Study of People With Generalized Arterial Calcification of Infancy (GACI) or Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2)
Condition: Generalized Arterial Calcification of Infancy; Autosomal Recessive Hypophosphatemic Rickets Type2
MeSH terms: Rickets; Rickets, Hypophosphatemic; Familial Hypophosphatemic Rickets; Arteriosclerosis; Calcinosis; Vascular Calcification
Study type: Observational

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. 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.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
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.@@@
      
Keywords: Generalized Arterial Calcification of Infancy; Autosomal Recessive Hypophosphatemic Rickets; Pseudoxanthoma Elasticum; Idiopathic Infantile Arterial Calcification; Natural History