Quiz Page December 2009:

Article Outline

• Clinical Presentation
• Discussion
  • What is the differential diagnosis in a patient with these features?
  • What is the most likely diagnosis?
  • How can this diagnosis be confirmed?
  • What treatment is indicated?
• Final Diagnosis
• Acknowledgements
• References
• Copyright

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Clinical Presentation 

A 33-year-old school teacher with no significant medical history or medication use presented with 3 months of lower back pain, proximal muscle weakness that limited his ability to stand, urinary frequency, and nocturia. Although denying dry mouth, dry eyes, or polydipsia, he describes frequent photophobia during this period. There was no blepharospasm, tearing, or decreased vision. On physical examination, blood pressure was 110/70 mm Hg and pulse rate was 72 beats/min. He had tenderness over his ribs bilaterally and painful restriction to flexion and extension of the ankle and knee joints. Proximal muscle strength in the upper and lower limbs was 4/5, deep tendon reflexes were present as a normal ankle jerk, superficial reflexes were normal, and there was no sensory deficit. Laboratory studies are listed in Table 1; in addition, serological tests for antinuclear antibodies and antibodies Ro and La were negative. An ultrasound of the abdomen showed kidney sizes of 9.8 × 4.5 cm (right) and 9.6 × 4.3 cm (left); there was normal echo texture and corticomedullary differentiation.

Table 1. Laboratory Studies

	US Units	International Equivalent or Reference Range
Serum studies
Sodium	132 mEq/L	132 mmol/L
Potassium	2.8 mEq/L	2.8 mmol/L
Chloride	98 mEq/L	98 mmol/L
Bicarbonate	18.2 mEq/L	18.2 mmol/L
Creatinine	1.7 mg/dL	150.28 μmol/L
Estimated GFR	50 mL/min/1.73 m2	0.83 mL/s/1.73 m2
Glucose (fasting)	96 mg/dL	5.3 mmol/L
Proteins	8.9 g/dL	89 g/L
Albumin	4.6 g/dL	46 g/L
Calcium	6.8 mg/dL	1.696 mmol/L
Phosphorus	2.7 mg/dL	0.87183 mmol/L
Uric acid	3.1 mg/dL	183.388 μmol/L
Ceruloplasmin	23.5 mg/mL	Reference: 13-36 mg/mL
Arterial blood gas analysis
pH	7.270
Pco2	47.8 mm Hg
Bicarbonate	18.2 mmol/L
Urinalysis
pH	6.0
Specific gravity	1.030
Albumin	2+
Glucose	2+
24-Hour urine
Total protein	1.9 g	Reference: 0.15 g
Potassium	250 mEq	Reference: 100 mEq
Calcium	450 mg	Reference: 200 mg
Uric acid	900 mg
Phosphate	1.3 g	Reference: 1.0 g

Abbreviation: GFR, glomerular filtration rate.

■ What is the differential diagnosis in a patient with these features?

■ What is the most likely diagnosis?

■ How can this diagnosis be confirmed?

■ What treatment is indicated?

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Discussion 

What is the differential diagnosis in a patient with these features? 

The features of polyuria, metabolic acidosis, hypokalemia, hypophosphataemia, glycosuria, and proteinuria suggest Fanconi syndrome. This diagnosis is confirmed by the demonstration of generalized aminoaciduria and tubular proteinuria and should be followed by identification of the underlying cause. In adults, the major causes of Fanconi syndrome are monoclonal gammopathies, amyloidosis, membranous nephropathy, focal segmental glomerulosclerosis, and tubulointerstitial nephritis.¹

The other feature in this patient was photophobia. Sjögren syndrome presents classically with distal renal tubular acidosis and photophobia, although without the other abnormalities seen in Fanconi syndrome. Tubulointerstitial nephritis with uveitis also may present with proximal tubular dysfunction and photophobia, but most commonly is a diagnosis of exclusion in adolescent girls.²

What is the most likely diagnosis? 

