.? | pathogenic | 3rd Intron |
| 15 | c.727T>C | p.(Ser243Pro) | pathogenic | 4th Exon |
| 16 | c.729del | p.(Val245Trpfs*4) | pathogenic | 4th Exon |
| 17 | c.742del | p.(Val248*) | pathogenic | 4th Exon |
| 18 | c.814dup | p.(Glu272Glyfs*39) | pathogenic | 4th Exon |
| 19 | c.875+1C>A | p.? | Likely pathogenic | 4th Intron |
| 20 | c.875+2dup | p.? | pathogenic | 4th Intron |
| 21 | c.979G>T | p.(Gly327Cys) | pathogenic | 5th Exon |
| 22 | c.997C>T | p.(Arg333Cys) | VUS | 5th Exon |
| 23 | c.1000G>A | p.(Ala334Thr) | benign | 6th Exon |
| 24 | c.1305del | p.(Tyr436Ilefs*46) | pathogenic | 8th Exon |
| 25 | c.1311del | p.(Arg438Glyfs*44) | pathogenic | 8th Exon |
| 26 | c.1339dup | p.(Tyr447Leufs*13) | pathogenic | 8th Exon |
| 27 | c.1344_1347dup | p.(His450Lysfs*11) | pathogenic | 8th Exom |
| 28 | c.1356del | p.(Trp453Glyfs*29) | pathogenic | 8th Exon |
| 29 | c.1358G>T | p.(Trp453Leu) | VUS | 8th Exon |
| 30 | c.1360+1G>T | p.? | pathogenic | 8th Intron |
| 31 | c.1361-2A>G | p.? | Pathogenic | 8th Intron |
| 32 | c.1435T>C | p.(Cys479Arg) | VUS | 9th Exon |
| 33 | c.1439+1G>C | p.? | Pathogenic | 9th Intron |
| 34 | c.1449del | p.(Tyr484Thrfs*13) | pathogenic | 10th Exon |
| 35 | c.1474C>T | p.(Arg492*) | pathogenic | 10th Exon |
| 36 | c.1477T>C | p.(Trp493Arg) | benign | 10th Exon |
| 37 | c.1522C>T | p.(Arg508*) | pathogenic | 11th Exon |
| 38 | c.1582_1584del | p.(Phe528del) | pathogenic | 12th Exon |
| 39 | c.1678G>A | p.(Gly560Ser) | pathogenic | 13th Exon |
| 40 | c.1684T>C | p.(Ser562Pro) | pathogenic | 13th Exon |
| 41 | c.1685C>T | p.(Ser562Leu) | pathogenic | 13th Exon |
| 42 | c.1772G>A | p.(Arg591Gln) | VUS | 13th Exon |
| 43 | c.1978A>G | p.(Ser660Gly) | likely benign | 13th Exon |
| 44 | c.1987A>G | p.(Thr663Ala) | benign | 13th Exon |
| 45 | c.2004dup | p.(Pro669AlafsTer62) | VUS | 13th Exon |
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