ENPP1遺伝子病的バリアントによる2型常染色体劣性骨形成不全症および汎発性動脈石灰化症の6例

Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) and generalized arterial calcification of infancy (GACI) occur secondary to biallelic ectonucleotide pyrophosphate/phosphodiesterase 1 (ENPP1) loss-of-function pathogenic variants. GACI is a life-threatening condition, often presenting in the neonatal period with heart failure and hypertension, caused by calcification of the media in large- and medium-sized arteries. ARHR2 typically manifests later in life. Children with ARHR2 commonly exhibit short stature, rachitic skeletal changes, progressive deformities of the lower limbs, skeletal fragility and bone/muscle pain. We present six cases of homozygous pathogenic variants in the ENPP1 gene causing ARHR2 and/or GACI. Case 1: Presented with lower limb deformities and pain with radiological evidence of rickets. Subsequent investigations displayed aortic and pulmonary arterial calcification. Case 2: Presented with lower limb deformities and knee pain. Confirmatory testing was undertaken following her brother's (Case 1) diagnosis. Case 3: The diagnosis was made antenatally. Bisphosphonate treatment was instituted in both the pre- and post-natal periods due to the presence of extensive arterial calcifications. Rickets were noted by two years of age. Case 4: Presented with lower limb deformities and pain. There is neither any current evidence of arterial calcification nor hypertension. Case 5: Presented at 3 mo of age in cardiogenic shock with widespread calcification of large and medium-sized arteries. Bisphosphonate treatment was instituted. Case 6: Presented at 2 wk of age with right shoulder discomfort, with evidence of glenohumeral joint calcification. Further imaging revealed aortic, mediastinal, sternoclavicular joint and vertebral spinous process calcification. Case 1 and 2 were also found to have a heterozygous pathogenic ALPL variant consistent with hypophosphatasia. Clinical features, biochemistry, imaging and genetic analyses assist in the diagnosis of ARHR2 and GACI. Conventional therapy, oral phosphate and calcitriol for ARHR2 and bisphosphonates for GACI, have been utilized for many years. ENPP1 replacement treatment remains an exciting prospect for future management of ARHR2 and GACI secondary to loss of function of ENPP1.