Renal pseudohypoaldosteronism type 1 – an adult case series including a novel gene variant

doi:10.21203/rs.3.rs-4925132/v1

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Renal pseudohypoaldosteronism type 1 – an adult case series including a novel gene variant

https://doi.org/10.21203/rs.3.rs-4925132/v1

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Purpose

Renal pseudohypoaldosteronism type 1 (PHA1) is a rare disease affecting infants. Symptoms are failure to thrive, vomiting and weight loss. It is caused by gene variants in NR3C2 by which the mineralocorticoid receptor is dysfunctional, and patients develop hyponatremia, elevated plasma aldosterone and renin but have normal blood pressure. Little is known about PHA1in adults. We present four adults with PHA1, their clinical, biochemistry and genetic data.

Methods

Clinical and biochemical data were collected from the medical files and clinical examination of the participants. Genetic testing was performed.

Results

Two adult dizygotic twins and their mother, as well as an adult man were included. One of the sisters and the man had had severe hyponatremia and been admitted several times as young infants, treated with sodium chloride and fludrocortisone. All had as adults elevated plasma aldosterone and normal potassium. The females now had normal plasma renin, but it was increased in the male. A novel genetic variant in NR3C2 were found in the twins and their mother (c.1816T > C, p.(Cys606Arg)). All had normal blood pressure and were asymptomatic.

Conclusion

In adulthood PHA1 seems to be asymptomatic and long-term consequences favorable.

salt-wasting

long-term

gene variants

symptoms

Renal pseudohypoaldosteronism type 1 (PHA1) affects young children with no sex preponderance [1]. It is characterized by symptoms as vomiting, loss of appetite and reduced growth and appears from birth to 8 months of age. In small infants this could be lethal. Biochemically low sodium, elevated potassium, increased plasma and urine aldosterone as well as renin concentrations are found. Metabolic acidosis is also present. This picture is also present in the more severe systemic form PHA1 which is caused by inactivating gene variants in sodium channels (SCNN1A, SCNN1B, SCNN1G) encoding subunits of the epithelial sodium channel, ENaC [2]. This is inherited autosomal recessive, but renal PHA1 is caused by gene variants affecting the mineralocorticoid receptor and is inherited in an autosomal dominant fashion. Secondary PHA1 can be found in patients with tubulointerstitial nephritis and urinary tract infection or obstructive uropathy. It is recommended to perform imaging of kidneys and adrenals to exclude such causes [3, 4]. In secondary cases PHA1 could be transient [5].

Aldosterone is synthesized in the zona glomerulosa in the adrenal cortex and is necessary to regulate sodium and water homeostasis [6]. In renal PHA1 there are abnormalities in ion transport channels responding to aldosterone in the renal tubule, caused by defects in the mineralocorticoid receptor. This is the mechanism in renal PHA1 with a genetic variant in nuclear receptor subfamily 3 group C member 2, NR3C2, which encodes the mineralocorticoid receptor [7]. Haploinsufficiency is sufficient to cause renal PHA1 [7]. More than 100 genetic variants in the NR3C2 gene have been detected [8, 9]. Genetic variants cause premature termination of translation of aldosterone or a loss of ligand binding. The effect of pathological variants causes a relative aldosterone resistance whereby re-uptake of sodium in the renal tubule is impaired. Substitution with salt rich food and sodium capsules or fludrocortisone can be necessary, but the need for treatment gradually decreases from 2–3 years of age.

Differential diagnosis could be Addison´s disease but it usually presents in adulthood if not a congenital primary adrenal insufficiency (PAI) is considered. The most common cause of salt-wasting in infancy is congenital adrenal hyperplasia (CAH) in its severest form which presents in the neonatal period and girls are also virilized [10]. However, both conditions present with low aldosterone and increased renin concentrations. In a series from China consisting of 187 infants with salt-wasting 169 had CAH and only 1 had renal PHA1 [11]. Very rarely familial primary aldosteronism could be encountered with elevated aldosterone and blood pressure at a young age [12]. Physical examination should also include external genitalia which could be atypical in CAH [10]. Pigmentation could also be found in CAH and Addison´s disease.

This case series aimed to describe the clinical picture with maturity in four adult cases with renal PHA1.

All recent cases with PHA1 and ICD10-code N25.8 and treated by us at the Endocrine Outpatient Clinic were reviewed. All specialist outpatient visits and admissions in Sweden are coded with ICD10-codes by the attending physician and are thereafter stored in both local and national databases [13]. The clinical, biochemical and genetic data of patients with PHA1 were recorded in detail. Additional clinical, biochemical and genetic data was supplemented when missing. This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Karolinska University Hospital and all participants gave written informed consent.

