Fibrous dysplasia: Difference between revisions
Sunny Kumar (talk | contribs) No edit summary |
|||
(42 intermediate revisions by 2 users not shown) | |||
Line 3: | Line 3: | ||
{{CMG}}{{AE}}{{SKA}} | {{CMG}}{{AE}}{{SKA}} | ||
==Overview== | ==Overview== | ||
Fibrous dysplasia is a disorder of bones which may occur with or without endocrinological and skin disorders. It may cause bony pain, deformity, fracture and / or entrapment of nerves, It is basically the acquired mis-sense mutation of gene coding for the α-subunit of the stimulatory G-protein, Gs, in the guanine nucleotide binding, alpha stimulating (GNAS) complex locus in chromosome 20q13. It leads to immature or poor differentiation of body tissue at the time of ossification and replacement of bone by fibrous tissue. Diagnosis depends on radiology and biopsic specimen. | Fibrous dysplasia [FD] is a disorder of [[bones]] which may occur with or without endocrinological and [[skin]] disorders. It may cause bony pain, deformity, [[Bone fracture|fracture]] and / or entrapment of nerves, It is basically the acquired [[Missense mutation|mis-sense mutation]] of [[gene]] coding for the α-subunit of the stimulatory [[G protein|G-protein]], Gs, in the guanine nucleotide binding, alpha stimulating (GNAS) complex locus in [[chromosome]] 20q13. It leads to immature or poor [[differentiation]] of body tissue at the time of [[ossification]] and replacement of bone by [[Fibrous connective tissue|fibrous tissue]]. Diagnosis depends on radiology and biopsic specimen. | ||
==Historical Perspective== | ==Historical Perspective== | ||
*Fibrous | *Fibrous dysplasia was first observed in bone radiography by Von Recklinghausen in 1891.<ref name="pmid29675824">{{cite journal| author=Cicek AF, Kilinc M, Safali M, Gunhan O| title=Lamellation in fibrous dysplasia: A clinicopathologic study. | journal=Histol Histopathol | year= 2018 | volume= | issue= | pages= 11991 | pmid=29675824 | doi=10.14670/HH-11-991 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29675824 }}</ref> | ||
*It was then entitled as separate entity by american pathologist Dr. Louis Lichtenstein in 1938 as fibrous | *It was then entitled as separate entity by american pathologist Dr. Louis Lichtenstein in 1938 as fibrous dysplasia polyostotic. | ||
*In 1942, Dr Lichtenstein and Dr. Jaffe together labeled syndrome named McCune-Albright syndrome (fibrous dysplasia-café au lait spots-endocrine dysfunction) or Mazabraud syndrome (fibrous dysplasia-myxomas). | *In 1942, Dr Lichtenstein and Dr. Jaffe together labeled syndrome named McCune-Albright syndrome (fibrous dysplasia-café au lait spots-endocrine dysfunction) or Mazabraud syndrome (fibrous dysplasia-myxomas). | ||
==Classification== | ==Classification== | ||
*Fibrous | *Fibrous dysplasia may be classified according to number of bony sites involved into two groups: | ||
:* | :*One [[bone]]: monostotic fibrous dysplasia | ||
:* | :*Multiple [[bones]]: polyostotic fibrous dysplasia | ||
*Other variants of FD include McCune-Albright | *Other variants of FD include:<ref name="pmid29672904">{{cite journal| author=Tessaris D, Boyce AM, Zacharin M, Matarazzo P, Lala R, de Sanctis L et al.| title=Growth hormone (GH) - insulin like growth factor 1 (IGF-1) axis hyperactivity on bone fibrous dysplasia in McCune-Albright Syndrome. | journal=Clin Endocrinol (Oxf) | year= 2018 | volume= | issue= | pages= | pmid=29672904 | doi=10.1111/cen.13722 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29672904 }}</ref><ref name="pmid29669167">{{cite journal| author=Berglund JA, Tella SH, Tuthill KF, Kim L, Guthrie LC, Paul SM et al.| title=Scoliosis in Fibrous Dysplasia/McCune-Albright Syndrome: Factors Associated with Curve Progression and Effects of Bisphosphonates. | journal=J Bone Miner Res | year= 2018 | volume= | issue= | pages= | pmid=29669167 | doi=10.1002/jbmr.3446 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29669167 }}</ref> | ||
**[[McCune-Albright syndrome]] | |||
**Mazabraud syndrome | |||
==Pathophysiology== | ==Pathophysiology== | ||
The | The pathophysiology of fibrous dysplasia is based on mechanism of [[G protein]] [[mutation]].<ref name="pmid29599748">{{cite journal| author=Utriainen P, Valta H, Björnsdottir S, Mäkitie O, Horemuzova E| title=Polyostotic Fibrous Dysplasia With and Without McCune-Albright Syndrome-Clinical Features in a Nordic Pediatric Cohort. | journal=Front Endocrinol (Lausanne) | year= 2018 | volume= 9 | issue= | pages= 96 | pmid=29599748 | doi=10.3389/fendo.2018.00096 | pmc=5863549 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29599748 }}</ref><ref name="pmid29547687">{{cite journal| author=Rivera-Rosado E, Beaton-Comulada D, Hernandez-Ortiz E, Marrero-Ortiz PV| title=Bilateral Tibial Fibrous Dysplasia in a Pediatric Patient treated with Intramedullary Nailing. | journal=P R Health Sci J | year= 2018 | volume= 37 | issue= 1 | pages= 58-61 | pmid=29547687 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29547687 }}</ref><ref name="pmid29544460">{{cite journal| author=Innamorati G, Wilkie TM, Kantheti HS, Valenti MT, Dalle Carbonare L, Giacomello L et al.| title=The curious case of Gαs gain-of-function in neoplasia. | journal=BMC Cancer | year= 2018 | volume= 18 | issue= 1 | pages= 293 | pmid=29544460 | doi=10.1186/s12885-018-4133-z | pmc=5856294 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29544460 }}</ref><ref name="pmid29517538">{{cite journal| author=Fournel L, Rapicetta C, Fraternali A, Bellafiore S, Paci M, Lococo F| title=Fibrous Dysplasia of the Rib Mimicking a Malignant Bone Tumor at SPECT/CT with 99mTc-MDP. | journal=Clin Nucl Med | year= 2018 | volume= 43 | issue= 5 | pages= 346-348 | pmid=29517538 | doi=10.1097/RLU.0000000000002015 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29517538 }}</ref> | ||
