Bartter syndrome and hypothyroidism masquerading cystinosis in a 3-year-old girl: rare manifestation of a rare disease

Abstract

Cystinosis is a multisystem disorder with varied presentations secondary to deposition of cystine crystals in different organ systems. Children with cystinosis typically present with renal tubular acidosis and failure to thrive. We report a 3-year-old girl, born to a third-degree consanguineous couple, who presented with failure to thrive and polyuria. Laboratory investigations showed metabolic alkalosis suggestive of a Bartter-like syndrome and acquired hypothyroidism. Although metabolic alkalosis is a rare manifestation of cystinosis, the presence of renal tubular dysfunction and hypothyroidism prompted consideration of a probable diagnosis of cystinosis in the index child. Slit-lamp examination revealed cystine crystals in the cornea and genetic analysis showed a mutation in exon 9 of the CTNS (cystinosin, lysosomal cystine transporter) gene on chromosome 17. We highlight the importance of considering cystinosis as a differential diagnosis for Bartter syndrome and hypothyroidism.

Background

Cystinosis is a rare metabolic disorder characterised by the accumulation of cystine crystals in various organs of the body leading to a myriad of clinical manifestations. Infantile presentations are highlighted by renal tubular dysfunction presenting as Fanconi’s syndrome and deposition of cystine crystals in the cornea. Children with cystinosis typically present with poor growth, metabolic acidosis and proximal renal tubular dysfunction. The diagnosis is not often straightforward and requires a high index of suspicion. Herein, we report a 3-year-old girl with cystinosis, who had a unique presentation with renal tubular dysfunction and metabolic alkalosis (instead of metabolic acidosis) along with early-onset acquired hypothyroidism.

Case presentation

A 3-year-old girl presented with increased thirst and frequency of micturition since 18 months of age. Additionally, she suffered with poor growth since early infancy. She did not have any other symptoms suggestive of a renal disorder, nor other systemic symptoms. She was diagnosed as having primary hypothyroidism by an elevated thyroid stimulating hormone (TSH) level of 10.9 μIU/mL at 2 years of age and was subsequently commenced on levothyroxine replacement therapy. She was first born to a third-degree consanguineous Muslim couple from Northern India, at term, with a low birth weight (2000 g) and with a smooth perinatal transition. She achieved her developmental milestones at an appropriate age. Physical examination was suggestive of stunting (height 75 cm, −6.16 z score), wasting (weight 8 kg, −4.86 z score) and microcephaly (head circumference 46 cm, <−3 z score). Her vitals were stable at presentation, with normal haemodynamics. Systemic examination was normal except for mild hepatomegaly, and no features of rickets were seen.

Investigations

This toddler had a normal anion gap metabolic alkalosis, with hyponatraemia, hypokalaemia and hypochloremia. There was increased urinary excretion of sodium, potassium (transtubular potassium gradient was elevated for the level of serum potassium), chloride and calcium (elevated urine calcium:creatinine ratio). There was also increased protein excretion in urine. Serum osmolality was normal and urine osmolality was low. Mild elevation in serum TSH was noted despite levothyroxine replacement therapy (25 µg/day). Renal and liver function tests were within normal limits. Ultrasonography of the neck showed normal size and echotexture of bilateral thyroid lobes and renal ultrasound revealed mild hydronephrosis. Laboratory investigations are summarised in table 1.

Table 1.

