SNOMEDCT: 30174008; ORPHA: 247667, 436; DO: 0110915;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.12 | Hypophosphatasia, childhood | 241510 | Autosomal recessive | 3 | ALPL | 171760 |
A number sign (#) is used with this entry because childhood hypophosphatasia (HPPC) is caused by homozygous, compound heterozygous, or heterozygous mutation in the ALPL gene (171760) on chromosome 1p36.
Hypophosphatasia (HPP) is an inborn error of metabolism characterized clinically by defective bone mineralization and biochemically by deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase. Fraser (1957) classified forms of hypophosphatasia according to age of onset: perinatal (see 241500), infantile (241500), childhood, and adult (146300). Whyte (1988) indicated a fifth form of hypophosphatasia with primarily only dental manifestations, referred to as odontohypophosphatasia (see 146300). All of these forms are allelic.
Hu et al. (2000) described a 4-generation Texas family segregating autosomal dominant hypophosphatasia in both children and adults. The probands were a 6-year-old girl and her twin brother, who exhibited enamel hypoplasia and the premature loss of fully rooted anterior teeth at age 3.5 years; histologic examination of a tooth demonstrated a complete absence of cementum on the root surface. Lateral cephalometric radiograph showed multiple radiolucent spots with wormian bone in the occipital region, and enlarged pulp chambers in the mandibular canines and first primary molars were evident in the panorex. Radiographs of the long bones and chest revealed no additional skeletal abnormalities. Serum PLP and urine phosphoethanolamine (PEA) were abnormally high in both of the twins and a definitive diagnosis of hypophosphatasia was made, which was supported by findings in other members of the kindred.
Lia-Baldini et al. (2001) reported a 15-month-old girl with a phenotype suggestive of childhood hypophosphatasia, whose father had recurrent dental caries in his third decade despite being raised with fluoridated water, which the authors suggested represented odontohypophosphatasia. A paternal aunt had died at 7 days of apparent neonatal hypophosphatasia, with x-rays showing poorly mineralized ribs and skull, and the paternal grandmother lost all her permanent teeth in her third decade and subsequently developed osteoporosis.
Whyte et al. (2015) evaluated clinical and molecular features in 173 pediatric patients with hypophosphatasia, including 64 patients with odontohypophosphatasia, 38 with a mild childhood form, 58 with a severe childhood form, and 13 with the infantile form. On average, the 173 patients were shorter than the average for American children but had BMI z-scores within the normal range. First tooth loss occurred on average in the second year of life and was earlier as the degree of HPP became more severe. Both spine and hip bone density were decreased across the population and correlated to disease severity score. Bone density was lower in the appendicular compared to axial skeleton in the patients.
Kishnani et al. (2021) reported outcomes of a phase 2 efficacy and safety study of asfotase alfa in 19 adolescents and adults with childhood or adult hypophosphatasia, including 14 patients with autosomal recessive disease and 5 patients with autosomal dominant disease. Median inorganic phosphate (PPi) and PLP concentrations were normalized over 5 years of treatment in patients with both recessive and dominant disease. Median predicted distance walked on the 6-minute walk test remained within the normal range for patients with dominant disease over 4 years of treatment, and improved from below normal to normal in patients with autosomal recessive disease. Pain scores also improved in both recessive and dominant groups.
Whyte et al. (2015) evaluated clinical and molecular features in 173 pediatric patients with hypophosphatasia, including 64 with odontohypophosphatasia, 38 with mild childhood HPP, 58 with severe childhood HPP, and 13 with infantile HPP. Sequencing of the ALPL gene was performed in 105 patients, of whom 63 had a single heterozygous mutation consistent with autosomal dominant inheritance and 42 had compound heterozygous mutations consistent with autosomal recessive inheritance. No homozygotes were identified. An autosomal recessive inheritance pattern predominated in infantile and severe childhood-onset HPP.
In 2 sibs with the mild childhood form of hypophosphatasia, Henthorn et al. (1992) identified compound heterozygosity for 2 missense mutations in the ALPL gene (171760.0003 and 171760.0008).
