Apert syndrome

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Apert syndrome
Other namesAcrocephalo-syndactyly type 1 [1]
Precis de psychiatrie 3.jpg
Woman with Apert syndrome, 1914
Specialty Medical genetics   OOjs UI icon edit-ltr-progressive.svg
CausesGenetic mutations; C to G mutation at the position 755 in the FGFR2 gene (two-thirds of cases)

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.

Contents

In 1906, Eugène Apert, a French physician, described nine people sharing similar attributes and characteristics. [2] Linguistically, in the term "acrocephalosyndactyly", 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.[ citation needed ]

In embryology, the hands and feet have selective cells that die in a process 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, [3] with estimates as low as 1 birth in 200,000 provided [4] and 160,000 given as an average by older studies. [5] [6] 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. [7] 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. [3]

Signs and symptoms

Craniosynostosis

Apert syndrome in a 5-year-old boy, showing characteristic features Casazza 4.jpg
Apert syndrome in a 5-year-old boy, showing characteristic features

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. [8] 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. [9] [10]

Syndactyly

Hand in Apert syndrome with syndactyly Hand in Apert syndrome (1).JPG
Hand in Apert syndrome with 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. [11] The hands in patients with Apert syndrome always show four common features: [12]

  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, three different types of hand deformation can be diffentiated:

Type I ("spade")Type II ("mitten")Type III ("rosebud")
First webspaceSimple syndactylySimple syndactylyComplex syndactyly
Middle three fingersSide-to-side fusion with flat palmFusion of fingertops forming a concave palmTight fusion of all digits with one conjoined nail
Fourth webspaceSimple and incomplete syndactylySimple and complete syndactylySimple and complete syndactyly

Dental significance

Teeth of a child with Apert syndrome Patient with Apert syndrome.jpg
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.

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. [13] [14]

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. [15] [16]

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. [17] This is a male-specific mutation hotspot: in a study of 57 cases, the mutation always occurred on the paternally derived allele. [18] 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. [17]

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. [19] 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. [20] 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.[ citation needed ]

Diagnosis

Diagnosis is typically by the apparent physical characteristics and can be aided by skull X-ray or head CT examination. Molecular genetic testing can confirm the diagnosis. [21]

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.[ citation needed ]

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. [22] 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: [23]

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

See also

Related Research Articles

<span class="mw-page-title-main">Say–Meyer syndrome</span> X-linked recessive disorder characterised by developmental delay

Say–Meyer syndrome is a rare X-linked genetic disorder that is mostly characterized as developmental delay. It is one of the rare causes of short stature. It is closely related with trigonocephaly. People with Say–Meyer syndrome have impaired growth, deficits in motor skills development and mental state.

<span class="mw-page-title-main">Polydactyly</span> Physical anomaly involving extra fingers or toes

Polydactyly or polydactylism, also known as hyperdactyly, is an anomaly in humans and non-human animals resulting in supernumerary fingers and/or toes. Polydactyly is the opposite of oligodactyly.

<span class="mw-page-title-main">Brachycephaly</span> Short, broad head

Brachycephaly is the shape of a skull shorter than average in its species. It is perceived as a cosmetically desirable trait in some domesticated dog and cat breeds, notably the pug and Persian, and can be normal or abnormal in other animal species.

<span class="mw-page-title-main">Scaphocephaly</span> Cephalic disorder involving premature fusion of the sagittal suture

Scaphocephaly, or sagittal craniosynostosis, is a type of cephalic disorder which occurs when there is a premature fusion of the sagittal suture. Premature closure results in limited lateral expansion of the skull resulting in a characteristic long, narrow head. The skull base is typically spared.

<span class="mw-page-title-main">Trigonocephaly</span> Congenital condition of premature fusion of the metopic suture

Trigonocephaly is a congenital condition due to premature fusion of the metopic suture, leading to a triangular forehead. The premature merging of the two frontal bones leads to transverse growth restriction and parallel growth expansion. It may occur as one component of a syndrome together with other abnormalities, or in isolated form. The term is from the Greek trigonon, "triangle", and kephale, "head".

<span class="mw-page-title-main">Crouzon syndrome</span> Genetic disorder of the skull and face

Crouzon syndrome is an autosomal dominant genetic disorder known as a branchial arch syndrome. Specifically, this syndrome affects the first branchial arch, which is the precursor of the maxilla and mandible. Because the branchial arches are important developmental features in a growing embryo, disturbances in their development create lasting and widespread effects. The syndrome is caused by a mutation in a gene on chromosome 10 that controls the body's production of fibroblast growth factor receptor 2 (FGFR2).

<span class="mw-page-title-main">Craniosynostosis</span> Premature fusion of bones in the skull

Craniosynostosis is a condition in which one or more of the fibrous sutures in a young infant's skull prematurely fuses by turning into bone (ossification), thereby changing the growth pattern of the skull. Because the skull cannot expand perpendicular to the fused suture, it compensates by growing more in the direction parallel to the closed sutures. Sometimes the resulting growth pattern provides the necessary space for the growing brain, but results in an abnormal head shape and abnormal facial features. In cases in which the compensation does not effectively provide enough space for the growing brain, craniosynostosis results in increased intracranial pressure leading possibly to visual impairment, sleeping impairment, eating difficulties, or an impairment of mental development combined with a significant reduction in IQ.

<span class="mw-page-title-main">Saethre–Chotzen syndrome</span> Medical condition

Saethre–Chotzen syndrome (SCS), also known as acrocephalosyndactyly type III, is a rare congenital disorder associated with craniosynostosis. This affects the shape of the head and face, resulting in a cone-shaped head and an asymmetrical face. Individuals with SCS also have droopy eyelids (ptosis), widely spaced eyes (hypertelorism), and minor abnormalities of the hands and feet (syndactyly). Individuals with more severe cases of SCS may have mild to moderate intellectual or learning disabilities. Depending on the level of severity, some individuals with SCS may require some form of medical or surgical intervention. Most individuals with SCS live fairly normal lives, regardless of whether medical treatment is needed or not.

Craniofacial surgery is a surgical subspecialty that deals with congenital and acquired deformities of the head, skull, face, neck, jaws and associated structures. Although craniofacial treatment often involves manipulation of bone, craniofacial surgery is not tissue-specific; craniofacial surgeons deal with bone, skin, nerve, muscle, teeth, and other related anatomy.

<span class="mw-page-title-main">Carpenter syndrome</span> Medical condition

Carpenter syndrome, also called acrocephalopolysyndactyly type II, is an extremely rare autosomal recessive congenital disorder characterized by craniofacial malformations, obesity, syndactyly, and polydactyly. Acrocephalopolysyndactyly is a variation of acrocephalosyndactyly that presents with polydactyly.

<span class="mw-page-title-main">Pfeiffer syndrome</span> Genetic disorder of the skull

Pfeiffer syndrome is a rare genetic disorder, characterized by the premature fusion of certain bones of the skull (craniosynostosis), which affects the shape of the head and face. The syndrome includes abnormalities of the hands and feet, such as wide and deviated thumbs and big toes.

<span class="mw-page-title-main">Acrocephalosyndactyly</span> Group of diseases

Acrocephalosyndactyly is a group of congenital conditions characterized by irregular features of the face and skull (craniosynostosis) and hands and feet (syndactyly). Craniosynostosis occurs when the cranial sutures, the fibrous tissue connecting the skull bones, fuse the cranial bones early in development. Cranial sutures allow the skull bones to continue growing until they fuse at age 24. Premature fusing of the cranial sutures can result in alterations to the skull shape and interfere with brain growth. Syndactyly occurs when digits of the hands or feet are fused together. When polydactyly is also present, the classification is acrocephalopolysyndactyly. Polydactyly occurs when the hands or feet possess additional digits. Acrocephalosyndactyly is usually diagnosed after birth, although prenatal diagnosis is sometimes possible if the genetic variation is present in family members, as the conditions are typically inherited in an autosomal dominant pattern Treatment often involves surgery in early childhood to correct for craniosynostosis and syndactyly.

<span class="mw-page-title-main">Craniofrontonasal dysplasia</span> Medical condition

Craniofrontonasal dysplasia is a very rare X-linked malformation syndrome caused by mutations in the ephrin-B1 gene (EFNB1). Phenotypic expression varies greatly amongst affected individuals, where females are more commonly and generally more severely affected than males. Common physical malformations are: craniosynostosis of the coronal suture(s), orbital hypertelorism, bifid nasal tip, dry frizzy curled hair, longitudinal ridging and/or splitting of the nails, and facial asymmetry.

<span class="mw-page-title-main">Muenke syndrome</span> Medical condition

Muenke syndrome, also known as FGFR3-related craniosynostosis, is a human specific condition characterized by the premature closure of certain bones of the skull during development, which affects the shape of the head and face. First described by Maximilian Muenke, the syndrome occurs in about 1 in 30,000 newborns. This condition accounts for an estimated 8 percent of all cases of craniosynostosis.

<span class="mw-page-title-main">Fibroblast growth factor receptor 2</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor receptor 2 (FGFR2) also known as CD332 is a protein that in humans is encoded by the FGFR2 gene residing on chromosome 10. FGFR2 is a receptor for fibroblast growth factor.

<span class="mw-page-title-main">Ectrodactyly</span> Congenital disorder of the hand

Ectrodactyly, split hand, or cleft hand involves the deficiency or absence of one or more central digits of the hand or foot and is also known as split hand/split foot malformation (SHFM). The hands and feet of people with ectrodactyly (ectrodactyls) are often described as "claw-like" and may include only the thumb and one finger with similar abnormalities of the feet.

<span class="mw-page-title-main">McGillivray syndrome</span> Medical condition

McGillivray syndrome is a rare syndrome characterized mainly by heart defects, skull and facial abnormalities and ambiguous genitalia. The symptoms of this syndrome are ventricular septal defect, patent ductus arteriosus, small jaw, undescended testes, and webbed fingers. Beside to these symptoms there are more symptoms which is related with bone structure and misshape.

Beare–Stevenson cutis gyrata syndrome is a rare genetic disorder characterized by craniosynostosis and a specific skin abnormality, called cutis gyrata, characterized by a furrowed and wrinkled appearance ; thick, dark, velvety areas of skin are sometimes found on the hands and feet and in the groin.

<span class="mw-page-title-main">Baller–Gerold syndrome</span> Medical condition

Baller–Gerold syndrome (BGS) is a rare genetic syndrome that involves premature fusion of the skull bones and malformations of facial, forearm and hand bones. The symptoms of Baller–Gerold syndrome overlap with features of a few other genetics disorders: Rothmund–Thomson syndrome and RAPADILINO syndrome. The prevalence of BGS is unknown, as there have only been a few reported cases, but it is estimated to be less than 1 in a million. The name of the syndrome comes from the researchers Baller and Gerold who discovered the first three cases.

<span class="mw-page-title-main">Craniosynostosis, Philadelphia type</span> Medical condition

Craniosynostosis, Philadelphia type is a rare autosomal dominant syndrome characterized by sagittal craniosynostosis (scaphocephaly) and soft tissue syndactyly of the hands and feet. This condition is considered a form of acrocephalosyndactyly.

References

  1. ↑ "Apert syndrome – About the Disease". Genetic and Rare Diseases Information Center. Archived from the original on 18 May 2019. Retrieved 25 April 2023.
  2. ↑ synd/194 at Who Named It?
  3. 1 2 Fearon, Jeffrey A. (July 2003). "Treatment of the Hands and Feet in Apert Syndrome: An Evolution in Management". Plastic and Reconstructive Surgery. 112 (1). Dallas, Texas: 1–12. doi:10.1097/01.PRS.0000065908.60382.17. ISSN   0032-1052. PMID   12832871. S2CID   8592940.
  4. ↑ Foreman, Phil (2009). Education of Students with an Intellectual Disability: Research and Practice (PB). IAP. p. 30. ISBN   978-1-60752-214-0.
  5. ↑ Carter, Charles H. (1965). Medical aspects of mental retardation. Thomas. p. 358. OCLC   174056103.
  6. ↑ Abe Bert Baker; Lowell H. Baker (1979). "Apert's Syndrome". Clinical Neurology. 3. Medical Dept., Harper & Row: 47. OCLC   11620265.
  7. ↑ Aitken, J. Kenneth (2010). An A-Z of Genetic Factors in Autism: A Handbook for Professionals. Jessica Kingsley. p. 133. ISBN   978-1-84310-976-1.
  8. ↑ "Apert Syndrome". NORD (National Organization for Rare Disorders). Retrieved 21 September 2022.
  9. ↑ "Apert syndrome". GOSH Hospital site. Retrieved 21 September 2022.
  10. ↑ "Apert Syndrome | Boston Children's Hospital". childrenshospital.org. Retrieved 21 September 2022.
  11. ↑ Kaplan, L C (April 1991). "Clinical assessment and multispecialty management of Apert syndrome". Clinics in Plastic Surgery. 18 (2): 217–25. doi:10.1016/S0094-1298(20)30817-8. ISSN   0094-1298. PMID   2065483.
  12. ↑ Upton, J (April 1991). "Apert Syndrome. Classification and pathologic anatomy of limb anomalies". Clinics in Plastic Surgery. 18 (2): 321–55. doi:10.1016/S0094-1298(20)30826-9. ISSN   0094-1298. PMID   2065493.
  13. ↑ Herman, TE; Siegel, MJ (October 2010). "Apert syndrome with omphalocele". J. Perinatol. 30 (10): 695–697. doi: 10.1038/jp.2010.72 . PMID   20877364.
  14. ↑ Ercoli, G; Bidondo, MP; Senra, BC; Groisman, B (September 2014). "Apert syndrome with omphalocele: a case report". Birth Defects Research Part A: Clinical and Molecular Teratology. 100 (9): 726–729. doi:10.1002/bdra.23270. PMID   25045033.
  15. ↑ Wilkie, A O; S F Slaney; M Oldridge; M D Poole; G J Ashworth; A D Hockley; R D Hayward; D J David; L J Pulleyn; P Rutland (February 1995). "Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome". Nature Genetics. 9 (2): 165–72. doi:10.1038/ng0295-165. PMID   7719344. S2CID   12423131.
  16. ↑ Conrady, Christopher D.; Patel, Bhupendra C.; Sharma, Sandeep (2022), "Apert Syndrome", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   30085535 , retrieved 21 September 2022
  17. 1 2 Goriely, A.; McVean, GA; Röjmyr, M; Ingemarsson, B; Wilkie, AO (2003). "Evidence for Selective Advantage of Pathogenic FGFR2 Mutations in the Male Germ Line". Science. 301 (5633): 643–6. Bibcode:2003Sci...301..643G. doi:10.1126/science.1085710. PMID   12893942. S2CID   33543066.
  18. ↑ Moloney, DM; Slaney, SF; Oldridge, M; Wall, SA; Sahlin, P; Stenman, G; Wilkie, AO (1996). "Exclusive paternal origin of new mutations in Apert syndrome". Nature Genetics. 13 (1): 48–53. doi:10.1038/ng0596-48. PMID   8673103. S2CID   26465362.
  19. ↑ Britto, J A; J C T Chan; R D Evans; R D Hayward; B M Jones (May 2001). "Differential expression of fibroblast growth factor receptors in human digital development suggests common pathogenesis in complex acrosyndactyly and craniosynostosis". Plastic and Reconstructive Surgery. 107 (6): 1331–1338. doi:10.1097/00006534-200105000-00001. PMID   11335797. S2CID   32124914.
  20. ↑ Hajihosseini MK, Duarte R, Pegrum J, Donjacour A, Lana-Elola E, Rice DP, Sharpe J, Dickson C (February 2009). "Evidence that Fgf10 contributes to the skeletal and visceral defects of an Apert syndrome mouse model". Dev. Dyn. 238 (2): 376–85. doi: 10.1002/dvdy.21648 . PMID   18773495. S2CID   39997577.
  21. ↑ "Apert syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 17 March 2018.
  22. ↑ Zucker, R M (April 1991). "Syndactyly correction of the hand in Apert syndrome". Clinics in Plastic Surgery. 18 (2): 357–64. doi:10.1016/S0094-1298(20)30827-0. ISSN   0094-1298. PMID   1648464.
  23. ↑ Braun, Tara L.; Trost, Jeffrey G.; Pederson, William C. (November 2016). "Syndactyly Release". Seminars in Plastic Surgery. 30 (4): 162–170. doi:10.1055/s-0036-1593478. ISSN   1535-2188. PMC   5115922 . PMID   27895538.
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