HoloprosencephalyNCT00088426
Clinical and Genetic Studies on Holoprosencephaly
An observational study of Holoprosencephaly and HPE, run by National Human Genome Research Institute (NHGRI) at 1 site in United States.
Trial summary
This study will examine how holoprosencephaly (HPE) affects people, how they change over time, and what genes may be involved in the cause of the disorder. HPE is a defect of brain development in utero in which the forebrain fails to sufficiently divide into two hemispheres, resulting in a single-lobed brain and skull… Read more about this study
- Who is it for?
- Ages 1 month and older
- Conditions the study is for
- Holoprosencephaly, HPE, Developmental Delay Disorders
- How many people
- 256 participants
- Where
- 1 siteUnited States
- Study dates
- 23 Jan 2004to 16 Apr 2020
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 month and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: Patients with known or suspected holoprosencephaly (HPE). To conserve resources and meet study objectives, subjects with known mutations will be given priority in selection for extensive clinical studies. Direct blood relatives (typically parents, and occasionally siblings of affected individuals) of patients with HPE are also eligible to participate.@@@
Who may be able to join
- Depending on their willingness to participate, subjects may enroll in DNA laboratory-only (98-HG-0249), psychosocial-only, or clinical-only. However, to conserve resources and meet study objectives, subjects with known mutations will be given priority in selection for extensive clinical studies. All races and genders are known to be at risk for HPE, anywhere in the world. Nationality or place of origin is not specific barrier to participation.
- Direct blood relatives (typically parents, and occasionally siblings of affected individuals) of patients with HPE are also eligible to participate.
Who cannot join
- Anyone unwilling to provide informed consent (for themselves as adults, or on behalf of their children as minors) or assent.
- Medical condition(s) or mental retardation are not in themselves reason for exclusion if in the judgment of the referring physician this would involve no more than minimal risk. We anticipate that children with mental handicaps would be included in the research population. We will make every effort to explain the study for the purpose of assent in a manner that the family feels is both age and developmentally appropriate for that child.
- We generally review a brief clinical description from the referring physician about a potential research subject to determine that the subject is appropriate to enter into the study. We reserve the right to exclude cases that are clearly not HPE or related to our direct research interests (e.g. HPE cases that are syndromic like Smith Lemli Opitz syndrome, Trisomy 13, Trisomy 18, drug-related, or teratogen-related). This almost never happens, and we would attempt to make referrals to a more appropriate investigator.
- It is our intention to try to remove as many economic, cultural, geographic, racial, and gender barriers as we reasonably can to promote participation of HPE cases for research purposes.
- Description and justification of clinical inclusion/exclusion criteria for environmental study arm control group (individuals with Williams syndrome) :
- Participants must have a confirmed diagnosis of Williams syndrome caused by deletions in chromosome 7q11 involving the Williams-Beuren Syndrome Critical Region (WBSCR). Children should be less than 6 years of age to allow for improved maternal recall of prenatal
- environmental exposures. The Williams syndrome cohort (PI: Dr. Beth Kozel; National Heart Lung Blood Institute) was chosen to allow for inherent biases in mothers who have children with multiple anomaly syndromes.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
This study will examine how holoprosencephaly (HPE) affects people, how they change over time, and what genes may be involved in the cause of the disorder. HPE is a defect of brain development in utero in which the forebrain fails to sufficiently divide into two hemispheres, resulting in a single-lobed brain and skull and facial malformations. In most cases, the defects are so severe that babies die before birth. There are three classifications of HPE. In alobar HPE the brain does not divide at all; this form is usually associated with severe facial deformities. In semilobar HPE the hemispheres divide somewhat, causing an intermediate form of the disorder. In lobar HPE, the mildest form, separation of hemispheres is nearly normal.
Patients with HPE and their direct blood relatives may participate in this study. Patients are seen by a team of medical specialists at the NIH Clinical Center for the following procedures:
Read more
- Physical and neurological examination
- Eye examination
- Imaging studies, such as echocardiogram, abdominal ultrasound, brain MRI
- Electroencephalogram (EEG)
- Hearing evaluation
- Blood and urine samples for genetic and endocrine studies, routine blood chemistries, urinalysis, and urine electrolytes
- Other consultations as needed
- Possibly photographs, including front and side views of the face and other body parts that may be involved in HPE, such as the eyes, teeth, hands, and feet
Parents will be asked questions about the child's prenatal, birth, newborn, and past medical history, growth, behavior and development, and therapy and medication.
