Clinical Characteristics of Perinatal Lethal Hypophosphatasia: A Report of 6 Cases

Abstract

Hypophosphatasia is a rare inherited disorder caused by deficient tissue-nonspecific alkaline phosphatase activity. It is classified into 6 subtypes, and the perinatal lethal form of hypophosphatasia is the most severe. Patients with this form suffer from various symptoms, including respiratory failure, premature craniosynostosis, rachitic changes in the metaphyses, convulsions and hypercalcemia. This report presents 6 cases of the perinatal lethal form of hypophosphatasia. All of the patients showed shortening of the long bones in utero in ultrasonographic examinations. Two of the six patients died at birth because they could not establish spontaneous breathing. Three of the remaining four patients also died before 1 yr of age. The major cause of death was respiratory failure due to hypoplastic lung. All of the patients, except for the two who died at birth, experienced convulsions in their clinical courses. Vitamin B6 therapy effectively reduced the frequency and severity of convulsions. However, it could not always make the patients convulsion free. Three patients underwent a genetic analysis. The 1559delT mutation, which abolishes Alkaline Phosphatase (ALP) activity, was a hot spot. A homozygous 1559delT mutation was observed in two patients. However, they differed in severity of symptoms. Although a good genotype-phenotype correlation has been reported in hypophosphatasia, the genotype alone does not always predict the life span of the patients. These cases therefore suggested the importance of genetic counseling.

Hypophosphatasia now draws more attention of both clinicians and researchers: A Commentary on prevelance of c. 1559delT in ALPL, a common mutation resulting in the perinatal (lethal) form of hypophosphatasias in Japanese and effects of the mutation on heterozygous carriers

“…However, some patients of this form can survive because of advances in neonatology. 3 Recently, non-lethal benign form of perinatal hypophosphatasia has been recognized, which is associated with no apparent defects of mineralization. 4,5 An infantile form is characterized by infantile onset and often associated with poor weight gain, hypercalcemia and respiratory difficulties.…”

Prevention of Lethal Murine Hypophosphatasia by NeonatalEx VivoGene Therapy Using Lentivirally Transduced Bone Marrow Cells

“…3A). On the other hand, incomplete osteogenesis, such as a widened metaphysis, which is frequently observed in the HPP patients, 38,39 persisted in both ALP-BMCtreated and mock-BMC-treated Akp2 -/-mice (Fig. 3B).…”

Identification of a molecular defect in a stillborn fetus with perinatal lethal hypophosphatasia using a disease-associated genome sequencing approach

“…This severe form of HPP represents an inborn defect of ossification resulting in either stillbirth or early postnatal death. Clinical features comprise shortened lower limbs often with femoral and tibial bowing, multiple fractures, short ribs, narrow thorax, poorly ossified epiphyses, large fontanelles, osteochondral spurs, apnoea, and hypercalcaemia [20,21,23]. The fetal demise results mainly from generalized bone hypomineralization and respiratory failure due to thorax deformities and lung hypoplasia [9].…”