'''Genetics''' | '''Genetics''' | ||
*The somatic mutation in GNAS1 gene located on the long arm (q) of chromosome 20 (20q13.2) | *The [[Mutation|somatic mutation]] in [[GNAS1|GNAS1 gene]] located on the long arm (q) of [[Chromosome 20 (human)|chromosome 20]] (20q13.2) has been associated with the development of FD, involving the gain-of-function mutation pathway. | ||
* | *[[Mutation]] of [[GNAS1|GNAS1 gene]] is a [[Mutation|somatic mutation]] and it is not [[Heritability|heritable]]. | ||
* | *The exact reason for post fertilization [[mutation]] remains unknown. | ||
* | *[[Mutation]] of [[GNAS1|GNAS1 gene]] results in the overproduction of this [[G protein|G-protein]], which in turn increases [[cyclic adenosine monophosphate]] ([[Cyclic adenosine monophosphate|cAMP]]). | ||
*Improper differentiation of osteoblasts due to mutation of the | *[[Cyclic adenosine monophosphate]] ([[Cyclic adenosine monophosphate|cAMP]]) is important regulatory molecule of differentiation modulating [[Osteoblast|osteoblasts]] and [[Osteoclast|osteoclasts]] while [[ossification]] and remodeling of [[Bone (disambiguation)|bones]]. | ||
*Osteoclasts removes ossified bones and creates space for immature osteoblasts to produce fibrous tissue and occupy space which may entrap nerves causing pain or | *Improper [[differentiation]] of [[Osteoblast|osteoblasts]] due to [[mutation]] of the [[GNAS1|GNAS1 gene]] considered as a cause of FD. | ||
*[[Osteoclast|Osteoclasts]] removes ossified bones and creates space for immature [[Osteoblast|osteoblasts]] to produce [[Fibrous connective tissue|fibrous tissue]] and occupy space which may entrap [[Nerve|nerves]] causing [[pain]] or [[Neurology|neurological]] deficit depending on the site involved. | |||
'''Gross pathology''' | |||
**Curvilinear trabeculae (Chinese letters) of metaplastic woven bone | *Following are characteristic gross pathology findings of fibrous dysplasia: | ||
**fibroblastic stroma | **Well circumscribed, [[intramedullary]] lesion | ||
**No osteoblastic rimming (due to maturation arrest) | **Tan-white-yellow, gritty, large lesions that distort [[bone]] | ||
** | **Thin and expanded [[cortical bone]] | ||
** | '''Microscopic histopathological analysis''' | ||
**No/rare mitotic figures | *Following are characteristic microscopic histopathological findings of fibrous dysplasia: | ||
** | **Curvilinear [[Trabecula|trabeculae]] (Chinese letters) of metaplastic woven [[bone]] | ||
**Hypocellular and [[Stroma|fibroblastic stroma]] | |||
== | **No osteoblastic rimming (due to [[maturation]] arrest) | ||
**[[Cartilage|Cartilaginous]] nodules (in 20% of cases particularly in femoral neck region) | |||
**Myxoid areas consist of rapidly growing secondary aneurysmal bone [[Cyst|cysts]], [[Bleeding|hemorrhage]], foamy [[Macrophage|macrophages]], calcified spherules, and focal [[hyaline cartilage]] | |||
**Abrupt transition of normal to abnormal [[bone]] | |||
**No/rare [[Mitosis|mitotic figures]] | |||
**No [[atypia]] (rarely is [[Degenerative disease|degenerative]]) | |||
**Resembling [[endochondral ossification]] in [[skull]] | |||
== Causes == | |||
==Differentiating Fibrous dyspepsia from other Diseases== | ==Differentiating Fibrous dyspepsia from other Diseases== | ||
*Fibrous | *Fibrous dysplasia must be differentiated from other diseases that cause [[bone pain]], [[deformity]], and extra-skeletal involvement, such as: | ||
{| | {| | ||
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Disease | |||
!Bone involvement | ! align="center" style="background:#4479BA; color: #FFFFFF;" + |Bone involvement | ||
!Bone pain | ! align="center" style="background:#4479BA; color: #FFFFFF;" + |Bone pain | ||
!Fever | ! align="center" style="background:#4479BA; color: #FFFFFF;" + |Fever | ||
!Fractures | ! align="center" style="background:#4479BA; color: #FFFFFF;" + |Fractures | ||
! | ! align="center" style="background:#4479BA; color: #FFFFFF;" + |Mechanism | ||
!ALK | ! align="center" style="background:#4479BA; color: #FFFFFF;" + |ALK level | ||
!Diagnosis | ! align="center" style="background:#4479BA; color: #FFFFFF;" + |Diagnosis | ||
|- | |- | ||
| | ! align="center" style="background:#DCDCDC;" + |Ossifying sarcoma | ||
| | | align="center" style="background:#F5F5F5;" + |Single | ||
| | | align="center" style="background:#F5F5F5;" + |Yes | ||
| | | align="center" style="background:#F5F5F5;" + |No | ||
| | | align="center" style="background:#F5F5F5;" + |Yes | ||
| | | align="center" style="background:#F5F5F5;" + |[[Neoplasm]] | ||
| | | align="center" style="background:#F5F5F5;" + |Normal | ||
| | | align="center" style="background:#F5F5F5;" + |[[Radiology]] and [[biopsy]] | ||
|- | |- | ||
| | ! align="center" style="background:#DCDCDC;" + |[[Paget's disease]] | ||
| | | align="center" style="background:#F5F5F5;" + |Multiple | ||
| | | align="center" style="background:#F5F5F5;" + |Yes | ||
| | | align="center" style="background:#F5F5F5;" + |No | ||
| | | align="center" style="background:#F5F5F5;" + |Yes | ||
| | | align="center" style="background:#F5F5F5;" + |Malfunction of [[Osteoblast|osteoblasts]] | ||
| align="center" style="background:#F5F5F5;" + |High | |||
| | | align="center" style="background:#F5F5F5;" + |[[Biopsy]] | ||
