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Take with a grain of salt.


A 5-day-old girl, born at term after an uncomplicated pregnancy, was admitted to the hospital after a routine midwife check showed that she had lost 15% of her original birth weight [6.2 lb (2.83 kg)]. She was being fed normal-term formula milk, and an initial assessment revealed only mild dehydration. The working diagnosis was a feeding problem, and her management plan was to be fed 150 mL/kg formula milk per day with regular monitoring of weight. The patient's serum concentrations of selected analytes were as follows: sodium, 135 mEq/L (135 mmol/L; reference interval, 135-145 mmol/L); potassium, 5.3 mEq/L (5.3 mmol/L; reference interval, 3.5-5.3 mmol/L); and urea, 11.7 mg/dL (4.2 mmol/L; reference interval, 3.5-6.5 mmol/L).

Five days after admission, the patient's weight was unchanged. Her serum analyte concentrations were nowas follows: sodium, 128 mEq/L (128 mmol/L); potassium, 6.7 mEq/L (6.7 mmol/L); urea, 5.8 mg/dL (2.1 mmol/L); creatinine, 0.3 mg/dL (28 [micro]mol/L; reference interval, 60-100 [micro]mol/L); and blood glucose, 77.4 mg/dL (4.3 mmol/L; reference interval, 4-7 mmol/L). These findings prompted more-detailed biochemical and endocrine tests. Her bicarbonate concentration was 30 mEq/L (30 mmol/L; reference interval, 24-32 mmol/L), and her chloride concentration was 94 mEq/L (94 mmol/L; reference interval, 95-105 mmol/ L). These results yielded an anion gap of 10.7 mmol/L. The urine sodium concentration was 10 mEq/L (10 mmol/L). Further blood results were available 2 days later: plasma renin, 854 mIU/L (reference interval, 4-190 mIU/L in >7 days to 1 year); serum aldosterone, >5786 ng/L (reference interval, 300-2000 ng/L in neonates). The results of blood gas, serum cortisol, ammonia, lactate, urine culture, and urine steroid profile tests were all normal.



Some weight loss is normal in the first few days of life. A loss of up to 10% can be normal in breast-fed babies, but a weight loss of only 5% is expected in formula-fed babies (1). Babies with excess weight loss in the context of difficulty establishing feeding--especially breast-fed infants--may show evidence of hypernatremic dehydration due to loss of body sodium, but with a greater deficit in body water (2). In this case, the hyponatremia did not correlate with the clinical scenario for a formula-fed baby failing to gain weight, despite the patient following a clear feeding plan.

There are many pathologic causes (3) for faltering growth in an infant, including the following: genetic and chromosomal abnormalities, such as trisomy 21, Turner syndrome, and cystic fibrosis; inborn errors of metabolism; endocrine disorders, such as congenital adrenal hyperplasia (CAH) [3]; anatomic abnormalities, such as a large ventricular septal defect or biliary atresia; and psychosocial factors (3), such as emotional deprivation, poverty, neglect, and maternal mental illness.


This combination in association with excessive weight loss indicates a problem with sodium chloride metabolism. CAH due to salt-wasting 21-hydroxylase deficiency (SW21-OHD) is the most common cause of hyponatremia and hyperkalemia in neonates. SW21-OHD presents with virilization in the female neonate, but rarer inborn errors of adrenal steroid metabolism, such as steroidogenic acute regulatory protein deficiency, may not. Other causes include adrenal hypoplasia, cystic fibrosis, cerebral salt-wasting syndrome, and secondary causes of aldosterone insensitivity in such conditions as urinary tract infections, pyelonephritis, and obstructive uropathy (4).


