| Radiographic analysis of 24 cases of hypophosphatasia (H) from 9 Paediatric Centres was performed. 3 cases were of neonatal (lethal), 18 cases of infantile (severe) and 3 cases of late (benign) type. Some of the patients were in reality borderline cases between these groups. In the authors' material all the patients showed radiographic signs of the disease. These were divided into diagnostic, characteristic and suggestive features. All of the patients had in common generalised (usually irregular) osteoporosis, generalised (usually irregular) metaphyseal changes, craniostenosis (13 of 18 infantile cases) or widened cranial sutures and ofter bowing of the long bones. Besides the well know radiographic features of hypophosphatasia some less well known, rare or 'new' ones such as, 1. spurs of the long bones (Bowdler sign), 2. distal femoral central metaphyseal defects and epiphyseal defects, 3. S-like deformities of the tibiae, 4. abnormal shape of the distal phalanges of the fingers, 5. multiple rib fractures and slender bones, 6. wedging of the lower thoracic and upper lumbar vertebrae, 7. partial premature fusion of the epiphyses, 8. nephrocalcinosis, 9. loss of lamina dura around the teeth, 10. variation in radiographic appearances of a pair of siblings with lethal form, and, 11. rapid changes in roentgen appearances. are discussed. In two of our patients (siblings) phosphoethanolamine was undetectable in the urine. The authors doubt if a normal skeletal survey may be present at any stage in any of the three major types of hypophosphatasia. ( info) |
| hypophosphatasia (HOPS) is an inherited disorder characterized by the defect of skeletal mineralization due to tissue-nonspecific alkaline phosphatase (TNSALP) deficiency. In this study we analyzed the TNSALP gene from a Japanese patient with HOPS, his parents, his brother, and unrelated normal controls. The proband is a 25-year-old Japanese male diagnosed with childhood hypophosphatasia. The patient reported premature exfoliation of the deciduous teeth and severe periodontal destruction of the permanent dentition. Genomic dna was extracted from peripheral leukocytes of subjects. Eleven pairs of the polymerase chain reaction (PCR) primers were used to amplify the coding exons according to the published sequence data of the TNSALP gene. The PCR amplified samples were subjected to PCR-single strand conformation polymorphism (SSCP) analysis and PCR-allele specific oligonucleotide (ASO) analysis. In PCR-SSCP analysis of the patient's genomic dna, the fragments containing exons 9 and 10 revealed abnormal mobilities. These abnormal mobilities (exons 9 and 10) were also found from his mother and father's genomic dna, respectively. The sequencing analysis of the abnormal bands extracted from the SSCP gel showed a T to C transition at nucleotide position 1155 (T1155C) in exon 9 and G1320A in exon 10. PCR-ASO analysis confirmed these missense point mutations. PCR-ASO analysis also confirmed that mutation-specific oligonucleotides corresponded to the new mutations and did not hybridize with PCR products from normal control genomic DNAs. These results indicated that the proband was a compound heterozygote who inherited T1155C mutation in exon 9 from the mother and G1320A mutation in exon 10 from the father. Both of them are new missense point mutations and appear to cause significant changes in the structure and function of TNSALP. ( info) |
| 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. ( info) |
| We report on two families in which one or two children had a severe disorder of skeletal development detected by prenatal ultrasonography. The children died postnatally and showed typical radiological and biochemical findings of perinatal hypophosphatasia. Biochemical analysis revealed a low activity of alkaline phosphatase (AP) and a high value of pyridoxal-5-phosphate (PLP), one of its natural substrates. The screening for mutations of the tissue nonspecific alkaline phosphatase (TNSALP) gene showed homozygosity for a point mutation (G 317 --> D) in the two affected children of the first family. The affected child of the second family was homozygous for a nonsense mutation (R 411 --> X). family screening revealed that the determination of AP and PLP is helpful for detection of heterozygotes. However, heterozygote children had values of AP in the lower normal range during phases of rapid growth. The determination of PLP proved to be more sensitive in these cases. It should be kept in mind that during the last trimester of gestation there is an increase in maternal AP activity and a normalization of PLP due to placental AP, which is not affected. Therefore, in the course of a prenatal diagnosis in an index case, paternal blood should be analyzed in parallel. For detailed genetic counseling and early prenatal diagnosis in following pregnancies, the possibility of mutation analysis should be used. ( info) |
