Apert Syndrome

National Organization for Rare Disorders, Inc.

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Disorder Subdivisions

  • None

General Discussion

Apert syndrome, also known as acrocephalosyndactyly type I (ACS1), is a rare genetic disorder that is apparent at birth (congenital). The disorder is character-ized by distinctive malformations of the head that lead to distinctive facial features. In addition, the hands and/or feet may be webbed (syndactyly) and in some cases, mental retardation may also be present.



Among babies born with Apert syndrome, the fibrous joints between bones of the skull (sutures) close prematurely (craniosynostosis). The pressure of continued brain growth distorts various bones of the skull and the face. The skull is forced into one of several characteristic shapes. Often the head appears abnormally pointed at the top (acrocephaly). The distortion of the skull plates create changes in the facial bones leading to characteristic facial abnormalities, such as widely spaced eyes (ocular hypertelorism), abnormal protrusion of the eyes (exophthalmos), underdevelopment of midfacial regions (midface hypoplasia), and/or a narrow roof of the mouth (palate).



Malformations of the hands and feet may include unusually broad thumbs and great toes, short fingers, and/or partial to complete fusion (syndactyly) of certain fingers and toes (digits). Most commonly, there is complete fusion of bones within the second to the fourth fingers and the presence of a single common nail ("mitten-like" syndactyly).



In almost all instances, Apert syndrome results from new genetic changes (mutations) that appear to occur randomly for unknown reasons (sporadically). In rare cases, the disorder may be inherited as an autosomal dominant trait.

Symptoms

Apert syndrome is characterized by premature closure of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis) and malformations of the face, hands, and feet. The degree of craniosynostosis may be variable and depend on the specific cranial sutures involved. However, in most affected individuals, there is premature fusion of the suture (i.e., coronal suture) between the bones forming the forehead and the upper sides of the skull (i.e., frontal and parietal bones). As a result, the head tends to appear abnormally pointed at the top (acrocephaly) and the diameter from the front to the back of the skull (anterior-posterior diameter) may be shortened. In addition, the back portion of the skull (occiput) may appear flattened and the forehead is unusually prominent.



Apert syndrome is also characterized by partial to complete fusion (syndactyly) of certain fingers and toes (digits). The syndactyly may involve soft tissues only (cutaneous syndactyly) or include fusion of bone (osseous syndactyly). In many affected individuals, there is complete fusion of the second, third, and fourth fingers and the presence of a single, continuous nail (synonychia). However, in some instances, the thumb and the fifth finger (or "pinky") may also be involved. The bones of the ends of the thumbs (distal phalanges) tend to be unusually broad and may deviate outward (valgus deformity), and the fingers are often unusually short (brachydactyly). In addition, finger joints tend to become stiff by about four years of age. Syndactyly also typically involves the second, third, and fourth toes. The toenails may be partially continuous or separate. Some affected individuals may have syndactyly involving the fifth toes and the great toes; unusually broad, deviating great toes (hallux varus); or other bony abnormalities.



In addition to these characteristic signs and symptoms, Apert syndrome affects several other organ systems of the body. The database, Online Mendelian Inheritance in Man, presents the following as a Clinical Synopsis of Apert syndrome:



* Growth



Decrease in the rate of growth leading to short stature, in spite of normal birth weight and birth length



* Head and Neck



Head



Pointed but broad skull



Large, late-closing "soft spot" on the skull (fontanelle)



* Face



High, broad forehead



Flat face



Jutting jaw



Right and left asymmetry



* Ears



Hearing loss



Chronic ear infections (otitis media)



* Eyes



Shallow orbits in which the eyes sit



Wide separation between eyes



Down-slanting eyelids



Bulging eyes



Cross-eyes



* Nose



Flattened nose with low bridge



The openings between the nose and throat (choana) may be blocked or narrowed, interfering with breathing and swallowing.



* Mouth



Narrow "roof" of the mouth (palate)



Cleft palate especially of the form known as "bifid uvula"



* Teeth



Bad "bite" (malocclusion)



Delayed dentition teeth are late in coming



* Cardiovascular



Hole(s) in ventricular wall



Overriding aorta develops when the aorta is positioned directly over a hole in ventricular wall, instead of over the left ventricle. As a result, the aorta contains some blood from the right ventricle reducing the amount of oxygen transported.