The urine sodium concentration is helpful because it confirms renal salt wasting if it is inappropriately high. If the renal function is normal, renin and aldosterone tests should be requested. A low serum aldosterone result is seen in primary adrenal insufficiency. In the absence of excessive virilization, normal results for random serum cortisol, adrenocorticotropic hormone stimulation, testosterone, 17-hydroxyprogesterone, and aldosterone exclude CAH due to SW21-OHD. In suspected cases of other inborn errors of adrenal metabolism, a urine steroid profile is crucial to confirm the site of the block in order to direct future genetic mutation testing. Cystic fibrosis may present with low sodium concentrations. Such testing is included in the UK newborn-screening test and is indicated by an increased concentration of immunoreactive trypsinogen. The sweat test, however, remains the gold standard to confirm the diagnosis.

Secondary causes of aldosterone insensitivity, such as a urinary tract infection, are excluded by a normal urine microscopy result, and culture and a normal renal ultrasound scan will exclude an obstructive uropathy. Cerebral salt wasting shows an excessively high urinary sodium concentration, >100 mmol/L (4).


The increased renin and aldosterone concentrations in the presence of hyponatremia and hyperkalemia were consistent with a diagnosis of pseudohypoaldosteronism type 1 (PHA1).The lowurine sodium result seen in this case does not exclude renal salt wasting, because of the dilutional effect in a random sample. Fractional excretion of sodium is more specific because it is not affected by urine volume.


PHA comprises a collection of rare electrolyte imbalance disorders due to aldosterone (mineralocorticoid) resistance (5). Renin is produced in response to hypovolemia, and aldosterone secretion (under stimulation from angiotensin II) is augmented in the presence of hyperkalemia. The biochemical abnormalities of PHA can be explained by the functions of aldosterone. Aldosterone crosses the plasma membrane of epithelial cells and binds to the cytosolic mineralocorticoid receptor. The receptor-hormone complex activates intracellular signaling cascades, increasing the luminal epithelial sodium channels in many organs, including kidney, lung, colon, and sweat and salivary glands. These channels control sodium absorption at the luminal surfaces of epithelial cells (5-7). Sodium is then secreted at the basolateral surface into extracellular space via the [Na.sup.+]-[K.sup.+] ATPase pumps. This process is coupled with potassium secretion at the luminal surface. Therefore, epithelial sodium channel dysfunction leads to hyponatremia and hyperkalemia.


There are 3 types of PHA (Table 1). PHA1 has 2 clinical subtypes, each with a distinct pattern of inheritance. Type 2 is characterized by hypertension and hyperkalemic metabolic acidosis with low renin and aldosterone values (4, 8); it is therefore excluded in the present case. Type 3 is an acquired variety (4), in which transient aldosterone insensitivity is seen in such conditions as urinary tract infection, obstructive uropathy, or pyelonephritis. Type 3 PHA resolves with the resolution of the initial clinical condition. In our case, urine microscopy and renal ultrasound scan results were normal.


The autosomal recessive PHA1 is caused by mutations within the genetic subunits that code for the epithelial sodium channel (5-7, 9). It is the most severe form, because the salt wasting occurs in numerous mineralocorticoid-sensitive tissues, including the lungs, kidneys, colon, and sweat and salivary glands. These patients require lifelong salt-replacement therapy.

Autosomal dominant PHA1 is the likely explanation for the case described. Salt wasting is restricted to the kidneys, and the mutation lies in the gene encoding the mineralocorticoid receptor (9, 10). The mineralocorticoid receptor mutation leads to a lack of renal sensitivity to aldosterone, and the prognosis is better than for autosomal recessive PHA1. Genetic testing is available for PHA, but such testing is possibly more of academic interest. Genetic testing was not done in our case in light of a clear clinical diagnosis and a good response to sodium chloride supplementation. There was no known family history of the disease.


This disease is a pan-ethnic disorder with equal incidences in males and females, and it usually presents in the newborn period, often within the first 2 weeks of life, with excessive weight loss, failure to thrive, feeding difficulties, vomiting, and dehydration. Laboratory findings include hyponatremia, hyperkalemia, and metabolic acidosis. The glomerular filtration rate is normal, but it is rarely measured in infants. Hypovolemia and hypotension may also occur (4, 7). These presenting symptoms are similar in infants with true hypoaldosteronism and CAH.


