The correct answer is A

Comment: The acute metabolic alkalosis is due to the citrate load from the multiple blood transfusions. Acetazolamide is the preferred therapy, both to remove the excess fluid and to cause a preferential HCO ₃ ⁻ diuresis. Saline loading is not indicated since it will result in a marked increase in ascites formation.

The correct answer is C

Comment: The patient’s blood tests indicate a simple metabolic alkalosis characterized by three clinical features: an increase in plasma pH (> 7.40), an increase in plasma bicarbonate concentration, and an increase in PCO ₂ due to adaptive hypoventilation. Although the differential diagnosis of metabolic alkalosis is broad, simple blood and urine tests combined with a detailed history can often lead to a diagnosis. Urine pH is an important and often overlooked initial step in this process. The patient’s elevated urine pH indicates alkali loading, resolving metabolic alkalosis, or very recent vomiting prior to establishing a new steady state. With an alkaline urine pH, additional testing often is unnecessary because all other causes of metabolic alkalosis are associated with aciduria. It should be noted that although urine chloride is usually advocated as the initial diagnostic test in the case of alkali loading, urine pH could reveal the diagnosis prior to testing urinary chloride. Caution also should be used when interpreting urine chloride results after administration of diuretics because this would mask the presence of a chloride-dependent alkalosis. In our patient, urine chloride levels were found to be elevated on admission.

Further examination of the patient’s history revealed that she was unsure of the dose of sodium polystyrene she took after the medication’s formulation was changed from liquid to powder 1 month prior to admission. The patient’s family believed that she might have been taking higher doses than prescribed. Coadministration of sodium polystyrene and antacids (calcium carbonate and magnesium oxide, in this case) has been reported to cause metabolic alkalosis in patients with end-stage renal disease and advanced stages of CKD.

In the absence of sodium polystyrene, antacids containing calcium and magnesium first react with hydrogen chloride secreted in the stomach to form calcium chloride and magnesium chloride, respectively. These moieties enter the duodenum, where they react with the secreted sodium bicarbonate to subsequently form carbonates of the cations. Because there is equal secretion and consumption of hydrogen chloride and sodium bicarbonate, there is no change in the net acid-base balance.

When calcium-, magnesium-, or even aluminum-containing antacids are administered concomitantly with sodium polystyrene, there is a similar equal secretion of hydrogen chloride and sodium bicarbonate. However, the sodium bicarbonate secreted in the duodenum is not consumed; rather, it is reabsorbed, resulting in a salt and alkali load. Alkali loading in the presence of reduced kidney function leads to metabolic alkalosis despite alkaline urine pH.

It is not known yet whether the newer agents for management of hyperkalemia (patiromer and sodium zirconium cyclosilicate) may have a similar complication. ^, Patiromer reportedly has nonspecific cation binding similar to sodium polystyrene, whereas sodium zirconium cyclosilicate selectively binds potassium. Based on this consideration, we would hypothesize that a similar effect could be seen with patiromer use.

Hypokalemia can contribute to maintenance of the metabolic alkalosis through several mechanisms including increased ammoniagenesis and increased hydrogen secretion at the intercalated epithelial cell in the collecting duct.

In this case, we attributed hypokalemia to cellular shift along with enhanced gastrointestinal and kidney losses. It is difficult to know whether hypokalemia was contributing to maintenance of the metabolic alkalosis via increased tubular hydrogen secretion in the setting of alkaline urine.

In previous case reports, it has been shown that stopping coadministration of sodium polystyrene and oral antacids results in improvement in metabolic alkalosis.

This should be adequate unless serum pH requires rapid correction for symptoms related to electrolyte abnormalities or alkalemia. This can be achieved by administration of acetazolamide (with close monitoring of serum potassium level) or rarely with dilute hydrochloric acid.

In our patient, both metabolic alkalosis and hypokalemia improved after withdrawing sodium polystyrene and administering supplemental potassium and acetazolamide. The alkalosis and hypokalemia did not recur with appropriate sodium polystyrene dosing (changed back to liquid formulation) and spacing of calcium carbonate and magnesium oxide administration.

