Dent Disease 1 Presented Early with Bartter-Like Syndrome Features and Rickets: A Case Report

Dent disease (DD) is a very rare X-linked recessive disorder of the proximal tubules generally presenting with low-molecular-weight proteinuria (LMWP), nephrocalcinosis, and hypercalciuria [1]. The disease is classified according to the underlying mutations in the chloride channel-gated 5 gene (CLCN5), known as DD 1 (DD1) (OMIM #300009) or the inositol polyphosphate-5-phosphatase gene (OCRL1), known as DD 2 (DD2) (OMIM #300555) [2]. Patients with DD phenotypes without CLCN5 or OCRL1 mutations are classified as DD 3 (DD3), a new classification first described in 2004 [3, 4]. Some cases of DD have uncommon presentations, namely, Bartter-like syndrome, which to our knowledge, only four cases have been reported worldwide [5‒8].

The presentation of DD1 at an early age could be atypical and lead to delay in diagnosis, particularly in low-middle income countries with limited diagnostic facilities, including Indonesia. Nevertheless, in high-resource countries, for example, in the UK, almost 50% of rare diseases have been under diagnosed and require more than 5 years for clinicians to confirm a final diagnosis. Misdiagnoses of rare diseases occur in 52% of cases before receiving the correct diagnosis [9]. Herein, we describe a case of Bartter-like syndrome presentation in a boy who was osteopenic during childhood, causing a knock-knee appearance. He was misdiagnosed with bone malformation while the important signs of failure to thrive, recurrent vomiting, and constipation were overlooked.

A thirteen-year-old Indonesian boy was referred to the emergency department of a tertiary hospital for recurrent nausea and vomiting since the previous month. Nausea and vomiting were suspected to be the gastrointestinal manifestations of COVID-19 infection, due to close contact with his parents, who were COVID-19 positive on reverse transcription polymerase-chain-reaction. The patient was positive for SARS-CoV-2 and was treated with oral paracetamol and ondansetron. Although his reverse transcription polymerase-chain-reaction turned out to be negative after 10 days of self-isolation, his nausea and vomiting persisted and he had blood tests which revealed severe hypokalemia, hypochloremia, and elevated serum creatinine (Table 1). He then received oral potassium slow release and was referred to our hospital for a pediatric nephrologist assessment.

In the previous medical history, the patient was noted to have an abnormal circumduction gait since the age of 4 and was eventually diagnosed with rickets at the age of 8 after the apparent presentation of knock-knees requiring a leg brace daily to support his stature. He could not withhold his stance for longer than 1 min and felt more comfortable sitting most of the time. He denied symptoms of generalized muscle weakness, fatigue, and cramps. He was seen by a pediatric endocrinologist and orthopedics who treated him with oral vitamin D supplementation, and he was planned for corrective surgery for the knock-knees. His growth pattern was typical of failure to thrive. The symptoms of polyuria, polydipsia (4.0–4.5 L of drink per day), nocturia, and salt craving were also noticed by the parents. The patient had neither developmental delay nor a history of convulsions and had normal cognitive development.

The patient was born following a vanishing twin pregnancy complicated by polyhydramnios at full-term, weighing 3,450 g, by Caesarean section due to placenta previa. The vanished twin was diagnosed at 6 weeks of pregnancy. The parents are non-consanguineous of Indian-Chinese-Indonesian origins. The mother had a history of still-birth labour and miscarriages (shown in Fig. 1a).

When presenting in the hospital emergency department at the age of thirteen, on physical examination, his body height was 140 cm (<3rd percentile, inconsistent with his genetic potential), body weight was 37.6 kg (10th–25th percentile), and body mass index (BMI) was 19.2 kg/m² (50th–75th percentile). His blood pressure (BP) was 100/50 mm Hg (<5th percentile). The sight and hearing were normal. The patient had bilateral genu valgum with excessive femoral anteversion and external tibial torsion (shown in Fig. 1b). His sexual development was at Tanner Stage II.

