Endocrine Abstracts

JOINT851

Introduction: Hypophosphatasia (HPP) is a rare inherited disease caused by mutations in the ALPL gene which encodes tissue-nonspecific alkaline phosphatase (ALP). The clinical presentation of HPP varies from lethal neonatal forms, severe skeletal dysplasia to minimal symptoms in adults.

Clinical case: We present a clinical case of a family with HPP, who were diagnosed after evaluation of a 20-year-old male patient due to complaints of short-statue. His height was 155 cm (SDS: -2.96), weight 52kg, no visual bone deformities. Hypopituitarism or any other endocrine abnormalities were excluded. Repeated tests showed low alkaline phosphatase (ALP -13 IU/l; ALP – 18IU/l reference range (40-150 IU/l) and elevated phosphate 1.76 mmol/l (0.74 - 1.52) along with all other parameters including calcium and bone remodeling markers within the reference range. On genetic evaluation we found a compound heterozygote variant ALPL c.1068C>A (p.Asp356Glu), c.1349G>A, (p.(Arg450His). At the moment of evaluation, short statue was the only clinical presentation of HPP, therefore no treatment was prescribed. His mother, sister, father (height 176cm) and both grandmothers (height 148cm) had low alkaline phosphatase levels. The patient’s mother (age 43, height 149 cm, weight 54 kg) complained of pain in the spine and knee joints. Upon evaluation nephrocalcinosis was revealed. Her ALP levels were -19-24 IU/l (40.0-150.0) but all the other tests were within the reference range. DXA showed normal BMD at femur neck -1,1 SD, L1-L4 -0,2 SD Z-score. Exome sequencing showed the heterozygous variant in ALPL c.1068C>A (p.Asp356Glu). The patient’s sister age 14 (height 146cm (SDS: -2.2), weight 41 kg) was diagnosed with primary hypothyroidism at the age of 6, since then she has taken Levothyroxine. The level of ALP was repeatedly low 19-24 IU/l (40.0-150.0) along with elevated phosphate 1.94- 2.1 mmol/l (0.74 - 1.52), all the other tests were within the reference range. Genetic testing revealed ALPL heterozygous variant c.1349G>A, (p.Arg450His). All three evaluated family members had excellent physical performance based on 6-minute walking, 10 second chair rise and grip strength tests.

Conclusion: This clinical case emphasizes a compound heterozygous variant in the ALPL gene as a plausible cause of short-statue. It is not clear if treatment with asfotase alfa would have improved this patient’s height if it were given at a younger age.