Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 55236002; ORPHA: 247623, 247651, 436; DO: 0110914;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.12 | Hypophosphatasia, infantile | 241500 | Autosomal recessive | 3 | ALPL | 171760 |
A number sign (#) is used with this entry because infantile hypophosphatasia (HPPI) and perinatal hypophosphatasia (HPPN) are caused by homozygous or compound heterozygous mutation in the gene encoding tissue-nonspecific alkaline phosphatase (ALPL; 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, infantile, childhood (HPPC; 241510), and adult (HPPA; 146300). Whyte (1988) indicated a fifth form of hypophosphatasia with primarily only dental manifestations, referred to as odontohypophosphatasia (HPPO; see 146300). All of these forms are allelic.
Hypophosphatasia was first described by Rathbun (1948) in a 9-week-old male infant. In most cases, recessively inherited hypophosphatasia is a grave disorder, fatal in infancy. However, Bethune and Dent (1960) described 2 sisters in their 40s with skeletal trouble dating from childhood. Rathbun et al. (1961) stated that the heterozygote can be recognized by low serum levels of alkaline phosphatase. Pimstone et al. (1966) pointed out that premature shedding of teeth may be the only overt manifestation of the adult form. Three more or less distinct types can be identified: (1) type 1 with onset in utero or in early postnatal life, craniostenosis, severe skeletal abnormalities, hypercalcemia, and death in the first year or so of life; (2) type 2 with later, more gradual development of symptoms, moderately severe 'rachitic' skeletal changes and premature loss of teeth; (3) type 3 with no symptoms, the condition being determined on routine studies.
Eisenberg and Pimstone (1967) described a 50-year-old woman with hypophosphatasia but provided no family data. Macey (1940) reported 2 brothers with very low values for serum phosphatase who had 'rickets' in childhood and femoral pseudofractures in adulthood. O'Duffy (1970) reported on the occurrence of attacks of monoarthritis and widespread calcification of articular cartilage in a 51-year-old woman with hypophosphatasia. In a black kindred earlier reported by Whyte et al. (1986), Moore et al. (1990) observed 3 infants with hypophosphatasia. Although consanguinity was absent, the fathers of the 2 involved sibships were related as first cousins and the mothers were related as double first cousins.
Mehes et al. (1972) studied an inbred Hungarian village where among 198 school children they found 3 homozygotes and 12 heterozygotes for the juvenile form of hypophosphatasia. Study of the families brought to light 19 further cases. The study suggests that the severe infantile form and the mild juvenile type are separate. There was no instance of the infantile form in this group. Heterozygotes excreted phosphoethanolamine in the urine and suffered early loss of teeth. Among the offspring of a consanguineous marriage, Macfarlane et al. (1992) observed 1 sib with the lethal perinatal form of hypophosphatasia and a second with the infantile form. Although they were impressed with the differences in the 2, it is noteworthy that the child with the infantile form was severely affected and that the infant with the lethal perinatal form was 1 of dizygotic twins.
Scriver and Cameron (1969) described a female infant with classic clinical features of hypophosphatasia but consistently normal levels of alkaline phosphatase in plasma by the usual tests which use high substrate concentrations. It was found that at low substrate concentrations the patient's plasma hydrolyzed phosphoethanolamine more slowly than did normal plasma. This may be an allelic form of hypophosphatasia. Cole et al. (1985) restudied the patient of Scriver and Cameron (1969) at the age of 21 years. She was short (148 cm) and almost edentulous. She had had repeated midshaft femoral fractures that healed poorly, as well as scintigraphic evidence elsewhere of microfractures associated with bone pain. Although routine enzyme inhibition studies using p-nitrophenylphosphate yielded normal activity of the putative bone enzyme, serum and urinary phosphoethanolamine were elevated and serum pyridoxal-PO4 concentrations were markedly elevated--all characteristics of classic hypophosphatasia (Cole et al., 1986). Thus, pseudohypophosphatasia is an enzymopathy in which activity toward artificial substrates is preserved; lack of activity toward endogenous substrates results in a clinical picture indistinguishable from that of classic hypophosphatasia. Fedde et al. (1990) studied the substrate specificity of ALP and its subcellular localization in fibroblasts cultured from this patient. Defects in both were identified. There appeared to be 2 aberrant ALP species. One form had appropriate ecto-orientation as a lipid-anchored ectophosphatase of the plasma membrane but was preferentially deficient in activity toward natural substrates; the other ALP species had appropriate substrate specificity but was sequestered from substrates by its intracellular location. Moore et al. (1990) described a second case of pseudohypophosphatasia.
