Symptoms and General Pathology

All Conditions

Diseases and Abnormalities at or Before Birth

Nervous System Diseases

Musculoskeletal Diseases

Neoplasms

Rare Diseases

Syndrome

Congenital Abnormalities

Seizures

Polydactyly

Hamartoma

Abnormalities, Multiple

Pallister-Hall Syndrome

Limb Deformities, Congenital

Musculoskeletal Abnormalities

Hypothalamic Neoplasms

Supratentorial Neoplasms

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Hypothalamic Diseases

Autosomal Dominant Multiple Pterygium Syndrome

Leslie G Biesecker, M.D.

We aim to delineate the range of severity, natural history, molecular etiology, and pathophysiology of Pallister-Hall syndrome (PHS), Greig cephalopolysyndactyly syndrome (GCPS), McKusick-Kaufman syndrome (MKS), Bardet-Biedl syndrome (BBS), Oro-facial digital syndromes (OFDs), and other overlapping phenotypes. These disorders comprise a syndrome community of overlapping manifestations and we hypothesize that this is a reflection of a common mechanistic pathway. This hypothesis be addressed by a combined clinical-molecular approach where we bring up to 50-100 patients with each disorder to the NIH clinical center for a comprehensive clinical evaluation with follow-up at a frequency appropriate to the disorder. Specimens will be collected and evaluated in the laboratory by linkage analysis, physical mapping, candidate gene characterization, mutation screening, and cell biologic studies of normal mutant proteins.

We aim to use the power of modern molecular genetics and clinical research to delineate the

range of severity, natural history, molecular etiology, and pathophysiology of a number of

congenital anomaly syndromes. The goal of the research is to develop a knowledge base that allows proper clinical and molecular diagnosis of patients with rare congenital anomaly

disorders. Our paradigm is the previous work we have done with Pallister-Hall syndrome (PHS) and Greig cephalopolysyndactyly syndrome (GCPS), where we have successfully used a combined clinical-molecular approach. Using this strategy, we have brought 50-100 patients or families with these disorders to the NIH clinical center (NIH CC) for a comprehensive clinical evaluation with follow-up at a frequency appropriate to the disorder. We have also clinically and/or molecularly evaluated many additional patients with atypical or non-classic presentations of PHS and GCPS and have conducted exploratory studies of other phenotypes to determine how they might fit into the more general models generated to explain PHS and GCPS. We are currently generalizing this approach to a number of disorders including talipes equinovarus, atrial septal defect, Robin sequence, and persistent left superior vena cava (TARP) syndrome. Specimens from patients participating in both the laboratory and clinical arms of the protocol will be collected and evaluated in the laboratory by linkage analysis, physical mapping, candidate gene characterization, mutation screening and targeted exome sequencing, and cell biologic studies of normal and mutant proteins.

Phenotype and Etiology of Pallister-Hall Syndrome

Genetic and Clinical Studies of Congenital Anomaly Syndromes

National Human Genome Research Institute (NHGRI)

Gland and Hormone Related Diseases

Pituitary Diseases

Pituitary Neoplasms

Dwarfism

Dwarfism, Pituitary

Endocrine System Diseases

Bone Diseases

Bone Diseases, Developmental

Bone Diseases, Endocrine

Hypopituitarism

Growth Hormone Deficiency

Isolated Growth Hormone Deficiency

All Drugs and Chemicals

Hormones

Estrogens

Stratified based on age and estrogen status from 3 to 6 mcg/kg/day

Somatropin

Dosage based on age and estrogen status ranging from 3 to 6 mcg/kg/day

Placebo

Anne Klibanski, M.D

The purpose of the study is to evaluate the effects of growth hormone replacement on women with growth hormone deficiency. Growth hormone deficiency means the body no longer produces growth hormone due to a tumor or some kind of disease of the brain in an area called the pituitary/hypothalamic region. This is the area of the brain where growth hormone is normally produced. We, the researchers at Massachusetts General Hospital, will establish the effects of growth hormone replacement on cardiovascular parameters (laboratory tests, the flexibility of the arteries, changes in heart rate) in women with growth hormone deficiency. Our goal is to see if this therapy:

* has effects on women's cardiovascular risk markers (special blood tests which indicate how healthy the heart and arteries are)
* has effects on women's types and levels of various substances circulating in their blood
* in women affects the stiffness of their arteries and heart rate variability in parallel with changes in cardiovascular risk markers
* has different effects depending on whether women are pre or post menopausal.

Participation in this study is expected to last approximately 12 months.

The aim of the study is to evaluate the gender specific effects of physiologic Growth Hormone (GH) replacement in women with GH deficiency on the basis of pituitary/hypothalamic region tumors, radiation, or surgery on cardiovascular risk markers and arterial distensibility. Cardiovascular mortality in growth hormone (GH) deficient adults has been shown to be increased in a number of retrospective studies. Increased arterial intima-media thickness, increased prevalence of atherosclerotic plaques and endothelial dysfunction have been reported in growth hormone deficient adults both in childhood and adulthood onset forms.

