Bartter syndrome was originally described by Dr. Frederic Bartter et al. in 1962. It is characterized by hypokalemia, hypochloremia, metabolic alkalosis and hyperreninemia with normal blood pressure. I recall a case of recurrent polyhydramnios in three successive pregnancies due to fetal Bartter's syndrome, which I published in 1991. It was believed to be a salt-losing tubulopathy. Now advances in molecular diagnostics have shown that Bartter syndrome is an autosomal recessive disorder due to mutations in many genes which affect the function of ion channels and transporters responsible for salt reabsorption in the distal renal tubules. Based on genetic changes, six types of Bartter syndrome have been described. Type 1 is antenatal Bartter syndrome due to mutations in SLC12A1 (the sodium-chloride-potassium cotransporter gene). Type 2 is antenatal-neonatal Bartter syndrome due to mutations in the ROMK gene. Type 3 is the classic Bartter syndrome due to mutations of the chloride CLCNKB gene. Type 4 is Bartter syndrome associated with sensorineural deafness due to mutations in BSND. Type 5 is Gitelman syndrome due to mutations in SLC12A3 (the sodium-chloride cotransporter). Type 6 is a severe but transient X-linked disorder showing polyhydramnios, prematurity due to mutations in MAGED2. Bartter's syndrome needs to be differentiated from Gitelman syndrome, congenital adrenal hyperplasia, nephrogenic diabetes insipidus, pseudohypoaldosteronism, cystic fibrosis, chronic accidental intake of loop-acting or thiazide diuretics, pyloric stenosis, hyperprostaglandin E syndrome, congenital chloride diarrhea, familial hypomagnesemia and Gullner syndrome.
The obstetric problems are polyhydramnios, preterm labor, fetal growth restriction, placenta abruption from uncontrolled escape of amniotic fluid after spontaneous rupture of membranes, growth restriction. Without treatment there can be neonatal dehydration nephrocalcinosis, hypokalemia, hypochloremia, metabolic alkalosis, hyperreninemia, failure to thrive and developmental delay. Electrolyte imbalance may cause cardiac arrhythmia and sudden death. Bone mineral density decreases significantly over time. Sensorineural deafness may be seen. Slowly progressive chronic renal failure may occur due to interstitial fibrosis.
Antenatal diagnosis is based on findings of polyhydramnios without fetal anatomical defects and uncontrolled maternal diabetes mellitus, fetal growth restriction and elevation of amniotic chloride and and aldosterone levels. Laboratory tests used to diagnose Bartter's syndrome baby after birth include serum levels of electrolytes including magnesium, renin, aldosterone, and urinary levels of prostaglandin E2, sodium and potassium. A genetic analysis to detect abnormal gene function like loss-of-function, frame-shift, missense and large deletion mutations is a good method of assessment, but is not easily available in most parts of the world and is quite expensive too. Ultrasonography of an older child may show diffuse increase in echogenicity, hyperechoic pyramids and interstitial deposition of calcium.
The condition is not curable (except type 6) and supportive treatment is required lifelong. Conventional treatment of Bartter syndrome includes maintaining fluid and electrolyte balance and indomethacin to prevent the production of prostaglandin 2. Recent advances in treatment include renin-aldosterone-angiotensin system antagonists (including aldosterone antagonists, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers). Growth hormone is used to treat growth restriction. Calcium and magnesium may have to be given for tetany. Sensorineural deafness can be managed by cochlear implants. Stressful situations like trauma, surgery and infection tend to aggravate electrolyte imbalance and aggressive electrolyte balance is required. Renal transplant can be done for end stage renal disease. It not only improves renal function, but also corrects many of the associated endocrine abnormalities.
We have an interesting case of Bartter syndrome reported in this issue of the journal. I hope the readers benefit from it.