Rupprecht and Doerfel (1966) described sibs with an unusual syndrome characterized by micromelia with normal stature at birth, sometimes microcephaly, and severe epiphyseal and metaphyseal disturbances in the long bones, vertebrae and ribs. Of 6 sibs, a female and 2 males died at the age of a few weeks. All showed clonic convulsions, and at autopsy leptomeningeal hemorrhages. Spranger (1974) subsequently determined that the disorder in these sibs was hypophosphatasia.
Wolff and Zabransky (1982) described a case of the congenital and lethal form. There was no bony cranial vault and all 4 limbs were short, thick and bowed. In addition to phosphoethanolamine (PEA), inorganic pyrophosphate (PPi), which is also a substrate of alkaline phosphatase, is elevated in plasma and in the urine. The pathogenesis of the bone disease may be related to PPi, a putative endogenous inhibitor of bone mineralization. The designation phosphoethanolaminuria is obviously inappropriate. Cementogenesis as well as osteogenesis is defective in hypophosphatasia; the defect in the former leads to early exfoliation of teeth. The observations of Eastman and Bixler (1982, 1983) suggested that the infantile and adult forms of HPP may be allelic.
Olsson et al. (1996) described the dental abnormalities in a 23-year-old man with hypophosphatasia first diagnosed at the age of 8 months. Histologically and radiographically verified signs of the condition were present in the permanent dentition. The findings included a reduced level of the marginal alveolar bone supporting the upper central incisors, which had to be extracted. The molars displayed large coronal pulp chambers. Histologically, the upper incisors demonstrated abnormal root cementum, with areas of dentin resorption, as well as disturbances of the mineralization of the coronal dentin. The patient also had signs of abnormal root resorption of molars.
The clinical signs in the perinatal type of hypophosphatasia show considerable overlap with osteogenesis imperfecta congenita (166210) and with achondrogenesis type IA (200600). Vandevijver et al. (1998) pointed out that, if present, 'spurs of the limbs are diagnostic for hypophosphatasia.' They presented a case of the lethal neonatal form of hypophosphatasia in which large skin-covered thornlike structures (spurs) extended from the lateral and medial sides of the knee joints and smaller ones from the lateral side of both elbows. Typical 'Bowdler spurs' are located symmetrically on the midshaft of the long bones (fibula, ulna, and radius) and underlie skin dimples. They can only be seen by x-ray. In contrast to the midshaft type of spurs, the joint variety as described in this case had been found by Goldstein et al. (1987), Spranger (1988), and Shohat et al. (1991). Sections of these spurs show disorganized bone and irregular calcification.
Unger et al. (2002) and Morava et al. (2002) reported 3 patients with cleidocranial dysplasia (CCD; 119600) and secondary hypophosphatasia.
The transmission pattern of infantile hypophosphatasia in the family reported by Weiss et al. (1988) was consistent with autosomal recessive inheritance.
Igbokwe (1985) proposed a multiple allele system to explain the inheritance of hypophosphatasia in its several forms. He designated the 3 alleles as H(N), H(C), and H(I). H(I) homozygosity is lethal. The genotype of childhood hypophosphatasia is H(C)H(C) or H(C)H(I). Adult hypophosphatasia results from heterozygosity for either H(C) or H(I).
Whyte et al. (2015) evaluated clinical and molecular features in 173 pediatric patients with hypophosphatasia, including 64 with HPPO, 38 with mild HPPC, 58 with severe HPPC, and 13 with HPPI. 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.