The correct answer is B

Comment: Metabolic alkalosis, with the elevated PCO ₂ reflecting the appropriate respiratory compensation. ^,

The correct answer is C

Comment: The patient has both diabetic ketoacidosis and a superimposed metabolic alkalosis due to vomiting. ^, Notice that the anion gap is 28 mmol/L (16 mmol/L above normal), which should be associated with a reduction in the plasma bicarbonate concentration to about 10 mmol/L. The substantially high value in this case is indicative of the underlying metabolic alkalosis. Dehydration undoubtedly is responsible for much of the decline in renal function. In addition, acetoacetate is measured as creatinine in the standard assay, resulting in a further apparent elevation in the plasma creatinine concentration.

The major electrolyte problems in this patient are hypokalemia and volume depletion. The hyperglycemia and metabolic acidosis are relatively mild; immediate correction of these disturbances with insulin is not necessary and may be deleterious by driving potassium into the cells, possibly inducing arrhythmias. Thus, the initial therapy should consist of isotonic or half-isotonic saline to which 40 mmol/L of KCl is added. This regimen will correct the hypokalemia and volume depletion and will slowly ameliorate the hyperglycemia, both by dilution and by improving renal function, thereby enhancing glucose excretion. The patient should also be started on antimicrobial therapy for presumed acute pyelonephritis. This infection was probably responsible for the loss of diabetic control.

The correct diagnosis is D

Comment: The differential diagnosis of this patient’s electrolyte disorders rests between renal failure of undetermined cause, which results in uremia and vomiting, and vomiting which results in severe volume depletion and prerenal azotemia. The finding of high urine sodium might point to the former diagnosis. ^, The urine sodium as a means of distinguishing between renal failure due to parenchymal disease and renal failure due to under perfusion is not useful in patients who have metabolic alkalosis secondary to vomiting. The rise in bicarbonate concentration seen in this disorder results in spillage of some bicarbonate into the urine. This bicarbonaturia obligates the excretion of cations, some of which will be sodium. The critical test in this patient is to measure the urine chloride concentration. In this patient, this was 1 mEq/L. Thus, the kidney retained the capacity to reabsorb all the filtered chloride. This finding, plus the patient’s severe hypokalemic metabolic alkalosis, suggests vomiting is the primary disorder. The BUN, which is typically elevated out of proportion to the rise in creatinine in patients with prerenal azotemia, will not rise in this fashion in patients who vomit, owing to the lack of nitrogen intake. The infusion of large amounts of sodium chloride and potassium chloride not only corrected the hypokalemic metabolic alkalosis in this patient, but also resulted in the restoration of renal function to normal within 13 days.

The correct answer is C

Comment: This patient presented with hypertension associated with hypokalemic metabolic alkalosis, and low plasma renin and aldosterone levels. Our patient also had medullary nephrocalcinosis.

The differential diagnosis of severe hypertension and hypokalemia and metabolic alkalosis includes glucocorticoid remediable aldosteronism, the syndrome of apparent mineralocorticoid excess, congenital adrenal hyperplasia (11 beta hydroxylase and 17 alpha hydroxylase deficiencies), pseudohypoaldosteronism type 2 (Gordon syndrome), and Liddle syndrome. The combination of hypertension with hypokalemia and metabolic alkalosis is also seen with hyperaldosteronism. Genetic testing confirms the correct diagnosis.

Liddle syndrome is inherited in an autosomal dominant fashion and characterized by early onset hypertension with low plasma renin and aldosterone levels together with hypokalemic metabolic alkalosis. The renal epithelial sodium channel (ENaC) consists of alpha, beta, and gamma subunits. ^{, ,} Mutations in the sodium channel in the distal collecting tubules cause an increase in sodium reabsorption, leading to intravascular volume expansion resulting as hypertension. Together with sodium reabsorption, potassium and hydrogen ion wasting occurs mimicking hyperaldosteronism.

When we evaluate the genetic heterogeneity of the disease, there are three different genes involved: SCNN1A , SCNN1B , and SCNN1G . LS-1 is caused by heterozygous mutation in the SCNN1B gene, encoding the beta subunit of ENaC. LS-2 is caused by mutation in the SCNN1G gene encoding the ENaC gamma subunit. More than 20 pathogenic variants in the β and γ subunits of the ENaC have been identified. A newly discovered type, LS-3, is caused by mutation in the SCNN1A gene encoding the ENaC alpha subunit. ^{, ,}

In our patient, we could only screen for genetic mutation in the SCNN1B gene, and we were not able to demonstrate any mutation. However, it is known that in addition to the SCNN1B gene, the SCNN1G and SCNN1A genes are involved. When there is a high clinical suspicion of LS, and in the presence of hypertensive family members such as in our patient, to confirm the genetic diagnosis, other genes such as SCNN1G and SCNN1A should also be screened.

Liddle syndrome should be suspected in hypertensive young patients when there is a history of a family member with early-onset hypertension and accompanying hypokalemia. There may also be mild or atypical cases with vague features. Liddle syndrome should always be kept in mind for the diagnosis of early-onset (typically between late childhood and adolescence) hypertension even when there is no positive family history since certain cases without hypertensive family members were previously reported.

The suppression of renin and aldosterone is the hallmark of the disease. Due to the continuous reabsorption of sodium from ENaC, potassium is lost via the Na ⁺ /K ⁺ -ATPase pump. Enhanced sodium reabsorption results in negative ion charge in the lumen of the renal tubules, leading to a rise in the excretion of hydrogen ion from the ROMK (renal outer medullary potassium) channel and hydrogen-ATPase pump on alpha-intercalated cells leading to mild metabolic alkalosis. Increased sodium levels and associated volume expansion result in suppression of renin. Suppression of aldosterone is relatively less when compared with renin, yielding an elevated aldosterone/renin ratio, which may also be used as a screening test.

Treatment mainly involves a low-salt diet and the use of a direct ENaC inhibitor and potassium-sparing diuretics such as amiloride or triamterene to control blood pressure. Our patient’s hypertension could be controlled after triamterene administration. Mutated ENaC channels are not regulated by mineralocorticoids; for this reason, spironolactone is not beneficial. In the management of hypertension, a low-sodium diet is advised which is also useful in the regulation of the mutated ENaC.

The correct diagnosis is D

Comment: The child had normal anion gap metabolic acidosis (NAGMA) with hypokalemia. This is mainly caused by an increased bicarbonate loss from either the kidney or gut or impaired acidification in the kidney. She did not have any history of diarrhea, making the bicarbonate loss from the gut unlikely. The constellation of symptoms—polyuria since childhood, hypokalemia, and NAGMA—in the presence of normal estimated glomerular filtration rate favored the diagnosis of renal tubular acidosis (RTA). Considering the fractional excretion of bicarbonate (4.1%), alkaline urine pH, and increased urinary calcium:creatinine ratio in our patient, a diagnosis of distal RTA (dRTA) was more likely. The major etiologies for dRTA include hereditary tubulopathies (due to mutations in SLC4A1 , ATP6V0A4 , and ATP6V1B1 ) or acquired disorders such as drugs or Sjögren syndrome. However, the child had some features of proximal tubular dysfunction in the form of phosphaturia and aminoaciduria. Hence, the major etiologies of proximal tubular dysfunction—namely Wilson disease, cystinosis, and Lowe syndrome—were ruled out with appropriate investigations and clinical tests. Our patient additionally had yellowish-brown discoloration of her teeth. This abnormality in the background of dRTA aroused the suspicion of amelogenesis imperfecta (AI). Clinical exome sequencing unveiled a pathogenic homozygous nonsense variation in exon 2 of the WDR72 gene (chr15: g.54025259G > A; Depth: 58x) that resulted in a stop codon and premature truncation of the protein at codon 30 (p. Arg30Ter; ENST00000396328.1), confirming the diagnosis of AI (hypomaturation type).

