Rare Presentation of Cystinosis Mimicking Bartter's Syndrome: Reports of Two Patients and Review of the Literature

Abstract

We present here two girls with cystinosis initially diagnosed as Bartter syndrome. Both cases were admitted with hypokalemic, hypochloremic alkalosis. Their proximal tubular functions, ophthalmologic and bone marrow examinations were normal. They were started on therapies with the diagnosis of Bartter syndrome. The first patient developed signs of rickets, and the second patient was lost to follow-up and readmitted with chronic renal failure. On reevaluation cystine crystals were detected in cornea and bone marrow aspirates of both patients. We aimed to remind the rare presentation of cystinosis with metabolic alkalosis mimicking Bartter syndrome by these two cases and review the literature.

Keywords:

• cystinosis
• Bartter syndrome
• metabolic alkalosis

INTRODUCTION

Cystinosis is a severe autosomal recessive inherited metabolic disease characterized by accumulation of cystine crystals in the kidney, liver, eye, and brain. Its estimated incidence is 1 in 100,000 live births.^[1] The gene for cystinosis (CTNS) was mapped to chromosome 17p13 in 1995^[2] and isolated in 1998.^[3,4] There are three variants of clinically recognizable cystinosis:

1. The infantile (nephropathic) form, which was first described in the early twentieth century, leads to tubular dysfunction, fluid and electrolyte loss, aminoaciduria, glycosuria, phosphaturia (Fanconi syndrome) and renal insufficiency in the first decade, with metabolic acidosis, failure to thrive, hypophosphatemia, dehydration, rickets, and glomerular insufficiency.^[4,5]

2. The juvenile (intermediate) form presents with kidney disease evident in the second decade.^[6]

3. The adult (benign) form presents with photophobia, rather than renal disease, and crystals form in the cornea and bone marrow.^[7]

In general, metabolic acidosis is prominent in cystinosis; however, in rare instances, patients may present with the findings of Bartter Syndrome such as hypokalemic and hypochloremic metabolic alkalosis. Only seven cases of cystinosis (one of them siblings) associated with Bartter syndrome has been reported in the literature.^[8–13] This report describes further two infants who presented with metabolic alkalosis mimicking Bartter syndrome.

CASE 1

An 11-month-old girl was referred to our hospital with a history of failure to thrive, polyuria, and polydipsia. She was born after term gestation with birth weight of 3000 g; the pregnancy and delivery were uncomplicated. The parents were second-degree relatives and healthy. Upon physical examination, her weight was 5.5 kg (<3rd percentile) and height was 71 cm (10–25th percentile). She had blond hair and fair skin. Blood pressure was 85/50 mm.Hg, pulse rate 138 beats/min, and temperature 36.8˚C. There was clinical evidence of dehydration, with dry oral mucosa, sunken eyes, decreased skin turgor, and tonus. Complete blood count revealed hemoglobin (Hb) 10.5 g/dL, hematocrit (Htc) 32.2%, white blood cell count (WBC) 10,600/mm³ with a normal differential, and platelets 370,000/mm³. Urinalysis revealed a specific gravity of 1002 and pH of 7.5; glucose and protein were negative and microscopic examination were normal. Urine amino acids were normal. Serum sodium level was 132 mEq/L, potassium 2.9 mEq/L, chloride 86 mEq/L, blood urea nitrogen 12 mg/dL, creatinine 0.48 mg/dL, calcium 11 mg/dL, phosphorus 4 mg/dL, alkaline phosphatase 585 U/L, and glucose 88 mg/dL. Liver and thyroid function tests were normal. The arterial blood gas analysis showed metabolic alkalosis (pH 7.51, HCO₃ 25.8 mmol/L). Blood renin and aldosterone levels were found to be high (58 mg/mL and 720 ng/dL, respectively). Radiologic examination of the wrists did not show any sign of active rickets. Renal ultrasonographic examination revealed bilateral grade 1 hydronephrosis. Voiding cystoureterography revealed no vesico-ureteral reflux. In view of her fair skin, polyuria, polydipsia, and parental consanguinity, she was considered for cystinosis. However, her ophthalmologic examination and bone marrow aspiration did not show any crystal deposition. The patient was diagnosed to have Bartter syndrome because of the presence of metabolic alkalosis, hypokalemia, and hypochloremia. She was started on indomethacin, hydrochlorothiazide plus amiloride combination, and potassium citrate.

After six months, radiological examination of the wrists showed signs of active rickets and her diagnosis was reevaluated. Slit-lamp reexamination of the cornea showed cystine crystal deposition. Bone marrow smear revealed cystine crystals. The patient was diagnosed to have cystinosis, and cysteamine, cysteamine eye drop, and 1,25-dihydroxycholecalciferol were added to the treatment.

