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| | | {{Short description|A genetic disorder characterized by the premature fusion of certain skull bones}} |
| == Introduction ==
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| '''Apert syndrome''' is a congenital disorder that falls under the umbrella of [[acrocephalosyndactyly]]. It is characterized by distinct malformations of the skull, face, and extremities, specifically the hands and feet.
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| [[File:Hand in Apert syndrome (1).JPG|thumb|right|Illustration of the characteristic features of Apert syndrome.]] | | [[File:Hand in Apert syndrome (1).JPG|thumb|right|Illustration of the characteristic features of Apert syndrome.]] |
| | {{Infobox medical condition (new) |
| | | name = Apert syndrome |
| | | synonyms = Acrocephalo-syndactyly type 1 |
| | | image = Précis de psychiatrie 3.jpg |
| | | alt = |
| | | caption = Woman with Apert syndrome, 1914 |
| | | pronounce = |
| | | field = [[Medical genetics]], [[Craniofacial surgery]], [[Pediatrics]] |
| | | symptoms = [[Craniosynostosis]], [[syndactyly]] of hands and feet, abnormal facial development |
| | | complications = Hearing loss, vision problems, developmental delay, dental issues, obstructive sleep apnea |
| | | onset = Congenital (present at birth) |
| | | duration = Lifelong |
| | | types = |
| | | causes = Genetic mutation in the [[FGFR2]] gene (typically a C to G mutation at position 755) |
| | | risks = Sporadic mutation, autosomal dominant inheritance |
| | | diagnosis = [[Clinical examination]], [[genetic testing]], [[imaging studies]] |
| | | differential = [[Crouzon syndrome]], [[Pfeiffer syndrome]], [[Saethre–Chotzen syndrome]] |
| | | prevention = None |
| | | treatment = Surgical correction of skull and limb deformities, supportive therapies |
| | | medication = Symptomatic treatments as needed |
| | | prognosis = Variable; improved with early intervention |
| | | frequency = Rare (estimated 1 in 65,000–88,000 live births) |
| | | deaths = Rare; typically associated with complications or severe forms |
| | }} |
| | '''Apert syndrome''' is a rare genetic disorder characterized by the premature fusion of certain [[skull]] bones, a condition known as [[craniosynostosis]]. This early fusion prevents the skull from growing normally and affects the shape of the head and face. Apert syndrome is also associated with [[syndactyly]], where fingers and toes are fused together. |
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| == Historical Background == | | ==Genetics== |
| | | Apert 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 mutations lead to the abnormal fusion of bones, particularly in the skull, hands, and feet. 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 1906, the French physician [[Eugène Apert]] was the first to detail the attributes of nine individuals exhibiting similar features, subsequently leading to the syndrome being named in his honor.<ref>{{WhoNamedIt|synd|194}}</ref>
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| Findings for the incidence of the syndrome in the population have varied,<ref name="Fearson">{{Cite journal|issn=0032-1052|volume=112|issue=1|pages=1–12|last=Fearon|first=Jeffrey A.|title=Treatment of the Hands and Feet in Apert Syndrome: An Evolution in Management|journal=Plastic and Reconstructive Surgery|date=July 2003|pmid=12832871|location=Dallas, Texas|doi=10.1097/01.PRS.0000065908.60382.17}}</ref> with estimates as low as 1 birth in 200,000 provided<ref>{{cite book|last=Foreman|first=Phil|title=Education of Students with an Intellectual Disability: Research and Practice (PB)|url=https://books.google.com/books?id=zR8H1YwOsVgC&pg=PA30|year=2009|publisher=IAP|isbn=978-1-60752-214-0|page=30}}</ref> and 160,000 given as an average by older studies.<ref>{{cite book|last=Carter|first=Charles H.|title=Medical aspects of mental retardation|url=https://books.google.com/?id=KNtrAAAAMAAJ&dq=%22Apert+syndrome%22+%22one+in+*+births%22&q=160%2C000#search_anchor|year=1965|publisher=Thomas|oclc=174056103|page=358}}</ref><ref>{{cite journal|author1=Abe Bert Baker|author2=Lowell H. Baker|title=Apert's Syndrome|journal=Clinical Neurology|url=https://books.google.com/?id=Zc9rAAAAMAAJ&dq=%22Apert+syndrome%22+%22one+in+*+births%22&q=160%2C000#search_anchor|year=1979|publisher=Medical Dept., Harper & Row|volume=3|page=47|oclc=11620265}}</ref> A study conducted in 1997, however, by the California Birth Defects Monitoring Program found an incidence rate of 1 in 80,645 out of almost 2.5 million live births.<ref>{{cite book|last=Aitken|first=J. Kenneth|title=An A-Z of Genetic Factors in Autism: A Handbook for Professionals|url=https://books.google.com/books?id=UG7Ezl_OAZcC&pg=PA133|year=2010|publisher=Jessica Kingsley|isbn=978-1-84310-976-1|page=133}}</ref> Another study conducted in 2002 by the Craniofacial Center, North Texas Hospital For Children, found a higher incidence of about 1 in 65,000 live births.<ref name="Fearson" />
