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Clinical features of osteogenesis imperfecta (OI) by type

Clinical features of osteogenesis imperfecta (OI) by type
Type
(MIM#)		 Inheritance Gene/protein Severity Fractures Stature DI Sclerae Hearing loss Other
Defects in collagen synthesis, structure, and assembly
I
(#166200)[1]		 AD COL1A1 (type 1 collagen [alpha 1]) Mild Few to 100 Normal height or mild short stature Rare Blue Present in approximately 50% 70 to 75% of OI is type I
II
(IIA – #166210, IIB – #610854)		 AD (new mutations or parental mosaicism) COL1A1, COL1A2 (type 1 collagen [alpha 1 and 2]) Perinatal lethal Multiple at birth Severely short stature Yes Dark blue/gray – –
AR CRTAP, P3H1 (cartilage-associated protein/prolyl 3-hydroxylase 1)
III
(#259420)		 AD COL1A1, COL1A2 (type 1 collagen [alpha 1 and 2]) Severe Multiple at birth Very short stature Yes Grayish Frequent –
AR CRTAP, LEPRE1, PP1B (cartilage-associated protein/prolyl 3-hydroxylase 1/cyclophilin B)
IV
(#166220)[2]		 AD COL1A1, COL1A2 (type 1 collagen [alpha 1 and 2]) Mild to moderate Multiple in neonatal period or infancy Moderate short stature Some patients Grayish Reported in some –
Histologically distinct defects in bone mineralization
V
(#610967)[3-6]		 AD IFITM5 (bone-restricted IFITM-like) Moderate to severe Multiple Moderate short stature No White No –
VI
(#613982)[7-9]		 AR SERPINF1 (pigment epithelium-derived factor) Moderate to severe Multiple between 6 and 18 months of age Mild short stature No White No –
Collagen-folding protein abnormalities in prolyl-3-hydroxylation complex[10-13]
VII
(#610682)		 AR CRTAP (cartilage-associated protein) Moderate Multiple Mild short stature No White No –
VIII
(#610915)		 AR P3H1 (prolyl 3-hydroxylase 1) Lethal or severe Multiple Short-limbed dwarfism No White Not reported –
IX
(#259440)		 AR PP1B (cyclophilin B) Lethal or severe Multiple Short-limbed dwarfism Yes Blue No –
Collagen-processing and cross-linking defects[14,15]
X
(#613848)		 AR SERPINH1 (heat shock protein 47) Lethal or severe Multiple Severe short stature Yes Blue at birth Not reported –
XI
(#610968)[16,17]		 AR FKBP10 (FK506-binding protein 65) Severe Multiple Severe short stature No Gray/white Not reported Pathogenic variants in FKBP10 also cause Bruck syndrome type 1
XII
(#613849)[18]		 AR BMP1 (bone morphogenetic protein 1) Moderate to severe Multiple Short stature No White Reported in some Can have osteopenia or bone fragility
Osteoblast lineage abnormality
XIII
(#614856)[19-22]		 AR SP7 (osterix) Moderate to severe Multiple Short stature No White No –
XIV
(#615066)[23-25]		 AR TMEM38B (trimeric intracellular cation type B) Moderate to severe Multiple Short stature No White to blue No Cardiovascular defects and endocrine concerns
XV
(#615220)[26-28]		 AR WNT1 (Wnt family member 1) Moderate to severe Multiple Short stature No White No Muscle hypotonia and possible neurologic defects including intellectual disability
XVI
(#616229)[29,30]		 AR CREB3L1 (old astrocyte specifically induced substance [OASIS]) Severe Multiple Short stature No White to blue Reported in some Antenatal presentation
XVII
(#616507)[31,32]		 AR SPARC (osteonectin) Severe Multiple Severe short stature Yes White/gray Yes May present initially as significant neuromuscular weakness with fractures
Newer forms of OI
XVIII
(#617952)[33]		 AR TENT5A (family with sequence similarity 46 member A) Severe Multiple Severe short stature Yes Blue/bluish gray Yes

Developmental and speech delays and autonomic nervous system dysfunction

Overlap with Stuve-Wiedemann syndrome
XIX
(#301014)[34]		 XLR MBTPS2 (site 2 protease) Severe Multiple Severe short stature No Blue Yes Elevated urinary pyridinoline cross-links
XX
(#618644)[35]		 AR MESD (mesoderm development LRP chaperone) Lethal in the early neonatal period or severe Multiple Severe short stature Yes Blue Reported in 1 individual

