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Report on Research on Rare Diseases in Children: FY 2000 to FY 2005

National Institute of Child Health and Human Development (NICHD)

Overview of NICHD Rare Diseases in Children Research, FY 2000–FY 2005

The mission of NICHD is to ensure that babies are born healthy and develop, through childhood and adolescence, into productive adults. NICHD works to achieve this mission in part by conducting and supporting a broad range of innovative research activities that address the issue of rare diseases in children. Some of NICHD's activities have recently resulted in significant stories of discovery and scientific advances. In addition, to spur further discoveries and advances, NICHD is leading and supporting a variety of initiatives and workshops related to rare diseases or conditions in children. This report highlights some of the many NICHD activities related to rare diseases or conditions in children.

NICHD will continue to support research into FYs 2002 to 2005 that improves the lives of children, including research that ameliorates the symptoms or reduces the incidence of rare diseases in children. NICHD recently developed and published six strategic plans and research agendas to guide the direction of the Institute's research over the next five years. Three of these strategic plans address issues that are particularly related to rare diseases and conditions: 1) "Developmental Biology: Understanding Normal and Abnormal Development" helps to clarify the underlying mechanisms of normal and abnormal developmental processes needed to provide the bases for understanding how birth defects form; 2) "Genetics and Fetal Antecedents of Disease Susceptibility" targets understanding the early genetic pathways and processes that may lead to various diseases and conditions over the life span; and 3) "Sudden Infant Death Syndrome: New Directions" outlines a research agenda on SIDS for the next five years.

For each of the extramural activities listed below, the funding years since FY 2000 and the project period of the research project are indicated. The intramural projects are ongoing; therefore, the funding years and project period for all of these projects are listed as FY 2000-FY 2005.

Recent Scientific Advances in Rare Diseases in Children Research

Rett Syndrome

Rett syndrome is a neurodevelopmental disorder reported only in girls. The girls develop normally for the first 6 to 18 months of age, then begin to regress in speech development and develop repetitive hand motions, such as hand wringing or hand "washing." Although they may survive to adulthood, most affected girls never regain the ability to walk or even learn to feed themselves. While the disorder currently has no cure, scientists have found a faulty gene that fails to switch off other genes that are related to Rett syndrome. Previous findings suggested that the disorder was passed through the mother's X chromosome. After searching through the X chromosome, NICHD scientists found the disorder results from the mutation of the gene that makes methyl cytosine-binding protein 2 (MECP2). MECP2 is the lynchpin in one of the elaborate networks of proteins needed to switch off a group of genes. The discovery of a gene for the disorder holds the promise of a test that may lead to an earlier and more accurate diagnosis of Rett syndrome. In addition, new studies on the faulty gene itself may lead to effective treatments for the disorder. Furthermore, this discovery may also explain why only females are affected by the syndrome. Because they have only one X chromosome, males with the Rett syndrome gene possess only the mutant version of MECP2. Presumably, because they do not have a "backup" copy of the normal gene, males with the gene for Rett syndrome die before birth. (FY 2000 through FY 2001; project period 1998-2001)

Osteogenesis Imperfecta (OI)

"Brittle bone disease" is a genetic defect of collagen, the connective tissue scaffolding upon which bones are built. Technically known as OI, this hereditary disorder ranges from mild to severe. Mild cases may go undiscovered, but individuals with the most severe form break so many bones during birth that they do not survive. Currently, there is no cure for OI, and treatment is usually directed toward preventing bone fractures and caring for fractures that have occurred. NICHD scientists, who sought to prevent the abnormal collagen from being made in patients with more severe cases of OI, examined a comparatively new gene technology that involves a plant virus. The RNA of the tobacco mosaic virus, which scientists have dubbed the "hammerhead ribozyme," can be tailor-made to bind to particular kinds of RNA. Taking advantage of that fact, the scientists engineered ribozymes that break apart the RNA that codes for the defective Type I collagen RNA, inserted the ribozymes into laboratory cultures of skin cells from patients with OI, and succeeded in stopping the skin cells from producing the abnormal collagen. Building on this achievement, the scientists are exploring ways to introduce the ribozymes into the bone marrow stem cells that manufacture bone. Using mouse models, the scientists are now attempting to insert the ribozyme into the cells of the mice in hopes of providing a treatment for this disorder. (FY 2000 through FY 2005; project period 2000-2005 [intramural])

