Utility of Genetic Analysis in Rare Tubulopathies Presenting with Bilateral Nephrocalcinosis in Adults - Avoiding Harm with Precision Care: A Case Series

Introduction

Nephrocalcinosis (NC) is a condition associated with a wide variety of genetic and metabolic causes, which poses a significant diagnostic challenge.¹ We report two such cases of NC where genetic testing helped resolve the diagnosis odyssey and stop unnecessary interventions.

Case Series

Case 1

A 19-year-old male, born out of consanguineous marriage marriage, had bilateral renal NC diagnosed by imaging [Figure 1]. He had a history of painless graveluria. Investigations showed raised serum creatinine with hypocalcemia, hypokalemia, hypomagnesemia, and hypouricemia [Table 1]. Renal biopsy showed a pattern of chronic tubulo interstitial disease [Figure 2a-b]. Genetic evaluation identified a homozygous pathogenic mutation of the MOCOS gene, confirming undiagnosed xanthinuria type 2. He suffered once metabolic seizure from hypocalcemia. He was receiving low-dose sodium bicarbonate, magnesium supplementation, calcitriol, levetiracetam, high fluid intake, and a purine-restricted low-protein diet, remained well with one episode of passing two small stones during 1 year follow up.

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Figure 1:

Radiograph of the kidney, ureter, bladder (KUB) region demonstrates bilateral nephrocalcinosis along with two radiographic densities adjacent to L2and L3 vertebrae on the right and a radiopaque density on the left side of the pelvis, suggesting ureteric calculi.

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Table 1: Important clinical and laboratory characteristics

Parameters	Case 1	Case 2
Age at presentation (years)	19	25
Family history	Nil, consanguinity present	Nil
Presenting problem	Nephrocalcinosis with renal dysfunction	Polyuria, nephrocalcinosis post parathyroidectomy
Clinical examination	No bony deformity or extra renal abnormality	No bony deformity, dental caries, and mild deafness
Blood pressure (mmHg)	110/70	110/70
Height (cm)	153	173
Weight (Kg)	45	57
BMI (kg/m2)	19	19
Hemogram
Hemoglobin	12.6	14.6
TLC	3,400	11,500
Platelets	1.2 lakhs	2.48 lakhs
Complete urine examination
Protein	Trace	Nil
RBC (/hpf)	3-4	10-12
WBC (/hpf)	3-4	2-3
Specific gravity	1010	1005
UPCR	1.4	0.22
Serum creatinine (eGFR) (mg/dL)
Initial	3.6	1.49
Follow-up	3.15	1.32 (last)
Serum Na/K/Cl/Bicarb (mEq/L)
Na (mEq/L)	143	139
K (mEq/L)	3.4	2.8
Cl (mEq/L)	107	99
Bicarbonate (meq/L)	22	28
Ca (mg/dL)	5.3	8.9
P (mg/dL)	5	3.2
Alkaline phosphatase (IU/L)	212	220
VitD (ng/mL)
Initial	29	23
Last follow-up	35	45
PTH (pg/mL)
Initial	679.3	440
Last follow-up	539	212
Serum magnesium (mg/dL)	1.4 (1.1 last follow-up) (unexplained)	1.4 (1.6 last follow-up)
Serum uric acid (mg/dL)	0.1	9.2
Serum glucose (mg/dL)	88	90
24-hour urine calcium (mg/day)	137	312
24-hour urine-uric acid (mg/day)	11.47	Not done
ABG
pH	7.44	7.41
pO2 (mmHg)	70	110
pCO2 (mmHg)	39	44
HCO3 (mmol/L)	24.9	29.7
Abdominal imaging (X-ray KUB/USG)	Bilateral nephrocalcinosis and ureteric calculi on X-ray [Figure 1] confirmed as medullary nephrocalcinosis with normal size kidney	Bilateral nephrocalcinosis and osteoporosis [Figure 3] confirmed on sonography, as medullary nephrocalcinosis, with normal size kidney
Renal biopsy	Chronic tubulointerstitial nephritis (nephronophthisis [Figure 2a-b]	Not needed
DEXA scan	Not done	Severe osteoporosis-T score 2.7 at spine and 2.8 at femur
Genetic mutation (Whole exome sequencing)	Homozygous pathogenic mutation at exon 7 of the MOCOS gene-xanthine oxidase function gets inhibited (c.1255C>T p. Arg419Ter(127x/127x)]	Homozygous pathogenic mutation at exon 3 of KCNJ1 makes the ROMK channel dysfunctional (c.601C>T(p.Leu201.phe.)
Final diagnosis	Xanthinuria type 2	Bartter’s syndrome type 2
Follow-up status	Asymptomatic, preserved GFR (26 mL/m), persistent biochemical derangement (low uric acid, calcium, and magnesium) at 1 year	Improvement in muscle cramps, preserved GFR (77 nL/m), persistent biochemical derangement low K, Magnesium, high bicarbonate) at 2 years