In the acute phase, the neonate may need treatment for hypovolemic shock or correction of hyperkalemia and metabolic acidosis (4). It may be necessary to treat the baby with steroids before confirmation of the PHA diagnosis, because a similar clinical picture can be caused by the salt-losing crisis of CAH.

Long-term treatment involves judicious fluid management and sodium chloride supplementation. After sodium chloride supplementation is initiated, the potassium concentration will normalize. The adequacy of supplementation can be measured by monitoring the serum potassium concentration (4); however, the plasma renin concentration gives the best estimate of salt replacement and should be measured every 3 to 12 months, depending on age. Total suppression will be seen with excessive sodium chloride replacement, and there may be no other clinical or biochemical indicators.


In autosomal dominant PHA1, the renal tubules mature throughout infancy and urinary sodium wastage gradually decreases, with remission occurring by about 2 years of age because the child will take an adequate amount of salt in the diet by this age. The prognosis is very good (5), with resolution of the electrolyte disturbances. Symptoms may recur at times of sodium chloride restriction and during periods of illness or heat stress.


Regular sodium chloride supplementation (3 mmol/kg per day) was started on day 12, and weight gain was noted from day 21. The patient's serum sodium and potassium concentrations remain normal. At 10 months of age, she is growing normally, and her weight has increased from the 0.4th centile to the 75th centile.


1. What are common causes for excess weight loss in a neonate who presents in the first few days of life?

2. What are the possible explanations for hyponatremia with hyperkalemia in a neonate with excessive weight loss?

3. What laboratory investigations are appropriate?


* Excessive neonatal weight loss may be associated with hypernatremic dehydration in breast-fed babies.

* Hyponatremia in a neonate with clinically important weight loss warrants further investigation to consider less common endocrine causes, such as PHA or CAH.

* PHA1 may present symptomatically before the development of electrolyte abnormalities.

* PHA1 (autosomal dominant) is managed by sodium supplementation and monitoring of serum sodium and potassium concentrations.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.


(1.) Lawrence RA, Lawrence RM. Breastfeeding: a guide for the medical profession. 7th ed. Maryland Heights, Missouri: Elsevier/Mosby, 2011.

(2.) Modi N. Avoiding hypernatraemic dehydration in healthy term infants. Arch Dis Child 2007;92:474-5.

(3.) Krugman SD, Dubowitz H. Failure to thrive. Am Fam Physician 2003;68: 879-84.

(4.) Medscape Reference. Pseudohypoaldosteronism. http://emedicine.medscape. com/article/924100 (Accessed December 2011).

(5.) Lee SE, Jung YH, Han KH, Lee HK, Kang HG, Ha IS, et al. A case of pseudohypoaldosteronism type 1 with a mutation in the mineralocorticoid receptor gene. Korean J Pediatr 2011;54:90-3.

(6.) Kanda K, Nozu K, Yokoyama N, Morioka I, Miwa A, Hashimura Y, et al. Autosomal dominant pseudohypoaldosteronism type 1 with a novel splice site mutation in MR gene. BMC Nephrol 2009;10:37.

(7.) Bonny O, Rossier B. Disturbances of Na/K balance: pseudohypoaldosteronism revisited. J Am Soc Nephrol 2002;13:2399-414.

(8.) Zhou B, Wang D, Feng X, Zhang Y, Wang Y, Zhuang J, et al. WNK4 inhibits NCC protein expression through MAPK ERK1/2 signaling pathway. Am J Physiol Renal Physiol 2011;302:F533-9.

(9.) Geller DS, Zhang J, Zennaro MC, Vallo-Boado A, Rodriguez-Soriano J, Furu L, et al. Autosomal dominant pseudohypoaldosteronism type 1: mechanisms, evidence for neonatal lethality, and phenotypic expression in adults. J Am Soc Nephrol 2006;17:1429-36.

