Biennial and Annual Report on the Rare Diseases Research Activities at the National Institutes of Health FY 2004

National Institute of Child Health and Human Development (NICHD)

Overview of Rare Diseases Research Activities

The National Institute of Child Health and Human Development (NICHD) mission is to ensure that babies are born wanted, timely, and healthy and that they develop to their full physical, emotional, and cognitive potential. The Institute achieves its mission in part by conducting and supporting a broad range of innovative research activities, a portion of which specifically addresses rare diseases and conditions. These activities not only yield significant scientific advances but also provide a means to fill research gaps and better understand the origins of rare diseases and conditions. Below are some of the NICHD’s activities related to possible ways to prevent or treat rare diseases and conditions as they affect children, women, and families.

Recent Scientific Advances and Related Activities

Study identifies novel puberty gene. The mechanisms that control sexual maturation heralding the onset of adult reproductive function are one of the great mysteries of human biology. Puberty begins when a brain structure known as the hypothalamus begins secreting gonadotropin-releasing hormone, the “master” reproductive hormone that regulates fertility. However, NICHD-supported researchers came a step closer to understanding the maturation process when they examined several members of a family who did not experience normal sexual maturation. The researchers found that all of these individuals, along with another, unrelated person, had abnormalities in a gene known as GPR54. The researchers then developed an experimental mouse that did not have the gene in any form.2 Like their human counterparts with mutations in GPR54, the mice also did not undergo puberty. The researchers found that while GnRH was lacking in its other tissues, the mouse hypothalamus did contain normal amounts of unreleased GnRH. These findings open the door to new ways of treating the ovaries and testes that fail to mature and other conditions of human infertility associated with inadequate release of GnRH.

Rett syndrome protein involved in early development. Rett syndrome (RTT) is a genetic disorder that gradually halts the healthy development of infant and toddler girls. Among other problems, girls with RTT lose their ability to talk, to interact with other people, and to move independently. Currently, no treatment exists to halt its progression. Researchers have determined that the disorder results from a defect in a particular gene, known as MeCP2, but were unsure of the gene’s function. Recently, scientists gained an understanding of the gene’s function by studying the underwater frog, Xenopus. The researchers determined that a mutant form of the gene affects early embryonic development, resulting in an excess number of the precursor cells that give rise to the brain. Xenopus tadpoles with the mutant gene developed neurological anomalies similar to those seen in RTT.3 The researcher’s findings contribute to an improved understanding of RTT, which may eventually lead to new treatments for the disorder.

Gene discovered for Cornelia de Lange syndrome. For the first time, scientists have found a mutated gene that is associated with Cornelia de Lange syndrome, a rare, multi-system disorder characterized by mental retardation, heart defects, and multiple other physical and behavioral anomalies.4 Researchers studied 12 families in which one or more members have the disorder and identified a gene that had multiple mutations and was widely expressed in fetal and adult tissues. The gene appears to be involved in the very early stages of embryonic development and contains information needed to switch on a number of other genes during that period. The gene’s discovery is expected to speed development of a prenatal test for the syndrome. A similar test will also be developed to diagnose Cornelia de Lange syndrome in young children who may have the condition. Discovery of the gene is an important step not only toward understanding and helping to diagnose the disorder but also for possibly developing future interventions to prevent it.