* Respiratory



Malformed cartilage supports of the trachea, interfering with breathing and swallowing



* Abdomen



Narrowing of the opening between the lower part of the stomach and the upper part of the small intestine (duodenum).



Blockage of the esophagus



Anus out of position



* Genitourinary



Failure of the testicles to fall



Blockage of vagina



Enlarged kidneys due to blockage



* Skeletal



Fusion of cervical vertebrae (C5 and C6)



Fusion of the two bones of the arms



Fusion of bones of the wrist



Fusion (syndactyly) of the bones and/or skin of hands and feet



Spatulate end joint of the thumb



* Skin, Nails & Hair



Moderate to severe acne



Single nail across the fused digits from 2-4



* Neurologic



Varying degrees of mental retardation



Failure to form the fibrous tissue that joins the cerebral hemispheres of the brain



Enlarged brain cavity



Failure to form the membranes that separate the various cavities of the brain



Malformations of parts of the brain's limbic system that deals in part with the autonomous nervous system

Causes

In most affected individuals, Apert syndrome results from new genetic changes (mutations) that appear to occur randomly for unknown reasons (sporadically). According to reports in the medical literature, sporadic cases may be associated with increased age of the father advanced paternal age). Estimates suggest that as many as 95% of new cases may be due to sporadic mutations.



Rarely, the disorder may be inherited as an autosomal dominant trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.



In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed "dominating" the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. The risk is the same for each pregnancy.



Researchers have shown that Apert syndrome results from certain mutations in a gene known as fibroblast growth factor receptor-2 (FGFR2). According to reports in the medical literature, in almost all cases, the disorder appears to be caused by one of two specific mutations of the FGFR2 gene. (These mutations are designated "Ser252Trp" and "Pro253Arg.") The gene has been mapped to the long arm (q) of chromosome 10 (10q26). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q". Chromosomes are further subdivided into bands that are numbered.



Evidence indicates that different mutations in the FGFR2 gene may cause a number of other related disorders, including some cases of Pfeiffer syndrome, Crouzon syndrome, and Jackson-Weiss syndrome. (For further information on these disorders, please see the "Related Disorders" section of this report below.)

Affected Populations

Apert syndrome appears to affect males and females in relatively equal numbers. Since the disorder was originally described in the medical literature in 1894 (Wheaton SW) and 1906 (Apert E), over 300 cases have been reported. The disorder is estimated to occur in about one in 165,000 to 200,000 births.

Diagnosis

In some instances, a diagnosis of Apert syndrome may be suggested before birth (prenatally) by specialized testing, such as fetoscopy or ultrasound. During fetoscopy, a flexible viewing instrument (endoscope) may be introduced into the uterus through the abdominal wall to directly observe the fetus and, in some cases, to obtain fetal blood or tissue samples (e.g., for DNA analysis). Fetal ultrasonography is a noninvasive diagnostic procedure during which reflected sound waves are used to create an image of the developing fetus.



In most cases, the diagnosis is made or confirmed at birth or during early infancy based upon a thorough clinical evaluation, identification of characteristic physical findings, and a variety of specialized tests (e.g., molecular DNA analysis). Advanced imaging techniques, such as computerized tomography (CT) scanning or magnetic resonance imaging (MRI), or other diagnostic tests may be used to help detect or characterize certain abnormalities that may be associated with the disorder (e.g., skeletal abnormalities, hearing impairment, congenital heart defects, etc.).

Standard Therapies

Treatment



The treatment of Apert syndrome is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; surgeons, physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists), physicians who specialize in disorders of the ears, nose, and throat (otolaryngologists), physicians who diagnose and treat heart abnormalities (cardiologists), hearing specialists, and/or other health care professionals.



Specific therapies for Apert syndrome are symptomatic and supportive. Craniosynostosis and, in some cases, associated hydrocephalus may result in abnormally increased pressure within the skull (intracranial pressure) and on the brain. In such cases, early surgery (within 2 to 4 months after birth) may be advised to correct craniosynostosis and, for those with hydrocephalus, to insert a tube (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed. Early corrective and reconstructive surgery may also be performed in some infants with Apert syndrome to help correct certain associated craniofacial abnormalities.



Additional surgical and/or medical treatment may be required to treat and correct other symptoms.



