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Hyperphosphatasemia with bone disease(PDB5)

MedGen UID:
75678
Concept ID:
C0268414
Disease or Syndrome
Synonyms: Hyperostosis corticalis deformans juvenilis; Hyperphosphatasemia, chronic congenital idiopathic; Hyperphosphatasia, familial idiopathic; Osteoectasia familial; Paget disease of bone 5; PAGET DISEASE OF BONE 5, JUVENILE-ONSET; Paget Disease, Juvenile; PDB5
SNOMED CT: Hyperphosphatasemia with bone disease (9723006); Chronic congenital idiopathic hyperphosphatasemia (9723006); Familial idiopathic hyperphosphatasemia (9723006); Familial osteoectasia (9723006); Hyperostosis corticalis deformans juvenilis (9723006); Juvenile Paget disease (9723006); Osteochalasia desmalis familiaris (9723006); Osteoectasia with hyperphosphatasia (9723006)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): TNFRSF11B (8q24.12)
 
Monarch Initiative: MONDO:0009394
OMIM®: 239000
Orphanet: ORPHA2801

Definition

Paget disease of bone-5 is an autosomal recessive, juvenile-onset form of Paget disease, a disorder of the skeleton resulting from abnormal bone resorption and formation. Clinical manifestations include short stature, progressive long bone deformities, fractures, vertebral collapse, skull enlargement, and hyperostosis with progressive deafness. There is phenotypic variability, with some patients presenting in infancy, while others present later in childhood (summary by Naot et al., 2014). For discussion of genetic heterogeneity of Paget disease of bone, see 167250. [from OMIM]

Additional descriptions

From MedlinePlus Genetics
A rare type of bone cancer called osteosarcoma has been associated with Paget disease of bone. This type of cancer probably occurs in less than 1 in 1,000 people with this disease.

Other complications of Paget disease of bone depend on which bones are affected. If the disease occurs in bones of the skull, it can cause an enlarged head, hearing loss, headaches, and dizziness. If the disease affects bones in the spine, it can lead to numbness and tingling (due to pinched nerves) and abnormal spinal curvature. In the leg bones, the disease can cause bowed legs and difficulty walking.

Many people with classic Paget disease of bone do not experience any symptoms associated with their bone abnormalities. The disease is often diagnosed unexpectedly by x-rays or laboratory tests done for other reasons. People who develop symptoms are most likely to experience pain. The affected bones may themselves be painful, or pain may be caused by arthritis in nearby joints. Arthritis results when the distortion of bones, particularly weight-bearing bones in the legs, causes extra wear and tear on the joints. Arthritis most frequently affects the knees and hips in people with this disease.

The classic form of Paget disease of bone typically appears in middle age or later. It usually occurs in one or a few bones and does not spread from one bone to another. Any bones can be affected, although the disease most commonly affects bones in the spine, pelvis, skull, or legs.

Paget disease of bone is a disorder that causes bones to grow larger and weaker than normal. Affected bones may be misshapen and easily broken (fractured).

Early-onset Paget disease of bone is a less common form of the disease that appears in a person's teens or twenties. Its features are similar to those of the classic form of the disease, although it is more likely to affect the skull, spine, and ribs (the axial skeleton) and the small bones of the hands. The early-onset form of the disorder is also associated with hearing loss early in life.  https://medlineplus.gov/genetics/condition/paget-disease-of-bone
From MedlinePlus Genetics
Juvenile Paget disease is a disorder that affects bone growth. This disease causes bones to be abnormally large, misshapen, and easily broken (fractured).

The signs of juvenile Paget disease appear in infancy or early childhood. As bones grow, they become progressively weaker and more deformed. These abnormalities usually become more severe during the adolescent growth spurt, when bones grow very quickly.

