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pseudohypoaldosteronism type 1 ( pha1 ) is a rare disease manifested by mineralocorticoid 
 resistance of the kidney and/or other mineralocorticoid target tissues . despite very high 
 plasma aldosterone and renin levels , patients with pha1 have excessive salt wasting ( 1,2,3 ) .
the systemic form of pha 
 is inherited in an autosomal recessive manner and manifests severe life - long salt wasting 
 resulting from mineralocorticoid resistance in multiple target tissues , such as sweat 
 glands , salivary glands , the colonic epithelium ; and the lung . on the other hand , with the 
 renal form of pha1
, aldosterone resistance is shown only in the kidney , and its inheritance 
 is autosomal dominant . in this latter form
the renal form of pha is caused by mutations of nr3c2 , which encodes the 
 mineralocorticoid receptor ( mr ) , and many mutations have been reported thus far ( 1,2,3,4,5,6 ) .
moreover , it 
 is noted that phenotypic variability is present even in patients sharing identical mutations 
 ( 3,4,5 ) .
here we report one novel mutation and one previously reported mutation of 
 nr3c2 in two japanese infants with the renal form of pha1 .
the institutional review board committee of hokkaido university school of medicine approved 
 this study . each patient
the nr3c2 exon was amplified by 
 polymerase chain reaction ( pcr ) as reported previously ( 7 ) .
pcr products were purified and sequenced directly using an applied biosystems 
 3130 genetic analyzer ( applied biosystems , foster city , ca , usa ) .
she was the first child in her family and was delivered by 
 caesarian section at 38 wk gestation because of fetal distress .
body weight at birth was 
 2010 g. there was no consanguinity , and the parents were healthy .
at one mo of age , her body weight was 2420 g. as her weight gain 
 was insufficient , she was followed by regular health examinations . because her weight gain 
 continued to lag ( 2556 g ) at 2 mo of age ,
laboratory examinations showed hyponatremia ( 124 mmol / l ) and hyperkalemia ( 5.9 
 mmol / l ) .
in addition , an extremely elevated plasma aldosterone concentration ( 5318 pmol / l ; 
 normal range at 2 mo , 746.22102 pmol / l ) and extremely elevated plasma rennin activity 
 ( pra , > 20 g / l / h ; normal range 3.6612.05 g / l / h ) were found .
her urinary na and k 
 levels were 28 mmol / l and 56.2 mmol / l , respectively , and urinary na excretion was thought 
 to be inappropriately high in spite of hyponatremia .
, she was diagnosed as having the renal form of pha1 , and 
 oral salt supplementation ( 2 g / d ) was initiated .
thereafter , her weight gain improved , and 
 at this time , her growth is satisfactory .
the patient was born at 40 wk gestation with a 
 body weight of 2768 g. she had normal female genitalia . at one mo of age ,
however , her growth 
 failure continued and developmental milestones were delayed . because she could not sit on 
 her own or roll over at 10 mo of age , she was referred to us . at this time , her body 
 weight was 5230 g ( 3.5 sd for a normal japanese girl of this age ) and height was 63.3 cm 
 ( 3.3 sd for a normal japanese girl ) .
laboratory examinations showed hyponatremia ( 125 
 mmol / l ) and hyperkalemia ( 5.1 mmol / l ) .
endocrinological evaluation revealed extremely 
 elevated plasma aldosterone ( 30999 pmol / l ) and pra ( > 20 g / l / h ) levels .
she was therefore thought to have the renal form of pha1 , 
 and salt supplementation ( 5 g / d ) was started , after which her serum sodium level returned 
 to the normal range and body weight gain improved .
she is now 22 mo of age and her height 
 is 75.4 cm ( 2.0 sd for a normal japanese girl ) , and her weight is 10.0 kg ( 0 sd for a 
 normal japanese girl ) . her development has gradually improved but is still delayed .
she 
 was not able to walk alone until the age of 21 mo , and her speech was limited to only 
 babbling .
she was the first child in her family and was delivered by 
 caesarian section at 38 wk gestation because of fetal distress .
body weight at birth was 
 2010 g. there was no consanguinity , and the parents were healthy .
at one mo of age , her body weight was 2420 g. as her weight gain 
 was insufficient , she was followed by regular health examinations . because her weight gain 
 continued to lag ( 2556 g ) at 2 mo of age ,
laboratory examinations showed hyponatremia ( 124 mmol / l ) and hyperkalemia ( 5.9 
 mmol / l ) .
in addition , an extremely elevated plasma aldosterone concentration ( 5318 pmol / l ; 
 normal range at 2 mo , 746.22102 pmol / l ) and extremely elevated plasma rennin activity 
 ( pra , > 20 g / l / h ; normal range 3.6612.05 g / l / h ) were found .
her urinary na and k 
 levels were 28 mmol / l and 56.2 mmol / l , respectively , and urinary na excretion was thought 
 to be inappropriately high in spite of hyponatremia .