| | ==Signs and Symptoms== |
| | | Individuals with Apert syndrome typically present with: |
| ==Signs and symptoms==
| | * [[Craniosynostosis]], leading to a [[brachycephalic]] (short and broad) skull shape. |
| | | * [[Midface hypoplasia]], where the middle of the face appears sunken. |
| ===Craniosynostosis===
| | * [[Syndactyly]] of the fingers and toes, often involving fusion of the second, third, and fourth digits. |
| The cranial malformations are the most apparent effects of acrocephalosyndactyly. [[Craniosynostosis]] occurs, in which the cranial sutures close too soon, though the child's brain is still growing and expanding. [[Brachycephaly]] is the common pattern of growth, where the [[coronal sutures]] close prematurely, preventing the skull from expanding frontward or backward and causing the brain to expand the skull to the sides and upwards. This results in another common characteristic, a high, prominent forehead with a flat back of the skull. Due to the premature closing of the coronal sutures, increased cranial pressure can develop, leading to mental deficiency. A flat or concave face may develop as a result of deficient growth in the mid-facial bones, leading to a condition known as pseudomandibular prognathism. Other features of acrocephalosyndactyly may include shallow bony orbits and broadly spaced eyes. Low-set ears are also a typical characteristic of branchial arch syndromes.
| | * Intellectual disability, which can vary from mild to moderate. |
| | | * Hearing loss due to [[ear]] abnormalities. |
| ===Syndactyly===
| | * Dental problems, such as crowded teeth and malocclusion. |
| All acrocephalosyndactyly syndromes show some level of limb anomalies, so it can be hard to tell them apart. However, the typical hand deformities in patients with Apert syndrome distinguish it from the other syndromes.<ref>{{Cite journal| issn = 0094-1298| volume = 18| issue = 2| pages = 217–25| last = Kaplan| first = L C| title = Clinical assessment and multispecialty management of Apert syndrome| journal = Clinics in Plastic Surgery| date = April 1991| pmid = 2065483}}</ref> The hands in patients with Apert syndrome always show four common features:<ref>{{Cite journal| issn = 0094-1298| volume = 18| issue = 2| pages = 321–55| last = Upton| first = J| title = Apert Syndrome. Classification and pathologic anatomy of limb anomalies| journal = Clinics in Plastic Surgery| date = April 1991| pmid = 2065493}}</ref>
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| # a short thumb with radial deviation
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| # complex [[syndactyly]] of the index, long and ring finger
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| # [[symbrachyphalangism]]
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| # simple syndactyly of the fourth webspace
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| The deformity of the space between the index finger and the thumb may be variable. Based on this first webspace, we can differentiate three different types of handdeformation:
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| * Type I: Also called a "spade hand". The most common and least severe type of deformation. The thumb shows radial deviation and [[clinodactyly]] but is separated from the index finger. The index, long and ring finger are fused together in the distal interphalangeal joints and form a flat palm. During the embryonic stage, the fusion has no effect on the longitudinal growth of these fingers, so they have a normal length. In the fourth webspace, we always see a simple syndactyly, either complete or incomplete. | |
| * Type II: Also called a "spoon" or "mitten" hand. This is a more serious anomaly since the thumb is fused to the index finger by simple complete or incomplete syndactyly. Only the distal phalanx of the thumb is not joined in the osseous union with the index finger and has a separate nail. Because the fusion of the digits is at the level of the distal interphalangeal joints, a concave palm is formed. Most of the time, we see complete syndactyly of the fourth webspace.