| | |||
|- | |- | ||
| | ! align="center" style="background:#DCDCDC;" + |[[Osteosarcoma]] | ||
| | | align="center" style="background:#F5F5F5;" + |Single | ||
| | | align="center" style="background:#F5F5F5;" + |Yes | ||
| | | align="center" style="background:#F5F5F5;" + |No | ||
| | | align="center" style="background:#F5F5F5;" + |Yes | ||
| | | align="center" style="background:#F5F5F5;" + |[[Neoplasm]] | ||
| | | align="center" style="background:#F5F5F5;" + |Normal | ||
| | | align="center" style="background:#F5F5F5;" + |[[Radiology]] and [[biopsy]] | ||
|- | |- | ||
| | ! align="center" style="background:#DCDCDC;" + |[[Cherubism]] | ||
| | | align="center" style="background:#F5F5F5;" + |Single | ||
| | | align="center" style="background:#F5F5F5;" + |Yes | ||
| | | align="center" style="background:#F5F5F5;" + |No | ||
| | | align="center" style="background:#F5F5F5;" + |No | ||
| | | align="center" style="background:#F5F5F5;" + |Malfunction of [[Osteoblast|osteoblasts]] | ||
| align="center" style="background:#F5F5F5;" + |High | |||
| | | align="center" style="background:#F5F5F5;" + |[[Radiology]] and [[biopsy]] | ||
| | |||
|- | |- | ||
| | ! align="center" style="background:#DCDCDC;" + |[[Hyperparathyroidism]] | ||
| | | align="center" style="background:#F5F5F5;" + |Multiple | ||
| | | align="center" style="background:#F5F5F5;" + |Yes | ||
| | | align="center" style="background:#F5F5F5;" + |Yes | ||
| | | align="center" style="background:#F5F5F5;" + |Yes | ||
| | | align="center" style="background:#F5F5F5;" + |High [[PTH]] | ||
| | | align="center" style="background:#F5F5F5;" + |Normal | ||
| | | align="center" style="background:#F5F5F5;" + |[[Hormone]] level | ||
|- | |- | ||
| | ! align="center" style="background:#DCDCDC;" + |Solitary endocytosis | ||
| | | align="center" style="background:#F5F5F5;" + |Single | ||
| | | align="center" style="background:#F5F5F5;" + |Yes | ||
| | | align="center" style="background:#F5F5F5;" + |No | ||
| | | align="center" style="background:#F5F5F5;" + |No | ||
| | | align="center" style="background:#F5F5F5;" + |[[Neoplasm]] | ||
| | | align="center" style="background:#F5F5F5;" + |Normal | ||
| | | align="center" style="background:#F5F5F5;" + |[[Radiology]] and [[biopsy]] | ||
|- | |- | ||
| | ! align="center" style="background:#DCDCDC;" + |[[Osteoblastoma]] | ||
| | | align="center" style="background:#F5F5F5;" + |Single | ||
| | | align="center" style="background:#F5F5F5;" + |Yes | ||
| | | align="center" style="background:#F5F5F5;" + |No | ||
| | | align="center" style="background:#F5F5F5;" + |Yes | ||
| | | align="center" style="background:#F5F5F5;" + |[[Neoplasm]] | ||
| | | align="center" style="background:#F5F5F5;" + |High | ||
| | | align="center" style="background:#F5F5F5;" + |[[Radiology]] and [[biopsy]] | ||
|- | |- | ||
| | ! align="center" style="background:#DCDCDC;" + |[[Osteomyelitis]] | ||
| | | align="center" style="background:#F5F5F5;" + |Single | ||
| | | align="center" style="background:#F5F5F5;" + |Yes | ||
| | | align="center" style="background:#F5F5F5;" + |Yes | ||
| | | align="center" style="background:#F5F5F5;" + |No | ||
| | | align="center" style="background:#F5F5F5;" + |[[Infection]] | ||
| | | align="center" style="background:#F5F5F5;" + |Normal | ||
| | | align="center" style="background:#F5F5F5;" + |[[Radiology]] and [[biopsy]] | ||
|- | |- | ||
| | ! align="center" style="background:#DCDCDC;" + |[[Brodie's abscess]] | ||
| | | align="center" style="background:#F5F5F5;" + |Single | ||
| | | align="center" style="background:#F5F5F5;" + |Yes | ||
| | | align="center" style="background:#F5F5F5;" + |Yes | ||
| | | align="center" style="background:#F5F5F5;" + |No | ||
| | | align="center" style="background:#F5F5F5;" + |[[Infection]] | ||
| | | align="center" style="background:#F5F5F5;" + |Normal | ||
| | | align="center" style="background:#F5F5F5;" + |[[Radiology]] and [[biopsy]] | ||
|} | |} | ||
==Epidemiology and Demographics== | ==Epidemiology and Demographics== | ||
* The prevalence and incidence of | * The prevalence and incidence of fibrous dysplasia is not known exactly.<ref name="pmid28965204" /><ref name="pmid28839487" /> | ||
*FD is more commonly found in age group from 3 -15 years of life. | *FD is more commonly found in age group from 3 -15 years of life. | ||
* | *Polyostotic does not become symptomatic before age 10 years. | ||
* | *Monostotic is asymptomatic until age of 20-30 years of life. | ||
*FD affects men and women equally. | *FD affects men and women equally. | ||
*There is no racial predilection for FD. | *There is no racial predilection for FD. | ||
==Risk Factors== | ==Risk Factors== | ||
*Common risk factor in the development of | *Common risk factor in the development of fibrous dysplasia is [[Mutation|gain-of-function mutation]]. | ||
== Screening == | |||
== Natural History, Complications and Prognosis== | == Natural History, Complications and Prognosis== | ||
*The majority of patients with FD remain asymptomatic for first decade of life. | *The majority of patients with FD remain asymptomatic for the first decade of life. | ||
*Early clinical features include bone pain, bony deformity, fever, pathological fractures | *Early clinical features include [[bone pain]], bony [[deformity]], [[fever]], and pathological [[Bone fracture|fractures]]. | ||
*Common complications of FD include neurological deficit, endocrine abnormality, and in rare cases soft tissue tumors. | *Patients with fibrous dysplasia might develop skin/endocrine/malignancies depending on the variant. | ||