, she was diagnosed as having the renal form of pha1 , and 
 oral salt supplementation ( 2 g / d ) was initiated .
thereafter , her weight gain improved , and 
 at this time , her growth is satisfactory .
the patient was born at 40 wk gestation with a 
 body weight of 2768 g. she had normal female genitalia . at one mo of age ,
however , her growth 
 failure continued and developmental milestones were delayed . because she could not sit on 
 her own or roll over at 10 mo of age , she was referred to us . at this time , her body 
 weight was 5230 g ( 3.5 sd for a normal japanese girl of this age ) and height was 63.3 cm 
 ( 3.3 sd for a normal japanese girl ) .
laboratory examinations showed hyponatremia ( 125 
 mmol / l ) and hyperkalemia ( 5.1 mmol / l ) . endocrinological evaluation revealed extremely 
 elevated plasma aldosterone ( 30999 pmol / l ) and pra ( > 20 g / l / h ) levels .
she was therefore thought to have the renal form of pha1 , 
 and salt supplementation ( 5 g / d ) was started , after which her serum sodium level returned 
 to the normal range and body weight gain improved .
she is now 22 mo of age and her height 
 is 75.4 cm ( 2.0 sd for a normal japanese girl ) , and her weight is 10.0 kg ( 0 sd for a 
 normal japanese girl ) . her development has gradually improved but is still delayed .
she 
 was not able to walk alone until the age of 21 mo , and her speech was limited to only 
 babbling .
sequence analysis demonstrated a heterozygous two - base insertion ( c.492_493instt ) in exon 
 2 , resulting in a premature stop codon ( p.met166leufsx8 ) in patient 1 ( fig .
( a ) in patient 1 , a heterozygous two - base insertion 
 ( c.492_493instt ) in exon 2 resulting in a premature stop codon ( p.met166leufsx8 ) was 
 found .
( b ) patient 2 had a nucleotide change at position 2683 and a nonsense mutation 
 of p.r861x in exon 8 . ) .
patient 2 had a nucleotide change at position 2683 and a nonsense mutation of 
 p.r861x in exon 7 ( fig .
( a ) in patient 1 , a heterozygous two - base insertion 
 ( c.492_493instt ) in exon 2 resulting in a premature stop codon ( p.met166leufsx8 ) was 
 found .
( b ) patient 2 had a nucleotide change at position 2683 and a nonsense mutation 
 of p.r861x in exon 8 .
in the current study , we identified a novel mutation and one previously reported mutation 
 of nr3c2 .
the two mutations had premature stop codons resulting in 
 haploinsufficiency of the mr , and they were the causes of aldosterone resistance in the 
 kidney .
oral nacl supplementation improved her physical 
 development ; however , psychomotor development is still delayed at 22 mo .
this strongly 
 indicates that early awareness of the renal form of pha1 is critical , although this disease 
 gradually improves with advancing age .
it was reported that in adult cases carrying nr3c2 mutations systolic and 
 diastolic blood pressure and serum sodium and serum potassium values were normal in spite of 
 high plasma aldosterone and renin levels ( 9 ) . 

recently , two detailed studies of adults carrying mutations of nr3c2 were reported ( 10 , 11 ) .
one study 
 demonstrated that these adults had elevated plasma cortisol levels and urinary cortisol 
 excretion ( 11 ) .
in addition , low hdl cholesterol and 
 central adiposity were found . because it is considered that the mr plays a role in the 
 negative feedback loop of the hypothalamic - pituitary - adrenal ( hpa ) axis ( 12 , 13 ) , 
 haploinsufficieny of the mr may cause activation of the hpa system and lead to 
 hypersecretion of cortisol ( 11 ) .
however , this notion suggests that regular health examinations should be considered for 
 children and adults with mutations of nr3c2 even though they do not require 
 medical treatment . from this point of view , confirmation of mutations of 
 nr3c2 is also important for clinical management the renal form of pha1 in 
 addition to its diagnosis . in conclusion ,
we report three japanese patients with the renal form of pha1 and confirm 
 the importance of a genetic diagnosis .
pseudohypoaldosteronism type 1 ( pha1 ) is a disease characterized by neonatal salt loss 
 due to aldosterone resistance . 
 two types of pha1 are known : an autosomal recessive 
 systemic form and an autosomal dominant renal form . 
 the cause of the renal form of pha1 is 
 heterozygous mutations in nr3c2 , which encodes the mineralocorticoid 
 receptor ( mr ) . 
 we encountered two female japanese infants with the renal form of pha1 and 
 analyzed nr3c2 . 
 the two patients had poor weight gain , and one was 
 developmentally delayed . 
 genetic analysis identified one novel mutation ( c.492_493instt , 
 p.met166leufsx8 ) and one previously reported mutation ( p.r861x ) . 
 the two produced a 
 premature stop codon , resulting in haploinsufficiency of the mr . in conclusion , 
 genetic 
 analysis of nr3c2 is useful for diagnosis and planning therapeutic 
 strategies .