Long-Term Follow-Up of Survivors of Pediatric Cushing Disease

Objective:

Cushing Disease (CD) describes the state of hypercortisolemia secondary to cortisol producing
pituitary adenomas. The rarity of the disease (2-5 new cases per million, 1 out of 10 in
children) and the subtle initial findings result in prolonged undiagnosed hypercortisolemia,
that increases the risk for significant complications, including obesity, height
deceleration, hyperlipidemia, hyperglycemia, hypertension, osteoporosis, immunodeficiency,
and others. Although hypercortisolemia usually resolves after successful resection of the
pituitary adenoma, the reversal of the abovementioned complications and the long-term effects
of the previous prolonged exposure of the body to supraphysiologic levels of cortisol have
not been clarified, especially when hypercortisolemia occurs during childhood.

Previous studies have addressed the possible complications after resolution of
hypercortisolemia, but most of them refer to adult patients. Amongst the described
complications, suppression of the pituitary hormones, such as the growth and thyroid hormone
axes, and persistent increase of the body mass index (BMI) and abnormal fat distribution,
have been described in limited number of pediatric patients followed for a few years after
cure. Other complications, such as components of the metabolic syndrome or cardiovascular
dysfunction, have not been extensively studied in children. Furthermore, equally important
are the long-term effects of glucocorticoids on other aspects of health. For example, it has
been previously described that the neurocognitive function of children with CD declines the
first year after treatment. This can potentially result in impaired quality of life, lower
education level, and lower job and life satisfaction in the future; however, the long-term
neurocognitive sequelae of Cushing syndrome (CS) diagnosed in childhood have not been
studied.

This study aims to provide novel insight on the long-term effects of hypercortisolemia on the
developing child, their underlying pathogenetic mechanisms, their evolution over time, and
the risk factors for developing them. This will assist in designing methods to closely
monitor or prevent them in the future. Certain results of this study could potentially apply
to children with iatrogenic CS, which is much more common due to the widespread use of
pharmacologic doses of glucocorticoids in malignancies, autoimmune and atopic disorders.

- INCLUSION CRITERIA:

1. Males and females 10-42 years old (subjects) who were previously diagnosed and
had successful treatment of CD before the age of 21 years old. Patients who have
undergone therapies other than surgical resection (such as radiation or medical
treatment) will be eligible to participate.

2. Normocortisolemia or hypocortisolemia at the time of the study (as documented
within past 6 months of recruitment) documented as urine free cortisol or
midnight/afternoon serum or salivary cortisol levels within or below the normal
range.

3. Patients or a legal guardian (in case of cognitively impaired adults or children)
must provide assent/consent at the time of the recruitment.

4. Family members (2- 90 yrs.) of patients with a family history of pituitary tumors
and who agree to participate in the DNA/linkage analysis study.

EXCLUSION CRITERIA:

1. Pregnancy (for the inpatient admission). Pregnant patients will still be offered the
online questionnaire. Pregnant females will also be able to participate at the
inpatient visit after delivery if they wish and they are medically cleared to do so.

2. Patients with any medical, physical, psychiatric, or social conditions, which, in the
opinion of the investigators, would make participation in this protocol not in their
best interest, will be excluded from the on-site visit of the study. Patients who are
critically ill, unstable, or with severe organ failure that may affect/limit the
endocrine evaluation and place unsustainable demands on Clinical Center or NICHD
resources will be excluded. They will still be offered the opportunity to participate
in the online questionnaire part of the study.