ESPE Abstracts

Background: Hypophosphatasia (HPP) is an inherited bone disorder caused by ALPL gene mutations. It is classified into 6 clinical types (perinatal lethal form, prenatal benign form, infantile form, childhood form, adult form, and odontohypophosphatasia). Severe types show autosomal recessive inheritance, and mild types show autosomal recessive or autosomal dominant inheritance. The adult form is asymptomatic in childhood. Treatment includes ALP enzyme replacement therapy, but there are no clear treatment-initiation criteria for asymptomatic HPP.

Case: A 3-year-old girl with normal growth and development. She was born at 38 weeks of gestation with a birth weight of 2162 g and length of 48.0 cm. She was admitted to NICU due to low birth weight, had no symptoms of respiratory distress or convulsions, and her physical and radiographic findings were unremarkable. HPP was suspected because blood tests showed low ALP of 57-88 U/L (reference value: 186-564 U/L) during hospitalization, and her low ALP level persisted after discharge from NICU. After obtaining informed consent for genetic analysis from her parents, Sanger sequencing analysis for the ALPL gene in her and her parents revealed the heterozygous missense variant c.1354G>A in the patient and her father. Furthermore, her paternal grandmother had experienced body pain after the age of 50, and her great-grandmother had severe osteoporosis and a history of three fractures after the age of 70. Because of the sequence of events, informed consent was obtained from each individual, and analysis of the ALPL gene identified the same mutationsin her paternal grandmother and great-grandmother, respectively. Her only sibling, an older brother, had ALP of 287 IU/L at age of 3 years old and was considered to be unaffected.

Discussion: ALPL gene c.1354G>A mutation has been reported to be a perinatal lethal form as a compound heterozygous mutation with c.331G>A, and a heterozygous form of this mutation has been reported as adult-type HPP with a dominant-negative effect. This case is also considered to involve the adult-type HPP based on the symptoms of the family.

Conclusion: We identified ALPL mutations in adult-form HPP inherited over four generations. We report this case because we consider it to be a valuable familial case in which differences in natural history and individual symptoms in adult-form HPP can be simultaneously observed. We did not administer enzyme replacement therapy in this case, but we will follow-up the patient cautiously to promptly identify future manifestations.