Hartford, Connecticut 06103

  • Albright Hereditary Osteodystrophy

Purpose:

We, the researchers, are following the natural history of Albright hereditary osteodystrophy. We 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 or those who are growth hormone sufficient and were found to have a positive clinical response to growth hormone in a prior clinical trial under R01 FD003409, IND 67148 or those who meet the criteria of idiopathic short stature or SGA. 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 -- Growth hormone study: FDA OOPD [R01 FD003409 (which has ended) and R01 FD002568 (which has ended)] Cognitive/behavior: NICHD R21 HD078864


Study summary:

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 final adult height. 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 completed a study in which we treated children with PHP1a who are not GH deficient (i.e., 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. The supply of growth hormone has ended for this study, and we are following those participants who were in this study and received the growth hormone supply. Some of these patients remain on growth hormone as per clinical care secondary to their responses. 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.


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. As of now, the growth hormone sufficient participants must meet the criteria of idiopathic short stature or SGA indication. Exclusion Criteria: - Absence of above diagnosis Inclusion for cognitive/behavioral studies: - Confirmed diagnosis of Pseudohypoparathyroidism type 1a and Pseudopseudohypoparathyroidism - Ages 6 - 65 yrs Exclusion: - Absence of above


Study is Available At:


Original ID:

16-110


NCT ID:

NCT00209235


Secondary ID:

R21HD078864


Study Acronym:


Brief Title:

Albright Hereditary Osteodystrophy: Natural History, Growth, and Cognitive/Behavioral Assessments


Official Title:

Natural History Study of Albright Hereditary Osteodystrophy: Includes Substudies on Effects of Growth Hormone in Patients With Pseudohypoparathyroidism Type 1a and Cognitive & Behavioral Studies in Albright Hereditary Osteodystrophy


Overall Status:

Recruiting


Study Phase:

N/A


Genders:

N/A


Minimum Age:

2 Months


Maximum Age:

89 Years


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

Connecticut Children's Medical Center


Oversight Authority:

United States: Food and Drug Administration


Reasons Why Stopped:


Study Type:

Interventional


Study Design:


Number of Arms:

1


Number of Groups:

0


Total Enrollment:

600


Enrollment Type:

Anticipated


Overall Contact Information

Official Name:Emily L Germain-Lee, MD
Principal Investigator
Connecticut Children's Medical Center and University of Connecticut School of Medicine
Primary Contact:Emily L Germain-Lee, MD
860-837-6700
egermain@connecticutchildrens.org
Backup Contact:Alexzandrea Buscarello, B.S.
860-837-6763
abuscarello@connecticutchildrens.org

Study Dates

Start Date:January 2003
Completion Date:December 2027
Completion Type:Anticipated
Primary Completion Date:October 2026
Primary Completion Type:Anticipated
Verification Date:January 2020
Last Changed Date:January 2, 2020
First Received Date:September 13, 2005

Study Outcomes

Outcome Type:Primary Outcome
Measure:Cognitive and behavioral function in Albright hereditary osteodystrophy
Time Frame:participant will be assessed on day 1; assessment may extend into day 2
Safety Issues:False
Description:Cognitive and behavioral function assessments
Outcome Type:Primary Outcome
Measure:PHP1a: Effect of GH on height, growth velocity, final height in children. Effect on weight, BMI, lipids, self-esteem in all ages.
Time Frame:until achieve final height (approximately 12-15 years)
Safety Issues:False
Description:Effect of growth hormone

Study Interventions

Intervention Type:Behavioral
Name:Neurocognitive and psychosocial testing
Description:Neurocognitive and psychosocial testing
Arm Name:AHO:neurocognitive and pyschosocial

Study Arms

Study Arm Type:Experimental
Arm Name:AHO:neurocognitive and pyschosocial
Description:Neurocognitive and psychosocial testing

Study Agencies

Agency Class:Other
Agency Type:Lead Sponsor
Agency Name:Connecticut Children's Medical Center
Agency Class:Other
Agency Type:Collaborator
Agency Name:Johns Hopkins University

