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

National Institute on Deafness and Other Communication Disorders (NIDCD)

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

NIDCD conducts and supports research and research training on normal mechanisms as well as on diseases and disorders of hearing, balance, smell, taste, voice, speech, and language. Many of these disorders occur in children. NIDCD achieves its mission through a wide range of research performed in its own laboratories, a program of research grants, individual and institutional research training awards, career development awards, center grants, cooperative clinical trials, and contracts to public and private research institutions and organizations. NIDCD also conducts and supports research and research training that is related to disease prevention and health promotion. NIDCD addresses special biomedical and behavioral problems associated with communication impairments or disorders and supports efforts to create devices that substitute for lost and impaired sensory and communication functions.

Recent Scientific Advances in Rare Diseases in Children Research

Mitochondrial Genes and Deafness

Mitochondria are specialized structures within cells that play a crucial role in metabolism and energy production. Mitochondria contain their own genes, which act to replicate the mitochondria during cell division. All of the mitochondria present in individuals are derived from the mother's egg. Therefore, diseases that appear to be passed exclusively through the maternal lineage are often linked to defective mitochondrial genes.

NIDCD-supported investigators have identified several specific mitochondrial mutations that predispose an individual to hearing damage from aminoglycoside ototoxicity. Most recently, these investigators have identified a genetic locus, in the nucleus of the cell, which acts to modify the effects of the mitochondrial mutations. These findings could be used to develop genetic tests to determine whether an individual has an increased risk for minoglycoside-induced hearing damage. (FY 2000 through FY 2002)

Usher's Syndrome

Usher's syndrome is characterized by hearing loss, retinitis pigmentosa, and/or vestibular areflexia. The frequency of this syndrome has been estimated at 5% of the deaf population, with more than half of the deaf and blind individuals (>10,000) in the United States afflicted with this disease. The severity of the hearing loss and the presence of vestibular dysfunction distinguishes two clinical subtypes of Usher's syndrome, types I and II. A third form of Usher's syndrome (type III), which has a late onset, has recently been described. These three phenotypes are genetically distinct. The NIDCD Intramural Research Program is continuing to support the Hereditary Hearing Impairment Consortium, the members of which are working to identify and characterize all the genes responsible for Usher's syndrome. A major advance in this area of research was the finding that the gene for Usher's type Ib codes for an unconventional myosin protein, information that led to the realization that a known animal model of deafness was a homolog for this type of Usher's syndrome.

Recently, several NIDCD-supported scientists reported the cloning of the gene for Usher's syndrome type IIa. The USH2A gene encodes a protein ("Usherin") that has structures similar to other proteins involved in assembling cells and tissues into functional organs. In addition, within the last six months NIDCD-supported scientists have identified the genes responsible for Usher type Ic and Usher type Id. The cloning of these genes and analysis of the proteins they produce are critical steps towards developing strategies to treat this devastating disease. (FY 2000 through FY 2005)

Waardenburg's Syndrome (WS)

WS is an autosomal dominant disorder characterized by pigmentary disturbances and cochlear deafness in some individuals. There are at least three distinct forms of this syndrome (types I, II, and III). A transcription factor gene, microphthalmia-associated transcription factor (MITF), was cloned by NIDCD intramural scientists and was assigned to chromosome 3p14.1-p12.3. This gene is a human homolog of the mouse mi gene. Phenotypes of mice with mutations at mi alleles are closely related to those of WS type II (WS2), and mutations of MITF have been found in some WS type II families. Mutation of a second gene, PAX3, also encoding a transcription factor, causes WS type I as well as WS type III. Current evidence suggests that variable disease expression depends on the genetic background provided by both parents. Importantly, recent characterization of the PAX3 regulation by NIDCD intramural scientists will enable a comprehensive mutation screen for individuals with WS. (FY 2000 through FY 2002)

Stickler's Syndrome

Stickler's syndrome is a rare autosomal dominant disorder causing progressive sensorineural hearing loss, myopia, retinal detachments, arthropathy, and craniofacial abnormalities in affected individuals. It may be caused by mutations in any of the genes encoding the three polypeptide subunits of type XI collagen: COL2A1, COL11A1, and COL11A2. In conjunction with scientists from NHGRI, NIDCD intramural scientists are characterizing the otolaryngologic and auditory phenotypes of individuals affected by Stickler's syndrome. (FY 2000 through FY 2001)

