{{Short description|A genetic disorder characterized by the premature fusion of certain skull bones}}
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'''Crouzon syndrome''' is a rare genetic disorder characterized by the premature fusion of certain [[skull]] bones, a process known as [[craniosynostosis]]. This early fusion prevents the skull from growing normally and affects the shape of the head and face. Crouzon syndrome is named after the French neurologist Octave Crouzon, who first described the condition in 1912.
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==Genetics==
movie_url=http://www.youtube.com/v/-N7iSXpzdIY
Crouzon syndrome is caused by mutations in the [[FGFR2]] gene, which provides instructions for making a protein involved in the development and maintenance of bone and tissue. The condition is inherited in an [[autosomal dominant]] pattern, meaning one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, the mutation occurs as a new (de novo) mutation, with no family history of the disorder.
Individuals with Crouzon syndrome typically present with distinctive facial features due to the premature fusion of skull bones. These features may include:
'''Crouzon syndrome''' is an [[Dominance (genetics)|autosomal dominant]] genetic disorder known as a [[branchial arch]] syndrome. Specifically, this syndrome affects the [[first branchial arch|first branchial]] (or pharyngeal) arch, which is the precursor of the [[maxilla]] and [[Human mandible|mandible]]. Since the branchial arches are important developmental features in a growing [[embryo]], disturbances in their development create lasting and widespread effects.
Other possible features include [[hearing loss]], [[dental abnormalities]], and [[cleft palate]].
This syndrome is named after [[Octave Crouzon]],<ref>{{WhoNamedIt|synd|1383}}</ref><ref>L. E. O. Crouzon. Dysostose cranio-faciale héréditaire. Bulletin de la Société des Médecins des Hôpitaux de Paris, 1912, 33: 545-555.</ref> a [[France|French]] [[physician]] who first described this disorder. First called "craniofacial dysostosis" ("[[craniofacial]]" refers to the [[Human skull|skull]] and [[face]], and "[[dysostosis]]" refers to malformation of bone), the disorder was characterized by a number of clinical features which can be described by the rudimentary meanings of its former name. This syndrome is caused by a mutation in the [[fibroblast growth factor receptor 2]] (''FGFR2''), located on [[chromosome 10]]. The developing fetus's skull and facial bones fuse early or are unable to expand. Thus, normal bone growth cannot occur. Fusion of different sutures leads to abnormal patterns of growth of the skull.
==Signs and symptoms ==
[[File:Patient with Crouzon syndrome (1912).jpg|thumb|Child with Crouzon syndrome showing characteristic facial features.]]
[[File:Sutures from top.png|thumb|left|Cranial sutures]]
A defining characteristic of Crouzon syndrome is [[craniosynostosis]], which results in an abnormal head shape. This is present in combinations of: [[turricephaly]], [[frontal bossing]], [[trigonocephaly]] (fusion of the [[metopic suture]]), [[brachycephaly]] (fusion of the coronal suture), [[dolichocephaly]] (fusion of the [[sagittal suture]]), [[plagiocephaly]] (unilateral premature closure of [[lambdoid]] and [[coronal suture]]s), [[oxycephaly]] (fusion of [[coronal suture|coronal]] and [[lambdoidal suture]]s), and complex [[craniosynostosis]] (premature closure of some or all sutures).
[[Exophthalmos]] (bulging [[human eye|eye]]s due to shallow eye sockets after early fusion of surrounding bones), [[hypertelorism]] (greater than normal distance between the eyes), and [[psittichorhina]] (beak-like nose) are also very common features. Other facial characteristics that are present in many cases include external [[strabismus]] and [[hypoplastic maxilla]] (insufficient growth of the midface), which results in relative [[mandibular prognathism]] (protruding chin) and gives the effect of the patient having a concave face.<ref name="nih">{{cite web |title=Crouzon syndrome {{!}} Genetic and Rare Diseases Information Center (GARD) – an NCATS Program |url=https://rarediseases.info.nih.gov/diseases/6206/crouzon-syndrome |website=rarediseases.info.nih.gov |accessdate=21 November 2018 |language=en}}</ref>
