Pediatric Dent disease presenting with rickets and end-stage renal disease: case report and literature review

Abstract

Dent disease is a rare disease with proximal renal tubular dysfunction, and is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and chronic kidney disease. Renal failure slowly progresses and end-stage renal disease may develop in the late decades of life. We report a case of a 15-year-old boy who was diagnosed with Dent disease 1 with a CLCN5 truncating mutation. The patient presented with arthralgia and rickets at the onset of Dent disease and he was diagnosed with end-stage renal disease at the age of 15 years. His only symptoms were arthralgia and rickets during the disease course. The findings in this case suggest that patients with arthralgia and rickets could have a rare cause such as Dent disease.

Introduction

Dent disease is an X-linked disorder of proximal renal tubular dysfunction, characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and chronic kidney disease.^1–3 Dent disease has a pathogenic variant in CLCN5 (known as Dent disease 1) or in OCRL (known as Dent disease 2). ⁴ More than 60% of Dent disease is caused by CLCN5 mutation. ⁵ Low-molecular-weight proteinuria and hypercalciuria are most commonly observed in affected male patients and may be asymptomatic with onset of Dent disease. Affected male patients may slowly progress to chronic kidney failure, while end-stage renal disease (ESRD) may occur in the late adult ages, and occasionally, ESRD does not develop until the sixth decade of life or later. ⁴ Male patients with Dent disease 2 may also have mild intellectual disability, cataracts, and hypotonia.

We report here a 15-year-old boy who presented with symptoms of rickets and arthralgia, followed by detection of ESRD, and he was diagnosed with Dent disease 1 with a CLCN5 truncating mutation. We also review the relevant literature on progression of Dent disease to ESRD. The reporting of this study conforms to the CARE guidelines. ⁶

Case presentation

A 15-year-old boy was first referred to the Endocrinology Department because of his short stature. His mother complained that his height had not increased much in the last 2 years. The boy also complained he had intermittent arthralgia of both knee joints in the last 2 years. Initially, he had dull pain in both knee joints. The pain became aggravated and he could not even walk normally sometimes because of the knee joint pain. He went to a local orthopedics outpatient clinic and had an X-ray performed on his knee joints. He received analgetic treatment with plaster and diclofenac emulsion. He did not have a rash or frequent fever. There was no diarrhea, no vomiting, and his appetite was normal as usual. He also did not have encephalalgia, cough, polypnea, or gross hematuria. He tended to drink a lot of water. At the first visit to the Endocrinology outpatient clinic, over-pronation and the appearance of rickets were observed. He had a blood test for liver and renal function, and electrolytes. He was then transferred to the Nephrology Department for his renal dysfunction. All of the patient’s details have been de-identified.

Physical examination

A physical examination showed that the patient had a short stature of 145 cm in height (<3rd percentile). His weight was 55 kg. He had strephenopodia and genu valgum. The dorsal flexion angle of both ankle joints was limited. His blood pressure was 110/70 mmHg. A cardiac examination was normal, with no rashes and no periorbital or pedal edema.

Laboratory tests

An electrolyte test showed hypocalcemia and hypophosphatemia. A renal function test showed elevated creatinine and uric acid concentrations. A complete blood count showed anemia. The parathyroid hormone concentration was elevated, erythropoietin and hydroxyvitamin D3 concentrations were decreased, and the triglyceride concentration was slightly increased (Table 1). Liver function and complement concentrations were within the normal range. Autoimmune antibodies were negative. Urinalysis showed proteinuria and hematuria. Proteinuria was 2.4 g/day (Table 2). Urinary protein component analysis showed elevation of urinary excretion of albumin and low-molecular-weight protein concentrations (Table 2).

Table 1.

Laboratory test results.

Serum variables	Value at diagnosis	Reference range	Value at the 3-month follow-up
BUN (mmol/L)	17.2	3.2–7.1	28
Creatinine (mg/dL)	4.42 mg/dL	0.1–0.99	7.1
Uric acid (µmol/L)	505	208–506	558
Ccr (mL/min/1.73 m2)	13	90–120	8
Sodium (mmol/L)	140	135–145	142
Potassium (mmol/L)	3.37	3.5–5.1	4.22
Chloride (mmol/L)	104	98–107	106
Bicarbonate (mmol/L)	22	22–30	18
Total protein (g/L)	81	63–82	71
Albumin (g/L)	47.8	35–50	48
Calcium (mmol/L)	1.47	2.23–2.8	2.11
Phosphorus (mmol/L)	0.91	1.45–2.1	1.16
Alkaline phosphatase (U/L)	1379	38–126	548
Parathyroid hormone (pmol/L)	51.87	1.6–6.9	34.2
Vitamin D, 25-hydroxy (ng/mL)	20.29	>30	35.5

BUN, blood urea nitrogen; Ccr, creatinine clearance.

