A case of crystals in the cornea, but wait first…

HOSP #		WARD	Red Cross Padiatric Hospital
CONSULTANT	George van der Watt / Surita Meldau	DOB/AGE	1y 5m

Abnormal Result

Inorganic phosphate 0.85 L mmol/L (1.00 – 1.95)

Presenting Complaint

It is unknown what this patient’s presenting complaint was.

Common complaints in similar patients are:

1. Photophobia (see slit lamp picture below, which explains why).
2. Bone pain
3. Weakness

History

The items below illustrates the recorded information on the laboratory request forms as they were captured by our lab staff on the respective samples:

      SEPSIS
      Vit D Deficiency
      Vit D Deficiency
      HYPOCALCAEMIA
      ?LOSSES
      ?PTB
      ?PTB
      ?FANCONI
      ?SEPSIS
      ?SEPSIS
      ?SEPSIS
      ? FANCONI SYNDROME
      ? Cystinosis
      Risk factor:
      Contact
      Cough
      Fanconi's ? cystinosis
      Hypocalcaemia
      Pneumonia.
      Pneumonia.
      Fanconi syndrome
      ? Hypoglycaemia
      post iv calcium for hypo
      Sepsis. Cystinosis
      Sepsis. Cystinosis
      Cystinosis
      FANCONIS SYNDROME
      Fanconi's syndrome
      Cystinosis
      Cystinosis
      Sepsis. Fanconi syndrome, hypocalcaemia
      Hypocalceamia
      CYSTINOSIS- HUNGRY BONE D

It can be seen above that the clinicians were noting Fanconi’s syndrome and were querying Cystinosis.

Examination

Data not available. Generally patients with Fanconi’s syndrome present with loss of electrolytes from the proximal and distal renal tubuli:

• Nephropathic cystinosis in untreated children is characterized by renal Fanconi syndrome, poor growth, hypophosphatemic/calcipenic rickets, impaired glomerular function resulting in complete glomerular failure, and accumulation of cystine in almost all cells, leading to cellular dysfunction with tissue and organ impairment. The typical untreated child has short stature, rickets, and photophobia. Failure to thrive is generally noticed after approximately age six months; signs of renal tubular Fanconi syndrome (polyuria, polydipsia, dehydration, and acidosis) appear as early as age six months; corneal crystals can be present before age one year and are always present after age 16 months. Prior to the use of renal transplantation and cystine-depleting therapy, the life span in nephropathic cystinosis was no longer than ten years. With these interventions, affected individuals can survive at least into the mid-forties or fifties with satisfactory quality of life.
• Intermediate cystinosis is characterized by all the typical manifestations of nephropathic cystinosis, but onset is at a later age. Renal glomerular failure occurs in all untreated affected individuals, usually between ages 15 and 25 years.
• The non-nephropathic (ocular) form of cystinosis is characterized clinically only by photophobia resulting from corneal cystine crystal accumulation.

Because the thyroid glands are actively translating and resorbing thyroglobulin, the thyrocytes (thyroid colloid epithelial cells) are prone to accumulation of cysteine within their lysosomes, hence these children often also develop hypothyroidism with a palpable thyroid gland.

Laboratory Investigations

Biochemistry:

Genetic screening

PCR with enzyme digest:

1st PCR with enzyme digest:

Upon the first PCR for a gene screen which was done, there occurred some evaporation in the third tube (lane no. 3 – positive control), upon incubation with the enzyme digest mix. This incubation step is minimum 3 hours at 37 degrees Celcius and do not have the high temperatures associated with the PCR process. Thus the reason for evaporation remains unclear and may have been an incompletely closed lid or a defective PCR tube rim or cap.

It is not expected to see an undigested PCR product (>200bp) as can be seen in the top band in lane 3, hence it is clear that there was incomplete digestion of PCR product in this PCR tube. Even though it is clear that the patient sample ( lane 1) represents a homozygous positive result (lane 2), one cannot authorize results when both the positive and normal control worked well.

Thus the PCR was repeated.

2nd PCR with enzyme digest:

In the second PCR it can be well seen how the Positive control did undergo complete digestion. No evaporation was noted in this run.

Other Investigations

Leucocyte cystine is another investigation which helps make the diagnosis in patients with presumed cystinosis.

Leucocyte cystine report in this patient:

Protein 0.58 g/L

Leucocyte Cystine 1.16 nmol/mg protein

Reference range:

• Normal < 0.1 nmol cystine/mg protein
• Cystinosis > 1.0 nmol cystine/mg protein
• Cystinosis on Rx (target level) < 0.5 nmol cystine/mg protein

Our reporting comment on the Lab Information Systems reads as follows:

Please note that the diagnosis of cystinosis can be confirmed in the majority of South African patients by screening for the common South African Black mutation CTNS-c.971-12G>A which results in an estimated newborn incidence of 1/10 000 in this population. A molecular diagnosis is of value in that siblings of index cases can be screened and identified for early intervention which improves the outcome in this disorder.

Final Diagnosis

Patient is homozygous positive for cystinosis by the common South African mutation, as confirmed on leucocyte cystine as well as on the gene screen.

Take Home Message