WDR72 mutation has recently been implicated in the causation of dRTA. The index case, although having dRTA, showed some features of proximal RTA in the form of aminoaciduria and phosphaturia. The exact pathogenesis in the occurrence of additional proximal tubular dysfunction in some cases of dRTA is not clear. The common hypotheses proposed are that defective vacuolar-ATPase (V-ATPase) and hypokalemic nephropathy resulted in defective acidification of the endosome, which is in turn responsible for proximal tubular dysfunction. However, the proximal tubular cells of the kidney do not express β1 subunit of V-ATPase, and therefore, in patients harboring ATP6V1B1 mutation, proximal RTA cannot be attributed to a defective V-ATPase. Hypokalemia, in the long run, causes a tubulointerstitial injury that can lead to dysfunction of proximal tubules. Emery et al. demonstrated increased excretion of β2 microglobulin in 45% of hypokalemic patients, which was corrected after potassium supplementation. Hypokalemic nephropathy is outlined by tubular cell atrophy and destruction and vacuolization of proximal tubular cells. This leads to intrarenal hypoxia due to microvascular injury, which in turn is responsible for tubulointerstitial damage. CLC-5 chloride channel and V-ATPase activity are essential for orderly acidification of the sorting endosomes. V-H ⁺ ATPase is contained on both the apical membranes of proximal and distal renal tubular cells. V-H ⁺ ATPase dysfunction leads to a more severe intracellular acidosis in proximal tubular cells in the presence of preexisting acidosis, which results in endosomal dysfunction that culminates in proximal tubular dysfunction. Acidosis also hinders CLC-5 function as an aftermath of a decrease in driving force for exchange caused by the pH gradient. This may contribute to proximal renal tubular dysfunction in dRTA patients prior to initiating treatment.

The management of this patient can be summarized into two aspects: management of the complications and management of the underlying disease. Our index child presented with hypokalemic paralysis, which is a life-threatening complication. Therefore, she was immediately started on potassium correction at 40 mmol/L in the maintenance intravenous fluids under strict cardiac monitoring, until potassium normalized and then switched to oral potassium supplements. Her limbs restored normal power after potassium correction. Management of the underlying disease involves correction of acidosis and hypokalemia. Correction of acidosis restores normal growth rate and reduces calcium losses associated with bone buffering of some of the retained acid, thereby diminishing the risk of osteopenia. Alkali therapy also reverses hypercalciuria and reduces the rate of nephrolithiasis and nephrocalcinosis. Additionally, it reduces urinary potassium losses, correcting the associated hypokalemia. A part of potassium depletion is also due to a reduction in proximal sodium reabsorption induced by metabolic acidosis. The goal of alkali therapy must be to achieve a normal serum bicarbonate level (22 to 24 mmol/L). Our patient required potassium citrate (4 mmol/kg/day) to neutralize the acidosis and hypokalemia. The child also had hypophosphatemia due to phosphaturia and required treatment with neutral phosphate supplementation at 50 mg/kg/day initially. On follow-up at 2 months, the serum bicarbonate was 22.5 mmol/L, serum potassium was 3.7 mEq/L, and serum phosphorus was 3.5 mmol/L. She gradually outgrew the neutral phosphate supplementation on follow-up. She was advised to follow up in dentistry to plan regarding crowns or tooth implants for the teeth discoloration.

The correct answer is B

Comment: Hypokalemia can be caused by an intracellular shift of potassium, a decrease in potassium intake, or an increase in potassium loss (GI or renal). The patient did not take medications that can cause intracellular shift, such as beta-adrenergic agonist, antipsychotic medications, insulin, and catecholamines. There was no family history to suggest familial hypokalemic periodic paralysis (FHPP), which causes transient hypokalemia and muscle weakness and is inherited in an autosomal dominant trait, and in addition, metabolic acidosis is not characteristic of FHPP. The patient was on a normal diet, which makes decreased potassium intake unlikely. There was no history of vomiting or diarrhea, which makes gastrointestinal loss unlikely. Urine tests confirmed renal K ⁺ loss. The majority of renal K ⁺ wasting conditions such as diuretic use, Bartter syndrome, Gitelman syndrome, Liddle syndrome, or primary hyperaldosteronism are accompanied by metabolic alkalosis not metabolic acidosis.

