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Other entities represented in this entry:
SNOMEDCT: 20756002, 708672004; ORPHA: 247676, 247685, 436; DO: 0110913;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.12 | Hypophosphatasia, adult | 146300 | Autosomal dominant; Autosomal recessive | 3 | ALPL | 171760 |
| 1p36.12 | Odontohypophosphatasia | 146300 | Autosomal dominant; Autosomal recessive | 3 | ALPL | 171760 |
A number sign (#) is used with this entry because of evidence that adult hypophosphatasia (HPPA) is caused by heterozygous or compound heterozygous mutation in the gene encoding tissue-nonspecific alkaline phosphatase (ALPL; 171760) on chromosome 1p36.
Fraser (1957) classified forms of hypophosphatasia (HPP) according to age of onset: perinatal (see 241500), infantile (241500), childhood (241510), and adult. Whyte (1988) indicated a fifth form of hypophosphatasia with primarily only dental manifestations, referred to as odontohypophosphatasia (HPPO). All of these forms are allelic.
In the family reported by Silverman (1962), a father and 2 sons had hypophosphatasia. The paternal grandmother may have been affected. No evidence of heterozygosity was obtained in the propositus' wife or 2 unaffected children. Clinical features were early loss of teeth, bowed legs diagnosed as rickets and requiring osteotomy, and beaten-copper appearance of skull x-ray. The propositus had served in the U.S. Air Force. Danovitch et al. (1968) also suggested dominant inheritance as the mechanism in the family they studied. Three female cousins, the daughters of 3 sisters, and their mothers had low serum alkaline phosphatase and elevated urinary phosphoethanolamine. Two of the cousins had premature loss of primary teeth. Intestinal alkaline phosphatase was normal. Jardon et al. (1970) described a woman who was asymptomatic until age 50 years. She showed pseudofracture of the proximal femur and calcification of paraspinous ligaments like those in adults with hypophosphatemic rickets (see 307800). Bixler et al. (1974) observed affected persons in 3 generations. Bixler (1976) referred to 4 kindreds showing autosomal dominant inheritance, and a fifth described to him by another worker. Electrophoretic abnormality of isozymes were described by Hosenfeld and Hosenfeld (1973). The diagnosis often can be made first by the dentist who is asked to explain a child's early loss of deciduous incisors, usually before 3 years of age. Males were less severely affected in the kindred reported by Whyte et al. (1979). Expression is so mild in many of the persons presumed to have the dominant disorder that the mating of 2 such individuals might present as the phenotype of infantile hypophosphatasia (241500) in an offspring. 'A correct diagnosis is important, since vitamin D therapy, appropriate for most forms of osteomalacia, is of no benefit in hypophosphatasia and has led to inordinate hypercalcemia with resultant kidney damage' (Weinstein and Whyte, 1981).
Whyte et al. (1982) described a family in which 3 sisters had chondrocalcinosis and arthropathy as a complication. Whyte et al. (1982) showed that cultured skin fibroblasts are low in alkaline phosphatase; thus, since the enzyme deficiency is not limited to bone, the disorder is not a selective abiotrophy of osteoblasts. Whyte et al. (1985) found markedly increased circulating concentrations of pyridoxal-5-prime-phosphate (PLP) in all clinical forms of hypophosphatasia. The findings indicated that tissue-nonspecific alkaline phosphatase acts in vitamin B6 metabolism. The enzyme appears to function as an ectoenzyme to regulate extracellular but not intracellular levels of PLP substrate. Assays of circulating PLP concentration may be misleading in assessing vitamin B6 nutrition in disorders associated with altered alkaline phosphatase activity. The degree of plasma PLP elevation generally reflected the clinical severity of the disorder (Whyte, 1988). A small oral dose of pyridoxine (which is converted to PLP) has been shown to discriminate patients from normals and may be useful for heterozygote detection (Whyte, 1988). The elevation of PLP was observed in all forms of hypophosphatasia, which Whyte (1988) indicated as 5 in number: perinatal, infantile (241500), childhood (241510), adult, and a form with primarily only dental manifestations, which is referred to as odontohypophosphatasia.
