Short StatureNCT02311322
Genetic Causes of Growth Disorders
An observational study of Short Stature and Growth Disorder, run by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at 1 site in United States.
Trial summary
Background: Some growth disorders are caused by a change in genes. Genes are the instructions the body uses to function. Changes in genes often cause them not to work correctly. Researchers want to use a new technology called exome sequencing, to look at many genes at once. Read more about this study
- Who is it for?
- Any ageHealthy volunteers can take part
- Conditions the study is for
- Short Stature, Growth Disorder, Syndromic Growth Disorder
- How many people
- 334 participants
- Where
- 1 siteUnited States
- Study dates
- 2 Dec 2014to 14 Mar 2023
- 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 Any age
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Study population: subjects with growth disorders
Who may be able to join
- If a subject meets any one of these criteria, he/she will potentially be eligible to participate:
- Short stature (height less than - 2 SDS), either currently or previously - or
- Tall stature (height greater than + 2 SDS) or
- Bone age delay (greater than 3 years) or
- Bone age advancement (>1.5 years) or
- Predicted adult height < - 2SD
Show all 15Show fewer
- Predicted adult height - mid-parental height < -2SDS or > 2SDS
- Growth disorder that was treated promptly, thus maintaining the child s height within the normal range, e.g. a subject with congenital growth hormone deficiency or multiple pituitary hormone deficiency of unknown genetic etiology who received growth hormone treatment beginning in early life or
- Family member of subjects who meet any of the above criteria
- Subjects have a current height at a low normal percentile but has short adult height prediction based on bone age (> 5 inches shorter than mid-parent height)
- Any subject who has more than one of the above criteria and elevated DHEA-S concentration for age
- In addition, subjects are only eligible, if, the pedigree suggests a monogenic inheritance, and, in the judgement of the investigators, there is a reasonable likelihood of identifying a novel gene responsible for the condition.
- Investigators may recruit study subjects through The Genomic Ascertainment Cohort (TGAC) to identify specific subjects with sequence variants in genes of interest associated with growth disorders to investigate the phenotype spectrum, regardless of the above criteria.
- Investigators may recruit study additional subjects through the NIDDK repository to identify specific subjects with sequence variants in genes of interest associated with growth disorders to investigate the phenotype spectrum, regardless of the above criteria. Investigators may first identify subjects with height < 3rd% from these cohorts, request their DNA samples and sequence their DNA to identify a variant in a gene of interest.
- If subjects have abnormal bone age x-ray findings, investigators may use the findings as a maker for chondrodysplasia and study subjects with the findings. To recruit subjects, bone age x-rays obtained under teaching protocol (00-CH-0180 and 16-CH-0113) may be reviewed. If the subjects with abnormal findings are still followed by NIH, this study will be introduced to the patient and family. However, if subjects had been discharged from NIH care, they will not be re-contacted but their data may be still included in the prevalence of the abnormal finding. If collaborators wish to review their bone age x-rays obtained from their patients with short stature to identify the eligible subjects, they will obtain approval from their IRB. If some subjects are identified and the family agrees to participate, then collaborators refer them to our research team.
Who cannot join
- A non-genetic disorder or condition, either congenital or acquired, that explains the growth abnormality, for example, pituitary injury, chronic thyroiditis, whole body irradiation, or celiac disease.
- In the opinion of the investigators, there is an established diagnosis of a genetic disorder or condition that explains the growth abnormality and for which the molecular genetic etiology has already been identified, for example, SHOX deficiency, hypochondroplasia, or Noonan syndrome.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
Background:
- Some growth disorders are caused by a change in genes. Genes are the instructions the body uses to function. Changes in genes often cause them not to work correctly. Researchers want to use a new technology called exome sequencing, to look at many genes at once. This is done by looking at DNA from blood or saliva in a lab. This method may help find the cause of disorders that researchers haven t been able to find using past methods.
Read more
Objectives:
- To better understand genetic causes of growth disorders.
Eligibility:
- Children and adults with growth disorders and their family members.
Design:
- Participants will give a small sample of blood and/or saliva.
- Researchers will purify DNA from the sample. They will perform exome sequencing and other tests to look for changes in genes. Some participants may receive limited or no genetic tests. Researchers will let them know if exome sequencing is performed.
- Participants may have a medical history, physical exam, and lab tests. They may have x-rays or ultrasound tests to study the disorder in their family.
- Some participants may be recommended for a specific genetic test from a commercial lab. They may have to pay for that test.
- Participants will be told about test results that relate to the growth disorder. This may happen up to years after the testing. They may have to give another blood and/or saliva sample.
- Some participants may get results about other health conditions. This will only happen if the information would help the person or their family protect their health. They may have to give another blood and/or saliva sample.