Juvenile Paget disease affects the entire skeleton, resulting in widespread bone and joint pain. The bones of the skull tend to grow unusually large and thick, which can lead to hearing loss. The disease also affects bones of the spine (vertebrae). The deformed vertebrae can collapse, leading to abnormal curvature of the spine. Additionally, weight-bearing long bones in the legs tend to bow and fracture easily, which can interfere with standing and walking.  https://medlineplus.gov/genetics/condition/juvenile-paget-disease

Clinical features

From HPO
Hypercalciuria
MedGen UID:
43775
Concept ID:
C0020438
Finding
Abnormally high level of calcium in the urine.
Hydroxyprolinuria
MedGen UID:
215298
Concept ID:
C0948585
Finding
An increased concentration of 4-hydroxy-L-proline in the urine.
Increased urine deoxypyridinoline level
MedGen UID:
1783581
Concept ID:
C5539536
Finding
An increased level of deoxypyridinoline in the urine. Deoxypyridinoline is a crosslink product of collagen molecules found in bone and excreted in urine during bone degradation, has been described as a marker of bone turnover.
Short humerus
MedGen UID:
316907
Concept ID:
C1832117
Congenital Abnormality
Underdevelopment of the humerus.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Delayed gross motor development
MedGen UID:
332508
Concept ID:
C1837658
Finding
A type of motor delay characterized by a delay in acquiring the ability to control the large muscles of the body for walking, running, sitting, and crawling.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Ankylosis
MedGen UID:
8101
Concept ID:
C0003090
Pathologic Function
A reduction of joint mobility resulting from changes involving the articular surfaces.
Recurrent fractures
MedGen UID:
42094
Concept ID:
C0016655
Injury or Poisoning
The repeated occurrence of bone fractures (implying an abnormally increased tendency for fracture).
Kyphosis
MedGen UID:
44042
Concept ID:
C0022821
Anatomical Abnormality
Exaggerated anterior convexity of the thoracic vertebral column.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Osteopenia
MedGen UID:
18222
Concept ID:
C0029453
Disease or Syndrome
Osteopenia is a term to define bone density that is not normal but also not as low as osteoporosis. By definition from the World Health Organization osteopenia is defined by bone densitometry as a T score -1 to -2.5.
Osteoporosis
MedGen UID:
14535
Concept ID:
C0029456
Disease or Syndrome
Osteoporosis is a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility. According to the WHO criteria, osteoporosis is defined as a BMD that lies 2.5 standard deviations or more below the average value for young healthy adults (a T-score below -2.5 SD).
Increased bone mineral density
MedGen UID:
10502
Concept ID:
C0029464
Disease or Syndrome
An abnormal increase of bone mineral density, that is, of the amount of matter per cubic centimeter of bones which is often referred to as osteosclerosis. Osteosclerosis can be detected on radiological examination as an increased whiteness (density) of affected bones.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Barrel-shaped chest
MedGen UID:
120497
Concept ID:
C0264172
Finding
A rounded, bulging chest that resembles the shape of a barrel. That is, there is an increased anteroposterior diameter and usually some degree of kyphosis.
Macular scar
MedGen UID:
140842
Concept ID:
C0423428
Acquired Abnormality
Scar tissue in the macula.
Relative macrocephaly
MedGen UID:
338607
Concept ID:
C1849075
Congenital Abnormality
A relatively mild degree of macrocephaly in which the head circumference is not above two standard deviations from the mean, but appears dysproportionately large when other factors such as body stature are taken into account.
Bowing of the long bones
MedGen UID:
340849
Concept ID:
C1855340
Congenital Abnormality
A bending or abnormal curvature of a long bone.
Thickened calvaria
MedGen UID:
346823
Concept ID:
C1858452
Finding
The presence of an abnormally thick calvaria.
Lateral femoral bowing
MedGen UID:
401070
Concept ID:
C1866737
Finding
A lateral bending or abnormal curvature of the femur.
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
Hyperphosphatemia
MedGen UID:
39326
Concept ID:
C0085681
Disease or Syndrome
An abnormally increased phosphate concentration in the blood.
Hyperhydroxyprolinemia
MedGen UID:
75691
Concept ID:
C0268531
Disease or Syndrome
Hydroxyproline is an imino acid normally present in human plasma. It is derived primarily from endogenous collagen turnover and the breakdown of dietary collagen. The finding of elevated (5- to 10-fold increase from the normal of less than 50 micromoles) serum hydroxyproline is thought to be an inherited defect in the catabolism of hydroxyproline.
Hyperuricemia
MedGen UID:
149260
Concept ID:
C0740394
Disease or Syndrome
An abnormally high level of uric acid in the blood.
Elevated circulating alkaline phosphatase concentration
MedGen UID:
727252
Concept ID:
C1314665
Finding
Abnormally increased serum levels of alkaline phosphatase activity.
Premature loss of teeth
MedGen UID:
66678
Concept ID:
C0232513
Finding
Exfoliation of a tooth more than 2 SD earlier than the normal age for the deciduous teeth and not related to traume or neglect. Exfoliation of a permanent tooth is per se abnormal.
Angioid streaks
MedGen UID:
1541
Concept ID:
C0002982
Disease or Syndrome
Angioid streaks are irregular tapering linear breaks in the Bruch membrane that typically emanate from the optic disk (summary by Karacorlu et al., 2002).
Retinal degeneration
MedGen UID:
48432
Concept ID:
C0035304
Finding
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells.
Retinopathy
MedGen UID:
11209
Concept ID:
C0035309
Disease or Syndrome
Any noninflammatory disease of the retina. This nonspecific term is retained here because of its wide use in the literature, but if possible new annotations should indicate the precise type of retinal abnormality.
Elevated serum acid phosphatase
MedGen UID:
326597
Concept ID:
C1839866
Finding