Investigations revealed severe hypokalemia with metabolic alkalosis, hypomagnesemia, hypophosphatemia, rising creatinine with decreased creatinine clearance, and increased alkaline phosphatase. Additionally, vitamin D, thyroid hormone, and parathyroid hormone levels were normal. Our early differential diagnoses were Bartter and Gitelman syndromes. Urine laboratory tests showed normal calcium/creatinine ratio and proteinuria without hematuria (Table 2).

Osteopenia was prominent in the X-ray of all four extremities, with metaphyseal fraying, cupping, and Harris lines (shown in Fig. 1c). In addition, the patient had unremarkable dental histories (normal tooth eruption and exfoliation) with a normal panoramic radiograph. Kidney ultrasonography (US) revealed contracted kidneys bilaterally without nephrocalcinosis and nephrolithiasis. Kidney biopsy displayed a few global glomerulosclerosis and segmentally sclerosed glomerulus. In the viable glomeruli, there was a slight mesangial matrix and cellular expansion in some glomeruli (shown in Fig. 2a, b).

After obtaining written informed consent from his legal guardian, the patient underwent whole-genome sequencing (WGS), which identified a hemizygous likely pathogenic variant in the CLCN5 gene. This finding confirmed the genetic diagnosis of X-linked DD1. The CLCN5 variant NM_001127898.3:c.2260del p.(Asp754Ilefs*7) created a shift in the reading frame starting at codon 754. The new reading frame ended in a stop codon 6 positions downstream, and the variant was classified as likely pathogenic according to American College of Medical Genetics and Genomics (ACMG) criteria [10]. No additional variants, including those linked to Bartter or Gitelman syndromes, were detected in the WGS result. Subsequent investigation requiring laboratory tests with samples sent overseas showed normal angiotensin II, increased renin and aldosterone, and increased urine beta-2-microglobulin (Tables 1, 2).

The patient was treated with oral potassium dihydrogen phosphate (1 g twice daily) and magnesium (500 mg daily) supplementations. As an additional treatment for hypokalemia, we gave him oral ramipril (2.5 mg daily), but his BP dropped to 86/55 mm Hg, and thus it was discontinued. The urine beta-2-microglobulin of his younger brother was high; therefore, the genetic test (carrier testing) was recommended. The parents were informed about the possibility of inheritance of DD in the family and progressivity to end-stage kidney disease. The patient is being followed up in our nephrological outpatient clinic, and his electrolyte levels have been maintained well with oral supplementations.

A less common feature of DD1 is rickets, observed in 19% of cases, which can result in skeletal deformities such as genu valgum [11]. Most parents become aware of the genu valgum at the age of 3–5 years. Our patient was noted to have an unusual gait since the age of four. In spite of this, the gait was not treated as an abnormality until eight. A delay in bone abnormality management in DD1 cases presented with secondary rickets could happen because the rickets diagnosis might be unconsidered, as bilateral genu valgum in this age group is generally physiologic [12].

In the early stages, manifestations of DD in children are mostly LMWP and/or hypercalciuria which are usually asymptomatic [1]. Hypokalemia is typically found when the patients experience skeletal muscle weakness. However, they could be asymptomatic until their potassium levels decreased to less than 2.5 mEq/L. Our patient is immobilized and does not move his lower extremities in particular because he needs a brace to help him walk. For this reason, hypokalemia was missed from a diagnosis during his childhood. The hypokalemia symptoms in our patient manifested as ileus; he complained of nausea, vomiting, and constipation. His hypokalemia was then identified when he had severe vomiting due to COVID medications causing his hypokalemia to become severe (exhibiting potassium levels of 2.11 mEq/L).

