Medullary Nephrocalcinosis as the Initial Manifestation of Joubert Syndrome with a Novel INPP5E Mutation: A Case Report

Introduction

Joubert syndrome (JS) is a rare, autosomal recessive, neurodevelopmental disorder characterized by hypotonia, developmental delay, and distinctive brain malformations. When associated with renal, hepatic, or ocular involvement, it is termed JS and related disorders (JSRD). First described in 1969, JS has an estimated incidence of 1 in 80,000 to 100,000 live births.¹ Diagnosis relies on clinical features, characteristic MRI findings such as the “molar tooth sign” and “batwing fourth ventricle,” and genetic testing. Over 30 genes linked to primary cilia function have been implicated, INPP5E being among the most frequently affected.^1,2 Early diagnosis supports multidisciplinary care and genetic counseling.²

Case Report

A 13-year-old male with global developmental delay presented with right-sided abdominal pain and nausea. He was hemodynamically stable and had truncal obesity and tenderness of the right flank. Ultrasonography revealed bilateral echogenic medullary pyramids and hyperechoic foci, consistent with medullary nephrocalcinosis.

Given his developmental delay, obesity, and nephrocalcinosis, a metabolic workup was performed. Arterial blood gas analysis showed respiratory alkalosis (pH 7.50, PCO₂ 29.5 mmHg, bicarbonate 23.1 mmol/L). Serum calcium (9.3 mg/dL), phosphorus (4.2 mg/dL), parathyroid hormone (38 pg/mL), and vitamin D₃ (32 ng/mL) were normal. Hypercalcemia and renal tubular acidosis were excluded. Urinary calcium was elevated (654 mg/day; normal <200 mg/day), with regular citrate, oxalate, magnesium, and potassium levels. Urinalysis was unremarkable. Bartter syndrome, Dent disease, and familial hypomagnesemia with hypercalciuria and Nephrocalcinosis were considered unlikely based on the absence of characteristic features. Idiopathic hypercalciuria was suspected initially.

Upon further questioning, the patient’s mother reported that the patient frequently stumbled in dim light. Neurological examination revealed truncal ataxia and peripheral visual field restriction. Ophthalmologic evaluation confirmed bilateral retinitis pigmentosa. Brain MRI demonstrated the classic molar tooth sign and batwing-shaped fourth ventricle [Figure 1].

Close

Figure 1:

T1W axial cut showing (a) molar tooth sign (red arrow) and (b) T2W axial cut showing batwing-shaped fourth ventricle (red arrow).

Export to PPT

Whole-exome sequencing revealed a novel homozygous INPP5E variant, c.1304G>A (p.Arg435Gln) in exon 6, confirming JS with renal, retinal, and neurological involvement.

The patient’s abdominal pain resolved with hydration and analgesics. Physical therapy was initiated for ataxia. A renal stone-prevention diet was recommended, including moderate calcium intake, reduced oxalate and sodium, limited animal protein, and increased fluids and citrate. Ophthalmological findings required no intervention but warranted ongoing surveillance.

Discussion

While JS is primarily known for its neurological features, renal involvement typically follows a fibrocystic pattern, such as nephronophthisis (NPHP) or autosomal recessive polycystic kidney disease (ARPKD).³ Our patient exhibited subtle neurological signs and mild retinal involvement, likely contributing to the delayed diagnosis.

INPP5E is one of the more commonly implicated genes in JS,¹ but renal manifestations are reported in only about 4% of cases, usually limited to fibrocystic changes.^3-5 The identified c.1304G>A (p.Arg435Gln) missense mutation has not been previously reported.^4,5 The substitution of positively charged arginine with neutral glutamine may subtly impair ciliary function, which could explain the milder neurological and retinal features.

The renal presentation, however, is unusual. Isolated hypercalciuria and medullary nephrocalcinosis without cystic changes may represent an atypical form of medullary sponge kidney (MSK), a pattern sometimes observed in ciliopathies. However, no specific association with JS has been reported.³ Alternatively, a defect in calcium handling similar to that seen in Dent disease may underlie the findings.⁶ The possibility of hypercalciuria being unrelated to the genetic defect cannot be ruled out.

This case expands the renal phenotype associated with INPP5E-related JS. Isolated medullary nephrocalcinosis with hypercalciuria may be an underrecognized manifestation. Genetic evaluation should be considered in patients with developmental delay and unexplained nephrocalcinosis, even in the absence of classic syndromic features.