Introduction

Bartter syndrome refers to a group of rare genetic disorders that cause problems with how the kidneys absorb salt, resulting in the drastic loss of salt and water. It is characterised by several subtypes, each associated with different genetic mutations, and the condition leads to a range of symptoms that impact various aspects of health and development. There are five main types of Bartter syndrome, with Types 1, 2, 4A, and 4B generally presenting before birth and often exhibiting more severe symptoms. In contrast, Type 3, also known as classic Bartter syndrome, typically manifests in early childhood with milder symptoms. However, individual cases can vary widely, and the presence or severity of symptoms can differ among subtypes. Symptoms may include dehydration, muscle cramps, and growth issues, with the condition often leading to significant developmental challenges.

Clinical features of Bartter syndrome

Types of Bartter syndrome

There are 5 main types of Bartter syndrome each of which involves different mutations but leads to similar overall problems with salt and water balance, resulting in symptoms like dehydration, muscle cramps, and growth issues.

Bartter syndromes Types 1, 2, 4a, and 4b are linked to an early age of onset (before birth) and typically presents with more severe symptoms, while Type 3 Bartter syndrome, also referred to as classic Bartter syndrome, describes cases that typically have milder symptoms and present in early childhood (although they can also present before birth).¹

There are, of course, exceptions to this general rule. Affected individuals may not have all the symptoms mentioned, and some symptoms that are more common in one subtype of Bartter syndrome can occur in another subtype. Each case is unique and will follow its own course.

Symptoms

Prenatal and neonatal signs (those that appear before birth) of a child that may have Bartter syndrome include polyhydramnios – an excessive accumulation of amniotic fluid around the fetus, which can lead to premature birth. Generally, the earlier the symptoms appear, the more severe the condition.²

Bartter syndrome that develops in infancy or early childhood can affect males and females equally. Symptoms may include failure to thrive, associated with growth difficulties. Infants exhibit thirst but have difficulty in feeding, often vomit, and seem very tired. Older children may experience vomiting, fatigue, weakness, and have muscle cramps or spasms.²

If children with Bartter syndrome get an infection like the flu or diarrhea, they can become very sick quickly and may need to go to the hospital to get fluids through an IV. Blood tests help determine how much salt and fluid they need.²

Additionally, there is often increased calcium in the urine, which can cause calcium deposits in the kidneys. While this can be harmful to the kidneys, people with Bartter syndrome are unlikely to need dialysis or a kidney transplant.²

Causes

Bartter syndromes result from genetic mutations in specific genes: SLC12A1 gene for Type 1, KCNJ1 gene for Type 2, CLCNKB gene for Type 3, BSND gene for Type 4A, and both the CLCNKA and CLCNKB genes for Type 4B. Genes provide instructions for making proteins that are crucial for many bodily functions. When these genes are mutated, the resulting proteins can be faulty, inefficient, or missing altogether. This can disrupt the function of various organ systems. Bartter syndrome is inherited in an autosomal recessive pattern, meaning that a child must inherit two copies of the defective gene (one from each parent) to develop the condition.

Growth and developmental issues in children with Bartter syndrome

Research on growth and development on individuals with Bartter syndrome indicate that affected children frequently have delayed growth and development during infancy and early childhood compared to their peers. This growth retardation is a common consequence of the condition, reflecting the challenges in maintaining normal development. A delayed adolescent growth spurt has been observed in all individuals studied who showed symptoms of Bartter syndrome in infancy. However, they generally achieve normal stature by the end of their growth period.³

Several factors contribute to growth problems in Bartter syndrome. Electrolyte imbalances (such as low potassium or sodium levels) and impaired renal function affect the body's ability to maintain normal growth. These imbalances can disrupt various bodily functions, including those necessary for proper growth.³

Early detection of growth issues is crucial for timely intervention. Addressing growth problems early can help optimise treatment strategies, such as adjusting medications or dietary changes, to better support normal growth and development.³

Children with Bartter syndrome may also face delays in cognitive and motor development. Mental development can vary widely, ranging from normal to significant brain damage and dysfunction. Most patients, however, exhibit some degree of mental retardation. These delays can manifest as difficulties in learning, problem-solving, and physical coordination.³

Treatments

There is no cure for Bartter syndrome so treatment is often directed towards mitigating specific symptoms present in each individual.

