Apert Syndrome


A number sign (#) is used with this entry because Apert syndrome is caused by heterozygous mutation in the FGFR2 gene (176943) on chromosome 10q26.

Crouzon syndrome (123500) and Pfeiffer syndrome (101600) are allelic disorders with overlapping features.


Apert syndrome is a congenital disorder characterized primarily by craniosynostosis, midface hypoplasia, and syndactyly of the hands and feet with a tendency to fusion of bony structures. Most cases are sporadic, but autosomal dominant inheritance has been reported (Mantilla-Capacho et al., 2005).

Cohen (1973) provided a review of all the 'craniosynostosis syndromes.'

Clinical Features

Apert (1906) defined a syndrome comprising skull malformation characterized by acrocephaly of brachysphenocephalic type and syndactyly of the hands and feet with complete distal fusion with a tendency to fusion of bony structures. The hand, when all the fingers are webbed, has been compared to a spoon and, when the thumb is free, to an obstetric hand.

Blank (1960) assembled case material on 54 patients with Apert syndrome born in Great Britain. Two clinical categories were distinguished: (1) 'typical' acrocephalosyndactyly, to which Apert's name is appropriately applied; and (2) other forms lumped together as 'atypical' acrocephalosyndactyly. The feature distinguishing the 2 types is a middigital hand mass with a single nail common to digits 2-4, found in Apert syndrome and lacking in the others. Thirty-nine of the 54 were of Apert type. Six of 12 autopsies showed visceral anomalies, but in none were these identical. Schauerte and St-Aubin (1966) pointed out that progressive synostosis in Apert syndrome occurs in the feet, hands, carpus, tarsus, cervical vertebrae, and skull, and proposed 'progressive synosteosis with syndactyly' as a more appropriate designation.

In a report on Crouzon disease, Dodge et al. (1959) described 2 sporadic cases of Crouzon-type craniofacial changes with syndactyly of both hands and feet. Most conclude that this disorder is actually Apert syndrome with unusually marked facial features (Temtamy and McKusick, 1978).

Kreiborg et al. (1992) found fusion of cervical vertebrae in 68% of patients with Apert syndrome: single fusions in 37% and multiple fusions in 31%. C5-C6 fusion was most common. In contrast, cervical fusion occurs in 25% of patients with Crouzon disease and most commonly involves C2-C3 only. Kreiborg et al. (1992) concluded that when fusions are present, C5-C6 involvement in the Apert syndrome and C2-C3 involvement in Crouzon disease can be used to distinguish the 2 conditions. Radiographic study of the cervical spine is imperative before undertaking anesthesia for surgery in these patients.

Wilkie et al. (1995) scored the severity of the syndactyly in Apert syndrome according to a modified version of the classification of Upton (1991). In the Apert hand, the central 3 digits are always syndactylous; in the least severe instance, type 1, the thumb and part of the fifth finger are separate from the syndactylous mass; in type 2, the little finger is not separate; and in type 3, the thumb and all fingers are included. Similarly, syndactyly in the foot may involve mainly the 3 lateral digits (type 1) or digits 2-5 with a separate big toe (type 2), or be continuous (type 3).

Cohen and Kreiborg (1995) studied 44 pairs of hands and 37 pairs of feet in Apert syndrome, using clinical, dermatoglyphic, and radiographic methods. They also studied histologic sections of the hand from a 31-week stillborn fetus. They noted that in general the upper limb is more severely affected than the lower limb. Coalition of distal phalanges and synonychia found in the hands was never present in the feet.

Other Features

Varying degrees of mental deficiency have been associated with Apert syndrome; however, individuals with normal intelligence have also been reported. Individuals who have craniectomy early in life may have improved intelligence. Patton et al. (1988) did a long-term follow-up on 29 patients of whom 14 (48%) had a normal or borderline IQ, 9 had mild mental retardation (IQ, 50-70), 4 were moderately retarded (IQ, 35-49), and 2 (7%) were severely retarded (IQ less than 35). Early craniectomy did not appear to improve intellectual outcome. Six of 7 school drop-outs with normal or borderline intelligence were in full-time employment or vocational training. Contrary to early conclusions such as that of Park and Powers (1920), Cohen and Kreiborg (1990) concluded that many patients with Apert syndrome are mentally retarded. They had information on 30 patients with malformations of the corpus callosum, the limbic structures, or both, and suggested that these malformations may be responsible for mental retardation. Progressive hydrocephalus seemed to be uncommon and was frequently confused with nonprogressive ventriculomegaly.