*Prognosis is generally good, and the patients with | *Common complications of FD include neurological deficit, [[Endocrine system|endocrine]] abnormality, and in rare cases soft tissue [[Tumor|tumors]]. | ||
*Prognosis is generally good, and the patients with polyostotic form may have frequent [[Bone fracture|fractures]]. | |||
== Diagnosis == | == Diagnosis == | ||
===Diagnostic | ===Diagnostic Study of Choice=== | ||
*The diagnosis of FD is made | *The diagnosis of FD is made on the basis of clinical manifestations, [[radiology]] findings, and [[genetic testing]] to verify presence of [[GNAS1|GNAS]] mutation.<ref name="pmid29485574">{{cite journal| author=Ogul H, Keskin E| title=Locally Aggressive Fibrous Dysplasia Mimicking Malign Calvarial Lesion. | journal=J Craniofac Surg | year= 2018 | volume= | issue= | pages= | pmid=29485574 | doi=10.1097/SCS.0000000000004453 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29485574 }}</ref><ref name="pmid29471062">{{cite journal| author=Karaca A, Malladi VR, Zhu Y, Tafaj O, Paltrinieri E, Wu JY et al.| title=Constitutive stimulatory G protein activity in limb mesenchyme impairs bone growth. | journal=Bone | year= 2018 | volume= 110 | issue= | pages= 230-237 | pmid=29471062 | doi=10.1016/j.bone.2018.02.016 | pmc=5878747 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29471062 }}</ref><ref name="pmid29434178">{{cite journal| author=Akashi M, Matsuo K, Shigeoka M, Kakei Y, Hasegawa T, Tachibana A et al.| title=A Case Series of Fibro-Osseous Lesions of the Jaws. | journal=Kobe J Med Sci | year= 2017 | volume= 63 | issue= 3 | pages= E73-E79 | pmid=29434178 | doi= | pmc=5826023 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29434178 }}</ref><ref name="pmid294880042">{{cite journal| author=Ostertag H, Glombitza S| title=[The activating GNAS mutation : A survey of fibrous dysplasia, its associated syndromes, and other skeletal and extraskeletal lesions]. | journal=Pathologe | year= 2018 | volume= 39 | issue= 2 | pages= 146-153 | pmid=29488004 | doi=10.1007/s00292-018-0417-y | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29488004 }}</ref><ref name="pmid29335001">{{cite journal| author=Mierzwiński J, Kosowska J, Tyra J, Haber K, Drela M, Paczkowski D et al.| title=Different clinical presentation and management of temporal bone fibrous dysplasia in children. | journal=World J Surg Oncol | year= 2018 | volume= 16 | issue= 1 | pages= 5 | pmid=29335001 | doi=10.1186/s12957-017-1302-5 | pmc=5769533 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29335001 }}</ref><ref name="pmid28965204">{{cite journal| author=Yepes JF| title=Dental Manifestations of Pediatric Bone Disorders. | journal=Curr Osteoporos Rep | year= 2017 | volume= 15 | issue= 6 | pages= 588-592 | pmid=28965204 | doi=10.1007/s11914-017-0409-5 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28965204 }}</ref><ref name="pmid28839487">{{cite journal| author=Gupta D, Garg P, Mittal A| title=Computed Tomography in Craniofacial Fibrous Dysplasia: A Case Series with Review of Literature and Classification Update. | journal=Open Dent J | year= 2017 | volume= 11 | issue= | pages= 384-403 | pmid=28839487 | doi=10.2174/1874210601711010384 | pmc=5543691 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28839487 }}</ref> | ||
=== Symptoms === | === History and Symptoms === | ||
*FD is usually asymptomatic. | *FD is usually asymptomatic. | ||
*Symptoms of FD may include | *Symptoms of FD may include: | ||
**[[Fever]] | |||
**[[Bone pain]] | |||
**Bony [[deformity]] | |||
**Pathological [[Bone fracture|fractures]] | |||
=== Physical Examination === | === Physical Examination === | ||
*Patients with FD usually appear normal unless | *Patients with FD usually appear normal unless there is any bony [[deformity]] or [[skin]] involvement | ||
*Physical examination may be remarkable according to the classification of disease: | *Physical examination may be remarkable according to the classification of disease: | ||
: | :Monostotic | ||
:* Single bone involved | :* Single [[bone]] involved. | ||
:* Mostly affects rib, femur, and tibia. | :* Mostly affects [[rib]], [[femur]], and [[tibia]]. | ||
:* | :* Craniofacial bone and [[humerus]] bone | ||
:* Fracture at age of 10 years | :* [[Bone fracture|Fracture]] at age of 10 years | ||
:* | :* Less severe bone [[deformity]] | ||
:* | :* Painless [[Edema|swelling]] of [[jaw]] | ||
:* | :* Swelling of [[buccal]] and [[Labial|labial plate]] | ||
:* Protuberance of inferior border of mandible | :* Protuberance of inferior border of [[mandible]] | ||
: | :Polyostotic | ||
:* Multiple bones involved | :* Multiple bones involved | ||
:* Involve rib, femur, clavicle, | :* Involve [[rib]], [[femur]], [[clavicle]], [[lumbar spine]], and [[tibia]]. | ||
:* Asymmetrical involvement | :* Asymmetrical involvement | ||
:* Mainly | :* Mainly misalignment of [[Bone (disambiguation)|bones]] | ||
:* Tenderness over involved bone | :* [[Tenderness]] over involved bone | ||
:* Bowing of weight bearing bone and | :* Bowing of weight bearing [[bone]] and increasing curvature of [[femur]] and [[tibia]] | ||
: | :Craniofacial | ||
:* Involvement of | :* Involvement of maxillofacial bones | ||
:* Maladjustment | :* Maladjustment | ||
:* Tappering | :* Tappering | ||
:* | :* [[Displacement (fluid)|Displacement]] | ||
:* Intact over lesion | :* Intact over lesion | ||
:* Maxillary sinus and Zygomatic bone involved mostly | :* [[Maxillary sinus]] and [[Zygomatic bone]] involved mostly | ||