Medication¹

One of the primary treatments for Bartter syndrome involves restoring the proper balance of fluids and electrolytes in the body by replacing lost electrolytes such as potassium and sodium. This may include oral supplements or intravenous fluids, depending on the severity of the imbalance.

Medications can also be used to manage symptoms and correct imbalances. Nonsteroidal anti-inflammatory drugs (NSAIDs) can help reduce excessive prostaglandin levels, which contribute to salt and water loss. For example, indomethacin has been used extensively and has demonstrated to be beneficial in people with Bartter syndrome. However, in premature babies in particular, there is a risk of serious adverse effects, including perforation of the stomach and other intestinal tracts.

Diet²

A balanced diet rich in sodium and potassium may be recommended to counteract electrolyte losses. Specific dietary adjustments are tailored to each patient’s needs to ensure they get adequate amounts of essential nutrients. In addition to this, it is vital that patients receive enough calories and nutrients, as they may have increased nutritional needs due to ongoing losses and metabolic demands.

Growth hormone therapy

Growth hormone therapy might be considered for children with Bartter syndrome who experience significant growth delays. The therapy aims to support normal growth patterns and help children reach a typical height.

While growth hormone therapy can be beneficial, it carries potential risks such as increased pressure on the body’s metabolic processes. Monitoring and careful management are required to balance the benefits of improved growth with potential side effects.

FAQ’s

What is Bartter syndrome?

Bartter syndrome is a group of rare genetic disorders that affect the kidneys' ability to reabsorb salt and water properly, leading to imbalances in electrolytes and fluids in the body.

Who does Bartter Syndrome normally affect?

Bartter syndrome is usually seen in children and adolescents.

What are the common symptoms of Bartter syndrome?

Symptoms can include dehydration, muscle cramps, growth delays, and electrolyte imbalances. Infants may experience difficulty feeding, vomiting, and lethargy, while older children may exhibit muscle weakness and fatigue.

How is Bartter syndrome diagnosed?

Diagnosis typically involves a combination of clinical evaluation, laboratory tests to check electrolyte levels, and genetic testing to identify specific mutations.

What are the main goals of treatment for Bartter syndrome?

Treatment aims to manage symptoms and correct electrolyte imbalances. This may involve electrolyte replacement, medications like NSAIDs, and dietary modifications. Growth hormone therapy might be considered for children with significant growth delays.

Summary of Bartter syndrome

A summary of the different types of Bartter syndrome:

• Type 1:
  • Gene involved: SLC12A1
  • Protein affected: Sodium-potassium-chloride cotransporter (NKCC2)
  • Features: Often presents before birth with polyhydramnios (excess amniotic fluid), severe salt and water loss, and risk of dehydration. Symptoms can include failure to thrive (difficulty gaining weight appropriately), vomiting, and muscle weakness
• Type 2 Bartter Syndrome:
  • Gene involved: KCNJ1
  • Protein affected: Renal outer medullary potassium channel (ROMK)
  • Features: Similar to Type 1, often presenting before birth with polyhydramnios, and severe salt and water loss. Infants may have difficulty feeding, vomiting, and muscle weakness
• Type 3 Bartter Syndrome (Classic Bartter Syndrome):
  • Gene involved: CLCNKB
  • Protein affected: Chloride channel (ClC-Kb)
  • Features: Typically presents in childhood or later, with symptoms including growth delay, muscle weakness, cramps, and sometimes increased urination and thirst. This type is generally less severe than Types 1 and 2
• Type 4A Bartter Syndrome:
  • Genes involved: BSND
  • Protein affected: Barttin (a protein that affects chloride channels)
  • Features: Often presents before birth with polyhydramnios, and severe salt and water loss. These patients also have sensorineural deafness (hearing loss)
• Type 4B Bartter Syndrome:
  • Genes involved: CLCNKA and CLCNKB (chloride channels)
  • Features: Similar to Type 4A, with severe symptoms and hearing loss. These cases also present early, often before birth