Altered Bone Matrix Proteins
Disorders of Alkaline Phosphatase
Adult hypophosphatasia (HPP) is an inherited disorder of bone metabolism caused by inactivating mutations of the ALPL gene, encoding tissue non-specific alkaline phosphatase (see also Perinatal - Infantile - Childhood Hypophosphatasia (HPP))
(OMIM #146300)
Adult hypophosphatasia (HPP) is an inherited disorder of bone metabolism caused by inactivating mutations of the ALPL gene, encoding tissue non-specific alkaline phosphatase (see also Perinatal - Infantile - Childhood Hypophosphatasia (HPP)). The adult form of hypophosphatasia appears after middle age, and it is mainly characterized by osteomalacia, pseudofractures, pathologic fractures after minimal trauma, chondrocalcinosis, osteoarthropathy, as well as by muscle and joint pain. Sometimes the disease can be asymptomatic except the typical laboratory findings.
Bisphosphonates should not be used, since they may worsen the hypomineralization in HPP. Currently, Recombinant Human Tissue-Nonspecific Alkaline Phosphatase (Asfotase Alfa) was approved for HPP treatment in adults where evidence of the disease was present in childhood (see also Perinatal - Infantile – Childhood HPP).
Gene
ALPL gene, 1p36.12 (OMIM gene/locus number #171760). HPP is caused by any mutation in the ALPL gene that causes decreased TNSALP activity and increased levels of its substrates (about 275 mutations have been identified). The inheritance mechanism can be autosomal recessive or dominant.
Phenotype
Premature loss of primary and secondary teeth, severe dental caries, decreased alveolar bone, enlarged pulp chamber; osteomalacia recurrent fractures, long bone pseudofractures, calcium pyrophosphate arthropathy, chondrocalcinosis metatarsal, and stress fracture.
Main biochemical alterations
Low ALP, normal Ca, high Pi due to high TmP/GFR, high levels of ALP substrates: inorganic pyrophosphate (PPi), pyridoxal-5’-phosphate (PLP, the active metabolite of vitamin B6), and phosphoethanolamine (PEA).
Image
Fig. (a) X-ray (oblique view) and (b) MRI (axial view) of the left lateral proximal femur of a 32-year-old male patient diagnosed with adult HPP. A pseudofracture in the femoral neck is indicated by the arrow.
Reproduced from Osteoporos Int, Skeletal mineralization defects in adult hypophosphatasia - a clinical and histological analysis, 2011;22:2667-75, Barvencik F, Beil FT, Gebauer M, et al., with permission of Springer
Other resources:
Hypophosphatasia is a rare and heterogeneous inherited disorder characterised by defective bone mineralisation due to the impaired activity of the tissue-non-specific (liver/bone/kidney) iso- enzyme of ALP (TNSALP). TNSALP activity has an essential role for bone and teeth mineralization.
(OMIM phenotype number #241500)
Hypophosphatasia is a rare and heterogeneous inherited disorder characterised by defective bone mineralisation due to the impaired activity of the tissue-non-specific (liver/bone/kidney) iso- enzyme of ALP (TNSALP). TNSALP activity has an essential role for bone and teeth mineralization. Several forms of HPP exist, ranging from lethal to mild. HPP is divided into five types: perinatal, infantile, childhood and adult forms, and odontohypophosphatasia. Recently, a mild prenatal form has been described, as a sixth clinical form. The clinical diagnosis of HPP is based on radiological findings, bone mineral density measurements, and on biochemical assays. The clinical manifestations are highly variable, and depend on the type of mutation, inheritance mechanism, and age of onset. Perinatal, infantile, and childhood HPP are the most severe forms. The main clinical signs are: rickets, osteomalacia, fractures, teeth loss. Other systemic manifestations, in the case of severe forms, include: seizures, respiratory and kidney problems, chronic pain, etc.. The main diagnostic laboratory alterations include: low serum ALP and TNSALP activity and high levels of ALP substrates (inorganic pyrophosphate (PPi), pyridoxal-5’-phosphate (PLP, the active metabolite of vitamin B6), and phosphoethanolamine (PEA).
