Hypokalemic Salt-Losing Tubulopathy With Chronic Renal Failure and Sensorineural Deafness

Abstract

ABSTRACT.Objective. To characterize a rare inherited hypokalemic salt-losing tubulopathy with linkage to chromosome 1p31.Methods. We conducted a retrospective analysis of the clinical data for 7 patients in whom cosegregation of the disease with chromosome 1p31 had been demonstrated. In addition, in 1 kindred, prenatal diagnosis in the second child was established, allowing a prospective clinical evaluation.Results. Clinical presentation of the patients was homogeneous and included premature birth attributable to polyhydramnios, severe renal salt loss, normotensive hyperreninemia, hypokalemic alkalosis, and excessive hyperprostaglandin E-uria, which suggested the diagnosis of hyperprostaglandin E syndrome/antenatal Bartter syndrome. However, the response to indomethacin was only poor, accounting for a more severe variant of the disease. The patients invariably developed chronic renal failure. The majority had extreme growth retardation, and motor development was markedly delayed. In addition, all patients turned out to be deaf.Conclusion. The hypokalemic salt-losing tubulopathy with chronic renal failure and sensorineural deafness represents not only genetically but also clinically a disease entity distinct from hyperprostaglandin E syndrome/antenatal Bartter syndrome. A pleiotropic effect of a single gene defect is most likely causative for syndromic hearing loss. Pediatrics 2001;108(1). URL: http:// www.pediatrics.org/cgi/content/full/108/1/e5; tubulopathy, Bartter syndrome, polyhydramnios, renal failure, syndromic deafness, pleiotropic gene.ABBREVIATIONS. HPS/aBS, hyperprostaglandin E syndrome/ antenatal Bartter syndrome; TAL, thick ascending limb of Henle's loop; PGE 2 , prostaglandin E 2 ; NKCC2, furosemide-sensitive Na-K-2Cl cotransporter; ROMK, renal outer-medullary potassium channel; SND, sensorineural deafness; GFR, glomerular filtration rate; BERA, brainstem-evoked response audiometry; PPN, partial parenteral nutrition. I nherited salt-losing tubulopathies with hypokalemic alkalosis involve an overlapping set of renal tubular disorders that can be subdivided into at least 3 phenotypes: 1) classic Bartter syndrome, 2) Gitelman syndrome, and 3) hyperprostaglandin E syndrome/antenatal Bartter syndrome (HPS/aBS). 1,2 Whereas patients with classic Bartter syndrome and Gitelman syndrome typically present in early infancy and childhood or adolescence, manifestation of HPS/aBS occurs in utero and the neonatal course is severe. 3 The first clinical sign is maternal polyhydramnios caused by fetal polyuria, which regularly results in premature birth between 28 and 34 weeks of gestation. 4,5 Postnatally, affected infants present with the typical pattern of impaired tubular reabsorption in the thick ascending limb of Henle's loop (TAL), including salt wasting, isosthenuric or hyposthenuric polyuria, and hypercalciuria with subsequent medullary nephrocalcinosis. 6 -8 Characteristically, endogenous formation of prostaglandin E 2 (PGE 2 ) is stimulated markedly, resulting in additional aggravation of saluretic polyuri...

Disease-Causing Dysfunctions of Barttin in Bartter Syndrome Type IV

“…5,10 In contrast, renal function was preserved in all patients carrying barttin mutations that do not prevent insertion into the surface membrane (i.e., homozygous patients with R8L [Dr. Georges Deschênes, Hôpital Robert-Debré, Paris, France; personal communication, January 29, 2008]), G10S, 11 G47R, 12,22,23 or E88X mutations. 14 Clinical data for the R8W mutation were not available.…”

“…2,3 Among them, Bartter syndrome type IV usually exhibits a severe phenotype. Fetal polyuria causes maternal polyhydramnios, 4,5 and, postnatally, salt wasting and polyuria occur as consequences of impaired tubular reabsorption. In some patients, renal failure occurs at a young age.…”

Recent Advances in Molecular Genetics of Hereditary Magnesium-Losing Disorders

“…Hypercalciuria and nephrocalcinosis are uncommon, and the response to indomethacin therapy is poor. In addition, many patients develop progressive renal failure of unknown etiology (83). By homozygosity mapping in a large Bedouin kindred, Brennan et al mapped this disease to chromosome 1p31 (84).…”

Activating Mutation of the Renal Epithelial Chloride Channel ClC-Kb Predisposing to Hypertension

“…The significance of these transport pathways for blood pressure regulation is illustrated by the fact that inhibitors of NKCC2, ie, loop diuretics, are highly effective in antihypertensive treatment. 12,13 Moreover, loss of function mutations of genes encoding NKCC2, 14 ROMK, 15,16 ClC-Kb, [17][18][19] barttin, 20,21 or ClC-Ka and ClCKb 22 lead to renal salt wasting and hypotension. 23,24 Beyond their localization in the TAL of Henle's loop, ClC-Kb and barttin are expressed in the macula densa and more distal segments of the nephron.…”