Cinalli et al. (1995) found that only 4 of their series of 65 patients with Apert syndrome required shunting for progressive hydrocephalus. Only 1.9% of their patients had chronic herniation of the cerebellar tonsils, the finding present in 72.7% of patients with Crouzon syndrome.

In reviewing their series of 70 children with Apert syndrome, Reiner et al. (1996) found an IQ greater than 70 in 50% of the children who had a skull decompression before 1 year of age versus only 7.1% in those operated on later in life. Malformations of the corpus callosum and ventricular size did not correlate with the final IQ, whereas anomalies of the septum pellucidum did. The third significant factor in intellectual achievement was the setting in which the children were raised. IQ was normal in 39.3% of patients living with their family, but in only 12.5% of those institutionalized.

Pelz et al. (1994) reported an 18-month-old girl who had distal esophageal stenosis in addition to typical manifestations of Apert syndrome.

Cohen and Kreiborg (1995) commented on the cutaneous manifestations in a series of 136 cases of Apert syndrome (Cohen and Kreiborg, 1993). Hyperhidrosis was found in all patients. The skin became oily at adolescence and thereafter, with acniform lesions on the face, chest, back, and upper arms. The authors commented on and illustrated the phenomenon of 'interrupted eyebrows,' which may be due to the underlying bony defect. The orbital plate of the frontal bone is very short, resulting in early fusion of the sphenoparietal suture. This leads to marked retrusion and elevation of the supraorbital wings, most pronounced laterally. Interruption of the eyebrows corresponds to this defect. Several patients had excessive skin wrinkling of the forehead.

Maroteaux and Fonfria (1987) reported a patient with seemingly typical Apert syndrome except for the presence of postaxial polydactyly of the hands and preaxial polydactyly of the feet. The authors could not discern whether the findings represented a low frequency feature of Apert syndrome or a distinct syndrome. Sidhu and Deshmukh (1988) reported a somewhat similar case in the child of a first-cousin couple. However, Gorlin (1989) doubted the existence of a separate recessive entity and stated that polysyndactyly in the feet, especially replication of metatarsals, is not rare in Apert syndrome.

Lefort et al. (1992) reported a patient with Apert syndrome and partial preaxial polydactyly characterized by duplication of the first metatarsal and presence of 6 phalanges.

Cohen and Kreiborg (1995) observed postaxial polydactyly of the hands in 3 (7%) of 44 patients with Apert syndrome, noting that while it is uncommon, it is not a rare finding. The authors suggested that 'acrocephalosyndactyly' versus 'acrocephalopolysyndactyly' represents a pseudodistinction and that use of these terms should be discontinued.

Mantilla-Capacho et al. (2005) reported a female child with typical features of Apert syndrome and preaxial polydactyly of the hands and feet with distal bony fusion. She did not have cleft palate. Genetic analysis revealed the common FGFR2 mutation (S252W; 176943.0010). The authors noted that only 8 patients with Apert syndrome and polydactyly had been reported, and that their case was the first confirmed by genetic analysis. Mantilla-Capacho et al. (2005) concluded that polydactyly, although rare, should be considered part of the spectrum of abnormalities found in Apert syndrome, and suggested that Apert syndrome be considered part of the group of acrocephalopolysyndactylies.

In a review of cranial imaging in 30 patients with Apert syndrome, Quintero-Rivera et al. (2006) reported ventriculomegaly (76% of patients), hydrocephalus (13%), complete absence of the septum pellucidum (17%), partially absent septum pellucidum (23%), and defects of the corpus callosum (23%). In addition, 21 patients had abnormal semicircular canals, 28 had jugular foraminal stenosis, 5 patients had Chiari I malformation, 5 had low-lying cerebellar tonsils, and 2 had posterior fossa arachnoid cysts.