The treatment of HPP comprise the management of different clinical problems, such as chronic pain, musculo-articular-skeletal alterations, fractures, renal complications, psychological and neurological problems, and dental problems. Bisphosphonates or too high doses of vitamin D are contraindicated and potentially dangerous in the case of HPP. Currently, enzyme replacement therapy (ERT) with recombinant tissue non-specific alkaline phosphatase (TNSALP) is commercially available for patients with a confirmed diagnosis of pediatric onset HPP. Asfotase alfa replaces TNSALP activity at the site of deficiency, resulting in reductions in PPi and the availability of phosphate to bind to calcium and form hydroxyapatite with restoration of bone mineralization. Access to treatment is determined by clinical criteria and varies from country to country. Moreover, this treatment should be prescribed by specialists in a reference care center with expertise in the treatment of severe HPP.
Gene
ALPL gene, 1p36.12 (OMIM gene/locus number *171760). HPP is caused by any mutation in the ALPL gene that causes decreased TNSALP activity and increased levels of its substrates (about 275 mutations have been identified). The inheritance mechanism can be autosomal recessive or dominant.
Phenotype
- Perinatal HPP: Almost always fatal, irritability, periodic apnea with cyanosis, bradycardia, unexplained fever, myelophthisic anemia (due to excess osteoid and unmineralized cartilage), intracranial hemorrhage, profound bone hypomineralization with bone deformities, fractures, craniosynostosis, osteochondral spurs that may pierce the skin and protrude laterally from midshaft of the ulnas and fibulas, and dental abnormalities with deciduous teeth poorly formed.
- Infantile HPP: Postnatal but before 6 months of age, failure to thrive, hypotonia, bulging of the anterior fontanel, raised intracranial pressure and papilledema, proptosis, mild hypertelorism, brachycephaly, sclera may be blue, vitamin B6-responsive seizures, and rickets.
- Childhood HPP: After 6 months of age, premature loss of primary teeth (before 5 years) without tooth root resorption, non progressive myopathy, rickets, radiographic focal defect if cartilage that project from the growth plates into the metaphyses (tongues of radiolucency).
Main biochemical alterations
- Perinatal HPP: Low ALP, high Ca.
- Infantile HPP: Low ALP, high Ca, high Ur Ca, high Pi (in heterozygotes), high Pi, high Ur Pi.
- Childhood HPP: Low ALP, high Ca, normal Ca, high Pi due to high TmP/GFR, high Pi, high Ur PPi.
Fig. X-ray abnormalities of a patient affected by HPP (aged 9 years). (a) Distorted trabeculae and irregular osteoporosis with projection of non-ossified tissue (“tongue” of radiolucency, the upper limit shown by the arrows) into the medial metaphysis present in the proband at onset. The tibial curvature was clinically normal, not suggesting soft bone. (b) Fracture of the right femoral neck discovered on X-ray analysis performed because of hip pain in the proband at onset.
Reproduced from Eur J Pediat, Hypophosphatasia may lead to bone fragility: don't miss it, 2009;168:783-8, Moulin P, Vaysse F, Bieth E, et al., with permission of Springer.
Other resources:
Hyperphosphatasia with mental retardation syndrome (HPMRS), also called "Mabry syndrome", is a rare autosomal recessive form of intellectual disability, with facial dysmorphism, seizures, brachytelephalangy, and consistently elevated serum alkaline phosphatase (ALP)
(OMIM phenotype number #239300)
Hyperphosphatasia with mental retardation syndrome (HPMRS), also called "Mabry syndrome", is a rare autosomal recessive form of intellectual disability, with facial dysmorphism, seizures, brachytelephalangy, and consistently elevated serum alkaline phosphatase (ALP).
HPMRS type 1 is caused by homozygous or compound heterozygous mutation in the PIGV gene, which is a member of the glycosylphosphatidylinositol (GPI) anchor synthesis pathway. PIGV mutations leads to a defect in GPI anchor synthesis with a consequent reduction in the level of GPI-anchored substrates such as ALP localized at the cell surface. PIGV mutations have been reported in eight families affected by HPMRS1 so far.
