Internal Medicine



Autosomal recessive (AR) lysosomal storage disorder caused by mutations in the CTNS gene encoding for the carrier protein cystinosin, transporting cystine out of the lysosomal compartment.

  • M/C hereditary cause of renal Fanconi syndrome in children


Cystinosis was first described in literature in 1903 by the Swiss biochemist Emil Abderhalden (1877–1950) as the familial cystine accumulation disease. Abderhalden referred to a child initially encountered by Eduard Kaufmann, Basel, Switzerland (1860–1931). This patient died at the age of 21 months with massive cystine accumulation in multiple organs that were discovered at the postmortem examination. The Dutch pathologist George Lignac (1891–1954) was the first to provide a clear systematic description of the disease in 1924, and the first to associate cystinosis with its major clinical manifestations such as rickets, renal disease and growth retardation. This is why cystinosis was initially termed as the Abderhalden-Kaufmann-Lignac syndrome. Guido Fanconi (1892–1979), the Swiss pediatrician, also substantially contributed to the understanding of cystinosis by explaining the urinary substance losing nature of the disease. Hence, cystinosis was also recognized in the literature as the Lignac-Fanconi syndrome.


CTNS gene (17p13.2) 
bi-allelic mutations

Lysosomal cystine-proton co-transporter

Accumulates in lysosomes of affected cells
Forms crystals in low lysosomal pH

Cystine depleting action of cysteamine. In the left panel, a normal lysosome is presented; cystine located in the lysosomes is exported via cystinosin. In the cytosol, cystine is reduced to two cysteine residues. The middle panel shows a cystinotic lysosome, where cystinosin is absent (or dysfunctional), resulting in increased levels of lysosomal cystine. Upon cysteamine treatment in the cystinotic lysosome, cystine is degraded into cysteine and cysteine–cysteamine, as presented in the right panel. Both degradation products can be exported via cysteine and as yet unidentified “system c” transporters, encompassing the defective cystinosin | Wilmer, M. J., Schoeber, J. P., van den Heuvel, L. P., & Levtchenko, E. N. (2011). Cystinosis: practical tools for diagnosis and treatment. Pediatric Nephrology (Berlin, Germany), 26(2), 205–215.

Clinical features

Spectrum of disease:

  • Infantile nephropathic cystinosis (M/severe, M/C 95% cases)
  • Juvenile (late-onset) intermediate cystinosis
  • Adult, non-nephropathic ocular cystinosis (L/severe)

Infantile nephropathic cystinosis:

Renal Fanconi syndrome
Asymptomatic aminoaciduria (initially) → Excessive urinary loss of amino acids, electrolytes, glucose and low molecular (LMW) to intermediate molecular weight (IMW) proteins

Progressive loss of glomerular function

End-stage renal failure 

  • At birth: Normal birth length & weight
  •  Infants:
    • Failure to thrive, polyuria, polydipsia, episodes of severe dehydration and electrolyte imbalance, vomiting, constipation
    • Vitamin D resistant rickets (rare)

Juvenile (late-onset) intermediate cystinosis:

  • Variable spectrum of features: Ranging from isolated asymptomatic proteinuria, a mild renal Fanconi syndrome, to an overt nephrotic syndrome
    • Slower progression rate to ESRD and extra-renal complications
  • No remarkable growth retardation

Adult, non-nephropathic ocular cystinosis:

  • Photophobia due to corneal cystine accumulation (rarely presents before adulthood)
Corneal cystine crystals. Slit lamp examination of corneal cystine deposits | Prof. Dr. Akmal Rizk, Dr. Mohamed Gamal and Prof. Dr. Neveen Soliman

Extrarenal manifestations:

  • Corneal cystine accumulation + crystal formationPhotophobia & blepharospasm 
    • 1st extra-renal finding affecting all cystinosis patients
  • Progressive cystine accumulation and crystal formation in thyroid follicular cells → Fibrosis & atrophy → Primary hypothyroidism (50-70% cases)
  • Endocrine & exocrine pancreatic insufficiency (usually after renal allograft transplantation)
    • 50% cases: By age 18 → Slow progressive loss of insulin secretion and C-peptide production → Glucose intolerance and diabetes mellitus
  • Hepatomegaly ± splenomegaly (⅓ cases by 15 years)
    • However, liver function usually remains unaffected
  • Males: Primary hypogonadism (70 % cases)
  • Central nervous system involvement


Differential diagnosis

Differential diagnosis of renal Fanconi syndrome: other metabolic diseases:

  • Tyrosinemia, galactosemia, glycogen storage diseases
  • Wilson’s disease
  • Dent’s disease
  • Lowe’s syndrome


Cystinosis is one of the few rare diseases having a specific treatment.

Flowchart for the diagnosis and follow-up of patients with cystinosis |

Aminothiol cysteamine (β-mercaptoethylamine)

  • Deplete the intralysosomal cystine through the reduction of cystine, and the formation of cysteine and a cysteamine-cysteine mixed disulfide which exits the lysosome via the cationic amino acid transporter PQLC2, thus bypassing the original genetic and biochemical defects of the disease
The effect of cysteamine treatment in two siblings with nephropathic cystinosis. The growth in the 30-months old younger sibling (right side, 86 cm, 11.5 kg) who received pre-symptomatic cysteamine therapy at 3 months of age exceeded that of his 56-months old elder brother (left side, 80 cm, 10.5 kg) with later diagnosis and treatment at the age of 20 months | Dr. Rasha Helmy and Prof. Dr. Neveen Soliman

Leave a Reply

%d bloggers like this: