A case of Menkes’ disease with nephrocalcinosis and chronic renal failure

Sirs, Renal tubule disorders have been reported in Menkes’ disease (MNK) [1–5]. Among others, hypercalciuria has been observed [3, 5]. We report the details of a child with MNK and nephrocalcinosis due to hypercalciuria. A 35-day-old boy was referred to our hospital with a diagnosis of MNK. He was the third child of an unrelated couple, and a previous son had died at 11 months of age from the same disease. The diagnosis of MNK was made on the basis of the following findings: hypotonia, seizures, sparse hypopigmented hair, low serum levels of copper (Cu) (30 μg/dl, normal range 70–140 μg/dl) and caeruloplasmin (7 mg/dl, normal range 15–54mg/dl). Light microscopy of his hair showed pili torti. Subcutaneous Cu histidine therapy (350 μg/day) was initiated. With this treatment, Cu and caeruloplasmin levels were maintained within the normal ranges. When he was 7 months of age renal ultrasonography revealed multiple bladder diverticula and marked bilateral medullary hyperechogenicity suggestive of nephrocalcinosis. He had no history of calcium or vitamin D supplementation or other drugs linked to hypercalciuria. Malabsorption was ruled out. Because of the nephrocalcinosis, his renal function was investigated. On initial evaluation his blood laboratory parameters were as follows: urea 32 mg/dl, creatinine 0.46 mg/dl, sodium (Na) 140 mEq/l, potassium (K) 4.2 mEq/l, chloride (Cl) 105 mEq/l, pH 7.34, bicarbonate 22 mEq/l, calcium (Ca) 9.3 mg/dl, phosphate (P) 4.5 mg/dl, alkaline phosphatase 440 IU/l, intact parathyroid hormone (iPTH) 26 pg/ml, magnesium (Mg) 1.95 mg/dl, uric acid 1.6 mg/dl. Urinary parameters were: urine flow 4.1 ml/kg body weight per hour, specific gravity 1.015 g/l, calciuria 8.2 mg/kg per day (normal < 4 mg/kg per day), magnesiuria 1.9 mg/kg per day (normal < 2.5 mg/kg per day), uricosuria 15.5 mg/kg per day (normal < 18 mg/kg per day), tubular reabsorption of phosphate (TRP) 94.4% (normal 80–95%), proteinuria 12 mg/kg per day (normal <5 mg/kg per day), microalbumin 8 μg/min (normal <20 μg/min), β-2 microglobulin 1,575 μg/l (normal <137 μg/l), uroproteinogram tubular pattern, citraturia 267 mg/day (normal 140–900 mg/day), oxaluria 22.2 mg/day (normal 13–38 mg/day), and results for glucose and aminoaciduria were negative. Blood pressure was always within the normal ranges. Restriction of sodium intake up to 1 g/day, hydrochlorothiazide 2 mg/kg per day and potassium citrate 2 mEq K/kg per day were indicated to reduce the hypercalciuria. During 4 years of follow-up, his urinary β2-microglobulin levels rose to 8,040 μg/l and microalbumin to 188 μg/min; hypercalciuria persisted, despite treatment, and creatinine clearance decreased from 81 ml/min per 1.73 m body surface area to 58.7 ml/min per 1.73 m body surface area. An excessive amount of Cu accumulates in the proximal convoluted tubular cells of patients with MNK, and increased Cu was found in the form of Cu-metallothionein (Cu-MT) [2, 3]. Metallothioneins are low molecular weight heavy metal-binding proteins, and Cu-MT overproduction is thought to contribute to cell necrosis [6]. Proximal tubule dysfunction has previously been reported in children with MNK. Two patients in the original observation of Menkes et al. were found to have albuminuria and aminoaciduria, respectively [1]. Ozawa et al. demonstrated a high rate of excretion of urinary β2Pediatr Nephrol (2009) 24:1255–1256 DOI 10.1007/s00467-008-1104-7