Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI)

Carlos R. Ferreira; Mary E. Hackbarth; Shira G. Ziegler; Kristen S. Pan; Mary S. Roberts; Douglas R. Rosing; Margaret S. Whelpley; Joy C. Bryant; Ellen F. Macnamara; Sisi Wang; Kerstin Müller; Iris R. Hartley; Emily Y. Chew; Timothy E. Corden; Christina M. Jacobsen; Ingrid A. Holm; Frank Rutsch; Esra Dikoglu; Marcus Y. Chen; M. Zulf Mughal; Michael A. Levine; Rachel I. Gafni; William A. Gahl

doi:10.1038/s41436-020-00983-0

Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI)

Carlos R. Ferreira, Mary E. Hackbarth, Shira G. Ziegler, Kristen S. Pan, Mary S. Roberts, Douglas R. Rosing, Margaret S. Whelpley, Joy C. Bryant, Ellen F. Macnamara, Sisi Wang, Kerstin Müller, Iris R. Hartley, Emily Y. Chew, Timothy E. Corden, Christina M. Jacobsen, Ingrid A. Holm, Frank Rutsch, Esra Dikoglu, Marcus Y. Chen, M. Zulf MughalMichael A. Levine, Rachel I. Gafni, William A. Gahl

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

Purpose: Generalized arterial calcification of infancy (GACI), characterized by vascular calcifications that are often fatal shortly after birth, is usually caused by deficiency of ENPP1. A small fraction of GACI cases result from deficiency of ABCC6, a membrane transporter. The natural history of GACI survivors has not been established in a prospective fashion. Methods: We performed deep phenotyping of 20 GACI survivors. Results: Sixteen of 20 subjects presented with arterial calcifications, but only 5 had residual involvement at the time of evaluation. Individuals with ENPP1 deficiency either had hypophosphatemic rickets or were predicted to develop it by 14 years of age; 14/16 had elevated intact FGF23 levels (iFGF23). Blood phosphate levels correlated inversely with iFGF23. For ENPP1-deficient individuals, the lifetime risk of cervical spine fusion was 25%, that of hearing loss was 75%, and the main morbidity in adults was related to enthesis calcification. Four ENPP1-deficient individuals manifested classic skin or retinal findings of PXE. We estimated the minimal incidence of ENPP1 deficiency at ~1 in 200,000 pregnancies. Conclusion: GACI appears to be more common than previously thought, with an expanding spectrum of overlapping phenotypes. The relationships among decreased ENPP1, increased iFGF23, and rickets could inform future therapies.

Original language	English (US)
Pages (from-to)	396-407
Number of pages	12
Journal	Genetics in Medicine
Volume	23
Issue number	2
DOIs	https://doi.org/10.1038/s41436-020-00983-0
State	Published - Feb 2021

Keywords

ABCC6 deficiency
autosomal recessive hypophosphatemic rickets type 2
ENPP1 deficiency
generalized arterial calcification of infancy
pseudoxanthoma elasticum

ASJC Scopus subject areas

Genetics(clinical)

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10.1038/s41436-020-00983-0

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Ferreira, C. R., Hackbarth, M. E., Ziegler, S. G., Pan, K. S., Roberts, M. S., Rosing, D. R., Whelpley, M. S., Bryant, J. C., Macnamara, E. F., Wang, S., Müller, K., Hartley, I. R., Chew, E. Y., Corden, T. E., Jacobsen, C. M., Holm, I. A., Rutsch, F., Dikoglu, E., Chen, M. Y., ... Gahl, W. A. (2021). Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI). Genetics in Medicine, 23(2), 396-407. https://doi.org/10.1038/s41436-020-00983-0

Ferreira, CR, Hackbarth, ME, Ziegler, SG, Pan, KS, Roberts, MS, Rosing, DR, Whelpley, MS, Bryant, JC, Macnamara, EF, Wang, S, Müller, K, Hartley, IR, Chew, EY, Corden, TE, Jacobsen, CM, Holm, IA, Rutsch, F, Dikoglu, E, Chen, MY, Mughal, MZ, Levine, MA, Gafni, RI & Gahl, WA 2021, 'Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI)', Genetics in Medicine, vol. 23, no. 2, pp. 396-407. https://doi.org/10.1038/s41436-020-00983-0

@article{7e99c5847c73479cbb55673cc0f29c07,

title = "Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI)",

abstract = "Purpose: Generalized arterial calcification of infancy (GACI), characterized by vascular calcifications that are often fatal shortly after birth, is usually caused by deficiency of ENPP1. A small fraction of GACI cases result from deficiency of ABCC6, a membrane transporter. The natural history of GACI survivors has not been established in a prospective fashion. Methods: We performed deep phenotyping of 20 GACI survivors. Results: Sixteen of 20 subjects presented with arterial calcifications, but only 5 had residual involvement at the time of evaluation. Individuals with ENPP1 deficiency either had hypophosphatemic rickets or were predicted to develop it by 14 years of age; 14/16 had elevated intact FGF23 levels (iFGF23). Blood phosphate levels correlated inversely with iFGF23. For ENPP1-deficient individuals, the lifetime risk of cervical spine fusion was 25%, that of hearing loss was 75%, and the main morbidity in adults was related to enthesis calcification. Four ENPP1-deficient individuals manifested classic skin or retinal findings of PXE. We estimated the minimal incidence of ENPP1 deficiency at ~1 in 200,000 pregnancies. Conclusion: GACI appears to be more common than previously thought, with an expanding spectrum of overlapping phenotypes. The relationships among decreased ENPP1, increased iFGF23, and rickets could inform future therapies.",