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| * Type III: Also called the "hoof" or "rosebud" hand. This is the most uncommon but also most severe form of hand deformity in Apert syndrome. There is a solid osseous or cartilaginous fusion of all digits with one long, conjoined nail. The thumb is turned inwards and it is often impossible to tell the fingers apart. Usually proper imaging of the hand is very difficult, due to overlap of bones, but physical examination alone is not enough to measure the severity of deformation. | |
| {| class="wikitable"
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| ! !! Type I ''("spade")'' !! Type II ''("mitten")'' !! Type III ''("rosebud")''
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| | First webspace || Simple syndactyly || Simple syndactyly || Complex syndactyly
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| | Middle three fingers || Side-to-side fusion with flat palm || Fusion of fingertops forming a concave palm || Tight fusion of all digits with one conjoined nail
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| | Fourth webspace || Simple and incomplete syndactyly || Simple and complete syndactyly || Simple and complete syndactyly
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| |}
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| ===Dental significance===
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| [[File:Patient with Apert syndrome.jpg|thumb|Teeth of a child with Apert syndrome]]
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| Common relevant features of acrocephalosyndactyly are a high-arched palate, [[pseudomandibular prognathism]] (appearing as [[prognathism|mandibular prognathism]]), a narrow palate and crowding of the teeth.
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| ===Other signs===
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| [[Omphalocele]] has been described in two patients with Apert syndrome by Herman T.E. et al. (USA, 2010) and by Ercoli G. et al. (Argentina, 2014). An omphalocele is a birth defect in which an intestine or other abdominal organs are outside of the body of an infant because of a hole in the bellybutton area. However, the association between omphalocele and Apert syndrome is not confirmed yet, so additional studies are necessary.<ref>{{cite journal|last=Herman|first=TE|last2=Siegel|first2=MJ|date=October 2010|title=Apert syndrome with omphalocele|journal=J. Perinatol.|volume=30|issue=10|pages=695–697|doi=10.1038/jp.2010.72|pmid=20877364|doi-access=free}}</ref><ref>{{cite journal|last=Ercoli|first=G|last2=Bidondo|first2=MP|last3=Senra|first3=BC|last4=Groisman|first4=B|date=September 2014|title=Apert syndrome with omphalocele: a case report|journal=Birth Defects Res a Clin Mol Teratol.|volume=100|issue=9|pages=726–729|doi=10.1002/bdra.23270|pmid=25045033}}</ref>
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| ==Causes==
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| Acrocephalosyndactyly may be an [[autosomal dominant]] disorder. Males and females are affected equally; however research is yet to determine an exact cause. Nonetheless, almost all cases are sporadic, signifying fresh mutations or environmental insult to the [[genome]]. The offspring of a parent with Apert syndrome has a 50% chance of inheriting the condition. In 1995, A.O.M. Wilkie published a paper showing evidence that acrocephalosyndactyly is caused by a defect on the [[fibroblast growth factor receptor 2]] [[gene]], on [[chromosome 10]].<ref>{{Cite journal| volume = 9| issue = 2| pages = 165–72| last = Wilkie| first = A O|author2=S F Slaney |author3=M Oldridge |author4=M D Poole |author5=G J Ashworth |author6=A D Hockley |author7=R D Hayward |author8=D J David |author9=L J Pulleyn |author10=P Rutland | title = Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome| journal = Nature Genetics| date = February 1995| pmid = 7719344| doi = 10.1038/ng0295-165}}</ref>