Can include developmental delay/intellectual disability

Several patients died from respiratory failure
XXI
(#609024)[36]		 AR KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) Moderate to severe Multiple Short stature Yes Blue/bluish gray Yes Low bone mass
XXII
(#619795)[37]		 AR CCDC134 (coiled-coin domain-containing protein 134) Moderate to severe or lethal in the neonatal period Multiple Short stature Yes White to gray (variable) Reported in 1 individual Antenatal presentation
Seventy to 75% of OI is type I; the other forms are rare. Radiographic findings of OI are covered separately (refer to companion UpToDate table of radiographic findings).
DI: dentinogenesis imperfecta; AD: autosomal dominant; AR: autosomal recessive; LEPRE1: leucine- and proline-enriched proteoglycan 1; PPIB: peptidyl-prolyl isomerase B; IFITM5: interferon-induced transmembrane protein 5; SERPINF1: serpin peptidase inhibitor, clade F, member 1; SERPINH1: serpin peptidase inhibitor, clade H, member 1; FKBP10: FK506-binding protein 10; SP7: Sp7 transcription factor; TMEM38B: transmembrane protein 38B; CREB3L1: cAMP-responsive element-binding protein 3-like 1; SPARC: secreted protein acidic and cysteine rich; TENT5A: terminal nucleotidyltransferase 5A; XLR: X-linked recessive; MBTPS2: membrane-bound transcription factor peptidase, site 2.
References:
  1. Maioli M, Gnoli M, Boarini M, et al. Genotype-phenotype correlation study in 364 osteogenesis imperfecta Italian patients. Eur J Hum Genet 2019; 27:1090.
  2. Byers PH, Wallis GA, Willing MC. Osteogenesis imperfecta: Translation of mutation to phenotype. J Med Genet 1991; 28:433.
  3. Balasubramanian M, Parker MJ, Dalton A, et al. Genotype-phenotype study in type V osteogenesis imperfecta. Clin Dysmorphol 2013; 22:93.
  4. Cho TJ, Lee KE, Lee SK, et al. A single recurrent mutation I the 5'-UTR of IFITM5 causes osteogenesis imperfect type V. Am J Hum Genet 2012; 91:343.
  5. Semler O, Garbes L, Keupp K, et al. A mutation I the 5'UTR of IFITM5 creates an in-frame start codon and causes autosomal-dominant osteogenesis imperfecta type V with hyperplastic callus. Am J Hum Genet 2012; 91:349.
  6. Hanagata N, Li X, Morita H, et al. Characterization of the osteoblast-specific transmembrane protein IFITM5 and analysis of IFITM5-deficienc mice. J Bone Miner Metab 2011; 29:279.
  7. Becker J, Semler O, Gilissen C, et al. Exome sequencing identifies truncating mutation in human SERPINF1 in autosomal-recessive osteogenesis imperfecta. Am J Hum Genet 2011; 88:362.
  8. Hoyer-Kuhn H, Semler O, Garbes L, et al. A nonclassical IFITM5 mutation located in the coding region causes severe osteogenesis imperfecta with prenatal onset. J Bone Miner Res 2014; 29:1387.
  9. Farber CR, Reich A, Barnes AM, et al. A novel IFITM5 mutation in severe atypical osteogenesis imperfecta type VI impairs osteoblast production of pigment epithelium-derived factor. J Bone Miner Res 2014; 29:1402.
  10. Morello R, Bertin TK, Chen Y, et al. CRTAP is required for prolyl 3-hydoxylation and mutations cause recessive osteogenesis imperfecta. Cell 2006; 127:291.
  11. Barnes AM, Chang W, Morello R, et al. Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta. N Engl Med 2006; 355:2757.
  12. Cabral WA, Chang W, Barnes AM, et al. Prolyl 3-hyroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfect. Nat Genet 2007; 39:359.
  13. Marini JC, Cabral WA, Barnes AM, Chang W. Components of the collagen prolyl 3-hydroxylation complex are crucial for normal bone development. Cell Cycle 2009; 6:1675.
  14. Christiansen HE, Schwarze U, Pyott SM et al. Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta. Am J Hum Genet 2019; 86:389.
  15. Marshall C, Lopez J, Crookes L, et al. A novel homozygous variant in SERPINH1 associated with a severe, lethal presentation of osteogenesis imperfecta with hydranencephaly. Gene 2016; 595:49.
