[Fetal therapy of skeletal dysplasias].

Three types of fetal therapy of skeletal dysplasias, as enzyme replacement, in utero stem cell transplantation, and gene therapy, are reviewed. Clinical trial of recombinant ALP for infantile hypophosphatasia has already started in Japan. In future, such enzyme replacement therapy is expected to be adapted to fetus. There are several reports of mesenchymal stem cell transplantation for osteogenesis imperfecta fetus. These case reports have showed that stem cell transplantation is safe and to some extent works in patients. No clinical trial for gene therapy has been reported. Recently, the study of gene therapy of using HPP fetal mouse showed an excellent therapeutic effect. Fetal therapy of skeletal dysplasias is still the stage of research because of the safety and the ethical issues. However, in order to treat severe cases of skeletal dysplasias which abnormal development has been already completed at birth, fetal therapy at an early stage would be demanded.

The role of phosphatases in the initiation of skeletal mineralization.

Endochondral ossification is a carefully orchestrated process mediated by promoters and inhibitors of mineralization. Phosphatases are implicated, but their identities and functions remain unclear. Mutations in the tissue-nonspecific alkaline phosphatase (TNAP) gene cause hypophosphatasia, a heritable form of rickets and osteomalacia, caused by an arrest in the propagation of hydroxyapatite (HA) crystals onto the collagenous extracellular matrix due to accumulation of extracellular inorganic pyrophosphate (PPi), a physiological TNAP substrate and a potent calcification inhibitor. However, TNAP knockout (Alpl(-/-)) mice are born with a mineralized skeleton and have HA crystals in their chondrocyte- and osteoblast-derived matrix vesicles (MVs). We have shown that PHOSPHO1, a soluble phosphatase with specificity for two molecules present in MVs, phosphoethanolamine and phosphocholine, is responsible for initiating HA crystal formation inside MVs and that PHOSPHO1 and TNAP have nonredundant functional roles during endochondral ossification. Double ablation of PHOSPHO1 and TNAP function leads to the complete absence of skeletal mineralization and perinatal lethality, despite normal systemic phosphate and calcium levels. This strongly suggests that the Pi needed for initiation of MV-mediated mineralization is produced locally in the perivesicular space. As both TNAP and nucleoside pyrophosphohydrolase-1 (NPP1) behave as potent ATPases and pyrophosphatases in the MV compartment, our current model of the mechanisms of skeletal mineralization implicate intravesicular PHOSPHO1 function and Pi influx into MVs in the initiation of mineralization and the functions of TNAP and NPP1 in the extravesicular progression of mineralization.

Specific osseous spurs in a lethal form of hypophosphatasia correlated with 3D prenatal ultrasonographic images.

BACKGROUND: Hypophosphatasia is an osseous dysplasia with highly variable clinical expression, ranging from a recessive lethal prenatal type to late onset dominant short stature with premature shedding of teeth. Lethal forms of hypophosphatasia include short limb dwarfism with lack of ossification, especially on the vertebral bodies, very slender ribs and clavicles, and bowed, short lower extremities, with a bifid aspect of the diaphyses. Alkaline phosphatase is abnormally low in liver, bone, kidney and plasma. METHODS: We present here the prenatal images of a lethal form of hypophosphatasia, diagnosed precociously because of specific osseous spurs in a context of recurrent short limb dwarfism. RESULTS: Prenatal 3D ultrasonography has shown these spurs as early as 18 weeks. Molecular biology found compound heterozygous mutations in the gene TNSALP. CONCLUSION: In a context of short limb dwarfism, the search for these specific osseous spurs orient strongly toward the diagnosis of lethal hypophosphatasia.

Mild hypophosphatasia mimicking severe osteogenesis imperfecta in utero: bent but not broken.

We describe a fifth instance of hypophosphatasia presenting with prenatal findings suggestive of a very severe bone dysplasia but with a subsequently benign course. Spontaneous improvement of long-bone angulation began prenatally. The postnatal course has been encouraging. This sixth clinical form of hypophosphatasia, which we suggest should be called the benign prenatal form of hypophosphatasia, should be added to the differential diagnostic possibilities considered when angulation or bowing of long bones is discovered prenatally.