Nephrogenic diabetes insipidus with idiopathic Fanconi's syndrome in a child who presented as vitamin D resistant rickets

Abstract

Fanconi's syndrome is a complex of multiple tubular dysfunctions of proximal tubular cells occurring alone or in association with a variety of inherited (primary) or acquired (secondary) disorders. It is characterized by aminoaciduria, normoglycaemic glycosuria, tubular proteinuria without hematuria, metabolic acidosis without anion gap and excessive urinary excretion of phosphorous, calcium, uric acid, bicarbonate, sodium, potassium, and magnesium. Whereas diabetes insipidus is a disease of collecting tubules and child mainly presents with dehydration and hypernatremia. Though all the cases published till date were secondary to drugs, myeloma, hematological disorders, etc., we are reporting the first case of idiopathic Fanconi's syndrome along with nephrogenic diabetes insipidus in a child who presented to us as resistant rickets. Medline search did not reveal any case of nephrogenic diabetes insipidus associated with idiopathic Fanconi syndrome. We hypothesized that the NDI may be due to of severe hypokalemia induced tubular dysfunction.

INTRODUCTION

Fanconi's syndrome is a complex of multiple tubular dysfunctions of proximal tubular cells occurring alone or in association with a variety inherited (primary) or acquired (secondary) disorders, idiopathic variety of Fanconi syndrome being an exception to this. Most cases are sporadic with few are inherited; the mode of inheritance appears to vary (autosomal dominant, autosomal recessive, Xlinked).[1] It is characterized by aminoaciduria, normoglycaemic glycosuria, aminoaciduria, nonanion gap metabolic acidosis and excessive urinary excretion of phosphorous, calcium, uric acid, bicarbonate, sodium, potassium and magnesium resulting in hypocalcaemia, hypophosphatemia, hypouricaemia, hypokalemia. Sometimes, hypophosphatemic rickets are the presenting complaint of it.[1] Whereas nephrogenic diabetes insipidus (NDI) is a disease of collecting tubules and child mainly presented with dehydration and hypernatremia.[2] There are few cases in which combined features of these two disorders are reported, mainly in association with antiretroviral therapy, hematological diseases like multiple myeloma and chemotherapy induced.

CASE REPORT

A 6-year-old male child presented with complaints of generalized weakness, polyuria, polydipsia, inability to stand and walk, failure to gain weight since 6 month of age. There is a past history of repeated fractures with trivial trauma. He was born after a second degree consanguineous marriage and birth history was uneventful. He had not received any long-term medications though there was history of receiving repeated injection of vitamin D for at least four times and oral calcium for rickets without any improvement. There was no history suggestive of heavy metals poisoning or regular drug intake. In developmental history he had delayed gross motor milestones; however social, speech, and fine motor development were comparatively preserved. On general physical examination, the patient was severely wasted and stunted. Florid rachitic changes were present which included frontal bossing, pectus carinatum, lordosis, prominent costochondral junction, wrist widening, genu valgum, and previous healed fractures. Abdomen was protruded but had no organomegaly. Cardio respiratory and central nervous system examination did not show any abnormalities.

Routine blood investigations revealed that Hb% –11.2 mg%, total leukocyte–9870/cmm, Platelets –2.2 lacs/cmm, serum calcium –10.5 mg/dL, phosphorus –2 mg/dL, sodium –157 meq/L, potassium –2.8 meq/L, blood urea –26 mg/dL, serum creatinine –0.6 mg/dL, Alkaline phosphatise –543 IU/L, serum albumin –4 gm/dL. Liver function test was found to be in normal range. Arterial blood gas analysis showed metabolic acidosis pH 7.255, HCO3 12.7 mmol/L, BE –13.1 mmol/L with anion gap 7.9 mmol/L.

Urine analysis showed pH 5.2, bicarbonaturia, glycosuria 2+ (corresponding blood sugar was normal), proteinuria (1+), phosphaturia, aminoaciduria, urinary sodium –53 meq/L, K –13.2 meq/L, Chloride –16 meq/L, positive urine anion gap, and measured urine output was >2 L/m²/day. In view of hypernatremia which was present in this patient serum and urine osmolarity was measured and found to be urine osmolarity –286 mosm/L and corresponding serum osmolarity –316 mosm/L. Skeletal survey revealed features of florid rickets and USG abdomen was normal. To find out the underlying etiology of proximal RTA, work up for tyrosenemia, cystinosis, galactosemia, Wilson's disease, fructose intolerance, mitochondrial disease, Dent's disease, Lowe's syndrome was done and the metabolic screen was found to be negative.

DI was confirmed by repeated tests with less urine osmolarity than serum osmolarity and hypernatremia. A vasopressin test was done using 5 iu as im single dose which did not show any improvement in urine osmolarity. Prevasopressin urine osmolarity was 260 mosm/L postvasopressin hourly readings were 264, 270, 256, and 262 mosm/L at 1, 2, 3, and 4 h respectively. Hence nephrogenic DI was confirmed.

With the above history and relevant supportive clinical and investigations results, the diagnosis of idiopathic Fanconi's syndrome with resistant rickets associated with NDI was made.

Patient was put on oral bicarbonates, phosphates, potassium, calcium supplements with indomethacin, hydrochlorothiazide, and calcitriol. Child was followed in OPD and is showing gradual improvement clinically and radiological features of healed rickets. He is still having severe restriction in his height.

DISCUSSION

The case presented with florid resistant rickets, polyuria, polydipsia, hypernatremia, and hypokalemia, metabolic acidosis with normal serum anion gap, positive urinary anion gap with bicabonaturia, phosphaturia, glycosuria, and aminoaciduria. The urine osmolarity was less than serum osmolarity and urine output was more than 2 L/m². Vasopressin stimulation test did not show further improvement in urine osmolarity. Different causes of RTA type 2 was ruled out as above and hence the diagnosis of idiopathic Fanconi's syndrome and RTA type 2 with NDI was finally made.

The review of various case reports published shows antiretro viral therapy, hematological malignancies and cystinosis (very common in children) as a common cause of NDI with Fanconi syndrome.[1–4] Ours is the first case report of idiopathic Fanconi syndrome with NDI in a paediatric population who presented as vitamin D resistant rickets.

NDI is characterized by resistance of the kidney to the action of argininevasopressin (AVP); it may be due to genetic or acquired causes. Acquired NDI most commonly is secondary to drugs such as lithium or metabolic disturbances, such as hypokalemia and hypercalcemia. Disturbance of the aquaporin 2 shuttle is the underlying molecular basis of acquired NDI.[5] This water channel is expressed at the apical membrane of principal cells of collecting ducts and mediates water transport across the apical plasma membrane of these cells. It is regulated by AVP in two ways. First, AVP has a short-term effect in triggering translocation of aquaporin 2 containing intracytoplasmic vesicles to the apical membrane.[5] Second, AVP has a long-term effect in increasing the expression of aquaporin 2 in collecting duct. The mechanism of these acquired NDI is a decrease of aquaporin 2 in the renal collecting duct.[5] Recent data show that hypokalemia reduces the expression of AQP 2.[6] Possible cause of NDI in our case is hypokalemia induced tubular dysfunction.