:* Floor of orbit may extend to skull | :* Floor of [[Orbit (anatomy)|orbit]] may extend to skull | ||
:* No extracranial involvement | :* No extracranial involvement | ||
:* | :* [[Hypertelorism]], facial asymmetry, visual impairment, exophthalmos and blindness | ||
:* Vestibular dysfuntion, hearing loss and tinnitus. | :* [[Vestibular system|Vestibular dysfuntion]], hearing loss and tinnitus. | ||
:McCune-Albright syndrome | :[[McCune-Albright syndrome]] | ||
:* | :* May involve all the [[Bone (disambiguation)|bones]] | ||
:* Cafe au lait spots | :* [[Café au lait spot|Cafe au lait spots]] | ||
:* Endocrine abnormality of parathyroid hormone, gonadotropins Mazabraud syndrome | :* Endocrine abnormality of [[parathyroid hormone]], [[gonadotropins]] Mazabraud syndrome | ||
:* Involve variable number of bones | :* Involve variable number of bones | ||
=== Laboratory Findings === | === Laboratory Findings === | ||
*There are no specific laboratory findings associated with FD | *There are no specific laboratory findings associated with FD. However, we may find normal [[Parathyroid hormone|PTH]], Ca levels, and increased level of [[alkaline phosphatase]] due to increased [[bone turnover]] and increased [[basal metabolic rate]]. | ||
=== | ===Electrocardiogram=== | ||
===X-ray=== | |||
*Radiology is the imaging modality of choice for FD. | *Radiology is the imaging modality of choice for FD. | ||
*On | *On [[X-rays|x-ray]], FD is characterized by: | ||
**Network of fine bone trabeculae | **Network of fine bone [[Trabecula|trabeculae]] | ||
**Increased | **Increased trabeculation | ||
**Opaque | **Opaque trabeculation forming [[Ground glass opacification on CT|ground glass appearance]] | ||
**Cortical thinning | **Cortical thinning | ||
** | **Separated root of teeth | ||
=== Echocardiography or Ultrasound === | |||
=== CT scan === | |||
=== MRI === | |||
=== Other Imaging Findings === | |||
=== Other Diagnostic Studies === | === Other Diagnostic Studies === | ||
* | *[[Magnetic resonance imaging|MRI]] and [[Computed tomography|CT scan]] may be helpful in diagnosis of fibrous dysplasia. | ||
*Bone biopsy will | *Bone [[biopsy]] will reveal the histological findings such as: | ||
**Curvilinear trabeculae (Chinese letters) of metaplastic woven bone | **Curvilinear [[Trabecula|trabeculae]] (Chinese letters) of metaplastic woven [[bone]] | ||
**fibroblastic stroma | **Hypocellular and [[Stroma|fibroblastic stroma]] | ||
**No osteoblastic rimming (due to maturation arrest) | **No osteoblastic rimming (due to [[maturation]] arrest) | ||
** | **[[Cartilage|Cartilaginous]] nodules (in 20% of cases particularly in femoral neck region) | ||
**Myxoid areas consist of rapidly growing secondary aneurysmal bone [[Cyst|cysts]], [[Bleeding|hemorrhage]], foamy [[Macrophage|macrophages]], calcified spherules, and focal [[hyaline cartilage]] | |||
{{Family tree/start}} | {{Family tree/start}} | ||
{{Family tree | A01 |-|v|-| A02 | | | |A01=Incidental finding|A02=Dull, aching pain and subsequent radiographs}} | {{Family tree | A01 |-|v|-| A02 | | | |A01=Incidental finding|A02=Dull, aching pain and subsequent radiographs}} | ||
Line 239: | Line 254: | ||
{{Family tree/end}} | {{Family tree/end}} | ||
== Treatment == | == Treatment == | ||
Treatment of FD is mostly symptomatic and it can be either medical or surgical depending on severity and presentation of disease. | Treatment of FD is mostly symptomatic and it can be either medical or surgical depending on severity and presentation of disease.<ref name="pmid29504223">{{cite journal| author=Simm PJ, Biggin A, Zacharin MR, Rodda CP, Tham E, Siafarikas A et al.| title=Consensus guidelines on the use of bisphosphonate therapy in children and adolescents. | journal=J Paediatr Child Health | year= 2018 | volume= 54 | issue= 3 | pages= 223-233 | pmid=29504223 | doi=10.1111/jpc.13768 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29504223 }}</ref><ref name="pmid29496222">{{cite journal| author=Gresky J, Kalmykov A, Berezina N| title=Benign fibro-osseous lesion of the mandible in a Middle Bronze Age skeleton from Southern Russia. | journal=Int J Paleopathol | year= 2018 | volume= 20 | issue= | pages= 90-97 | pmid=29496222 | doi=10.1016/j.ijpp.2017.09.001 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29496222 }}</ref><ref name="pmid29488004">{{cite journal| author=Ostertag H, Glombitza S| title=[The activating GNAS mutation : A survey of fibrous dysplasia, its associated syndromes, and other skeletal and extraskeletal lesions]. | journal=Pathologe | year= 2018 | volume= 39 | issue= 2 | pages= 146-153 | pmid=29488004 | doi=10.1007/s00292-018-0417-y | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29488004 }}</ref><ref name="pmid29157551">{{cite journal| author=Ahmad M, Gaalaas L| title=Fibro-Osseous and Other Lesions of Bone in the Jaws. | journal=Radiol Clin North Am | year= 2018 | volume= 56 | issue= 1 | pages= 91-104 | pmid=29157551 | doi=10.1016/j.rcl.2017.08.007 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29157551 }}</ref><ref name="pmid28692759">{{cite journal| author=Gatimel N, Moreau J, Parinaud J, Léandri RD| title=Sperm morphology: assessment, pathophysiology, clinical relevance, and state of the art in 2017. | journal=Andrology | year= 2017 | volume= 5 | issue= 5 | pages= 845-862 | pmid=28692759 | doi=10.1111/andr.12389 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28692759 }}</ref> | ||
=== Medical Therapy === | === Medical Therapy === | ||