Macfarlane et al. (1992) were impressed with the difference in severity in 2 sisters with hypophosphatasia. Both had early loss of primary teeth, but only 1 of them had clinical or radiologic manifestations: joint pains and peri- and intraarticular calcifications of joints of the hands, feet, and knees and calcification of the anterior spinous ligament in the lumbar area. The parents shared a common ancestor '6 generations back.' Chapple et al. (1992) described a family with affected members in 3 generations.
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.
Unger et al. (2002) and Morava et al. (2002) reported 3 patients with cleidocranial dysplasia (CCD; 119600) and secondary hypophosphatasia.
In Utero Manifestations
Moore et al. (1999) described 2 families with mild hypophosphatasia, apparently transmitted as an autosomal dominant trait, in which ultrasonography detected 4 affected fetuses with severe long bone bowing. In contrast to the progressive deterioration typical of both the perinatal and infantile forms of hypophosphatasia, these skeletal defects improved spontaneously during infancy and early childhood. Biochemical evidence of hypophosphatasia was present in both families, and in 1 family, a mutation in the ALPL gene was identified (171760.0009). The authors noted that the prognosis for this condition was considerably better than for more severe forms of hypophosphatasia and for many other disorders that cause long bone bowing in utero.
Pauli et al. (1999) described an additional case with hypophosphatasia presenting with prenatal findings suggestive of a very severe bone dysplasia but with a subsequently benign course. Repeat late-gestation ultrasonography documented that improvement was already occurring prior to delivery. The authors emphasized the need to add spontaneously improving hypophosphatasia to the list of disorders presenting with in utero bony angulation or bowing.
Whyte et al. (2007) reported treatment of a middle-aged woman who sustained a slowly healing metatarsal stress fracture (MTSF) and then 2 enlarging MTSFs and a spontaneous proximal femur fracture. She carried a heterozygous ALPL missense mutation (D378V; 171760.0009). Pain persisted at all fracture sites. Hypophosphatasia was diagnosed as a result of low ALP activity and elevated inorganic phosphate and pyridoxal 5-prime-phosphate concentrations in serum. Teriparatide (TPTD) (recombinant human PTH 1-34), 20 micrograms, was injected subcutaneously daily in an attempt to enhance osteoblast synthesis of tissue-nonspecific ALP (TNSALP). Six weeks later, all fracture pain improved, and resolved after 4 months. Radiographs of the enlarging MTSFs showed repair after 2-4 months. The femur fracture partially mended after 2 months and then healed. Additionally, hypophosphatasemia and hyperphosphatemia corrected, and biochemical markers of bone remodeling increased as long as TPTD (given for 18 months) was continued.
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.
In a 65-year-old woman with adult hypophosphatasia, Henthorn et al. (1992) identified compound heterozygosity for missense mutations in the ALPL gene (171760.0003 and 171760.0008).
Mornet (1999) tested 2 large families with adult hypophosphatasia. In 1 family, hypophosphatasia was dominantly inherited and was due to a missense mutation in the ALPL gene; in the other family, adult hypophosphatasia was recessively transmitted and was due to compound heterozygosity for a missense mutation and a splicing mutation in the ALPL gene.
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 mother and son with odontohypophosphatasia, low serum alkaline phosphatase, and no evidence of fractures, Herasse et al. (2003) identified heterozygosity for a missense mutation in the ALPL gene (171760.0018).
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.
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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]
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Morava, E., Karteszi, J., Weisenbach, J., Caliebe, A., Mundlos, S., Mehes, K. Cleidocranial dysplasia with decreased bone density and biochemical findings of hypophosphatasia. Europ. J. Pediat. 161: 619-622, 2002. [PubMed: 12424590] [Full Text: https://doi.org/10.1007/s00431-002-0977-x]
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