In total, four adult cases were included and are described in detail below. Case number 1 and 2 was recently seen by us, together with Case number 3. Case 4 had been followed at the Endocrine Outpatient Clinic as an adult from the age of 18.

Case 1

A 21-year-old female presented to the adult Endocrine Outpatient Clinic. She had been born with cesarean section in a Mediterranean country. During her first year she had electrolyte disturbances with hyponatremia and elevated aldosterone, treated with salt supplementation initially and later fludrocortisone. She was repeatedly admitted and treated with sodium infusion during her first years of life. After 3 years of age all treatment ceased, and she was followed up to 12 years of age. During her childhood she had experienced a fluctuating craving for salt but also for water. At presentation to the Endocrine Outpatient Clinic as an adult she reported regular menstruations, previous surgery for breast asymmetry and no intake of any medications. Clinically there were no hirsutism or acne. Sitting office blood pressure was 100/70. Her height was 160 cm and weighs 83 kg, equivalent to a BMI of 32.4 kg/m². The biochemical tests revealed high aldosterone with normal renin concentrations (Table 1). Additionally, biochemical tests showed morning serum cortisol 387 nmol/L (normal 135–540), testosterone 1.4 nmol/L (normal 0.3–1.7), DHEAS 8.8 micromol/L (4.0–11), 17-hydroxyprogesterone < 1 nmol/L (< 5 nmol/L follicular phase) and androstenedione 4.5 nmol/L (1.0-7.2). Computed tomography of the adrenals was normal. Due to suspicion of renal PHA1 a genetic test was performed, and it revealed a novel heterozygous gene variant with unknown significance in NR3C2, c.1816T > C, p.(Cys606Arg), which was suspicious for renal PHA1, and could be inherited autosomal dominant.

Case 2

The dizygotic twin of Case 1 presented together with her sister to the adult Endocrine Outpatient Clinic. She was also a 21-year-old female. Menarche was at 12 years and menstruations were regular. She also had had surgical reduction due to breast asymmetry. There were no hirsutism or acne. Blood pressure was 115/70, height 159 cm, weighs 82 kg and a BMI of 32.4 kg/m². In contrast to her twin sister (Case 1) she had not had any low sodium concentrations, not even in infancy, and had thus not been treated with sodium nor fludrocortisone. As an adult the biochemical tests revealed high aldosterone with normal renin concentrations (Table 1). Additionally biochemical tests showed serum cortisol 325 nmol/L (normal 135–540), DHEAS 10 micromol/L (normal 4.0–11), testosterone 1.0 nmol/L (0.3–1.7) and 17-hydroxyprogesterone < 1.0 nmol/L (< 5 in follicular phase). Her genetic test also revealed the novel heterozygous gene variant with unknown significance in NR3C2, i.e., c.1816T > C, p.(Cys606Arg).

Case 3

Due to family screening both parents to Case 1 and 2 were also examined. The father had normal plasma aldosterone and renin concentrations (150 pmol/L and 18 IU/L, respectively) and no variant in the NR3C2 gene. The mother aged 54 years, had bronchial asthma and liver steatosis but was otherwise healthy with no salt-wasting in infancy. She had, however, increased plasma aldosterone and normal renin concentrations when measured as an adult (Table 1). Blood pressure was 110/80, height was 158 cm and weight 74 kg, i.e., a BMI of 29.6 kg/m². She reported having salt but also sugar cravings during her youth, but these ceased when she was married. Her genetic test also revealed the novel heterozygous gene variant with unknown significance in NR3C2, i.e., c.1816T > C, p.(Cys606Arg). There was no history of any salt-wasting in any other relative.

Case 4

This Swedish man had been followed at the adult Endocrine Outpatient Clinic since transitioning from the Pediatric Endocrinologists. At the time of the last visit, he was a 29-year-old. He was born with acute cesarean section at week 34 because of preeclampsia and deaccelerations on cardiotocography (CTG). He weighed 1550 g. At three weeks, still at hospital with failure to thrive a plasma sodium of 101 nmol/L (normal 136–146) with a plasma potassium of 6.7 mmol/L (normal 3.3–5.3) were noted, and adrenal insufficiency was suspected. There was no pigmentation. Intravenous hydrocortisone with a dose of 25 mg was given with slight improvement. Morning serum cortisol concentration was, however, normal (310 nmol/L), and there were no signs of CAH, with plasma 17-hydroxyprogesterone 0.8 nmol/L (normal < 5) and urine pregnantriole 0.1 umol/24h (normal < 1). Sodium was from 1 month of age supplemented orally with 4 mmol/L, 1 mmol twice daily. Repeated treatment with sodium infusion was done and at times fludrocortisone had to be added. Blood pressure was normal all the time. Ultrasound of the kidneys did not display obstruction, and urine sodium was 172 mmol/L (normal 50–300). When he was 4 months plasma aldosterone concentration was investigated and found to be 11200 pmol/L (normal < 470) and renin 15 nmol/L (normal 0.5–4.5). He was diagnosed with renal PHA1. From that time sodium substitution with powder was continued orally with 500 mg thrice. In all he was admitted 8 times during his first year with vomiting, hyponatremia, weight loss and respiratory distress with Kussmaul breathing. With sodium infusions symptoms vanished. Later he was prescribed capsules with 500 mg sodium chloride which he kept taking 6 times a day, totally 18 tablets/day until he became an adult.

