Cases reported • Nephrocalcinosis

1/12. Hypotensive ischemic optic neuropathy and peritoneal dialysis.

PURPOSE: To report anterior ischemic optic neuropathy associated with systemic hypotension in a patient undergoing continuous ambulatory peritoneal dialysis. methods: Case report. A 58-year-old man undergoing continuous ambulatory peritoneal dialysis developed painless blurred vision in both eyes and bilateral optic disk swelling with an altitudinal field defect in the left eye. Twenty-four-hour ambulatory blood pressure monitoring was requested in addition to other routine investigations. RESULTS: Routine blood pressure measurement in the clinic was 130/86 mm Hg, but ambulatory blood pressure monitoring demonstrated pronounced early morning hypotension with individual readings as low as 91/41 mm Hg. CONCLUSIONS: renal dialysis can render patients hypotensive, and this may be associated with anterior ischemic optic neuropathy. The overnight drop in blood pressure may not be appreciated with routine blood pressure measurement. Therefore, 24-hour ambulatory blood pressure monitoring should be considered when investigating patients with suspected anterior ischemic optic neuropathy who are undergoing renal replacement.

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2/12. The syndrome of renal tubular acidosis with nerve deafness.

Two brothers with renal tubular acidosis and nerve deafness are described. Studies of the physiopathological characteristics of the renal acidification defect show that the defect is limited to the distal tubule. Renal tubular acidosis with nerve deafness is a distinct nosologic entity that is determined by an autosomal recessive trait.

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3/12. Two heterozygous mutations of CLDN16 in a Japanese patient with FHHNC.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC, MIN 248250) is a rare autosomal recessive tubular disorder that eventually progresses to renal failure. However, the progression to end-stage renal failure can vary from patient to patient. A primary defect is related to impaired tubular resorption of magnesium and calcium in the thick ascending limb of Henle's loop. Recently, paracellin-1 was identified as a renal tight junction protein predominantly expressed in TAL. Mutations of its gene (CLDN16) have been shown to cause FHHNC. We describe a sporadic Japanese case of FHHNC. The male patient showed hematuria, hypercalciuria, and nephrocalcinosis at 5 years of age. Hypomagnesemia was also noticed at this time. As renal function gradually deteriorated, further evaluation was performed at 14 years of age and a diagnosis of FHHNC was made. Despite several medications (magnesium supplementation, citrate, and hydrochlorothiazide), he eventually progressed to renal insufficiency at 19 years of age. Analysis of the CLDN16 gene demonstrated two heterozygous mutations (R149Q and R216C). Mutations of the same amino acids have already been described in FHHNC and thus these mutations might be the cause of the disease in our patient. Hence, we confirm the genetic impairment of the CLDN16 gene in a Japanese patient with FHHNC.

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4/12. Familial hypomagnesemia--hypercalciuria and pseudotumor cerebri.

Approximately 30 patients with familial hypomagnesemia-hypercalciuria have been reported. We describe an 8-year-old girl with cardinal findings of familial hypomagnesemia-hypercalciuria (hypomagnesemia, hypermagnesiuria, hypercalciuria, renal insufficiency, hyperuricemia, elevated serum parathormone, hyposthenuria and nephrocalcinosis), who received combination therapy consisting of magnesium salts, thiazide diuretic and potassium supplementation. At the 4-year follow-up investigation under this treatment, the patient was found to have cerebral pseudotumor (increased intracranial pressure with normal or small ventricles on neuroimaging, no evidence of an intracranial mass and normal cerebrospinal fluid composition) with papilledema and visual field defects. Thiazide therapy was terminated and the cerebral pseudotumor disappeared. The authors hypothesize that cerebral pseudotumor in this patient was related to severe hypocalcemia, as a consequence of profound hypomagnesemia induced by protracted thiazide treatment. To our knowledge, this is the first report of a child with familial hypomagnesemia-hypercalciuria who developed pseudotumor cerebri after thiazide therapy.

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5/12. Case report of a rare syndrome associating amelogenesis imperfecta and nephrocalcinosis in a consanguineous family.

A rare syndrome associating amelogenesis imperfecta (AI) with nephrocalcinosis has been reported. The purpose of this study is to characterise the phenotype of a consanguineous family presenting amelogenesis imperfecta, delayed permanent teeth eruption and nephrocalcinosis. Six family members were examined. Ground sections of the case index deciduous teeth and biopsies of enlarged dental follicles were analysed. The patients's parents were first cousins. The case index had yellow discoloration and altered teeth shapes, retention of deciduous teeth, and delayed eruption. Panoramic radiographs revealed multiple enlarged pericoronal follicles in unerupted teeth and generalised intrapulpal calcifications. Renal ultrasound showed the presence of nephrocalcinosis. No other family members presented enamel defects or nephrocalcinosis. Histologically, the enamel appeared hypoplastic, and dental follicles indicated pericoronal hamartoma. The consanguineous marriage suggests an autosomal recessive mode of inheritance. Further studies are necessary to clarify the genetic defect behind this syndrome that associates AI, nephrocalcinosis and impaired tooth eruption.

