PRENATAL DIAGNOSIS, VOL. 14 996-998 (1994)

SHORT COMMUNICATION

PRENATAL DIAGNOSIS OF BARTTER SYNDROME

H. SHALEV*, M. OHALYt, I. MEIZNERt AND R. C W $

*Pediatric Division, $Obstetrics and Gynecology Division-Sonography Unit, §Clinical Genetics Unit, The Soroka Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, and tThe

Department of Pediatrics, Barzilai Medical Center, Ashkelon, Israel

Received 25 March I993 Revised May 1994

Accepted 10 May I994

SUMMARY Bartter syndrome, an autosomal recessive disorder of hyperaldosteronism and increased plasma renin, was

suspected in an at-risk pregnancy due to the early occurrence of polyhydramnios. Further establishment of the diagnosis was accomplished by demonstrating increased levels of aldosterone in amniotic fluid and fetal cord blood. Electrolyte levels did not differ significantly from reported controls. It is thus suggested that polyhydramnios is the result of increased fetal urine output in Bartter syndrome and that amniotic fluid aldosterone is a reliable marker for the prenatal diagnosis of this condition.

KEY worms-Bartter syndrome, polyhydramnios, aldosterone, prenatal diagnosis.

INTRODUCTION

The role of fetal polyuria in the aetiology of maternal polyhydramnios is controversial (Kirshon, 1989; Abramovich ef al., 1979; Sieck and Ohlsson, 1984). However, several case reports have suggested that a primary defect in fetal renal function, such as nephrogenic diabetes insipidus (Kirshon, 1989), pseudo-hypoaldosteronism (Abramson et al., 1992), and Bartter syndrome (Proesmans et al., 1987), may be associated with fetal polyuria, resulting in polyhydramnios.

Bartter syndrome, a condition clinically as- sociated with polyuria, is characterized by hy- perreninaemia and hyperaldosteronism with hypokalaemic metabolic alkalosis accompanied by renal sodium wasting, plasma volume contraction, and, in some cases, hypomagnesaemia. Hyper- trophy of the renal juxtaglomerular apparatus and

Addressee for correspondence: R. Carmi, MD, Clinical Genetics Unit, Soroka Medical Center, P.O. Box 151, Beer- Sheva 84101, Israel.

CCC 0 197-385 1/94/100996-03 01994 by John Wiley & Sons, Ltd.

excess renal prostaglandins are additional hall- marks of the disorder, which is inherited as an autosomal recessive (Radgigues Pereira and van Wersch, 1983).

Pregnancies with affected fetuses with Bartter syndrome are complicated with early onset of polyhydramnios and result in premature deliveries. Prenatal diagnosis of this disorder is important from several aspects. Firstly, indomethacin treat- ment, which is of proven efficiency in Bartter syndrome (Dillon et al., 1979), might be specifi- cally indicated in such pregnancies. Secondly, the knowledge of an affected fetus will enable early neonatal treatment of a potentially life-threatening condition involving severe electrolyte imbalance and fluid loss. Thirdly, early detection of this disorder will provide at-risk families with the option of pregnancy termination.

We report the prenatal diagnosis of an affected fetus with a familial variant of Bartter syndrome in which, in addition to the classical manifestations of the disease, there was also hypermagnesaemia responsive to indomethacin treatment.

BARTTER SYNDROME 997

Table I-Aldosterone and electrolyte levels in amniotic fluid

Aldosterone (ng/dl) C1 (mEqA) Na (mEq/l) K ( m w

Affected fetus 115 104 134 3.6 Control* Mean 246 f 17.1 96.5 f 4.5t 126 + 7.1 3.5 f 57

Range 5.8-5 1.9 88-lOOt 108-132 2.8-4.2t

*Abramson et a]., 1992 (same laboratory as that used for our case). tunpublished data from Abramson et al. (1992).

Table II-Aldosterone and electrolyte levels in fetal cord blood

Mected fetus 57.2 97 131 5-2 Control, second trimester 36 (Hill et aZ., 1990) Control, term 102-1 12 135-143 3.7-6.8 (Perkins et al., 1993)

(999 pmol/l)

CASE REPORT

A 19-year-old Bedouin woman married to her first cousin was diagnosed to have polyhydramnios on the 20th week of her third pregnancy. Her first pregnancy resulted in a full-term normal newborn who is a healthy child. Her second pregnancy was complicated by polyhydramnios and premature delivery at 31 weeks of gestation. The female newborn suffered severe electrolyte imbalance and was subsequently diagnosed to have Bartter syn- drome. An unusual and previously unreported finding in Bartter syndrome was hypermagne- saemia, which responded to indomethacin treat- ment, as did the other manifestations of the disease. However, lack of compliance with the treatment resulted in severe failure to thrive and frequent hospitalization of the child.