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| Apert syndrome is an autosomal dominant disorder; approximately two-thirds of the cases are due to a C to G mutation at the position 755 in the [[FGFR2]] gene, which causes a Ser to Trp change in the protein.<ref name="Goriely">{{cite journal|last1=Goriely|first1=A.|last2=McVean|first2=GA|last3=Röjmyr|first3=M|last4=Ingemarsson|first4=B|last5=Wilkie|first5=AO|title=Evidence for Selective Advantage of Pathogenic FGFR2 Mutations in the Male Germ Line|journal=Science|volume=301|issue=5633|pages=643–6|year=2003|pmid=12893942|doi=10.1126/science.1085710|bibcode=2003Sci...301..643G}}</ref> This is a male-specific mutation hotspot: in a study of 57 cases, the mutation always occurred on the paternally derived allele.<ref name="Moloney">{{cite journal|last1=Moloney|first1=DM|last2=Slaney|first2=SF|last3=Oldridge|first3=M|last4=Wall|first4=SA|last5=Sahlin|first5=P|last6=Stenman|first6=G|last7=Wilkie|first7=AO|title=Exclusive paternal origin of new mutations in Apert syndrome|journal=Nature Genetics|volume=13|issue=1|pages=48–53|year=1996|pmid=8673103|doi=10.1038/ng0596-48}}</ref> On the basis of the observed birth prevalence of the disease (1 in 70,000), the apparent rate of C to G mutations at this site is about .00005, which is 200- to 800-fold higher than the usual rate for mutations at CG dinucleotides. Moreover, the incidence rises sharply with the [[paternal age effect|age of the father]]. Goriely et al. (2003) analyzed the allelic distribution of mutations in sperm samples from men of different ages and concluded that the simplest explanation for the data is that the C to G mutation gives the cell an advantage in the male germline.<ref name="Goriely"/>
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| It is still not very clear why people with Apert syndrome have both craniosynostosis and syndactyly. There has been one study that suggests it has something to do with the expression of three [[isoforms]] of FGFR2, the gene with the [[point mutations]] that causes the syndrome in 98% of the patients.<ref>{{Cite journal| volume = 107| issue = 6| pages = 1331–1338| last = Britto| first = J A|author2=J C T Chan |author3=R D Evans |author4=R D Hayward |author5=B M Jones | title = Differential expression of fibroblast growth factor receptors in human digital development suggests common pathogenesis in complex acrosyndactyly and craniosynostosis| journal = Plastic and Reconstructive Surgery| date = May 2001| pmid = 11335797 | doi=10.1097/00006534-200105000-00001}}</ref> KGFR, keratinocyte growth factor receptor, is an isoform active in the [[metaphysis]] and interphalangeal joints. FGFR1 is an isoform active in the [[diaphysis]]. FGFR2-Bek is active in the metaphysis, as well as the diaphysis, but also in the interdigital [[mesenchyme]]. The point mutation increases the ligand-dependent activation of FGFR2 and thus of its isoforms. This means that FGFR2 loses its specificity, causing binding of FGFs that normally do not bind to the receptor.<ref name="pmid18773495">{{cite journal |vauthors=Hajihosseini MK, Duarte R, Pegrum J, Donjacour A, Lana-Elola E, Rice DP, Sharpe J, Dickson C | title = Evidence that Fgf10 contributes to the skeletal and visceral defects of an Apert syndrome mouse model | journal = Dev. Dyn. | volume = 238 | issue = 2 | pages = 376–85 |date=February 2009 | pmid = 18773495 | doi = 10.1002/dvdy.21648 | url = }}</ref> Since FGF suppresses [[apoptosis]], the interdigital mesenchyme is maintained. FGF also increases replication and differentiation of [[osteoblasts]], thus early fusion of several sutures of the skull. This may explain why both symptoms are always found in Apert syndrome.
