Clinical Manifestations of Pseudohypoaldosteronism with Genotype-phenotype Correlation. A Single Center Experience, A Retrospective Cohort Study.

Clinical Manifestations of Pseudohypoaldosteronism with Genotype-phenotype Correlation. A Single Center Experience, A Retrospective Cohort Study. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical Manifestations of Pseudohypoaldosteronism with Genotype-phenotype Correlation. A Single Center Experience, A Retrospective Cohort Study. Bassam Bin-Abbas, Alhanouf Aljaser, Afaf AlSagheir, Faisal Joueidi, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4102368/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Pseudohypoaldosteronism (PHA) is a rare endocrine disorder characterized by unresponsiveness, multi-organ involvement affecting sodium salt wasting, poor renal excretion, and severe volume depletion resulting in electrolyte imbalance (hyponatremia, hyperkalaemia, and metabolic acidosis) and further classified into type 1 and 2. Ali et al. reported that PHA1b geno-phenotype correlation has not been well described. As such, in our study, we propose how the clinical behaviour of this subtype can be predictable. Moreover, the diagnosis of any of the PHA types is made by the clinical presentation and laboratory findings during a clinical suspicion setting. Methods: A descriptive retrospective study includes 22 patients diagnosed with PHA during 2023 in the endocrine subdivision of paediatric service in KFSHRC. The informed consent was obtained from either the patients or their guardians. Results: Of a total of 22 patients, ages ranged between 3 days to 2 years at presentation, 95% of them presented with vomiting, 63.3% had respiratory symptoms, 50% had hypotension 31% had dermatitis, and 31% had polyurea, 27% had HTN, 22% had UTI only one patient had arrhythmia, none of them had gallstone. Labs were Lowest Na; 110–132 Lowest Cl: 81–108 Lowest HCO3: 10–18 Highest K: 5.5-8 Aldosterone: 7510 − 1659, half of the patient did not do Aldosterone level. Renin: 50–751 Number of admissions: range from 0 to 20 times. Treatment: NaCl dose range (2-480 meq/kg/day) NaHCO3 (1–34 meq/kg/day) Kayexalate (0.5–45 g/kg/day) One patient needed a gastrostomy tube. One patient was off treatment at the age of 6 years. Severity at presentation ranges from very severe to 4 severe, Then improved with age to range between very mild to moderate. Discussion: PHA1a has a heterogeneous inactivating mutation in the NR3C2 gene; it encodes for a mineralocorticoid receptor responsible for aldosterone binding. Therefore, mutations are associated with a phenotype restricted to the kidneys. As a course, this disease has an early life onset, which is almost always in the neonatal period, presenting with fever, feeding difficulties, nausea, vomiting, weight loss, recurrent pulmonary infection, and sudden cardiac arrest alongside laboratory findings in the form of electrolyte imbalance which includes hyponatremia, hyperkalaemia and salt wasting with elevated plasma renin and aldosterone levels. On the other hand, PHA1b is multi-systemic and mainly caused by mutations in the ENaC channel, affecting sodium reabsorption in the body. It manifests in the first week of life with electrolyte imbalance with nonspecific symptoms such as nausea and vomiting alongside hypotension, with salt-wasting episodes. It has been demonstrated that PHA1b usually presents with a more severe clinical phenotype than PHA1a. Furthermore, complications with the PHA1b subtype are more prone to develop. Conclusion: PHA is a rare genetic endocrine disorder that needs awareness by the endocrinologist of its existence. It is a clinical diagnosis that requires monitoring, follow-up, and close observation of affected patients. Hence, this is because pheno-genotype correlation is an expandable process in the endocrine medical literature. Our single-centre experience gives an insight into the predictable clinical behaviour of this under-diagnosed condition to improve further the physicians related to the paediatric population's understanding of the PHA natural course. Also, to have a better provisional plan and management care for affected individuals to increase the likelihood of a better prognosis further, better quality of life, and survival. Introduction Pseudohypoaldosteronism (PHA) was first described by Cheek and Perry in 1958 as a rare aldosterone unresponsiveness that is characterized by multi-organ involvement affecting sodium salt wasting, poor renal excretion, and severe volume depletion resulting in hyponatremia, hyperkalaemia, and metabolic acidosis [ 1 , 2 ]. In such cases, it can be acquired. However, it is most commonly an inherited condition. The incidence rate of autosomal dominant Pseudohypoaldosteronism (PHA) was estimated to be 1:47,000, whereas autosomal recessive PHA was estimated to be 1:66,000 [ 3 ]. Classification-wise, pseudohypoaldosteronism (PHA) is classified into type 1 and type 2. Furthermore, Type 1 PHA is classified further into two subtypes based on their genetic mode of inheritance [ 3 ]. The diagnosis of PHA is made via laboratory and radiological investigations that include plasma renin activity, cortisol levels, aldosterone, 17 OHP, and renal ultrasound [ 3 ]. Methodology A descriptive retrospective study that includes a total of 22 patients diagnosed with PHA during the period of 2023 in the endocrine subdivision of paediatric service in KFSHRC. Informed consent was obtained from the patients. The data was then summarised into an Excel sheet and incorporated into SPSS for systemic analysis. The study was approved by the Institutional Review Board of the King Faisal Specialist Hospital & Research Centre (KFSHRC), Riyadh, Saudi Arabia. Results The study included a total number of 22 patients, with ages ranging between 3 days to 2 years at presentation. The clinical manifestations of the patients presented as follows: 95% presented with vomiting, 63.3% had respiratory symptoms, 50% had hypotension, 31% had dermatitis, 31% had polyurea, 27% had hypertension, 22% had urinary tract infection (UTI), and only one patient had arrhythmia. Laboratory investigations showed: Lowest sodium (Na), 110–132; Lowest chloride (Cl): 81–108; Lowest HCO3: 10–18; Highest potassium: 5.5–8 Aldosterone: 7510 − 1659, half of the patient did not do Aldosterone level. Renin: 50–751 Number of admissions: range from 0 to 20 times. The management includes a sodium chloride dose of 2-480 meq/kg/day, sodium bicarbonate (NaHCO3) of 1–34 meq/kg/day, and Kayexalate 0.5–45 g/kg/day. One patient needed a gastrostomy tube, and one patient was off treatment at the age of 6 years. Severity at presentation ranges from very severe to severe, then improved with age to range between very mild to moderate. Discussion Renal PHA 1 (PHA1a) is an autosomal dominant inherited disorder with a heterogeneous NR3C2 gene mutation characterized by an inactivating mutation [ 2 , 4 ]. This gene encodes for mineralocorticoid receptors that can result in the absence of binding the aldosterone to the receptor with a phenotypic expression restricted to the kidney [ 3 , 5 ]. Renal PHA1 (PHA1a) clinically manifests in early life, particularly during the neonatal period, with fever, feeding difficulties, nausea, vomiting, weight loss, recurrent pulmonary