Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6.
Spontaneous pathologic arterial calcifications in childhood can occur in generalized arterial calcification of infancy (GACI) or in pseudoxanthoma elasticum (PXE). GACI is associated with biallelic mutations in ENPP1 in the majority of cases, whereas mutations in ABCC6 are known to cause PXE. However, the genetic basis in subsets of both disease phenotypes remains elusive. We hypothesized that GACI and PXE are in a closely related spectrum of disease. We used a standardized questionnaire to retrospectively evaluate the phenotype of 92 probands with a clinical history of GACI. We obtained the ENPP1 genotype by conventional sequencing. In those patients with less than two disease-causing ENPP1 mutations, we sequenced ABCC6. We observed that three GACI patients who carried biallelic ENPP1 mutations developed typical signs of PXE between 5 and 8 years of age; these signs included angioid streaks and pseudoxanthomatous skin lesions. In 28 patients, no disease-causing ENPP1 mutation was found. In 14 of these patients, we detected pathogenic ABCC6 mutations (biallelic mutations in eight patients, monoallelic mutations in six patients). Thus, ABCC6 mutations account for a significant subset of GACI patients, and ENPP1 mutations can also be associated with PXE lesions in school-aged children. Based on the considerable overlap of genotype and phenotype of GACI and PXE, both entities appear to reflect two ends of a clinical spectrum of ectopic calcification and other organ pathologies, rather than two distinct disorders. ABCC6 and ENPP1 mutations might lead to alterations of the same physiological pathways in tissues beyond the artery.
Department of General Pediatrics, Münster University Children's Hospital, Germany.
Yvonne
Y
Nitschke
Geneviève
G
Baujat
Ulrike
U
Botschen
Tanja
T
Wittkampf
Marcel
M
du Moulin
Jacqueline
J
Stella
Martine
M
Le Merrer
Geneviève
G
Guest
Karen
K
Lambot
Marie-Frederique
MF
Tazarourte-Pinturier
Nicolas
N
Chassaing
Olivier
O
Roche
Ilse
I
Feenstra
Karen
K
Loechner
Charu
C
Deshpande
Samuel J
SJ
Garber
Rashmi
R
Chikarmane
Beat
B
Steinmann
Tatevik
T
Shahinyan
Loreto
L
Martorell
Justin
J
Davies
Wendy E
WE
Smith
Stephen G
SG
Kahler
Mignon
M
McCulloch
Elizabeth
E
Wraige
Lourdes
L
Loidi
Wolfgang
W
Höhne
Ludovic
L
Martin
Smaïl
S
Hadj-Rabia
Robert
R
Terkeltaub
Frank
F
Rutsch
D000793:Angioid Streaks / Q000235:genetics; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009154:Mutation; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D011561:Pseudoxanthoma Elasticum / Q000235:genetics* / Q000473:pathology; D011755:Pyrophosphatases / Q000235:genetics*; D012189:Retrospective Studies; D011795:Surveys and Questionnaires; D061205:Vascular Calcification / Q000235:genetics* / Q000473:pathology
D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; C102029:ABCC6 protein, human; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1