| The authors describe a neonate who was diagnosed with "perinatal hypophosphatasia". The clinical manifestations in this patient were small head size, soft calvarium (caput membranaceum), and short bowing forearms and legs. Laboratory investigations revealed hypercalcemia at 12.7 mg/dl, hyperphosphatemia 8.6 mg/dl, and extremely low alkaline phosphatase 0 unit/L. Roentgenographic studies of the skull showed calcification only at frontal bone and base of the skull. Spines were small and flattened. Long bones were hypomineralized and deformed. The functions of alkaline phosphatase to bone development and mineralization were reviewed. Because perinatal hypophosphatasia is a fatal condition and inherited as an autosomal recessive pattern, prenatal diagnosis is necessary. The most reliable and suitable method in our facility is serial ultrasonography from which the diagnosis can be made by the second trimester. ( info) |
6/107. Asp361Val Mutant of alkaline phosphatase found in patients with dominantly inherited hypophosphatasia inhibits the activity of the wild-type enzyme. hypophosphatasia is characterized by the hypomineralization of bone associated with the mutation of the tissue-nonspecific alkaline phosphatase (TNSALP) gene. Although the disease is usually autosomal recessive, an autosomal dominant form is also recognized. Approximately 50 mutations have been found in the TNSALP gene in patients with hypophosphatasia. However, the mutations identified to date do not seem to account for the dominantly inherited form of the disease. We have examined a German family in which the father and all 4 children were affected with hypophosphatasia, whereas the mother was healthy. The affected members of this family showed premature loss of deciduous teeth at or shortly before 2 yr of age and low levels of serum ALP with elevated levels of urinary phosphoethanolamine. dna analysis by direct sequencing revealed a heterozygous missense mutation that caused the conversion of amino acid Asp to Val at position 361 (D361V) in the patients. Another substitution was detected in exon 12 (Val to Ala conversion at codon 505: V505A) in 1 allele of the mother and 3 children, indicating no association of the substitution with the disease. Reconstruction experiments demonstrated that the D361V mutant protein lost its enzymatic activity and that it inhibited the function of wild-type enzyme when coexpressed in COS-7 cells. On the other hand, the V505A mutant exhibited enzymatic activities equal to those of the wild-type ALP. It is likely that the mutant D361V protein forms dimers with the wild-type protein, and the protein-protein interaction contributes to the dominant effect of the mutant D361V. The mutation that causes D361V is the first one proven to be associated with the dominant form of hypophosphatasia. ( info) |
7/107. Pseudohypophosphatasia. Two rare cases of pseudohypophosphatasia in two siblings which so far, to best of our knowledge have not been reported. ( info) |
| coffin-lowry syndrome was first described by Coffin in 1966 and later by Lowry in 1971. Several oral manifestations have been described previously. We report a case with additional information on the histology of prematurely exfoliated teeth. ( info) |
| We report the case of a male patient with infantile hypophosphatasia associated with severe hypercalcaemia and mild respiratory insufficiency. At the age of 2 months, severe hypercalcaemia, low levels of serum alkaline phosphatase activity, and elevated urinary excretion of calcium and phosphoethanolamine were noted. Radiological findings showed generalized osteopenia and disturbed and irregular ossification of the metaphyses. Their involvement had spontaneously improved at the age of 6 months. A genetic study revealed that the tissue-nonspecific alkaline phosphatase gene of the patient had two novel mutations, K207E and G409C, derived from the mother and father, respectively. A reconsitution experiment revealed that both mutant gene products had low but significant enzymatic activity. CONCLUSION: The detection of tissue-nonspecific alkaline phosphatase gene mutations and expression studies to determine the enzymatic activity of mutant gene products was useful for assessing the clinical course of this patient with hypophosphatasia. ( info) |
10/107. Early prenatal sonographic diagnosis of congenital hypophosphatasia. A pregnant woman of 14 weeks' gestation was sonographically examined due to large-for-dates uterine size. The ultrasound examination showed poor ossification of all bony structures. All limbs were shortened with no evidence of fractures. The echodensity approximated that of the surrounding organs. No acoustic shadowing was observed. Based on these sonographic findings, skeletal dysplasia and short-limb dwarfism were diagnosed, the most likely condition being congenital hypophosphatasia. Early cordocentesis was successfully performed at 15 weeks' gestation to determine fetal alkaline phosphatase concentration. This was undetectable. The prenatal diagnosis of congenital hypophosphatasia was made. After counselling, the woman decided to opt for termination of pregnancy which was performed vaginally. Post-abortion findings confirmed the prenatal diagnosis. To our knowledge, this is the earliest sonographic diagnosis of this condition reported. ( info) |