Zachary D. Chonka, BS; Douglas P. Beall, MD; Bryan T. Jennings, MD; Dee H. Wu, PhD; Justin Q. Ly, MD; James D. Wolff, MD

Disclosures

Appl Radiol. 2004;33(9) 

In This Article

Discussion

As described by Dr. Eugene Apert in 1906, Apert's syndrome is characterized by the clinical triad of craniosynostosis, midface hypoplasia, and symmetric syndactyly of the hands and feet.[1] These children present with irregular craniosynostosis characterized by a high, full forehead and a fiat occiput and early fusion of the coronal sutures. In infancy, there is a wide and gaping defect in the region of the sagittal and metopic sutures, resulting in an enlarged fontanelle. They have fiat facies, shallow orbits, hypertelorism, small nose, maxillary hypoplasia, and a narrow palate with or without a bifid uvula (Figure 1). These children have varying forms of osseous and cutaneous syndactyly leading to fusion of fingers and toes (Figure 2). Occasionally, synostosis of the radius and humerus is seen. Other associated anomalies that have been observed are pyloric stenosis, ectopic anus, pulmonary aplasia, pulmonary arterial and valve abnormality, heart defects, polycystic kidneys, and bicornuate uterus.[2]

The genetic basis for this syndrome has been well-elucidated. Prevalence has been calculated to be approximately 15.5 per million live births.[3] Inherited in an autosomal dominant fashion, most cases arise as spontaneous mutations that appear to originate almost exclusively in the paternal germ line. Two mutations found in adjacent codons have been identified as being responsible for the defects seen in Apert's syndrome. Leading to altered structure in the fibroblast growth factor receptor (FGFR) 2, the two mutations on chromosome 10q are 755C G, resulting in a Ser252 to Trp change, which is found in about two-thirds of patients, and 758C G, resulting in a Pro253 to Arg change, seen in the remaining third of patients.[4] The specificity of this change could be a useful tool in making an early diagnosis. Associated craniosynostosis in which point mutations of the FGFR have been identified include Crouzon's, Jackson-Weiss, and Pfeiffer's syndromes. The connection between variations in the clinical expression of the other features of these syndromes is partly attributed to the mutations altering different regions of the final protein.[5] It should also be noted that craniosynostosis related to recognized syndromes are the exception rather than the norm, with some 80% of cases arising sporadically. The two most common of the syndromic craniosynostoses, collectively known as acrocephalosyndactyly, are Crouzon's and Apert's, which together make up 70% of such cases.[6]

In total, there are five defined acrocephalosyndactyly syndromes. While the malformations seen in each overlap to a significant degree, there are notable clinical findings that can distinguish a case as being Apert's. This is of significance due to the fact that Apert's syndrome patients typically experience greater mental deficiency and more profound skeletal deformities than do patients suffering from other acrocephalosyndactyly syndromes. Craniosynostosis and midface hypoplasia, while seen in each of the five syndromes to a varying degree, are most pronounced in Apert's (Figure 1). In addition, the clinical hallmark of Apert's syndrome is symmetric syndactyly of the hands and feet. Commonly seen is a fusion of digits 2, 3, and 4, with the occasional addition of digit 5 (Figure 3). While other bony abnormalities indicative of one of the other syndromes may be present, when seen in combination with significant facial dysmorphism, abnormally fused hands and feet are indicative of a diagnosis of Apert's syndrome.[7]

There are a variety of clinical problems associated with the skull malformations typically seen in Apert's syndrome. A wide range of brain malformations occur as a result of skull compression; the most frequent includes agenesis or hypoplasia of the corpus callosum. Other abnormalities, such as migrational anomalies and gyral abnormalities, can be present and may lead to mental deficiency.[8] Nonprogressive ventriculomegaly is also commonly seen. Care should be taken not to confuse this with progressive hydrocephalus, which is seen in only approximately 7% of cases.[9] Craniotomy within the first year of life has been found to result in higher adult intelligence levels, with 50% of such patients having an IQ ≥70, as compared with only 7% of those patients in whom such a procedure is performed later in life.[10]

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