Infantile variant of Bartter syndrome and sensorineural deafness: A new autosomal recessive disorder
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American Journal of Medical Genetics 59:454459 (1995)
Infantile Variant of Bartter Syndrome and Sensorineural Deafness: A New Autosornal Recessive Disorder
Daniel Landau, Hana Shalev, Meli Ohaly, and Rivka Carmi Department of Pediatrics (D.L., H.S.), Clinical Genetics Unit (R.C.), Soroka Medical Center, Ben Gurion University of the Negev, Beer Sheva, and Department of Pediatrics, Barzilai Medical Center (M.O.), Ashkelon, Israel
The infantile variant of Bartter syndrome (IBS) is usually associated with maternal polyhydramnios, premature birth, postnatal polyuria and hypokalemic hypochloremic metabolic alkalosis and a typical appear- ance. IBS is thought to be an autosomal recessive trait. Several congenital tubular defects are associated with sensorineural deafness (SND). However, an association be- tween the IBS and SND has not been re- ported so far. Here we describe 5 children of an extended consanguineous Bedouin fam- ily with IBS and SND. In 3 of the cases, the typical electrolyte imbalance and facial appearance were detected neonatally. SND was detected as early as age 1 month, sug- gesting either coincidental homozygotiza- tion of 2 recessive genes or a pleiotropic ef- fect of one autosomal recessive gene. This association suggests that evaluation of SND is warranted in every case of IBS. 0 1995 Wiley-Liss, Inc.
KEY WORDS: Bartter Syndrome, deafness, recessive inheritance
INTRODUCTION Bartter syndrome (BS) was originally described by
Bartter et al. , and is characterized clinically by normotensive hyperreninism, hyperaldosteronism, and hypokalemic hypochloremic metabolic alkalosis. Renal biopsy shows juxtaglomerular hyperplasia. Renal prosta- glandin metabolism is upregulated [Gill et al., 19761, manifesting itself, in renal biopsy, as hyperplasia of
Received for publication December 29, 1994; revision received April 20, 1995.
Address reprint requests to Daniel Landau, M.D., Department of Pediatrics, Soroka Medical Center, P.O.Box 151, Beer Sheva 84101, Israel.
0 1995 Wiley-Liss, Inc.
renal medullary interstitial cells, which are capable of substantial prostaglandin synthesis.
An infantile variant of BS (IBS) was previously de- scribed by Seyberth et al. in 1985. It usually causes ma- ternal polyhydramnion, premature birth and postnatal polyuria, associated with severe salt loss and failure to thrive. Some of the infants also have severe hypercalciuria. This particular variant is thought to be inherited as an autosomal recessive trait [Hogewind et al., 1981; Ohlson et al., 1984; De Rovetto et al., 1989; Leonhardt et al., 19921. Some of the infants with the IBS variant have been described as having a prominent forehead, trian- gular facies with drooping mouth and large eyes and pinnae [James et al., 1975; Ohlson et al., 19841. The patho- genesis of this, as well as the other BS variants, is not well understood. Different theories exist regarding the primary renal defect, and include, among others: impair- ment in sodium and chloride reabsorption [Rodriguez- Portales et al., 19861, increased tubular potassium loss [Korff et al., 19841, increased prostaglandin synthesis [Fujita et al., 1982; Calo et al., 19901 and angiotensin re- sistance [Bourke and Delaney, 1981; Sasaki et al., 1976; Kurtzman and Gutierrez, 19751. Treatment with prosta- glandin synthetase inhibitors, mainly indomethacin, with or without potassium supplements or potassium sparing diuretics, has been shown to be effective in this disorder [Bommen and Brook 1982; Seyberth et al., 1985; Matsumoto et al., 19891.
Sensorineural deafness (SND) has been described in association with various congenital renal diseases. These include glomerular diseases, such as Alport syn- drome, in which SND is typically a late phenomenon [Gubler et al., 19811, and several tubular disorder, in- cluding: familial distal renal tubular acidosis [Dunger et al., 1980; Anai et al., 1984; Bentur et al., 1989; Caldas et al., 19921, pseudohypoaldosteronism [Tungland et al., 19901, Fanconi syndrome [Chevalier, 19831 and others [Kobayashi et al., 1985; Goto et al., 19901. SND in these cases manifests itself early in life, potentially impair- ing language development. So far, no case of SND has been described in association with the IBS variant. Here we describe 5 patients with IBS and congenital SND, all of whom are members of an extended, inbred Bedouin family.