When the patient was first presented in our center, Bartter and Gitelman syndromes were some of the differential diagnoses considered due to hypokalemic metabolic alkalosis presentation and a maternal history of fetal polyhydramnios and multiple miscarriages. In DD1 cases presenting with pseudo-Bartter, hypokalemia is an important trait, and all were reported to have inappropriate kaliuresis, low-range blood pressure, and hyperreninemic and hyperaldosteronism [5‒7, 11]. Although a few hallmarks of Bartter and Gitelman syndromes were prominent in our case, namely, salt-craving and polyuria, the parents did not consider these symptoms unusual. Despite the physical abnormality being first presented at age 5, the patient remained undiagnosed until age 13 because he had not been referred to a clinician with the appropriate expertise. The DD condition is so rare that our clinicians are unaware of the uncommon diagnosis. Delayed diagnosis in rare diseases such as DD is a situation that can happen not only in developing countries but also in developed ones. In fact, in the UK, rare cases could be undiagnosed for more than 5 years from the first presentation because of difficulties in confirming the diagnosis. Furthermore, 37% of patients had received three or more incorrect diagnoses before getting a final diagnosis [9].

A strong suggestion of DD is a marked increase in LMWP, which can reach five-fold the normal range [4]. The absence of hypoalbuminemia despite a significant proteinuria in our case raised suspicion of a rare tubular problem. Further diagnostic approaches for tubular disorders, such as urinary LMW protein, prostaglandin E2, and amino acid, do not exist in Indonesia. While urine samples were sent abroad for an LMW protein test, the kidney biopsy in our case revealed significant findings as were reported in a previous DDs cohort, specifically tubular atrophy (61%), inflammatory fibrosis (61%), mesangial proliferation (7.7%), and focal global glomerulosclerosis (3.8%) [12].

To obtain the genetic diagnosis of the possible rare disease, WGS was performed because it has complete exomic coverage and includes the identification of noncoding pathogenic variation to obtain a final diagnosis [13]. The genetic test concluded a diagnosis of DD1 in our case. As the result confirmed a likely pathogenic variant in the CLCN5 gene, we recommended a carrier testing to diagnose the genetic problem in the patient’s younger brother for a possible DD1 diagnosis.

Although the CLCN5 gene is shown to be likely pathogenic in our patient, he has an atypical presentation. This conforms with a previous cohort of DD patients, which showed no phenotype/genotype correlation due to phenotypic diversity, as summarized in online supplementary Table 1 (for all online suppl. material, see https://doi.org/10.1159/000543719) [6‒8, 11, 14, 15]. The heterogenous clinical presentation of DD is suggested to be the widespread expression of ClC-5 protein in the kidney, encoded by the CLCN5 gene. ClC-5 is mainly expressed on the early proximal tubular cell endosomes and, to a lesser extent, in medullary thick ascending limb cells and the intercalated cells of the collecting duct [7, 11, 16]. The protein maintains intraluminal acidification by colocalizing with the V-type H⁺-ATPase. Hence, functional loss of ClC-5 impairs endocytosis and impairment of distal acidification due to H⁺-ATPase trafficking defect in the proximal tubules. This leads to diminished reabsorption and increased urinary albumin, LMWP, electrolytes, and solute excretion [16, 17]. In response to water and salt loss, the renin-angiotensin system might be activated, resulting in hypokalemic metabolic alkalosis, which manifests as pseudo-Bartter features, as shown in our patient [11, 18].

Other defects in proximal tubular function, such as phosphaturia, aminoaciduria, and glycosuria manifesting as the complete Fanconi syndrome (FS) or incomplete FS, could be caused by consequent abnormalities in membrane recycling [19]. Complete FS is defined as an impairment of proximal tubule reabsorption of sodium, bicarbonate, potassium, phosphate, glucose, amino acids, uric acid, LMWP, peptide, and other organic solutes. Incomplete FS, defined as LMWP and hypercalciuria with 1–3 proximal defects, was seen in 73% of DD1 patients [11, 19].

Our patient had severe rickets. Despite a normal vitamin D level and calcium/creatinine ratio, he had severe phosphate loss, as indicated by his low serum phosphate level. The mechanisms of hypercalciuria and nephrocalcinosis are unclear, decreasing with age and eGFR, with up to 30% of patients with CLCN5 mutations not showing hypercalciuria [11, 20].