Most symptoms are secondary to the abnormal skull structure. Approximately 30% of people with Crouzon syndrome develop [[hydrocephalus]]. [[Sensorineural hearing loss]] is present in some cases. The abnormalities in the manner in which the eyes fit in the eye sockets can cause vision problems, the most common of which is corneal exposure that can lead to visual impairment.<ref>{{Cite journal|last=|first=|date=|title=Ophthalmic sequelae of Crouzon syndrome|url=|journal=Ophthalmology|volume=112|pages=1129–1134|via=}}</ref> Some people with the condition have a restricted airway and can experience severe problems breathing.<ref name="nord">{{cite web |title=Crouzon Syndrome - NORD (National Organization for Rare Disorders) |url=https://rarediseases.org/rare-diseases/crouzon-syndrome/ |website=NORD (National Organization for Rare Disorders) |accessdate=21 November 2018}}</ref>
Common features are a narrow/high-arched palate, posterior bilateral crossbite, [[hypodontia]] (missing some teeth), and crowding of [[tooth|teeth]]. Due to maxillary hypoplasia, people with Crouzon syndrome generally have a considerable permanent [[underbite]].<ref>{{cite book |last1=Flint |first1=Paul |title=Cummings Otolaryngology |date=2015 |publisher=Elsevier |pages=2891–2914 |edition=6}}</ref>
==Causes==
The current research indicates [[fibroblast growth factor receptors]] (FGFR) [[FGFR2]] and [[FGFR3]] as the leading factors in causing the autosomal dominant Crouzon syndrome.<ref name="pmid20133659">{{cite journal | vauthors = Snyder-Warwick AK, Perlyn CA, Pan J, Yu K, Zhang L, Ornitz DM | title = Analysis of a gain-of-function FGFR2 Crouzon mutation provides evidence of loss of function activity in the etiology of cleft palate | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 107 | issue = 6 | pages = 2515–20 | date = February 2010 | pmid = 20133659 | pmc = 2823872 | doi = 10.1073/pnas.0913985107 | bibcode = 2010PNAS..107.2515S }}</ref><ref name=ghr/> These two [[transmembrane proteins]] are two of four fibroblast growth factor receptors involved in [[osteoblast]] [[Cellular differentiation|differentiation]] during [[embryonic development]]; mutations amongst these receptors are involved in several genetic disorders.<ref name="pmid20133659"/> There are 40 known mutations, most of which are caused by a missense mutation.<ref name="pmid25174698">{{cite journal | vauthors = Fenwick AL, Goos JA, Rankin J, Lord H, Lester T, Hoogeboom AJ, van den Ouweland AM, Wall SA, Mathijssen IM, Wilkie AO | title = Apparently synonymous substitutions in FGFR2 affect splicing and result in mild Crouzon syndrome | journal = BMC Med. Genet. | volume = 15 | issue = | pages = 95 | date = August 2014 | pmid = 25174698 | pmc = 4236556 | doi = 10.1186/s12881-014-0095-4 }}</ref> FGFR2 is the most commonly mutated gene, a missense at [[cysteine]] 342 in [[exon]] 9, which creates a gain-of-function.<ref name="pmid25174698"/> The FGFR2lllc [[isoform]], created via [[alternative splicing]] of exon 3 of the FGFR2 gene, uses exon 9 and is used in [[mesenchymal stem cells]] to control [[ossification]]. However, the mutation [[Constitutive activity|constitutively activates]] the transmembrane protein via a [[disulfide bond]] formed incorrectly due to the loss of cysteine 342.<ref name="pmid25174698"/> FGFR3 is expressed more in the [[frontal bones]] during embryonic development, guiding cranial bone development. A point mutation causes constitutive activation of [[tyrosine]] in the activation loop, located in the [[cytosolic]] region of the protein, leading to accelerated differentiation of frontal osteoblasts,<ref name="pmid24419316">{{cite journal | vauthors = Di Rocco F, Biosse Duplan M, Heuzé Y, Kaci N, Komla-Ebri D, Munnich A, Mugniery E, Benoist-Lasselin C, Legeai-Mallet L | title = FGFR3 mutation causes abnormal membranous ossification in achondroplasia | journal = Hum. Mol. Genet. | volume = 23 | issue = 11 | pages = 2914–25 | date = June 2014 | pmid = 24419316 | doi = 10.1093/hmg/ddu004 | doi-access = free }}</ref> resulting in premature fusion of frontal cranial bones.<ref name="pmid24419316"/>
==Diagnosis==
==Diagnosis==
Diagnosis of Crouzon syndrome usually can occur at birth by assessing the physical appearance of the infant. Further analysis, including radiographs, [[magnetic resonance imaging]] (MRI) scans, genetic testing, X-rays and CT scans can be used to confirm the diagnosis of Crouzon syndrome.{{cn|date=November 2018}}
Diagnosis of Crouzon syndrome is based on clinical evaluation, family history, and genetic testing. Imaging studies such as [[CT scan]]s or [[MRI]]s can be used to assess the extent of craniosynostosis and other skeletal abnormalities.
==Management==
==Treatment==
Management of Crouzon syndrome typically involves a multidisciplinary approach, including:
[[File:Crouzon4.jpg|thumb|Abnormal fusion of the skull bones is characteristic of Crouzon syndrome.]]
