Bartter Syndrome Type 2 in Adolescence: Clinical Features and Genetic Confirmation

doi:10.21203/rs.3.rs-4823180/v1

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Case Report

Bartter Syndrome Type 2 in Adolescence: Clinical Features and Genetic Confirmation

https://doi.org/10.21203/rs.3.rs-4823180/v1

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Background

Bartter Syndrome (BS) is a rare salt-losing tubulopathy characterized by impaired sodium reabsorption and excessive salt excretion. Type II Bartter Syndrome, usually presenting in the neonatal period, is associated with mutations in the KCNJ1 gene. Reporting this case adds to the limited data on late-onset presentations of BS type 2, highlighting its clinical variability.

Case Presentation:

An 18-year-old female presented with polydipsia, frequent urination, muscle cramps, and fatigue. She was found to have hypokalemic metabolic alkalosis, hypercalciuria, and hypomagnesemia. Imaging revealed bilateral renal medullary nephrocalcinosis. Genetic testing identified heterozygous mutations in the KCNJ1 gene, confirming BS type 2. The patient's birth weight was 2.7 kg, with no history of polyhydramnios or post-natal complications. Management included potassium and magnesium supplementation, and NSAIDs to inhibit prostaglandin synthesis.

Conclusions

This case underscores the importance of considering rare genetic renal tubular disorders like BS type 2 in patients with persistent electrolyte abnormalities, polyuria, and nephrocalcinosis. Genetic testing is crucial for diagnosis and management, which can significantly improve the patient's quality of life and prevent disease progression.

Bartter Syndrome (BS)

KCNJ1 gene

Renal tubular disorder

Electrolyte abnormalities

Genetic testing

Salt-losing (or salt-wasting) tubulopathies are characterized by impaired salt reabsorption (i.e. sodium), resulting in the excretion of salt above what is required for homeostasis. These tubulopathies are among the most commonly encountered in clinical practice(1). Bartter Syndrome is manifested by typical gene-specific patterns resulting from dysfunctional proteins causing impaired sodium chloride (NaCl) reabsorption in the cortical and medullary thick ascending limb (TAL) of the loop of Henle(2).

Bartter syndrome consists of a group of rare autosomal recessive renal tubulopathies characterized by renal salt wasting, hypokalemic metabolic alkalosis, hypercalciuria, and hyperreninemic hyperaldosteronism. It is classified into five types (Fig. 1.)(3) Mutations in the KCNJ1 gene (classified as type II) usually cause the neonatal form of Bartter syndrome(4).

The pathophysiology of Bartter syndrome involves defects in salt transport within the kidney's thick ascending limb and distal convoluted tubule. In the thick ascending limb, sodium chloride (NaCl) is reabsorbed by the NaK2Cl cotransporter NKCC2, which is mutated in BS type 1. Potassium ions are recycled into the tubular lumen through the apical potassium channel KCNJ1 (ROMK), mutated in BS type 2. In the distal convoluted tubule, NaCl is absorbed by the NaCl cotransporter NCC. Chloride leaves the cell in both segments through chloride-permeable ion channels ClC-Ka and ClC-Kb. A defect in ClC-Kb results in BS type 3. Mutations in either the accessory subunit barttin or a combined defect in both chloride channels ClC-Ka and ClC-Kb cause BS types 4a and 4b. Transient BS type 5 is associated with mutations in MAGE-D2, which aids in the trafficking and protection of NKCC2 and NCC from intracellular degradation through HSP40, and promotes their apical targeting via Gs-alpha12(5) .

Of the very few published cases of Bartter syndrome type 2 in adolescence(4)(6)(7)(8), we present a case of an 18-year-old female with heterozygous ROMK mutation.

This is an 18-year-old female with a history of polydipsia and polyuria with recurrent hospital visits for muscle cramps and fatigue since childhood. On evaluation, she was found to have hypokalemia which was treated with intravenous and oral potassium chloride. She was subsequently evaluated and found to have bilateral renal medullary nephrocalcinosis (Fig. 2.) She was delivered at term via spontaneous vaginal delivery with a birth weight of 2.7kg. There was no history of polyhydramnios and postal natal hospital admission as per her mother.

On examination, her Blood pressure is 110/70 mm of Hg, her height is 154cm, and her weight is 42.5kg. The rest of the examination findings were normal with well-developed secondary sexual characters.