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6/12. Unusual clinical presentation and possible rescue of a novel claudin-16 mutation.

CONTEXT: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is caused by a dysfunction of Claudin-16 (CLDN16) and characterized by renal wasting of Mg(2+) and Ca(2+). OBJECTIVE: The objectives of this study were to study the clinical parameters in suspected FHHNC patients, identify mutations in the CLDN16 gene, and analyze molecular defects associated with the mutant protein. DESIGN, SETTING, AND PARTICIPANTS: CLDN16 genes from two siblings diagnosed with FHHNC were sequenced. Expression and characterization of the mutant protein in renal MDCK cells were studied. OUTCOME MEASURES: Standard urine and serum parameters to diagnose FHHNC were determined. Mutations in the CLDN16 gene were identified. The subcellular distribution of the mutant protein was analyzed by immunofluorescence microscopy. RESULTS: urine and blood analysis showed signs typical for FHHNC. One patient, in addition, presented with hypocalcemic tetany, a phenomenon so far not described for FHHNC. Both siblings carry a novel mutation in CLDN16, Y207X. The review of medical records showed that hypocalcemia is not uncommon in the early childhood of FHHNC patients. Expressed in MDCK cells, the Y207X mutant is not detected at tight junctions but instead is found in lysosomes and, to a lesser extent, the endoplasmic reticulum. Surface expression can be rescued by inhibiting clathrin-mediated internalization. CONCLUSIONS: We propose that mutations in CLDN16 are considered in childhood hypocalcemia. CLDN16 Y207X is transiently delivered to the plasma membrane but not retained and is rapidly retrieved by internalization. Inhibitors of endocytosis may provide novel therapeutic strategies.

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7/12. nephrocalcinosis in siblings--familial hypomagnesemia, hypercalciuria with nephrocalcinosis (FHHNC syndrome).

Familial Hypomagnesemia, hypercalciuria with nephrocalcinosis is a rare autosomal recessive inherited disease associated with renal failure. Two girls born of consanguineous parentage aged 16 and 17 presented to us with renal failure, nephrocalcinosis and bone deformities. On evaluation they were found to have hypomagnesemia, hypercalciuria, increased fractional excretion of magnesium, hypocitraturia, renal failure and elevated PTH. Their parental screening was normal. There were no extra-renal features in them. One sibling had nephrolithiasis and the stone analysis revealed calcium phosphate stones. Both were treated with sodium bicarbonate, thiazides, calcitriol and calcium carbonate. They did not require dialysis during hospital stay. Both of them were treated conservatively. They are on regular outpatient follow up. The primary defect in this syndrome is impaired paracellular reabsorption of magnesium and calcium in the medullary thick ascending limb. Mutations in the PCLN-1gene which encodes for the tight junction protein paracellin -1 is identified as the underlying genetic defect. Ocular abnormalities and deafness are the commonly reported associations. End stage renal failure usually occurs in second to third decade. Renal transplantation is the definite treatment.

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8/12. growth failure associated with medullary sponge kidney, due to incomplete renal tubular acidosis type 1.

A girl, 12 years of age, was referred for short stature. Clinical examination and laboratory investigations currently performed in a case of growth failure gave normal results. Renal echography revealed a hyper-echogenic renal medulla. An excretory urogram showed medullary sponge kidney with bilateral renal calculi. An ammonium chloride loading test revealed a defect in acid excretion and led to the diagnosis of incomplete renal tubular acidosis. Treatment with oral bicarbonate was associated with an increase in growth velocity.

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9/12. Renal magnesium wasting, incomplete tubular acidosis, hypercalciuria and nephrocalcinosis in siblings.

polyuria, hyposthenuria, hypomagnesemia, hypercalciuria, advanced nephrocalcinosis, low citrate excretion and low glomerular filtration rates were observed in two female siblings who were followed over 10 years. Acid loading revealed incomplete distal tubular acidosis. Hypomagnesemia was due to renal magnesium wasting. It is suggested that the defect in tubular transport of magnesium is an important factor in the pathogenesis of this syndrome.

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10/12. Oxalosis of bone.

Skeletal survey in an 8-year-old girl with primary hyperoxaluria and in chronic renal failure revealed wide translucent metaphyseal bands and defects at the ends of the long bones. Similar disordered bone growth was seen as rims of rarefaction around the large epiphyses, the patella and the tarsal bones. bone density was generally increased. The translucent metaphyseal bands were separated from the diaphyses by an irregular line of increased bone density. biopsy of a bone defect showed massive deposition of oxalate crystals indicative of advanced oxalosis of bone.

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