Subsequent to the diagnosis of polyhydramnios, the woman was referred for further evaluation, but she sought medical attention only 6 weeks later. Amniocentesis was performed at 26 weeks of ges- tation; 1000 ml of amniotic fluid was removed and samples were sent for electrolyte and aldosterone evaluation (Table I). Fetal blood was obtained via cordocentesis for the same purpose (Table 11). Aldosterone levels were significantly increased in both compartments. Amniotic fluid chloride and sodium were only mildly elevated over controls.

Fetal blood electrolytes reflected the normal range for gestational age.

Treatment with indomethacin was initiated but the woman refused hospitalization and was lost to follow-up for almost 5 weeks. She returned in labour at 32 weeks of gestation. The premature female newborn weighed 1800 g. Soon after birth, the newborn developed polyuria with excessive weight loss, hypochloraemia, hyponatraemia, hypo- kalaemia, and hypermagnesaemia. Indomethacin treatment was started at age 4 days, with good response evident by adequate weight gain and normalization of blood electrolytes. Aldosterone and renin levels at 1 month of age were signifi- cantly elevated (120 ng/dl and >50 ng/dl per h, respectively).

DISCUSSION

Polyhydramnios, as well as premature delivery, is a well-established phenomenon in pregnancies affected with Bartter syndrome (Ohlsson et al., 1984; Proesmans et aZ., 1987). Hydramnios has been reported with this condition as early as 20 (Sieck and Ohlsson, 1984) and 22 weeks of ges- tation (Marlow and Chiswick, 1982), so that in at-risk families careful monitoring of the amount of amniotic fluid might give an early indication of

998 H. SHALEV ET A L

the existence of an affected fetus. Although it has been suggested that amniotic fluid chloride is elevated in pregnancies affected with Bartter syn- drome and can thus serve as a diagnostic test for this disorder (Proesmans et al., 1987), it has been shown that the level is not that much higher than in controls (Sieck and Ohlsson, 1984). Our case further supports this notion, since chloride and sodium were only slightly elevated over published controls from the same reference laboratory (Abramson et al., 1992). This is not surprising in view of the fact that these ions are freely exchange- able across the placenta (Sieck and Ohlsson, 1984).

Conjugated aldosterone, which is excreted by the fetal kidneys, is expected to show a significant increase in amniotic fluid, though little is known about its disappearance rate by permeation to the maternal compartment and by fetal swallowing. Failure to demonstrate such an increase in poly- hydramnios associated with Bartter syndrome has been attributed to a negative feedback effect of maternal betamethasone treatment on the fetal pituitary gland (Sieck and Ohlsson, 1984). Recently it has been shown that aldosterone was significantly elevated in the amniotic fluid of an affected fetus with pseudohypoaldosteronism (Abramson et al., 1992). Our case also demonstrates an increase of amniotic fluid aldosterone (compared to 16-19 week amniotic fluid (Abramson et al., 1992)) in a disorder where this hormone is markedly elevated postnatally. Moreover, the simultaneously in- creased level of aldosterone in fetal cord blood provides direct evidence that Bartter syndrome is manifested in fetal life and is the cause of the rather early onset of polyhydramnios.

It thus seems that conditions associated with increased urinary excretion of aldosterone are amenable to prenatal diagnosis by way of measur- ing this hormone in amniotic fluid. Since those conditions are commonly hereditary, prenatal diagnosis should be offered to every family at risk. Whether the determination of amniotic fluid aldos- terone should await the onset of polyhydramnios is as yet unclear.

Prenatal diagnosis of disorders associated with excess urinary excretion of aldosterone is encour- aged in every case of polyhydramnios of unknown aetiology, regardless of the family history. Even if termination of pregnancy is no longer an option when polyhydramnios is evident, the prenatal diagnosis of such conditions might be crucial for

early adequate treatment of the affected newborn, who may face life-threatening complications.

Indomethacin, which is an accepted treatment of polyhydramnios (Smith et al., 1990; Rosenberg et al., 1992) might be indicated in fetal Bartter syndrome since it has been shown to be effective postnatally. Early introduction of indomethacin therapy might improve the prognosis by pre- venting premature delivery and thus allowing a better postnatal course of an affected newborn with Bartter syndrome.

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