A Young Female with Spitzer-Weinstein Syndrome Diagnosed by Thiazide Test

Abstract

Spitzer-Weinstein syndrome is a rare disorder characterized by thiazide responsive hyperkalemia and normal anion gap metabolic acidosis, similar to Gordon syndrome. The hyperfunction of thiazide-sensitive Na⁺-Cl⁻ cotransporter (TSC) is the main pathophysiological mechanism. We presented a 19-year-old female with short stature, normal blood pressure, persistently elevated serum potassium, and metabolic acidosis. The diagnosis of Spitzer-Weinstein Syndrome was made by clinical pictures and thiazide test. After taking 4 mg hydrochlorothiazide, her daily urine potassium excretion increased from 18.1 mmol to 41.8 mmol, urine pH decreased from 7.32 to 6.50, and urinary net charge decreased from 65.7 to 54.4. This patient then took hydrochlorothiazide 4 mg daily. The persistent hyperkalemia and metabolic acidosis were corrected. Thiazide, a powerful inhibitor of TSC, proved to be a useful tool for the diagnosis and treatment of Spitzer-Weinstein syndrome.

Keywords:

• hyperkalemia
• Spitzer-Weinstein Syndrome
• Gordon Syndrome
• hypertension

INTRODUCTION

Spitzer-Weinstein Syndrome with characteristic features of hyperkalemic normal anion gap metabolic acidosis, short stature, and normal blood pressure make up the early manifestations of Gordon syndrome.[1] Hyperfunction of thiazide-sensitive Na⁺-Cl⁻ cotransporter (TSC) is the basic pathophysiological defect of Spitzer-Weinstein and Gordon's syndrome.[2],[3] Thiazide is a useful tool to diagnose the overactivity of TSC. We described the clinical features and diagnosis of the Spitzer-Weinstein Syndrome in a young female with persistent hyperkalemia and normal anion gap metabolic acidosis.

CASE REPORT

A 19-year-old woman with congenital mental retardation was admitted to our neurology ward due to an episode of seizure. No medicine or other chemical use could be traced by history. Physical examinations revealed normal blood pressure (101 mmHg/62 mmHg), normal respiratory rate (18/min), and a short stature (body height 137 cm). During admission, biochemical tests showed serum potassium [K⁺] 5.7 meq/L, creatinine 0.9 mg/dL, sodium 138 meq/L, and chloride [Cl⁻] 110 meq/L. One week later, serum potassium 6.1 meq/L was still noted. The serum aldosterone and renin level in an upright position were within normal range. The serum aldosterone was 218 pg/mL (normal: 38–313 pg/mL) and serum renin was 25.6 pg/mL (normal: 5–47 pg/mL). Arterial blood gas analysis under room air revealed pH 7.27, PCO2 33.3 mmHg, and HCO3 18.3 meq/L. Urinary pH 7.33 was also noted. Normal anion gap metabolic acidosis, hyperkalemia, and alkaline urine suggested possible renal tubular acidosis (RTA). Twenty-four-hour urine K⁺ excretion was 18.1 meq and suggested an impairment of urinary K⁺ excretion. We then performed bicarbonate loading test and thiazide test (see Table 1) to differentiate the type of RTA.[2],[3] The protocol for the bicarbonate loading test is as follows:

1. Add six ampules (20mL/ampule) of 7% sodium bicarbonate to 500 mL 5% dextrose water. This solution is infused to the patient intravenously at the rate of 125 mL/hour.

2. Measure bicarbonate concentration and pCO2 of both arterial blood and urine every 30 minutes until blood bicarbonate concentration level reaches 24 meq/L.

3. Calculate the fractional excretion of bicarbonate (FeHCO3).

Table 1 Bicarbonate loading test and thiazide test

		Thiazide
Bicarbonate loading		Urinary Cl excretion (mmol/day)		Urinary K excretion (mmol/day)		Urine pH		UNC (mmol/L)
FeHCO3	Urine PCO2 (mmHg)	Before	After	Before	After	Before	After	Before	After
<15%	84.6	72	259.2	18.09	41.76	7.32	6.505	65.7	54.4

Abbreviation: UNC = urinary net charge.

The protocol for thiazide test is as follows:

1. Take 4 mg hydrochlorothiazide orally.

2. Measure urine sodium, chloride, potassium, bicarbonate and pH before and four hours after taking hydrochlorothiazide and record 24-hour urine amount.

3. Calculate 24-hour urinary excretion of potassium and chloride and urinary net charge (UNC) which equals to urine [Na⁺]+[Cl⁺]-[HCO3⁻]

The result of the bicarbonate loading test ruled out type I and type II RTA. Thiazide test revealed increased urinary excretion of chloride and potassium and decreased urinary pH and urine net charge. All of these tests and physical examination findings strongly suggested the diagnosis of Spitzer-Weinstein syndrome. Hydrochlorothiazide was prescribed after the diagnosis of Spitzer-Weinstein syndrome, and the hyperkalemia with normal anion gap metabolic acidosis was corrected.

