National Institute of Child Health and Human Development (NICHD)

Overview of Rare Disease Research Activities

The mission of the National Institute of Child Health and Human Development (NICHD) is to conduct and support research on the reproductive, physiologic and behavioral processes that determine the health of individuals and populations. The Institute's programs are based on the concept that adult health and well-being are determined in part by episodes early in life and that human development continues throughout the life span. Diseases or conditions that interfere with healthy development are of concern to the Institute and thus, the NICHD supports research in the prevention, diagnosis, evaluation and treatment of many rare diseases and disorders.

Recent Scientific Advances in Rare Diseases Research

Adrenoleukodystrophy

Adrenoleukodystrophy (ALD) is an X-linked disorder associated with the accumulation of very long chain fatty acids, caused by an impaired capacity to degrade these substances. The disorder manifests with a progressive neurologic disability, and adrenocortical insufficiency; the latter could be treated successfully by steroid replacement. A wide range of conditions has been described in ALD. The most serious is called childhood ALD. Affected boys develop normally until 4 to 8 years of age, then develop progressive behavioral and cognitive deficits, impaired vision and hearing, and abnormalities of motor function that may lead to a vegetative state within 2 years. The ALD gene has been mapped to the terminal segment of the long arm of the X chromosome. Investigators funded by NICHD have developed a mouse model for ALD by targeted gene disruption. This mouse model will be used to investigate underlying mechanisms of pathophysiology and to test various modes of therapy including dietary, pharmacologic, and gene therapy.

Rett Syndrome

Rett syndrome (RS) is a disorder which affects females. It has an incidence of 1:10,000-20,000. Girls appear normal for the first 12-24 months. After this time they develop characteristic movement disorders, such as hand wringing, seizures, respiratory irregularities, and mental retardation. As the girls grow older they develop other stigmata such as scoliosis. Once thought to be a neurodegenerative disorder, current evidence suggests that Rett syndrome results from failure to form proper neuronal connections, i.e., it is probably a developmental disorder. NICHD-supported investigators have biopsied nasal mucosa of affected girls which will provide the first direct look at in vitro neuronal development in RS and is a clever approach to study a variety of markers that define developmental stages of the cell types. Preliminary investigations already indicate that this method may detect early developmental abnormalities in RS.

New Treatment for Hypoparathyroidism

Hypoparathyroidism is one of the few remaining hormonal deficiencies for which hormone replacement therapy is not available. Moreover, the existing treatment, vitamin D or its analogs and calcium, lacks the full kidney calcium-retaining action of parathyroid hormone (PTH), and thus, treated patients often exhibit elevated calcium in the urine. To test the hypothesis that treatment with PTH 1-34 can achieve simultaneous normalization of both serum and urine calcium, a randomized, crossover trial of PTH 1-34 compared with calcitrol was conducted in patients with hypoparathyroidism. The study showed daily treatment with PTH 1-34 maintained normal serum and urine calcium. In addition, biochemical markers of bone turnover increased significantly during PTH 1-34 treatment.

Inherited Lymphedema

Lymphedema is a chronic, disabling condition resulting in the swelling of the extremities either as a result of impaired lymphatic flow or overproduction of lymph. Patients with lymphedema require life-long attention and suffer from recurrent local infections, are unable to move about normally, are socially stigmatized and may be at increased risk for developing certain cancers, such as lymphangiosarcoma. In spite of the general understanding regarding the pathophysiology resulting in the development of lymphedema, little is known about the genes regulating the development of the lymphatic system and the gene products mediating the physiology of lymph flow. Early onset lymphedema [Milroy-Nonne syndrome] and late onset lymphedema [lymphedema praecox/Meige syndrome] are described as separate entities. Variations in presentation in different families may represent different mutations of the same gene segregating in different families or mutations of independent genes. Within the same pedigree, variation in expression may be due to unknown environmental factors. A study is currently underway to identify genetically informative families in order to define linkage and potential loci and to isolate genes involved in the pathogenesis of inherited lymphedema. The investigators recently have identified two large families with infantile/early onset lymphedema, one large family with lymphedema praecox, and another with lymphedema tarda, each of which is large enough to provide significant evidence of linkage.