*The mainstay of therapy for FD is | *The mainstay of therapy for FD is [[Bisphosphonate|bisphosphonates]], which help in improving [[pain]], slow down process of [[bone turnover]], and also lower the [[Bone fracture|fracture]] risk factor. | ||
* | *[[Bisphosphonate|Bisphosphonates]] acts by inhibiting [[Osteoclast|osteoclasts]]. | ||
*In the absence of a fracture or symptoms, the follow-up for a child with FD consists of twice yearly clinical evaluations with special attention to limited range of motion, obvious angular deformity and limb length discrepancy. | *In the absence of a [[Bone fracture|fracture]] or symptoms, the follow-up for a child with FD consists of twice yearly clinical evaluations with special attention to limited range of motion, obvious angular deformity, and limb length discrepancy. | ||
=== Surgery === | === Surgery === | ||
*Conventional surgical procedures can only be performed for patients with symptomatic FD patients in conjugation of over all evaluation of disease and the age of child. | *Conventional surgical procedures can only be performed for patients with symptomatic FD patients in conjugation of over all evaluation of disease and the age of child. | ||
*Adult | *Adult monostotic lesion may be observed with subsequent radiography if it is not symptomatic. surgical removal and grafting the defect is considered for patients who have symptoms or excessively growing deformity or when disease produces deficit. | ||
*Child age group may have skin lesions and endocrinopathies which needs prompt attention and surgery will be delayed until bones are mature and in case of neurological defect or significant deformity surgery is advised immediately. | *Child age group may have skin lesions and endocrinopathies which needs prompt attention and surgery will be delayed until bones are mature and in case of [[Neurology|neurological]] defect or significant deformity surgery is advised immediately. | ||
=== Primary Prevention === | |||
=== Secondary Prevention === | |||
==References== | ==References== | ||
{{Reflist|2}} | {{Reflist|2}} |
Latest revision as of 21:56, 25 April 2018
WikiDoc Resources for Fibrous dysplasia |
Articles |
---|
Most recent articles on Fibrous dysplasia Most cited articles on Fibrous dysplasia |
Media |
Powerpoint slides on Fibrous dysplasia |
Evidence Based Medicine |
Cochrane Collaboration on Fibrous dysplasia |
Clinical Trials |
Ongoing Trials on Fibrous dysplasia at Clinical Trials.gov Trial results on Fibrous dysplasia Clinical Trials on Fibrous dysplasia at Google
|
Guidelines / Policies / Govt |
US National Guidelines Clearinghouse on Fibrous dysplasia NICE Guidance on Fibrous dysplasia
|
Books |
News |
Commentary |
Definitions |
Patient Resources / Community |
Patient resources on Fibrous dysplasia Discussion groups on Fibrous dysplasia Patient Handouts on Fibrous dysplasia Directions to Hospitals Treating Fibrous dysplasia Risk calculators and risk factors for Fibrous dysplasia
|
Healthcare Provider Resources |
Causes & Risk Factors for Fibrous dysplasia |
Continuing Medical Education (CME) |
International |
|
Business |
Experimental / Informatics |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sunny Kumar MD [2]
Overview
Fibrous dysplasia [FD] is a disorder of bones which may occur with or without endocrinological and skin disorders. It may cause bony pain, deformity, fracture and / or entrapment of nerves, It is basically the acquired mis-sense mutation of gene coding for the α-subunit of the stimulatory G-protein, Gs, in the guanine nucleotide binding, alpha stimulating (GNAS) complex locus in chromosome 20q13. It leads to immature or poor differentiation of body tissue at the time of ossification and replacement of bone by fibrous tissue. Diagnosis depends on radiology and biopsic specimen.
Historical Perspective
- Fibrous dysplasia was first observed in bone radiography by Von Recklinghausen in 1891.[1]
- It was then entitled as separate entity by american pathologist Dr. Louis Lichtenstein in 1938 as fibrous dysplasia polyostotic.
- In 1942, Dr Lichtenstein and Dr. Jaffe together labeled syndrome named McCune-Albright syndrome (fibrous dysplasia-café au lait spots-endocrine dysfunction) or Mazabraud syndrome (fibrous dysplasia-myxomas).
Classification
- Fibrous dysplasia may be classified according to number of bony sites involved into two groups:
- Other variants of FD include:[2][3]
- McCune-Albright syndrome
- Mazabraud syndrome
Pathophysiology
The pathophysiology of fibrous dysplasia is based on mechanism of G protein mutation.[4][5][6][7]
Genetics
- The somatic mutation in GNAS1 gene located on the long arm (q) of chromosome 20 (20q13.2) has been associated with the development of FD, involving the gain-of-function mutation pathway.
- Mutation of GNAS1 gene is a somatic mutation and it is not heritable.
- The exact reason for post fertilization mutation remains unknown.
- Mutation of GNAS1 gene results in the overproduction of this G-protein, which in turn increases cyclic adenosine monophosphate (cAMP).
- Cyclic adenosine monophosphate (cAMP) is important regulatory molecule of differentiation modulating osteoblasts and osteoclasts while ossification and remodeling of bones.
- Improper differentiation of osteoblasts due to mutation of the GNAS1 gene considered as a cause of FD.
- Osteoclasts removes ossified bones and creates space for immature osteoblasts to produce fibrous tissue and occupy space which may entrap nerves causing pain or neurological deficit depending on the site involved.