DISCUSSION

Gordon syndrome is a clinical syndrome featuring a salt-dependent hypertension, hyperkalemia, and hyperchloremic metabolic acidosis with evidence of renin-angiotensin suppression. High arterial blood pressure does not appear in young patients with Gordon syndrome until adulthood.[4] The pathogenic mechanism of Gordon syndrome is hyperfunction of TSC.[5] Spitzer-Weinstein syndrome patients manifest characteristic features of Gordon syndrome except for a short stature and normal blood pressure.[1] The clinical pictures implicate Spitzer-Weinstein syndrome as possibly an early form of Gordon syndrome.

The differential diagnosis for Spitzer-Weinstein syndrome in this patient includes hyporeninemic hypoaldosteronism, type I renal tubular acidosis with hyperkalemia, isolated potassium secretory impairment, and Gordon syndrome.[6] A major consequence of true hyporeninemic hypoaldosteronism is not salt wasting but rather a condition of severe hyperkalemia associated with a modest metabolic acidosis. These aberrations indicate abnormalities in the secretion of potassium and protons. Hyporeninemic hypoaldosteronism is commonly seen in children with interstitial nephritis due to various causes and also in adolescents with diabetic nephropathy. The renin and aldosterone level of our female patient was in the normal range, and hyporeninemic hypoaldosteronism could be ruled out. Type I RTA with hyperkalemia is a subtype of distal RTA caused by defect in acid secretion. Patients of type I RTA are not able to increase urine PCO2 to over 70 mmHg after bicarbonate loading. The urine PCO2 of our patient after bicarbonate loading was PCO2 84.6 mmHg so the diagnosis of type I RTA with hyperkalemia was unlikely. Isolated potassium secretory impairment is a relatively rare disorder and can be seen in patients of acute renal allograft rejection, lupus nephritis, or in patients using cyclosporine. Tracing her medical history, the diagnosis of isolated potassium secretory impairment can be excluded. After rejecting the first three diagnoses, Gordon or Spitzer-Weinstein syndrome might be the possible causes remained to be differentiated.

We performed bicarbonate loading and thiazide tests to confirm the diagnosis of Gordon or Spitzer-Weinstein syndrome. Thiazide test results showed that 24-hour urine potassium and chloride excretion increased but urinary net charge and pH decreased after thiazide. Besides, hyperkalemia and metabolic acidosis responded well to thiazide. These findings all suggested an overactivity of the TSC. With short body stature, normal blood pressure, and an overactivity of the TSC, the diagnosis of Spitzer-Weinstein Syndrome was made.

Gordon syndrome is transmitted by an autosomal dominant trait. The mutation of WNK1 gene or WNK4 gene encoding WNK1 or WNK4 kinase has been known as the etiology of Gordon syndrome.[7] WNK1 and WNK4 are localized in the distal convoluted tubule and collecting duct cells. They play a key role in the homeostasis of Na⁺ reabsorption and H⁺ and K⁺ secretion. WNK4 can down-regulate the activity of apical TSC and apical K⁺ secretory channel ROMK. WNK1, on the contrary, can counteract the effects of WNK4. When mutations of these genes occur, there is an increased NaCl absorption in the distal tubule. This causes first a decreased delivery of sodium to the collection ducts, thereby disturbing the electrical gradient in the tubules. The electrical gradient defect impairs H+ and K+ secretion and leads to hyperkalemia and metabolic acidosis.[8]

Hypertension, a characteristic feature of Gordon's syndrome, usually does not appear until the third or fourth decade of life. This phenomenon could be the result of inactivating behavior of WNK4 mutations in just one allele, which probably takes longer to express through haploinsufficiency or dominantly negative effects.[9] This hypothesis could explain the finding of normal arterial blood pressure in our patient with Spitzer-Weinstein Syndrome, the early manifestations of Gordon syndrome. In contrast, hyperkalemia, which usually occurs during childhood, could be due to an activating behavior of WNK4 mutations in which one affected allele is enough.

Without volume overload and hypertension, the patient did not have low level of serum renin and aldosterone. On the contrary, the serum aldosterone level was normal-to-high because hyperkalemia in this patient strongly stimulated the secretion of aldosterone,[10] which could explain the normal-to-high aldosterone levels in this patient.

In conclusion, adolescents presenting with short stature, hyperkalemic metabolic acidosis with normal anion gap, normal blood pressure, normal serum rennin, and normal-to-high serum aldosterone levels can be diagnosed as Spitzer-Weinstein syndrome. A thiazide test is a powerful tool to diagnose the overactivity of TSC, which causes the pathophysiological defect of Spitzer-Weinstein and Gordon syndrome.