Clinical Guidance

Some genotype-phenotype correlations have been reported :

• Truncating CTNS pathogenic variants and the 57-kb deletion result in nephropathic cystinosis when present in homozygous form .

• Individuals with apparent residual activity (and lower levels of cystine accumulation in leukocytes) often have missense pathogenic variants in CTNS . Individuals with later-onset (juvenile) cystinosis or non-nephropathic (ocular) cystinosis generally have one severe CTNS pathogenic variant, typical for nephropathic cystinosis, and one mild pathogenic variant. The mild pathogenic variants include c.589GA (p.Gly197Arg) and c.853-3CG .

• The pathogenic variant c.416CT (p.Ser139Phe) may cause later-onset (juvenile) phenotype when the other allele is a nonsense variant.

Source: GeneReviews — "Cystinosis"

Diagnostic Criteria

Suggestive Findings

Nephropathic cystinosis should be suspected in infants and young children with the following clinical, laboratory, and imaging features and family history.

Clinical features

• Typically, birth weight and initial growth are normal. Poor weight gain and growth deficiency occurs by age six to 12 months.

• Vomiting and feeding difficulties

• Severe polyuria, polydipsia, and dehydration

• Progressive rachitic skeletal changes; failure to walk at a normal age

• Tetany

• Corneal crystals, typically observed by slit lamp examination in most individuals by age 12 months and in virtually all individuals by age 18 months (See .)

Laboratory features

Source: GeneReviews — "Cystinosis"

Differential Diagnosis

Renal tubular Fanconi syndrome. Untreated nephropathic cystinosis is the most common identifiable cause of renal tubular Fanconi syndrome in childhood. Genetic disorders associated with renal tubular Fanconi syndrome are listed in . Table 2. Genetic Disorders Associated with Renal Tubular Fanconi Syndrome in the Differential Diagnosis of Cystinosis

Management Guidelines

Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients is available, including clinical recommendations [, , , ].

Evaluations Following Initial Diagnosis

Table 3.

Cystinosis: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Growth/Nutrition

| • Height weight, plotted on age-appropriate growth charts

• Assessment of feeding nutrition

• Lipid panel to assess nutritional status in those w/feeding difficulties requiring formula feeding by gastrostomy tube

|

Kidney incl glomerular function

| • Serum concentrations of creatinine, phosphate, bicarbonate, potassium

• Urine concentrations of creatinine, phosphate, bicarbonate, sodium, potassium, magnesium, glucose, protein

• Quantitative measurement of urine amino acids GFR or creatinine clearance test

| Measurement of urine amino acids helps to identify severity of renal Fanconi syndrome.1

Skeletal radiographs DXA scan to assess skeletal involvement/ rickets | Beginning at age ~2 yrs

Renal US to assess for nephrocalcinosis |

Dental

| Dental eval to assess abnormal dental eruption | Beginning at age ≥1 yr

Eyes | Ophthalmologic eval incl:

• Slit lamp exam of cornea for cystine crystals

• ERG to assess retinal involvement

• Fundoscopic exam to assess for intracranial hypertension

|

Endocrine

| Thyroid function studies to assess hypothyroidism |

Measurement of serum concentration of testosterone, FSH, LH | Beginning in pre- postpubertal males

Source: GeneReviews — "Cystinosis"

Clinical Guidance

Avoid the following:

• Dehydration, which compromises remaining kidney function

• Sun exposure, which can exacerbate photophobia

Source: GeneReviews — "Cystinosis"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Cystinosis"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Clinical and laboratory examinations should be performed in individuals with nephropathic cystinosis according to disease severity and may include renal, endocrine, ophthalmologic, neurologic, and cardiac examinations . Table 6. Cystinosis: Recommended Surveillance

Source: GeneReviews — "Cystinosis"