On her evaluation, she has bilateral medullary Nephrocalcinosis, and bilateral renal doppler ultrasound is normal. Her chest X-ray and ECG are normal.

Her serial investigations are in the Table 1 and Table 2:

Table 1

Showing serial metabolic profile
Serum Sodium(135–145 meq/L)	140	140	141	139	142	143	140
Serum Potassium (3.5-5 meq/L)	3.8	2.76	3.0	3.08	2.73	2.97	2.7
Serum creatinine (0.3–1.4 mg/dl)	0.9	0.7	0.8	0.75	0.8
Total calcium (8–11 mg/dl)	8			10.42	9.6		9.2
Albumin (3.5-5 g/dl)	3.5			3.8			4
Serum Phosphorous (2.5–3.5 mg/dl)	4.5			2.95	3.62		3.7
Serum magnesium(1.8–2.5 mg/dl)					1.44	1.47	1.8
iPTH (7.5–53.5 pg/ml)							129
1,25 dihydroxy Vitamin D (19.9–79.3 pg/ml)							9.6
ABG	pH:7.46, HCO3: 24, Pco2:31.8						pH: 7.45, HCO3: 24PCO2:34
TSH(0.5–4.4 mIU/L)		5	4.9
CA199: <39				26
CEA: <3.8				1.46
Serum Cortisol(140–690 nmol/l)		434

Table 2

Showing serial Serum osmolality and 24-hour urine studies
Serum Osmolality		289	293	290
Urine Osmolality	159	170	161	190
Calcium(20-300mg/24hrs)		274	234	325.3 Spot urinary Calcium:6.38mg/dl
Phosphorus
Oxalate(< 40mg/dl)	36.6
Citrate(250-1153mg/24hr)	157			204
Creatinine(500-2000mg/24h)	1320	584		660.4 Spot Urinary Creatinine:12.95mg/dl
Potassium(20-125mmol/24hr)		48	38	64.9 Spot Urinary Potassium: 12.73mmol/L TTKG = 7.18
Magnesium (24–255 mg/24hrs)				117.3 urinary Magnesium:2.3mg/dl

Her serum sodium is 140-143meq/l, serum potassium is 2.7-3.8meq/l, corrected serum calcium is 8.7–10.6 mg/dl, serum phosphorus is 2.95-4 mg/dl, serum magnesium is 1.44-1.8mg/dl, Arterial blood gas showed metabolic alkalosis with pH of 7.46, bicarbonate of 24.

Her 24-hour urine analysis showed total urine volume of 5L, Urine osmolality of 170, Urine potassium of 12.73mmol/L (serum K:2.7, serum osmolality 290), with TTKG of > 7 suggestive of Urinary potassium loss. Her 24-hour urinary calcium was 325.3 mg/24 hr. suggestive of hypercalciuria and magnesium was 117.3 mg/24 hr.

On further evaluation her serum cortisol was 434 nmol/l Intact PTH was 129 pg/ml and 1,25 dihydroxy Vitamin D was 9.6 pg/ml.

With the finding of hypokalemic metabolic alkalosis with hypercalciuria and hypomagnesemia her genetic study was done showing heterozygous mutation in KCNJ1 gene suggestive of Bartter syndrome, type 2 (OMIM# 241200)

Genetic Study:

The following KCNJ1 mutations were identified:

1.KCNJ1- NM_153766.3: c.601C > T;p.Leu201Phe,, heterozygote, exon 3

In silico prediction tools predict the identified variant to be damaging by EIGEN, FATHMM-MKL, MVP, LRT, DANN, DEOGEN2, LIST-S2, M-CAP, mutation Taster, Mutation assessor and PrimateAI.

2.KCNJ1- NM_153766.3: c.89G > A;p.Cys30Tyr, heterozygote, exon 3

In silico prediction tools predict the identified variant to be damaging by MutPred, DEOGEN2, EIGEN, FATHMM-XF, Mutation assessor, PROVEAN, LRT, MVP, PrimateAI, SIFT, DANN, LIST-S2, M-CAP and Mutation Taster

The overall prevalence of all types of BS in North America and Western European countries is estimated between 1 per 40,000 to 50,000, based on data from the Framingham Heart Study that found a prevalence of 1:100,000 for BS types 1 and 2 due to SLC12A1 and KCNJ1 variants(9).