Relevant laboratory investigations of the index case

Investigation	Reference value	Result*
Blood gas
pH	7.35–7.45	7.49
pO2	83–108	80.9
pCO2	40±4	41.4
HCO3−	21.8–26.9	31.4
Serum metabolic profile
Na (mmol/L)	135–145	121
K (mmol/L)	3.5–5	2.8
Cl (mEq/L)	96–106	85
Urea (mg/dL)	10-50	16
Creatinine (mg/dL)	0.5–1.2	0.5
Mg (mg/dL)	1.58–2.55	2.3
Ca (mg/dL)	8.8–10.2	9.5
PO4 (mg/dL)	2.7–4.5	2.8
Cholesterol (mg/dL)	<170	132
Urinalysis
Na (mmol/L)	<20	52
K (mmol/L)		13
Transtubular potassium gradient	<2–3	7.8
Chloride (mEq/L)	15–40	53
Calcium:creatinine ratio (mg/mg)	<0.2	0.35
Urea (mg/dL)		366
Protein (mg/dL)		150.8
Protein:creatinine ratio (mg/mg)	<0.2	18.9
Urine microscopy
Sugar/protein	Nil/nil	Nil/nil
Leucocytes	<5/HPF	Absent
Red blood cells	<5/HPF	Absent
Serum osmolality (mOsm/kgH2O)	275–295	274
Urine osmolality (mOsm/kgH2O)	300–900	161
Hormonal assays (serum)
Thyroid stimulating hormone (μIU/mL)	0.27–4.2	24.79
Total T3 (ng/mL)	0.8–2.0	1.15
Total T4 (μg/dL)	4.8–12.7	10.16
Adrenocorticotropic hormone (pg/mL)	7.2–63.3	47.32
Cortisol (nmol/L)	171–536	552.3
Luteinising hormone (mIU/mL)	<0.45	0.203
Follicle-stimulating hormone (mIU/mL)	0.5–4.5	3.6
Growth hormone basal (ng/mL)	0–2.5	4.21
Prolactin (ng/mL)	5-24	26.78
Vitamin D (ng/mL)	11.1–42.0	32.97
Parathyroid hormone (pg/mL)	15–65	149.8

*Results in bold refer to abnormal values

HPF, high power field.

Differential diagnosis

As she had failure to thrive, polyuria and renal tubular dysfunction, a clinical possibility of renal tubular acidosis with underlying hypothyroidism was considered. However, the laboratory investigations revealed persistent metabolic alkalosis associated with hyponatraemia, hypokalaemia and increased urinary excretion of electrolytes, which was more suggestive of a Bartter-like syndrome. Nephrogenic diabetes insipidus (DI) was not considered due to the presence of hyponatraemia instead of hypernatraemia (seen in DI) and normal plasma osmolality along with polyuria, polydipsia and failure to thrive. Urinary tract infection was ruled out and her blood sugar was normal. On reviewing the list of causes of hypothyroidism with kidney dysfunction, a possibility of nephropathic cystinosis was considered. Slit-lamp examination revealed cystine crystals in the cornea. Genetic analysis was done, which showed a 17-base pair insertion in exon 9 of the CTNS (cystinosin, lysosomal cystine transporter) gene on chromosome 17. This defect resulted in a frameshift mutation and premature truncation of cystinosin, the transporter of cystine, hence confirming cystinosis as our diagnosis. Sanger sequencing of the same gene confirmed heterozygous carrier state in both parents.

Treatment

She was initially started on indomethacin, spironolactone and potassium replacement. Hormonal profile revealed elevated serum TSH for which the levothyroxine dose was increased. However, despite the above measures, polyuria and hyponatraemia persisted. She was continued on indomethacin and potassium replacement at a dose of 3 meq/kg/day. Parents were counselled for aminothiol cysteamine therapy; however, it could not be started, as the cost was prohibitive. Unavailability of the drug in India was another limitation.

Outcome and follow-up

The child continued to have a progressive disease course with onset of renal dysfunction at 6 years of age with blood urea 51.7 mg/dL (normal: 13–43), creatinine 2.25 mg/dL (normal: 0.6–1.1) and anaemia. She was started on weekly erythropoietin injections and oral supplementation with bicarbonate, phosphate, calcium, activated vitamin D and iron in view of chronic kidney disease. At 7 years of age, she had severe anaemia (haemoglobin 29 g/L) requiring multiple packed red cell transfusions. Peripheral smear showed normocytic normochromic anaemia. Bone marrow biopsy revealed marked histiocytic proliferation and clusters of macrophages containing rectangle-shaped cysteine crystals with associated marrow fibrosis. She continues to require frequent blood transfusions.