Immune Mechanisms to Suppress Leukemia

Throughout life, white blood cells, a critical component of the immune system, begin developing from immature precursor cells in the bone marrow and complete their development in the thymus gland. Scientists have recently studied the biological effects of one of the many gene products involved in this process, interferon consensus-binding protein (ICSBP), on the cellular immune system. The researchers discovered that ICSBP is essential to the development of macrophages, a type of white blood cell that devours foreign organisms and constitutes one of the body's most powerful weapons against diseasecausing microbes. By creating transgenic mice lacking ICSBP, these scientists also learned that this regulatory protein prevents the uncontrolled cell growth of another type of white blood cell that typically causes a condition similar to chronic myelogenous leukemia in humans. These insights into the function of ICSBP shed light on normal and abnormal immune system development, on the biochemical mechanisms involved in fighting infections, and on pathological processes leading to leukemia. (FY 2000 through FY 2005; project period: 2000-2005 [intramural])

Ongoing, New, and Planned Research Initiatives in Rare Diseases in Children

Wiskott-Aldrich Syndrome (WAS)

NICHD scientists are focusing on factors that characterize the molecular mechanisms and clarify the signal transduction pathways that result in the primary immunodeficiency WAS. Scientists have found that a WAS protein plays a major role in forming the cytoskeleton and influencing cell signaling and development, as well as the programmed death of platelets and hematopoietic cells in WAS patients. These findings may lead to the development of a prenatal genetic test for WAS mutations. (FY 2000 through FY 2002; project period 1995-2004)

Sudden Infant Death Syndrome (SIDS)

Recent research has led to new insights into the neurological basis of SIDS. Building on earlier findings of brain abnormalities in babies who died of SIDS, scientists have now discovered that many babies have flaws in a neural network that likely plays a role in controlling breathing, heartbeat, temperature, and waking during sleep. Defects in this network could interfere with a baby's ability to awaken itself when he or she has trouble breathing or becomes overheated while asleep. Further research in this area could lead to a better way to screen newborns for the defective network. (FY 2000 through FY 2001; project period 1992-2005)

Beckwith-Wiedemann Syndrome (BWS)

NICHD scientists are studying the genomic imprinting of a gene cluster on chromosome 7 in mice, which is similar to chromosome 11 in humans. Disruptions in the genomic imprinting at chromosome 11 are associated with BWS, a developmental disorder in children characterized by a spectrum of symptoms such as excessive size and height, enlarged abdominal organs, and enlargement of cells related around the adrenal glands. Furthermore, BWS patients are also more susceptible to developing childhood tumors. Continued research using genomic imprinting in mice may result in methods to prevent or treat BWS. (FY 2000 through FY 2005; project period 2000-2005 [intramural])

Carney Complex (CNC)

NICHD scientists are investigating how genetic and molecular mechanisms of rare disorders, especially those that are hereditary and associated with multiple tumors and abnormalities in other endocrine glands, affect the adrenal cortex. Studies of families with CNC, a combination of myxomas, spotty skin pigmentation, endocrine hyperactivity and schwannomas, and other related syndromes, have revealed that chromosomes 2 and 17 harbor genes for CNC. Genetic and physical mapping of chromosome 2 was conducted to clone the CNC-causing gene. In addition, studies of chromosome 17 show that a novel tumor suppressor gene, abbreviated PRKAR1A, is responsible for many CNC cases.

