Apert syndrome

WordNet

1. a pattern of symptoms indicative of some disease
2. a complex of concurrent things; "every word has a syndrome of meanings"

PrepTutorEJDIC

1. (疾患の徴候となる一群の)症徴候,症候群 / (事件・社会的状態などのパターンを示す)徴候形態

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/01/25 07:25:19」(JST)

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Apert syndrome
Classification and external resources
Specialty	medical genetics
ICD-10	Q87.0
ICD-9-CM	755.55
OMIM	101200
DiseasesDB	33968
MedlinePlus	001581
eMedicine	ped/122
MeSH	D000168

Apert syndrome is a form of acrocephalosyndactyly, a congenital disorder characterized by malformations of the skull, face, hands and feet. It is classified as a branchial arch syndrome, affecting the first branchial (or pharyngeal) arch, the precursor of the maxilla and mandible. Disturbances in the development of the branchial arches in fetal development create lasting and widespread effects.

In 1906, Eugène Apert, a French physician, described nine people sharing similar attributes and characteristics. Linguistically, "acro" is Greek for "peak", referring to the "peaked" head that is common in the syndrome. "Cephalo", also from Greek, is a combining form meaning "head". "Syndactyly" refers to webbing of fingers and toes.

In embryology, the hands and feet have selective cells that die, called selective cell death or apoptosis, causing separation of the digits. In the case of acrocephalosyndactyly, selective cell death does not occur and skin, and rarely bone, between the fingers and toes fuses.

The cranial bones are affected as well, similar to Crouzon syndrome and Pfeiffer syndrome. Craniosynostosis occurs when the fetal skull and facial bones fuse too soon in utero, disrupting normal bone growth. Fusion of different sutures leads to different patterns of growth on the skull. Examples include: trigonocephaly (fusion of the metopic suture), brachycephaly (fusion of the coronal suture and lambdoid suture bilaterally), dolichocephaly (fusion of the sagittal suture), plagiocephaly (fusion of coronal and lambdoidal sutures unilaterally), and oxycephaly or turricephaly (fusion of coronal and lambdoid sutures).

Findings for the incidence of the syndrome in the population have varied, with estimates as low as 1 birth in 200,000 provided and 160,000 given as an average by older studies. 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. 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.

Signs and symptoms

Craniosynostosis

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 conditir 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.

Syndactyly

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. The hands in patients with Apert syndrome always show four common features:

1. a short thumb with radial deviation
2. complex syndactyly of the index, long and ring finger
3. symbrachyphalangism
4. simple syndactyly of the fourth webspace

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:

• 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.
• 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

	Type I ("spade")	Type II ("mitten")	Type III ("rosebud")
First webspace	Simple Syndactyly	Simple Syndactyly	Complex Syndactyly
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
Fourth webspace	Simple and incomplete syndactyly	Simple and complete syndactyly	Simple and complete syndactyly

Other signs

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.

Causes

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.

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. This is a male-specific mutation hotspot: in a study of 57 cases, the mutation always occurred on the paternally derived allele. 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 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.

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. 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. 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.

Treatments

Craniosynostosis

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.

Syndactyly

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. 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:

• 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.
• 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.
• 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.

With growing of a child and respectively the hands, secondary revisions are needed to treat the contractures and to improve the aesthetics.

Dental significance

Teeth of a child with Apert syndrome

Common relevant features of acrocephalosyndactyly are a high-arched palate, pseudomandibular prognathism (appearing as mandibular prognathism), a narrow palate, and crowding of the teeth.

See also

• Crouzon syndrome
• Pfeiffer syndrome
• Hearing loss with craniofacial syndromes
• Saethre-Chotzen syndrome

References

External links

• Information from Teeter's Page at www.apert.org
• Apert Syndrome information from Seattle Children's Hospital Craniofacial Center
• cleftAdvocate – Non-profit support organization for all craniofacial conditions; on-line and in-person family support, insurance and advocacy assistance, and more.
• GeneReviews/NIH/NCBI/UW entry on FGFR-Related Craniosynostosis Syndromes
• The National Craniofacial Association
• Short explanation

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

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English Journal

• "Selfish Spermatogonial Selection": A Novel Mechanism for the Association Between Advanced Paternal Age and Neurodevelopmental Disorders.