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHyperphosphatasemia with bone disease
Follow this link to review classifications for Hyperphosphatasemia with bone disease in Orphanet.

Professional guidelines

PubMed

Brunetti G, Marzano F, Colucci S, Ventura A, Cavallo L, Grano M, Faienza MF
Endocrine 2012 Oct;42(2):266-71. Epub 2012 May 26 doi: 10.1007/s12020-012-9705-0. PMID: 22638612

Recent clinical studies

Etiology

Solé-Enrech G, Cano-Corres R, Nuez-Zaragoza E, Pineda-Solas V, Berlanga-Escalera E
Clin Biochem 2021 May;91:67-69. Epub 2021 Feb 9 doi: 10.1016/j.clinbiochem.2021.01.015. PMID: 33571512
Whyte MP, Tau C, McAlister WH, Zhang X, Novack DV, Preliasco V, Santini-Araujo E, Mumm S
Bone 2014 Nov;68:153-61. Epub 2014 Jul 23 doi: 10.1016/j.bone.2014.07.019. PMID: 25063546Free PMC Article

Diagnosis

Prata AR, Saraiva J, Salgado M, Estanqueiro P
Joint Bone Spine 2021 Dec;88(6):105243. Epub 2021 Jun 21 doi: 10.1016/j.jbspin.2021.105243. PMID: 34166796
Solé-Enrech G, Cano-Corres R, Nuez-Zaragoza E, Pineda-Solas V, Berlanga-Escalera E
Clin Biochem 2021 May;91:67-69. Epub 2021 Feb 9 doi: 10.1016/j.clinbiochem.2021.01.015. PMID: 33571512
Naot D, Wilson LC, Allgrove J, Adviento E, Piec I, Musson DS, Cundy T, Calder AD
Bone 2020 Jan;130:115098. Epub 2019 Oct 23 doi: 10.1016/j.bone.2019.115098. PMID: 31655221
Grasemann C, Unger N, Hövel M, Arweiler-Harbeck D, Herrmann R, Schündeln MM, Müller O, Schweiger B, Lausch E, Meissner T, Kiewert C, Hauffa BP, Shaw NJ
J Clin Endocrinol Metab 2017 Jan 1;102(1):210-219. doi: 10.1210/jc.2016-2905. PMID: 27809640
Gottesman GS, Madson KL, McAlister WH, Nenninger A, Wenkert D, Mumm S, Whyte MP
Am J Med Genet A 2016 Apr;170A(4):978-85. Epub 2016 Jan 14 doi: 10.1002/ajmg.a.37536. PMID: 26762549Free PMC Article

