Generalized Arterial Calcification of InfancyNCT03478839
Study of People With Generalized Arterial Calcification of Infancy (GACI) or Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2)
An observational study of Generalized Arterial Calcification of Infancy and Autosomal Recessive Hypophosphatemic Rickets Type2, run by National Human Genome Research Institute (NHGRI) at 1 site in United States.
Trial summary
Background: Generalized Arterial Calcification of Infancy (GACI) is a very rare disorder. It can be fatal before birth or by age 6 months. Anumber of people with GACI survive into adulthood. Those adults suffer from side effects of the disease, including rickets. Read more about this study
- Who is it for?
- Ages 1 year to 110 years
- Conditions the study is for
- Generalized Arterial Calcification of Infancy, Autosomal Recessive Hypophosphatemic Rickets Type2
- How many people
- 48 participants
- Where
- 1 siteUnited States
- Study dates
- 17 Apr 2018to 31 Dec 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 year to 110 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: Individuals with a diagnosis of GACI or ARHR2 who are males or females with sufficient chart data to be included in the study will be eligible for enrollment, as well as all their male and female siblings and both parents.@@@
Who may be able to join
- Based upon study purpose, participants enrolled in this protocol must:
- Have genetic confirmation of one of the following:
- GACI due to ENPP1 or ABCC6 mutations
- ARHR2 due to ENPP1 mutations
- PXE due to ABCC6 or ENPP1 mutations
- AND/OR
Show all 9Show fewer
- Carry the clinical diagnosis of GACI, ARHR2 or PXE
- Consent or, if applicable, assent to participate in the study
- Have sufficient chart information to allow for the completion of at least one of the protocol s objectives.
Who cannot join
None listed.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
Official title: A Natural History Study of Patients With Generalized Arterial Calcification of Infancy (GACI) or Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2)
Background:
Generalized Arterial Calcification of Infancy (GACI) is a very rare disorder. It can be fatal before birth or by age 6 months. Anumber of people with GACI survive into adulthood. Those adults suffer from side effects of the disease, including rickets. It is unknown how common the disease Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2) is. It also has side effects. GACI and ARHR2 are usually caused by the mutations in the same gene. There are no approved treatments for the two diseases. Researchers want to study people with these diseases and their family members. This may help understand these rare and unique diseases better. The data could lead to new treatments for GACI and ARHR2.
Read more
Objectives:
To better understand the progression of GACI and ARHR2 and how genes might play a role in them.
Eligibility:
People with GACI or ARHR2, both living and deceased, and their parents and siblings.
Design:
Participants will allow researchers to access their medical records. They will give this consent by mail, email, or fax.
Data will be taken from the records. Participants names will not be used. Instead, they will be identified by a code.
Participants may give a blood sample.
If a participant withdraws from the study, their data and samples will be destroyed. However, the coded clinical data in the official medical record and data in databases will NOT be destroyed.
Read the detailed description
This is a natural history study of patients with Generalized Arterial Calcification of Infancy (GACI) or Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2).
GACI is an ultra-rare disorder with an estimated birth prevalence of around 1 in 200,000. GACI is characterized by extensive arterial calcifications, arterial stenosis, myointimal proliferation and periarticular calcifications. Individuals with GACI also experience calcification in other body areas, such as joints and parenchymal organs.
GACI is generally fatal before birth or within the first six months after birth. The cause of death is frequently myocardial infarction or stroke, and hypertension and congestive heart failure are common in fetuses and infants with GACI. The first six months of life are considered a critical period for GACI patients, and approximately 85% of infants with GACI do not survive beyond this period (Moran 1975). However, the mortality rate decreases substantially among patients who do survive beyond the critical period. Reports exist of patients with GACI who survived into adulthood, but the frequency of this occurrence is unknown, and adult patients suffer from a number of sequelae such as cognitive impairment related to stroke. ARHR2 is characterized by short stature, dental caries, and bone deformities, and biochemically by hypophosphatemia, hyperphosphaturia and elevated plasma alkaline phosphatase. The disease frequency is unknown.
GACI and ARHR2 are most commonly due to mutations of ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1), or less often from mutations in ABCC6 (adenosine triphosphate binding cassette transporter protein subfamily C member 6). No founder mutations are known, and thus no ethnic predilection is known. Both the GACI and ARHR2 phenotypes are potentially fatal or associated with severe morbidity, with no FDA-approved drugs or proven treatments. Animal data suggest that enzyme replacement therapy with ENPP1-Fc may be effective in preventing morbidity or mortality of GACI and ARHR2.
PXE (pseudoxanthoma elasticum) is an autosomal recessive disorder due to mutations in ABCC6 or, less often, ENPP1. PXE is characterized by ectopic calcification of the skin, eyes, cardiovascular system and gastrointestinal system. This study will not focus on PXE but will collect data on PXE patients, particularly when their presentation suggests elements of the GACI or ARHR2 phenotypes.