Workup for the etiology of hypokalemia and non-anion gap metabolic acidosis was initiated. Calculation of transtubular potassium gradient (TTKG = 8) and fractional excretion of potassium (28.4%) indicated renal potassium wasting. Renal tubular acidosis (RTA) was suspected due to the inappropriately high urine pH relative to the metabolic acidosis. The low serum K ⁺ level ruled out type 4 RTA. Bicarbonate wasting from the proximal tubule (type 2 RTA) as part of Fanconi syndrome was entertained, especially since the initial serum phosphorus level was low; however, there was no glucosuria or evidence of renal phosphate wasting (urine phosphorus < 10), and subsequent serum PO ₄ levels were normal. Type 1 distal RTA was confirmed due to positive urine anion gap, presence of hypercalciuria with urine calcium creatinine ratio of 0.47, and a kidney ultrasound that demonstrated a non-obstructing 6-mm lower pole calculus in the left kidney.

RTA in pediatrics is generally caused by a genetic abnormality or congenital urinary tract anomalies. We suspected that this was an acquired RTA due to the absence of short stature, which is typically seen in longstanding untreated metabolic acidosis, and we had lab evidence that she had normal serum K ⁺ and total CO ₂ levels 8 and 10 months prior to presentation.

Further investigation revealed that 8 months prior to the presentation, because of the elevated erythrocyte sedimentation rate (ESR) and ANA titer, the allergist treating the patient for recurrent urticaria had referred her to a pediatric rheumatologist at another medical facility. A more extensive evaluation for autoimmune disease was initiated which included a repeat CBC that was unremarkable, urinalysis that demonstrated a specific gravity of 1.028, pH of 6.0, negative for blood or protein, repeat ESR of 22 (patient was on prednisone 10 mg BID), elevated ANA titer of 1280, negative anti-dsDNA, normal C3 and C4 complements, normal C1Q binding assay, SM antibody IgG negative, normal TSH, negative thyroperoxidase antibody, negative thyroglobulin antibody, RNP IgG negative, SM antibody IgG negative, SCL 70 IgG negative, and SSA IgG positive. The patient was diagnosed with primary Sjogren syndrome. ^, Due to improvement of ESR, albeit the patient was on prednisone at that time, and absence of sicca symptoms, the rheumatologist elected not to treat the patient, with notation that hydroxychloroquine would be considered if the patient becomes symptomatic. With this new information, we repeated SS-A/Ro IgG which came back elevated at greater than 8.0; SS-B/La IgG also came back elevated at 2.1. Repeat ANA was again positive at 1:1280, anti-dsDNA was negative, and C3 and C4 complements were normal. Additional tests were conducted to support the diagnosis of Sjogren syndrome, and this included a positive rheumatoid factor, hyperimmunoglobulinemia (elevated IgG and IgA levels). Despite the absence of symptoms of dry mouth and dry eyes, we performed a Schirmer test to assess for adequate tear production, and this was positive with only 3 and 5 mm of tear production (normal should be ≥ 10 mm) in the patient’s right and left eyes, respectively.

The correct answer is A

Comment: Sensorineural hearing loss is seen in Pendred syndrome, Jervell and Lange-Nielsen syndrome, Waardenburg syndrome, Usher syndrome, CHARGE syndrome (Coloboma, Heart Anomaly, Choanal Atresia, Retardation, Genital, and Ear anomalies), and Alport syndrome, and in other rare syndromes like CINCA (Chronic Infantile Neurologic Cutaneous and Articular) syndrome, Bartter syndrome type 4, and Donnai-Barrow syndrome. Diagnosing these rare syndromes might be difficult in a patient group who has mild symptoms. The patient presented in the case was not symptomatic and hypokalemia was detected in routine laboratory workup before surgery.

In this child, the sensorineural hearing loss was associated with polyuria, renal salt wasting, hypokalemic metabolic alkalosis, and normotensive hyperreninemic hyperaldosteronism, which point to the diagnosis of Bartter syndrome type 4.