infection, and sudden cardiac arrest [ 6 ]. Furthermore, it is mainly characterized by hyponatremia, hyperkalaemia, and salt wasting with elevated plasma renin and aldosterone levels [ 6 ]. The mechanism of hyperaldosteronism and hyperreninemia is associated with a decrease in extracellular fluid volume rather than peripheral mineralocorticoid resistance [ 6 ]. Whereas systemic PHA 1 (PHA1b) is an autosomal recessive inheritance pattern that involves multiple organs and is mainly caused by mutation of the epithelial sodium channel (ENaC) that affects the distal convoluted tubules and the collecting ducts [ 3 , 7 ]. The role of the ENaC channel in transporting sodium can affect several other organs containing this channel, including the lungs, kidneys, colon, and salivatory glands [ 3 ]. Furthermore, many factors can affect sodium reabsorption in the distal tubule, such as prematurity, infection, and unknown gene function [ 4 ]. PHA1b occurs in the first week of life and manifests with electrolyte imbalances such as hyperkalaemia and metabolic acidosis alongside nausea, vomiting, and hypotension with salt-wasting episodes after birth [ 3 , 7 ]. However, symptoms are usually severe and persistent to adulthood [ 3 ]. Systemic PHA 1 can also present with cutaneous and ocular manifestations [ 8 ]. Cutaneous manifestations include miliaria rubra-like rash, atopic dermatitis, and pustules [ 8 , 9 ]. The postulated mechanism of miliaria rubra is that increased sodium chloride concentration in sweat damages the eccrine ducts because of the mutation of the ENaC channel [ 8 ]. Studies showed that PHA1b usually presents with a more severe clinical phenotype than PHA1a [ 6 ]. Complication-wise, the PHA1b is more prone to develop complications such as infections, which were more common, including recurrent tonsillitis, femoral head osteomyelitis, and recurrent respiratory tract infections requiring long-term observation [ 9 ]. In the literature, there have been cases reported in different articles. Here, we try to summarise them further to delineate our discoveries for comparison with the earlier cases. A study by Attia and Marzouki reported a case of severe hyponatremia and hyperkalaemia who developed cardiac arrest and was found to develop PHA later in life [ 7 ]. Su Jin Kim reported a 20-day-old girl who was born at 38 weeks’ gestation via C-section and presented with a complaint of poor oral intake and lethargy. Dysmorphism was revealed on physical examination in the form of frontal bossing, frontal scalp hair, permanent upper lip, high arch palate, and bilateral fifth digit clinodactyly. Laboratory investigations showed elevated plasma renin activity and serum aldosterone to 142.0 ng/mL/h. Renal ultrasonography revealed mild hydronephrosis in the right kidney. Accordingly, the patient received IV fluid and 60 ml of 3% sodium chloride [ 4 ]. Hanukoglu et al. reported in a family study spanning 40 years that even families with the same mutation had different clinical manifestations and renin/aldosterone levels [ 4 ]. Alshaikh reported that two Omani siblings presented in the first week with complaints of nausea and vomiting [10]. Laboratory investigations showed hyperkalaemia, hypotension, and metabolic acidosis [10]. WES test confirmed the presence of SCNN1A gene mutation (c.385G > A, p.Gly129Ser) [10].N. Amin reported a total of 6 cases with the diagnosis of PHA confirmed via clinical and biochemical results. Cayrin et al. reported 3 cases of PHA 1b with four existing novel variants in SCNN1A and SCNNA1B with two novel pathogenic variants SCNN1B (c.87C > A[p.Tyr29*]/IVS9 + 1G > A [c.1346 + 1G > A]), SCNN1A (p.His69Arg [c.206A > G]). They concluded that missense mutations are documented in a few cases with a milder disease phenotype [10]. Hanokugolu et al. reported 4 PHA 1b patients with a heterozygous mutation of (Gly327Cys) with monoallelic missense mutation combined with nonsense mutation [10]. Managing PHA requires monitoring serum electrolytes and tailoring treatment; this includes low potassium diet, high-volume supplements, and potassium binders [ 8 ]. Also, a gastrostomy tube can be used in patients with systemic PHA1 with poor oral intake [ 8 ]. Dirlewanger et al. reported a homozygous missense mutation in SCNNA1 (Ser243Pro) encoding α-ENaC of a preterm baby whose sodium requirements decreased rapidly with age. They were stopped at the age of 9 months [ 9 ]. The mortality rate is considered high during the neonatal period and often requires prolonged hospitalization [ 1 ]. Neonatal salt wasting can reduce the function of epithelium sodium channels secondary to variable sodium channel gene mutations, including SCNN1A, SCNN1B, and SCNN1G, which can pose a significant life-threatening sequela [ 2 ]. Studies showed that patients with the gene-structured disrupted mutation, including gross deletion, deletion with frameshift and truncation, and nonsense mutation, can interfere with the normal function of the encoded protein subunit of SCNN1A and tend to develop severe phenotype form of PHA at the onset of diagnosis with less improvement over-time. However, missense mutations of SCNN1A SCNN1B can experience milder phenotypes [7,10]. In our study, 22 patients between 3 days and two years were diagnosed with Pseudohypoaldosteronism (PHA). The number of admission ranges from 0–20 times. Of these patients, 95% had vomiting, 63.3% had respiratory symptoms, 50% had hypotension, 31% had dermatitis, 31% had polyurea, 27% had hypertension, 22% had urinary tract infection (UTI), and arrhythmia. Laboratory investigations showed hyperkalaemia (5.5-8) hyponatremia (110–132), hypochloraemia (81–108), and renin levels of 50–751. Accordingly, the patients received sodium chloride (2-480 meq/kg/day), sodium bicarbonate (1–34 meq/kg/day), kayexalate (0.5–45 g/kg/day), one patient underwent gastrostomy tube, one patient stopped treatment at the age of 6 years. The severity of cases at presentation ranges between mild to moderate. Conclusion In final remarks, PHA is a rare genetic endocrine disorder that needs endocrinologists to be aware of its existence as it is a clinical diagnosis entity that requires close monitoring of affected patients due to the fact that the clinical pheno-genotype correlation is still an expandable process in the medical literature. Our single-centre experience tries to shed light on the possible clinical behaviour of this under-diagnosed disorder further to strengthen our understanding of the natural course of PHA. Also, having a better plan and management in the care of diagnosed individuals will further increase the likelihood of a better prognosis. Declarations Acknowledgment: The authors would like to thank all patients involved in the study, as well as their caregivers, care team and research staff in participating institutions. Consent For Publication: Written informed consent was obtained from participants, a cope of consent form will be kindly provided upon journal request. Ethical consideration: The research project will be conducted in accordance with the ethical principles contained in the Declaration of Helsinki (2000), the WHO Operational Guidelines for Ethical Committee that review Biomedical research (2000), the International Ethical Guidelines for biomedical research involving human subjects (2002) and the policies of the Research Advisory Committee (RAC)at King Faisal Specialist Hospital and Research Centre, as well as the laws of the Kingdom of Saudi Arabia. The data collected and al the files related to the research project will be locked in a secure location in the Department of Family Medicine and will be available to the RAC as per the guidelines of KFSH&RC. This study proposes no additional interventions to patients. This proposal is primarily about collecting data and no clinical interventions are planned. This study poses no risk to patients; we consider the risk-benefit ratio to be very favourable. Therefore, waiver of informed consent will be required. Disclosure: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Conflict of interest: The authors declare no conflict of interest. Funding: Not Applicable References Gomes MM, Martins S, Marques O, Silva ND, Antunes A. (2016). Severe systemic type 1 pseudohypoaldosteronism: 5 years of evolution. Endocrinologia y nutricion: organo de la Sociedad Espanola de Endocrinologia y Nutricion, 63(9), 502–505. https://doi.org/10.1016/j.endonu.2016.08.002 . Pugh CP. Pseudohypoaldosteronism Type 1: The Presentation and Management of a Neonate With a Novel Mutation of the SCNN1B Gene Found in Two Hispanic Siblings. Cureus. 2022;14(4). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9076053/ . Amin N, Alvi NS, Barth JH, Field HP, Finlay E, Tyerman K, Frazer S, Savill G, Wright NP, Makaya T, Mushtaq T. Pseudohypoaldosteronism type 1: clinical features and management in infancy. Endocrinol Diabetes Metabolism Case Rep. 2013;2013(1). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922296/ . Kim SJ, Park D, Jang W, Lee J. A Neonate with Autosomal Dominant Pseudohypoaldosteronism Type 1 Due to a Novel Microdeletion of the NR3C2 Gene at 4q31. 23. Children. 2021;8(12):1090. https://www.mdpi.com/2227-9067/8/12/1090 . Bowden SA, Cozzi C, Hickey SE, Thrush DL, Astbury C, Nuthakki S. Autosomal dominant pseudohypoaldosteronism type 1 in an infant with salt wasting crisis associated with urinary tract infection and obstructive uropathy. Case Reports in Endocrinology. 2013;2013. https://www.hindawi.com/journals/crie/2013/524647/ . Gao Z, Sun J, Cai C, Gong X, Ma L. Pseudohypoaldosteronism type 1b in fraternal twins of a Chinese family: report of two cases and literature review. Archives Endocrinol Metabolism. 2023;67:e000620. https://www.scielo.br/j/aem/a/SXQCr3GLpbpyM7pMP . 5Kfs8K/?format=pdf⟨=en. Alzahrani AS, Alswailem M, Abbas BB, Qasem E, Alsagheir A, Al Shidhani A, Al Sinani A, Al Badi M, Al-Maqbali A, Al Shawi M, Albunyan A. A unique genotype of pseudohypoaldosteronism type 1b in a highly consanguineous population. J Endocr Soc. 2021;5(8):bvab095. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272535/ . Agarwal N, Gupta A, Dhasmana R, Mehta A, Agrawal N. Cutaneous and Ocular Findings in Systemic Pseudohypoaldosteronism I: Early Clinical Pointers. INDIAN JOURNAL OF NEONATAL MEDICINE AND RESEARCH; 2022. p. 10. https://doi.org/10.7860/IJNMR/2022/50253.2324 . Gopal-Kothandapani JS, Doshi AB, Smith K, Christian M, Mushtaq T, Banerjee I, Padidela R, Ramakrishnan R, Owen C, Cheetham T, Dimitri P. Phenotypic diversity and correlation with the genotypes of pseudohypoaldosteronism type 1. J Pediatr Endocrinol Metab. 2019;32(9):959–67. 10.1515/jpem-2018-0538/html?lang=en . https://www.degruyter.com/document/doi/ . Tables Table 1: Descriptive Summary of Reported Cases Article Age Gender Symptoms Management Complications Su Jin Kim 20 days Female poor oral intake, and lethargy. IV fluid and 60ml of 3% sodium chloride - N. Amin 3 weeks Male vomiting and weight loss Sodium supplements at a dose of 3–5 mmol/kg per day - 4 weeks - poor feeding, poor weight gain, hair loss and dry skin IV fluids of 0.45% saline with 5% dextrose, oral sodium supplements with mineralocorticoids, potassium formula milk - 8 days Female Weight loss sodium, hydrocortisone, fludrocortisone, and calcium resonium supplementation - 33 weeks Male hypoglycaemic and macrosomia - 23 day old Female profuse vomiting and failure to thrive IV fluids, sodium supplementation, anti-reflux medications and an elemental milk formula. - 5 days old Female jaundice and weight loss Recurrent episodes of weight loss, hyperkalaemia, peritonitis new-born Male weight loss and drowsiness IV fluids, anti-reflux medications and an elemental milk Recurrent lower respiratory tract infections, and recurrent tonsilitis Table 2: A descriptive summary genotype-phenotype correlation of PHA cases. Our cases Symptoms Our cases gene variant Documented genotype (Dr. Ali study) The suggested genotype-phenotype correlation Case 1 Vomiting, dehydration, polyuria SCNN1A: ex.9: c.1496 A>G:p.Q499R (hom) Novel SCNN1A: 1496 A>G p.Q499R Positive Case 2 Vomiting, dehydration, SCNN1A: ex.9: c.1453 C>T:p.Q485X (hom) Novel SCNN1A: c.1453 C>T p.Q485X Positive Case 3 Vomiting, dehydration, respiratory disease, polyuria, hypotension, UTI SCNN1A: ex.7: c.1322 delA (hom) Novel SCNN1A: c.1322_1322delA N441Tfs*76 Positive Case 4 Vomiting, dehydration, respiratory disease SCNN1A: ex.7: c.1322 delA (hom) Novel SCNN1A: c.1322_1322delA N441Tfs*76 Positive Case 5 Vomiting, dehydration, respiratory disease, dermatitis, polyuria, hypotension, HTN SCNN1A: IVS3 +2 del GAGT or c.876 +2 del GAGT (hom) Novel SCNN1A: IVS3 +2 del GAGT (c.876 +2 del GAGT) Positive Case 6 Vomiting, dehydration, respiratory disease, dermatitis, polyuria, hypotension, UTI, HTN SCNN1A: IVS3 +2 del GAGT or c.876 +2 del GAGT (hom) Novel SCNN1A: IVS3 +2 del GAGT (c.876 +2 del GAGT) Positive Case 7 Vomiting, dehydration., respiratory disease, dermatitis, polyuria, hypotension, UTI, hypertension SCNN1A: IVS3 +2 del GAGT or c.876 +2 del GAGT (hom) Novel SCNN1A: IVS3 +2 del GAGT (c.876 +2 del GAGT) Positive Case 8 Vomiting, dehydration., respiratory disease, hypotension, UTI, hypertension SCNN1A: ex.1: c.203_204 delTC:p.I68T fs*76 (hom) SCNN1A: c.203_204 delTC p.I68T fs*76 Positive Case 9 Vomiting, dehydration, respiratory disease, hypotension, UTI, hypertension SCNN1A: ex.1: c.203_204 delTC:p.I68T fs*76 (hom) SCNN1A: c.203_204 delTC:p.I68T fs*76 Positive Case 10 Vomiting, dehydration, respiratory disease, hypotension, hypertension SCNN1A: ex.1: c.203_204 delTC:p.I68T fs*76 (hom) SCNN1A: c.203_204 delTC:p.I68T fs*76 Positive Case 11 Vomiting, dehydration, respiratory disease, hypotension SCNN1A: ex.1: c.203_204 delTC:p.I68T fs*76 (hom) SCNN1A: c.203_204 delTC:p.I68T fs*76 Positive Case 12 Vomiting, dehydration, SCNN1A: ex.1: c.203_204 delTC:p.I68T fs*76 (hom) SCNN1A: c.203_204 delTC:p.I68T fs*76 Positive Case 13 Vomiting, dehydration, respiratory disease, dermatitis, hypotension SCNN1A: ex.1: c.203_204 delTC:p.I68T fs*76 (hom) SCNN1A: c.203_204 delTC:p.I68T fs*76 Positive Case 14 Vomiting, dehydration, polyuria SCNN1A: ex.1: c.203_204 delTC:p.I68T fs*76 (hom) SCNN1A: c.203_204 delTC:p.I68T fs*76 Positive Case 15 Vomiting, dehydration, respiratory disease, hypotension SCNN1A: ex.1: c.203_204 delTC:p.I68T fs*76 (hom) SCNN1A: c.203_204 delTC:p.I68T fs*76 Positive Case 16 Vomiting, dehydration, SCNN1A: del. ex.2-12 except exon 1 SCNN1A: Unique Positive Case 17 Vomiting, dehydration, respiratory disease, arrhythmias, polyuria, hypotension SCNN1A: del. ex.2-12 except exon 1 SCNN1A: Unique Positive Case 18 Vomiting, dehydration, dermatitis SNCC1B c.1694 C>A S565X SCNN1B: c.1694 C>A S565X Positive Case 19 Vomiting, dehydration, SNCC1B c.1694 C>A S565X SCNN1B: c.1694 C>A S565X Positive Case 20 Asymptomatic SNCC1B c.1694 C>A S565X SCNN1B: c.1694 C>A S565X Positive Case 21 Vomiting, dehydration, respiratory disease, dermatitis SNCC1G c.527_528 del CA T176Rfs*184 SCNN1G: c.527_528 del CA T176Rfs*184 Positive Case 22 Vomiting, dehydration, respiratory disease, dermatitis SNCC1G c.527_528 del CA T176Rfs*184 SCNN1G: c.527_528 del CA T176Rfs*184 Positive Additional Declarations No competing interests reported. 