Gene
PIGV gene, 1p36.11 (OMIM gene/locus number #610274)
Phenotype
Mental retardation, various neurologic abnormalities such as seizures and hypotonia, facial dysmorphism, variable degrees of hypoplastic terminal phalanges (brachytelephalangy). Midface hypoplasia, prognathism, hypertelorism, long palpebral fissures, arched eyebrows, broad nasal bridge and tip, cleft palate (rare), short philtrum, downturned corners of the mouth, tented mouth, ventral septal defect (rare), feeding problems necessitating tube feeding (in some patients), anteriorly displaced anus (in some patients), anovestibular fistula (in some patients), anorectal anomalies (in some patients), plagiocephaly, tapered fingers, hypoplastic toes (in some patients), bilateral adducted forefoot (rare), hypoplastic nails (in some patients), curved nails (in some patients), severe athetoid and dystonic hand movements (in some patients), moderate cortical atrophy (in some patients), delayed myelinization (in some patients), speech delay (in some patients), and no speech development (in most patients).
Main biochemical alterations:
High ALP, high Pi, normal Ca, markedly high ALP, high acid phosphatase, high uric acid.
Images
Fig. 1) Hand anomalies of patients with PIGV mutations. (a) Brachytelephalangy with missing and hypoplastic nails of fingers. (b) Hand radiograph showing hypoplastic distal phalanges. (c) Broad hallux and hypoplastic toenails. Reproduced by permission from Macmillan Publishers Ltd: Eur J Hum Genet 22(6):762-7, copyright 2014.
Fig. 2) (d, e, f) The distinct pattern of facial anomalies present in a patient with PIGV mutation consisted of wide-set eyes, often with a large appearance, a short nose with a broad nasal bridge and tip, and a tented upper lip.
Reproduced by permission from Macmillan Publishers Ltd: Eur J Hum Genet 22(6):762-7, copyright 2014
Hyperphosphatasia with mental retardation syndrome 2 (HPRMS2) is a rare autosomal recessive form of HPRMS (see also HPMRS1) , and it is caused by compound heterozygous mutation in the PIGO gene.
(OMIM phenotype number #614749)
Hyperphosphatasia with mental retardation syndrome 2 (HPRMS2) is a rare autosomal recessive form of HPRMS (see also HPMRS1) , and it is caused by compound heterozygous mutation in the PIGO gene. PIGO gene, such as PIGV gene, is coinvolved in the glycosylphosphatidylinositol (GPI) anchor synthesis pathway, and PIGO mutations lead to a defect in GPI anchor synthesis with a consequent reduction in the level of GPI-anchored substrates such as serum alkaline phosphatase (ALP) localized at the cell surface. PIGO mutations have been identified in two families with HPMRS2 so far.
Gene
PIGO gene, 9p13.3 (OMIM gene/locus number #614730)
Phenotype
Moderately to severely delayed psychomotor development, mental retardation, various neurologic abnormalities such as seizures and hypotonia, hypoplastic or absent nails, long palpebral fissures, facial dysmorphism, and variable degrees of brachytelephalangy. Poor growth, microcephaly (1 patient), moderate to severe delayed speech and language development, plagiocephaly (1 patient), coronal synostosis (1 patient), hypertelorism, short nose, broad nasal bridge and tip, tented mouth, atrial septal defect (1 patient), anal stenosis and atresia, vesicoureteral reflux (1 patient), broad halluces, and enlarged ventricles (1 patient).
Main biochemical alterations:
High ALP, high Pi, normal Ca, markedly high ALP, high acid phosphatase, high uric acid.
Image
Fig. (a) Facial appearance of a patient affected by HPRMS2 at the age of 15 years, and (b) an other patient (sister) at the age of 12 years. (c) Nail hypoplasia of the second and fourth digits and absent nail of the fifth digit. (d) Broad hallux, small nails of the second and third toes, and aplasia of the nails of the fourth and fifth digits.
Reproduced from Am J Hum Genet, Vol 91, Krawitz PM, Murakami Y, Hecht J, et al., Mutations in PIGO, a member of the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation, Pages 146-51, Copyright 2012, with permission from Elsevier.
Hyperphosphatasia with mental retardation syndrome 3 (HPRMS3) is a rare autosomal recessive form of HPRMS (see also HPMRS1). This disease is caused by homozygous or compound heterozygous mutation in the PGAP2 gene. PGAP2 encodes a protein involved in fatty-acid glycosylphosphatidylinositol (GPI)-anchor remodeling, which occurs in the Golgi apparatus.