CASE 2

An 18-month-old girl was admitted to our hospital with a history of delayed growth and vomiting. She was born after uncomplicated pregnancy. Her parents were second-degree relatives and healthy. Upon physical examination, her weight was 6.9 kg (< 3rd percentile) and height was 81 cm (50th percentile). Blood pressure was 90/50 mm.Hg, pulse rate 129 beats/min, and temperature 37˚C. There was clinical evidence of advanced stage malnutrition. Complete blood count revealed Hb:10.5 g/dL, Htc: 33%, WBC 16,200/mm³ with a normal differential, and platelets 297,000/mm³. Urinalysis showed a specific gravity of 1003 and pH 7.0; glucose and protein were negative and microscopic examination was normal. Urine amino acids were normal. Serum sodium level was 129 mEq/L, potassium 2.7 mEq/L, chloride 88 mEq/L, blood urea nitrogen 5 mg/dL, creatinine 0.7 mg/dL, calcium 9.5 mg/dL, phosphorus 2.6 mg/dL, alkaline phosphatase 327 U/L, and glucose 93 mg/dL. The arterial blood gas analysis showed metabolic alkalosis; pH 7.5, and HCO₃ 25.6 mmol/L. Both blood renin and aldosterone levels were high (61 mg/mL and 695 ng/dL, respectively). Renal ultrasonographic examination revealed bilateral dilatation of collecting systems. Voiding cystoureterography revealed no vesico-ureteral reflux. The patient was diagnosed as Bartter syndrome because of the presence of metabolic alkalosis, hypokalemia, and hypochloremia. She was started on indomethacin and potassium citrate. Afterward, she was lost to follow-up. Five years later, she was referred to our hospital with the findings of chronic renal failure. Urinalysis showed gravity of 1008, glucosuria, proteinuria, and microscopic hematuria. Serum creatinine was 7.35 mg/dL, sodium 129 mEq/L, potassium 4.67 mEq/L, chloride 86 mEq/L, blood urea nitrogen 168 mg/dL, calcium 5.1 mg/dL, and phosphorus 16 mg/dL. The artery blood gas analysis showed metabolic acidosis, pH 7.38, and HCO₃ 12.2 mmol/L. Examination of the cornea and bone marrow smear revealed cystine crystals. The patient was diagnosed to have cystinosis and chronic renal failure. Cysteamine, cysteamine eye drop, 1,25-dihydroxycholecalciferol, and supportive treatment of chronic renal failure were added.

DISCUSSION

Cystinosis is a rare autosomal recessive disorder characterized by the accumulation of cystine, because of impaired transport of this amino acid out of cellular lysosomes. Usually, the typical clinical picture is renal Fanconi syndrome in most patients with cystinosis. On the other hand, cystinosis is the most common inherited cause of Fanconi syndrome. Tubular disfunction in cystinosis usually demonstrates with glucosuria, aminoaciduria, bicarbonaturia, phosphaturia, signs of rickets, and failure to thrive in the first decade of life. However, there are rare cases in the literature presenting with the findings of Bartter syndrome, such as hypochloremic metabolic alkalosis. The cause of this unusual presentation of cystinosis with metabolic alkalosis, which is similar to the Bartter syndrome findings, is still unknown.

As shown in Table 1, in 1978, Berio^[8] reported an Italian boy at five years of age with cystinosis and hypochloremic metabolic alkalosis. In 1980, O'Regan^[9] reported a two-year-old girl presenting with the features of Bartter syndrome and diagnosed to have cystinosis two years later. In 1984, Lemire and Kaplan^[10] reported three cases with nephropathic cystinosis, and only one of them had transient features of Bartter syndrome, which preceded the manifestations of renal Fanconi syndrome. Subsequently, in 1985, Whyte et al.^[11] reported a five-year-old black child with cystinosis and renal Fanconi syndrome. Review of his medical records revealed hypokalemia, hypochloremic metabolic alkalosis, and normal blood pressure despite hyperreninemia and hyperaldosteronism. He was diagnosed with Bartter syndrome at two years of age. In 2005, Pennesi et al.^[12] described two siblings with nephropathic cystinosis presenting with features of Bartter syndrome and demonstrated their genetic pattern. Both affected siblings were compound heterozygotes showing a 57,257-bp deletion and a new nonsense mutation (1044G > A) that produced a stop codon in the transmembrane region of the cystinosin protein. The mother was heterozygous for the 57,257-bp deletion, while the father was heterozygous for the new missense mutation (1044G > A). They concluded that further genetic study of other similar cases and correlation between genotype and phenotype might produce more useful evidence. Finally, in 2006, Yildiz et al.^[13] reported a 16-month-old boy that presented with the signs of Bartter syndrome. However, he was diagnosed as cystinosis with cystine crystals seen in the conjunctiva biopsy and increased leukocyte cystine level. They speculated that sodium-dependent transtubular transport defect causes increasing distal tubular delivery of sodium, which results in enhanced exchange of sodium for potassium and hydrogen ion. In addition, hyperreninemia and hyperaldosteronemia may have contributed to metabolic alkalosis.