Sample and Retention Information

There are no available Sample and Retention Information

Study References

Reference Type:Results Reference
Citation:Germain-Lee EL. Management of pseudohypoparathyroidism. Curr Opin Pediatr. 2019 Aug;31(4):537-549. doi: 10.1097/MOP.0000000000000783.
PMID:31145125
Reference Type:Results Reference
Citation:Salemi P, Skalamera Olson JM, Dickson LE, Germain-Lee EL. Ossifications in Albright Hereditary Osteodystrophy: Role of Genotype, Inheritance, Sex, Age, Hormonal Status, and BMI. J Clin Endocrinol Metab. 2018 Jan 1;103(1):158-168. doi: 10.1210/jc.2017-00860.
PMID:29059381
Reference Type:Results Reference
Citation: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;28(7-8):911-8. doi: 10.1515/jpem-2014-0435.
PMID:25894639
Reference Type:Results Reference
Citation: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.
PMID:24030943
Reference Type:Results Reference
Citation:Joseph AW, Shoemaker AH, Germain-Lee EL. Increased prevalence of carpal tunnel syndrome in albright hereditary osteodystrophy. J Clin Endocrinol Metab. 2011 Jul;96(7):2065-73. doi: 10.1210/jc.2011-0013. Epub 2011 Apr 27.
PMID:21525160
Reference Type:Results Reference
Citation:Long DN, Levine MA, Germain-Lee EL. Bone mineral density in pseudohypoparathyroidism type 1a. J Clin Endocrinol Metab. 2010 Sep;95(9):4465-75. doi: 10.1210/jc.2010-0498. Epub 2010 Jul 7.
PMID:20610593
Reference Type:Results Reference
Citation:Plagge A, Kelsey G, Germain-Lee EL. Physiological functions of the imprinted Gnas locus and its protein variants Galpha(s) and XLalpha(s) in human and mouse. J Endocrinol. 2008 Feb;196(2):193-214. doi: 10.1677/JOE-07-0544. Review.
PMID:18252944
Reference Type:Results Reference
Citation:Hsu SC, Groman JD, Merlo CA, Naughton K, Zeitlin PL, Germain-Lee EL, Boyle MP, Cutting GR. Patients with mutations in Gsalpha have reduced activation of a downstream target in epithelial tissues due to haploinsufficiency. J Clin Endocrinol Metab. 2007 Oct;92(10):3941-8. Epub 2007 Jul 24.
PMID:17652219
Reference Type:Results Reference
Citation:Long DN, McGuire S, Levine MA, Weinstein LS, Germain-Lee EL. Body mass index differences in pseudohypoparathyroidism type 1a versus pseudopseudohypoparathyroidism may implicate paternal imprinting of Galpha(s) in the development of human obesity. J Clin Endocrinol Metab. 2007 Mar;92(3):1073-9. Epub 2006 Dec 12.
PMID:17164301
Reference Type:Results Reference
Citation:Long DN, Levine MA, Germain-Lee EL. Bone mineral density in patients with pseudohypoparathyroidism type 1a. EndoTrends 12(4):4,2006.
Reference Type:Results Reference
Citation:Germain-Lee EL. Short stature, obesity, and growth hormone deficiency in pseudohypoparathyroidism type 1a. Pediatr Endocrinol Rev. 2006 Apr;3 Suppl 2:318-27. Review.
PMID:16675931
Reference Type:Reference
Citation:Mantovani G, Bastepe M, Monk D, de Sanctis L, Thiele S, Usardi A, Ahmed SF, Bufo R, Choplin T, De Filippo G, Devernois G, Eggermann T, Elli FM, Freson K, García Ramirez A, Germain-Lee EL, Groussin L, Hamdy N, Hanna P, Hiort O, Jüppner H, Kamenický P, Knight N, Kottler ML, Le Norcy E, Lecumberri B, Levine MA, Mäkitie O, Martin R, Martos-Moreno GÁ, Minagawa M, Murray P, Pereda A, Pignolo R, Rejnmark L, Rodado R, Rothenbuhler A, Saraff V, Shoemaker AH, Shore EM, Silve C, Turan S, Woods P, Zillikens MC, Perez de Nanclares G, Linglart A. Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement. Nat Rev Endocrinol. 2018 Aug;14(8):476-500. doi: 10.1038/s41574-018-0042-0. Review.
PMID:29959430
Reference Type:Reference
Citation: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.
PMID:21062265
Reference Type:Reference
Citation: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.
PMID:21747923
Reference Type:Reference
Citation: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.
PMID:20443919
Reference Type:Reference
Citation: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.
PMID:12858292
Reference Type:Reference
Citation: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.
PMID:14671404
Reference Type:Reference
Citation: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.
PMID:16099856
Reference Type:Reference
Citation: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.
PMID:12147228
Reference Type:Reference
Citation: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.
PMID:12970262

Data Source: ClinicalTrials.gov

Date Processed: April 03, 2020

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