Genetic counseling will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222



TTY: (866) 411-1010



Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:



www.centerwatch.com

References

TEXTBOOKS



Long MD, Lin KYK. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:154-55.



Gorlin RJ, Cohen MMJr, Hennekam RCM. Eds. Syndromes of the Head and Neck. 4th ed. Oxford University Press, New York, NY; 2001:654.



Jones KL. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W.B. Saunders Company; 1997:418-19.



Castriota-Scanderberg A, Dallapiccola B. Abnormal Skeletal Phenotypes. Springer Verlag. Berlin, Germany. 2005:593.



JOURNAL ARTICLES



Lam H, Lo TK, Lau E, Chin R, Tang L. The use of 2- and 3- dimensional sonographic scans in the evaluation of cranial sutures: prenatal diagnosis of apert syndrome. J Ultrasound Med. 2006;25:1481-84.



Wryobek AJ, Eskenazi B, Young S, Arnheim M, et al. Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm. Proc Natl. Acad Sci U S A 2006;103:9601-606.



Quintero-Rivera F, Robson CD, Reiss RE, Levine D, et al. Intracranial anomalies detected by imaging studies in 30 patients with Apert syndrome. Am J Med Genet A. 2006;140:1337-38.



Meling TR, Hans-Erik H, Per S, Due-Tonnessen BJ. Le Fort III distraction osteogenesis in syndrome craniosynostosis. J Craniofac Surg. 2006;17:28-39.



Schulten A, Lim AA, Bruun RA, Hayes C, Mulliken JB, Padwa BL. Combined push-pull distraction for correction of syndromic midfacial hypoplasia. J Oral Maxillofac Surg. 2006;64:23-30.



Guero SJ. Algorithm for treatment of apert hand. Tech hand Up Extrem Surg. 2005;9:126-33.



Sgouros S. Skull vault growth in craniosynostosis. Childs Nerv Syst. 2005;21:861-70.



Ibrahami OA, Chiu ES, McCarthy JG, Mohammadi M. Plast Reconstr Surg. 2005;115:264-70.



Kubbani H, Raghuveer TS. Am Fam Physician. 2004;69:2863-74.



Panchal J, Uttchin V. Management of Craniosynostosis. Plast Reconstr Surg. 2003;111:2032-49.



FROM THE INTERNET



McKusick VA, Ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Apert Syndrome. Entry Number; 101200: Last Edit Date; 10/12/2006.



Sindheimer N. Apert syndrome. Medical Encyclopedia. MedlinePlus. Update Date: 4/20/2005. 3pp.



www.nlm.nih.gov/medlineplus/ency/article/001581.htm



Accessed 10/25/2006



Apert syndrome. Genetics Home Reference. Published: October 20, 2006. 4pp.



http://ghr.nlm.gov/condition=apertsyndrome



Accessed 10/25/2006

Supporting Organizations

AboutFace International

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American Heart Association

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Tel: (214)784-7212
Fax: (214)784-1307
Tel: (800)242-8721
Email: Review.personal.info@heart.org
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Apert Syndrome Support Group

8708 Kathy
St. Louis, MO 63126
Tel: (314)965-3356
Website: //www.dailystrength.org/c/Apert-Syndrome/support-group

Children's Craniofacial Association

13140 Coit Road
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Fax: (214)570-8811
Tel: (800)535-3643
Email: contactCCA@ccakids.com
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Craniofacial Clinic at University of Virginia

University of Virginia Medical Center
Dept. of Plastic and Maxillofacial Surgery
Charlottesville, VA 22908
Tel: (434)924-2528
Email: tjg6f@virginia.edu
Website: //www.medicine.virginia.edu/

Craniofacial Foundation of America

975 East Third Street
Chattanooga, TN 37403
Tel: (423)778-9176
Fax: (423)778-8172
Tel: (800)418-3223
Email: terry.smyth@erlanger.org
Website: //www.craniofacialfoundation.org/www

Danish Apert Syndrome Association (Danmarks Apertforening)

Dronningeengen 17
Vedbaek, DK-2950
Denmark
Tel: 4545890300
Fax: 4545890350
Email: soeren@lildal.com

FACES: The National Craniofacial Association

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Genetic and Rare Diseases (GARD) Information Center

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Headlines - Craniofacial Support Group

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Bristol, BS36 2JP
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Let's Face It

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For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.