A challenging patient with graves disease, developmental delay, premature adrenarche endocrinology

A girl ۶.۵ years old who referred to endocrine clinic because of pubic and axillary hair. On examination, her height=۱۱۷ (۵۰th), weight=۱۸ kg (۲۵th), pubic hair= III, axillary hair, hair and oily skin, thelarche= I. Laboratory test showed, ۱۷OHP= ۱.۲۷ ng/dl, ACTH= ۹۴.۷, DHEAS ۲۳۶, Testosterone= ۰.۱۳ cholesterol=۱۸۵, LDL= ۹۹, BA=۸.۵ year. At this age hydrocortisone (۱۰ mg/m۲/day) has been started. In the sonography bilateral adrenal was normal. After ۶ months, she developed to staring, thyromegaly and poor weight gain. In thyroid function test: TSH=۰.۰۰۳, Free T۴=۲۵.۲, TPO Ab=۲۳.۷, TRAb=۱۲۰. Thyroid sonography showed, generalized thyroid enlargement with homogenous echo pattern. Graves' disease was diagnosed for her and methimazole was started. At age of ۸ years old, thelarche tanner stage reached to stage II, at this time BA=۱۰.۵ years, GnRH agonist was started for her and methimazole and hydrocortisone continued. At age of ۱۰ years and bone age ۱۲, GH treatment was started. Brain MRI showed increase signal in putamen. In urine organic acid, glucoronid-۵-beta-cholestan pentol was revealed. Whole Exome Sequencing showed c.۱۲۱۴GA:p.Arg۴۰۵Gln, cerebrotendinous xanthomatosis. Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive genetic disorder caused by an abnormality in the CYP۲۷A۱ gene, resulting in a deficiency of mitochondrial enzyme sterol ۲۷-hydroxylase. The lack of this enzyme prevents cholesterol from being converted into a bile acid called chenodeoxycholic acid. Deposits of cholesterol and a related compound called cholestanol accumulate in the nerve cells and membranes potentially causing damage to the brain, spinal cord, tendons, lens of the eye and arteries. Affected individuals can experience neonatal cholestasis, diarrhea and cataracts in childhood and may develop benign, fatty tumors (xanthomas) of the tendons during adolescence. If untreated, CTX can lead to progressive neurologic problems such as seizures, cognitive impairment, and difficulties with coordination and balance (ataxia). Coronary heart disease is common. Long-term therapy with chenodeoxycholic acid has been effective in treating affected individuals.