case_images: PMC7775725_01
case_images: Clinical and molecular findings in a patient with hypophosphatasia. (A) X-ray examinations of the wrist and knee showed typical features of hypophosphatasia, whereas the head and chest showed no abnormal features (a and b). X-ray examinations of the wrist and knee after initiation of asfotase alfa (AA) therapy with the standard dose (2 mg/kg, three times per week = 6 mg/kg/week) showed substantial improvement of rickets (c. 59 days of age). Temporary interruption of AA therapy did not worsen skeletal features, as indicated by reduction of Rickets Severity Scale score from 4.5 to 2.0 and maintenance of Radiographic Global Impression of Change rating +2 (d). Lower doses of AA (2 mg/kg/week) maintained normalized skeletal features (e and f). X-ray examination of knee revealed slight distal metaphyseal demineralization (g); increased dose from 2 mg/kg/week to 2.4 mg/kg/week led to recovery of mineralization (h). "Day" represents days of age. (B) Electrochromatography showed a compound heterozygous missense mutation of TNSALP (c.406C>T, p.Arg136Cys and c.979T>C, p.Phe327Leu) in this patient, as well as a heterozygous missense mutation at c.406C>T in her father and sister, and a heterozygous missense mutation c.979T>C in her mother. Mutations are indicated by asterisks. (C) Clinical course of disease in this patient. Upper graph shows changes in serum calcium levels after Payne's correction. Lower graph shows changes in serum ionic phosphate levels. Gray areas indicate age-matched reference ranges. AA therapy at the dose of (i): 6 mg/kg/week, (ii): 2 mg/kg/week, and (iii): 2.4 mg/kg/week. Monitoring frequencies differed among clinical phases, such that monitoring was performed at 4-7-day intervals during pretreatment, initiation of therapy, and interruption of therapy; at 2-4-week intervals during resumption of therapy at a reduced dose; and at 2-3-month intervals during follow-up. Thus, the horizontal line axis from birth to 134 days of age was set to a period of 14 days; from 214 to 1,108 days, it was set to be a period of 90 days. "Day" represents age in days.
case_images: fendo-11-590455-g001.jpg
case_images: PMC7775725_03_fendo-11-590455-g001.jpg
case_images: f1
case_images: The patient's clinical course is summarized in  Figure 1C . When the patient reached the age of 59 days, X-ray examinations showed remarkable improvement of skeletal features ( Figures 1A , c), which comprised a reduction of Rickets Severity Scale score from 8.0 to 4.5, as well as enhancement of +2 in the Radiographic Global Impression of Change rating, which is considered to indicate substantial recovery from HPP-associated rickets. AA therapy until the age of 79 days (an interval of 20 days) resulted in a reduction of serum ionic phosphate levels by 2.18 mmol/L without the reappearance of typical skeletal manifestations ( Figures 1A , d), along with further reduction in Rickets Severity Scale score from 4.5 to 2.0. At the age of 80 days, the patient's AA therapy was resumed with a reduced dose (2 mg/kg, once per week). Lower doses of AA therapy enabled maintenance of improved skeletal features according to the Rickets Severity Scale score (0 point) and Radiographic Global Impression of Change rating (+3, defined as complete or near complete healing rating) ( Figures 1A , e and f). When the patient reached the age of 926 days, her AA dose was increased from 2 mg/kg/week to 2.4 mg/kg/week, because slight distal metaphyseal demineralization in the knee was detected by X-ray examination ( Figures 1A , g). No signs of deterioration in bone mineralization were observed thereafter, which was consistent with the +3 Radiographic Global Impression of Change rating at the age of 1,107 days ( Figures 1A , h).
case_images: PMC7775725_02
case_images: Clinical and molecular findings in a patient with hypophosphatasia. (A) X-ray examinations of the wrist and knee showed typical features of hypophosphatasia, whereas the head and chest showed no abnormal features (a and b). X-ray examinations of the wrist and knee after initiation of asfotase alfa (AA) therapy with the standard dose (2 mg/kg, three times per week = 6 mg/kg/week) showed substantial improvement of rickets (c. 59 days of age). Temporary interruption of AA therapy did not worsen skeletal features, as indicated by reduction of Rickets Severity Scale score from 4.5 to 2.0 and maintenance of Radiographic Global Impression of Change rating +2 (d). Lower doses of AA (2 mg/kg/week) maintained normalized skeletal features (e and f). X-ray examination of knee revealed slight distal metaphyseal demineralization (g); increased dose from 2 mg/kg/week to 2.4 mg/kg/week led to recovery of mineralization (h). "Day" represents days of age. (B) Electrochromatography showed a compound heterozygous missense mutation of TNSALP (c.406C>T, p.Arg136Cys and c.979T>C, p.Phe327Leu) in this patient, as well as a heterozygous missense mutation at c.406C>T in her father and sister, and a heterozygous missense mutation c.979T>C in her mother. Mutations are indicated by asterisks. (C) Clinical course of disease in this patient. Upper graph shows changes in serum calcium levels after Payne's correction. Lower graph shows changes in serum ionic phosphate levels. Gray areas indicate age-matched reference ranges. AA therapy at the dose of (i): 6 mg/kg/week, (ii): 2 mg/kg/week, and (iii): 2.4 mg/kg/week. Monitoring frequencies differed among clinical phases, such that monitoring was performed at 4-7-day intervals during pretreatment, initiation of therapy, and interruption of therapy; at 2-4-week intervals during resumption of therapy at a reduced dose; and at 2-3-month intervals during follow-up. Thus, the horizontal line axis from birth to 134 days of age was set to a period of 14 days; from 214 to 1,108 days, it was set to be a period of 90 days. "Day" represents age in days.
