Making a “dent” in hereditary hypercalciuric nephrolithiasis☆
Article Outline
Abstract
J Pediatr 1998;132:764-5
See related article, p. 859.
Urinary stone disease is a major worldwide health problem. As many as 12% of adults in the United States have a urinary stone at some time in their lives.1 Although much more frequent in adults, stones are sufficiently common in children that most pediatricians will care for patients with this condition. In both children and adults increased urinary calcium excretion is the most common specific metabolic abnormality associated with urolithiasis.2, 3 An autosomal dominant pattern of genetic transmission has been proposed for idiopathic hypercalciuria, the most frequently encountered type of hypercalciuria.4 Among patients with hypercalciuria and urolithiasis, more than 40% of first-degree relatives will have urolithiasis. Idiopathic hypercalciuria is found with nearly equal frequency among boys and girls with urinary stones. The gene defect(s) that causes idiopathic hypercalciuria remains unknown.
In 1991 a unique and severe form of nephrolithiasis, termed “X-linked re cessive nephrolithiasis with renal failure,” was described by Frymoyer et al.5 Patients with this condition have nephrolithiasis and proteinuria in childhood and progress to nephrocalcinosis and renal insufficiency as adults. X-linked recessive nephrolithiasis is associated with mutations in the renal-specific chloride channel (CLCN5) gene, located on chromosome Xp11.22.6 In this issue of The Journal, Schurman et al.7 alert pediatricians to this intriguing and progressive disorder. They describe a family in which two boys had microscopic hematuria, heavy proteinuria, and hypercalciuria, with a history of renal failure, nephrolithiasis, or both in male relatives. Low molecular weight protein excretion (α1-microglobulin and retinol-binding protein) was increased in affected male patients. Renal biopsies excluded hereditary glomerular diseases. Other clinical characteristics included nephrocalcinosis, glycosuria, aminoaciduria, and phosphaturia. In this family affected male and female carriers had a mis-sense mutation in the CLCN5 gene.7
Three additional disorders of hereditary hypercalciuric nephrolithiasis (Dent's disease, X-linked recessive hypercalciuric hypophosphatemic rickets and idiopathic low-molecular weight proteinuria, hypercalciuria, and nephrocalcinosis of Japanese children) also have been associated with mutations of the CLCN5 gene.8 The four X-linked hypercalciuric conditions with nephrolithiasis have a rather wide spectrum of clinical manifestations. Lloyd et al.8 have proposed that these conditions, collectively, be termed Dent's disease, because they share a common genetic cause. Each of these conditions is characterized by varying degrees of proximal renal tubular dysfunction, hypercalciuria, low molecular weight proteinuria, nephrocalcinosis, and occasionally renal failure or rickets.9, 10, 11 Metabolic bone disease may be severe in some patients.9, 11
Why mutations in the CLCN5 gene produce these unusual clinical syndromes is unknown. The role of the CLCN5 in calcium transport is undetermined and appears to be distinct from the proximal tubulopathy. CLCN5 belongs to a family of chloride channels.12 Some chloride channels are widely expressed, whereas others are tissue-specific such as the renal-related CLCN5.12 The human CLCN5 gene has a 2238 bp coding sequence that consists of 12 exons that span 25 to 30 kb of genomic DNA and encodes a 746 amino acid protein.6 CLCN5 has 12 transmembrane domains.6 Nineteen different CLCN5 mutations have been detected in the various forms of Dent's disease. To date no correlation has been found between specific CLCN5 mutations and clinical phenotypes.
Children with Dent's disease clearly differ from patients with urinary stones and idiopathic hypercalciuria; children with the latter disorder seldom, if ever, have proteinuria. When a boy with hypercalciuria, urinary stones, and proteinuria is encountered, Dent's disease should be suspected and the proteinuria studied to see whether it is low molecular weight protein. A careful family history may further suggest the diagnosis of X-linked recessive nephrolithiasis. Carrier mothers have asymptomatic low molecular weight proteinuria.13 Boys with hypercalciuria and low molecular weight proteinuria or other signs of Dent's disease should be monitored closely, and their parents should be cautioned of the potential for nephrocalcinosis or renal insufficiency.
Urinary stones have afflicted mankind throughout recorded medical history. Therapies for urolithiasis continue to be suboptimal and often can be initiated only after an excruciatingly painful stone episode occurs. As the genetic bases for urinary stone disease are clarified, exciting possibilities for effective preventive or curative therapies finally will emerge.
References
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