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| ==Diagnosis== | | ==Diagnosis== |
| Diagnosis is typically by the apparent physical characteristics and can be aided by skull [[Radiography|X-ray]] or [[Computed tomography of the head|head CT examination]]. Molecular [[genetic testing]] can confirm the diagnosis.<ref>{{Cite web|url=https://rarediseases.info.nih.gov/diseases/5833/apert-syndrome|title=Apert syndrome {{!}} Genetic and Rare Diseases Information Center (GARD) – an NCATS Program|website=rarediseases.info.nih.gov|language=en|access-date=2018-03-17}}</ref> | | Diagnosis of Apert syndrome is based on clinical examination and the characteristic physical features. Genetic testing can confirm the presence of mutations in the FGFR2 gene. Prenatal diagnosis is possible through [[amniocentesis]] or [[chorionic villus sampling]] if there is a known family history of the condition. |
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| ==Treatments==
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| ===Craniosynostosis===
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| Surgery is needed to prevent the closing of the coronal sutures from damaging brain development. In particular, surgeries for the [[LeFort III]] or monobloc midface [[distraction osteogenesis]] which detaches the midface or the entire upper face, respectively, from the rest of the skull, are performed in order to reposition them in the correct plane. These surgeries are performed by both plastic and oral and maxillofacial (OMS) surgeons, often in collaboration.
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| ===Syndactyly===
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| There is no standard treatment for the hand malformations in Apert due to the differences and severity in clinical manifestations in different patients. Every patient should therefore be individually approached and treated, aiming at an adequate balance between hand functionality and aesthetics. However, some guidelines can be given depending on the severity of the deformities. In general it is initially recommended to release the first and fourth interdigital spaces, thus releasing the border rays.<ref>{{Cite journal| issn = 0094-1298| volume = 18| issue = 2| pages = 357–64| last = Zucker| first = R M| title = Syndactyly correction of the hand in Apert syndrome| journal = Clinics in Plastic Surgery| date = April 1991| pmid = 1648464}}</ref> This makes it possible for the child to grasp things by hand, a very important function for the child's development. Later the second and third interdigital spaces have to be released. Because there are three handtypes in Apert, all with their own deformities, they all need a different approach regarding their treatment:
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| * Type I hand usually needs only the interdigital web space release. First web release is rarely needed but often its deepening is necessary. Thumb clynodactyly correction will be needed.
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| * In type II hands it is recommended to release the first and fifth rays in the beginning, then the second and the third interdigital web spaces have to be freed. The clynodactyly of the thumb has to be corrected as well. The lengthening of the thumb phalanx may be needed, thus increasing the first web space. In both type I and type II, the recurrent syndactyly of the second web space will occur because of a pseudoepiphysis at the base of the index metacarpal. This should be corrected by later revisions. | | ==Treatment== |
| | Management of Apert syndrome requires a multidisciplinary approach, involving: |
| | * [[Craniofacial surgery]] to correct skull and facial deformities. |
| | * [[Orthopedic surgery]] to separate fused fingers and toes. |
| | * [[Speech therapy]] and [[occupational therapy]] to support developmental needs. |
| | * Regular monitoring and treatment of [[hearing loss]] and [[dental issues]]. |
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| * Type III hands are the most challenging to treat because of their complexity. First of all, it is advised to release the first and fourth webspace, thus converting it to type I hand. The treatment of macerations and nail-bed infections should also be done in the beginning. For increasing of the first web space, lengthening of the thumb can be done. It is suggested that in severe cases an amputation of the index finger should be considered. However, before making this decision, it is important to weigh the potential improvement to be achieved against the possible psychological problems of the child later due to the aesthetics of the hand. Later, the second and/or third interdigital web space should be released.
| | ==Prognosis== |
| | The prognosis for individuals with Apert syndrome varies depending on the severity of symptoms and the success of surgical interventions. With appropriate treatment, many individuals can lead fulfilling lives, although they may require ongoing medical care and support. |
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| With growing of a child and respectively the hands, secondary revisions are needed to treat the contractures and to improve the aesthetics.
| | ==Related pages== |
| | | * [[Craniosynostosis]] |
| == Characteristics and Development == | | * [[Syndactyly]] |
| | | * [[FGFR2]] |
| === Cranial and Facial Anomalies ===
| | * [[Genetic disorder]] |
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| Apert syndrome leads to a fusion of cranial and facial bones, a condition known as [[Craniosynostosis]]. This premature fusion disrupts normal bone growth, and depending on which [[Suture (anatomical)|sutures]] are affected, it can result in different growth patterns:
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| * [[trigonocephaly]] - Resulting from the fusion of the [[metopic suture]].