(10.) Viemann M, Peter M, Lopez-Siguero JP, Simic-Schleicher G, Sippell WG. Evidence for genetic heterogeneity of pseudohypoaldosteronism type 1: identification of a novel mutation in the human mineralocorticoid receptor in one sporadic case and no mutations in two autosomal dominant kindreds. J Clin Endocrinol Metab 2001;86:2056-9.


Abby S. Hollander *

The authors describe the interesting case of a 5-day-old girl with poor weight gain, hyperkalemia, and mild to moderate hyponatremia due to resistance to aldosterone--or type 1 pseudohypoaldosteronism (PHA). The diagnosis was confirmed by the demonstration of an extremely increased serum aldosterone concentration at the time of hyponatremia, and the child was successfully treated with sodium chloride supplementation. Adrenal insufficiency is appropriately mentioned in the differential diagnosis. Note that adrenal insufficiency should be empirically treated if it is suspected in a sick neonate.

The diagnosis that is most likely for an infant with hyponatremia, hyperkalemia, and hypovolemia is salt-wasting congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. CAH is an autosomal recessive disorder with an incidence of 1 in 10 000 to 1 in 20 000 births. Females with 21-hydroxylase deficiency typically have clitoromegaly due to excess androgen production, so examination of the genitalia is a crucial part of the evaluation of a baby girl with hyponatremia and hyperkalemia. Newborn screening for 21-hydroxylase deficiency is performed in all US states and at least 12 other countries. This newborn screening has led to earlier diagnosis, thereby reducing the likelihood of a life-threatening adrenal crisis.

The clinical presentations of type 1 PHA and salt-wasting CAH in the neonate can be very similar. As the authors discuss, type 1 PHA can be primary, due to mutations in the gene encoding the mineralocorticoid receptor (autosomal dominant) or in the genes encoding the epithelial sodium channel (autosomal recessive), or it can occur secondary to urologic problems such as obstructive uropathy or pyelonephritis. Careful physical examination for female virilization, evaluation for genitourinary anomalies, and evaluation of results for the appropriate laboratory tests (17-hydroxyprogesterone, cortisol, renin, aldosterone) will lead the clinician to the appropriate diagnosis and treatment for the neonate with hyponatremia and hyperkalemia.

Washington University St. Louis, St. Louis Children's Hospital, St. Louis, MO.

* Address correspondence to the author at: Washington University St. Louis, St. Louis Children's Hospital, One Children's Place, St. Louis, MO 63110. Fax 314-454-6225; e-mail

Received May 1, 2012; accepted May 21, 2012.

DOI: 10.1373/clinchem.2012.185678

Author Contributions: All authors confirmedtheyhavecontributedto the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared anypotential conflicts of interest.

Siba P. Paul, [1] * Bryony A. Smith, [1] Timothy M. Taylor, [1] and Joanna Walker [2]

[1] Department of Paediatrics, St. Richard's Hospital, Chichester, UK; [2] Department of Paediatrics, Queen Alexandra Hospital, Cosham, UK.

* Address correspondence to this author at: Department of Paediatrics, St. Richard's Hospital, Spitalfield Lane, Chichester PO19 6SE, UK. Fax +44-1243-831431; e-mail

An abstract of this case (in part) has been published (Clin Biochem 2011;44:540).

Received October 22, 2011; accepted January 30, 2012.

Previously published online at DOI: 10.1373/clinchem.2011.178111

[3] Nonstandard abbreviations: CAH, congenital adrenal hyperplasia; SW21-OHD, salt-wasting 21-hydroxylase deficiency; PHA1, pseudohypoaldosteronism type 1.


Patricia Jones [1,2] *

The constellation of findings in this case study, including hyponatremia, hyperkalemia, and weight loss, led the authors in the correct direction for determining the underlying cause. Hyponatremia accompanied by weight loss in infancy is indicative of sodium depletion.