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A Single Center Experience, A Retrospective Cohort Study.","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePseudohypoaldosteronism (PHA) was first described by Cheek and Perry in 1958 as a rare aldosterone unresponsiveness that is characterized by multi-organ involvement affecting sodium salt wasting, poor renal excretion, and severe volume depletion resulting in hyponatremia, hyperkalaemia, and metabolic acidosis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In such cases, it can be acquired. However, it is most commonly an inherited condition. The incidence rate of autosomal dominant Pseudohypoaldosteronism (PHA) was estimated to be 1:47,000, whereas autosomal recessive PHA was estimated to be 1:66,000 [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Classification-wise, pseudohypoaldosteronism (PHA) is classified into type 1 and type 2. Furthermore, Type 1 PHA is classified further into two subtypes based on their genetic mode of inheritance [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The diagnosis of PHA is made via laboratory and radiological investigations that include plasma renin activity, cortisol levels, aldosterone, 17 OHP, and renal ultrasound [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e"},{"header":"Methodology","content":"\u003cp\u003eA descriptive retrospective study that includes a total of 22 patients diagnosed with PHA during the period of 2023 in the endocrine subdivision of paediatric service in KFSHRC. Informed consent was obtained from the patients. The data was then summarised into an Excel sheet and incorporated into SPSS for systemic analysis. The study was approved by the Institutional Review Board of the King Faisal Specialist Hospital \u0026amp; Research Centre (KFSHRC), Riyadh, Saudi Arabia.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe study included a total number of 22 patients, with ages ranging between 3 days to 2 years at presentation. The clinical manifestations of the patients presented as follows: 95% presented with vomiting, 63.3% had respiratory symptoms, 50% had hypotension, 31% had dermatitis, 31% had polyurea, 27% had hypertension, 22% had urinary tract infection (UTI), and only one patient had arrhythmia. Laboratory investigations showed: Lowest sodium (Na), 110\u0026ndash;132; Lowest chloride (Cl): 81\u0026ndash;108; Lowest HCO3: 10\u0026ndash;18; Highest potassium: 5.5\u0026ndash;8 Aldosterone: 7510\u0026thinsp;\u0026minus;\u0026thinsp;1659, half of the patient did not do Aldosterone level. Renin: 50\u0026ndash;751 Number of admissions: range from 0 to 20 times. The management includes a sodium chloride dose of 2-480 meq/kg/day, sodium bicarbonate (NaHCO3) of 1\u0026ndash;34 meq/kg/day, and Kayexalate 0.5\u0026ndash;45 g/kg/day. One patient needed a gastrostomy tube, and one patient was off treatment at the age of 6 years. Severity at presentation ranges from very severe to severe, then improved with age to range between very mild to moderate.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eRenal PHA 1 (PHA1a) is an autosomal dominant inherited disorder with a heterogeneous NR3C2 gene mutation characterized by an inactivating mutation [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This gene encodes for mineralocorticoid receptors that can result in the absence of binding the aldosterone to the receptor with a phenotypic expression restricted to the kidney [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Renal PHA1 (PHA1a) clinically manifests in early life, particularly during the neonatal period, with fever, feeding difficulties, nausea, vomiting, weight loss, recurrent pulmonary infection, and sudden cardiac arrest [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Furthermore, it is mainly characterized by hyponatremia, hyperkalaemia, and salt wasting with elevated plasma renin and aldosterone levels [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The mechanism of hyperaldosteronism and hyperreninemia is associated with a decrease in extracellular fluid volume rather than peripheral mineralocorticoid resistance [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Whereas systemic PHA 1 (PHA1b) is an autosomal recessive inheritance pattern that involves multiple organs and is mainly caused by mutation of the epithelial sodium channel (ENaC) that affects the distal convoluted tubules and the collecting ducts [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The role of the ENaC channel in transporting sodium can affect several other organs containing this channel, including the lungs, kidneys, colon, and salivatory glands [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurthermore, many factors can affect sodium reabsorption in the distal tubule, such as prematurity, infection, and unknown gene function [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. PHA1b occurs in the first week of life and manifests with electrolyte imbalances such as hyperkalaemia and metabolic acidosis alongside nausea, vomiting, and hypotension with salt-wasting episodes after birth [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, symptoms are usually severe and persistent to adulthood [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Systemic PHA 1 can also present with cutaneous and ocular manifestations [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Cutaneous manifestations include miliaria rubra-like rash, atopic dermatitis, and pustules [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The postulated mechanism of miliaria rubra is that increased sodium chloride concentration in sweat damages the eccrine ducts because of the mutation of the ENaC channel [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Studies showed that PHA1b usually presents with a more severe clinical phenotype than PHA1a [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Complication-wise, the PHA1b is more prone to develop complications such as infections, which were more common, including recurrent tonsillitis, femoral head osteomyelitis, and recurrent respiratory tract infections requiring long-term observation [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the literature, there have been cases reported in different articles. Here, we try to summarise them further to delineate our discoveries for comparison with the earlier cases. A study by Attia and Marzouki reported a case of severe hyponatremia and hyperkalaemia who developed cardiac arrest and was found to develop PHA later in life [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Su Jin Kim reported a 20-day-old girl who was born at 38 weeks\u0026rsquo; gestation