Endocrine Complications of Cystinosis.

Thyroid dysfunction chronologically follows kidney dysfunction and develops in about 50% of untreated children by 5-10 years of age. In 1970, Chan et al were the first to describe primary hypothyroidism in cystinosis and performed a histologic examination of the thyroid gland showing cystine crystal accumulation and fibrosis. Biochemically, hypothyroidism usually manifests with elevated thyroid stimulating hormone (TSH), but normal T4 levels (subclinical disease), and progresses toward overt hypothyroidism over subsequent years, requiring thyroxin supplementation. In some patients, pituitary resistance to thyroxin has been reported and is characterized by elevated TSH levels despite absence of clinical or biochemical signs of hypoor hyperthyroidism. In such patients, TSH fails to normalize even if serum T4 concentrations are at the upper limit of normal because of adequate thyroxin therapy. The pathogenesis of thyroid dysfunction appears to be more complex than merely thyroid gland destruction by lysosomal cystine. In early disease, accelerated thyrocyte turnover with increased cell proliferation plus enhanced apoptosis linked to endoplasmic reticulum stress yields impaired thyroglobulin production and altered endolysosomal trafficking and iodothyroglobulin processing as has been recently demonstrated in the knockout mouse model of cystinosis. Importantly, cysteamine treatment prevents hypothyroidism in the majority of patients with cystinosis underscoring the essential role of cystine accumulation in the development of thyroid dysfunction (Figure 1).