When dealing with cases involving hyponatremia, there are 2 basic considerations to take into account. First, analytical error should always be considered, including the possibility that the hyponatremia is in fact pseudohyponatremia. Indirect ion-specific electrode measurement of electrolytes is the most commonly used method of electrolyte analysis, and hyperlipidemia and/or hyperproteinemia will produce artificially low sodium concentrations, owing to the electrolyte exclusion effect (1). Although uncommon, such disorders as inborn errors of lipid metabolism with exceptionally high serum lipids can occur in infants and produce falsely low electrolyte values. In the current case, the hyperkalemia is inconsistent with this type of measurement artifact unless the sample was also hemolyzed. The second consideration when dealing with hyponatremia in infancy is incorrect mixing or dilution of formula (2). In addition, hyponatremia in hospitalized infants is not an uncommon finding; it is believed to be related to the practice of using hypotonic fluids in pediatric populations. In this particular case, in which the infant was hospitalized, on a specific feeding regimen, and receiving no fluids when the hyponatremia occurred, these causes can be ruled out; however, a good medical history and a physical examination that includes analysis of formula, diet, and water consumption are necessary for evaluating any infant presenting with hyponatremia.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.


(1.) Scott MG, LeGrys VA, Klutts JS. Electrolytes and blood gases. In: Burtis CA, Ashwood ER, Bruns DE, eds. Tietz textbook of clinical chemistry and molecular diagnostics. 4th ed. St. Louis: Elsevier Saunders; 2006. p 983-1018.

(2.) Moritz ML, Ayus JC. Disorders of water metabolism in children: hyponatremia and hypernatremia. Pediatr Rev 2002;23:371-9.

[1] Department of Pathology, Division of Pediatric Pathology, University of Texas Southwestern Medical Center; [2] Department of Pathology, Children's Medical Center, Dallas, TX.

* Address correspondence to the author at: Children's Medical Center, Pathology department, 1935 Medical District Dr., Dallas, TX 75235. Fax 214-456-471 3; e-mail

Received March 20, 2012; accepted March 28, 2012.

DOI: 10.1373/clinchem.2012.185686
Table 1. Types of PHA.

                    Genetic or
PHA type            acquired?           Genes involved (a)

Type 1 PHA     Autosomal recessive   SCNN1A, SCNN1B,
                 PHA1 (MTODb)          SCNN1G

               Autosomal dominant    NR3C2 (MR)
                 (renal PHA)

Type 2 PHA     Autosomal dominant    WNK1, WNK4
Type 3 PHA     Acquired              No genes known; reverses
  (secondary                           with treatment of
  PHA)                                 primary pathology

PHA type         Biochemical abnormalities         Organs involved

Type 1 PHA     High serum renin and            Lungs, kidneys, colon,
                 aldosterone, hyponatremia,      sweat and salivary
                 hyperkalemia                    glands
               High serum renin and            Kidneys
                 aldosterone, hyponatremia,
Type 2 PHA     Hyperkalemia, hyperchloremic    Kidneys
 (Gordon         metabolic acidosis, low
  syndrome)      aldosterone and renin
Type 3 PHA     Transient aldosterone           Seen with urinary
  (secondary     insensitivity,                  tract infection,
  PHA)           hyponatremia,                   obstructive uropathy,
                 hyperkalemia, metabolic         pyelonephritis
(a) SCNN1A, sodium channel, non-voltage-gated 1 alpha subunit;
SCNN1B, sodium channel, non-voltage-gated 1, beta subunit; SCNN1G,
sodium channel, non-voltage-gated 1, gamma subunit; NR3C2, nuclear
receptor subfamily 3, group C, member 2 (also known as MR); WNK1,
WNK lysine deficient protein kinase 1; WNK4, WNK lysine deficient
protein kinase 4.

(b) MTOD, multiple target organ defect.
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Title Annotation:Clinical Case Study
Author:Paul, Siba P.; Smith, Bryony A.; Taylor, Timothy M.; Walker, Joanna
Publication:Clinical Chemistry
Date:Feb 1, 2013
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