Bartter Syndrome, Type 3

A number sign (#) is used with this entry because classic Bartter syndrome type 3 (BARTS3) is caused by homozygous or compound heterozygous mutation in the kidney chloride channel B gene (CLCNKB; 602023) on chromosome 1p36.

Description

Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997).

Patients with antenatal (or neonatal) forms of Bartter syndrome (e.g., BARTS1, 601678) typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome present later in life and may be sporadically asymptomatic or mildly symptomatic (summary by Simon et al., 1996 and Fremont and Chan, 2012).

Genetic Heterogeneity of Bartter Syndrome

Antenatal Bartter syndrome type 1 (601678) is caused by loss-of-function mutations in the butmetanide-sensitive Na-K-2Cl cotransporter NKCC2 (SLC12A1; 600839). Antenatal Bartter syndrome type 2 (241200) is caused by loss-of-function mutations in the ATP-sensitive potassium channel ROMK (KCNJ1; 600359). One form of neonatal Bartter syndrome with sensorineural deafness, Bartter syndrome type 4A (602522), is caused by mutation in the BSND gene (606412). Another form of neonatal Bartter syndrome with sensorineural deafness, Bartter syndrome type 4B (613090), is caused by simultaneous mutation in both the CLCNKA (602024) and CLCNKB (602023) genes.

Also see autosomal dominant hypocalcemia-1 with Bartter syndrome (601198), which is sometimes referred to as Bartter syndrome type 5 (Fremont and Chan, 2012), caused by mutation in the CASR gene (601199).

See Gitelman syndrome (GTLMN; 263800), which is often referred to as a mild variant of Bartter syndrome, caused by mutation in the thiazide-sensitive sodium-chloride cotransporter SLC12A3 (600968).

Clinical Features

Bartter syndrome (Bartter et al., 1962) is an unusual form of secondary hyperaldosteronism in which hypertrophy and hyperplasia of the juxtaglomerular cells are associated with normal blood pressure and hypokalemic alkalosis in the absence of edema. The primary defect resides in active chloride reabsorption in the loop of Henle. The features are short stature, hyperactive renin-angiotensin system, lack of effect of angiotensin on blood pressure, renal potassium wasting, increased renal prostaglandin production, and occasionally hypomagnesemia.

Arant et al. (1970) reported 2 brothers with features of Bartter syndrome but with severe azotemia at the onset and in one of them renal osteodystrophy. Renal biopsy showed only mild hyperplasia of juxtaglomerular cells and severe glomerulonephritis. Most of the patients have shown retardation of growth and mental development, but the patient of Tarm et al. (1973) represented an exception. Erkelens and Statius van Eps (1973) described a patient with erythrocytosis in addition to the Bartter syndrome. They interpreted this as evidence that both renin and erythropoietin are produced in the juxtaglomerular apparatus. Dillon et al. (1979) studied 10 affected children, 2 of whom were sibs. Severity varied widely. Ages varied from 3 months to 15 years; sex distribution was equal. Hypercalcemia, hyperphosphatemia, hypercalciuria, nephrocalcinosis, rickets, and urine acidification defects were seen in some patients. Indomethacin effected remarkable clinical and biochemical improvement. Simopoulos (1979) observed a delayed growth spurt in Bartter syndrome resulting in attainment of normal stature. Two-thirds of the children have some degree of mental retardation.

The relation of the disorder reported by De Jong et al. (1980) to the Bartter syndrome was unclear. They studied an adult brother and sister with hyperaldosteronism and hyperkalemia who differed from cases of Bartter syndrome in the presence of hypertension. Response to indomethacin suggested excessive prostaglandin production which may have been primary. The sibs also showed tachycardia.

Ramos et al. (1980) demonstrated that the Bartter syndrome can be simulated by habitual vomiting, as in anorexia nervosa. Renal biopsy showed hyperplasia of the juxtaglomerular apparatus. Hyperkalemic alkalosis, normotensive hyperreninism, hyperaldosteronism, increased levels of urinary and plasma prostaglandin E (PGE), and vascular hyporesponsivity to angiotensin II were features identical to those of idiopathic Bartter syndrome, but unlike that disorder the patient showed low urinary chloride and no increase in the fractional chloride clearance. Any process that leads to hypokalemia can result in the Bartter syndrome. Wolfsdorf and Senior (1980) reported pseudo-Bartter syndrome in 2 infants fed exclusively with soybean-based formula which as a result of a manufacturing error was severely deficient in chloride.

