Physician: Education: Descriptions of Disorders

1 in 100,000 to 1 in 160,000 births.

Within the spectrum of craniosynostosis disorders caused by mutations in the fibroblast growth factor receptor genes, Apert syndrome is somewhat unique. Not only is the pattern and development of craniosynostosis different from the related disorders of Crouzon and Jackson-Weiss syndromes (see Pathophysiology), but the extracranial effects are strikingly different. Hand and foot abnormalities are generally symmetric and severe. Internal abnormalities of the cardiovascular, genitourinary, respiratory, and central nervous systems are found at a rate higher than in other craniosynostosis disorders. A significant percentage are mentally retarded, although above average intelligence has also been reported.

Cranial features include a head shape which is brachycephalic (short from front to back), with acrocephaly (a high, tower like forehead). The back of the skull may be flattened. The eyes usually appear prominent, may slant downward, or be widely spaced (hypertelorism). There is a high incidence of strabismus (malalignment of the eyes), and congenital abnormalities or absence of the ocular muscles has been reported. The ears may be lowset, and the incidence of hearing loss is increased. This is even more likely in those individuals with cleft palate who also tend to have repeated bouts of middle ear infection. The nose has a beaked appearance. Acne vulgaris may be quite severe in teens and may extend on to the trunk and upper arms. There are multiple dental abnormalities, including malocclusion, crowding of teeth, delayed tooth eruption, high arched narrow palate, and thickened alveolar ridges.

Apert syndrome is the craniosynostosis condition associated with the most striking and recognizable digital abnormalities. Specifically, the hands and feet are affected with a non-separation of the fingers and toes (syndactyly). Since four fingers are often connected, leaving only the thumb free, this type of deformity has been called "mitten type syndactyly". The toes are similarly affected, and in fact, all five digits may be involved. There may be five distinct finger or toe nails, or they, too, may be connected across the digits. With time, the bones of the hands and feet gradually become fused together, causing a progressive stiffening of the fingers and toes. In addition, this gradual fusion also affects the shoulders, elbows, and hips and knees. Adult height is reduced, due partly to shortened lower limbs.

Apert syndrome is an autosomal dominant condition caused by a mutation in the fibroblast growth factor receptor 2 (FGFR2) gene. One of two mutations, Ser252Trp and Pro253Arg, occur in over 99% of Apert syndrome patients. Each affected individual has a 50 percent risk of passing the disorder on to his or her offspring. However, because there is decreased reproductive fitness (affected individuals are less likely to have children), the majority of cases arise as new or spontaneous gene changes in children born to unaffected parents. There is an association between older paternal age and an increase in this new mutation rate. It has been shown that all new mutations occur exclusively in the FGFR2 genes of fathers. There are also rare cases of germinal mosaicism, which means that one parent may carry the changed genetic information in an egg or sperm cell, but not themselves be affected. This situation, however, can lead to more than one affected child being born to apparently unaffected parents.

The development of craniosynostosis in the Apert syndrome occurs in a somewhat unusual manner. The coronal sutures are typically fused at birth. In addition, an affected individual has a wide open gap of the skull bones extending from the forehead back to the posterior fontanel. Although this encompasses the area normally occupied by the metopic and sagittal sutures, there is no sutural material present. Over the following 2 to 3 years, this open gap generally fills in with islands of bone until the defect is closed. However, since there are no sutures in this area, there is no potential for further expansion and growth, causing a functional craniosynostosis.

The diagnosis of Apert syndrome is generally done on a clinical basis. Physical examination alone generally reveals the craniosynostosis and the characteristic mitten type syndactyly of the hands and feet. The gene defect is known, and molecular methods can be used for confirmation or prenatal diagnosis.

Treatment of the Apert syndrome is surgical, and patients often require multiple operations. Craniosynostosis is released surgically, and later procedures such as an advancement of the midface typically follow. Such procedures may be needed to improve the upper airway, address severe eye problems, or correct dental issues.

Multiple surgeries are also typical to improve the function and appearance of the hands, and to a lesser degree, the feet. In total, the time course for surgical procedures may extend well into adolescence and early adulthood.

Internal organ abnormalities are found in a small but significant percentage of Apert patients, ranging in the order of approximately 1-10 percent. These may include heart defects, abnormalities of the trachea (windpipe), uterus, and brain.

Apert Syndrome Support Group
8708 Kathy
St. Louis, MO
U.S.A.
(314) 965-3356

Apert Syndrome Pen Pals
P.O. Box 115
Providence, RI
U.S.A.
02901
(401) 421-9076

Danish Apert Syndrome Association (Danmarks Apertforening)
Dronningeengen 17
Vedbaek, DK-2950
Denmark
+45 (45) 89-0300

Apert Support and Information Network
National Organization for Rare Disorders, Inc.
OMIM 101200
FGFR2 [MIM176943]
Gene Reviews: Craniosynostosis Syndromes (FGFR-Related)

Chang CC, Tsai FJ, Tsai HD, Tsai CH, Hsieh YY, Lee.
Prenatal diagnosis of Apert syndrome.
Prenat Diagn 18(6):621-625, 1998. abstract

Filkins K, Russo JF, Boehmer S, Camous M, Przylepa.
Prenatal ultrasonographic and molecular diagnosis of Apert syndrome.
Prenat Diagn 17(11):1081-1084, 1997. abstract

Lomri A, Lemonnier J, Hott M, de Parseval N, Lajeu.
Increased calvaria cell differentiation and bone matrix formation induced by fibroblast growth factor receptor 2 mutations in Apert syndrome.
J Clin Invest 101(6):1310-1317, 1998. abstract

Moloney DM, Slaney SF, Oldridge M, Wall SA, Sahlin.
Exclusive paternal origin of new mutations in Apert syndrome.
Nat Genet 13(1):48-53, 1996. abstract

Park WJ, Theda C, Maestri NE, Meyers GA, Fryburg J.
Analysis of phenotypic features and FGFR2 mutations in Apert syndrome.
Am J Hum Genet 57(2):321-328, 1995. abstract

Sarimski K.
Cognitive functioning of young children with Apert's syndrome.
Genet Couns 8(4):317-322, 1997. abstract

Tolarova MM, Harris JA, Ordway DE, Vargervik K.
Birth prevalence, mutation rate, sex ratio, parents' age, and ethnicity in Apert syndrome.
Am J Med Genet 72(4):394-398, 1997. abstract

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