Deafness in Infantile Bartter Syndrome 455
by polyhydramnios. Birth weight was 1445 g. On the third day of life polyuria and weight loss of up to 25% of birth weight were evident. This caused a transient azotemia that was corrected by intravenous fluids. In addition, hyponatremia, hypochloremia and hypo- kalemic alkalosis were found together with increased excretion of these salts in urine (Table 11). Marked hy- percalciuria (calciudcreatinine ratio in spot urine = 0.42, normal
456 Landau et al.
TABLE I. Patient Data
Age at Dx" Gestational age Developmental Deafness Pt. no. (months) Polyhydramnios (weeks) AGAISGA~ FTT' delay v-2 0.5 + v-3 0.5 + v-4 42 + V-5 180 + v- 1 Birth +
32 AGA + + + 31 AGA + + + 33 AGA 33 AGA + 38 SGA + ? +
- + -
"Dx age: age of diagnosis of BS. b ~ ~ ~ ~ ~ A appropriate or small for gestational age. 'FTT: failure to thrive.
as the high levels of calcium, magnesium and phospho- rus. However, growth improvement was only slight. At the age of 3 years the child is still developmentally and physically delayed. Deafness and lack of compliance with special education programs do not enable appro- priate estimation of her true developmental potential.
Case 2 V-2, a 21-month-old girl, is V-3's younger sister. Pre-
natal course was complicated by polyhydramnios, for which the mother was treated with repeated amniocen- teses and oral indomethacin. She was born a t 32 weeks of gestation, weighing 1,800 g. Like her sister she pre- sented soon after birth with polyuria, which caused a 16% loss of birth weight. Hyponatremia associated with natriuresis but without hypokalemia was noted and was treated with NaCl supplementation. Serum mag- nesium was elevated transiently. Plasma renin activity and aldosterone levels were markedly elevated (Table 11). NaCl supplementation could be weaned off at age one month. However, hypokalemia and kaliuresis, as- sociated with metabolic alkalosis were noted at that age, and were treated with oral KC1 supplementation. Urinary PGE, excretion was evaluated at age 3 months, one week after the discontinuation of indomethacin
therapy, and was found elevated. A typical facial ap- pearance was noted during the first year of life. SND was diagnosed by BAER test a t the age of 8 months. Since this was the second case of BS in this family, in- domethacin treatment was introduced rather early. This caused an improvement in weight gain, as well as normalization of serum sodium and potassium levels. At age 21 months the child still suffers from severe fail- ure to thrive and developmental delay.
Case 3 V-4, a 4-year-old boy is a cousin of the two previously
described sister. His mother had had five previous preg- nancies, one of which ended at 22 weeks of gestation in stillbirth. The other four pregnancies produced 4 healthy girls. The course of the current pregnancy was complicated by polyhydramnios which was treated with indomethacin. The child was born a t 33 weeks of gestation, weighing 1,995 g. After birth, polyuria was noted which caused a weight loss of 20%, azotemia, hy- ponatremia, and natriuresis (Table 11). Hypochloremia and hypokalemia were also found during the first week of life. He was treated with intravenous infusion of sodium and potassium chloride solutions, which halted the weight loss and corrected the electrolyte imbal-
Fig. 2. a: Patient V-3; b: Patient V-5.
Deafness in Infantile Bartter Syndrome 457
TABLE 11. Biochemical Data
Age a t Dx Pt. no. (months)
v-2 1 v-3 1 v-4 15 v- 5 15 y rs v- 1 1 week Normal
-____ S N a a S K
120 2.3 128 2.5 117 2.5 140 2.1 128 2.8
SCl S H C 0 3 PRAb SAldo UN: U K meq/L mey/L mgAIUL/hr pg/L meq/L mey/L
>1,200 70 50 80 31 >50 78 31 >50 >1,200 100 55 90 N A ~ >so 647 52 20
460 NA 20 90 34 19.35 85 39 >50 >1,200 74 31
30 0.42 230 30 NA 149
NA NA NA NA NA NA 107 0.8 NA
458 Landau et al.
with oculocerebral hypopigmentation syndrome [White et al., 19931, which is clearly different from our cases. Both BS [Hogewind et al., 19811 and SND have been re- ported to be autosomally recessively transmitted. In- deed, our pedigree with multiple consanguineous mar- riages illustrates this mode of inheritance. Three explanations for the cosegregation of BS and SND in our family can be put forward. The first is a coinciden- tal homozygotization of two independent recessive genes. The occurrence of five affected individuals, all manifesting both traits and the absence of patients with either IBS or SND in spite of a high rate of con- sanguinity, necessitates the assumption of a very close linkage between the two gene loci. The second explana- tion is that SND is a complication of IBS. Two clinical presentations, a rare adolescent form of renal tubular acidosis (RTA) with mild to moderate SND and a rela- tively more common infantile type with severe SND, have been reported [Konigsmark and Gorlin, 19761. One of the forms of RTA associated with SND is due to the absence of the enzyme carbonic anhydrase 2 [Sly et al., 19831. The differences in severity of the SND could argue for a causal effect of the renal disease on hearing. Indeed, it has been shown that brisk serum electrolyte imbalances in end-stage renal disease patients may cause deafness [Bergst