There are several reports about SLC12A1 , KCNJ1 , BSND , CLCNKA , CLCNKB , and CASR mutations that cause Bartter syndrome BSND and CLCNKA and CLCNKB mutations cause BS with sensorineural hearing loss (BS type 4a and 4b, respectively). BSND gene is located at chromosome 1p31 locus, and it codes barttin protein, which is a subunit for CLC-Ka and ClC-Kb chloride channels. Barttin is expressed at tubular segments beginning from thick ascending limb to cortical collecting tubules. At inner ear, barttin is also expressed at potassium-secreting epithelial cells, and this is the reason BSND -mutated patients have sensorineural hearing loss. There are several “disease-causing mutations” in BSND gene, affecting function of ClC-K channels. Some of these are R8L, R8W, G10S, Q32X, G47R, and G10S. Three of them (R8L, R8W, G10S) disturb the function of ClC-K channels; however, insertion of channel-to-surface membrane is not affected. On the other hand, G47R mutation causes mild renal phenotype, and in this type of mutation, bounding of mutant barttin to ClC-K channel is less effective.

In our patient, sequence analysis of all coding exons and exon-intron boundaries presented “NM_057176.2:c.139G greater than C (p. Gly47Arg)(p. G47R) (homozygote) mutation” in exon 1 of 4 of BSND gene, while his parents were heterozygotes. This is a known variant (rs74315289/HGMD (Human Gene Mutation Database)-Public-CM035675) and closely related with BS type 4a but mostly presents a mild clinical phenotype. This variant was also given in OMIM (Online Mendelian Inheritance in Man) database. As clinical confirmations and segregations were documented before, this variant was classified as a “pathogenic variant” due to ACMG (American College of Medical Genetics and Genomics) criteria.

In Bartter syndrome, prompt treatment with intravenous fluids is needed. Indomethacin has limited effects in type 4 Bartter syndrome. Oral sodium and potassium supplements were sufficient to normalize his serum electrolytes.

The correct diagnosis is A

Comment: The patient presented multiorgan-involving symptoms and signs sequentially: lower extremity muscle weakness at 3 years and 5 months, sensorineural hearing loss at 6 years, and Bartter-like renal tubulopathy and hypoparathyroidism at 7 years. The initial clinical diagnosis made at the age of 7 years was that of Bartter syndrome with an uncertain genotype. The presence of Gitelman syndrome-like features, i.e., normal or low urinary calcium excretion level and hypomagnesemia, suggested Bartter syndrome type III due to mutations in CLCNKB . Meanwhile, sensorineural hearing loss and hyperparathyroidism are typical findings of Bartter syndrome type IV due to mutations in BSND and Bartter syndrome type V due to gain-of-function mutations in CASR , respectively. Initially, we thought that the muscle weakness was related to chronic hypokalemia and/or hypocalcemia. However, mutational studies of all five genes ( SLC12A1 , KCNJ1 , CLCNKB , BSND , and CASR ) implicated in Bartter syndrome revealed no pathogenic mutation.

Notably, the patient also presented other proximal tubular dysfunctions, including low-molecular-weight proteinuria and hypouricemia, which are not detected in patients with the classic forms of Bartter syndrome. Therefore, at the age of 8 years, a biopsy of the left thigh muscle was performed to enable a correct diagnosis, with the biopsy revealing findings typical of mitochondrial myopathy. Genetic analysis using a peripheral blood sample then revealed a homoplasmic 8932-bp deletion (m.6130_15061del) in the mitochondrial DNA (mtDNA). In addition, an electrocardiogram taken before the muscle biopsy revealed left axis deviation, left bundle branch block, and borderline degree of left ventricular hypertrophy and QT interval prolongation. One month after the muscle biopsy, a decrease in visual acuity with bilateral ptosis was noted in the school physical examination, and the results of an ophthalmologic examination revealed pigmentary retinopathy. With these additional cardiac and ocular findings, the diagnostic criteria for Kearns-Sayre syndrome (KSS) were fulfilled.

