Albright Hereditary Osteodystrophy: Growth Hormone Trial and Cognitive/Behavioral Assessments

Condition(s) targeted: Pseudohypoparathyroidism Type 1a; Albright Hereditary Osteodystrophy

Intervention: Growth hormone (Drug); Growth Hormone (Drug)

Phase: Phase 2/Phase 3

Status: Recruiting

Sponsored by: Hugo W. Moser Research Institute at Kennedy Krieger, Inc.

Official(s) and/or principal investigator(s):
Emily L Germain-Lee, MD, Principal Investigator, Affiliation: Kennedy Krieger Institute and Johns Hopkins University School of Medicine

Overall contact:
Emily L Germain-Lee, MD, Phone: 443-923-2703, Email: germainlee@kennedykrieger.org

We, the researchers, have found that growth hormone deficiency is very common in patients with pseudohypoparathyroidism type 1a, which falls under the broader condition termed Albright hereditary osteodystrophy. Patients with pseudohypoparathyroidism type 1a typically are short and obese. Some of these patients are not short during childhood, but due to a combination of factors, they end up short as adults. We are evaluating the effect of growth hormone treatment in those patients with pseudohypoparathyroidism type 1a who are found to be growth hormone deficient. We hypothesize that growth hormone deficiency may contribute to the short stature and obesity found in this condition. We are also evaluating the effect of growth hormone on patients with pseudohypoparathyroidism type 1a who are not growth hormone deficient (ie., growth hormone sufficient). We are also evaluating neurocognitive and psychosocial functioning in participants with AHO in order to determine the specific impairments that are most common in the condition and to determine the best approach toward management.

Funding source - - FDA OOPD [R01 FD003409 (in no-cost extension year) and R01 FD002568 (which

has ended)]

Official title: Study of Growth Hormone Use in Patients With Pseudohypoparathyroidism Type 1a and Assessment of Cognitive/Behavioral Status in Albright Hereditary Osteodystrophy

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

PHP1a: Effect of GH on height, growth velocity, final height in children. Effect on weight, BMI, lipids, self-esteem in all ages.

Cognitive and behavioral function in Albright hereditary osteodystrophy

Detailed description: Pseudohypoparathyroidism type 1a (PHP1a) is a disorder that causes many endocrine and developmental problems. To date, medical treatment has focused primarily on maintenance of normal serum levels of calcium, phosphorous, and thyroid hormone. However, these therapeutic interventions do not address the problems of short stature, obesity, and subcutaneous ossifications, which for many are a source of considerable morbidity and personal distress. These patients require frequent medical care, blood tests, and medication adjustments. PHP1a is an inherited condition with an estimated prevalence in the United States of 1: 15,000- 20,000, and the studies that we propose provide an opportunity to improve the quality of life in affected patients. We have found that growth hormone (GH) deficiency is common in these patients, and our data suggest that GH testing should be part of their routine standard of care. We are investigating whether GH treatment can increase linear growth velocity and final adult height in children. We are also investigating whether GH treatment can reduce weight and improve a variety of metabolic disturbances and overall health in both children and adults. GH deficiency not only leads to short stature and obesity, but also to osteoporosis, hyperlipidemia, depressed cardiac and renal function, as well as an overall lack of energy. It is quite possible that treatment of GH-deficient patients with PHP1a could improve any or all of the above problems. GH treatment has been FDA approved for use in both children and adults with GH deficiency. Therefore, it may be possible to provide improvement in health and overall quality of life in these patients. Additionally, we have initiated a research study for which we are treating children with PHP1a who are not GH deficient (ie., GH sufficient). The rationale is that GH treatment could maximize linear growth velocity prior to the premature bone fusion that occurs in this condition and potentially improve final adult height. This study also seeks to define the specific neurocognitive and psychosocial disabilities in individuals with AHO in order to develop therapies and improve quality of life.

Minimum age: 2 Months. Maximum age: 89 Years. Gender(s): Both.