The main objective of this study is to collect historical control data for future comparison to data from patients treated with ENPP1-Fc so we can develop ENPP1-Fc as a treatment for GACI or ARHR2. In addition, this study will allow for a better understanding of the disease course to design future treatment trials. The study will utilize data obtained predominantly from chart review. The goal is to enroll 100 participants, which include both living and deceased individuals with GACI or ARHR2, and/or their parents and siblings. Our study will be jointly and collaboratively conducted by the NIH and Inozyme.
- Conditions
- Generalized Arterial Calcification of Infancy, Autosomal Recessive Hypophosphatemic Rickets Type2
- Keywords
- Generalized Arterial Calcification of Infancy, Autosomal Recessive Hypophosphatemic Rickets, Pseudoxanthoma Elasticum, Idiopathic Infantile Arterial Calcification, Natural History
- Medical subject headings
- Arterial calcification of infancy, Hypophosphatemic Rickets, Autosomal Recessive, 1, Pseudoxanthoma Elasticum
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 |
|---|---|---|
| CRF completion | Individuals with a diagnosis of GACI or ARHR2 with sufficient chart data to be included in the study will be eligible for enrollment, as well as all their siblings and parents. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Natural History
The main objective of this study is to determine the natural history of patients with GACI or ARHR2.
Measured: ongoing
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Mar 2018
- Study start17 Apr 2018
- Primary completion31 Dec 2020
- Study completion31 Dec 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 Generalized Arterial Calcification of InfancyStudies 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
- 48 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Human Genome Research Institute (NHGRI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Carlos R Ferreira Lopez, M.D., Principal investigator, National Human Genome Research Institute (NHGRI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03478839
- Sponsor's protocol ID
- 180064
- Other IDs
- 18-HG-0064
- Status last verified
- Jul 2026
- First submitted
- 14 Mar 2018
- Last updated
- 16 Jul 2026
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Albright RA, Stabach P, Cao W, Kavanagh D, Mullen I, Braddock AA, Covo MS, Tehan M, Yang G, Cheng Z, Bouchard K, Yu ZX, Thorn S, Wang X, Folta-Stogniew EJ, Negrete A, Sinusas AJ, Shiloach J, Zubal G, Madri JA, De La Cruz EM, Braddock DT. ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy. Nat Commun. 2015 Dec 1;6:10006. doi: 10.1038/ncomms10006.
PubMed 26624227Ziegler SG, Ferreira CR. Generalized Arterial Calcification of Infancy. 2014 Nov 13 [updated 2026 May 19]. In: Adam MP, Bick S, Mirzaa GM, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK253403/
PubMed 25392903Rutsch F, Boyer P, Nitschke Y, Ruf N, Lorenz-Depierieux B, Wittkampf T, Weissen-Plenz G, Fischer RJ, Mughal Z, Gregory JW, Davies JH, Loirat C, Strom TM, Schnabel D, Nurnberg P, Terkeltaub R; GACI Study Group. Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy. Circ Cardiovasc Genet. 2008 Dec;1(2):133-40. doi: 10.1161/CIRCGENETICS.108.797704.
PubMed 20016754
Study at a glance
From the registry record, last updated by the sponsor on 16 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Natural History Study of Patients With Generalized Arterial Calcification of Infancy (GACI) or Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2)
- ClinicalTrials.gov ID
- NCT03478839
- Acronym / sponsor ID
- 180064
- Conditions
- Generalized Arterial Calcification of Infancy, Autosomal Recessive Hypophosphatemic Rickets Type2
- Keywords
- Generalized Arterial Calcification of Infancy, Autosomal Recessive Hypophosphatemic Rickets, Pseudoxanthoma Elasticum, Idiopathic Infantile Arterial Calcification, Natural History
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 48 participants (actual)
- Lead sponsor
- National Human Genome Research Institute (NHGRI)US National Institutes of Health
- Study start
- 17 Apr 2018 (actual)
- Primary completion
- 31 Dec 2020 (actual)
- Study completion
- 31 Dec 2020 (actual)
- First posted
- 27 Mar 2018 (actual)
- 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:
Generalized Arterial Calcification of Infancy (GACI) is a very rare disorder. It can be fatal before birth or by age 6 months. Anumber of people with GACI survive into adulthood. Those adults suffer from side effects of the disease, including rickets. It is unknown how common the disease Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2) is. It also has side effects. GACI and ARHR2 are usually caused by the mutations in the same gene. There are no approved treatments for the two diseases. Researchers want to study people with these diseases and their family members. This may help understand these rare and unique diseases better. The data could lead to new treatments for GACI and ARHR2.
Objectives:
To better understand the progression of GACI and ARHR2 and how genes might play a role in them.
Eligibility:
People with GACI or ARHR2, both living and deceased, and their parents and siblings.
Design:
Participants will allow researchers to access their medical records. They will give this consent by mail, email, or fax.
Data will be taken from the records. Participants names will not be used. Instead, they will be identified by a code.
Participants may give a blood sample.
If a participant withdraws from the study, their data and samples will be destroyed. However, the coded clinical data in the official medical record and data in databases will NOT be destroyed.