The correct answer is B

Comment: Chronic diarrhea and absence of polyuria and polydipsia are not typical for patients with Bartter syndrome. Congenital chloride diarrhea (CLD) is a rare autosomal recessive disease occurring mainly in people in Arabian countries, Finland, and Poland. It is characterized by unremitting watery diarrhea with high fecal losses of chloride, failure to thrive, and renal impairment in older children and adults if the disease is left untreated. ^, Prenatal symptoms include polyhydramnios and dilated intestinal loops; birth is often premature, and postnatal mortality rates are high due to severe dehydration and electrolyte imbalances. The disease is caused by a defective anion exchange protein, an epithelial chloride/bicarbonate exchanger located in the brush border of the ileum and colon, resulting in defective intestinal chloride absorption and secretion of bicarbonate, with a secondary defect in sodium/hydrogen (Na ⁺ /H ⁺ ) transport, altogether leading to intestinal losses of both sodium and water, hypochloremia, hyponatremia, and metabolic alkalosis.

Some of the clinical features may resemble Bartter syndrome, which had been suspected in this case, namely, polyhydramnios, failure to thrive, and hypochloremic metabolic alkalosis. However, all forms of Bartter syndrome are characterized by high urinary losses of Na ⁺ , K ⁺ , and Cl ⁻ due to defective tubular reabsorption. Thus, a simple spot urine measurement may rule out Bartter syndrome, as in this case. Urinary concentrations of Na ⁺ and Cl ⁻ were 14 mmol/L and 15 mmol/L, respectively. However, misdiagnosis of Bartter syndrome in CLD patients has been described in a number of cases. Differential diagnosis further includes cystic fibrosis, which (especially in hot climates) may result in high Cl ⁻ losses, hypochloremic metabolic alkalosis, gastrointestinal symptoms, and failure to thrive and should be ruled out by a sweat chloride test (normal in this case).

Measuring chloride in stool is a simple clinical test to confirm the clinical diagnosis of CLD. Chloride concentrations of greater than 90 mmol/L are reportedly diagnostic for the disease. In this case, the value was 89 mmol/L (after rehydration and chloride substitution). However, genetic testing is now available in specialized laboratories to establish the definitive diagnosis.

Patients with CLD harbor mutations in both copies of the SLC26A3 (solute carrier family 26, member 3, or DRA) gene on chromosome 7q31. Altogether, 36 different mutations distributed within exons 3 to 19 of the gene have been identified in patients with CLD. However, certain founder mutations are particularly frequent in patients in Arabian countries, Finland, and Poland, and account for the majority of CLD cases. No genotype-phenotype correlation has emerged. Direct sequencing of the SLC26A3 gene detects point and splice-site mutations and small insertions and deletions, with an overall mutation detection rate of greater than 95%. In this case, both parents were found to harbor the heterozygous mutation c.559G > T (p. G187X), resulting in a homozygous mutation of the patient at this locus. This mutation results either in severe protein truncation or in nonsense-mediated RNA decay, with no protein produced at all.

The correct answer is C

Comment: Our patient presented with hypertension, hypokalemic metabolic alkalosis with elevated plasma renin activity (PRA), aldosterone, and cortisol concentrations.

Liddle syndrome, congenital adrenal hyperplasia, apparent mineralocorticoid excess, primary aldosteronism, glucocorticoid-remediable aldosteronism, pheochromocytoma, and renovascular disease was ruled out because none of these conditions are associated with elevation of both PRA and serum aldosterone concentration. Diagnosis of renin-secreting tumor (reninoma) was considered as in this condition that hypertension and hypokalemic metabolic alkalosis is associated with the high serum aldosterone and PRA. ^, This diagnosis was supported by the findings on renal sonogram and MRI imaging studies.

Reninoma is a renal juxtaglomerular apparatus tumor (JGA) that produces excessive amounts of renin, resulting in secondary hyperaldosteronism, associated hypokalemia, and hypertension. Other renin-secreting tumors, such as Wilms tumor or rhabdoid tumor of the kidney, should be considered in the differential diagnosis.