via C-section and presented with a complaint of poor oral intake and lethargy. Dysmorphism was revealed on physical examination in the form of frontal bossing, frontal scalp hair, permanent upper lip, high arch palate, and bilateral fifth digit clinodactyly. Laboratory investigations showed elevated plasma renin activity and serum aldosterone to 142.0 ng/mL/h. Renal ultrasonography revealed mild hydronephrosis in the right kidney. Accordingly, the patient received IV fluid and 60 ml of 3% sodium chloride [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Hanukoglu et al. reported in a family study spanning 40 years that even families with the same mutation had different clinical manifestations and renin/aldosterone levels [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Alshaikh reported that two Omani siblings presented in the first week with complaints of nausea and vomiting [10]. Laboratory investigations showed hyperkalaemia, hypotension, and metabolic acidosis [10]. WES test confirmed the presence of SCNN1A gene mutation (c.385G\u0026thinsp;\u0026gt;\u0026thinsp;A, p.Gly129Ser) [10].N. Amin reported a total of 6 cases with the diagnosis of PHA confirmed via clinical and biochemical results. Cayrin et al. reported 3 cases of PHA 1b with four existing novel variants in SCNN1A and SCNNA1B with two novel pathogenic variants SCNN1B (c.87C\u0026thinsp;\u0026gt;\u0026thinsp;A[p.Tyr29*]/IVS9\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A [c.1346\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A]), SCNN1A (p.His69Arg [c.206A\u0026thinsp;\u0026gt;\u0026thinsp;G]). They concluded that missense mutations are documented in a few cases with a milder disease phenotype [10]. Hanokugolu et al. reported 4 PHA 1b patients with a heterozygous mutation of (Gly327Cys) with monoallelic missense mutation combined with nonsense mutation [10].\u003c/p\u003e \u003cp\u003eManaging PHA requires monitoring serum electrolytes and tailoring treatment; this includes low potassium diet, high-volume supplements, and potassium binders [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Also, a gastrostomy tube can be used in patients with systemic PHA1 with poor oral intake [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Dirlewanger et al. reported a homozygous missense mutation in SCNNA1 (Ser243Pro) encoding α-ENaC of a preterm baby whose sodium requirements decreased rapidly with age. They were stopped at the age of 9 months [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe mortality rate is considered high during the neonatal period and often requires prolonged hospitalization [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Neonatal salt wasting can reduce the function of epithelium sodium channels secondary to variable sodium channel gene mutations, including SCNN1A, SCNN1B, and SCNN1G, which can pose a significant life-threatening sequela [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Studies showed that patients with the gene-structured disrupted mutation, including gross deletion, deletion with frameshift and truncation, and nonsense mutation, can interfere with the normal function of the encoded protein subunit of SCNN1A and tend to develop severe phenotype form of PHA at the onset of diagnosis with less improvement over-time. However, missense mutations of SCNN1A SCNN1B can experience milder phenotypes [7,10].\u003c/p\u003e \u003cp\u003eIn our study, 22 patients between 3 days and two years were diagnosed with Pseudohypoaldosteronism (PHA). The number of admission ranges from 0\u0026ndash;20 times. Of these patients, 95% had vomiting, 63.3% had respiratory symptoms, 50% had hypotension, 31% had dermatitis, 31% had polyurea, 27% had hypertension, 22% had urinary tract infection (UTI), and arrhythmia. Laboratory investigations showed hyperkalaemia (5.5-8) hyponatremia (110\u0026ndash;132), hypochloraemia (81\u0026ndash;108), and renin levels of 50\u0026ndash;751. Accordingly, the patients received sodium chloride (2-480 meq/kg/day), sodium bicarbonate (1\u0026ndash;34 meq/kg/day), kayexalate (0.5\u0026ndash;45 g/kg/day), one patient underwent gastrostomy tube, one patient stopped treatment at the age of 6 years. The severity of cases at presentation ranges between mild to moderate.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn final remarks, PHA is a rare genetic endocrine disorder that needs endocrinologists to be aware of its existence as it is a clinical diagnosis entity that requires close monitoring of affected patients due to the fact that the clinical pheno-genotype correlation is still an expandable process in the medical literature. Our single-centre experience tries to shed light on the possible clinical behaviour of this under-diagnosed disorder further to strengthen our understanding of the natural course of PHA. Also, having a better plan and management in the care of diagnosed individuals will further increase the likelihood of a better prognosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgment:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank all patients involved in the study, as well as their caregivers, care team and research staff in participating institutions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent For Publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from participants, a cope of consent form will be kindly provided upon journal request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical consideration:\u0026nbsp;\u003c/strong\u003eThe research project will be conducted in accordance with the ethical principles contained in the Declaration of Helsinki (2000), the WHO Operational Guidelines for Ethical Committee that review Biomedical research (2000), the International Ethical Guidelines for biomedical research involving human subjects (2002) and the policies of the Research Advisory Committee (RAC)at King Faisal Specialist Hospital and Research Centre, as well as the laws of the Kingdom of Saudi Arabia. The data collected and al the files related to the research project will be locked in a secure location in the Department of Family Medicine and will be available to the RAC as per the guidelines of KFSH\u0026amp;RC. This study proposes no additional interventions to patients. This proposal is primarily about collecting data and no clinical interventions are planned. This study poses no risk to patients; we consider the risk-benefit ratio to be very favourable. Therefore, waiver of informed consent will be required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure:\u003c/strong\u003e The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cspan\u003eGomes MM, Martins S, Marques O, Silva ND, Antunes A. (2016). Severe systemic type 1 pseudohypoaldosteronism: 5 years of evolution. Endocrinologia y nutricion: organo de la Sociedad Espanola de Endocrinologia y Nutricion, 63(9), 502\u0026ndash;505.\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.endonu.2016.08.002\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003ePugh CP. Pseudohypoaldosteronism Type 1: The Presentation and Management of a Neonate With a Novel Mutation of the SCNN1B Gene Found in Two Hispanic Siblings. Cureus. 2022;14(4).