In studies of 3 sibs, a boy and 2 girls aged 17, 11, and 18 years, Stoff et al. (1980) found a defect in platelet aggregation. They suggested that this may be caused by an increase in plasma cAMP resulting from excessive prostaglandins. Increased renal synthesis of these long chain fatty acids is presumably responsible for many features of the syndrome: vascular insensitivity, impaired urinary concentrating ability, and obligatory renal sodium loss. O'Regan et al. (1979) had demonstrated that presumed obligatory heterozygotes (parents) have impairment of epinephrine-induced platelet aggregation, thought to reflect an abnormality of prostaglandin metabolism. Furthermore, a circulating inhibitor of platelet aggregation, probably a prostaglandin, was found. The inhibition of platelet aggregation was aggravated by salt depletion (Stoff et al., 1980) although renal features improved. Baehler et al. (1980) reported a 43-year-old man with Bartter syndrome who had suffered from generalized weakness, muscle cramps, and chest pain since his teens, with aggravation of these symptoms in the previous 6 months. Family information was not provided.

Kurtz et al. (1981) described a family in which 5 of 9 sibs (aged 20 to 30 years) had bilateral nephrocalcinosis, hypercalciuria, chronic chloride-resistant renal metabolic alkalosis, and hypokalemia due to renal wasting. Creatinine clearance was little reduced. Plasma renin activity and urinary aldosterone excretion were abnormally high. Blood pressure was normal. No defect in the loop of Henle could be demonstrated. No further information and no definitive report was available (Sebastian, 1989). Ruvalcaba and Martinez (1992) described 3 sibs with a combination of isolated growth hormone deficiency and Bartter syndrome. The mother had short stature with growth hormone deficiency. Other members of the kindred had average stature. All the patients were normotensive. Treatment of the 2 youngest sibs with growth hormone in addition to potassium and magnesium resulted in greater than doubled growth velocity. Smilde et al. (1994) described a family in which 7 members had hypokalemic alkalosis with hypomagnesemia and hyperreninemic hyperaldosteronism. Also, as a major symptom, they had chondrocalcinosis, a known complication of Bartter syndrome. The proband was a female who presented at age 39 with acute attacks of arthritis and was found to have chondrocalcinosis of several joints. The metabolic changes of Bartter syndrome were found 15 years later and a decreased serum magnesium was found at the age of 61. Magnesium therapy was instituted at that time and over a period of 10 years a significant reduction of the calcifications was noted. Calcium pyrophosphate crystals were demonstrated in synovial fluid of the knee by polarized microscopy. In addition, 3 brothers out of a total of 9 sibs were also affected, as were a daughter and 2 sons of the proband. Symptomatic involvement of the symphysis pubis by the chondrocalcinosis was a feature in this family. The pattern of inheritance is consistent with autosomal recessive transmission if the proband were married to a heterozygote; none of the 16 children of her 3 affected brothers was affected. In all of the patients, urinary magnesium excretion was inappropriately high and urinary calcium excretion inappropriately low. Chondrocalcinosis by itself is usually an autosomal dominant (118600); combined potassium and magnesium wasting (263800) is an autosomal recessive disorder.

Simon et al. (1997) reported 17 kindreds with Bartter syndrome type 3, confirmed by genetic analysis. A review of index cases from each kindred showed that all had spontaneous hypokalemia (serum K+ levels as low as 1.1), all had elevation of serum bicarbonate, and all had evidence of salt-wasting. Age at presentation ranged from birth to 16 years. Six studied patients had elevation of serum renin and aldosterone. The fractional reabsorption of chloride in the TAL is normally 80 to 95%; in the index patients from 2 families, the fractional chloride reabsorption was profoundly depressed at 24% and 25%, respectively, indicating a striking defect in chloride reabsorption in the TAL. Hypercalciuria was present in 11 of 17 index cases, while 6 had calcium values in the normal range. The clinical picture in the cases described by Simon et al. (1997) varied in severity from near-fatal volume depletion with hypokalemic alkalosis and respiratory arrest or requirement for massive intravenous potassium replacement to very mild disease presenting with only polyuria and weakness at age 16. Even among patients with homozygous deletions, age at presentation and clinical severity were highly variable. A feature that distinguished the disorder clearly from other forms of Bartter syndrome was the absence of renal calcification (nephrocalcinosis) in all examined patients.