Table 1  Patients with cystinosis presented with findings of Bartter Syndrome (review of literature)

	Berio, 1978	O'Regan, 1980	Lemire and Kaplan, 1984	Whyte, 1985	Pennesi, 2005		Yildiz, 2006	Our cases, 2009
Case number	1	2	3	4	5*	6*	7	8	9
Age at presentation	5 years	2 years	4 years	2 years	4 years 9 months	1 year 7 months	1 year 4 months	11 months	1 year 6 months
Sex	Boy	Girl	Girl	Boy	Boy	Girl	Boy	Girl	Girl
Initial complaint	Growth retardation	Growth retardation	Growth retardation, polyuria, polydipsia	Growth retardation	Extreme malnutrition, growth retardation, polyuria, polydipsia	Extreme malnutrition, growth retardation, polyuria, polydipsia	Vomiting, growth retardation	Failure to thrive, polyuria, polydipsia	Growth retardation, vomiting
Laboratory findings	Hypochloremic metabolic alkalosis	Hypochloremic metabolic alkalosis	Hypochloremia, hypokalemia, hyperreninemia	Hypochloremic metabolic alkalosis, hypokalemia, hyperreninemia and hyperaldosteronemia	Hypochloremic metabolic alkalosis, hypokalemia, hyperreninemia and hyperaldosteronemia	Hypochloremic metabolic alkalosis, hypokalemia, hyperreninemia and hyperaldosteronemia	Hypochloremic metabolic alkalosis, hypokalemia, hyperreninemia and hyperaldosteronemia	Hypochloremic metabolic alkalosis, hypokalemia, hyperreninemia and hyperaldosteronemia	Hypochloremic metabolic alkalosis, hypokalemia, hyperreninemia and hyperaldosteronemia
Initial treatment	Prostaglandin inhibitors	Prostaglandin inhibitors	Prostaglandin inhibitors, potassium chloride	Sodium and potassium chloride supplements	Prostaglandin inhibitors, potassium chloride, carnitine, phosphate, vitamin D supplements	Prostaglandin inhibitors, potassium chloride, carnitine, phosphate, multivitamin complex	Captopril, 1,25-dihydroxycholecalciferol, potassium, Joulie's solution	Prostaglandin inhibitors, potassium citrate, hydrochlorothiazide + amiloride combination	Prostaglandin inhibitors, potassium citrate.
Age at diagnosis	?	4 years	?	5 years	5 years 7 months	2 years 5 months	1 year 5 months	1 year 5 months	6 years 6 months

*Case numbers 5 and 6 were brother and sister.

In our first patient, urinalysis did not show the findings of Fanconi syndrome. She showed hyperreninemia, hyperaldosteronemia, and metabolic alkalosis. Initial cornea and bone marrow investigations did not demonstrate any cystine crystals. Therefore, she was diagnosed and followed-up as having Bartter syndrome. However, six months later, she showed the signs of rickets and her reevaluation with ophthalmologic and bone marrow examinations revealed the diagnosis as cystinosis.

The second case also presented with the findings suggesting Bartter syndrome, though she was since lost to follow-up for years. She readmitted after the development of end-stage renal disease (ESRD). Besides initiation of renal replacement therapy, she was reinvestigated for the etiology revealing cystinosis as the cause of ESRD. Although leucocyte cystine levels could not be measured, the diagnosis of cystinosis was confirmed by demonstrating the cystine crystals either in cornea or bone marrow aspiration of both patients.

Progression of the infantile cystinosis is characterized by especially renal failure, growth retardation, rickets, and visual impairment, but early diagnosis and therapy with cysteamine is effective in slowing down or preventing some complications. Presenting with the findings mimicking Bartter syndrome and the lack of crystals early in the life resulted in a delay in the diagnosis of both patients. Being lost to follow-up for years, the second patient had the diagnosis after the ESRD had already developed. Therefore, regardless of the possible reasons, metabolic alkalosis especially in the early infantile period should not exclude the diagnosis of cystinosis and the patients should be reevaluated for the diagnosis with repeating investigations when necessary. However, we need further genetic and clinic study to understand the reasons of transient Bartter syndrome signs in patients with cystinosis.

ACKNOWLEDGMENTS

The authors declare no conflicts of interest.