Overview of Bartter Syndrome Type IVa

遺伝子領域 | Implicated Genomic Region

BSND

Overview of Bartter Syndrome Type IVa

Bartter syndrome is a rare inherited disorder that affects how the kidneys regulate salt and electrolyte balance. Among its subtypes, Type IVa is one of the more severe forms, caused by mutations in the BSND gene. These mutations interfere with the normal functioning of kidney ion channels and also affect the inner ear, leading to a combination of kidney dysfunction and sensorineural hearing loss. This subtype, sometimes referred to as infantile Bartter syndrome with sensorineural deafness or DFNB73, often becomes apparent in the womb or shortly after birth.

Children with this condition commonly present with dehydration, poor growth, and significant electrolyte disturbances, along with bilateral hearing loss that persists throughout life. Understanding the genetic, clinical, and biochemical basis of this syndrome is crucial for accurate diagnosis and management.

Genetic and Molecular Basis

The BSND gene is located on the short arm of chromosome 1 (region 1p32.3) and encodes a protein known as Barttin. This protein plays a critical role in supporting the function of two chloride channels, ClC-Ka and ClC-Kb, encoded by the genes CLCNKA and CLCNKB respectively. These chloride channels are found in specific tissues where electrolyte handling is vital: the thick ascending limb of the loop of Henle in the kidneys and the inner ear.

When the BSND gene carries mutations, the production or function of Barttin is disrupted. Without properly functioning Barttin, the chloride channels cannot assemble or operate as needed. In the kidneys, this leads to significant salt and fluid losses, while in the inner ear, it disrupts the potassium circulation needed to generate the endolymphatic potential, which is essential for hearing. This dual disruption explains why patients present with both renal abnormalities and sensorineural hearing loss.

Epidemiology

Bartter syndrome is extremely rare, with an estimated frequency of about 1 in 100,000 live births. Type IVa is rarer still. Certain regions such as Costa Rica and Kuwait report higher numbers of cases, often linked to consanguinity, where parents are related by blood. In such populations, autosomal recessive conditions like this one are more common, since both parents are more likely to carry the same pathogenic gene variant.

Etiology

The condition follows an autosomal recessive inheritance pattern, meaning that a child must inherit two defective copies of the BSND gene, one from each parent, to develop the disorder. When Barttin is absent or malfunctioning, the chloride channels in both the kidneys and inner ear are compromised. The kidneys lose the ability to reclaim sodium and chloride efficiently, resulting in excessive urinary losses and electrolyte imbalance. At the same time, the inner ear cannot maintain the ionic gradient required for normal auditory function, leading to congenital bilateral sensorineural hearing loss.

Clinical Presentation

Symptoms in Pregnancy and the Newborn Period

The earliest signs often develop during pregnancy. Around 22 to 28 weeks of gestation, the fetus begins producing unusually large amounts of urine, which leads to polyhydramnios, or excessive amniotic fluid. This excess fluid increases uterine pressure, raising the risk of premature birth. Babies are often born with low birth weight and present shortly after birth with dehydration and difficulties in gaining weight due to ongoing salt and fluid losses. Severe polyuria, or high urine output, is common, as are electrolyte imbalances, particularly low levels of potassium and chloride. In nearly all cases, bilateral sensorineural hearing loss is present at birth, though the severity can vary.

Symptoms in Infancy and Childhood

As children grow, additional complications become evident. Persistent hypokalemia can lead to muscle weakness, cramping, and occasional nausea. Many children crave salt and may develop constipation due to electrolyte imbalance. Growth is often delayed, and children may remain shorter than their peers or experience delayed puberty. Low muscle tone and delayed motor milestones are also frequently observed. Over time, children may develop subtle but characteristic facial features, such as a pointed chin, downturned corners of the mouth, and relatively prominent ears.

Diagnostic Evaluation

Blood and Urine Testing

The diagnostic process often begins with biochemical testing. Blood tests typically reveal hypokalemia (potassium levels below 3 mmol/L), hypochloremia (low chloride levels), and metabolic alkalosis, where blood becomes abnormally alkaline. Hormone testing usually shows elevated renin and aldosterone, reflecting the body’s attempt to compensate for salt losses. Urinary analysis often detects excessive excretion of sodium and calcium, reinforcing the diagnosis of a salt-wasting renal disorder.

