Pseudoxanthoma elasticum with prominent arterial calcifications evoking CD73 deficiency

Abstract

Pseudoxanthoma elasticum (PXE) is a rare disorder characterized by skin, eye, and cardiovascular lesions due to ectopic mineralization and fragmentation of elastic fibers of connective tissues. We present an atypical case of PXE with diffuse vascular calcification and negligible skin and eye lesions. The patient was a 37-year-old man suffering from severe bilateral arterial calcifications in superficial femoral and posterior tibial arteries. Eye fundoscopy and skin examination were first considered normal. This phenotype suggested first the diagnosis of Arterial Calcification due to Deficiency of CD73 (ACDC) characterized by mutations in NT5E gene. However, we found two variants in ABCC6 gene, and no variant in NT5E. Skin reexamination revealed few lateral skin papules confined to the scalp. Phenotypic overlap was described in vascular calcification disorders, between GACI and PXE phenotypes, and we discuss here expansion of this overlap, including ACDC phenotype. Identification of these expanding and overlapping phenotypes was enabled by genetic screening of the corresponding genes, in a systematic approach. We propose to create a calcification next generation sequencing (NGS) panel with NT5E, GGCX, ENPP1, and ABCC6 genes to improve the molecular diagnosis of vascular calcification.

ENPP1, an Old Enzyme with New Functions, and Small Molecule Inhibitors—A STING in the Tale of ENPP1

“…Thus, many inherited mineralization, calcium handling or calcification-related disorders have been linked to loss-of-function mutations in ENPP1, including autosomal recessive hypophosphatemic rickets type 2 (ARHR2), ossification of the posterior longitudinal ligament of the spine, generalized arterial calcification of infancy (GACI), arterial calcification due to CD73 deficiency (ACDC), and pseudoxanthoma elasticum (PXE), also referred to as Gronblad-Strandberg Syndrome (GSS) in some reports [10,11,12,13]. Some classical manifestations of these diseases, such as vascular involvement, are common in ACDC, PXE, and GACI [13,14,15]. These conditions are all ectopic mineralization disorders that occur in the presence of ENPP1 mutations, and have led to the hypothesis that PXE and GACI are actually different manifestations of the same clinical spectrum [13,15].…”

“…Some classical manifestations of these diseases, such as vascular involvement, are common in ACDC, PXE, and GACI [13,14,15]. These conditions are all ectopic mineralization disorders that occur in the presence of ENPP1 mutations, and have led to the hypothesis that PXE and GACI are actually different manifestations of the same clinical spectrum [13,15]. Recently, Staretz-Chacham et al reported a fatal multisystemic phenotype of GACI that mimics severe congenital infections and was caused by a novel homozygous ENPP1 mutation [16].…”

Severe early‐onset manifestations of pseudoxanthoma elasticum resulting from the cumulative effects of several deleterious mutations inENPP1,ABCC6andHBB: transient improvement in ectopic calcification with sodium thiosulfate

“…STS proved to be transiently effective in improving calcified cutaneous and vascular lesions in our PXE+ phenotype patient. STS therapy was adopted by virtue of its similarity to uraemic and nonuraemic calciphylaxis . STS chelates divalent cations and possesses antioxidant and vasodilatory properties .…”

“…Given the severity of the phenotype, its rapid progression and an extremely unfavourable, potentially fatal prognosis, intravenous (IV) STS was initiated at a dose of 25 g three times weekly for 6 months, resulting in impaired quality of life with numerous side‐effects, including metabolic acidosis, vomiting and dizziness . This prompted dosage adjustment to 10 g IV daily .…”

“…Phenotype and genotype overlapping between GACI and PXE has been reported . Recently, a phenotype resembling arterial calcification due to deficiency of CD73 (OMIM #211800) commonly linked to NT5E mutations was reported in a carrier of two ABCC6 mutations . A PXE‐like phenotype has also been reported in a subset of patients with inherited haemoglobinopathies, such as sickle cell disease (SCD; OMIM #603903) or β‐thalassaemia (OMIM #613985) related to HBB mutations…”