UPCR: Urine protein/creatinine ratio, BMI: Body mass index, PTH: Parathyroid hormone, X-ray KUB: Kidney, ureter, bladder, USG: Ultrasonography, DEXA scan: Dual energy X-ray absorptiometry, ABG: Arterial blood gas, TLC: Total leucocyte count.

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Figure 2:

(a) Panel A shows sclerosed glomeruli (red arrows) with foci of tubular atrophy of the classic ( bluearrow) and endocrine (green arrow) type. (PAS X100). (b) Panel B shows irregularly branched and convoluted tubules with irregular thickening and laminationof the basement membrane (red arrows) (PAS X 100).

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Case 2

A 25-year-old was diagnosed with bilateral medullary NC [Figure 3], osteoporosis, and raised parathyroid hormone (PTH) during evaluation for backache. He had undergone parathyroidectomy 2 years ago for a parathyroid adenoma. However, his postoperative PTH did not normalize. He gave a history of excessive thirst with polyuria from childhood. He had dental caries and deafness. Biochemical evaluation showed abnormalities consistent with Bartter’s syndrome (BS) (hypokalemic metabolic alkalosis, hypercalciuria, hyperuricemia, hypomagnesemia). Genetic evaluation confirmed it as type 2 BS due to a homozygous KCNJ1 gene mutation. He received potassium, magnesium, and salt supplements along with urate-lowering therapy, calcium carbonate, and cinacalcet, and has been doing well at 2 years.

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Figure 3:

Radiograph of the KUB region demonstrates bilateral nephrocalcinosis with osteoporosis. KUB: Kidney, ureter, bladder.

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Discussion

NC represents a final common pathway of several genetic, metabolic, and acquired disorders, and often poses a formidable diagnostic challenge. Conventional clinical and biochemical evaluations may not sufficiently discriminate between overlapping phenotypes, leading to prolonged diagnostic odysseys and at times, inappropriate interventions. Both cases presented here illustrate how genetic testing was pivotal in unravelling the underlying etiology and guiding targeted management.

In the first patient, nonspecific manifestations such as NC, electrolyte abnormalities, and chronic tubulointerstitial nephropathy obscured the diagnosis. Identification of a homozygous MOCOS mutation established xanthinuria type 2, a rare and treatable metabolic disorder.^2,3 Renal hypouricemia (tubular transport defect due to genetic mutation) can be distinguished by high urinary uric acid excretion though serum biochemistry may mimic xanthinuria and and needs special recognition because of its peculiar association with exercise-induced AKI.⁴ This obviated unnecessary invasive investigations and facilitated rational therapy, including dietary purine restriction, supplementation of deficient electrolytes, and seizure prevention, with sustained clinical stability avoiding preemptive transplant.⁵

In the second patient, biochemical features suggested BS, but prior parathyroidectomy for presumed primary hyperparathyroidism reflected the diagnostic uncertainty. Genetic confirmation of type 2 BS⁶ due to a homozygous KCNJ1 mutation not only clarified the pathophysiology of persistent hyperparathyroidism and NC but also permitted optimization of therapy with electrolyte, salt, and calcimimetic supplementation.

Thus, in both instances, genetic testing resolved complex diagnostic dilemmas, prevented further misdirected interventions, and enabled personalized, effective treatment strategies.