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The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
Orpha Number: 51608
A rare genetic vascular disease characterized by early onset (between in utero to infancy) of extensive calcification and stenosis of the large and medium sized arteries. Presentation is typically with respiratory distress, congestive heart failure and systemic hypertension.
Approximately 300 cases have been reported worldwide in the medical literature. The prevalence is unknown; however, based on carrier frequency of the recognized pathogenic variants, the frequency of 1/566,000 has been suggested.
Disease onset is either early (in utero to within the first week of life) or late (median age three months). Early-onset disease presents variably with fetal distress, heart failure, polyhydramnios, hypertension, respiratory distress, hydrops fetalis, edema, visceral effusions, cyanosis, cardiomegaly, and ascites. Presentation of late-onset disease variably includes respiratory distress, cyanosis, feeding difficulties, congestive heart failure, vomiting, irritability, failure to thrive, fever, hypertension, and edema. Additional findings can include extravascular calcifications (particularly periarticular), typical skin and retinal manifestations of pseudoxanthoma elasticum, hearing loss, and development of rickets after infancy. Pathologically, the condition is characterized by deposition of calcium along the internal elastic membrane of arteries, accompanied by fibrous thickening of the intima, which causes luminal narrowing.
Causal mutations have been identified in the genes ENPP1 (chromosome 6q23.2) and ABCC6 (chromosome 16p13.11) respectively encoding ectonucleotide pyrophosphatase/ phosphodiesterase 1 and multidrug resistance-associated protein 6, a transmembrane protein belonging to the family of ATP-binding cassette (ABC) transport proteins. Pathological variants lead to aberrant tissue mineralization, and the subsequent luminal narrowing invariably leads to coronary arterial occlusion and myocardial ischemia or stenoses of different arteries leading to end-organ damage. ENPP1 mutations also cause autosomal recessive hypophosphatemic rickets, which is associated with longer survival.
Diagnosis of is made by the combination of clinical, imaging or histopathological findings, together with genetic results. The preferred imaging modality to assess calcifications extension is whole-body computed tomography combined with CT angiography.
Differential diagnosis includes endocardial fibroelastosis, myocardititis, storage disorders, infarction, anomalous insertion of the coronary arteries, cardiac anomalies, metastatic calcification due to renal disease, hypervitaminosis D, infections, and non-immune fetal hydrops, Takayasu arteriitis.
Antenatal diagnosis has been reported, with findings of arterial calcifications, hydrops, abnormal cardiac contractility, and hyperechoic kidneys. The diagnosis is essential for genetic counseling, and for screening of siblings at risk for developing the disease.
The pattern of inheritance is autosomal recessive. The sibling-recurrence risk is 25%. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family are known.
Management and treatment
Use of bisphosphonates appears to significantly increase survival. Standard anti-hypertensive therapy is warranted for hypertension. Aspirin therapy is warranted in those with severe coronary stenosis who are at increased risk for coronary thrombosis. Anti-hypertensive therapy is warranted for hypertension. Treatment of hypophosphatemic rickets involves calcitriol and oral phosphate supplements. It seems prudent to avoid the use of warfarin if possible. Where endotracheal intubation is required, lateral cervical spine x-ray is recommended to evaluate for cervical spine fusion, and thereby avoid secondary complications.
Prognosis is poor; most infants die from myocardial infarction within the first year of life, with the greatest number of deaths occurring within the first six months. Nevertheless, long-term survival into the second and third decade has been reported.
Visit the Orphanet disease page for more resources.
Source: GARD Last updated on 05-27-20
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