As an adult the sodium chloride medication was gradually reduced without clinical problems, and he had now no sodium medication. The biochemical tests at 29 years of age are shown in Table 1. He also had dyslexia, and attention deficit disorder (ADHD) treated with dexamphetamine. He also had severe demyelinating polyneuropathy, Charcot-Marie-Tooth 1 (HSMN1, CMT1) disease and used a wheelchair. Blood pressure was 115/85, his height 162 cm, weight 52 kg and BMI 19.8 kg/m². Genetic test found a heterozygous pathogenic genetic variant in NR32C gene, c.1308T > A p.(Cys436). This nonsense variant has been deemed as symptomatically fluctuating between individuals and compatible with renal PHA1. His mother had vomiting problems as a small child and preferred a salty diet. She had as an adult at an age of 26 years also elevated plasma aldosterone concentration (1540 pmol/L, normal < 470) and elevated plasma renin (0.97 pkat/L, normal 0.17–0.43). A younger sister, aged 28 years, had also renal PHA1 and CMT1. His grandmother also liked a salty diet and had difficulties in eating as a young child and weighed 7.5 kg when she was 1.5 years old.

Table 1

Biochemical test results in Case 1–4, as adults free from interfering medications. Reference levels in upper panel within brackets.
	Plasma aldosterone ambulatory (60–980 pmol/l)	Plasma renin (4.4–46 mIU/L)	Plasma aldosterone/ renin ratio (< 60 pmol/L)	Plasma potassium (3.5–4.6 mmol/L)	Plasma sodium (137–145 mmol/L)
Case 1	2680	35	77	3.9	139
Case 2	3330	34	98	3.6	141
Case 3	2390	22	107	4.3	138
Case 4	1250	95	13	3.2	140

These four cases describe patients harboring two different gene variants in NR32C as cause for renal PHA1, one variant being novel. Two of them had symptoms in childhood but could abstain from medication later. Case 4 would most likely been able to cease medication much earlier.

Case 1

3 with a previously not described genetic variant in the NR32C gene had still elevated aldosterone and normal renin concentration and normal blood pressure in adulthood while Case 4 had elevated both aldosterone and renin concentrations and normal blood pressure. This is in line with the different clinical pictures in renal PHA1, which is also seen within kindreds with the identical genetic variants. Thus, of the two dizygotic patients and their mother only one had salt-wasting manifestations during infancy.

In neonatal kidneys glomerular filtration is reduced and the distal nephron is immature, leading to impaired ability of sodium and water reabsorption. In an investigation of 48 healthy neonates these had increased plasma potassium and aldosterone concentrations, but equivalent sodium levels compared to their mothers [14]. This suggests a partial mineralocorticoid resistance in newborns. This may be caused by a low expression of mineralocorticoid receptor in infants [15]. With age renal maturity may overcome this resistance possibly by an increased expression of mineralocorticoid receptors [14]. Another explanation could be a potential reduction of the hyperactivity in the renin-angiotensin-aldosterone system in childhood [16], reducing the mineralocorticoid resistance with age.

When symptomatic renal PHA1 is present, substitution with mineralocorticoid treatment with fludrocortisone 0.05-2 mg/d divided in 1–2 doses is recommended similar to salt-wasting CAH [6, 17]. Doses are adjusted considering clinic, potassium, sodium and renin concentrations. During infancy sodium is also supplemented with 1–2 g/d (17–34 mEq/d)[17]. With improvement in aldosterone sensitivity supplementation can gradually decrease and is rarely necessary after 3 years of age [1, 7]. This in contrast to our Case 4 who was treated with sodium chloride 9 g/d for a prolonged period. Without medication some patients may still as adolescents and adults experience symptoms co-occurring with infections or dehydration.