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| * [[brachycephaly]] - Caused by the fusion of both the [[coronal suture]] and [[lambdoid suture]].
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| * [[dolichocephaly]] - Due to the fusion of the [[sagittal suture]].
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| * [[plagiocephaly]] - Arising from unilateral fusion of the coronal and [[lambdoidal suture]]s.
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| * [[oxycephaly]] or turricephaly - Occurs from the fusion of both the coronal and lambdoid sutures.
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| === Limb Anomalies ===
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| The syndrome's hallmark is the fusion of skin, and occasionally bone, between fingers and toes, termed ''[[syndactyly]]''. This is attributed to a failure in the process of selective cell death, or [[apoptosis]], which ordinarily separates the digits during fetal development.
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| == Linguistic Origins ==
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| The term "acrocephalosyndactyly" breaks down linguistically as:
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| * ''acro'' - Derived from the [[Greek language|Greek]] word for "peak", alluding to the common "peaked" head observed in the syndrome. | |
| * ''cephalo'' - A Greek [[combining form]] meaning "head". | |
| * ''syndactyly'' - Denotes the webbing or fusion of fingers and toes. | |
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| == Pathophysiology ==
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| Apert syndrome is classified as a branchial arch syndrome, predominantly impacting the first [[Pharyngeal arch|branchial (or pharyngeal) arch]]. This arch is the embryonic precursor to the [[maxilla]] and [[Human mandible|mandible]]. Disturbances during its development lead to the widespread effects observed in this syndrome.
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| == Comparison to Other Syndromes ==
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| The cranial bone anomalies seen in Apert syndrome are also present in other conditions, notably [[Crouzon syndrome]] and [[Pfeiffer syndrome]].
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| == Conclusion ==
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| Understanding Apert syndrome is vital for medical professionals and researchers to ensure timely diagnosis and intervention, offering affected individuals the best potential quality of life.
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| [[Category:Medical Conditions]] [[Category:Genetic Disorders]] [[Category:Craniofacial Disorders]]
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| ==See also==
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| *[[Crouzon syndrome]]
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| *[[Pfeiffer syndrome]]
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| *[[Hearing loss with craniofacial syndromes]]
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| *[[Saethre–Chotzen syndrome]]
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| ==References==
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| {{Reflist}}
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| == External links ==
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| {{Medical resources
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| | DiseasesDB = 33968
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| | ICD10 = {{ICD10|Q|87|0|q|80}}
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| | ICD9 = {{ICD9|755.55}}
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| | OMIM = 101200
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| | MedlinePlus = 001581
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| | eMedicineSubj = ped
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| | eMedicineTopic = 122
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| | MeshID = D000168
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| | Orphanet = 87
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| | SNOMED CT = 205258009
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| }}
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| *[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=craniosynostosis GeneReviews/NIH/NCBI/UW entry on FGFR-Related Craniosynostosis Syndromes]
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| {{Phakomatoses and other congenital malformations not elsewhere classified}} | | {{Phakomatoses and other congenital malformations not elsewhere classified}} |
| {{Receptor deficiencies}} | | {{Receptor deficiencies}} |
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| {{DEFAULTSORT:Apert Syndrome}} | | {{DEFAULTSORT:Apert Syndrome}} |
| [[Category:Cell surface receptor deficiencies]] | | [[Category:Cell surface receptor deficiencies]] |
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| [[Category:Congenital oral disorders]] | | [[Category:Congenital oral disorders]] |
| [[Category:Pharyngeal arches]] | | [[Category:Pharyngeal arches]] |
| {{stub}}
| | [[Category:Genetic disorders]] |
| | [[Category:Craniofacial conditions]] |
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