Phenotypically dissimilar hypophosphatasia in two sibships

Macfarlane, J. D.; Kroon, Herman M.; Harten, J.J. van der

doi:10.1002/ajmg.1320420124

Cited by 31 publications

(15 citation statements)

References 22 publications

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“…Therefore, patients with different clinical types existed in the same family in this case. Similar cases have been described in the same family with childhood-type and adult-type disease [3,24].…”

Section: Discussionsupporting

confidence: 78%

Importance of deletion of T at nucleotide 1559 in the tissue-nonspecific alkaline phosphatase gene in Japanese patients with hypophosphatasia

Orimo

Goseki‐Sone

Inoue

et al. 2002

Journal of Bone and Mineral Metabolism

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The tissue-nonspecific alkaline phosphatase (TNSALP) gene in four unrelated patients with hypophosphatasia was analyzed using polymerase chain reaction-single strand conformation polymorphism and the direct sequencing method. Of the participating patients, one had childhood-type and three had perinatal-type disease. All carried a deletion of T at cDNA number 1559, which causes a frameshift downstream from codon L503, as a heterozygote. In the childhood-type patient, an F310L mutation was detected in the opposite allele. Similarly, a perinatal-type patient carried a V3651 mutation in the opposite allele. Mutations in the opposite alleles were not detected in the other two patients with perinatal-type disease. In addition, although both parents carried the deletion as a heterozygote in two families with childhood-type and perinatal-type disease, patients from those families were not homozygous for the deletion. Several single-nucleotide polymorphisms (SNPs) were also detected, which were shown to be useful for haplotype analysis. Allele frequency of the deletion among Japanese patients was 36% (10 of 28 alleles) but none occurred in Caucasian patients. These findings indicate that regardless of clinical type, deletion in the TNSALP gene occurs frequently among Japanese patients. Furthermore, haplotype analysis using SNPs suggested that the deletion might have derived from more than a single founder.

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Section: Discussionsupporting

confidence: 78%

Importance of deletion of T at nucleotide 1559 in the tissue-nonspecific alkaline phosphatase gene in Japanese patients with hypophosphatasia

Orimo

Goseki‐Sone

Inoue

et al. 2002

Journal of Bone and Mineral Metabolism

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“…Two siblings of HPP in our case showed considerable discordant severity in the fetal period. Although genotype-phenotype correlations have been widely described with regard to HPP (Zurutuza et al, 1999), several reports have demonstrated the discordance in calcification and fetal growth in HPP siblings with the same ALPL gene mutation (Macfarlane, Kroon, & van der Harten, 1992). Stevenson et al (2008) showed discordant phenotype of HPP siblings, although both had compound heterozygous mutation in ALPL gene (c.526G>A and c.814C>T).…”

Section: Discussionmentioning

confidence: 96%

“…Although genotype-phenotype correlations have been widely described with regard to HPP (Zurutuza et al, 1999), several reports have demonstrated the discordance in calcification and fetal growth in HPP siblings with the same ALPL gene mutation (Macfarlane, Kroon, & van der Harten, 1992). Although genotype-phenotype correlations have been widely described with regard to HPP (Zurutuza et al, 1999), several reports have demonstrated the discordance in calcification and fetal growth in HPP siblings with the same ALPL gene mutation (Macfarlane, Kroon, & van der Harten, 1992).…”

Section: Discussionmentioning

confidence: 99%

Discordant fetal phenotype of hypophosphatasia in two siblings

Ikenoue

Miyakoshi

Ishii

et al. 2017

American J of Med Genetics Pt A

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Hypophosphatasia (HPP) is an autosomal recessive metabolic disorder with impaired bone mineralization due to mutations in the ALPL gene. The genotype-phenotype correlation of this disorder has been widely described. Here, we present two affected siblings, whose fetal phenotypes were discordant. A 31-year-old Japanese woman, G0P0, was referred to our institution because of fetal micromelia. After obstetric counseling, the pregnancy was terminated at 21 weeks' gestation. Post-mortem radiographs demonstrated severely defective mineralization of the skeleton. The calvarial, spinal, and tubular bones were mostly missing. Only the occipital bones, mandible, clavicles, ribs, one thoracic vertebra, ilia, and tibia were relatively well ossified. The radiological findings suggested lethal HPP. Genetic testing for genomic DNA extracted from the umbilical cord identified compound heterozygous mutations in the ALPL gene (c.532T>C, p.Y178H; c.1559delT, p.Leu520Argfs*86). c.532T>C was a novel variant showing no residual activity of the protein by the functional analysis. The parents were heterozygous carriers. In the next pregnancy, biometric values on fetal ultrasonography at 20 and 26 weeks' gestation were normal. At 34 weeks, however, a small chest and shortening of distal long bones came to attention. The neonate delivered at 41 weeks showed serum ALP of <5U/L. Radiological examination showed only mild thoracic hypoplasia and metaphyseal mineralization defects of the long bones. ALP replacement therapy was introduced shortly after birth, and the neonate was discharged at day 22 without respiratory distress. Awareness of discordant fetal phenotypes in siblings with HPP precludes a diagnostic error, and enables early medical intervention to mildly affected neonates.

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“…Seizures have also been reported in severe cases (Heitzman and Ferguson, 1967;. Hypophosphatasia is usually inherited as an autosomal recessive trait, although it can display variable expressivity and incomplete penetrance (Whyte et al, 1982;MacFarlane et al, 1992). Autosomal dominant inheritance of the adult form of hypophosphatasia has also been observed (Whyte et al, 1979).…”

Section: Introductionmentioning

confidence: 99%

Inactivation of two mouse alkaline phosphatase genes and establishment of a model of infantile hypophosphatasia

1997

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We report the inactivation, via homologous recombination, of two of the three active mouse alkaline phosphatase genes, i.e., embryonic (EAP) and tissue nonspecific (TNAP). Whereas expression of the EAP isozyme was abolished in all tissues that express EAP developmentally (such as the preimplantation embryo, thymus, and testis), the EAP knock‐out mice show no obvious phenotypic abnormalities. They reproduce normally and give birth to live offspring, indicating the nonessential role of EAP during embryonic development. Mice deficient in the TNAP gene mimic a severe form of hypophosphatasia. These TNAP −/− mice are growth impaired, develop epileptic seizures and apnea, and die before weaning. Examination of the tissues indicates abnormal bone mineralization and morphological changes in the osteoblasts, aberrant development of the lumbar nerve roots, disturbances in intestinal physiology, increased apoptosis in the thymus, and abnormal spleens. Our results indicate that, in the mouse, TNAP appears not to be essential for the initial events leading to bone mineral deposition but that TNAP seems to play a role in the maintenance of this process after birth. The other phenotypic manifestations may be a consequence of the lack of TNAP in the developing neural tube between stages E8.5 and E13.5 of embryogenesis. We hypothesize that the autonomic nervous system is compromised in these TNAP −/− mice. Dev. Dyn. 208:432–446, 1997. © 1997 Wiley‐Liss, Inc.

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Phenotypically dissimilar hypophosphatasia in two sibships

Cited by 31 publications

References 22 publications

Importance of deletion of T at nucleotide 1559 in the tissue-nonspecific alkaline phosphatase gene in Japanese patients with hypophosphatasia

Importance of deletion of T at nucleotide 1559 in the tissue-nonspecific alkaline phosphatase gene in Japanese patients with hypophosphatasia

Discordant fetal phenotype of hypophosphatasia in two siblings

Inactivation of two mouse alkaline phosphatase genes and establishment of a model of infantile hypophosphatasia

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