Clinical characteristics: Generalized arterial calcification of infancy (GACI) is characterized by infantile onset of widespread arterial calcification and/or narrowing of large and medium-sized vessels resulting in cardiovascular findings (which can include heart failure, respiratory distress, edema, cyanosis, hypertension, and/or cardiomegaly). Additional findings can include typical skin and retinal manifestations of pseudoxanthoma elasticum (PXE), periarticular calcifications, development of rickets after infancy, cervical spine fusion, and hearing loss. While mortality in infancy is high, survival into the third and fourth decades has occurred.
Diagnosis/testing: The diagnosis of GACI is established in a proband with cardiovascular symptoms during infancy associated with widespread arterial calcification on imaging (once secondary causes have been ruled out) and biallelic pathogenic variants in ENPP1 or ABCC6 identified on molecular genetic testing.
Management: Treatment of manifestations: It remains unclear whether bisphosphonates (most commonly used is etidronate) increase survival. Standard anti-hypertensive therapy is warranted for hypertension. Aspirin therapy is warranted in those with severe coronary stenosis. Intravitreal VEGF inhibitors for choroidal neovascularization, calcitriol and oral phosphate supplement for hypophosphatemic rickets, and hearing aids (as indicated) are all used in the management of this disorder.
Surveillance: No specific guidelines address the issue of surveillance. The appropriate intervals for monitoring depend on the clinical findings. Low-dose CT scan every 3-4 months is used for the first year of life to monitor arterial calcification; echocardiography and troponin are used at regular intervals to monitor cardiovascular issues. Annual (or more frequent) retinal exam for PXE retinal findings and regular lab testing to assure mineral homeostasis associated with the development of rickets. Due to risk for nephrocalcinosis with treatment for rickets, urine calcium is monitored to maintain calciuria below 4 mg/kg/d and yearly renal ultrasound is performed. Evaluate for cervical spine fusion prior to elective endotracheal intubation by a lateral cervical spine x-ray.
Agents/circumstances to avoid: Although no clinical studies have been conducted, it seems prudent to avoid the use of warfarin if possible. Similarly, the use of burosumab, an anti-FGF23 monoclonal antibody, remains controversial due to theoretic concerns.
Evaluation of relatives at risk: It is appropriate to evaluate the younger sibs of a proband with GACI in order to identify as early as possible those who would benefit from treatment.
Genetic counseling: GACI is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a GACI-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither pathogenic variant. Carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if the pathogenic variants in the family are known.
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