Read the detailed description
Children often present to pediatricians and pediatric endocrinologists because of abnormal body growth, including both childhood growth failure and, less commonly, overgrowth. Sometimes the cause is evident, for example, growth hormone deficiency for growth failure and growth hormone excess for overgrowth. In other children, the etiology remains unknown despite extensive evaluation, resulting in the unhelpful diagnosis of severe idiopathic short stature or tall stature. These conditions are quite heterogeneous, including children with isolated growth disorders and others who also have other abnormalities such as developmental delay or a constellation of congenital anomalies (syndromic growth disorders). Some cases of severe growth disorders have a polygenic inheritance while others appear to be inherited as a monogenic trait - recessive, dominant or X-linked. Because of recent advances in DNA sequencing technology, it is now feasible to sequence the exome (portion of the genome that encodes gene exons) in families with monogenic disorders and thereby determine the underlying molecular etiology.
We therefore propose a study to identify novel genetic causes of idiopathic growth disorders using whole-exome sequencing. The primary goal of this study is to identify novel causes of childhood growth disorders in order to improve clinical diagnosis, to provide a more precise characterization of associated medical problems, prognosis, and response to treatment based on etiology, and to gain new insights into the regulation of human growth, which may eventually lead to new therapeutic approaches.
Subjects will include children and adults with a clearly recognizable phenotype that includes either short stature or tall stature and a pedigree that strongly suggests a monogenic inheritance. Both syndromic and non-syndromic growth disorders and both proportionate and disproportionate growth disorders will be included. Affected and unaffected family members (who have informative meiotic inheritance relationships to the proband or index case) will also be studied because of their importance for this genetic approach. The phenotype will be characterized by medical history, physical exam, body measurements, and laboratory evaluation. Blood and saliva samples will be collected for whole-exome sequencing and single nucleotide polymorphism (SNP) array analysis. Candidate sequence variants will typically be verified by Sanger sequencing.
- Keywords
- Growth Disorder, Growth, Exome Sequencing
- Medical subject headings
- Dwarfism, Growth Disorders
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 |
|---|---|---|
| Children with growth disorders | Children with growth disorders | |
| Family members of subjects with growth disorders | Family members of subjects with growth disorders |
What is being measured
The primary outcome is the main question the study is designed to answer.
SNP array and whole exome sequencing data
identification of the causal variant
Measured: 1-5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Dec 2014 (estimated)
- Study start2 Dec 2014
- Primary completion14 Mar 2023
- Study completion14 Mar 2023
Why it stopped: PI left NIH
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Short StatureStudies 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
- Cohort
- Time perspective
- Prospective
- Enrolment
- 334 participants (actual)
Sponsor and investigators
- Lead sponsor
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Sponsor type
- US National Institutes of Health
- Collaborators
- National Institutes of Health (NIH)
- Responsible party
- Sponsor
- Investigators
- Youn H Jee, M.D., Principal investigator, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02311322
- Sponsor's protocol ID
- 150022
- Other IDs
- 15-CH-0022
- Status last verified
- Mar 2023
- First submitted
- 5 Dec 2014
- Last updated
- 16 Mar 2023
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Jee YH, Gangat M, Yeliosof O, Temnycky AG, Vanapruks S, Whalen P, Gourgari E, Bleach C, Yu CH, Marshall I, Yanovski JA, Link K, Ten S, Baron J, Radovick S. Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic. Front Genet. 2021 Aug 11;12:697549. doi: 10.3389/fgene.2021.697549. eCollection 2021.
PubMed 34456972
Study at a glance
From the registry record, last updated by the sponsor on 16 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Genetic Causes of Growth Disorders
- ClinicalTrials.gov ID
- NCT02311322
- Acronym / sponsor ID
- 150022
- Keywords
- Growth Disorder, Growth, Exome Sequencing
- Study type
- Observational
- Recruitment status
- TerminatedReason stopped: PI left NIH
- Enrolment
- 334 participants (actual)
- Lead sponsor
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)US National Institutes of Health
- Collaborators
- National Institutes of Health (NIH)
- Study start
- 2 Dec 2014 (actual)
- Primary completion
- 14 Mar 2023 (actual)
- Study completion
- 14 Mar 2023 (actual)
- First posted
- 8 Dec 2014 (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.
Background:
- Some growth disorders are caused by a change in genes. Genes are the instructions the body uses to function. Changes in genes often cause them not to work correctly. Researchers want to use a new technology called exome sequencing, to look at many genes at once. This is done by looking at DNA from blood or saliva in a lab. This method may help find the cause of disorders that researchers haven t been able to find using past methods.
Objectives:
- To better understand genetic causes of growth disorders.