BS type 2 (MIM #241200) is caused by defects in KCNJ1 which encodes an ATP-sensitive inwardly rectifying potassium channel (ROMK). ROMK is expressed in the apical membrane of the thick ascending limb and cortical collecting duct(10).ROMK recycles reabsorbed potassium from the intracellular space back into the intraluminal space and thereby provides the amount of potassium ions necessary for Na+-K+-2Cl- co-transporter. In the case of our patient with Bartter syndrome type II, malfunction of ROMK results in malfunction of Na+-K+-2Cl- co-transporter, causing hypokalemia, activated renin-aldosterone axis due to volume depletion, and metabolic alkalosis due to H + loss(11). Reabsorption of Ca2 + is a passive process coupled to Na + reabsorption. Impaired Na + reabsorption results in hypercalciuria and nephrocalcinosis. The biochemical profile of this patient supports the diagnosis of BS type 2, characterized by hypokalemia, metabolic alkalosis, hypercalciuria, and hypomagnesemia. Notably, the patient exhibited an increased level of intact parathyroid hormone, as seen in another case report(12).

The diagnosis of BS type 2 was confirmed through genetic testing revealing compound heterozygous mutations in the KCNJ1 gene, specifically the c.601C > T; p. Leu201Phe and c.89G > A;p.Cys30Tyr variants on exon 3. Bioinformatic tools predicted these variants to be damaging, reinforcing their pathogenic significance. To date, over 40 KCNJ1 mutations have been reported. Most of these mutations are missense/nonsense mutations substituting conserved amino acids residues, predominantly within the coding exon 2, the most influential putative functional domain of ROMK(6). Most of the reported cases with KCNJ1 mutations presented a severe BS phenotype in infancy. However, our case has heterozygous mutations on exon 3 with a mild phenotype.

Management of BS type 2 primarily involves addressing electrolyte imbalances and renal salt wasting. Since increased prostaglandin-E₂ (PGE₂) production plays a core role in the pathogenesis of BS. Prostaglandins (PGs) are the potential inhibitors of sodium reabsorption in the collecting duct(5). Thus NSAIDs, such as cyclooxygenase-2 (COX-2) inhibitors, are recommended as first-line therapy to inhibit prostaglandin synthesis and ameliorate renal salt wasting. Additionally, potassium and magnesium supplementation are essential to correct electrolyte disturbances. Adolescents and adults should be followed every 6 to 12 months to assess hypovolemia, degree of polyuria, signs of muscular weakness, fatigue, palpitation, and assessment of muscular strength. Laboratory evaluation of serum electrolytes, creatinine, BUN, determination of acid-base status either by blood gas or venous total CO₂, and PTH should be obtained. Kidney ultrasound should be performed every 12 to 24 months to detect kidney stones(2).

In conclusion, this case underscores the importance of considering rare genetic renal tubular disorders like BS type 2 in the differential diagnosis of patients presenting with persistent electrolyte abnormalities, polyuria, and nephrocalcinosis. Genetic testing is pivotal in confirming the diagnosis and guiding appropriate management strategies to optimize electrolyte balance and renal function, improving the patient's quality of life and preventing disease progression.

Bartter Syndrome

TAL

Thick Ascending Limb of the loop of Henle

ROMK

Renal outer Medullary Potassium Channel

PGE₂

Prostaglandin-E₂

NSAIDs

Non-steroidal anti-inflammatory drugs

Ethics approval and consent to participate: - As case reports are exempt from ethical approval in our institution, our article which describes a case report does not require additional permissions from the Ethics committee.

Consent for publication: - Full written informed consent was obtained from the patient for publication of her case, clinical images, and radiographic images. A copy of written consent can be made available to the editor in chief of this journal upon request.

Availability of data and materials: - all the data generated or analyzed during this study are included in the manuscript.

Competing interests: - The authors would like to declare that they have no competing interests.

Funding: - No funding was generated for this case study.

Authors' contributions:-

1. Seshkanta Lamichhane: design of study, data collection, evidence collection, manuscript writing and revision, involved in patient management, corresponding author.

2. Kushal Wasti: involved in patient management, data collection, design of study, manuscript writing and revision.

3. Manil Ratna Bajracharya: - involved in patient management, data collection, design of study, manuscript writing and revision.