(OMIM phenotype number #614207)
Hyperphosphatasia with mental retardation syndrome 3 (HPRMS3) is a rare autosomal recessive form of HPRMS (see also HPMRS1). This disease is caused by homozygous or compound heterozygous mutation in the PGAP2 gene. PGAP2 encodes a protein involved in fatty-acid glycosylphosphatidylinositol (GPI)-anchor remodeling, which occurs in the Golgi apparatus. It is required for stable association between GPI-anchored proteins (GPI-APs) and the cell-surface membrane rafts. Patients with PGAP2 mutations have secondary reduced GPI-AP surface levels also as a result of increased secretion into the extracellular space, resulting in high serum alkaline phosphatase (ALP). Germline mutations in six genes (PIGA, PIGL, PIGM, PIGV, PIGN, and PIGO) in the ER-located part of the GPI-anchor-biosynthesis pathway have been described. All these mutations are associated with phenotypes extending from malformation and lethality to severe intellectual disability, epilepsy, minor dysmorphisms, and high levels of ALP.
Gene
PGAP2 gene, 11p15.4 (OMIM gene/locus number #615187)
Phenotype
Delayed psychomotor development, severe mental retardation, intellectual disability mild (in some patients), hypotonia, seizures, disorder in sleep pattern (in some patients), cerebral atrophy (in some patients), microcephaly (in some patients), and cerebral atrophy (in some patients).
Main biochemical alterations
High ALP, high Pi, normal Ca, markedly high ALP, high acid phosphatase, high uric acid.
Images
Fig. Phenotypic features of HPMRS3 (a and b). Face of a patient at the ages of 3 (a) and 28 years (b). (c) Normal-appearing fingernails of a patient. (d and e) Facial dysmorphism of a patient with HPMRS3 at the age of 2 years includes wide palpebral fissures, a short nose with a broad nasal bridge, a tented upper lip, and a small jaw. (f) Distal tapering of fingers and mild nail hypoplasia of the fifth digit of a patient with HPMRS3.
Reproduced from Am J Hum Genet, Vol 92, Krawitz PM, Murakami Y, Rieß A, et al. PGAP2 mutations, affecting the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation syndrome, Pages 584-9, Copyright 2013, with permission from Elsevier.
Hyperphosphatasia with mental retardation syndrome 4 (HPRMS4) is a rare autosomal recessive form of HPRMS (see also HPMRS1). This disease is caused by homozygous or compound heterozygous mutation in the PGAP3 gene, encoding a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor maturation.
(OMIM phenotype number #615716)
Hyperphosphatasia with mental retardation syndrome 4 (HPRMS4) is a rare autosomal recessive form of HPRMS (see also HPMRS1). This disease is caused by homozygous or compound heterozygous mutation in the PGAP3 gene, encoding a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor maturation. PGAP2 and PGAP3 mutations suggest the importance of the later GPI-anchor remodelling steps for normal neuronal development (see also HPRMS3). HPRMS4 is characterized by severely delayed psychomotor development, mental retardation, lack of speech acquisition, seizures, and dysmorphic facial features.
Gene
PGAP3 gene, 17q12 (OMIM gene/locus number #611801)
Phenotype
Severely delayed psychomotor development with mental retardation, hypotonia, inability to walk, lack of speech development, generalized seizures, myoclonic seizures, involuntary movements and dysmorphic facial features. Poor growth (1 patient), microcephaly (-2 to -3 SD) (in some patients), large fleshy earlobes, hypertelorism, upslanting palpebral fissures, broad nasal bridge and tip, tented upper lip, thin upper lip, cleft palate (in some patients), and bruxism.
Main biochemical alterations
High ALP, high Pi, normal Ca, markedly high ALP, high acid phosphatase, high uric acid.
Images
Fig. Photographs of individuals with HPMRS4. Facial features of three patients (a,b,c) at the ages of 4, 10, and 2 years, respectively. These individuals bear a striking resemblance with a broad nasal bridge, long-appearing palpebral fissures, a broad nasal tip, a short nose, a long philtrum, a thin and wide upper lip, full cheeks, and large fleshy ear lobes.
Reproduced from Am J Hum Genet 2014;94:278-87 under the terms of the Creative Commons Attribution License (CC BY).
Odontohypophosphatasia is a form of Hypophosphatasia (see also HPP) with primarily only dental manifestations, in the absence of skeletal system abnormalities, such as rickets or osteomalacia. About 150 cases have been reported to date.
