Inactivating mutations of the ENPP1 gene are associated with generalized arterial calcification of infancy (GACI) and less often autosomal-recessive hypophosphatemic rickets type 2 (ARHR2). We aimed to investigate the spectrum of phenotypes in a family with monoallelic and biallelic mutations of ENPP1 after identification through whole exome sequencing of a 54-year-old female with biallelic mutation of ENPP1, c.323G > T; p.Cys108Phe and c.1441C > T; p.Arg481Trp. Including the proband, 2 subjects had biallelic mutations, 5 had monoallelic mutations, and 2 had no mutation of ENPP1. The maternal mutation, a known pathogenic variant associated with GACI, was found in 3 subjects with monoallelic mutations, while the paternal mutation, which was not previously reported, was present in 2 subjects with monoallelic mutations. Both subjects with biallelic mutations had bowing of bilateral femurs, periarticular mineral deposition, normocalcemic primary hyperparathyroidism with multigland parathyroidectomy, increased carotid intima-media thickness, and enthesopathy was also noted in one subject. Intact FGF23 was elevated in both subjects with biallelic mutations, while C-terminal FGF23 was only elevated in one and PPi was reduced in one. Subjects with monoallelic mutations did not have periarticular calcifications or bone deformities. To conclude, patients with biallelic GACI causing mutations can survive well into adulthood, and despite the same biallelic ENPP1 pathogenic variants, clinical and biochemical manifestations can significantly differ, and include enthesopathy and primary hyperparathyroidism, which have not been previously described. Although carriers of monoallelic ENPP1 variants appear unaffected by classic disease manifestations, there may be subtle biochemical and clinical findings that warrant further investigation. © 2019 American Society for Bone and Mineral Research.

中文翻译：

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ENPP1 突变家族的临床和生化表型。

ENPP1 基因的失活突变与婴儿期全身动脉钙化 (GACI) 和常染色体隐性低磷佝偻病 2 型 (ARHR2) 相关。我们旨在通过对一名 54 岁 ENPP1 双等位基因突变 (c.323G > T) 女性的全外显子组测序进行鉴定后，研究 ENPP1 单等位基因和双等位基因突变家系的表型谱；p.Cys108Phe 和 c.1441C > T；p.Arg481Trp。包括先证者，2名受试者有双等位基因突变，5名有单等位基因突变，2名没有ENPP1突变。在 3 名具有单等位基因突变的受试者中发现了母体突变，一种与 GACI 相关的已知致病变异，而在 2 名具有单等位基因突变的受试者中存在先前未报道的父系突变。具有双等位基因突变的两名受试者都有双侧股骨弯曲、关节周围矿物质沉积、血钙正常的原发性甲状旁腺功能亢进症伴多腺体甲状旁腺切除术、颈动脉内中膜厚度增加，并且一名受试者还发现附着点病变。具有双等位基因突变的两名受试者的完整 FGF23 均升高，而 C 端 FGF23 仅在一名受试者中升高，而 PPi 在一名受试者中降低。具有单等位基因突变的受试者没有关节周围钙化或骨骼畸形。总而言之，双等位基因 GACI 引起突变的患者可以很好地存活到成年，尽管双等位基因 ENPP1 致病变异相同，但临床和生化表现可能有显着差异，包括附着点病和原发性甲状旁腺功能亢进，这在以前没有被描述过。尽管单等位基因 ENPP1 变体的携带者似乎不受经典疾病表现的影响，但可能存在微妙的生化和临床发现，值得进一步研究。© 2019 美国骨与矿物研究学会。