keywords = "ABCC6 deficiency, autosomal recessive hypophosphatemic rickets type 2, ENPP1 deficiency, generalized arterial calcification of infancy, pseudoxanthoma elasticum",

author = "Ferreira, {Carlos R.} and Hackbarth, {Mary E.} and Ziegler, {Shira G.} and Pan, {Kristen S.} and Roberts, {Mary S.} and Rosing, {Douglas R.} and Whelpley, {Margaret S.} and Bryant, {Joy C.} and Macnamara, {Ellen F.} and Sisi Wang and Kerstin M{\"u}ller and Hartley, {Iris R.} and Chew, {Emily Y.} and Corden, {Timothy E.} and Jacobsen, {Christina M.} and Holm, {Ingrid A.} and Frank Rutsch and Esra Dikoglu and Chen, {Marcus Y.} and Mughal, {M. Zulf} and Levine, {Michael A.} and Gafni, {Rachel I.} and Gahl, {William A.}",

note = "Publisher Copyright: {\textcopyright} 2020, American College of Medical Genetics and Genomics.",

year = "2021",

month = feb,

doi = "10.1038/s41436-020-00983-0",

language = "English (US)",

volume = "23",

pages = "396--407",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Elsevier B.V.",

number = "2",

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TY - JOUR

T1 - Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI)

AU - Ferreira, Carlos R.

AU - Hackbarth, Mary E.

AU - Ziegler, Shira G.

AU - Pan, Kristen S.

AU - Roberts, Mary S.

AU - Rosing, Douglas R.

AU - Whelpley, Margaret S.

AU - Bryant, Joy C.

AU - Macnamara, Ellen F.

AU - Wang, Sisi

AU - Müller, Kerstin

AU - Hartley, Iris R.

AU - Chew, Emily Y.

AU - Corden, Timothy E.

AU - Jacobsen, Christina M.

AU - Holm, Ingrid A.

AU - Rutsch, Frank

AU - Dikoglu, Esra

AU - Chen, Marcus Y.

AU - Mughal, M. Zulf

AU - Levine, Michael A.

AU - Gafni, Rachel I.

AU - Gahl, William A.

PY - 2021/2

Y1 - 2021/2

N2 - Purpose: Generalized arterial calcification of infancy (GACI), characterized by vascular calcifications that are often fatal shortly after birth, is usually caused by deficiency of ENPP1. A small fraction of GACI cases result from deficiency of ABCC6, a membrane transporter. The natural history of GACI survivors has not been established in a prospective fashion. Methods: We performed deep phenotyping of 20 GACI survivors. Results: Sixteen of 20 subjects presented with arterial calcifications, but only 5 had residual involvement at the time of evaluation. Individuals with ENPP1 deficiency either had hypophosphatemic rickets or were predicted to develop it by 14 years of age; 14/16 had elevated intact FGF23 levels (iFGF23). Blood phosphate levels correlated inversely with iFGF23. For ENPP1-deficient individuals, the lifetime risk of cervical spine fusion was 25%, that of hearing loss was 75%, and the main morbidity in adults was related to enthesis calcification. Four ENPP1-deficient individuals manifested classic skin or retinal findings of PXE. We estimated the minimal incidence of ENPP1 deficiency at ~1 in 200,000 pregnancies. Conclusion: GACI appears to be more common than previously thought, with an expanding spectrum of overlapping phenotypes. The relationships among decreased ENPP1, increased iFGF23, and rickets could inform future therapies.

AB - Purpose: Generalized arterial calcification of infancy (GACI), characterized by vascular calcifications that are often fatal shortly after birth, is usually caused by deficiency of ENPP1. A small fraction of GACI cases result from deficiency of ABCC6, a membrane transporter. The natural history of GACI survivors has not been established in a prospective fashion. Methods: We performed deep phenotyping of 20 GACI survivors. Results: Sixteen of 20 subjects presented with arterial calcifications, but only 5 had residual involvement at the time of evaluation. Individuals with ENPP1 deficiency either had hypophosphatemic rickets or were predicted to develop it by 14 years of age; 14/16 had elevated intact FGF23 levels (iFGF23). Blood phosphate levels correlated inversely with iFGF23. For ENPP1-deficient individuals, the lifetime risk of cervical spine fusion was 25%, that of hearing loss was 75%, and the main morbidity in adults was related to enthesis calcification. Four ENPP1-deficient individuals manifested classic skin or retinal findings of PXE. We estimated the minimal incidence of ENPP1 deficiency at ~1 in 200,000 pregnancies. Conclusion: GACI appears to be more common than previously thought, with an expanding spectrum of overlapping phenotypes. The relationships among decreased ENPP1, increased iFGF23, and rickets could inform future therapies.

KW - ABCC6 deficiency

KW - autosomal recessive hypophosphatemic rickets type 2

KW - ENPP1 deficiency

KW - generalized arterial calcification of infancy

KW - pseudoxanthoma elasticum

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U2 - 10.1038/s41436-020-00983-0

DO - 10.1038/s41436-020-00983-0

M3 - Article

C2 - 33005041

AN - SCOPUS:85091763430

SN - 1098-3600

VL - 23

SP - 396

EP - 407

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 2

ER -

Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI)

Abstract

Keywords

ASJC Scopus subject areas

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