4. Buddha Bahadur Karki: involved in patient management, data collection, design of study, manuscript writing and revision.

5. Eliz Achhami: design of study, data collection, manuscript revision

Acknowledgements: - We would like to thank the Endocrinology Unit team at Bir Hospital for their exceptional care and cooperation during the treatment and management of the patient.

Blanchard A, Vallet M, Dubourg L, Hureaux M, Allard J, Haymann JP, et al. Resistance to Insulin in Patients with Gitelman Syndrome and a Subtle Intermediate Phenotype in Heterozygous Carriers: A Cross-Sectional Study. J Am Soc Nephrol. 2019;30(8):1534. https://doi.org/10.1681/ASN.2019010031.
Konrad M, Nijenhuis T, Ariceta G, Bertholet-Thomas A, Calo LA, Capasso G, et al. Diagnosis and management of Bartter syndrome: executive summary of the consensus and recommendations from the European Rare Kidney Disease Reference Network Working Group for Tubular Disorders. Kidney Int. 2021;99(2):324–35. https://doi.org/10.1016/j.kint.2020.10.035.
Kömhoff M, Reinalter SC, Gröne HJ, Seyberth HW. Induction of Microsomal Prostaglandin E2 Synthase in the Macula Densa in Children with Hypokalemic Salt-Losing Tubulopathies. Pediatr Res. 2004;55(2):261–6. https://doi.org/10.1097/MNH.0000000000000346.
Huang L, Luiken GPM, van Riemsdijk IC, Petrij F, Zandbergen AaM, Dees A. Nephrocalcinosis as adult presentation of Bartter syndrome type II. Neth J Med. 2014;72(2):91–3. [PubMed].
Kömhoff M, Reinalter SC, Gröne HJ, Seyberth HW. Induction of Microsomal Prostaglandin E2 Synthase in the Macula Densa in Children with Hypokalemic Salt-Losing Tubulopathies. Pediatr Res. 2004;55(2):261–6. https://doi.org/10.1203/01.PDR.0000101747.09626.6B.
Gollasch B, Anistan YM, Canaan-Kühl S, Gollasch M. Late-onset Bartter syndrome type II. Clin Kidney J. 2017;10(5):594–9. PMC free article] [PubMed] [Google Scholar].
Li J, Hu S, Nie Y, Wang R, Tan M, Li H, et al. A novel compound heterozygous KCNJ1 gene mutation presenting as late-onset Bartter syndrome: Case report. Med (Baltim). 2019;98(34):e16738. PMC free article] [PubMed] [Google Scholar].
Sharma A, Linshaw MA. A novel compound heterozygous ROMK mutation presenting as late onset Bartter syndrome associated with nephrocalcinosis and elevated 1,25(OH)(2) vitamin D levels. Clin Exp Nephrol. 2011;15(4):572–6. PubMed] [Google Scholar].
Ji W, Foo JN, O’Roak BJ, Zhao H, Larson MG, Simon DB, et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet. 2008;40(5):592–9. [PubMed] [Google Scholar.
Ho K, Nichols CG, Lederer WJ, Lytton J, Vassilev PM, Kanazirska MV, et al. Cloning and expression of an inwardly rectifying ATP-regulated potassium channel. Nature. 1993;362(6415):31–8. [PubMed].
Proesmans W. Bartter syndrome and its neonatal variant. Eur J Pediatr. 1997;156(9):669–79. [PubMed].
Yıldız G, Bayram MT, Çinleti T, Koç A, Soylu A, Kavukçu S. Late onset Bartter syndrome: Bartter syndrome type 2 presenting with isolated nephrocalcinosis and high parathyroid hormone levels mimicking primary hyperparathyroidism. J Pediatr Endocrinol Metab. 2022;35(10):1298–301. https://doi.org/10.1515/jpem-2022-0154.

No competing interests reported.

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You are reading this latest preprint version

Bartter Syndrome Type 2 in Adolescence: Clinical Features and Genetic Confirmation

Status:

Version 1

Abstract

Background

Case Presentation:

Conclusions

Figures

Background

Case presentation

Genetic Study:

1.KCNJ1- NM_153766.3: c.601C > T;p.Leu201Phe,, heterozygote, exon 3

2.KCNJ1- NM_153766.3: c.89G > A;p.Cys30Tyr, heterozygote, exon 3

Discussion and Conclusions

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1