Because HPE is a genetic disorder and gene changes can be passed on in a family, parents will also be asked to undergo the following procedures:
- Completion of a medical and family history form
- Physical and neurological examination
- Blood and urine samples (for mothers only)
- Specialty consultations as indicated
- Possibly photographs, including front and side views of the face and other body parts that may be involved in HPE, such as the eyes, teeth, hands, and feet
- Psychosocial study. Some parents will be asked to participate in a telephone interview or complete a questionnaire, or both, about their attitudes, beliefs, and concerns about how they and their family cope with their child's condition. Some questionnaires may include questions about aspects of their marriage and personal feelings and experiences.
Parents will meet with a doctor and a genetics nurse to discuss the results of the tests and answer questions. Parents may be asked to bring their child back to the NIH after 2 years for follow-up examination and possible additional or repeat testing.
...
Read the detailed description
Holoprosencephaly (HPE) is a defect of midline forebrain development that occurs soon after conception. It has a prevalence of 1 in 250 during early embryonic development, and 1 in 10,000 to 1 in 20,000 at term. In live born infants, the abnormalities associated with HPE are divided into three main categories: alobar, semilobar, and lobar HPE. A fourth variant, middle interhemispheric variant, has also been recognized. The purpose of this study is to increase our understanding of the genetic and clinical manifestations of HPE through detailed physical, psychological, developmental, neurologic, endocrinologic, and radiologic studies. We will examine the spectrum of clinical characteristics of HPE to facilitate early diagnosis and clinical management, including genetic counseling. Finally, we plan to assess the psychosocial impact of HPE on the family as a unit. Most patients and their families will be seen at the NIH Clinical Center. A subset may be examined outside the NIH, and a further subset, for the psychosocial studies, may be interviewed by phone.
- Conditions
- Holoprosencephaly, HPE, Developmental Delay Disorders, Brain Disorders
- Keywords
- GENETIC DISEASE, Multiple Abnormalies, Birth Defects, Holoprosencephaly, HPE
- Medical subject headings
- Holoprosencephaly, Developmental Disabilities, Brain Diseases, Genetic Diseases, Inborn, Congenital Abnormalities
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Control | Control group of Williams-Beuren (also known as Williams) syndrome | |
| Family | Direct blood relatives (typically parents, and occasionally siblings of affected individuals) ofpatients with HPE are also eligible to participate. | |
| HPE | Patients with HPE |
What is being measured
The primary outcome is the main question the study is designed to answer.
To characterize the physical, developmental, neurologic, endocrinologic and radiologic phenotype of HPE through this comprehensive natural history study.
To characterize the physical, developmental, neurologic, endocrinologic and radiologic phenotype of HPE through this comprehensive natural history study.
Measured: Once with possible followup at Year 2
To examine the spectrum of clinical characteristics of HPE and facilitate early clinical recognition, diagnostic confirmation, anticipatory management, prognostication, and proper genetic counseling.
(a) To compare gene mutations (with known or suspected abnormal functional effects) with the phenotypes observed in patients (i.e genotype-phenotype correlations) as documented in the study. (b) To determine the spectrum of brain malformations caused by genetic changes in HPE candidate genes that are known or suspected to cause human disease. (c) To correlate neurodevelopmental status/clinical outcome with neuroradiologic findings and genetic changes in HPE candidate genes. (d) To verify recurrence risks /inheritance patterns of HPE for each of the HPE candidate genes.
Measured: Once with possible followup at Year 2
To determine the spectrum of non-neurologic anomalies resulting from mutations in HPE-associated genes /pathways both in individuals with HPE and individuals without HPE.
(a) To determine the association between mutations in HPE-associated genes/pathways and the non- neurologic finding of fatty liver in individuals with HPE. (b) To determine the presence of other, previously unknown clinical manifestations in individuals with HPE.
Measured: Once with possible followup at Year 2
To assess the psychosocial impact of HPE on the family system.
(a) To describe characteristics of stress and coping in families of children affected by HPE. (b) To examine the relationships between specific child characteristics (e.g., chronological age, severity of disorder), family coping styles and family variables (e.g., stress, coping, marital satisfaction, parental anxiety and depression).(c) To examine the similarities and/or differences between mothers and fathers experiences of stress and coping in families of children with HPE. (d) To generate data for the development of a new instrument to quantify stress, coping and resilience in HPE families.
Measured: Once with possible followup at Year 2
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Jul 2004 (estimated)
- Study start23 Jan 2004
- Primary completion16 Mar 2020
- Study completion16 Apr 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for HoloprosencephalyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 256 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Human Genome Research Institute (NHGRI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Paul S Kruszka, M.D., Principal investigator, National Human Genome Research Institute (NHGRI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00088426
- Sponsor's protocol ID
- 040093
- Other IDs
- 04-HG-0093
- Status last verified
- Apr 2020
- First submitted
- 23 Jul 2004
- Last updated
- 20 Apr 2020
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Golden JA. Holoprosencephaly: a defect in brain patterning. J Neuropathol Exp Neurol. 1998 Nov;57(11):991-9. doi: 10.1097/00005072-199811000-00001. No abstract available.