  16. Alanay Y, Avayan H, Camacho N, et al. Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta. Am J Hum Genet 2010; 86:551.
  17. Duran I, Nevarez L, Sarukhanov A, et al. HSP47 and FKBPP65 cooperate in the synthesis of type I procollagen. Hum Mol Genet 2015; 24:1918.
  18. Lapunzina P, Alan M, Temtamy S, et al. Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta. Am J Hum Genet 2010; 87:110.
  19. Martínez-Glez V, Valencia M, Caparrós-Martín JA, et al. Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta. Hum Mutat 2012; 33:343.
  20. Pollitt RC, Saraff V, Dalton A, et al. Phenotype variability in patients with osteogenesis imperfecta caused by BMP1 mutations. Am J Med Genet A 2016; 170:3150.
  21. Asharani PV, Keupp K, Semler O, et al. Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish. Am J Hum Genet 2012; 90:661.
  22. Lindahl K, Barnes AM, Fratzl-Zelman N, et al. COL1 C-propeptide cleavage site mutations cause high bone mass osteogenesis imperfecta. Hum Mutat 2011; 32:598.
  23. Shaheen R, Alazami AM, Alshammari MJ, et al. Study of autosomal recessive osteogenesis imperfecta in Arabia reveals a novel locus defined by TMEM38B mutation. J Med Genet 2012; 49:630.
  24. Volodarsky M, Markus B, Cohen I, et al. A deletion mutation in TMEM38B associated with autosomal recessive osteogenesis imperfecta. Hum Mutat 2013; 34:582.
  25. Webb EA, Balasubramanian M, Fratzl-Zelman N, et al. Phenotypic spectrum in osteogenesis imperfecta due to mutations in TMEM38B: Unraveling a complex cellular defect. J Clin Endocrinol Metab 2017; 102:2019.
  26. Keupp K, Beleggia F, Kayserli H, et al. Mutations in WNT1 cause different forms of bone fragility. Am J Hum Genet 2013; 92:565.
  27. Pyott SM, Tran TT, Leistritz DF, et al. WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta. Am J Hum Genet 2013; 92:590.
  28. Faqeih E, Shahee R, Alkuraya FS. WNT1 mutation with recessive osteogenesis imperfecta and profound neurological phenotype. J Med Genet 2013; 50:491.
  29. Symoens S, Malfait F, D'hondt S, et al. Deficiency for the ER-stress transducer OASIS causes severe recessive osteogenesis imperfecta in humans. Orphanet J Rare Dis 2013; 8:154.
  30. Lindahl K, Aström E, Dragomir A, et al. Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy. Bone 2018; 114:268.
  31. Mendoza-Londono R, Fahiminiya S, Majewski J, et al. Recessive osteogenesis imperfecta caused by missense mutations in SPARC. Am J Hum Genet 2015; 96:979.
  32. Durkin A, DeVile C, Arundel P, et al. Expanding the phenotype of SPARC-related osteogenesis imperfecta: Clinical findings in two patients with pathogenic variants in SPARC and literature review. J Med Genet 2022; 59:810.
  33. Doyard M, Bacrot S, Huber C, et al. FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta. J Med Genet 2018; 55:278.
  34. Lindert U, Cabral WA, Ausavarat S, et al. MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta. Nat Commun 2016; 7:11920.
  35. Moosa S, Yamamoto GL, Garbes L, et al. Autosomal-recessive mutations in MESD cause osteogenesis imperfecta. Am J Hum Genet 2019; 105:836.
  36. van Dijk FS, Semler O, Etich J, et al. Interaction between KDELR2 and HSP47 as a key determinant in osteogenesis imperfecta caused by bi-allelic variants in KDELR2. Am J Hum Genet 202; 107:989.
  37. Dubail J, Brunelle P, Baujat G, et al. Homozygous loss-of-function mutations in CCDC134 are responsible for a severe form of osteogenesis imperfecta. J Bone Miner Res 2020; 35:1470.

Data from:

  • Steiner RD, Pepin MG, Byers PH. Osteogenesis imperfecta. GeneReviews at GeneTests: Medical Genetics Information Resource, January 2005.
  • Balasubramanian M. Clinical and Molecular Heterogeneity of Osteogenesis Imperfecta. Colloquium Series on Genomic and Molecular Medicine, Kumar D (Ed), Morgan & Claypool Publishers 2017.
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