Warshaw et al. (1971) demonstrated that long-chain triglycerides cause a rise in serum alkaline phosphatase in hypophosphatasia. Medium-chain triglycerides which are absorbed by the portal route cause no such rise. Residual phosphatase activity in this disorder is probably intestinal in origin to a significant extent, a conclusion supported by the finding of normal intestinal alkaline phosphatase by biopsy.
Vanneuville and Leroy (1979) found that alkaline phosphatase was normal in intestine and placenta from cases of hypophosphatasia but very low in liver, bone, kidney and plasma, indicating different genetic control.
In fibroblasts from 14 patients with perinatal or infantile hypophosphatasia, Weiss et al. (1989) found deficiency in liver/bone/kidney alkaline phosphatase activity but found expression of apparently full-sized liver/bone/kidney ALP mRNA at normal levels. Bone specimens from one of the patients were found to be deficient in histochemical ALP but contained immunologic cross-reactive material detected by anti-human liver ALP antiserum.
Chodirker et al. (1990) emphasized the usefulness of elevated serum phosphate level for carrier detection, in addition to serum alkaline phosphatase activity and urinary phosphoethanolamine excretion.
Prenatal Diagnosis
Greenberg et al. (1988) used RFLP markers to exclude infantile hypophosphatasia in a Mennonite fetus known to be at 25% risk. Both Greenberg et al. (1990) and Kishi et al. (1991) performed prenatal diagnosis using linked DNA markers. In the family they studied, Kishi et al. (1991) pointed out that serum alkaline phosphatase activities in the mother, a heterozygous carrier, fell within the normal range, while those in the father and paternal grandmother were below normal. Urinary phosphoethanolamine levels were not increased in any of the heterozygous carriers.
Zankl et al. (2008) reported ultrasonographic findings in a fetus with perinatal lethal hypophosphatasia later confirmed by genetic analysis. At 18 weeks' gestation, the long bones were very short with cupping of the metaphyses. The ribs were short and beaded, and there was decreased mineralization of the skull and spine, especially in the thoracic segment. There was also a large unilateral cleft lip and palate, which the authors believed was unrelated to the main disorder. Zankl et al. (2008) discussed the differential diagnosis, which includes includes other conditions presenting with short limbs and hypomineralization of the skeleton, in particular osteogenesis imperfecta type II and achondrogenesis/hypochondrogenesis (see, e.g., 200610). The authors concluded that prenatal diagnosis of perinatal lethal hypophosphatasia is possible through 2D and 3D ultrasound detection of characteristic features, including osseous spurs, patchy ossification pattern, undermineralization of thoracic spine, and cupped metaphyses.
Stevenson et al. (2008) reported a child with autosomal recessive hypophosphatasia diagnosed sonographically with long bone deformity at 18 weeks' gestation, but who had spontaneous prenatal and postnatal improvement. They concluded that prenatal detection by sonography of bowing of long bones from hypophosphatasia, even with autosomal recessive inheritance, does not necessarily predict lethality but can represent variable expressivity or the effects of modifiers on the alkaline phosphatase defects.
Whyte et al. (1984) found that enzyme replacement in the infantile form of hypophosphatasia by weekly intravenous infusions of bone alkaline phosphatase-rich plasma from patients with Paget disease (see 167250) resulted in no radiographic evidence of arrest of progressive osteopenia or improvement in the rachitic defect, despite substantial rise in circulating enzyme activity and in 1 patient maintenance of levels in the normal range for nearly 2 months. They interpreted the result as indicating that the isoenzyme functions in situ during normal skeletal mineralization.