Table 2.

Urinary laboratory test results.

Variable		Variable		Reference range
pH	7.0	Alb/Cr (mg/mmol)	94.69	<2.8
Specific gravity	1.005	IgG/Cr (mg/mmol)	16.19	<0.8
Glucose	+	α1-MG/Cr (mg/mmol)	54.01	<1.58
Ketones	–	TRF/Cr (mg/mmol)	4.34	<0.11
Protein	2+	RBP/Cr	6.37	/
RBC/HPF	0–1	RBP (mg/L)	16.2	<0.7
WBC/HPF	–
24-hour proteinuria (mg)	2300
24-hour urinary calcium, mg	83

Alb, albumin; Cr, creatinine; IgG, immunoglobulin G; MG, macroglobulin; TRF, transferrin; RBP, retinol-binding protein; RBC, red blood cells; HPF, high-power field; WBC, white blood cells.

Imaging studies

Abnormal signals of the distal right femur and proximal tibiofibular metaphysis and epiphysis shown by right knee joint magnetic resonance imaging suggested metabolic bone disease. Multiple skeletal deformities were observed in the pelvis by X-ray. The kidneys were small (right kidney: 75 × 40 mm, left kidney 80 × 38 mm), poorly defined, and diffuse signals were detected by an ultrasound scan. There was no nephrolithiasis detected in the kidney by ultrasound. The left ventricular wall was slightly thickened, and left ventricular systolic function was within the normal range as shown by echocardiography.

Course

The patient had proteinuria, hypophosphatemia, hypocalcemia, and rickets. He had renal failure at the age of 15 years. Renal tubular disease or other genetic kidney or metabolic causes were suspected. Next-generation sequencing was performed. A hemizygous truncating variant of CLCN5 (NM_000084.4, c.100C > T, p.R34*) was detected and confirmed by Sanger sequencing. This variant was inherited from his mother. This mutation has already been reported as causing Dent disease. ⁷ Creatinine clearance was <15 mL/minute/1.73 m² and both kidneys were shrunken. A renal biopsy was not performed. No other secondary causes could be found to explain chronic kidney disease and progression to ESRD. The final diagnoses were rickets, Dent disease, ESRD, and hyperparathyroidism secondary to renal failure.

Signed consent for treatment was obtained from the patient and the parents. The patient was provided a low fat, low salt, and low protein diet and compound α ketonic acid. He was supplemented with vitamin D3 and calcium. High-dose calcitriol was administered to inhibit secondary hyperparathyroidism. Iron polysaccharide complex and erythropoietin were provided to treat his anemia.

After 3 months of treatment, the hypophosphatemia and hypocalcemia were obviously improved. The parathyroid hormone concentration had greatly decreased. The general condition of the patient was good, and daily urine output was approximately 2000 to 3000 mL. The patient had no complaints of headache, palpitation, cough, or nausea. Arthralgia of both knees and ankle joints was relieved. However, his renal function has worsened and he is waiting for renal replacement treatment.

Discussion

We report a case of Dent disease type 1 with a CLCN5 truncating mutation, with presentation of metabolic bone disease and renal failure at the age of 15 years. Early clinical symptoms of the patient included arthralgia of both knees and ankles at the age of 13 years, and a short statue. At the age of 15 years, he was diagnosed with hypophosphatemia, rickets, proteinuria, and renal failure in the absence of any of the other criteria of hypercalciuria or nephrolithiasis.

In 1964, Dent and Friedman described two unrelated male individuals with “hypercalciuric rickets” for the first time; one presented with rickets, acidosis, and hypercalciuria. ⁸ In the 1990s, Wrong and colleagues called this condition “Dent disease” and suggested that it was inherited in an X-linked fashion. ⁹ Shortly thereafter, the first gene associated with the condition, CLCN5, was identified and fully characterized. ¹⁰ Dent disease, which is an X-linked disorder of proximal renal tubular dysfunction, is characterized by low-molecular-weight proteinuria, hypercalciuria, and at least one additional finding, such as nephrocalcinosis, nephrolithiasis, hematuria, hypophosphatemia, and chronic kidney disease (CKD).^11,12 Dent disease may also be accompanied by rickets or osteomalacia, growth restriction, and a short stature.^13–15 Large cohort studies reported that common features were tubular proteinuria (present in 100% of all patients), hypercalciuria (varied from 39% to 92%), nephrocalcinosis (from 22% to 56%) and rickets (from 9.4% to 19%).^16–18