Both sisters had significant breast asymmetry. We have not found any association with this and PHA1. Case 4 had several co-occurring conditions. CMT1 is driven by genetic variants in PMP22 in chromosome 17 degrading myelin but is to the best of our knowledge not linked to PHA1, nor is ADHD or dyslexia. Interestingly Case 4 had also a 1-year younger sister with both PHA1 and CMT1.

Very high concentrations of the mineralocorticoid receptor have been found in the rat brain and the hippocampus [18], but there has not been evidence for neurological impairment in renal PHA1. If this could be associated with Case 4 CMT1 or ADHD is not likely, since NR32C is located on chromosome 4q3 and PMP22 on chromosome 17. Possibly a partial mineralocorticoid resistance protects the brain from a negative effect or humans, in contrast to rats do not have an abundance of mineralocorticoid receptors in the brain.

In diagnosing hyponatremia and renal PHA1 several differential diseases are considered. The heredity, clinical picture with or without virilization and pigmentation could point to CAH or another PAI disorder. Blood pressure and aldosterone are generally low in PAI but aldosterone should be elevated and blood pressure low-normal in PHA1. In the salt-wasting series presented by Wijaya et al. 169/187 had CAH, 1 had SF-1 gene variant, 9 had X-linked adrenal hypoplasia congenita, 4 had

aldosterone synthase deficiency (primary hypoaldosteronism) with a genetic variant in

CYP11B2 [11]. The one child with renal PHA1 had a verified heterozygous variant in the

NR3C2 gene. Most salt-wasting conditions are hereditary, unless there are urinary tract

obstruction or infections, if so symptoms vanish when treated [11, 5, 19]. Hospital acquired

hyponatremia was found in 86 of 2012 neonates up to 100 days old and of these 30% were

iatrogenic [20].

Few studies have evaluated the consequences of renal PHA1 in adults. Patients with renal PHA1 have life-long elevation of plasma aldosterone, renin and angiotensin II concentrations [21]. There were no differences between 6 patients with renal PHA1 and 20 controls on blood pressure, congestive heart disease or potassium or sodium concentrations, despite that those adults with renal PHA1 had a 14-fold increase in aldosterone concentrations. Thus, affected patients with renal PHA1 could not be distinguished from other individuals, suggesting that they regulate sodium at the expense of chronically elevated aldosterone [21]. Aldosterone in renal PAH1 did not lead to volume expansion, hypertension, or heart failure in this study.

Elevated plasma aldosterone concentrations are linked to cardiac remodeling and fibrosis also ahead of increased blood pressure in familial hyperaldosteronism [22, 23]. In primary aldosteronism (PA) increased aldosterone is also linked to cardiac impairment and chronic kidney disease [24, 25]. Mortality is also increased, especially if PA is diagnosed in patients > 56 years old [26].

If elevated aldosterone also increases the risk of cardiovascular disease in renal PHA1 has been investigated by Escoubet et al. [27]. In a case-control investigation 39 patients with renal PHA1 and 39 controls were studied with cardiac and vascular ultrasound, cardiac MRI, pulse wave velocity and 24-hour ambulatory blood pressure. No cardiac dysfunction was found, surprisingly the left ventricular function was better in the patients with renal PHA1 than in controls. Further there was no thickening of the vascular wall, stiffness or remodeling, although the plasma aldosterone concentrations were in the same range as in patients with PA.

The deleterious effects of aldosterone thus require full activity of the mineralocorticoid receptor. Patients with renal PHA1 also had increased salt intake and hypotension more often and had increased miscarriages compared to controls [27].

In an investigation by Walker et al. 12 adult patients with renal PHA1 were compared with 10 controls [28]. Patients with renal PHA1 had increased plasma cortisol, which was associated with higher plasma renin, lower high-density lipoprotein and cholesterol. Waist

circumference was also larger but there was no difference in blood pressure, carotid intima thickness or when investigated with cardiac ultrasound. This gives support that PHA1 in adults have no or low impact on life.

Of note, all our patients were short. If this was a result from failure to thrive in infancy cannot be proven, as two of the cases did not have clinical symptoms during childhood. To investigate this series with a larger population is needed.

In conclusion, we present four adult cases with renal PHA1 with different phenotype and one novel variant in the NR3C2 gene. All seemed to be unaffected by their renal PHA1 in adulthood, two were affected in the childhood-adolescence while the other two were found in adulthood during family screening. Renal PHA1 seems to have good longtime prognosis.

Funding

HF was supported by Karolinska Institutet and Stockholm County Council.

Author contribution

Both authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by both authors. The first draft of the manuscript was written by JC and both authors revised the manuscript. Both authors read and approved the final manuscript.

Copeting interest

The authors have nothing to disclose.

Compliant with ethical standards

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Renal pseudohypoaldosteronism type 1 – an adult case series including a novel gene variant

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