Whyte et al. (1986) reported remarkable results of plasma therapy that they interpreted as indicating that the mutation in this disorder does not reside in the structural gene for tissue-nonspecific (bone/liver/kidney) alkaline phosphatase. After a 3-month course of weekly intravenous infusions of pooled normal plasma, they observed gradual and prolonged normalization of circulating alkaline phosphatase levels, roentgenographic and histologic evidence of remineralization of bone, and appearance of alkaline phosphatase activity in osteoblasts and chondrocytes. The enzyme that appeared in the circulation had properties suggesting skeletal origin. Clinical improvement accompanied the other changes. Whyte et al. (1986) suggested that infantile hypophosphatasia may result from absence or inactivation of a circulating factor(s) that regulates the expression of the gene for tissue-nonspecific alkaline phosphatase. Whyte (1990) had no further explanation for the dramatic result. Studies of DNA from these individuals failed to show abnormality in the coding region of the ALPL gene. This kindred was also reported by Moore et al. (1990) because of the interest of the pattern of inheritance.
Litmanovitz et al. (2002) reported a patient with neonatal presentation of hypophosphatasia who had significant hypotonia with down-gaze nystagmus. At 21 hours of age subtle seizures were detected. Infection and metabolic evaluations were normal except for a serum ALP level of 0-2 IU. A skeletal survey revealed hypomineralization of the skull with wormian bones, fracture of the right clavicle and distal radius, cupping of long bone metaphyses, and vertical striation of the distal femur but no bone spurs. On the sixth day of life, while being treated with phenobarbital, the patient had another episode of seizures. Intravenous administration of pyridoxine 100 mg immediately stopped the convulsions and slightly changed the burst-suppression pattern of the EEG. Pyridoxine was therefore continued at 50 mg twice daily, with subsequent normalization of the EEG within 2 weeks. No further seizures were noted, but the patient remained severely hypotonic. She died at 5 months due to recurrent pneumonia.
Cahill et al. (2007) reported follow-up on an 8-year-old girl who had been treated at age 9 months for infantile hypophosphatasia with implanted donor bone fragments and cultured osteoblasts. Four months after transplantation, her radiographs showed improved skeletal mineralization. Twenty months later, PCR analysis of adherent cells cultured from recipient bone suggested the presence of small amounts of paternal (donor) DNA despite the absence of hematopoietic engraftment. At age 8 years, the child was active and growing, and had the clinical phenotype of the more mild, childhood form of hypophosphatasia. Cahill et al. (2007) suggested that, after immune tolerance, donor bone fragments and marrow may provide precursor cells for distribution and engraftment in the skeletal microenvironment in patients with infantile hypophosphatasia to form tissue-nonspecific isoenzyme of alkaline phosphatase-replete osteoblasts that can improve mineralization.
Whyte et al. (2012) reported the results of a multinational, open-label study of treatment with ENB-0040, a recombinant human tissue-nonspecific alkaline phosphatase (TNSALP; 171760) coupled to a deca-aspartate motif for bone targeting, an enzyme replacement therapy for infantile hypophosphatasia. The primary objective was the healing of rickets, as assessed by means of radiographic scales. Motor and cognitive development, respiratory function, and safety were evaluated, as well as the pharmacokinetics and pharmacodynamics of ENB-0040. Of the 11 patients recruited, 10 completed 6 months of therapy, and 9 completed 1 year. Healing of rickets at 6 months in 9 patients was accompanied by improvement in developmental milestones and pulmonary function. Elevated plasma levels of the TNSALP substrates inorganic pyrophosphate and pyridoxal 5-prime-phosphate diminished. Increases in serum parathyroid hormone accompanied skeletal healing, often necessitating dietary calcium supplementation. There was no evidence of hypocalcemia, ectopic calcification, or definite drug-related serious adverse events. Low titers of anti-ENB-0040 antibodies developed in 4 patients, with no evident clinical, biochemical, or autoimmune abnormalities at 48 weeks of treatment. Whyte et al. (2012) concluded that ENB-0040 was associated with improved findings on skeletal radiographs and improved pulmonary and physical function in infants and young children with life-threatening hypophosphatasia. Five of the 11 patients had perinatal onset of hypophosphatasia and the other 6 had infantile onset. Consent for treatment was withdrawn for 1 of the 11 patients because of irritability, oxygen desaturation, rigors, and low-grade fever during receipt of the intravenous dose. That child showed substantial skeletal deterioration. The other 10 patients completed 6 months of treatment and entered the extension study. One patient died from sepsis after 7.5 months of therapy. Nine patients were receiving treatment at the conclusion of the study with an average treatment duration of 18 months (range, 12 to 26).