Estrogen, genetic deficiencies, and cognitive function in Turner syndrome. Girls and women with Turner Syndrome (TS) are born with just one X chromosome in some or all of their cells instead of the two X chromosomes found in normal women. Approximately 60,000 girls and women are affected in the United States, with approximately 800 new cases diagnosed each year.5 Individuals with TS lack normal estrogen production, are infertile, and may have coronary or other physical problems. Women and girls with TS usually have normal intelligence, but they may have specific cognitive deficits, including difficulty in learning math and performing visual-spatial coordination tasks such as mentally rotating objects in space. Although the evidence is mixed, some researchers have demonstrated positive effects of estrogen replacement on cognition and behavior in women who lack adequate levels of the hormone for various reasons. Whether this means that the lack of estrogen in TS explains the syndrome’s cognitive deficits or whether the cause is lack of an X chromosome or a combination of hormonal and genetic factors is not known. Recently, NICHD scientists reported that the missing X chromosome appeared to be largely responsible for the distinctive cognitive profile of women and girls with TS.6 Comprehensive cognitive evaluations of women with TS, women with premature ovarian failure (POF), and normal women indicated that the women with two X chromosomes—POF and normal—resembled each other and differed from the TS women in key cognitive tasks. The TS and POF women were treating their estrogen deficits with replacement therapy. Because they and the women without the conditions had comparable estrogen levels, researchers were able to attribute the cognitive deficits observed in the TS women to the missing chromosome.

Gender differences in Fragile X-related tremor/ataxia. Fragile X syndrome is the most common form of mental retardation in boys and men and appears less frequently in girls and women. This developmental disorder is caused by a mutated gene in the X chromosome. A less than fully mutated or “permutation” form of the gene does not generally cause the more serious neurodevelopmental consequences of the full mutation but may cause a progressive neurological disorder in individuals as they age. It is estimated that approximately one in 3,500 to 8,900 males is affected by the full mutation and that 1 in 1,000 males has the premutation form of the gene.7 Also, it is estimated that 1 in 250 to 500 females has the permutation and that 1 in 4,000 females is affected by the full mutation.8 The first symptoms of this disorder, known as fragile x-related tremor/ataxia syndrome or FXTAS, are involuntary trembling (tremors) that make it difficult to write and perform other tasks or problems with balance (ataxia) and frequent falls. FXTAS progresses slowly to dementia and other more serious symptoms. Until recently, FXTAS was reported only in men, but NICHD-supported researchers have now reported the syndrome in a small number of women.9 Unlike men, none of the women had dementia, suggesting that workups of families with the mutation or permutation should include neurological symptoms in older women as well as older men.

Outcomes of treating girls for abnormal exposure to masculinizing hormones. Girls with congenital adrenal hyperplasia (CAH) are genetically female but are exposed to abnormal levels of masculinizing hormones (androgens), beginning before birth. This condition affects about 1 in 10,000 to 18,000 children.10 The external genitals of newborn CAH girls may be ambiguous or resemble those of boys. As these girls grow, their elevated androgen production affects their cognitive functioning, behaviors, physical growth, and gender identity. The standard medical treatment of female CAH consists of surgery, within weeks of birth, to correct genital anomalies, plus ongoing endocrine treatment and advice to parents to raise these “intersex” children as girls. Little systematically gathered information exists, however, on the long-term effects of these interventions, and there are questions about optimal treatment, including the timing of surgery, to ensure the best psychosexual outcomes. NICHD-supported researchers are now studying a group of CAH women to determine the degree of their androgen exposure at various developmental stages, to assess their psychosexual development, and to examine the factors, including the timing and type of surgery, that influence that development. This research is expected to improve clinical treatment of female CAH and, more generally, to enhance understanding of androgens’ influence on individual differences in the development and expression of cognitive and sexual behavior.

Possible behavioral effects of gene causing abnormally early puberty in boys. A genetic defect that interferes with hormonal control of testosterone production in boys causes the rare condition familial male-limited precocious puberty (FMPP). Boys with FMPP can become sexually mature as young as age two. In addition to virilization and rapid physical growth and bone maturation, libido and aggressive behaviors are seen in young patients with FMPP. Until now, scientists have thought that these behaviors were secondary to FMPP—that is, that boys with FMPP experience behaviors seen in normal adolescent boys as they mature sexually. Recent studies suggest, however, that the same gene mutation that causes the early onset of puberty could also act in the brain to produce the abnormal behaviors seen in FMPP. To test this hypothesis, NICHD scientists are creating an experimental mouse with the same genetic defect and are using the animal model to study the location and distribution of the key hormone in the brain and the behaviors of mice with and without the mutation. While current treatments normalize rates of growth and improve other signs and symptoms of FMPP, understanding the causes of abnormal feelings and behaviors seen in these young boys would help scientists design better treatments for, and improve the management of, this disorder.

