Theophylline Treatment for Pseudohypoparathyroidism

Pseudohypoparathyroidism (PHP) is a rare, genetic disorder caused by impaired stimulatory G
protein (Gsα) signaling through downregulation of the gene, GNAS. The resultant hormone
abnormalities can be treated with hormone replacement therapy, but other aspects of the
disorder such as early-onset obesity and premature epiphyseal closure are without effective
treatment options. Gsα signaling is essential for the normal hormonal function of the
pituitary, thyroid, gonads, renal proximal tubules and hypothalamus. While many of the
resulting hormone deficiencies can be treated with hormone replacement therapy (HRT), HRT is
not an effective therapy for the severe early-onset obesity and short stature which are major
features of the PHP phenotype. Therefore, the goal of this proposal is to test the efficacy
of upstream therapy aimed at correcting the function of two Gsα-dependent receptors
responsible for the obesity (melanocortin-4 receptor, MC4R) and short stature (parathyroid
hormone, PTH, receptor) phenotype in children with PHP. Gsα-coupled receptor signaling
cascade begins with an increase in cyclic adenosine monophosphate (cAMP) which is rapidly
degraded by the enzyme phosphodiesterase (PDE). PDE inhibitors act by prolonging cAMP
signaling by decreasing the rate of degradation. Given that patients with PHP have reduced,
but not completely absent, cAMP production, the investigators seek to test the hypothesis
that the PDE inhibitor theophylline will reduce BMI, glucose intolerance, and hormone
resistance in children and young adults with PHP through improved Gsα-coupled receptor
signaling. The investigators will conduct a 52-week randomized, placebo controlled clinical
trial of theophylline in children and young adults with PHP. Theophylline is a non-selective
PDE inhibitor that is generically available and has a long history of use in pediatric
patients, making it an ideal drug for re-purposing in youth with PHP. Furthermore, the
pharmacokinetics of theophylline are well understood and serum drug levels are easily
measured. The investigators primary outcome is change in body mass index. Secondary outcome
measures include change in glucose tolerance and HRT dose. Anticipating a 10% dropout rate,
the investigators will enroll 34 patients and expect that 30 patients will complete the
study.

Inclusion Criteria:

1. Age 2 to 25 years old

2. Clinical diagnosis of PHP (per the EuroPHP network classification guidelines1):
Presence of PTH resistance or ectopic classification OR brachydactyly type E plus 2
minor criteria (TSH resistance, other hormonal resistance, developmental delay,
intrauterine or post-natal growth retardation, obesity/overweight, specific facial
features)

3. Obesity (BMI >95th percentile for age/gender and/or ≥30 kg/m2)

Exclusion Criteria:

1. Use of a PDE inhibitor in the past 30 days

2. History of a seizure disorder unrelated to hypocalcemia

3. History of a cardiac arrhythmia (not including bradycardia)

4. Hepatic insufficiency including cirrhosis and acute hepatitis (AST or ALT >3x upper
limit of normal)

5. Congestive heart failure

6. Current cigarette use or alcohol abuse

7. Pregnancy or intention to become pregnant during the next year

8. Untreated hypothyroidism (defined as free thyroxine below the lower limit of normal)

9. Active peptic ulcer disease

10. Current use of medications known to effect theophylline levels

11. History of hypersensitivity to theophylline or other medication components

12. History of Major Depressive Disorder in the past 2 years, lifetime history of suicide
attempt, history of any suicidal behavior in the past month, history of other sever
psychiatric disorders (e.g. schizophrenia, bipolar disorder)

13. PHQ-9 score is ≥15 or suicidal ideation of type 4 or 5 (C-SSR) in the past month

14. Unable to comply with study procedures in the opinion of the investigator