Therapy

Höppner J, Steff K, Lobert F, Heyer CM, Hauffa BP, Grasemann C
Horm Res Paediatr 2021;94(3-4):151-158. Epub 2021 Jul 14 doi: 10.1159/000517164. PMID: 34261073
Prata AR, Saraiva J, Salgado M, Estanqueiro P
Joint Bone Spine 2021 Dec;88(6):105243. Epub 2021 Jun 21 doi: 10.1016/j.jbspin.2021.105243. PMID: 34166796
Gonc EN, Ozon A, Buyukyilmaz G, Alikasifoglu A, Simsek OP, Kandemir N
Osteoporos Int 2018 Jun;29(6):1471-1474. Epub 2018 Mar 3 doi: 10.1007/s00198-018-4443-7. PMID: 29502293
Whyte MP, Tau C, McAlister WH, Zhang X, Novack DV, Preliasco V, Santini-Araujo E, Mumm S
Bone 2014 Nov;68:153-61. Epub 2014 Jul 23 doi: 10.1016/j.bone.2014.07.019. PMID: 25063546Free PMC Article
Polyzos SA, Anastasilakis AD, Litsas I, Efstathiadou Z, Kita M, Arsos G, Moralidis E, Papatheodorou A, Terpos E
J Bone Miner Metab 2010 Nov;28(6):706-12. Epub 2010 Jun 9 doi: 10.1007/s00774-010-0198-8. PMID: 20533067

Prognosis

Solé-Enrech G, Cano-Corres R, Nuez-Zaragoza E, Pineda-Solas V, Berlanga-Escalera E
Clin Biochem 2021 May;91:67-69. Epub 2021 Feb 9 doi: 10.1016/j.clinbiochem.2021.01.015. PMID: 33571512
Gonc EN, Ozon A, Buyukyilmaz G, Alikasifoglu A, Simsek OP, Kandemir N
Osteoporos Int 2018 Jun;29(6):1471-1474. Epub 2018 Mar 3 doi: 10.1007/s00198-018-4443-7. PMID: 29502293
Grasemann C, Unger N, Hövel M, Arweiler-Harbeck D, Herrmann R, Schündeln MM, Müller O, Schweiger B, Lausch E, Meissner T, Kiewert C, Hauffa BP, Shaw NJ
J Clin Endocrinol Metab 2017 Jan 1;102(1):210-219. doi: 10.1210/jc.2016-2905. PMID: 27809640
Naot D, Choi A, Musson DS, Simsek Kiper PÖ, Utine GE, Boduroglu K, Peacock M, DiMeglio LA, Cundy T
Bone 2014 Nov;68:6-10. Epub 2014 Aug 6 doi: 10.1016/j.bone.2014.07.034. PMID: 25108083
Whyte MP, Tau C, McAlister WH, Zhang X, Novack DV, Preliasco V, Santini-Araujo E, Mumm S
Bone 2014 Nov;68:153-61. Epub 2014 Jul 23 doi: 10.1016/j.bone.2014.07.019. PMID: 25063546Free PMC Article

Clinical prediction guides

Höppner J, Steff K, Lobert F, Heyer CM, Hauffa BP, Grasemann C
Horm Res Paediatr 2021;94(3-4):151-158. Epub 2021 Jul 14 doi: 10.1159/000517164. PMID: 34261073
Whyte MP, Campeau PM, McAlister WH, Roodman GD, Kurihara N, Nenninger A, Duan S, Gottesman GS, Bijanki VN, Sedighi H, Veis DJ, Mumm S
Bone 2020 Aug;137:115364. Epub 2020 Apr 13 doi: 10.1016/j.bone.2020.115364. PMID: 32298837Free PMC Article
Gonc EN, Ozon A, Buyukyilmaz G, Alikasifoglu A, Simsek OP, Kandemir N
Osteoporos Int 2018 Jun;29(6):1471-1474. Epub 2018 Mar 3 doi: 10.1007/s00198-018-4443-7. PMID: 29502293
Naot D, Choi A, Musson DS, Simsek Kiper PÖ, Utine GE, Boduroglu K, Peacock M, DiMeglio LA, Cundy T
Bone 2014 Nov;68:6-10. Epub 2014 Aug 6 doi: 10.1016/j.bone.2014.07.034. PMID: 25108083
Whyte MP, Tau C, McAlister WH, Zhang X, Novack DV, Preliasco V, Santini-Araujo E, Mumm S
Bone 2014 Nov;68:153-61. Epub 2014 Jul 23 doi: 10.1016/j.bone.2014.07.019. PMID: 25063546Free PMC Article

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