\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9076053/\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eAmin N, Alvi NS, Barth JH, Field HP, Finlay E, Tyerman K, Frazer S, Savill G, Wright NP, Makaya T, Mushtaq T. Pseudohypoaldosteronism type 1: clinical features and management in infancy. Endocrinol Diabetes Metabolism Case Rep. 2013;2013(1). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922296/\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eKim SJ, Park D, Jang W, Lee J. A Neonate with Autosomal Dominant Pseudohypoaldosteronism Type 1 Due to a Novel Microdeletion of the NR3C2 Gene at 4q31. 23. Children. 2021;8(12):1090. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.mdpi.com/2227-9067/8/12/1090\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eBowden SA, Cozzi C, Hickey SE, Thrush DL, Astbury C, Nuthakki S. Autosomal dominant pseudohypoaldosteronism type 1 in an infant with salt wasting crisis associated with urinary tract infection and obstructive uropathy. Case Reports in Endocrinology. 2013;2013. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.hindawi.com/journals/crie/2013/524647/\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eGao Z, Sun J, Cai C, Gong X, Ma L. Pseudohypoaldosteronism type 1b in fraternal twins of a Chinese family: report of two cases and literature review. Archives Endocrinol Metabolism. 2023;67:e000620. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.scielo.br/j/aem/a/SXQCr3GLpbpyM7pMP\u003c/span\u003e\u003c/span\u003e. 5Kfs8K/?format=pdf\u0026lang;=en.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eAlzahrani AS, Alswailem M, Abbas BB, Qasem E, Alsagheir A, Al Shidhani A, Al Sinani A, Al Badi M, Al-Maqbali A, Al Shawi M, Albunyan A. A unique genotype of pseudohypoaldosteronism type 1b in a highly consanguineous population. J Endocr Soc. 2021;5(8):bvab095. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272535/\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eAgarwal N, Gupta A, Dhasmana R, Mehta A, Agrawal N. Cutaneous and Ocular Findings in Systemic Pseudohypoaldosteronism I: Early Clinical Pointers. INDIAN JOURNAL OF NEONATAL MEDICINE AND RESEARCH; 2022. p. 10. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.7860/IJNMR/2022/50253.2324\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eGopal-Kothandapani JS, Doshi AB, Smith K, Christian M, Mushtaq T, Banerjee I, Padidela R, Ramakrishnan R, Owen C, Cheetham T, Dimitri P. Phenotypic diversity and correlation with the genotypes of pseudohypoaldosteronism type 1. J Pediatr Endocrinol Metab. 2019;32(9):959\u0026ndash;67. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1515/jpem-2018-0538/html?lang=en\u003c/span\u003e\u003c/span\u003e. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.degruyter.com/document/doi/\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1: Descriptive Summary of Reported Cases\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"610\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.80327868852459%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eArticle\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.950819672131148%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.98360655737705%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.34426229508197%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSymptoms\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.295081967213115%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eManagement\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.62295081967213%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eComplications\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.80327868852459%\" valign=\"top\"\u003e\n \u003cp\u003eSu Jin Kim\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.950819672131148%\" valign=\"top\"\u003e\n \u003cp\u003e20 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.98360655737705%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.34426229508197%\" valign=\"top\"\u003e\n \u003cp\u003epoor oral intake, and lethargy.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.295081967213115%\" valign=\"top\"\u003e\n \u003cp\u003eIV fluid and 60ml of 3% sodium chloride\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.62295081967213%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.80327868852459%\" valign=\"top\"\u003e\n \u003cp\u003eN. Amin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.950819672131148%\" valign=\"top\"\u003e\n \u003cp\u003e3 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.98360655737705%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.34426229508197%\" valign=\"top\"\u003e\n \u003cp\u003evomiting and weight loss\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.295081967213115%\" valign=\"top\"\u003e\n \u003cp\u003eSodium supplements at a dose of 3\u0026ndash;5 mmol/kg per day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.62295081967213%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.80327868852459%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.950819672131148%\" valign=\"top\"\u003e\n \u003cp\u003e4 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.98360655737705%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.34426229508197%\" valign=\"top\"\u003e\n \u003cp\u003epoor feeding, poor weight gain, hair loss and dry skin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.295081967213115%\" valign=\"top\"\u003e\n \u003cp\u003eIV fluids of 0.45% saline with 5% dextrose, oral sodium supplements with mineralocorticoids, potassium formula milk\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.62295081967213%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.80327868852459%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.950819672131148%\" valign=\"top\"\u003e\n \u003cp\u003e8 days\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.98360655737705%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.34426229508197%\" valign=\"top\"\u003e\n \u003cp\u003eWeight loss\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.295081967213115%\" valign=\"top\"\u003e\n \u003cp\u003esodium, hydrocortisone, fludrocortisone, and calcium resonium supplementation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.62295081967213%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.80327868852459%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.950819672131148%\" valign=\"top\"\u003e\n \u003cp\u003e33 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.98360655737705%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.34426229508197%\" valign=\"top\"\u003e\n \u003cp\u003ehypoglycaemic and macrosomia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.295081967213115%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.62295081967213%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.80327868852459%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.950819672131148%\" valign=\"top\"\u003e\n \u003cp\u003e23 day old\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.98360655737705%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.34426229508197%\" valign=\"top\"\u003e\n \u003cp\u003eprofuse vomiting and failure to thrive\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.295081967213115%\" valign=\"top\"\u003e\n \u003cp\u003eIV fluids, sodium supplementation, anti-reflux medications and an elemental milk formula.