Hypophosphatasia, Childhood

A number sign (#) is used with this entry because childhood hypophosphatasia can be caused by homozygous, compound heterozygous, or heterozygous mutation in the ALPL gene (171760) on chromosome 1p36.

Description

Hypophosphatasia 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 241500). All of these forms are allelic.

Clinical Features

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.

Molecular Genetics

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).