Hand-Foot-Genital Syndrome [HFG]

Candidate genes for human conditions are often determined by studying normal and abnormal animal development. An example of this strategy was the examination of mouse limb development that led to the discovery that human Hand-Foot-Genital syndrome (HFG) was caused by a mutation in the gene Hoxa-13. People with HFG have small, malpositioned phalanges, metacarpals, and metatarsals. Females with HFG have uterine, urethral and ureteral defects that often lead to infertility. Experiments in mice showed that Hoxa-13 was expressed in the right place and time to be involved in hand and foot formation, and that targeted mutations of Hox clusters 9-13 led to limb malformations. The probable involvement of a member of the Hoxa cluster, and data showing that Hoxa-13 was responsible for hypodactyly in the mouse, led investigators to sequence the coding region of Hoxa-13 in an individual affected with HFG. Comparison with the same coding regions from normal individuals showed that HFG is caused by an mutation in this gene. The exact role of this mutation in the limb and reproductive organs is being examined in mice engineered to have the HFG mutation.

Grebe Syndrome

Grebe syndrome is characterized by short stature, extra digits, short and deformed extremities with a proximal-distal gradient of severity. During the past year, the gene for Grebe syndrome has been mapped to chromosome 20. A gene on this chromosome which manufactures cartilage-derived morphogenic protein-1 [CDMP-1] has been identified as a candidate. Investigators have identified two distinct defects in the CDMP-1 gene of individuals affected with Grebe's syndrome. The more common of the two results in a substitution of a tyrosine for one of six highly conserved cysteines found in CDMP-1. These cysteines are involved in determining the structure and function of the mature molecule by enabling the protein to fold into a characteristic cysteine knot structure. The other, less common mutation is the deletion of a nucleotide resulting in a premature stop signal for protein processing.

Glycerol Kinase Deficiency (GKD) and Complex GKD

Glycerol kinase deficiency (GKD) is an X-linked disorder that is heterogeneous in nature. Clinically, it is recognized in three forms: infantile, juvenile and adult. The infantile form is the most severe and has the most extensive genetic damage associated with it. This form is referred to as complex GKD since the defect in the gene for the enzyme, glycerol kinase, is frequently complexed with defects in one or both of its contiguous genes that are responsible for Duchenne muscular dystrophy and adrenal hypoplasia congenita (AHC). These three genes are in close proximity on the X chromosome and large deletions in this region can leave all three genes damaged. Using a specific genomic scanning approach, the genes for glycerol kinase and DAX1, an adjacent gene responsible for adrenal hypoplasia congenita, were located and sequenced. The latter gene is also associated with hypogonadotropic hypogonadism and is expressed in the adrenal glands, gonads, pituitary and hypothalamus. Further studies of the genes involved in complex GKD will provide important information on the fundamental relationships between the clinical conditions and corresponding genetic defects in patients with contiguous gene syndromes.

Growth Hormone Therapy for Childhood Short Stature

There is concern in both the medical community and the general public about mechanisms of medical decision making and the interplay of physician and insurer decisions in determining access to care. NICHD-supported scientists at Case Western Reserve University examined the medical process influencing access to growth hormone (GH) therapy for childhood short stature by comparing coverage policies of U.S. insurers with the treatment recommendations of U.S. physicians. Surveys were mailed to insurers, primary care physicians, and pediatric endocrinologists. Each survey included identical case scenarios. Primary care physicians were asked to report decisions about referrals to pediatric endocrinologists. Endocrinologists were asked to report GH treatment recommendations. Insurers were asked about coverage decisions for GH therapy.

Physician recommendations and insurance coverage decisions differed strikingly. While 96 percent of pediatric endocrinologists recommended GH therapy for children with Turner syndrome, insurer policies covered GH therapy for only 52 percent of these children. Overall, referral and treatment decisions by physicians resulted in recommendations for GH therapy in 78 percent of children with GH deficiency, Turner syndrome, or renal failure; of those recommended for treatment, 28 percent were denied coverage by insurers. Similarly, GH therapy would be recommended by physicians for only 9 percent of children with idiopathic short stature, but insurers would not cover GH for the vast majority of these children. Access to GH therapy differs depending on the type of insurance coverage. The deep discord between physician recommendations and insurance coverage decisions, exemplified by these findings, represents a major challenge to mechanisms of health care decision making, access, and costs.