PubMed 9825935Matsunaga E, Shiota K. Holoprosencephaly in human embryos: epidemiologic studies of 150 cases. Teratology. 1977 Dec;16(3):261-72. doi: 10.1002/tera.1420160304.
PubMed 594909Roach E, Demyer W, Conneally PM, Palmer C, Merritt AD. Holoprosencephaly: birth data, benetic and demographic analyses of 30 families. Birth Defects Orig Artic Ser. 1975;11(2):294-313.
PubMed 1227533
Study at a glance
From the registry record, last updated by the sponsor on 20 Apr 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Clinical and Genetic Studies on Holoprosencephaly
- ClinicalTrials.gov ID
- NCT00088426
- Acronym / sponsor ID
- 040093
- Conditions
- Holoprosencephaly, HPE, Developmental Delay Disorders, Brain Disorders
- Keywords
- GENETIC DISEASE, Multiple Abnormalies, Birth Defects, Holoprosencephaly, HPE
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 256 participants (actual)
- Lead sponsor
- National Human Genome Research Institute (NHGRI)US National Institutes of Health
- Study start
- 23 Jan 2004 (actual)
- Primary completion
- 16 Mar 2020 (actual)
- Study completion
- 16 Apr 2020 (actual)
- First posted
- 26 Jul 2004 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will examine how holoprosencephaly (HPE) affects people, how they change over time, and what genes may be involved in the cause of the disorder. HPE is a defect of brain development in utero in which the forebrain fails to sufficiently divide into two hemispheres, resulting in a single-lobed brain and skull and facial malformations. In most cases, the defects are so severe that babies die before birth. There are three classifications of HPE. In alobar HPE the brain does not divide at all; this form is usually associated with severe facial deformities. In semilobar HPE the hemispheres divide somewhat, causing an intermediate form of the disorder. In lobar HPE, the mildest form, separation of hemispheres is nearly normal.
Patients with HPE and their direct blood relatives may participate in this study. Patients are seen by a team of medical specialists at the NIH Clinical Center for the following procedures:
- Physical and neurological examination
- Eye examination
- Imaging studies, such as echocardiogram, abdominal ultrasound, brain MRI
- Electroencephalogram (EEG)
- Hearing evaluation
- Blood and urine samples for genetic and endocrine studies, routine blood chemistries, urinalysis, and urine electrolytes
- Other consultations as needed
- Possibly photographs, including front and side views of the face and other body parts that may be involved in HPE, such as the eyes, teeth, hands, and feet
Parents will be asked questions about the child's prenatal, birth, newborn, and past medical history, growth, behavior and development, and therapy and medication.
Because HPE is a genetic disorder and gene changes can be passed on in a family, parents will also be asked to undergo the following procedures:
- Completion of a medical and family history form
- Physical and neurological examination
- Blood and urine samples (for mothers only)
- Specialty consultations as indicated
- Possibly photographs, including front and side views of the face and other body parts that may be involved in HPE, such as the eyes, teeth, hands, and feet
- Psychosocial study. Some parents will be asked to participate in a telephone interview or complete a questionnaire, or both, about their attitudes, beliefs, and concerns about how they and their family cope with their child's condition. Some questionnaires may include questions about aspects of their marriage and personal feelings and experiences.
Parents will meet with a doctor and a genetics nurse to discuss the results of the tests and answer questions. Parents may be asked to bring their child back to the NIH after 2 years for follow-up examination and possible additional or repeat testing.
...
Detailed description
Holoprosencephaly (HPE) is a defect of midline forebrain development that occurs soon after conception. It has a prevalence of 1 in 250 during early embryonic development, and 1 in 10,000 to 1 in 20,000 at term. In live born infants, the abnormalities associated with HPE are divided into three main categories: alobar, semilobar, and lobar HPE. A fourth variant, middle interhemispheric variant, has also been recognized. The purpose of this study is to increase our understanding of the genetic and clinical manifestations of HPE through detailed physical, psychological, developmental, neurologic, endocrinologic, and radiologic studies. We will examine the spectrum of clinical characteristics of HPE to facilitate early diagnosis and clinical management, including genetic counseling. Finally, we plan to assess the psychosocial impact of HPE on the family as a unit. Most patients and their families will be seen at the NIH Clinical Center. A subset may be examined outside the NIH, and a further subset, for the psychosocial studies, may be interviewed by phone.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Control | – | –Control group of Williams-Beuren (also known as Williams) syndrome |
| Family | – | –Direct blood relatives (typically parents, and occasionally siblings of affected individuals) ofpatients with HPE are also eligible to participate. |
| HPE | – | –Patients with HPE |
Who may qualify
- Ages
- 1 month and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Patients with known or suspected holoprosencephaly (HPE). To conserve resources and meet study objectives, subjects with known mutations will be given priority in selection for extensive clinical studies. Direct blood relatives (typically parents, and occasionally siblings of affected individuals) of patients with HPE are also eligible to participate.@@@
Key inclusion criteria (2 listed)
Key exclusion criteria (7 listed)
- Anyone unwilling to provide informed consent (for themselves as adults, or on behalf of their children as minors) or assent.