Detailed description
This is a natural history study of patients with Generalized Arterial Calcification of Infancy (GACI) or Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2).
GACI is an ultra-rare disorder with an estimated birth prevalence of around 1 in 200,000. GACI is characterized by extensive arterial calcifications, arterial stenosis, myointimal proliferation and periarticular calcifications. Individuals with GACI also experience calcification in other body areas, such as joints and parenchymal organs.
GACI is generally fatal before birth or within the first six months after birth. The cause of death is frequently myocardial infarction or stroke, and hypertension and congestive heart failure are common in fetuses and infants with GACI. The first six months of life are considered a critical period for GACI patients, and approximately 85% of infants with GACI do not survive beyond this period (Moran 1975). However, the mortality rate decreases substantially among patients who do survive beyond the critical period. Reports exist of patients with GACI who survived into adulthood, but the frequency of this occurrence is unknown, and adult patients suffer from a number of sequelae such as cognitive impairment related to stroke. ARHR2 is characterized by short stature, dental caries, and bone deformities, and biochemically by hypophosphatemia, hyperphosphaturia and elevated plasma alkaline phosphatase. The disease frequency is unknown.
GACI and ARHR2 are most commonly due to mutations of ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1), or less often from mutations in ABCC6 (adenosine triphosphate binding cassette transporter protein subfamily C member 6). No founder mutations are known, and thus no ethnic predilection is known. Both the GACI and ARHR2 phenotypes are potentially fatal or associated with severe morbidity, with no FDA-approved drugs or proven treatments. Animal data suggest that enzyme replacement therapy with ENPP1-Fc may be effective in preventing morbidity or mortality of GACI and ARHR2.
PXE (pseudoxanthoma elasticum) is an autosomal recessive disorder due to mutations in ABCC6 or, less often, ENPP1. PXE is characterized by ectopic calcification of the skin, eyes, cardiovascular system and gastrointestinal system. This study will not focus on PXE but will collect data on PXE patients, particularly when their presentation suggests elements of the GACI or ARHR2 phenotypes.
The main objective of this study is to collect historical control data for future comparison to data from patients treated with ENPP1-Fc so we can develop ENPP1-Fc as a treatment for GACI or ARHR2. In addition, this study will allow for a better understanding of the disease course to design future treatment trials. The study will utilize data obtained predominantly from chart review. The goal is to enroll 100 participants, which include both living and deceased individuals with GACI or ARHR2, and/or their parents and siblings. Our study will be jointly and collaboratively conducted by the NIH and Inozyme.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| CRF completion | – | –Individuals with a diagnosis of GACI or ARHR2 with sufficient chart data to be included in the study will be eligible for enrollment, as well as all their siblings and parents. |
Who may qualify
- Ages
- 1 year to 110 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Individuals with a diagnosis of GACI or ARHR2 who are males or females with sufficient chart data to be included in the study will be eligible for enrollment, as well as all their male and female siblings and both parents.@@@
Key inclusion criteria (9 listed)
- Have genetic confirmation of one of the following:
- AND/OR
- Carry the clinical diagnosis of GACI, ARHR2 or PXE
- Consent or, if applicable, assent to participate in the study
- Have sufficient chart information to allow for the completion of at least one of the protocol s objectives.
Key exclusion criteria (0 listed)
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
Natural History
Time frame: ongoing
The main objective of this study is to determine the natural history of patients with GACI or ARHR2.
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 16 Jul 2026.
- Background: PubMed 26624227Albright RA, Stabach P, Cao W, Kavanagh D, Mullen I, Braddock AA, Covo MS, Tehan M, Yang G, Cheng Z, Bouchard K, Yu ZX, Thorn S, Wang X, Folta-Stogniew EJ, Negrete A, Sinusas AJ, Shiloach J, Zubal G, Madri JA, De La Cruz EM, Braddock DT. ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy. Nat Commun. 2015 Dec 1;6:10006. doi: 10.1038/ncomms10006.
- Background: PubMed 25392903Ziegler SG, Ferreira CR. Generalized Arterial Calcification of Infancy. 2014 Nov 13 [updated 2026 May 19]. In: Adam MP, Bick S, Mirzaa GM, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK253403/
- Background: PubMed 20016754Rutsch F, Boyer P, Nitschke Y, Ruf N, Lorenz-Depierieux B, Wittkampf T, Weissen-Plenz G, Fischer RJ, Mughal Z, Gregory JW, Davies JH, Loirat C, Strom TM, Schnabel D, Nurnberg P, Terkeltaub R; GACI Study Group. Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy. Circ Cardiovasc Genet. 2008 Dec;1(2):133-40. doi: 10.1161/CIRCGENETICS.108.797704.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
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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.
Carlos R Ferreira Lopez, 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 Generalized Arterial Calcification of Infancy and Autosomal Recessive Hypophosphatemic Rickets Type2, 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 9 inclusion and 0 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 16 Jul 2026. 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?
Natural History (time frame: ongoing). 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 NCT03478839, 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 16 Jul 2026.