Animal Models for Necrotizing Enterocolitis (NEC)

Molecular Mechanisms of NEC

Necrotizing entercolitis is an acquired disease of the intestines of human preterm or sick neonates. Necrosis begins in the mucosal layer and may progress to involve the full thickness of the bowel wall. The cause of NEC is not clear. A mouse model of NEC induced by platelet activating factor (PAF) has been discovered and developed. PAF released into the blood stream appears to precipitate intestinal injury by activating white blood cells and by triggering the formation of injury-induced chemicals such as tumor necrosis factor (TNF), leukotrienes, oxygen radicals and adhesion molecules. The process by which PAF produces this chain reaction is under study. This model is the only one available in which NEC occurs by an event distant from the intestine. The findings of this investigation may help to provide the biochemical explanation for the protective effect of allopurinol against NEC in infants.

Nitric Oxide and NEC

Investigators are testing the innovative idea that peroxynitrates formed from nitric oxide (NO) are important in the pathogenesis of intestinal injury in NEC. Increasingly, the role of peroxynitrates in neonatal pathology is being recognized in a number of different organs such as the brain and lung. If peroxynitrates are important in NEC, then inhibitors specific for the inducible enzymes of NO should protect against bowel damage. The possibility of pharmacologic manipulation using NO enzyme inhibitors makes this line of investigation quite attractive. While the information so far presented seems to support the initial hypothesis, the results are far from conclusive. The role of NO synthesis in the development of NEC remains to be determined.

Injury Repair in NEC

The mechanisms of mucosal injury repair vary during perinatal gastrointestinal development, especially with respect to the expression of gastrointestinal growth factor receptors. Three animal model systems have been established for inducing gut injury: radiation, asphyxia-hypoxia and ischemia-reperfusion. The first system has the advantage of being the best characterized and the most reproducible, while the latter two are more likely to be related to the mechanisms of NEC intestinal damage in human infants. The studies are providing new information about stages of gastrointestinal maturation, as well as, the effect of maturation stage on injury repair. Differences in epithelial cell migration rate in newborn animals compared to adults, coupled with differences in patterns of expression of growth factors, may provide the basis to an understanding of the process of epithelial restitution following hypoxic ischemic injury to the gut.

Ongoing, New, and Planned Research Initiatives

Developmental Immunology

Currently the NICHD sponsors two program announcements on developmental and genetic defects that cause rare immunodeficiency diseases. "Developmental and Genetic Defects of Immunity" is a program announcement with set-aside funds jointly sponsored by the NICHD and the Jeffrey Modell Foundation. The purpose is to invite investigator-initiated basic research applications to identify the genes and elucidate the molecular and genetic mechanisms that are responsible for normal and defective development of the fetal, neonatal, infantile, and pediatric immune system. A similar program announcement, "Genes and Mechanisms Underlying Primary Immunodeficiency", is co-sponsored by the NIAID and NICHD. To date, at least 70 genes defects causing unique, rare primary immunodeficiencies have been identified.

Brain and Tissue Banks for Developmental Disorders

NICHD is planning to reissue an RFP to recompete the two existing brain and tissue banks for developmental disorders. The main objective in establishing brain and tissue banks is to develop research resources where biopsied and freshly autopsied tissues from "unaffected" (control) individuals and from patients who had been diagnosed to have various types of developmental disorders could be systematically collected, analyzed, stored and distributed to research investigators. Tissues from several rare diseases are stored in the brain and tissue banks. Examples are galactosemia, citrullinemia, glutaric acidemia, Miller-Dieker syndrome, Prader-Willi syndrome, tuberous sclerosis, Smith-Lemli-Opitz syndrome, and Wiskott-Aldrich syndrome.

Conferences

The section on Women's Health, Developmental Endocrinology Branch, NICHD, is organizing the First International Conference on the Genetic Origins of Premature Ovarian Failure. This meeting is designed to bring together investigators from diverse backgrounds with basic and clinical expertise pertinent to ovarian follilcle development, function and failure. The intention is to facilitate scientific and personal interactions that will advance the field as a whole and focus the power of current genetic research upon the ovary. The conference will be held April 2nd through 4th, 1998.

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