- Medical condition(s) or mental retardation are not in themselves reason for exclusion if in the judgment of the referring physician this would involve no more than minimal risk. We anticipate that children with mental handicaps would be included in the research population. We will make every effort to explain the study for the purpose of assent in a manner that the family feels is both age and developmentally appropriate for that child.
- We generally review a brief clinical description from the referring physician about a potential research subject to determine that the subject is appropriate to enter into the study. We reserve the right to exclude cases that are clearly not HPE or related to our direct research interests (e.g. HPE cases that are syndromic like Smith Lemli Opitz syndrome, Trisomy 13, Trisomy 18, drug-related, or teratogen-related). This almost never happens, and we would attempt to make referrals to a more appropriate investigator.
- It is our intention to try to remove as many economic, cultural, geographic, racial, and gender barriers as we reasonably can to promote participation of HPE cases for research purposes.
- Description and justification of clinical inclusion/exclusion criteria for environmental study arm control group (individuals with Williams syndrome) :
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
To characterize the physical, developmental, neurologic, endocrinologic and radiologic phenotype of HPE through this comprehensive natural history study.
Time frame: Once with possible followup at Year 2
To characterize the physical, developmental, neurologic, endocrinologic and radiologic phenotype of HPE through this comprehensive natural history study.
To examine the spectrum of clinical characteristics of HPE and facilitate early clinical recognition, diagnostic confirmation, anticipatory management, prognostication, and proper genetic counseling.
Time frame: Once with possible followup at Year 2
(a) To compare gene mutations (with known or suspected abnormal functional effects) with the phenotypes observed in patients (i.e genotype-phenotype correlations) as documented in the study. (b) To determine the spectrum of brain malformations caused by genetic changes in HPE candidate genes that are known or suspected to cause human disease. (c) To correlate neurodevelopmental status/clinical outcome with neuroradiologic findings and genetic changes in HPE candidate genes. (d) To verify recurrence risks /inheritance patterns of HPE for each of the HPE candidate genes.
To determine the spectrum of non-neurologic anomalies resulting from mutations in HPE-associated genes /pathways both in individuals with HPE and individuals without HPE.
Time frame: Once with possible followup at Year 2
(a) To determine the association between mutations in HPE-associated genes/pathways and the non- neurologic finding of fatty liver in individuals with HPE. (b) To determine the presence of other, previously unknown clinical manifestations in individuals with HPE.
To assess the psychosocial impact of HPE on the family system.
Time frame: Once with possible followup at Year 2
(a) To describe characteristics of stress and coping in families of children affected by HPE. (b) To examine the relationships between specific child characteristics (e.g., chronological age, severity of disorder), family coping styles and family variables (e.g., stress, coping, marital satisfaction, parental anxiety and depression).(c) To examine the similarities and/or differences between mothers and fathers experiences of stress and coping in families of children with HPE. (d) To generate data for the development of a new instrument to quantify stress, coping and resilience in HPE families.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Apr 2020.
- Background: PubMed 9825935Golden JA. Holoprosencephaly: a defect in brain patterning. J Neuropathol Exp Neurol. 1998 Nov;57(11):991-9. doi: 10.1097/00005072-199811000-00001. No abstract available.
- Background: PubMed 594909Matsunaga E, Shiota K. Holoprosencephaly in human embryos: epidemiologic studies of 150 cases. Teratology. 1977 Dec;16(3):261-72. doi: 10.1002/tera.1420160304.
- Background: PubMed 1227533Roach E, Demyer W, Conneally PM, Palmer C, Merritt AD. Holoprosencephaly: birth data, benetic and demographic analyses of 30 families. Birth Defects Orig Artic Ser. 1975;11(2):294-313.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Paul S Kruszka, M.D. principal investigator
National Human Genome Research Institute (NHGRI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Holoprosencephaly and HPE, run by National Human Genome Research Institute (NHGRI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Apr 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
To characterize the physical, developmental, neurologic, endocrinologic and radiologic phenotype of HPE through this comprehensive natural history study. (time frame: Once with possible followup at Year 2). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00088426, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Apr 2020.