Eligibility:
- Children and adults with growth disorders and their family members.
Design:
- Participants will give a small sample of blood and/or saliva.
- Researchers will purify DNA from the sample. They will perform exome sequencing and other tests to look for changes in genes. Some participants may receive limited or no genetic tests. Researchers will let them know if exome sequencing is performed.
- Participants may have a medical history, physical exam, and lab tests. They may have x-rays or ultrasound tests to study the disorder in their family.
- Some participants may be recommended for a specific genetic test from a commercial lab. They may have to pay for that test.
- Participants will be told about test results that relate to the growth disorder. This may happen up to years after the testing. They may have to give another blood and/or saliva sample.
- Some participants may get results about other health conditions. This will only happen if the information would help the person or their family protect their health. They may have to give another blood and/or saliva sample.
Detailed description
Children often present to pediatricians and pediatric endocrinologists because of abnormal body growth, including both childhood growth failure and, less commonly, overgrowth. Sometimes the cause is evident, for example, growth hormone deficiency for growth failure and growth hormone excess for overgrowth. In other children, the etiology remains unknown despite extensive evaluation, resulting in the unhelpful diagnosis of severe idiopathic short stature or tall stature. These conditions are quite heterogeneous, including children with isolated growth disorders and others who also have other abnormalities such as developmental delay or a constellation of congenital anomalies (syndromic growth disorders). Some cases of severe growth disorders have a polygenic inheritance while others appear to be inherited as a monogenic trait - recessive, dominant or X-linked. Because of recent advances in DNA sequencing technology, it is now feasible to sequence the exome (portion of the genome that encodes gene exons) in families with monogenic disorders and thereby determine the underlying molecular etiology.
We therefore propose a study to identify novel genetic causes of idiopathic growth disorders using whole-exome sequencing. The primary goal of this study is to identify novel causes of childhood growth disorders in order to improve clinical diagnosis, to provide a more precise characterization of associated medical problems, prognosis, and response to treatment based on etiology, and to gain new insights into the regulation of human growth, which may eventually lead to new therapeutic approaches.
Subjects will include children and adults with a clearly recognizable phenotype that includes either short stature or tall stature and a pedigree that strongly suggests a monogenic inheritance. Both syndromic and non-syndromic growth disorders and both proportionate and disproportionate growth disorders will be included. Affected and unaffected family members (who have informative meiotic inheritance relationships to the proband or index case) will also be studied because of their importance for this genetic approach. The phenotype will be characterized by medical history, physical exam, body measurements, and laboratory evaluation. Blood and saliva samples will be collected for whole-exome sequencing and single nucleotide polymorphism (SNP) array analysis. Candidate sequence variants will typically be verified by Sanger sequencing.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Children with growth disorders | – | –Children with growth disorders |
| Family members of subjects with growth disorders | – | –Family members of subjects with growth disorders |
Who may qualify
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
- Study population
- subjects with growth disorders
Key inclusion criteria (15 listed)
- If a subject meets any one of these criteria, he/she will potentially be eligible to participate:
- Short stature (height less than - 2 SDS), either currently or previously - or
- Tall stature (height greater than + 2 SDS) or
- Bone age delay (greater than 3 years) or
- Bone age advancement (>1.5 years) or
Key exclusion criteria (2 listed)
- A non-genetic disorder or condition, either congenital or acquired, that explains the growth abnormality, for example, pituitary injury, chronic thyroiditis, whole body irradiation, or celiac disease.
- In the opinion of the investigators, there is an established diagnosis of a genetic disorder or condition that explains the growth abnormality and for which the molecular genetic etiology has already been identified, for example, SHOX deficiency, hypochondroplasia, or Noonan 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
SNP array and whole exome sequencing data
Time frame: 1-5 years
identification of the causal variant
Results and safety
The study was stopped early (reason given: PI left NIH). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Mar 2023.
- Background: PubMed 34456972Jee YH, Gangat M, Yeliosof O, Temnycky AG, Vanapruks S, Whalen P, Gourgari E, Bleach C, Yu CH, Marshall I, Yanovski JA, Link K, Ten S, Baron J, Radovick S. Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic. Front Genet. 2021 Aug 11;12:697549. doi: 10.3389/fgene.2021.697549. eCollection 2021.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: No
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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.
Youn H Jee, M.D. principal investigator
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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 Short Stature and Growth Disorder, run by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) 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 15 inclusion and 2 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: stopped early, as of the sponsor's last update on 16 Mar 2023. 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 was stopped early (reason given: PI left NIH). Results are not available in the source record.
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?
SNP array and whole exome sequencing data (time frame: 1-5 years). 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 NCT02311322, which also lists 1 linked publication.
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 16 Mar 2023.