Hearing Assessment

Audiological testing is crucial. Otoacoustic emissions (OAE) testing usually shows no measurable response, indicating dysfunction of the cochlear hair cells. More detailed evaluations, such as brainstem evoked response audiometry (BERA) and auditory steady-state response (ASSR), help to quantify the degree of hearing loss and confirm the absence of normal auditory pathway signaling.

Genetic Testing

Definitive diagnosis is made through genetic testing, typically via a panel that includes the BSND gene. In some cases, testing of the CLCNKB and SLC12A1 genes is recommended to rule out other genetic subtypes of Bartter syndrome. For families with a known mutation, prenatal genetic testing through procedures such as amniocentesis can confirm whether the fetus is affected.

Management and Treatment

Management During Pregnancy

When polyhydramnios is detected, close monitoring is essential. In some cases, drugs such as indomethacin may be administered to reduce fetal urine production, though this requires careful oversight due to potential effects on the fetal cardiovascular system.

Postnatal and Long-Term Management

Treatment after birth focuses on correcting and maintaining electrolyte balance. Oral supplementation of sodium chloride (5–10 mEq/kg/day) and potassium chloride (2–5 mEq/kg/day) is the mainstay of therapy. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin or ibuprofen, may be prescribed to reduce renal salt loss, while potassium-sparing diuretics like spironolactone or amiloride help to minimize potassium depletion.

For hearing loss, early intervention is key. Many children benefit from hearing aids, while others may require cochlear implants depending on the severity of impairment. Early speech and occupational therapy support better language acquisition and cognitive development. In children with persistent short stature despite good metabolic control, growth hormone therapy may be considered under specialist supervision.

Prognosis

Hearing loss associated with Type IVa Bartter syndrome is irreversible, but early audiological support and consistent therapy significantly improve communication outcomes and quality of life. Kidney function varies among patients; while many maintain relatively stable renal health with good management, there is a recognized risk of progression to chronic kidney disease (CKD), particularly in more severe cases.

Growth and developmental outcomes also depend on early intervention. Many children grow into adulthood with near-normal height if treatment is optimized, though around 40% continue to experience some degree of short stature. With proper monitoring, adherence to therapy, and coordinated multidisciplinary care, most individuals with Type IVa Bartter syndrome can expect a normal life expectancy and a good quality of life.

Key Scientific Terms

A gene is a segment of DNA that carries the instructions for producing proteins that shape traits and biological functions. A gene mutation is a change in this DNA sequence that can disrupt the gene’s normal function and sometimes lead to disease. Autosomal recessive inheritance occurs when a child inherits a defective copy of a gene from both parents, resulting in the clinical manifestation of the condition.

The BSND gene specifically encodes Barttin, a protein that supports the function of kidney and ear chloride channels. These channels are vital for maintaining fluid and electrolyte balance in the kidneys and for preserving the ionic environment necessary for hearing in the inner ear. The thick ascending limb of the loop of Henle is a segment of the kidney nephron that plays a major role in reabsorbing salt and maintaining overall fluid balance. Salt-wasting tubulopathy refers to a group of disorders, including Bartter syndrome, where the kidneys fail to retain salts effectively.

Sensorineural hearing loss refers to hearing impairment caused by damage to the inner ear or auditory nerve pathways. Polyhydramnios describes excessive amniotic fluid accumulation during pregnancy and is often a sign of fetal kidney dysfunction. Growth hormone therapy is sometimes used in children with persistent growth failure to help them achieve improved height and developmental outcomes.

References

Florea L, et al. Genetic Heterogeneity in Bartter Syndrome: Clinical and Practical Importance. Frontiers in Pediatrics. 2022. https://doi.org/10.3389/fped.2022.908655

Zizlavsky S, et al. Sensorineural Hearing Loss in Bartter Syndrome. Oto Rhino Laryngologica Indonesiana. 2021. https://doi.org/10.32637/orli.v51i1.445