In future studies, scientists will examine the functional consequences of PRKAR1A mutations and how these mutant genes affect development in mouse models. (FY 2000 through FY 2001; project period 2000-2005 [intramural])

Xeroderma Pigmentosum

To better understand the development of xeroderma pigmentosum, NICHD scientists are examining proteins to determine which mechanisms facilitate errors in DNA repair and synthesis. Xeroderma pigmentosum is a rare condition that makes patients very sensitive to sunlight. As a result, patients with this disease often suffer multiple sunlight-induced cancers, and many die before reaching adulthood. In addition, these scientists are planning to apply the methods they developed in DNA synthesis and repair to the study of Hutchinson-Gilford progeria syndrome. (FY 2000 through FY 2005; project period 2000-2005 [intramural])

Ongoing, New, and Planned Research Initiatives in Rare Diseases in Children

Strategic Plans

NICHD recently developed and published five strategic plans designed to guide the direction of the Institute's research over the next five years. Two of these strategic plans address issues that are particularly related to rare diseases and conditions: 1) the "Developmental Biology: Understanding Normal and Abnormal Development" strategic plan helps to clarify the underlying mechanisms of normal and abnormal developmental processes needed to provide the bases for understanding how birth defects form; and 2) the "Genetics and Fetal Antecedents of Disease Susceptibility" plan serves to gain insight into how diseases form by defining early genetic pathways and processes that may lead to disease over the lifespan, and by identifying the role of "modifiers" such as gene-gene interactions or environmental influences that may influence the disease process. Another plan, "Sudden Infant Death Syndrome: New Directions," outlines a research agenda on SIDS for the next five years and should be completed during Summer 2001.


In FY 2000, NICHD led several initiatives to stimulate research related to rare diseases and conditions in children. For instance, NICHD is helping to lead the trans-NIH initiative, "Mutagenesis Screens/Phenotyping Tools for Zebrafish," which encourages scientists to use mutagenesis screening in the zebrafish model to detect and characterize genes, pathways, and phenotypes of interest in processes related to early development, behavior, organ formation, and disease progression. In addition, NICHD is leading an initiative, "Neurobiology and Genetics of Fragile X Syndrome," to stimulate research in areas such as developmental neurobiology, pathophysiology, genetics, proteomics, epidemiology, structure-function correlation, and clinical studies that have a direct link to fragile X syndrome.

In FY 2001, NICHD is participating in a trans-NIH initiative entitled, "Developing the Potential of Xenopus tropicalis as a Genetic Model," to stimulate research that examines the feasibility of using X. tropicalis for standard genetic manipulations such as mutagenesis, phenotyping, and gene cloning. The research will help identify and characterize genes that regulate cellular and developmental processes. In addition, NICHD is participating in autism initiatives aimed at stimulating research that clarifies the diagnosis, epidemiology, etiology, and genetics of (and develops innovative treatments for) autism and autism spectrum disorders.


Workshop on Laboratory and Clinical Research Strategies in OI

Together with ORD and NIAMS, NICHD conducted a workshop in March 2001 where researchers discussed the many exciting developments in the field of OI. Discussion covered new drug treatments and their testing in mouse models and humans, the development of new mouse models, bone cell biology, mesenchymal cell transplantation, bone cell biology, and new genetic therapy approaches. The outcomes from this workshop will influence and guide future OI research and collaborations with scientists in related fields.

Workshop on Research on Chromosome 18

A workshop, co-sponsored with ORD, will be convened in July 2001 to bring together basic and clinical scientists who are familiar with syndromes associated with Chromosome 18, and scientists who have expertise in related areas of research. The meeting should lead to a consensus concerning the state of research in the study of disorders associated with chromosome 18 and identify critical areas for future research.

Conference on Endocrine Hypertension

Hypertension is a major risk factor for cerebrovascular and cardiovascular diseases. Togther with ORD, NICHD will conduct a conference in Fall 2001 where researchers will discuss several recent genetic, biochemical, and radiological discoveries, as well as new approaches and surgical procedures that have influenced the management of endocrine hypertension. Researchers will also discuss how endocrine hypertension relates to Cushing's syndrome and endocrine tumors in children.

Pain in Children with Developmental Disabilities

In November 2001, a conference is planned to examine the basic and clinical aspects of pain in children with significant physical and neurological impairments (brain or spinal cord injury and other relatively rare neurodevelopmental disorders) and how these aspects may differ significantly from those identified in able-bodied adults. This conference will bring together scientists to discuss the neurological basis of pain, therapeutic strategies for pain management, psychosocial aspects of coping with pain, and how best to apply this research to children. This conference will have specific relevance for children with spina bifida or cerebral palsy and will help build the pediatric rehabilitation program at the National Center of Medical Rehabilitation Research.


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Last Reviewed: February 1, 2005
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