(OMIM phenotype number #146300)
Odontohypophosphatasia is a form of Hypophosphatasia (see also HPP) with primarily only dental manifestations, in the absence of skeletal system abnormalities, such as rickets or osteomalacia. About 150 cases have been reported to date. Autosomal recessive and autosomal dominant patterns of inheritance are reported in odonto-HPP. This disease may affect both children and adults, and it is caused by heterozygous mutation in the gene encoding tissue-nonspecific alkaline phosphatase (ALPL), with generalized reduction of activity of the tissue-non-specific (liver/bone/kidney) isoenzyme of ALP (TNSALP). Dental X-rays show reduced alveolar bone and enlarged pulp chambers and root canals.
Gene
ALPL gene, 1p36.12 (OMIM gene/locus number *171760)
Phenotype
Very mild form, early-onset periodontitis, premature loss of primary and secondary teeth, the anterior deciduous teeth are more likely to be affected and the most frequently lost are the incisors, severe dental caries, decreased alveolar bone, and enlarged pulp chamber.
Main biochemical alterations
Low ALP, high PLP (pyridoxal-5’-phosphate), PEA (phosphoethanolamine).
Fig. The radiograph shows decreased mineralization of the alveolar bone and enlarged pulp chambers.
Reproduced from Eur J Pediat, Infantile loss of teeth: odontohypophosphatasia or childhood hypophosphatasia, 2013;172:851-3, Haliloglu B, Guran T, Atay Z, et al., with permission of Springer.
Other resources:
Familial hydiopatic hyperphosphatasia, also called juvenile Paget’s disease of bone, is a rare autosomal recessive juvenile-onset form of Paget disease, characterized by markedly accelerated bone turnover caused by osteoprotegerin deficiency (for inactivating homozygous or compound heterozygous mutation in the TNFRSF11B gene).
(OMIM phenotype number #239000)
Familial hydiopatic hyperphosphatasia, also called juvenile Paget’s disease of bone, is a rare autosomal recessive juvenile-onset form of Paget disease, characterized by markedly accelerated bone turnover caused by osteoprotegerin deficiency (for inactivating homozygous or compound heterozygous mutation in the TNFRSF11B gene). This disorder is characterized by: an increase in bone turnover (elevated levels of serum alkaline phosphatase (ALP) and other markers of bone turnover), skeletal deformity, bone expansion, bone pain and an increased risk of pathological fractures. Clinical manifestations present from early infancy and include: skeletal deformity and failure to thrive followed by skull enlargement, difficulty in walking, progressive sensorineural deafness (due to cochlear involvement), kyphosis and acetabular protrusion. Disease severity generally increases during adolescence, but a milder form has been described in some patients.
Currently, there are not guidelines of therapeutic management for this rare disease. Nervetheless, there are some studies on the use of antiresorptive drugs such as calcitonin, bisphosphonates and denosumab, with improvement of clinical, biochemical and radiographic. Recombinant OPG has also been used successfully in treatment, but currently this is not available for routine clinical use.
Gene
TNFRSF11B gene, 8q24.12 (OMIM gene/locus number *602643), which encodes osteoprotegerin (OPG), a member of the TNF-receptor superfamily. OPG is a soluble decoy receptor for RANKL which inhibits osteoclast differentiation and bone resorption.
Phenotype
Muscular weakness, deafness in infancy, osteoporosis, expanded long bones, bowed long bones, fragile bones, increased bone formation and destruction, progressive skeletal deformity, short stature, mild involvement of cranial bones, islands of increased skull bone density, premature teeth loss, retinal degeneration in some individuals, and angioid streaks.
Main biochemical alterations
High Pi, normal Ca, markedly high ALP, high acid phosphatase, high uric acid.
Image
Fig. Radiographs from patient 1 at age 9 months, showing characteristic features of juvenile Paget’s disease of bone. (a) and (b) expanded and bowed femoral diaphysis, thin cortices, periosteal new bone formation, and disorganized trabecular architecture with (c) similar appearances in the humerus.
Reproduced from Bone, Vol 68, Naot D, Choi A, Musson DS et al. Novel homozygous mutations in the osteoprotegerin gene TNFRSF11B in two unrelated patients with juvenile Paget's disease, Pages 6-10 Copyright 2014, with permission from Elsevier.
Other resources: