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.
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:
Decrease in the rate of growth leading to short stature, in spite of normal birth weight and birth length
* Head and Neck
Pointed but broad skull
Large, late-closing “soft spot” on the skull (fontanelle)
High, broad forehead
Right and left asymmetry
Chronic ear infections (otitis media)
Shallow orbits in which the eyes sit
Wide separation between eyes
Flattened nose with low bridge
The openings between the nose and throat (choana) may be blocked or narrowed, interfering with breathing and swallowing.
Narrow “roof” of the mouth (palate)
Cleft palate especially of the form known as “bifid uvula”
Bad “bite” (malocclusion)
Delayed dentition teeth are late in coming
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.
Malformed cartilage supports of the trachea, interfering with breathing and swallowing
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
Failure of the testicles to fall
Blockage of vagina
Enlarged kidneys due to blockage
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
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
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.)
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.
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.).
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.
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FROM THE INTERNET
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