Bartter syndrome type 4 (ORPHA:89938)
A form of Bartter syndrome characterized by maternal polyhydramnios, premature delivery, salt loss, polyuria and sensorineural deafness, associated with hypokalemic and hypochloremic metabolic alkalosis, increased levels of plasma renin and aldosterone, and low to normal blood pressure. Urinary calcium excretion rates are variable, and nephrocalcinosis is typically absent.
Epidemiology
It is the least common of all recessive types of Bartter syndrome.
Clinical description
A severe type of antenatal Bartter syndrome that typically manifests prenatally with maternal polyhydramnios (due to fetal polyuria) usually evident by the end of second trimester, often leading to preterm labor and prematurity. Postnatally, patients present with polyuria, isosthenuria/hyposthenuria and are at high risk of dehydration, hypovolemic hypotension and shock. Virtually all patients are found to have complete sensorineural deafness. Recurrent vomiting, muscle cramps, spasms and failure to thrive are observed. Progression to renal failure is frequent. Hypokalemic and hypochloremic metabolic alkalosis, and in some cases hypomagnesemia, are noted (hypercalciuria is an inconsistent finding and only transient).
Etiology
The disorder is caused by a defect in chloride reabsorption in the thick ascending limb of the loop of Henle and the early distal convoluted tubule as a consequence of inactivating mutations of the BSND gene (1p32.3), encoding for the protein Barttin (Bartter syndrome type 4A), which is required for the location and proper function of the basolateral chloride channels ClC-Ka and ClC-Kb. Alternatively, the disorder may be caused by digenic mutations in CLCNKA (1p36.13) and CLCNKB (1p36.13) which inactivates the 4 alleles of the 2 genes (Bartter syndrome type 4B). ClC-Ka is highly expressed in the inner ear and contributes to maintaining the high potassium ion concentration in the endolymph necessary for normal hearing, and for which functional disruption leads to nerve deafness.
Diagnostic methods
Diagnosis is based on the clinical picture, blood gas analysis, plasma and urine electrolytes (sodium, potassium, chloride, bicarbonate, magnesium, calcium), renin and aldosterone levels. Urinary calcium excretion rates are variably ranging from low to normal or slightly increased. Objective hearing assessment is mandatory to identify sensorineural hearing loss. Only genetic testing provides the definite diagnosis.
Differential diagnosis
The most important differential diagnoses include congenital chloride diarrhea, pseudohypoaldosteronism type 1, and pseudo-Bartter syndrome (e.g. in cystic fibrosis).
Antenatal diagnosis
Prenatal diagnosis is technically feasible after genetic couseling and may be considered on an individual basis.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to any patient with Bartter syndrome and to parents with an affected child. In at-risk couples (both individuals are carriers of a disease-causing mutation) there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Especially in the perinatal period, treatment includes vigorous salt and fluid replacement therapy. Non-steroidal anti-inflammatory drugs (e.g. indomethacin or celecoxib) are the second mainstay of therapy. Beyond the neonatal period, next to liberal salt intake, long-term enteral salt and potassium supplements are necessary in most patients. In stressful situations (intercurrent illness with fever, gastroenteritis) blood electrolyte levels may change rapidly, requiring prompt and vigorous intravenous treatment. With respect to deafness, timely intervention ensuring that the child has access to developing receptive and expressive language is of paramount importance.
Prognosis
The perinatal course is critical because of the complications of severe prematurity. Life expectancy may be reduced in severe cases and chronic renal failure may develop in a subset of children. Reliable long term outcome data are still lacking.

                            Last update: 
                            September 2021


                            - Expert reviewer(s): 
                            Pr Martin KONRAD | ERKNet*


                                * European Reference Network