Significant Ongoing Rare Diseases Research Initiatives

Mental Retardation and Developmental Disabilities Research Centers (RFA-04-024). The NICHD continues to support the Mental Retardation and Developmental Disabilities Research Centers program to advance diagnosis, prevention, treatment, and amelioration of mental retardation and developmental disabilities. The purpose of the program is to provide core support and facilities for cohesive, interdisciplinary research and research training. Research projects may include genetic, molecular, and behavioral research to develop new treatment approaches for rare conditions or disorders.

Fragile X Syndrome Research Centers (RFA-HD-02-009). In response to Congressional priorities, the NICHD has created three new research centers for studies of Fragile X syndrome, the most common form of inherited mental retardation. To ensure the most productive research collaborations and to maximize efficient use of investigator expertise, study protocols, data collection and analysis, and other scientific resources, the NICHD established the new Fragile X sites as “centers within centers” in the Institute’s longstanding Mental Retardation and Developmental Disabilities Centers. Scientists leading the new centers report that this innovative research model is substantially increasing scientific collaborations, attracting new researchers to the field, and resulting in productive expansion of our research efforts in Fragile X.

New/Planned Extramural or Intramural Research Initiatives

Comparative Genetics of Structural Birth Defects (RFA-HD-03-024). Birth defects are the leading cause of infant mortality in the United States. Factors that change normal infant growth or development result in physical and functional defects. Physical or structure birth defects include cleft palate, heart defects, and neural tube defects. Spina bifida, one of the most severe structural birth defects, affects 1,500 to 2,000 babies in the United States each year.11 Scientists use animal models to better understand the causes of such outcomes; however, few scientists study structural birth defects in more than one animal model. Understanding the development of multiple animal models may speed our understanding of the genetic causes of structural birth defects. To stimulate collaborations among scientists who study different animal models, the NICHD developed a new program where scientists are comparing genes, gene products, or pathways known to be important in the development of one animal model to another, less-characterized model. New research projects include examining molecular mechanisms linked to congenital skeletal disorders and other basic mechanisms linked to normal embryonic development.

Rare Disease-specific Scientific Conferences, Symposia, or Workshops

The NICHD co-sponsored several meetings, conferences, and symposia with the NIH Office of Rare Diseases (ORD).

Signaling in Vertebrate Organogenesis (February 26 – March 2, 2004). One of the most challenging problems in human health is to understand what controls organ development and how this development can go awry to give rise to congenital malformations. To address this issue, the NICHD, with ORD support, held a conference to discuss how molecular mechanisms influence vertebrate organogenesis and how abnormalities in developmental processes can lead to structural birth defects and disease.

What Have We Learned about Collaborative Clinical Investigation and Trials for Rare Genetic Diseases? What Works, What Doesn’t, and Why? (March 4, 2004). The NICHD, with support from the ORD, held a meeting to organize and operate a series of future workshops to evaluate the needs and opportunities for collaborative research on the prevention, intervention, and epidemiology of rare genetic diseases. Participants discussed the need for a large national level collaborative study mechanism to facilitate research and development for thousands of rare/orphan and ultra-rare genetic diseases.

Rare Illnesses in Childhood: Emergency and Critical Care Presentation and Management to Maximize Outcomes (June 6–7, 2004). With ORD support, the NICHD held a symposium to highlight the current state-of-the-art care that minimizes disability and improves outcomes for critically ill children with rare diseases, rare disorders, and injuries. Presentations included care for cardiac failure, respiratory failure, status epilepticus, hepatic and renal failure, overwhelming acidosis and metabolic errors, and brain injury/coma.