case_images: fendo-11-590455-g001.jpg
case_images: PMC7775725_03_fendo-11-590455-g001.jpg
case_images: f1
case_images: The patient's clinical course is summarized in  Figure 1C . When the patient reached the age of 59 days, X-ray examinations showed remarkable improvement of skeletal features ( Figures 1A , c), which comprised a reduction of Rickets Severity Scale score from 8.0 to 4.5, as well as enhancement of +2 in the Radiographic Global Impression of Change rating, which is considered to indicate substantial recovery from HPP-associated rickets. AA therapy until the age of 79 days (an interval of 20 days) resulted in a reduction of serum ionic phosphate levels by 2.18 mmol/L without the reappearance of typical skeletal manifestations ( Figures 1A , d), along with further reduction in Rickets Severity Scale score from 4.5 to 2.0. At the age of 80 days, the patient's AA therapy was resumed with a reduced dose (2 mg/kg, once per week). Lower doses of AA therapy enabled maintenance of improved skeletal features according to the Rickets Severity Scale score (0 point) and Radiographic Global Impression of Change rating (+3, defined as complete or near complete healing rating) ( Figures 1A , e and f). When the patient reached the age of 926 days, her AA dose was increased from 2 mg/kg/week to 2.4 mg/kg/week, because slight distal metaphyseal demineralization in the knee was detected by X-ray examination ( Figures 1A , g). No signs of deterioration in bone mineralization were observed thereafter, which was consistent with the +3 Radiographic Global Impression of Change rating at the age of 1,107 days ( Figures 1A , h).
case_images: PMC7775725_03
case_images: Clinical and molecular findings in a patient with hypophosphatasia. (A) X-ray examinations of the wrist and knee showed typical features of hypophosphatasia, whereas the head and chest showed no abnormal features (a and b). X-ray examinations of the wrist and knee after initiation of asfotase alfa (AA) therapy with the standard dose (2 mg/kg, three times per week = 6 mg/kg/week) showed substantial improvement of rickets (c. 59 days of age). Temporary interruption of AA therapy did not worsen skeletal features, as indicated by reduction of Rickets Severity Scale score from 4.5 to 2.0 and maintenance of Radiographic Global Impression of Change rating +2 (d). Lower doses of AA (2 mg/kg/week) maintained normalized skeletal features (e and f). X-ray examination of knee revealed slight distal metaphyseal demineralization (g); increased dose from 2 mg/kg/week to 2.4 mg/kg/week led to recovery of mineralization (h). "Day" represents days of age. (B) Electrochromatography showed a compound heterozygous missense mutation of TNSALP (c.406C>T, p.Arg136Cys and c.979T>C, p.Phe327Leu) in this patient, as well as a heterozygous missense mutation at c.406C>T in her father and sister, and a heterozygous missense mutation c.979T>C in her mother. Mutations are indicated by asterisks. (C) Clinical course of disease in this patient. Upper graph shows changes in serum calcium levels after Payne's correction. Lower graph shows changes in serum ionic phosphate levels. Gray areas indicate age-matched reference ranges. AA therapy at the dose of (i): 6 mg/kg/week, (ii): 2 mg/kg/week, and (iii): 2.4 mg/kg/week. Monitoring frequencies differed among clinical phases, such that monitoring was performed at 4-7-day intervals during pretreatment, initiation of therapy, and interruption of therapy; at 2-4-week intervals during resumption of therapy at a reduced dose; and at 2-3-month intervals during follow-up. Thus, the horizontal line axis from birth to 134 days of age was set to a period of 14 days; from 214 to 1,108 days, it was set to be a period of 90 days. "Day" represents age in days.
case_images: fendo-11-590455-g001.jpg
case_images: PMC7775725_03_fendo-11-590455-g001.jpg
case_images: f1
case_images: The patient's clinical course is summarized in  Figure 1C . When the patient reached the age of 59 days, X-ray examinations showed remarkable improvement of skeletal features ( Figures 1A , c), which comprised a reduction of Rickets Severity Scale score from 8.0 to 4.5, as well as enhancement of +2 in the Radiographic Global Impression of Change rating, which is considered to indicate substantial recovery from HPP-associated rickets. AA therapy until the age of 79 days (an interval of 20 days) resulted in a reduction of serum ionic phosphate levels by 2.18 mmol/L without the reappearance of typical skeletal manifestations ( Figures 1A , d), along with further reduction in Rickets Severity Scale score from 4.5 to 2.0. At the age of 80 days, the patient's AA therapy was resumed with a reduced dose (2 mg/kg, once per week). Lower doses of AA therapy enabled maintenance of improved skeletal features according to the Rickets Severity Scale score (0 point) and Radiographic Global Impression of Change rating (+3, defined as complete or near complete healing rating) ( Figures 1A , e and f). When the patient reached the age of 926 days, her AA dose was increased from 2 mg/kg/week to 2.4 mg/kg/week, because slight distal metaphyseal demineralization in the knee was detected by X-ray examination ( Figures 1A , g). No signs of deterioration in bone mineralization were observed thereafter, which was consistent with the +3 Radiographic Global Impression of Change rating at the age of 1,107 days ( Figures 1A , h).
case_images: PMC7775725_04