Photophobia with Fanconi syndrome is suggestive of cystinosis. In classic nephropathic cystinosis, Fanconi syndrome appears at 6-12 months of age and end-stage renal disease develops at 9 years. It accounts for 95% of reported patients. Forms with later onset, as occurred in this patient, account for ∼5% of all cases of cystinosis.³ The late-onset forms are of 2 phenotypes. Intermediate cystinosis, also called late-onset or juvenile cystinosis, has the same features as the nephropathic form, but patients may retain kidney function into their 30s.⁴ Ocular or non-nephropathic cystinosis, previously called benign or adult cystinosis, is characterized by only ocular findings, with all systemic manifestations lacking.

How can this diagnosis be confirmed? 

The diagnosis usually is made by measuring the cystine content of peripheral leukocytes or cultured fibroblasts. The diagnosis also can be made through recognition of cystine crystals in corneal stroma, imparting a polychromatic luster on slit-lamp examination,⁵ as in this patient (Fig 1). Rectangular or hexagonal cystine crystals may be found in a bone marrow or kidney biopsy specimen. Because cystine crystals are water soluble, these are not retained in tissue sections after routine histological preparation with aqueous solutions. Cystine crystals are birefringent under polarized light in alcohol-fixed tissue or unfixed frozen tissue. In toluidine blue–stained sections of epoxy resin–embedded tissue prepared for electron microscopy, the presence of crystals can be inferred by the appearance of needle-shaped or rhomboid intracytoplasmic clefts. The bone marrow biopsy specimen in our patient did not show cystine crystals. The kidney biopsy specimen (Fig 2) included 8 glomeruli. Glomeruli were normal size with patent glomerular capillaries. There was neither thickening nor irregularity of the capillary wall. Mesangial cellularity was normal. Interstitium was edematous with lymphocytic infiltrate. Cystine crystals also were not identified in the kidney biopsy specimen. CTNS, the gene implicated in cystinosis, encodes the protein cystinosin and maps to chromosome 17p13.⁴ The mutations were detected easily using a multiplex polymerase chain reaction assay.⁴

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• Figure 1. 

  Slit-lamp examination of the cornea from (A) the patient shows cystine crystals (arrows) and (B) an unaffected individual. Courtesy of Sirisha Senthil, MS, FRCS.

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• Figure 2. 

  Kidney biopsy specimen shows glomeruli of normal size with patent glomerular capillaries.

What treatment is indicated? 

Oral cysteamine therapy is recognized as the treatment of choice for patients with nephropathic cystinosis who have not undergone transplant. Cysteamine depletes lysosomal cystine by a multistep mechanism. First, it enters into the lysosomal compartment through a specific transporter and reacts with cystine to form the mixed disulfide cysteamine-cysteine; this compound in turn exits the lysosomes through an intact lysine transporter, and when in the cytoplasm, is reduced by glutathione to cysteamine and cysteine. Cysteamine has the marked odor and taste of thiols and binds to oral mucosa and dental fillings.⁴ This patient, after 9 months of treatment with cysteamine, 50 mg/kg/d, had a serum creatinine level of 1.8 mg/dL (159.1 μmol/L). His joint pains, rib tenderness, and proximal muscle strength have improved.

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Final Diagnosis 

Fanconi syndrome caused by cystinosis, intermediate type.

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Acknowledgements 

The authors thank Sirisha Senthil, MS, FRCS, Consultant, VST Center for Glaucoma, LV Prasad Eye Institute, Hyderabad, India, for providing photographs of the slit-lamp examination of the patient and the clear cornea.

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References 

1. William G, Van't Hoff . Fanconi syndrome. In:  Davison AM,  Cameron JS,  Grunfeld JP editor. Oxford Textbook of Clinical Nephrology. Oxford: Oxford University Press; 2005;p. 961–973
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2. Vohra S, Eddy A, Levin AV, et al. Tubulointerstitial nephritis and uveitis in children and adolescents: four new cases and a review of the literature. Pediatr Nephrol. 1999;13(5):426–432
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3. Servais A, Morinière V, Grunfeld JP, et al. Late-onset nephropathic cystinosis: clinical presentation, outcome, and genotyping. Clin J Am Soc Nephrol. 2008;3(1):27–35
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4. Gahl WA, Theone JG, Schneider JA. Cystinosis. N Engl J Med. 2002;347(2):111–121
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5. Bonnardeaux A, Bichet DG. Inherited disorders of the renal tubule. In:  Brenner BM editors. Brenner and Rectors' The Kidney. Philadelphia: Saunders Elsevier; 2008;p. 1390–1427
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