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.62295081967213%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.80327868852459%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.950819672131148%\" valign=\"top\"\u003e\n \u003cp\u003e5 days old\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.98360655737705%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.34426229508197%\" valign=\"top\"\u003e\n \u003cp\u003ejaundice and weight loss\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.295081967213115%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.62295081967213%\" valign=\"top\"\u003e\n \u003cp\u003eRecurrent episodes of weight loss, hyperkalaemia, peritonitis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.80327868852459%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.950819672131148%\" valign=\"top\"\u003e\n \u003cp\u003enew-born\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.98360655737705%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.34426229508197%\" valign=\"top\"\u003e\n \u003cp\u003eweight loss and drowsiness\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.295081967213115%\" valign=\"top\"\u003e\n \u003cp\u003eIV fluids, anti-reflux medications and an elemental milk\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.62295081967213%\" valign=\"top\"\u003e\n \u003cp\u003eRecurrent lower respiratory tract infections, and recurrent tonsilitis\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: A descriptive summary genotype-phenotype correlation of PHA cases.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"570\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOur cases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSymptoms\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOur cases gene variant\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDocumented genotype (Dr. Ali study)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eThe suggested genotype-phenotype correlation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003eCase 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting, dehydration, polyuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: ex.9: c.1496 A\u0026gt;G:p.Q499R (hom) Novel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: 1496 A\u0026gt;G p.Q499R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003eCase 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting, dehydration,\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: ex.9: c.1453 C\u0026gt;T:p.Q485X (hom) Novel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: c.1453 C\u0026gt;T p.Q485X\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003eCase 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting, dehydration, respiratory disease, polyuria, hypotension, UTI\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: ex.7: c.1322 delA (hom) Novel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: c.1322_1322delA N441Tfs*76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003eCase 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting, dehydration, respiratory disease\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: ex.7: c.1322 delA (hom) Novel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: c.1322_1322delA N441Tfs*76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003eCase 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting, dehydration, respiratory disease, dermatitis, polyuria, hypotension, HTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: IVS3 +2 del GAGT or c.876 +2 del GAGT (hom) Novel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: IVS3 +2 del GAGT (c.876 +2 del GAGT)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003eCase 6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting, dehydration, respiratory disease, dermatitis, polyuria, hypotension, UTI, HTN\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: IVS3 +2 del GAGT or c.876 +2 del GAGT (hom) Novel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: IVS3 +2 del GAGT (c.876 +2 del GAGT)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003eCase 7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting, dehydration., respiratory disease, dermatitis, polyuria, hypotension, UTI, hypertension\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: IVS3 +2 del GAGT or c.876 +2 del GAGT (hom) Novel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: IVS3 +2 del GAGT (c.876 +2 del GAGT)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003eCase 8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting, dehydration., respiratory disease, hypotension, UTI, hypertension\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: ex.1: c.203_204 delTC:p.I68T fs*76 (hom)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: c.203_204 delTC p.I68T fs*76\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003eCase 9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting, dehydration, respiratory disease, hypotension, UTI, hypertension\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: ex.1: c.203_204 delTC:p.I68T fs*76 (hom)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: c.203_204 delTC:p.I68T fs*76\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003eCase 10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting, dehydration, respiratory disease, hypotension, hypertension\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: ex.1: c.203_204 delTC:p.I68T fs*76 (hom)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: c.203_204 delTC:p.I68T fs*76\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003eCase 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting, dehydration, respiratory disease, hypotension\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: ex.1: c.203_204 delTC:p.I68T fs*76 (hom)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: c.203_204 delTC:p.I68T fs*76\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003eCase 12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting, dehydration,\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: ex.1: c.203_204 delTC:p.I68T fs*76 (hom)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: c.203_204 delTC:p.I68T fs*76\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003eCase 13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting, dehydration, respiratory disease, dermatitis, hypotension\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: ex.1: c.203_204 delTC:p.I68T fs*76 (hom)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: c.203_204 delTC:p.I68T fs*76\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003eCase 14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting, dehydration, polyuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: ex.1: c.203_204 delTC:p.I68T fs*76 (hom)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: c.203_204 delTC:p.I68T fs*76\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003eCase 15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting, dehydration, respiratory disease, hypotension\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: ex.1: c.203_204 delTC:p.I68T fs*76 (hom)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: c.203_204 delTC:p.I68T fs*76\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003eCase 