How is Bartter syndrome diagnosed and differentiated between its subtypes?

Diagnosis and Differentiation of Bartter Syndrome Subtypes

Bartter syndrome diagnosis relies primarily on clinical presentation, biochemical findings, and genetic testing, with genetic analysis being the definitive method to confirm diagnosis and differentiate between subtypes. 1

Diagnostic Approach

Initial Clinical Evaluation

The diagnostic workup should systematically assess:

• Family history of polyhydramnios with or without premature birth 1
• Medical history focusing on polyuria, dehydration episodes, unexplained fever, failure to thrive, and recurrent vomiting 1
• Growth parameters using growth charts to assess height and weight development 1
• Specific symptoms including salt craving, muscle weakness, low blood pressure, and pubertal delay 1

Essential Laboratory Parameters

Core biochemical testing must include: 1

• Serum electrolytes (potassium, sodium, chloride)
• Blood gas analysis (metabolic alkalosis)
• Serum magnesium
• Plasma renin and aldosterone levels
• Urinary electrolytes (sodium, chloride, potassium, calcium)
• Fractional chloride excretion (typically >0.5% in Bartter syndrome) 1

Renal Imaging

Renal ultrasound should be performed to assess for nephrocalcinosis, which is characteristic of Types 1 and 2 but typically absent in Type 3 1. Computerized tomography should be reserved only for situations with direct therapeutic consequences, such as obstructive uropathy, due to radiation burden 1.

Subtype Differentiation

Age at Presentation (Critical Distinguishing Feature)

Antenatal/Neonatal Presentation:

• Types 1,2,4, and 5 present prenatally with polyhydramnios between 20-30 weeks gestation 1
• Type 4 shows the earliest and most severe polyhydramnios 1
• Type 5 always presents antenatally but symptoms spontaneously resolve around the estimated delivery date 1

Later Childhood/Adult Presentation:

• Type 3 typically manifests after age 1 year, presenting with failure to thrive, poor weight gain, or polyuria with polydipsia 1

Calcium Excretion Patterns

Hypercalciuria with nephrocalcinosis:

• Types 1 and 2 characteristically show hypercalciuria developing after 1-2 months of life with subsequent nephrocalcinosis 1

Variable or normal calciuria:

• Type 3 usually demonstrates normocalciuria, though hypercalciuria or even hypocalciuria may occur 1
• Type 4 typically shows normocalciuria 1
• Type 5 may show hypercalciuria but nephrocalcinosis is rare 1

Associated Clinical Features

Sensorineural deafness:

• Type 4 (barttin mutations) presents with deafness and increased risk for chronic kidney disease 1

Transient disease:

• Type 5 (MAGED2 mutations, X-linked) shows spontaneous resolution of symptoms around delivery 1

Gitelman-like phenotype:

• Type 3 may present with features virtually indistinguishable from Gitelman syndrome, including hypocalciuria and hypomagnesemia 1

Genetic Mutations by Subtype

Definitive subtype identification requires genetic testing: 1

• Type 1: SLC12A1 gene (NKCC2 transporter)
• Type 2: KCNJ1 gene (ROMK channel)
• Type 3: CLCNKB gene (ClC-Kb chloride channel)
• Type 4: BSND gene (barttin subunit)
• Type 5: MAGED2 gene (X-linked)

Genetic Testing Recommendations

Genetic testing with a gene panel should be offered to all patients with clinical suspicion of Bartter syndrome (Grade B recommendation) 1. This is the most reliable method for confirming diagnosis and differentiating subtypes 1.

Key considerations for genetic testing:

• Analytical sensitivity is 90-100%, with clinical sensitivity of ~75% in children but only 12.5% in adults 1
• Large rearrangements detected by next-generation sequencing should be confirmed by a second independent method (e.g., multiplex ligation-dependent probe amplification) 1
• Large rearrangements are particularly frequent in CLCNKB gene but also occur in KCNJ1, BSND, and MAGED2 1
• CLCNKB analysis is technically challenging, contributing to lower detection rates 1

Antenatal Diagnosis

When polyhydramnios is detected prenatally:

• Prenatal genetic testing is the most reliable diagnostic method when indicated 1
• Bartter index (total protein/alpha-fetoprotein ratio in amniotic fluid) may be considered when genetic testing is unavailable or non-diagnostic 1
• Other amniotic fluid parameters (chloride, aldosterone) have failed to reliably distinguish Bartter-related polyhydramnios from other causes 1

Critical Differential Diagnoses

Polyhydramnios is virtually always caused by Bartter syndrome when due to excessive fetal polyuria; other inherited tubular disorders do not cause severe polyhydramnios 1

Postnatal differential diagnoses to exclude:

• Gitelman syndrome: Distinguished by later presentation, hypocalciuria, and hypomagnesemia (though Type 3 Bartter can mimic this) 1
• Congenital chloride diarrhea: Presents with watery diarrhea causing hypokalemic, hypochloremic metabolic alkalosis 1
• Pseudo-Bartter syndrome: Seen in cystic fibrosis due to salt loss in sweat 1
• Diuretic or laxative abuse: Must be excluded, particularly in adults 1
• Primary hyperaldosteronism: Distinguished by hypertension and suppressed renin 1

Important Caveats

Phenotypic variability exists even within subtypes 2, 3. Type 1 may present with atypical features including low urinary sodium/chloride and later onset than expected 2. Type 2 has been reported with late-onset presentation despite carrying mutations typically associated with severe antenatal disease 3.

Diuretic function tests with furosemide or thiazides are obsolete and not recommended when genetic testing is accessible (Grade D recommendation) 1.

Genetic counseling should be offered to all affected families, including cascade screening and identification of heterozygous female carriers in families with MAGED2 mutations 1.