Auditory Neuropathy

A small but substantial number of patients with bilateral hearing loss that was assumed to be sensory in etiology, have, in fact, normal cochlear function. These patients have severely abnormal neural function as evidenced by poor or absent auditory brainstem responses. Standard remediation strategies for bilateral hearing loss, such as hearing aids, are of little use to these patients. When this disorder strikes young children or infants, it can cause severe disruption of normal language and speech development. The most likely etiology is a neuropathy of the auditory nerve, hence the term "auditory neuropathy." This disorder is rare but more common than previously expected. Investigation of the physiologic mechanisms, the genetic basis, and possible treatments for this disorder is ongoing. (FY 2000 through FY 2001)

Endolymphatic Sac Tumors in von Hippel-Lindau (VHL) Disease

Studies are being conducted in the intramural division of NIDCD on a group of individuals affected by VHL disease and tumors of the inner ear. These endolymphatic sac tumors (ELST) have been found to develop in approximately 10% of individuals carrying mutations of the VHL gene. Symptoms of hearing loss, balance disturbances, and tinnitus represent the primary clinical manifestations. Recent molecular genetic studies have confirmed the phenotypic association of ELST with VHL disease by demonstrating loss of heterozygosity at the VHL locus in tumor cells obtained from surgical specimens. Preliminary results from a clinical trial of hearing preservation surgery in individuals with early-stage ELST suggest that these tumors can be safely resected while preserving hearing at preoperative levels and maintaining or improving vestibular function.

Prospective studies of this population of individuals should provide insight into the natural history of hearing and balance disturbances associated with ELST while basic investigations will focus on the mechanisms by which ELSTs cause auditory and vestibular dysfunction. (FY 2000 through FY 2002)

Large Vestibular Aqueduct Syndrome (LVAS)

LVAS is characterized by progressive childhood sensorineural hearing loss in association with enlarged vestibular aqueducts. Recent data indicate that at least some cases are associated with mutations in the Pendred syndrome gene (PDS). NIDCD intramural scientists are working to identify the genetic basis of LVAS, including several cases where it is clearly not caused by mutations in PDS. Whether congenital cytomegalovirus infection is involved in this form of hearing loss is currently being investigated. (FY 2000 through FY 2005)

Hereditary Cerebellar Ataxia Syndrome of Early Onset

Several abnormal genes that are associated with inherited cerebellar syndromes of imbalance and incoordination have been identified. Relatively little is known about how different mutations lead to specific phenotypes, however. There is typically great heterogeneity in the clinical signs and symptoms within families with the same mutation and across families with mutations in the same gene. An NIDCD-funded group of investigators at the University of California, Los Angeles, has demonstrated linkage to chromosome 19p in four families with episodic vertigo and ataxia. This research group has identified a missense mutation in the calcium channel gene on chromosome 19p in a family with severe progressive cerebellar ataxia of early onset involving the trunk, the extremities, and speech.

More recent work has identified a number of related ataxias associated with different mutations in the same calcium channel gene. In addition, mutations in other calcium channel genes have been found to be associated with inherited ataxias. Thus, calcium channelopathies have emerged as important model systems to study the role of calcium channels in neuronal function. (FY 2000 through FY 2003)

Kallmann's Syndrome

Kallmann's syndrome is a rare genetic disorder with an absence of the sense of smell and a failure of the gonads to mature as primary symptoms. There is a 5- to 7-fold preponderance of affected males compared to females, suggesting that the X-linked form of the disease is the most frequent. NIDCD-supported research has led to the identification of a common developmental defect in neuronal migration, which links the two major disease symptoms. A unique family of proteins and their receptors that regulate neuronal migration and direction during development are under investigation by NIDCD-funded scientists. Additional research is focused on the isolation and cloning of an X-linked gene responsible for Kallmann's syndrome. (FY 2000 through FY 2003)

Papilloma and Carcinoma of the Vocal Tract

Papillomas and carcinomas are the most important neoplasms affecting the human vocal and speech tract. Carcinomas of the upper airway and vocal tract have affected the lives of more than 320,000 Americans and lead to more than 12,000 deaths annually in the United States. A major cause of these recurrent tumors is human papillomaviruses that infect the whole airway in these patients. NIDCD intramural scientists and an extramural team of molecular biologists/virologists and clinicians funded by NIDCD are addressing the molecular basis for the disease and possible new treatments. A recent finding is that these tumors show an accentuated response to growth factors when compared to other cells. The specific intracellular signaling molecules that mediate this effect have been identified. It has also been shown that these tumors produce factors that stimulate the blood supply and immune cells in ways that help promote tumor growth and spread. Drugs that block the effects of these factors may provide a new approach for prevention and therapy of these cancers.