* [[Craniofacial surgery]] to correct skull and facial deformities
* [[Orthodontic treatment]] for dental issues
[[Craniofacial surgery|Surgery]] is typically used to prevent the closure of sutures of the skull from damaging the brain's development. Without surgery, [[blindness]] and [[intellectual disability]] are typical outcomes. To move the orbits forward, surgeons expose the skull and orbits and reshape the bone. To treat the midface deficiency, surgeons can move the lower orbit and midface bones forward.{{cn|date=November 2018}}
* [[Ophthalmologic care]] for eye problems
* [[Audiological evaluation]] and management for hearing loss
People with Crouzon syndrome tend to have multiple sutures involved, most specifically bilateral coronal [[craniosynostoses]], and either open vault surgery or strip craniectomy (if child is under 6 months) can be performed. In the later scenario, a helmet is worn for several months following surgery.{{cn|date=November 2018}}
Early intervention and regular follow-up are crucial to address the various complications associated with the syndrome.
==Prognosis==
Once treated for the cranial vault abnormalities, Crouzon patients generally go on to live a normal lifespan.{{cn|date=November 2018}}
The prognosis for individuals with Crouzon syndrome varies depending on the severity of the condition and the presence of associated complications. With appropriate medical and surgical management, many individuals can lead healthy lives.
==See also==
==Epidemiology==
* [[Craniosynostosis]]
Incidence of Crouzon syndrome is currently estimated to occur in 1.6 out of every 100,000 people<ref name="pmid20301628">{{cite journal | vauthors = Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LH, Stephens K, Amemiya A, Robin NH, Falk MJ, Haldeman-Englert CR | title = FGFR-Related Craniosynostosis Syndromes.| journal = GeneReviews| volume = | issue = | pages = | date =October 20, 1998 | pmid = 20301628 }}</ref> and is the most common craniostenosis syndrome.<ref name="ghr">{{cite web |last1=Reference |first1=Genetics Home |title=Crouzon syndrome |url=https://ghr.nlm.nih.gov/condition/crouzon-syndrome |website=Genetics Home Reference |accessdate=21 November 2018 |language=en}}</ref>
== History ==
Crouzon syndrome was first described by [[Octave Crouzon]] in 1912.<ref name="rodriguez">{{cite book |last1=Rodriguez |first1=Eduardo |title=Plastic Surgery: Volume 3: Craniofacial, Head and Neck Surgery and Pediatric Plastic Surgery |date=2018 |publisher=Elsevier |edition=4}}</ref> He noted the affected patients were a mother and her daughter, implying a genetic basis.
== See also ==
* [[Apert syndrome]]
* [[Apert syndrome]]
* [[Treacher Collins syndrome]]
* [[Pfeiffer syndrome]]
* [[Hearing loss with craniofacial syndromes]]
* [[Genetic disorders]]
[[Category:Genetic disorders]]
==References==
[[Category:Craniofacial conditions]]
{{reflist}}
[[Category:Syndromes affecting the skull]]
== External links ==
{{Medical resources
| DiseasesDB = 3203
| ICD10 = {{ICD10|Q|75|1|q|65}}
| ICD9 = {{ICD9|756.0}}
| ICDO =
| OMIM = 123500
| MedlinePlus =
| eMedicineSubj = ped
| eMedicineTopic = 511
| eMedicine_mult = {{eMedicine2|derm|734}}
| MeshID = D003394
}}
{{Commons category|Crouzon syndrome}}
* [http://ghr.nlm.nih.gov/condition/crouzon-syndrome Crouzon syndrome] on Genetics Home Reference from U.S. National Library of Medicine & National Institutes of Health
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=craniosynostosis GeneReviews/NIH/NCBI/UW entry on FGFR-Related Craniosynostosis Syndromes]
{{Congenital malformations and deformations of musculoskeletal system}}
{{Receptor deficiencies}}
[[Category:Genodermatoses]]
[[Category:Hearing loss with craniofacial syndromes]]
[[Category:Congenital disorders of musculoskeletal system]]
A genetic disorder characterized by the premature fusion of certain skull bones
Crouzon syndrome is a rare genetic disorder characterized by the premature fusion of certain skull bones, a process known as craniosynostosis. This early fusion prevents the skull from growing normally and affects the shape of the head and face. Crouzon syndrome is named after the French neurologist Octave Crouzon, who first described the condition in 1912.
Crouzon syndrome is caused by mutations in the FGFR2 gene, which provides instructions for making a protein involved in the development and maintenance of bone and tissue. The condition is inherited in an autosomal dominant pattern, meaning one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, the mutation occurs as a new (de novo) mutation, with no family history of the disorder.
Individuals with Crouzon syndrome typically present with distinctive facial features due to the premature fusion of skull bones. These features may include:
Diagnosis of Crouzon syndrome is based on clinical evaluation, family history, and genetic testing. Imaging studies such as CT scans or MRIs can be used to assess the extent of craniosynostosis and other skeletal abnormalities.
The prognosis for individuals with Crouzon syndrome varies depending on the severity of the condition and the presence of associated complications. With appropriate medical and surgical management, many individuals can lead healthy lives.