Criteria:

Inclusion Criteria for GH study:

- Diagnosis of pseudohypoparathyroidism type 1a

- For the portion of the study in which growth hormone is used for participants who are

not growth hormone deficient (ie., growth hormone sufficient), the patient must be over 3 years of age (ie., after 3rd birthday) AND also be pre-pubertal at the time of GH initiation. Exclusion Criteria:

- Absence of above diagnosis

Inclusion for cognitive/behavioral studies:

- Confirmed diagnosis of Pseudohypoparathyroidism type 1a and

Pseudopseudohypoparathyroidism

- Ages 4 - 65 yrs

Exclusion:

- Absence of above

Emily L Germain-Lee, MD, Phone: 443-923-2703, Email: germainlee@kennedykrieger.org

Kennedy Krieger Institute and Johns Hopkins Hospital, Baltimore, Maryland 21205, United States; Recruiting
Emily L Germain-Lee, MD, Phone: 443-923-2703, Email: germainlee@kennedykrieger.org
Emily L Germain-Lee, MD, Principal Investigator

website for Dr. Germain-Lee's clinical trials and research

Related publications:

Germain-Lee EL, Groman J, Crane JL, Jan de Beur SM, Levine MA. Growth hormone deficiency in pseudohypoparathyroidism type 1a: another manifestation of multihormone resistance. J Clin Endocrinol Metab. 2003 Sep;88(9):4059-69.

Germain-Lee EL, Ding CL, Deng Z, Crane JL, Saji M, Ringel MD, Levine MA. Paternal imprinting of Galpha(s) in the human thyroid as the basis of TSH resistance in pseudohypoparathyroidism type 1a. Biochem Biophys Res Commun. 2002 Aug 9;296(1):67-72.

Germain-Lee EL, Schwindinger W, Crane JL, Zewdu R, Zweifel LS, Wand G, Huso DL, Saji M, Ringel MD, Levine MA. A mouse model of albright hereditary osteodystrophy generated by targeted disruption of exon 1 of the Gnas gene. Endocrinology. 2005 Nov;146(11):4697-709. Epub 2005 Aug 11.

Levine MA, Germain-Lee E, Jan de Beur S. Genetic basis for resistance to parathyroid hormone. Horm Res. 2003;60 Suppl 3:87-95. Review.

Jan de Beur S, Ding C, Germain-Lee E, Cho J, Maret A, Levine MA. Discordance between genetic and epigenetic defects in pseudohypoparathyroidism type 1b revealed by inconsistent loss of maternal imprinting at GNAS1. Am J Hum Genet. 2003 Aug;73(2):314-22. Epub 2003 Jul 11.

Crane JL, Shamblott MJ, Axelman J, Hsu S, Levine MA, Germain-Lee EL. Imprinting status of Galpha(s), NESP55, and XLalphas in cell cultures derived from human embryonic germ cells: GNAS imprinting in human embryonic germ cells. Clin Transl Sci. 2009 Oct;2(5):355-60. doi: 10.1111/j.1752-8062.2009.00148.x.

Huso DL, Edie S, Levine MA, Schwindinger W, Wang Y, Jüppner H, Germain-Lee EL. Heterotopic ossifications in a mouse model of albright hereditary osteodystrophy. PLoS One. 2011;6(6):e21755. doi: 10.1371/journal.pone.0021755. Epub 2011 Jun 29.

Myllylä RM, Haapasaari KM, Palatsi R, Germain-Lee EL, Hägg PM, Ignatius J, Tuukkanen J. Multiple miliary osteoma cutis is a distinct disease entity: four case reports and review of the literature. Br J Dermatol. 2011 Mar;164(3):544-52. doi: 10.1111/j.1365-2133.2010.10121.x. Epub 2011 Feb 17. Review.

Muniyappa R, Warren MA, Zhao X, Aney SC, Courville AB, Chen KY, Brychta RJ, Germain-Lee EL, Weinstein LS, Skarulis MC. Reduced insulin sensitivity in adults with pseudohypoparathyroidism type 1a. J Clin Endocrinol Metab. 2013 Nov;98(11):E1796-801. doi: 10.1210/jc.2013-1594. Epub 2013 Sep 12.

Lin MH, Numbenjapon N, Germain-Lee EL, Pitukcheewanont P. Progressive osseous heteroplasia, as an isolated entity or overlapping with Albright hereditary osteodystrophy. J Pediatr Endocrinol Metab. 2015 Jul 1;28(7-8):911-8. doi: 10.1515/jpem-2014-0435.

Starting date: January 2003
Last updated: June 25, 2015