Dual Phenotype of Bartter Syndrome Type 2 and Pseudohypoparathyroidism 1b Due to Classic Digenic Inheritance of KCNJ1 and GNAS - A Case Report

Introduction

Digenic inheritance is the coexistence of variants in two or more genes, leading to a single phenotype or disease.¹ Bartter syndrome (BS) Type 2 is an inherited tubular disease caused by mutations in the KCNJ1 gene. It manifests as hypokalemia, metabolic alkalosis, normal to low blood pressure, and hypercalciuria predisposing to nephrocalcinosis. While traditionally classified as antenatal BS, it can rarely present later in life.

Pseudohypoparathyroidism (PHP)1b is characterized by hypocalcemia due to renal resistance to parathormone (PTH) without the Albright Hereditary Osteodystrophy (AHO) phenotype.

Although BS type 2 and PHP 1b are individually well documented, their cooccurrence in adults is exceedingly rare. We report this case to highlight the diagnostic and therapeutic challenges and the complex interplay of two independently inherited mutations.

Case Report

A 34-year-old male, born of a third-degree consanguineous marriage, was incidentally diagnosed with nephrocalcinosis 7 years ago but was lost to follow-up. He presented with carpopedal spasms and perioral numbness. His mother experienced polyhydramnios during pregnancy.

Examination revealed positivity for Chvostek and Trousseau signs. There was no AHO phenotype. He was normotensive, and systemic examination was unremarkable. Investigations [Table 1] revealed hypokalemia, hypocalcemia, hypercalciuria, elevated PTH, and metabolic alkalosis. Creatinine was 1.0 mg/dL with an estimated glomerular filtration rate (eGFR) of 101 mL/min/1.73m². On repeat evaluation, renal function had worsened (eGFR: 64 mL/min/1.73m²). Abdominal computerized tomography (CT) showed bilateral medullary nephrocalcinosis [Figure 1]. Whole-exome sequencing (WES) identified a homozygous variant in the KCNJ1 gene, NM_153766.3:c.506G>A (p.Arg169His), and a heterozygous variant in the GNAS gene, NM_001077490.3:c.1049C>T (p.Thr350Ile), both classified as variants of uncertain significance (VUS). Sanger sequencing confirmed the variant segregation in the family. The father was heterozygous for the KCNJ1 variant, while the mother was heterozygous for both the KCNJ1 and GNAS variants. Maternal hypocalcemia supported the phenotypic relevance of the GNAS variant. Thus, KCNJ1 and GNAS variants may be reclassified as pathogenic and likely pathogenic, respectively.

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Figure 1:

Abdominal computerized tomography (CT) scan showing bilateral nephrocalcinosis (red arrows) in the patient.

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He was treated with oral potassium chloride (40 mmol twice daily), calcium (500 mg twice daily), and calcitriol (0.5 µg twice daily) to alleviate hypocalcemic symptoms. After correction of serum potassium, hydrochlorothiazide (12.5 mg twice daily) was added for hypercalciuria. Symptoms and biochemical parameters are being monitored every 3 months.

Discussion

Hypocalcemia with hypercalciuria initially raised suspicion of ADHH (also known as BS type 5). However, instead of the expected low PTH levels (due to an activating mutation of the CaSR gene), elevated iPTH (with normal D3) was observed. Hypocalcemia in the background of hyperparathyroidism led us to also consider PHP. WES identified two mutations, suggesting BS2 with PHP type 1b. To our knowledge, no prior cases of adult BS2 with PHP1b confirmed by genetic analysis have been reported.

Typically, BS2 is life-threatening, and its late presentation in adulthood may suggest a milder variant or the modifying effect of PHP1b. This scenario highlights digenic inheritance, where one genetic mutation potentially modifies another’s effect.

Two potential modifying effects of the GNAS mutation on BS2 may be proposed. First, the tissue-specific allelic expression of GNAS results in proximal renal tubule resistance to PTH, while the distal tubule retains its anticalciuric response. This selective resistance could protect against hypercalciuria and subsequent nephrocalcinosis, a common complication of BS2. Second, low baseline calcium due to PHP may inhibit the calcium-sensing receptor (CaSR), which typically inhibits the activity of the NKCC2 transporter.² Reduced inhibition of NKCC2 could lead to increased sodium and calcium reabsorption in the kidney, preventing severe dehydration, a common life-threatening feature of BS2.

The co-occurrence of these rare genetic disorders, each affecting mineral metabolism differently, one promoting hypercalciuria and the other counteracting it, illustrates the importance of genetic analysis, revealing how digenic inheritance can result in a unique and less severe clinical presentation.

Previous cases reported reflect a similar clinical picture. Kiuchi et al.³ described a case of BS1 with PHP type 2. Bando et al. and Iba et al.^4,5 reported two PHP cases with BS based on the Ellsworth-Howard test and renal biopsy. But without genetic analysis, BS could not be classified. Zuo et al. reported eight KCNJ1 mutation cases, including one with PTH resistance and three with PTH overactivity.⁶

Management involves careful titration of calcium, calcitriol, and potassium supplements to alleviate symptoms, normalize urine calcium levels, and maintain PTH at a normal level. Indomethacin, typically used in BS2 to reduce renal salt wasting, was avoided due to renal impairment. Thiazides, while useful in reducing hypercalciuria, can exacerbate distal sodium delivery, worsening hypokalemia and metabolic alkalosis. Therefore, the treatment strategy must be carefully balanced to address hypocalcemia and hypercalciuria without worsening other electrolyte imbalances.

This case illustrates the intricate interplay of genetic mutations in digenic inheritance and their impact on clinical manifestations, necessitating a nuanced approach to diagnosis and treatment.