Gross pathology
- Following are characteristic gross pathology findings of fibrous dysplasia:
- Well circumscribed, intramedullary lesion
- Tan-white-yellow, gritty, large lesions that distort bone
- Thin and expanded cortical bone
Microscopic histopathological analysis
- Following are characteristic microscopic histopathological findings of fibrous dysplasia:
- Curvilinear trabeculae (Chinese letters) of metaplastic woven bone
- Hypocellular and fibroblastic stroma
- No osteoblastic rimming (due to maturation arrest)
- Cartilaginous nodules (in 20% of cases particularly in femoral neck region)
- Myxoid areas consist of rapidly growing secondary aneurysmal bone cysts, hemorrhage, foamy macrophages, calcified spherules, and focal hyaline cartilage
- Abrupt transition of normal to abnormal bone
- No/rare mitotic figures
- No atypia (rarely is degenerative)
- Resembling endochondral ossification in skull
Causes
Differentiating Fibrous dyspepsia from other Diseases
- Fibrous dysplasia must be differentiated from other diseases that cause bone pain, deformity, and extra-skeletal involvement, such as:
Disease | Bone involvement | Bone pain | Fever | Fractures | Mechanism | ALK level | Diagnosis |
---|---|---|---|---|---|---|---|
Ossifying sarcoma | Single | Yes | No | Yes | Neoplasm | Normal | Radiology and biopsy |
Paget's disease | Multiple | Yes | No | Yes | Malfunction of osteoblasts | High | Biopsy |
Osteosarcoma | Single | Yes | No | Yes | Neoplasm | Normal | Radiology and biopsy |
Cherubism | Single | Yes | No | No | Malfunction of osteoblasts | High | Radiology and biopsy |
Hyperparathyroidism | Multiple | Yes | Yes | Yes | High PTH | Normal | Hormone level |
Solitary endocytosis | Single | Yes | No | No | Neoplasm | Normal | Radiology and biopsy |
Osteoblastoma | Single | Yes | No | Yes | Neoplasm | High | Radiology and biopsy |
Osteomyelitis | Single | Yes | Yes | No | Infection | Normal | Radiology and biopsy |
Brodie's abscess | Single | Yes | Yes | No | Infection | Normal | Radiology and biopsy |
Epidemiology and Demographics
- FD is more commonly found in age group from 3 -15 years of life.
- Polyostotic does not become symptomatic before age 10 years.
- Monostotic is asymptomatic until age of 20-30 years of life.
- FD affects men and women equally.
- There is no racial predilection for FD.
Risk Factors
- Common risk factor in the development of fibrous dysplasia is gain-of-function mutation.
Screening
Natural History, Complications and Prognosis
- The majority of patients with FD remain asymptomatic for the first decade of life.
- Early clinical features include bone pain, bony deformity, fever, and pathological fractures.
- Patients with fibrous dysplasia might develop skin/endocrine/malignancies depending on the variant.
- Common complications of FD include neurological deficit, endocrine abnormality, and in rare cases soft tissue tumors.
- Prognosis is generally good, and the patients with polyostotic form may have frequent fractures.
Diagnosis
Diagnostic Study of Choice
- The diagnosis of FD is made on the basis of clinical manifestations, radiology findings, and genetic testing to verify presence of GNAS mutation.[10][11][12][13][14][8][9]
History and Symptoms
- FD is usually asymptomatic.
- Symptoms of FD may include:
Physical Examination
- Patients with FD usually appear normal unless there is any bony deformity or skin involvement
- Physical examination may be remarkable according to the classification of disease:
- Monostotic
- Polyostotic
- Multiple bones involved
- Involve rib, femur, clavicle, lumbar spine, and tibia.
- Asymmetrical involvement
- Mainly misalignment of bones
- Tenderness over involved bone
- Bowing of weight bearing bone and increasing curvature of femur and tibia
- Craniofacial
- Involvement of maxillofacial bones
- Maladjustment
- Tappering
- Displacement
- Intact over lesion
- Maxillary sinus and Zygomatic bone involved mostly
- Floor of orbit may extend to skull
- No extracranial involvement
- Hypertelorism, facial asymmetry, visual impairment, exophthalmos and blindness
- Vestibular dysfuntion, hearing loss and tinnitus.
- McCune-Albright syndrome
- May involve all the bones
- Cafe au lait spots
- Endocrine abnormality of parathyroid hormone, gonadotropins Mazabraud syndrome
- Involve variable number of bones
Laboratory Findings
- There are no specific laboratory findings associated with FD. However, we may find normal PTH, Ca levels, and increased level of alkaline phosphatase due to increased bone turnover and increased basal metabolic rate.
Electrocardiogram
X-ray
- Radiology is the imaging modality of choice for FD.
- On x-ray, FD is characterized by:
- Network of fine bone trabeculae
- Increased trabeculation
- Opaque trabeculation forming ground glass appearance
- Cortical thinning
- Separated root of teeth
Echocardiography or Ultrasound
CT scan
MRI
Other Imaging Findings
Other Diagnostic Studies
- MRI and CT scan may be helpful in diagnosis of fibrous dysplasia.
- Bone biopsy will reveal the histological findings such as:
- Curvilinear trabeculae (Chinese letters) of metaplastic woven bone
- Hypocellular and fibroblastic stroma
- No osteoblastic rimming (due to maturation arrest)
- Cartilaginous nodules (in 20% of cases particularly in femoral neck region)
- Myxoid areas consist of rapidly growing secondary aneurysmal bone cysts, hemorrhage, foamy macrophages, calcified spherules, and focal hyaline cartilage
Incidental finding | Dull, aching pain and subsequent radiographs | ||||||||||||||||||||||
Full-body 99Tc-methylene diphosphonate bone scan | |||||||||||||||||||||||
Typical thinning of the cortex without periosteal reaction with a matrix appearance Ground glass | |||||||||||||||||||||||
If Yes no further studies | If no Bone Biopsy | ||||||||||||||||||||||
Treatment
Treatment of FD is mostly symptomatic and it can be either medical or surgical depending on severity and presentation of disease.[15][16][17][18][19]
Medical Therapy
- The mainstay of therapy for FD is bisphosphonates, which help in improving pain, slow down process of bone turnover, and also lower the fracture risk factor.
- Bisphosphonates acts by inhibiting osteoclasts.
- In the absence of a fracture or symptoms, the follow-up for a child with FD consists of twice yearly clinical evaluations with special attention to limited range of motion, obvious angular deformity, and limb length discrepancy.
Surgery
- Conventional surgical procedures can only be performed for patients with symptomatic FD patients in conjugation of over all evaluation of disease and the age of child.
- Adult monostotic lesion may be observed with subsequent radiography if it is not symptomatic. surgical removal and grafting the defect is considered for patients who have symptoms or excessively growing deformity or when disease produces deficit.