Around 30–80% of DD1 in males progress to end-stage kidney disease between the age of 30 and 50 [21]. At the age of 13, our patient had reached CKD stage 3B. Our case management was challenged in choosing the best approaches to delay the patient’s CKD progressivity. DD1 interventions are aimed at reducing hypercalciuria and kidney stones prevention, which are absent in our patient. In addition, kidney function decline in DD1 can occur without nephrocalcinosis. Hydrochlorothiazide was not given to our patient because the kidney US evidenced no nephrocalcinosis or active stones.

With regard to the treatment of the above conditions, ACE inhibitors and angiotensin receptor blockers have been used in children with proteinuria to delay further decrease of kidney function [21]. For this reason, the patient was started on ramipril 2.5 mg daily (0.07 mg/kgBW). Despite low dose, he became hypotensive, and thus, the ramipril dose was reduced to 1.25 mg daily (0.03 mg/kgBW). However, some recent studies suggested ACE inhibitors or angiotensin receptor blockers were not proven to improve proteinuria [11]. Furthermore, they are not known to be helpful for focal global glomerulosclerosis in DD, and angiotensin blockade is not believed to significantly affect LMWP or any potential ill effects of it [21]. We maintained him on oral potassium dihydrogen phosphate, the only form of oral phosphate available in Indonesia, to treat his hypophosphatemia and hypokalemia. In addition, he also received oral magnesium. His electrolyte levels remained normal, and no medication side effects were noted until our follow-up ended.

Overall, rare disease diagnosis and management in low-middle income countries, such as Indonesia, still face challenges mainly due to the absence of a formal governance structure for rare diseases. Although the Indonesian National Foundation for Rare Diseases was established in 2016, no report or national registry for DD exists. Laboratories for necessary tests, including urinary LMW protein, prostaglandin E2, and amino acid, serum renin and aldosterone, and genetic tests, are not readily available, thus requiring samples to be sent overseas, which are costly and not supported by the national health insurance [22‒27]. Increasing awareness among clinicians and promoting the use of urinary LMW protein analysis and genetic testing in suspected cases of DD can facilitate earlier identification, minimize diagnostic delays, and enhance patient outcomes [28].

In conclusion, differentiating DD from Bartter and Gitelman syndromes can be challenging due to overlapping clinical features. DD can initially present with Bartter-like features, including hypokalemic metabolic alkalosis. Therefore, the presence of proteinuria in such cases is a critical distinguishing factor. Moreover, DD remains a possible diagnosis even in the absence of nephrocalcinosis or hypercalciuria, as indicated by normal US findings and urine calcium/creatinine ratios. LMWP would be imperative for the DD diagnostic approach in countries with limited laboratory facilities, particularly in the absence of a genetic test. Patients with a history of intrauterine polyhydramnios not associated with congenital malformations, as well as multiple maternal miscarriages, should lead clinicians to suspect kidney tubular disorders.

This case report was presented as a poster with the title “Dent Disease 1 Presented Early with Bartter-like Syndrome Features and Rickets: A Case Report” in the 15th Asian Congress of Pediatric Nephrology on November 13–15, 2023, in Dubai, United Arab Emirates.

The study was ethically conducted in accordance with the World Medical Association Declaration of Helsinki. Ethical approval is not required for this study in accordance with local guidelines. Written informed consent was obtained from the parent/legal guardian of the patient for publication of the details of their medical case and any accompanying images. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material.

The authors have no conflicts of interest to declare.

The authors received no specific funding for this work.

C.G.A. and H.A.P.A. performed the literature search, data collection, analysis, and interpretation and wrote the first draft of the manuscript. M.S. performed data collection and analysis. C.G.A. and J.J.K. critically reviewed the manuscript. C.G.A. and H.A.P.A. revised the final version of the manuscript. All authors read and approved the final version of the manuscript.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.