The growth hormone deficiency (GHD) syndrome is associated with a cluster of cardiovascular-risk factors such as central adiposity, increased visceral fat, insulin resistance, dyslipoproteinemia and decreased plasma fibrinolytic activity. GH administration has effects on a number of these factors, but it is unknown which mechanisms are implicated in GH action on the process of atherosclerosis. In addition to alterations in atherosclerotic markers, abnormalities in cardiac function and structure have been reported among patients with GHD possibly contributing to the increased cardiovascular mortality. In addition, GHD is associated with cardiac autonomic dysfunction that may also contribute to cardiovascular mortality and improves with GH replacement therapy.

The vast majority of studies have focused primarily on men and the gender-specific effects of GH replacement on cardiovascular risk factors remain unknown. In addition to being of interest in terms of understanding the physiologic effects of GH therapy, there are important therapeutic implications regarding data in women. Cardiovascular disease is the leading cause of mortality in women. Effects of GH replacement on bone density may be less pronounced in women and because specific GH effects on cardiovascular risk factors in women are unknown, many adult women with GHD are untreated.

Long-term GH treatment decreases total body fat including visceral fat. Decreases in central fat as assessed by waist to hip ratio have been reported in some studies, but not in others. Administration of GH causes insulin resistance acutely but long-term therapy may restore glucose sensitivity. GH treatment increases lipoprotein (a) (Lp (a)) levels but its effects on other lipoproteins are still controversial. Some studies have reported decreases in LDL cholesterol with or without increases in HDL cholesterol with GH administration, while others have not. Twelve months of GH replacement improves left ventricular mass and cardiac performance in young adults with GHD. Key factors likely involved in the discrepant findings include heterogeneity of patients studied in terms of age of onset of the GH deficiency (childhood versus adulthood), gender, severity of GHD and methodologic issues such as dose and duration of GH administration. In addition, many of the studies have no control period.

Inflammation plays a central role in the pathophysiology of atherosclerosis. Each atherosclerotic lesion represents a different stage of a chronic inflammatory process in the arterial wall and different markers along the inflammatory cascade have been reported to predict cardiovascular risk \[34\]. Among those, high-sensitivity testing for C-reactive protein (CRP) is one of the best validated. Several prospective studies support a strong link between levels of CRP and future risk of coronary events. CRP adds considerable value to the total and HDL cholesterol measurement in the prediction of cardiovascular risk. Other distal indicators of inflammation such as serum-amyloid polypeptide A (SAA) likewise predict coronary risk. These distal markers reflect the consequences of elevated proinflammatory cytokines like interleukin-6 (IL-6). GH is known to have important immunomodulatory effects. We therefore hypothesized that the effects of GH on the process of atherosclerosis might be mediated through the cytokine-inflammatory pathway. We have recently investigated the effects of physiologic GH replacement in cardiovascular risk markers in men with GHD. In this study we found that CRP and IL-6 levels decreased in GH treated men compared to controls despite no significant change in serum lipid levels. We also recently have investigated levels of inflammatory markers in women with hypopituitarism compared with healthy controls. We found that women with hypopituitarism have increased levels of IL-6 and CRP suggesting that chronic inflammation may be involved in the pathogenesis of atherosclerosis in this population. It will be critical to determine whether physiologic GH replacement has beneficial effects in women, and whether these effects are influenced by estrogen.

We will investigate the effect of long-term physiologic GH administration on IL-6, CRP, SAA as well as other classic cardiovascular risk factors in women with GHD in a randomized, placebo-controlled study. In addition, we will evaluate structural/function correlates in women by measuring arterial wall distensibility and heart rate variability in parallel with cardiovascular risk markers.

We will establish the gender-specific effects of physiologic GH replacement on cardiovascular risk in women with GHD by investigating whether this therapy:

1. has gender-specific effects on cardiovascular risk markers
2. has gender-specific effects on lipid profiles
3. alters heart rate variability and arterial distensibility in parallel with changes in cardiovascular risk markers
4. has different effects depending upon gonadal status

Growth Hormone Administration and Its Effects on Cardiovascular Risk Factors in Growth Hormone Deficient Women

Gender-Specific Effects of Physiologic GH Administration on Cardiovascular Risk Factors in Women With Growth Hormone Deficiency

Massachusetts General Hospital

Anne Klibanski, MD

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phenotype and Etiology of Pallister-Hall Syndrome	NCT00001404	Malformations Multiple Abnorm... Polydactyly		-	National Institutes of Health Clinical Center (CC)
Growth Hormone Administration and Its Effects on Cardiovascular Risk Factors in Growth Hormone Deficient Women	NCT00136032	Growth Hormone ...	Somatropin Placebo	18 Years - 65 Years	Massachusetts General Hospital
Phenotype and Etiology of Pallister-Hall Syndrome	NCT00001404	Malformations Multiple Abnorm... Polydactyly		-	National Institutes of Health Clinical Center (CC)
Phenotype and Etiology of Pallister-Hall Syndrome	NCT00001404	Malformations Multiple Abnorm... Polydactyly		-	National Institutes of Health Clinical Center (CC)

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