The multiple recurrences of these respiratory papillomas and the importance of immune function in controlling viral infection has led to studies demonstrating that patients have a normal immune response to most infections but a suppressed immune response to papillomaviruses. NIDCD-supported investigators recently identified the mechanism by which papillomaviruses evade the immune system and subsequently developed a strategy to block this immune evasion. In parallel preclinical studies, NIDCD intramural scientists are testing the possibility of interleukin therapy to enhance the cytotoxic T cell response to these papillomas. Additional approaches being tested include photodynamic therapy with Foscan as an adjunct to surgery. These exciting findings, which have stimulated multiple new therapeutic approaches, could ultimately result in nonsurgical treatment of laryngeal papillomas. (FY 2000 through FY 2004)

Velocardiofacial Syndrome (VCFS)

VCFS is a disorder that has been associated with more than 30 different features, the most common being cleft palate, heart defects, characteristic facial features, minor learning problems, and speech and feeding problems. VCFS is also known as Shprintzen, DiGeorge, cardiofacial, or conotruncal anomaly unusual face syndrome. These syndromes have a missing chromosomal segment at 22q11. VCFS is inherited in only about 10% to 15% of cases. In most instances, neither parent has the syndrome nor carries the defective gene, and the cause of the deletion in the affected child is unknown. A team of NIDCD-supported researchers has completed a detailed sequence analysis of the DiGeorge chromosomal region (DGCR) of chromosome 22q11. The 22q11.2 deletion occurs more frequently than originally anticipated, and the endpoints of the deletions occur in clusters. There is considerable variability in the abnormalities associated with deletions of similar size. The presence of a deletion is not always sufficient to cause a palatal defect, strongly suggesting that modifier genes may interact with the genes of the deletion region. Due to the heterogeneity of chromosomal deletions it has been difficult to identify a single gene responsible for any of the observed phenotypes; however, recent work now suggests that the Clathrin heavy chain-like gene is a strong candidate gene for VCFS. (FY 2000 through FY 2004)

Williams Syndrome (WMS)

WMS is a rare (estimated incidence: 1 in 25,000 live births) genetic disorder in children, characterized by a constellation of distinctive facial features, cardiac and dental anomalies, hypercalcemia, mental retardation, and a unique behavioral profile (linguistic abilities selectively preserved in the face of severe general cognitive deficits). NIDCD-supported studies of young children with WMS have documented extreme retardation early on in all developmental milestones, including language. Results suggest that different cognitive domains in WMS (language, spatial cognition, affect) have different starting points and different trajectories, unlike patterns discerned in normal controls, and that some aspects of brain organization (e.g., cerebellar abnormalities) are present from a very early age. (FY 2000 through FY 2001)


NIDCD-supported researchers are investigating the communication difficulties/differences of children with autism. Research is being conducted to assess brain imaging as a means to study the neurodevelopmental origins and functional brain abnormalities thought to underlie autism in children. Progress is also being made in the development of effective language intervention techniques and the characterization of early communication behaviors in this population. (FY 2000 through FY 2005)

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

Rare Diseases Research Initiatives and Program Activities in FY 2000

On September 12, 2000, NICHD and ORD supported an NIH Workshop entitled, "The Olfactory Model System and Rett and Kallmann Syndromes: Sniffing Out Insights into Brain Development." Several of the less common neurologic developmental disorders, such as Rett's and Kallmann's syndromes, are associated with severe anomalies of the olfactory sensory system. There has been recent progress in characterizing the impact of these developmental disorders on the olfactory system and in characterizing molecular and genetic defects associated with these syndromes. The workshop focused on recent findings in these syndromes and explored the feasibility of using the olfactory system as an accessible sensorineural model for exploring primary molecular genetic defects at the level of the developing central nervous system.

Ongoing and Planned Rare Diseases Research Initiatives and Program Activities

NIDCD is participating with other members of the NIH Autism Coordinating Committee in the following initiatives:

  • A PA on autism and autism spectrum disorders has just been released and will be active from FY 2001 through FY 2004.

  • An RFA on innovative treatments for autism was published in FY 2001. Research awarded through this RFA will be active from FY 2001 through FY 2004.

  • An RFA for planning activities for autism centers will soon be released. Awards are planned to start in FY 2002.

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Last Reviewed: February 1, 2005
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