The World Congress on Chromosome Abnormalities (June 27–30, 2004). The ORD cofunded a meeting that the Institute held to discuss how specific treatments could be optimized for children born with chromosome abnormalities. Participants discussed the consequences of chromosomal abnormalities on specific organs and tissues. With this knowledge, researchers may be better able to devise treatment regimes specific to a chromosomal deletion or duplication. The overall goal is to help children with chromosome abnormalities to lead healthier and more independent lives.

At the Crossroads: Common Pathways in Fragile X and Autism (July 7–8, 2004). In collaboration with the ORD, the NICHD held a workshop that brought together leaders in the fields of autism spectrum disorders and Fragile X to examine future research directions to accelerate a comprehensive understanding of these disorders. Participants examined the basic science, clinical, and epidemiological evidence on the Fragile X permutation and its effects on reproduction. In addition, the meeting served to stimulate collaborative multidisciplinary research to examine the effects of fragile X permutation on premature ovarian failure.

Fetal Therapy: Needs Assessment and Future Directions (August 16–17, 2004). The NICHD, with ORD support, held a conference to stimulate researchers in a variety of fields, including fetal surgery, obstetrics, neonatology, maternal-fetal research, and pediatric surgery, to develop a plan to evaluate and disseminate fetal surgical innovations and to further the scientific evaluation of fetal surgery. The conference involved all groups that are practicing fetal surgery as well as specialists from other disciplines such as geneticists, genetic counselors, developmental pediatricians, ethicists, and statisticians, among others.

Pineal Cell Biology Gordon Research Conference (August 29–September 3, 2004). With cofunding from the ORD, the Institute held a meeting to discuss recent advances in circadian clock mechanisms controlling the pineal gland. Participants discussed the interactions of photoreception and metabolites, signal transduction, temporal gene expression patterns, and effects of melatonin on physiology and circadian biology.

2 Seminara SB, Seminara MD, Messager S, Chatzidaki EE, Thresher RR, et al. The GPR54 Gene as a Regulator of Puberty. N Eng J Med 349:1614–1627, 2003.

3 Stancheva I, Collins AL, Van den Veyver IB, Zoghbi H, Meehan RR. A Mutant Form of MeCP2 Protein Associated with Human Rett Syndrome Cannot Be Displaced from Methylated DNA by Notch in Xenopus Embryos. Mol Cell 12: 425–435, 2003.

4 Krantz ID, McCallum J, DeScipio C, Kaur M, Gillis LA, et al. Cornelia de Lange Syndrome Is Caused by Mutations in NIPBL, the Human Homolog of Drosophila melanogaster Nipped-B. Nat Genet 36:631–635, 2004.

5 Turner Syndrome Society of the United States. Available at: (cited December 2004).

6 Ross JL, Stefanatos GA, Lushner H, Bondy C, Nelson L, et al. The effect of genetic differences and ovarian failure: Intact cognitive function in adult women with premature ovarian failure versus Turner Syndrome. 2004 J Clin Endocrinol Metab 89:1817–1822.

7 Crawford, DC; Acuña, JM; and Sherman, SL (2001). FMR1 and the Fragile X Syndrome: Human Genome Epidemiology Review. Genetics in Medicine 3(5):359–371.

8 Bailey, DB, and Nelson, D (1995). The Nature and Consequences of Fragile X Syndrome. Mental Retardation and Developmental Disabilities Research Reviews 1:238–244.

9 Hageman RJ, Leavitt BR, Farzin F, Jacquemont CM, Greco JA, et al. Fragile-X-Associated Tremor/Ataxia Syndrome (FXTAS) in Females with the FMR1 Premutation. Am J Hum Genet 74:1051–1056.

10 Medline Plus. Medical Encyclopedia. Available at: (cited December 2003).

11 March of Dimes. Quick Reference and Fact Sheets. Available at: (cited December 2004).


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Last Reviewed: July 22, 2005