- Child age group may have skin lesions and endocrinopathies which needs prompt attention and surgery will be delayed until bones are mature and in case of neurological defect or significant deformity surgery is advised immediately.
Primary Prevention
Secondary Prevention
References
- ↑ Cicek AF, Kilinc M, Safali M, Gunhan O (2018). "Lamellation in fibrous dysplasia: A clinicopathologic study". Histol Histopathol: 11991. doi:10.14670/HH-11-991. PMID 29675824.
- ↑ Tessaris D, Boyce AM, Zacharin M, Matarazzo P, Lala R, de Sanctis L; et al. (2018). "Growth hormone (GH) - insulin like growth factor 1 (IGF-1) axis hyperactivity on bone fibrous dysplasia in McCune-Albright Syndrome". Clin Endocrinol (Oxf). doi:10.1111/cen.13722. PMID 29672904.
- ↑ Berglund JA, Tella SH, Tuthill KF, Kim L, Guthrie LC, Paul SM; et al. (2018). "Scoliosis in Fibrous Dysplasia/McCune-Albright Syndrome: Factors Associated with Curve Progression and Effects of Bisphosphonates". J Bone Miner Res. doi:10.1002/jbmr.3446. PMID 29669167.
- ↑ Utriainen P, Valta H, Björnsdottir S, Mäkitie O, Horemuzova E (2018). "Polyostotic Fibrous Dysplasia With and Without McCune-Albright Syndrome-Clinical Features in a Nordic Pediatric Cohort". Front Endocrinol (Lausanne). 9: 96. doi:10.3389/fendo.2018.00096. PMC 5863549. PMID 29599748.
- ↑ Rivera-Rosado E, Beaton-Comulada D, Hernandez-Ortiz E, Marrero-Ortiz PV (2018). "Bilateral Tibial Fibrous Dysplasia in a Pediatric Patient treated with Intramedullary Nailing". P R Health Sci J. 37 (1): 58–61. PMID 29547687.
- ↑ Innamorati G, Wilkie TM, Kantheti HS, Valenti MT, Dalle Carbonare L, Giacomello L; et al. (2018). "The curious case of Gαs gain-of-function in neoplasia". BMC Cancer. 18 (1): 293. doi:10.1186/s12885-018-4133-z. PMC 5856294. PMID 29544460.
- ↑ Fournel L, Rapicetta C, Fraternali A, Bellafiore S, Paci M, Lococo F (2018). "Fibrous Dysplasia of the Rib Mimicking a Malignant Bone Tumor at SPECT/CT with 99mTc-MDP". Clin Nucl Med. 43 (5): 346–348. doi:10.1097/RLU.0000000000002015. PMID 29517538.
- ↑ 8.0 8.1 Yepes JF (2017). "Dental Manifestations of Pediatric Bone Disorders". Curr Osteoporos Rep. 15 (6): 588–592. doi:10.1007/s11914-017-0409-5. PMID 28965204.
- ↑ 9.0 9.1 Gupta D, Garg P, Mittal A (2017). "Computed Tomography in Craniofacial Fibrous Dysplasia: A Case Series with Review of Literature and Classification Update". Open Dent J. 11: 384–403. doi:10.2174/1874210601711010384. PMC 5543691. PMID 28839487.
- ↑ Ogul H, Keskin E (2018). "Locally Aggressive Fibrous Dysplasia Mimicking Malign Calvarial Lesion". J Craniofac Surg. doi:10.1097/SCS.0000000000004453. PMID 29485574.
- ↑ Karaca A, Malladi VR, Zhu Y, Tafaj O, Paltrinieri E, Wu JY; et al. (2018). "Constitutive stimulatory G protein activity in limb mesenchyme impairs bone growth". Bone. 110: 230–237. doi:10.1016/j.bone.2018.02.016. PMC 5878747. PMID 29471062.
- ↑ Akashi M, Matsuo K, Shigeoka M, Kakei Y, Hasegawa T, Tachibana A; et al. (2017). "A Case Series of Fibro-Osseous Lesions of the Jaws". Kobe J Med Sci. 63 (3): E73–E79. PMC 5826023. PMID 29434178.
- ↑ Ostertag H, Glombitza S (2018). "[The activating GNAS mutation : A survey of fibrous dysplasia, its associated syndromes, and other skeletal and extraskeletal lesions]". Pathologe. 39 (2): 146–153. doi:10.1007/s00292-018-0417-y. PMID 29488004.
- ↑ Mierzwiński J, Kosowska J, Tyra J, Haber K, Drela M, Paczkowski D; et al. (2018). "Different clinical presentation and management of temporal bone fibrous dysplasia in children". World J Surg Oncol. 16 (1): 5. doi:10.1186/s12957-017-1302-5. PMC 5769533. PMID 29335001.
- ↑ Simm PJ, Biggin A, Zacharin MR, Rodda CP, Tham E, Siafarikas A; et al. (2018). "Consensus guidelines on the use of bisphosphonate therapy in children and adolescents". J Paediatr Child Health. 54 (3): 223–233. doi:10.1111/jpc.13768. PMID 29504223.
- ↑ Gresky J, Kalmykov A, Berezina N (2018). "Benign fibro-osseous lesion of the mandible in a Middle Bronze Age skeleton from Southern Russia". Int J Paleopathol. 20: 90–97. doi:10.1016/j.ijpp.2017.09.001. PMID 29496222.
- ↑ Ostertag H, Glombitza S (2018). "[The activating GNAS mutation : A survey of fibrous dysplasia, its associated syndromes, and other skeletal and extraskeletal lesions]". Pathologe. 39 (2): 146–153. doi:10.1007/s00292-018-0417-y. PMID 29488004.
- ↑ Ahmad M, Gaalaas L (2018). "Fibro-Osseous and Other Lesions of Bone in the Jaws". Radiol Clin North Am. 56 (1): 91–104. doi:10.1016/j.rcl.2017.08.007. PMID 29157551.
- ↑ Gatimel N, Moreau J, Parinaud J, Léandri RD (2017). "Sperm morphology: assessment, pathophysiology, clinical relevance, and state of the art in 2017". Andrology. 5 (5): 845–862. doi:10.1111/andr.12389. PMID 28692759.