Patients with Dent disease often present with proteinuria and CKD, but CKD progresses slowly. ESRD may occur in later decades, but some patients do not develop ESRD in their entire life. The biggest cohort of 108 patients with Dent disease 1 showed that the estimated glomerular filtration rate decreased with age by 1.0 to 1.6 mL/minute/1.73 m²/year. ¹⁶ Twelve (11.1%) patients reached ESRD at a median age of 40 years. The age at diagnosis was 11 years, and ranged from 5 to 21 years. Another study from Poland studied 24 patients with Dent disease 1 and reported that CKD (≤stage II) was found in 45% of patients. ¹⁷ One patient who was diagnosed at the age of 1 year developed ESRD at the age of 14 years. A recent study from China on 32 patients with Dent disease 1 showed that 12.5% presented with renal dysfunction. ¹⁸ However, there were no details of the stage of renal dysfunction, and no information on whether any patient developed ESRD. These studies suggest that patients with Dent disease 1 slowly progress to chronic renal failure with a disease course of decades. Besides tubular damage, mutations in CLCN5 may also lead to primary podocyte dysfunction, which results in a histological picture of focal segmental glomerulosclerosis. ¹⁹ Glomerulosclerosis and nephrotic-range proteinuria are also prominent in Dent disease.^20,21 Biopsies from Dent disease show prominent histological findings, such as focal global glomerulosclerosis, mild segmental foot process effacement, focal interstitial fibrosis, interstitial lymphocytic infiltration, and tubular damage, while foot process effacement is associated with a greater annual decline in the estimated glomerular filtration rate. These findings suggest that glomerular pathology, specifically involving podocytes, in disease progression deserves further study in Dent disease. ²²

In our patient, a renal biopsy was not performed because of his atrophied bilateral kidneys and ESRD at the diagnosis of Dent disease. Therefore, we did not know the pathological manifestation of the kidneys. Pathological findings from Dent disease include nephrocalcinosis, interstitial fibrosis, and focal segmental glomerulosclerosis and/or focal global glomerulosclerosis. Copelovitch et al. reported two patients who had Dent disease with a CLCN5 mutation and developed proteinuria and biopsy-proven focal glomerulosclerosis. ²³ In patients with unexplained proteinuria and idiopathic focal glomerulosclerosis, Dent disease should be considered. Frishberg et al. also reported four patients who only presented with symptoms of Dent disease and had nephrotic-range proteinuria and histological findings of focal segmental and/or global glomerulosclerosis with causal CLCN5 mutations. ²⁴ Therefore, in Dent disease, focal segmental glomerulosclerosis and/or focal global glomerulosclerosis may also contribute to the progression to ESRD along with tubular dysfunction and hypercalciuria. CLCN5 is highly expressed in the kidney, primarily in the proximal tubular cells, and also in the glomerulus. ²⁵

To date, 266 different CLCN5 pathogenic variants have been described. The following pathogenic variants have been found: 48% were truncating mutations (nonsense, frameshift or complex); 37% were non-truncating mutations (missense or in-frame insertions/deletions); 10% were splice site mutations; and 5% were other types (large deletions, Alu insertions, or 5′UTR mutations).^25–27 The spectrum of pathogenic CLCN5 variants shows great variety, and de novo pathogenic variants are common. These pathogenic variants are scattered throughout the gene’s coding sequence. There is no phenotype and genotype correlation. The mutation detected in this case was reported by Hoopes et al. ⁷ Their case showed the phenotype of rickets and slightly decreased renal function.

In this case, the patient presented with hypophosphatemia, rickets, proteinuria, and renal failure with ESRD, but not hypercalciuria. No hypercalciuria and ESRD at the diagnosis of Dent disease are uncommon. As mentioned above, hypercalciuria is common at the beginning of Dent disease, but at the late stage of this disease, hypercalciuria can disappear with a decline in renal function. Development of ESRD usually takes decades, but in this case, the patient already had ESRD at the time of his diagnosis, and the only onset symptoms were arthralgia and a short statue. Our findings suggest that the onset and progress of Dent disease are insidious. Physicians who treat patients with arthralgia and rickets should be aware of other causes such as Dent disease.