Discussion

Cystinosis is an autosomal recessive lysosomal storage disorder caused by a defect in the CTNS gene encoding a lysosomal cystine transporter cystinosin. This genetic defect leads to accumulation of cystine within lysosomes, ultimately leading to cell death.¹ Understandably, this leads to its varied clinical manifestations affecting many organs, most notably the kidney and the eye. Prevalence of cystinosis is poorly reported; however, being an autosomal recessive disorder, it is expected to be affected by consanguinity in a population. Over 100 pathogenic mutations of the CTNS gene have been reported, and nine of these mutations are seen in exon 9 of the gene, as in our case.²

It can present either as infantile or juvenile nephropathic cystinosis or as an adult-onset non-nephropathic ocular cystinosis. This varied clinical phenotype varies with mutations of the CTNS gene. Surprisingly, the older the age of presentation, the less severe the symptoms. Infantile forms, as seen in our child, present typically with Fanconi’s syndrome (a defect in proximal tubular transport, comprising aminoaciduria, glucosuria and phosphaturia). Progression to end-stage renal disease (ESRD) is seen in late childhood. Children with juvenile-onset nephropathic cystinosis have relatively preserved growth and present with ESRD in adult life while adult-onset ocular cystinosis typically presents with mild photophobia secondary to cystine crystal deposition in the cornea.³

Extrarenal manifestations typically involve retinal, endocrine and neuromuscular systems.³ Our child had hypothyroidism requiring replacement therapy. Cystine accumulation in the thyroid gland leads to progressive hypothyroidism, the most common endocrine manifestation seen in children with cystinosis. Hypothyroidism usually occurs between the end of the first decade, to the beginning of the second.⁴ However, in our child, it was detected before 2 years of age on thyroid hormone testing. A study on a mouse model suggested that decreased thyroglobulin synthesis due to endoplasmic reticulum stress or impaired lysosomal processing secondary to cystine deposition leads to hypothyroidism.⁵

Cystinosis can occasionally have associated metabolic alkalosis and present with features suggestive of Bartter syndrome. However, this is extremely rare and restricted to case reports dating as far back as the 1970s. Whyte et al reported children with cystinosis presenting with Bartter syndrome. Oddly, in these children, tubulopathy appeared late, suggesting perhaps a later manifestation of children presenting with a combination of these syndromes.⁶

In recent literature, Ozkan et al reported a 5-year-old boy with failure to thrive and features of rickets with laboratory evaluation suggestive of metabolic alkalosis, hypokalaemia and hypochloremia, with associated high renin and aldosterone levels. The child was initially diagnosed to have Bartter syndrome and was started on appropriate therapy. On follow-up, hyponatraemia and polyuria persisted with a new finding of metabolic acidosis. Ophthalmological evaluation then revealed classical cystine crystals in the cornea, hence making it plausible that the presence of metabolic alkalosis does not rule out the possibility of cystinosis.⁷ The authors postulated that in cystinosis, there is an added defect of proximal tubular excretion of sodium which, in turn, leads to increased distal tubular delivery of sodium. This favours an enhanced exchange of sodium with potassium and hydrogen ions leading to a contraction alkalosis (rather than acidosis commonly seen with cystinosis). Another explanation cited for metabolic alkalosis in cystinosis is that hyponatraemia induces hyperreninemia and hyperaldosteronemia, which leads to an exchange of sodium with potassium and hydrogen secondarily leading to metabolic alkalosis.⁸

The diagnosis of cystinosis is important as it is one of the lysosomal storage disorders, which can be reversed with appropriate therapy (if started early). The gold standard for diagnosis is detection of elevated cystine levels in white blood cells. Other methods include detection of cystine crystal deposition in the cornea and molecular genetic analysis of the CTNS gene.⁹ The mainstay of treatment is cystine depleting therapy with aminothiol cysteamine. Early diagnosis of cystinosis and institution of appropriate therapy can prevent the development of ESRD. Untreated patients can have significant morbidity and early-onset chronic kidney disease, as in our case.¹⁰ Supportive management in the form of fluid and electrolyte substitution, nutritional support and hormonal replacement is of vital importance.¹¹

Patient’s perspective.

I was shocked to learn about my child’s diagnosis. After a long period of almost 2 years, she was finally diagnosed with this rare disease. I was informed regarding the available treatment options, but affordability was a major issue. I am thankful for the support received from the treating doctors and staff.

Learning points.

• Cystinosis is a rare disease of childhood and should be considered in the differential for failure to thrive with polyuria and various electrolyte derangements.

• Nephropathic cystinosis can rarely present as Bartter syndrome with metabolic alkalosis.

• Cystine deposition in various organs can lead to a multisystem disease.

• Hypothyroidism is a common endocrinological manifestation of cystinosis.

Ethics statements

Patient consent for publication

Parents/guardians consent obtained.