ESPE Abstracts

Background: Hypophosphatasia (HPP) is a rare inherited disease of bone metabolism caused by inactivating mutations in the ALPL gene encoding tissue non-specific alkaline phosphatase (TNSAP). Infantile HPP is characterized by early onset abnormal skeletal mineralization with hypercalcemia and low alkaline phosphatase (ALP). It has been rarely reported from Thailand, resulting in limited disease awareness. We reported an infantile HPP Thai patient who presented with poor weight gain and hypercalcemia. Mutation analysis confirmed a novel compound heterozygous mutation of the ALPL gene in this patient.

Methods: The index patient’s and parents’ genomic DNA was extracted from the peripheral blood leukocytes. The exon 2-12 of the ALPL gene and exon-intron boundaries were amplified for direct sequencing.

Results: A 7-month-old male infant presented with hypotonia, feeding difficulty, constipation, and failure to thrive. He was born to non-consanguineous parents at term gestation with a birth weight of 3035 g. Physical examination showed underweight (weight 3870 g.), short stature (length 58 cm), microcephaly (head circumference 38.5 cm) with enlargement of the anterior fontanelle and widening sutures, small thorax, and marked hypotonia. Hypercalcemia with low parathyroid hormone (Ca 14.0 mg/dL (normal range, NR 8.5-11), P 3.6 mg/dL (NR 4.8-8.4), urine Ca/Cr 0.44 mg/mg (NR <0.6), PTH 7.74 pg/mL (NR 15-65)) were documented. His serum ALP was markedly low (16 IU/L (NR 150-420)), suggesting hypophosphatasia. Bone radiographs demonstrated generalized de-ossification of the skull, spine, and long bones with metaphyseal irregularity and thin ribs. After obtaining informed consent, the ALPL gene was sequenced, and both paternally inherited c.650delTinsCTAA and maternally inherited c.707A>G mutations were found in the patient. The later c.707A>G mutation is not in the public databases. Low calcium formula was prescribed to control his calcium levels. Unfortunately, Asfotase alfa, an enzyme replacement therapy (ERT) for HPP, was not given since it was unavailable in Thailand. Because of the underdeveloped ribcage and respiratory muscle hypotonia, he could not maintain his airway. He became ventilator dependent with recurrent pneumonia, resulting in respiratory failure and death at one year and four months old.

Conclusions: We reported an infantile HPP patient with a novel compound heterozygous mutation of the ALPL gene. Hypercalcemia with abnormal bone mineralization and low ALP are clues for diagnosis. This HPP type had been categorized as lethal until the era of Asfotase alfa. However, the availability of this ERT is still a considerable barrier to rescuing these patients.