Bartter Syndrome, Type 4a, Neonatal, With Sensorineural Deafness

A number sign (#) is used with this entry because neonatal Bartter syndrome type 4A with sensorineural deafness (BARTS4A) is caused by homozygous or compound heterozygous mutation in the BSND gene (606412) on chromosome 1p32.

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 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 (see BARTS3, 607364) present later in life and may be sporadically asymptomatic or mildly symptomatic (summary by Simon et al., 1996 and Fremont and Chan, 2012).

For a discussion of genetic heterogeneity of Bartter syndrome, see 607364.

Clinical Features

Seyberth et al. (1985) described an infantile variant of Bartter syndrome. that was usually associated with maternal polyhydramnios, premature birth, postnatal polyuria and hypokalemic hypochloremic metabolic alkalosis, and a typical appearance. Some of the infants with the infantile variant of Bartter syndrome had been described as having a prominent forehead, triangular facies with drooping mouth, and large eyes and pinnae. In 5 children of an extended consanguineous Bedouin family, Landau et al. (1995) observed the combination of the infantile variant of Bartter syndrome and sensorineural deafness. In 3 of the cases, the typical electrolyte imbalance and facial appearance were detected neonatally. Deafness was detected as early as age 1 month. Shalev et al. (2003) evaluated 13 affected members of the family described by Landau et al. (1995). Most did not have persistent hypercalciuria and nephrocalcinosis nor was early renal function deterioration uniformly present.

Jeck et al. (2001) reported clinical findings in 8 patients from 6 consanguineous families with hypokalemic salt-losing tubulopathy showing linkage to 1p31. Clinical presentation was homogeneous and included premature birth attributable to polyhydramnios, severe renal salt loss, stimulation of the renin-angiotensin-aldosterone axis, hypokalemic alkalosis, and hyperprostaglandin E-uria. Patients later developed potassium-wasting, inability to concentrate the urine, and chronic renal failure. All patients showed severe muscle hypotonia, motor retardation, and complete sensorineural hearing loss. Response to indomethacin was poor.

Miyamura et al. (2003) reported a Japanese man who was born of consanguineous parents and had congenital sensorineural deafness but was not diagnosed with Bartter syndrome until age 28 years, when he presented with fatigue, numbness and weakness in both legs, and polydipsia. Characteristic features such as maternal polyhydramnios, premature labor, or severe salt loss in the neonatal period were not present in this patient, although he reportedly had polydipsia with polyuria in childhood. On examination, he had a peculiar facies similar to that reported in Costa Rican children with antenatal-onset Bartter syndrome (601678), characterized by a triangularly shaped face, protruding ears, and drooping mouth (Madrigal et al., 1997). Plasma renin activity, aldosterone, angiotensin II, and vasopressin levels were elevated, and he had impaired urine-concentrating ability. A routine abdominal x-ray showed nephrocalcinosis, although he did not have hypercalciuria or a history of renal calculi. Neither parent manifested any clinical symptoms of Bartter syndrome, and audiograms revealed moderate hearing loss consistent with their age. Miyamura et al. (2003) stated that this was the first case report of Bartter syndrome from Japan.

Mapping

Using a DNA-pooling strategy, Brennan et al. (1998) performed a genomewide linkage screen in the kindred reported by Landau et al. (1995) and demonstrated linkage of Bartter syndrome with sensorineural deafness to 1p31. They excluded the CLCNKA and CLCNKB genes, which encode kidney-specific chloride channels and map to 1p36. They also excluded the gene encoding amiloride-sensitive Na(+)-H(+) antiporter (SLC9A1; 107310), which maps to 1p36.1-p35. The findings in this family demonstrate further genetic heterogeneity of Bartter syndrome. In addition, the cosegregation of deafness in Bartter syndrome in individuals in 5 separate sibships, some of whom are moderately distantly related, with the same haplotype of markers surrounding the locus appear to prove that this syndrome is due to the pleiotropic effects of a single gene.

Vollmer et al. (2000) demonstrated linkage to 1p31 in 9 consanguineous families with antenatal Bartter syndrome with sensorineural deafness. They refined the critical disease region to a 4.0-cM interval flanked by markers D1S2661 and D1S475.

Sensorineural Deafness With Mild Renal Dysfunction

Riazuddin et al. (2009) performed genomewide linkage analysis in 2 consanguineous Pakistani families segregating apparent nonsyndromic deafness, designated DFNB73, and found linkage to chromosome 1p32. Screening of approximately 700 Pakistani families using microsatellite markers in the DFNB73 linkage interval revealed 2 additional consanguineous families segregating deafness linked to DFNB73. Meiotic breakpoint information in the 4 families defined a 4.04-cM interval containing 26 genes, including BSND (606412).

Molecular Genetics

Birkenhager et al. (2001) identified 7 different mutations in the BSND gene (606412.0001-606412.0007) in 10 families with Bartter syndrome with sensorineural deafness. To clone the BSND gene, Birkenhager et al. (2001) generated combined YAC/BAC contigs spanning the 4-cM interval between flanking markers D1S2661 and D1S475. Extensive haplotype sharing was detected between 5 families of Turkish descent, which narrowed the critical genetic interval to less than 900 kb. Within this interval a cloning gap persisted even after extensive screening, prompting submission of a clone bridging this gap to the Sanger Center for sequencing. Ten genes other than BSND were identified within the critical region; no mutations were found other than those in BSND.

In a Japanese man who was born of consanguineous parents and had congenital sensorineural deafness and mild Bartter syndrome that went undiagnosed until 28 years of age, Miyamura et al. (2003) identified homozygosity for a missense mutation in the BSND gene (G47R; 606412.0008). The unaffected parents were heterozygous for the mutation.

Sensorineural Deafness With Mild Renal Dysfunction

In affected individuals of 3 consanguineous Pakistani families segregating apparent nonsyndromic deafness, designated DFNB73, and mapping to chromosome 1p32, Riazuddin et al. (2009) identified homozygosity for a missense mutation, ile12 to thr (I12T; 606412.0009), in the BSND gene. In a fourth consanguineous Pakistani DFNB73 family, 22 of 25 affected individuals were homozygous for I12T, whereas 3 were compound heterozygous for I12T and another missense mutation, glu4 to ter (E4X; 606412.0010). Neither mutation was found in 384 Pakistani control chromosomes. Audiometric evaluation showed severe hearing loss across all frequencies, with no difference between homozygotes and compound heterozygotes. Further evaluation revealed minimal renal dysfunction in the I12T homozygotes involving only elevated renin levels and hypocalciuria, whereas the 3 compound heterozygotes displayed nephrocalcinosis, elevated renin levels, and electrolyte levels consistent with borderline but clinically insignificant metabolic alkalosis and hypokalemia.