• Goriely A, McGrath JJ, Hultman CM, Wilkie AO, Malaspina D.AbstractThere is robust evidence from epidemiological studies that the offspring of older fathers have an increased risk of neurodevelopmental disorders, such as schizophrenia and autism. The authors present a novel mechanism that may contribute to this association. Because the male germ cell undergoes many more cell divisions across the reproductive age range, copy errors taking place in the paternal germline are associated with de novo mutations in the offspring of older men. Recently it has been recognized that somatic mutations in male germ cells that modify proliferation through dysregulation of the RAS protein pathway can lead to within-testis expansion of mutant clonal lines. First identified in association with rare disorders related to paternal age (e.g., Apert syndrome, achondroplasia), this process is known as "selfish spermatogonial selection." This mechanism favors propagation of germ cells carrying pathogenic mutations, increasingly skews the mutational profile of sperm as men age, and enriches de novo mutations in the offspring of older fathers that preferentially affect specific cellular signaling pathways. This mechanism not only offers a parsimonious explanation for the association between advanced paternal age and various neurodevelopmental disorders but also provides insights into the genetic architecture (role of de novo mutations), neurobiological correlates (altered cell cycle), and some epidemiological features of these disorders. The authors outline hypotheses to test this model. Given the secular changes for delayed parenthood in most societies, this hypothesis has important public health implications.
• The American journal of psychiatry.Am J Psychiatry.2013 May 3. doi: 10.1176/appi.ajp.2013.12101352. [Epub ahead of print]
• There is robust evidence from epidemiological studies that the offspring of older fathers have an increased risk of neurodevelopmental disorders, such as schizophrenia and autism. The authors present a novel mechanism that may contribute to this association. Because the male germ cell undergoes many
• PMID 23639989

• Reduces bone mass as in human apert syndrome.

• Zhou X, Pu D, Liu R, Li X, Wen X, Zhang L, Chen L, Deng M, Liu L.SourceDepartment of Stomatology, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing, China.
• American journal of medical genetics. Part A.Am J Med Genet A.2013 May;161(5):983-92. doi: 10.1002/ajmg.a.35824. Epub 2013 Mar 13.
• Apert syndrome is a common craniosynostosis caused by gain-of-function missense mutations of fibroblast growth factor receptor 2 (FGFR2). Mice with the FGFR2 S252W mutation can elucidate the mechanism by which the human Apert syndrome phenotypes arise. However, many studies have focused on mutant sk
• PMID 23495007

Japanese Journal

• Psychological and Behavioral Characteristics of Chromosomal Anomalies and Congenital Contiguous Gene Syndrome

• 研究集録 (159), 31-41, 2015
• NAID 120005649252

• 成人アペール症候群の気道管理に挿管用ラリンジアルエアウェイ(air-Q)を用いた1症例

• 麻酔 63(10), 1125-1127, 2014-10
• NAID 40020224377

Related Links

• Apert syndrome - Genetics Home Reference

Apert syndrome is a genetic disorder characterized by the premature fusion of certain skull bones (craniosynostosis). This early fusion prevents the skull from growing normally and affects the shape of the head and face. In addition, a ...

• Apert syndrome: MedlinePlus Medical Encyclopedia

Apert syndrome can be passed down through families (inherited) as an autosomal dominant trait. This means that only one parent needs to pass on the faulty gene for a child to have the condition. Some cases may occur without a ...

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★リンクテーブル★

リンク元	「アペール症候群」「Saethre-Chotzen syndrome」「acrocephalosyndactylia」
関連記事	「syndrome」

「アペール症候群」

　　[★]

英

Apert syndrome

同

尖頭合指症I型 acrocephalosyndactyly type I, ACSI、アペール病 Apert disease

関

パイフェル症候群、セートレ・ヒョツェン症候群、Apert症候群、尖頭合指症

頭蓋顔面異骨症、頭蓋顔面骨異骨症

「Saethre-Chotzen syndrome」

　　[★]

セートレ・ヒョツェン症候群、Saethre-Chotzen症候群

関

acrocephalosyndactylia、Apert syndrome、Pfeiffer syndrome

「acrocephalosyndactylia」

　　[★]

先端異形成症、尖頭合指症

関

Apert syndrome、Pfeiffer syndrome、Saethre-Chotzen syndrome

「syndrome」

　　[★]

• n.

• 症候群