16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting, dehydration,\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: del. ex.2-12 except exon 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: Unique\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003eCase 17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting, dehydration, respiratory disease, arrhythmias, polyuria, hypotension\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: del. ex.2-12 except exon 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1A: Unique\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003eCase 18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting, dehydration, dermatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003eSNCC1B c.1694 C\u0026gt;A S565X\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1B: c.1694 C\u0026gt;A\u003c/p\u003e\n \u003cp\u003eS565X\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003eCase 19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting, dehydration,\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003eSNCC1B c.1694 C\u0026gt;A S565X\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1B: c.1694 C\u0026gt;A\u003c/p\u003e\n \u003cp\u003eS565X\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003eCase 20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003eAsymptomatic \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003eSNCC1B c.1694 C\u0026gt;A S565X\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1B: c.1694 C\u0026gt;A\u003c/p\u003e\n \u003cp\u003eS565X\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003eCase 21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting, dehydration, respiratory disease, dermatitis\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003eSNCC1G c.527_528 del CA T176Rfs*184\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1G: c.527_528 del CA\u003c/p\u003e\n \u003cp\u003eT176Rfs*184\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.140350877192983%\" valign=\"top\"\u003e\n \u003cp\u003eCase 22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.42105263157895%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting, dehydration, respiratory disease, dermatitis\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.82456140350877%\" valign=\"top\"\u003e\n \u003cp\u003eSNCC1G c.527_528 del CA T176Rfs*184\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.771929824561404%\" valign=\"top\"\u003e\n \u003cp\u003eSCNN1G: c.527_528 del CA\u003c/p\u003e\n \u003cp\u003eT176Rfs*184\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4102368/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4102368/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003ePseudohypoaldosteronism (PHA) is a rare endocrine disorder characterized by unresponsiveness, multi-organ involvement affecting sodium salt wasting, poor renal excretion, and severe volume depletion resulting in electrolyte imbalance (hyponatremia, hyperkalaemia, and metabolic acidosis) and further classified into type 1 and 2. Ali et al. reported that PHA1b geno-phenotype correlation has not been well described. As such, in our study, we propose how the clinical behaviour of this subtype can be predictable. Moreover, the diagnosis of any of the PHA types is made by the clinical presentation and laboratory findings during a clinical suspicion setting.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eA descriptive retrospective study includes 22 patients diagnosed with PHA during 2023 in the endocrine subdivision of paediatric service in KFSHRC. The informed consent was obtained from either the patients or their guardians.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eOf a total of 22 patients, ages ranged between 3 days to 2 years at presentation, 95% of them presented with vomiting, 63.3% had respiratory symptoms, 50% had hypotension 31% had dermatitis, and 31% had polyurea, 27% had HTN, 22% had UTI only one patient had arrhythmia, none of them had gallstone. Labs were Lowest Na; 110\u0026ndash;132 Lowest Cl: 81\u0026ndash;108 Lowest HCO3: 10\u0026ndash;18 Highest K: 5.5-8 Aldosterone: 7510\u0026thinsp;\u0026minus;\u0026thinsp;1659, half of the patient did not do Aldosterone level. Renin: 50\u0026ndash;751 Number of admissions: range from 0 to 20 times. Treatment: NaCl dose range (2-480 meq/kg/day) NaHCO3 (1\u0026ndash;34 meq/kg/day) Kayexalate (0.5\u0026ndash;45 g/kg/day) One patient needed a gastrostomy tube. One patient was off treatment at the age of 6 years. Severity at presentation ranges from very severe to 4 severe, Then improved with age to range between very mild to moderate.\u003c/p\u003e\u003ch2\u003eDiscussion:\u003c/h2\u003e \u003cp\u003ePHA1a has a heterogeneous inactivating mutation in the NR3C2 gene; it encodes for a mineralocorticoid receptor responsible for aldosterone binding. Therefore, mutations are associated with a phenotype restricted to the kidneys. As a course, this disease has an early life onset, which is almost always in the neonatal period, presenting with fever, feeding difficulties, nausea, vomiting, weight loss, recurrent pulmonary infection, and sudden cardiac arrest alongside laboratory findings in the form of electrolyte imbalance which includes hyponatremia, hyperkalaemia and salt wasting with elevated plasma renin and aldosterone levels. On the other hand, PHA1b is multi-systemic and mainly caused by mutations in the ENaC channel, affecting sodium reabsorption in the body. It manifests in the first week of life with electrolyte imbalance with nonspecific symptoms such as nausea and vomiting alongside hypotension, with salt-wasting episodes. It has been demonstrated that PHA1b usually presents with a more severe clinical phenotype than PHA1a. Furthermore, complications with the PHA1b subtype are more prone to develop.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003ePHA is a rare genetic endocrine disorder that needs awareness by the endocrinologist of its existence. It is a clinical diagnosis that requires monitoring, follow-up, and close observation of affected patients. Hence, this is because pheno-genotype correlation is an expandable process in the endocrine medical literature. Our single-centre experience gives an insight into the predictable clinical behaviour of this under-diagnosed condition to improve further the physicians related to the paediatric population's understanding of the PHA natural course. Also, to have a better provisional plan and management care for affected individuals to increase the likelihood of a better prognosis further, better quality of life, and survival.\u003c/p\u003e","manuscriptTitle":"Clinical Manifestations of Pseudohypoaldosteronism with Genotype-phenotype Correlation. A Single Center Experience, A Retrospective Cohort Study.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-18 03:24:54","doi":"10.21203/rs.3.rs-4102368/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6cf420e2-144c-4eb5-89cd-efc25b8559f7","owner":[],"postedDate":"April 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-16T10:06:54+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-18 03:24:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4102368","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4102368","identity":"rs-4102368","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}