Fukuyama et al. (2004) reported 2 Japanese patients who suffered from clinically diagnosed classic Bartter syndrome but who had hypocalciuria. Hypocalciuria is believed to be a pathognomic finding of Na-Cl cotransporter malfunction. Two mutations in the CLCNKB gene were found (602023.0009, 602023.0010). The authors concluded that some CLCNKB mutations may affect calcium handling in renal tubular cells.

Sun et al. (2005) reported a patient with classic Bartter syndrome who had bilateral sclerochoroidal calcification. Optical coherence tomography showed normal retina and retinal pigment epithelium overlying the choroidal lesions. The patient had persistent hypomagnesemia and normocalcemia for 26 years despite magnesium supplementary treatment. The authors suggested that hypomagnesemia may have a pathogenic role in the development of sclerochoroidal calcification in this disorder.

Inheritance

Cannon et al. (1968) reviewed the subject and pointed out that affected twins were reported by Campbell et al. (1966) and affected sibs by Trygstad et al. (1967). Sutherland et al. (1970) described the disorder in 3 sibs (including a pair of female twins) and in the offspring of an incestuous (father-daughter) mating. Delaney et al. (1981) studied 6 affected sibs. Walker (1982) observed 3 affected sibs in a Filipino family. Rodrigues Pereira and van Wersch (1983) studied platelet aggregation in the parents and sibs of 8 patients with the Bartter syndrome and concluded that the findings supported autosomal recessive inheritance.

Pathogenesis

Gardner et al. (1970) presented evidence for a primary defect in membrane transport, based on studies of sodium content and outflux of erythrocytes. Ramos et al. (1980) suggested that the underlying mechanism in idiopathic Bartter syndrome appears to be a defect in chloride reabsorption in the ascending thick limb of Henle's loop, which allows excess secretion of potassium. Hypokalemia leads to increased prostaglandin synthesis. The distal fractional chloride reabsorption in the Bartter syndrome is about 0.4 rather than the normal of 0.92. Baehler et al. (1980) suggested that the 'proximate' cause of Bartter syndrome in a patient they studied was a primary defect in the reabsorption of sodium chloride in the ascending limb and not renal potassium wasting.

Scheinman et al. (1999) provided a comprehensive review of genetic disorders of renal electrolyte transport including Bartter and Gitelman syndromes.

Mapping

Simon et al. (1997) reported that their group had identified mutations in either NKCC2 or ROMK in 22 of 66 Bartter syndrome families. To ensure that the failure to find mutations in 44 families did not simply reflect incomplete mutation detection, they genotyped markers tightly linked to these 2 loci in 11 kindreds in which affected subjects were the offspring of consanguineous unions and tested for linkage by homozygosity. No evidence of linkage was found, indicating that mutations in other unlinked loci account for Bartter syndrome in the great majority, if not all, of the other kindreds. Considering CLCNKA (602024) and CLCNKB (603023) as candidate genes in these families, Simon et al. (1997) genotyped 3 polymorphic loci in these 11 kindreds. Affected subjects in 5 of these kindreds were homozygous at all loci, consistent with linkage to CLCNKA/CLCNKB (lod score of 4.72 at theta = 0), on chromosome 1.

Molecular Genetics

In affected members of 10 kindreds with Bartter syndrome type 3, Simon et al. (1997) found homozygous deletion of the CLCNKB gene. Two kindreds showed homozygous loss of part of CLCNKB. The authors also demonstrated 7 mutations altering the CLCNKB gene and cosegregating with the disease (see, e.g., 602023.0001-602023.0005).

Population Genetics

Hall (1971) reported that over three-fourths of families with Bartter syndrome in the United States are black. However, Gill (1980) reported that only 6 of 18 US families with Bartter syndrome in an NIH study were black.

History

In a family with 6 affected sibs out of 13, Graham et al. (1986) tested for concordance with a RFLP of the atrial natriuretic factor gene (ANF; 108780). The polymorphism did not cosegregate with the disease, thereby excluding ANF as the site of the abnormality in the Bartter syndrome.

Yabe et al. (1987) reported the case of a girl with Bartter syndrome associated with 21-hydroxylase deficiency (201910) and a balanced 6q;9p translocation. The 2 metabolic disorders were presumably unrelated; furthermore, neither seemed to be related to the translocation, since the healthy mother and 2 healthy sibs carried the same translocation.