Both MRI and CT scans are highly effective for determining the presence of a JGA. However, in general, only an ultrasound scan is performed during the routine evaluation of hypertensive patients, and this procedure can result in small tumors being missed due to the isoechoic nature of the tumor. A small tumor was most likely present at the first presentation of our patient, but at that time it was not possible to demarcate it from the parenchyma.

The definitive treatment for reninoma is surgery. Radical nephrectomy or partial nephrectomy can be performed. Tumors are often superficial and can easily be removed by nephron-sparing surgery, such as in our patient.

The correct answer is B

Comment: The raised plasma renin showed that the hypokalemic alkalosis was associated with secondary hyperaldosteronism, thus excluding an adrenal tumor and Liddle syndrome. ^, The differential diagnosis included Bartter syndrome and the causes of isolated sodium or chloride depletion: chloride diarrhea, surreptitious administration of laxatives or diuretics (as in Meadow’s syndrome), cystic fibrosis, and other causes of continued vomiting or diarrhea. The urinary excretion of prostaglandins (PGE 2) and (PGF 2) was increased 2- to 3-fold above the normal for his age, suggesting Bartter syndrome. However, this is not the primary abnormality in Bartter syndrome and other causes of hypokalemia may increase the urinary prostaglandins. The diagnosis of Bartter syndrome was confirmed by showing that during 5% dextrose infusion the fractional distal chloride reabsorption was less than 62 mL/100 mL glomerular filtration rate (GFR) and that the fractional chloride excretion was greater than 1.5 mL/100 mL GFR. In other causes of secondary hyperaldosteronism, including diuretic abuse, renal chloride reabsorption is not impaired. The demonstration of a reduced rate of erythrocyte sodium efflux and a reduced number of Na ⁺ -K ⁺ pump receptor sites would also have confirmed Bartter syndrome. Renal biopsy may be normal in young patients with Bartter syndrome, as in this case.

In the 1st year of treatment with indomethacin, 3 mg/kg/day in divided doses, his growth rate increased from 5 to 13 cm/year. Although the prostaglandin synthetase inhibitors often fail to fully correct the hypokalemia, they do usually abolish the clinical manifestations of Bartter syndrome. Treatment needs to be continued throughout childhood, but it is not yet known for how long it should be continued once growth has ceased.

The correct answer is A

Comment: The differential diagnosis in this patient with hypertension, hypokalemia, metabolic alkalosis, low plasma renin activity, and low serum and urine aldosterone levels is limited and includes such disorders as Cushing syndrome, congenital adrenal hyperplasia, aldosterone precursor secreting adrenal tumors, exogenous mineralocorticoid, Liddle syndrome, and syndrome of AME. This patient had a normal genital examination and normal pubertal development. She had no physical stigmata to suggest Cushing syndrome. She had no history of exposure to exogenous mineralocorticoid (i.e., glycyrrhetinic acid contained in licorice or prescription preparations such as Florinef). The family history was not consistent with Liddle syndrome, which is an autosomal dominant condition.

Based on her laboratory findings the patient was subsequently diagnosed with AME.

This syndrome is an inheritable disorder of cortisol metabolism and clearance due to l l β-hydroxysteroid dehydrogenase enzyme deficiency resulting in excessive, uninhibited stimulation by cortisol of the mineralocorticoid receptor in the kidney. As a result the urinary steroid profile of these patients reveals an abnormally high ratio of cortisol to cortisone metabolites.

AME is clinical picture, which is analogous to patients with primary or secondary hyperaldosteronism but differs in that both renin and aldosterone secretions are suppressed. These patients often present with other associated findings, including failure to thrive or short stature, muscle weakness, ileus, or polyuria/polydipsia secondary to an impaired renal concentrating ability. There is also an increased incidence of hypercalciuria in these patients. The mode of inheritance remains unclear. The age at the time of diagnosis has varied from 9 months to 27 years.

The therapy for patients with AME varies with the type. Patients with type I disease respond very nicely to mineralocorticoid receptor blockade with spironolactone with lowering of blood pressure and normalization of serum K ⁺ levels. Patients with type II AME fail to respond to spironolactone but can be effectively treated with dexamethasone. All patients should be maintained on a sodium-restricted diet.