Gene Editing
Nakano et al. (2019) derived induced pluripotent stem cells (iPSCs) from dermal fibroblasts from 2 individuals with hypophosphatasia. One patient was homozygous for a c.1559delT mutation in the ALPL gene, and the other was compound heterozygous for c.1559delT and a c.678G-A mutation. Nakano et al. (2019) used TALEN-mediated site-directed gene editing to correct one copy of the c.1559delT mutation in iPSCs from the patient with the homozygous mutation and to correct the c.1559delT mutation in iPSCs from the patient with compound heterozygous mutations. After removal of the selection cassette, the corrected, patient-derived iPSCs exhibited half of the ALP activity compared to control iPSCs, suggesting heterozygous correction of the ALPL mutations. Osteoblasts differentiated from the gene-edited patient-derived iPSCs similarly exhibited ALP activity that was elevated compared to the uncorrected patient-derived osteoblasts, but reduced compared to controls. Osteoblasts generated from the gene-edited patient-derived iPSCs also displayed calcification compared to uncorrected cells. Additionally, the gene-edited osteoblasts had increased expression of osteoblast-specific genes, including COL1A1 (120150) and osteocalcin (112260), compared to uncorrected cells. Nakano et al. (2019) concluded that gene correction in iPSCs may be a candidate treatment for patients with hypophosphatasia.
Chodirker et al. (1987) performed linkage analysis in 6 nuclear families with hypophosphatasia, all of Mennonite background but apparently unrelated. They demonstrated linkage between the disorder and the and the Rh locus (maximum lod score of 4.76 at theta = 0.04). This finding is consistent with the location of the structural gene for liver/bone/kidney alkaline phosphatase (171760), which has been linked to Rh on 1p.
Greenberg et al. (1990) obtained a maximum combined lod score of 13.25 at theta = 0.0 for linkage between the clinical phenotype of HOPS and RFLPs of the ALPL gene; this allowed for the regional assignment of the HOPS gene to chromosome 1p36.1-p34. They estimated that 1 in every 25 Manitoba Mennonites is a HOPS carrier.
In a male infant with hypophosphatasia who was born of second-cousin parents and died at 3 months of age, Weiss et al. (1988) identified homozygosity for a mutation in the ALPL gene (A162T; 171760.0001). Functional studies demonstrated that the A162T mutation abolished expression of active enzyme. The parents and other clinically unaffected relatives who were found to be heterozygous for the mutation all had liver/bone/kidney alkaline phosphatase activity levels that were below the normal range.
In studies of fibroblasts from 4 unrelated patients with infantile hypophosphatasia, Henthorn et al. (1992) identified compound heterozygosity for mutations in the ALPL gene (see, e.g., 171760.0002-171760.0009).
In Manitoba Mennonites with the perinatal, lethal form of hypophosphatasia, Greenberg et al. (1993) identified a homoallelic gly317-to-asp mutation in the ALPL gene (171760.0010).
Vandevijver et al. (1998) stated that D. Bowdler first described spurs in this disorder in an abstract at the 7th meeting of Pediatric Radiology of the German speaking countries in Zurich in 1970.
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Nakano, C., Kitabatake, Y., Takeyari, S., Ohata, Y., Kubota, T., Taketani, K., Kogo, M., Ozono, K. Genetic correction of induced pluripotent stem cells mediated by transcription activator-like effector nucleases targeting ALPL recovers enzyme activity and calcification in vitro. Molec. Genet. Metab. 127: 158-165, 2019. [PubMed: 31178256] [Full Text: https://doi.org/10.1016/j.ymgme.2019.05.014]
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