In an 11-year-old child with hypophosphatasia, Zurutuza et al. (1999) identified compound heterozygosity for 2 missense mutations in the ALPL gene (171760.0013 and 171760.0014).
In a 4-generation Texas family segregating autosomal dominant hypophosphatasia in both children and adults, Hu et al. (2000) identified a heterozygous missense mutation in the ALPL gene (171760.0015).
In a 15-month-old girl and her father, who had phenotypes suggestive of childhood hypophosphatasia and odontohypophosphatasia, respectively, Lia-Baldini et al. (2001) identified heterozygosity for a missense mutation in the ALPL gene (171760.0021).
In a study of 44 adolescents and adults with childhood or adult hypophosphatasia, Kishnani et al. (2021) compared clinical characteristics between patients with autosomal recessive disease (30 patients) and autosomal dominant disease (14 patients). Median age of onset of symptoms in patients with recessive disease was 1 year, with a range of 0-4 years, and the median age of onset of symptoms in patients with dominant disease was 4 years, with a range of 0 to 36 years. Baseline inorganic phosphate (PPi) and pyridoxal 5-prime phosphate (PLP) concentrations were significantly higher in patients with recessive disease compared to dominant disease. A large percentage of both groups experienced bone pain, abnormal gait, and fractures. Abnormally shaped head or chest, bowing of the limbs, and delayed walking were more common in patients with recessive disease. Patients with dominant disease had a higher number of fractures.
Fraser, D. Hypophosphatasia. Am. J. Med. 22: 730-746, 1957. [PubMed: 13410963] [Full Text: https://doi.org/10.1016/0002-9343(57)90124-9]
Henthorn, P. S., Raducha, M., Fedde, K. N., Lafferty, M. A., Whyte, M. P. Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia. Proc. Nat. Acad. Sci. 89: 9924-9928, 1992. [PubMed: 1409720] [Full Text: https://doi.org/10.1073/pnas.89.20.9924]
Hu, J. C.-C., Plaetke, R., Mornet, E., Zhang, C., Sun, X., Thomas, H. F., Simmer, J. P. Characterization of a family with dominant hypophosphatasia. Europ. J. Oral Sci. 108: 189-194, 2000. [PubMed: 10872988] [Full Text: https://doi.org/10.1034/j.1600-0722.2000.108003189.x]
Kishnani, P. S., del Angel, G., Zhou, S., Rush, E. T. Investigation of ALPL variant states and clinical outcomes: an analysis of adults and adolescents with hypophosphatasia treated with asfotase alfa. Molec. Genet. Metab. 133: 113-121, 2021. [PubMed: 33814268] [Full Text: https://doi.org/10.1016/j.ymgme.2021.03.011]
Lia-Baldini, A. S., Muller, F., Taillandier, A., Gibrat, J. F., Mouchard, M., Robin, B., Simon-Bouy, B., Serre, J. L., Aylsworth, A. S., Bieth, E., Delanote, S., Freisinger, P., Hu, J. C.-C., Krohn, H.-P., Nunes, M. E., Mornet, E. A molecular approach to dominance in hypophosphatasia. Hum. Genet. 109: 99-108, 2001. [PubMed: 11479741] [Full Text: https://doi.org/10.1007/s004390100546]
Whyte, M. P., Zhang, F., Wenkert, D., McAlister, W. H., Mack, K. E., Benigno, M. C., Coburn, S. P., Wagy, S., Griffin, D. M., Ericson, K. L., Mumm, S. Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients. Bone 75: 229-239, 2015. [PubMed: 25731960] [Full Text: https://doi.org/10.1016/j.bone.2015.02.022]
Whyte, M. P. Personal Communication. St. Louis, Mo. 7/21/1988.
Zurutuza, L., Muller, F., Gibrat, J. F., Taillandier, A., Simon-Bouy, B., Serre, J. L., Mornet, E. Correlations of genotype and phenotype in hypophosphatasia. Hum. Molec. Genet. 8: 1039-1046, 1999. [PubMed: 10332035] [Full Text: https://doi.org/10.1093/hmg/8.6.1039]