In a review of 63 patients with Apert syndrome prior to craniofacial surgery, Khong et al. (2006) found that, at a mean age of 4 years, at least 14% had amblyopia, 60% had strabismus, 19% had anisometropia, and 34% of eyes had ametropia. Exposure keratopathy and corneal scarring occurred in at least 8% of patients and optic atrophy in at least 8%.

Andreou et al. (2006) reported a 4-year-old girl with Apert syndrome associated with a heterozygous mutation (P253R; 176943.0011) in the FGFR2 gene. She also developed a low-grade papillary urothelial carcinoma of the bladder. No FGFR3 (134934) mutations were identified in the bladder tumor.


Although most cases of Apert syndrome are sporadic, it also follows autosomal dominant inheritance. Roberts and Hall (1971) observed affected mother and daughter. Van den Bosch (quoted by Blank, 1960) observed the typical deformity in mother and son, and Weech (1927) reported mother and daughter. The evidence strongly suggests autosomal dominant inheritance. Paternal age effect is demonstrable.

Allanson (1986) described 2 sisters with Apert syndrome, born to normal, unrelated parents. Germinal mosaicism was proposed.

Rollnick (1988) described what is purportedly the first example of male transmission of Apert syndrome in affected father and daughter.


Prenatal Diagnosis

Leonard et al. (1982) made the prenatal diagnosis of Apert syndrome by fetoscopy.

Chang et al. (1998) excluded the diagnosis of Apert syndrome in the fetus of an affected woman with a mutation in the FGFR2 gene (P253R; 176943.0011).


Lomri et al. (1998) analyzed proliferation and differentiation of calvaria cells derived from Apert syndrome infants and fetuses with FGFR2 mutations. Histologic analysis revealed premature ossification, increased extent of subperiosteal bone formation, and alkaline phosphatase-positive preosteoblastic cells in Apert fetal calvaria compared with age-matched controls. Preosteoblastic calvaria cells isolated from Apert syndrome infants and fetuses showed normal cell growth in basal conditions or in response to exogenous FGF2. In contrast, the number of alkaline phosphatase-positive calvaria cells was 4-fold higher than normal in mutant fetal calvaria cells with the most frequent Apert mutation, S252W (176943.0010), suggesting increased maturation rate of cells in the osteoblastic lineage. These and other results showed that Apert FGFR2 mutations lead to an increase in the number of precursor cells that enter the osteogenic pathway, leading ultimately to increased subperiosteal bone matrix formation and premature calvaria ossification during fetal development; thus, a connection was established between the altered genotype and the cellular phenotype in craniosynostosis of Apert syndrome.

Miraoui et al. (2010) used microarray analysis to investigate the signaling pathways that are activated by FGFR2 mutation in Apert craniosynostosis. Transcriptomic analysis revealed that EGFR (131550) and PDGFR-alpha (173490) expression was abnormally increased in human Apert calvaria osteoblasts compared with wildtype cells. Pharmacologic inhibition of EGFR and PDGFR reduced the pathologic upregulation of phenotypic osteoblast genes and in vitro matrix mineralization in Apert osteoblasts. Activated FGFR2 enhanced EGFR and PDGFR-alpha mRNA expression via activation of PKC-alpha (176960)-dependent AP1 (see JUN, 165160) transcriptional activity. The increased EGFR protein expression in Apert osteoblasts resulted in part from a posttranscriptional mechanism involving increased Sprouty2 (602466)-Cbl (165360) interaction, leading to Cbl sequestration and reduced EGFR ubiquitination.

Molecular Genetics

In all 40 unrelated patients with Apert syndrome, Wilkie et al. (1995) identified heterozygosity for 1 of 2 mutations in exon 7 of the FGFR2 gene: S252W (176943.0010) or P253R (176943.0011). The findings confirmed that Apert syndrome is allelic to Crouzon syndrome.

In a patient with Apert syndrome, Oldridge et al. (1997) identified a noncanonical mutation in exon 7 of the FGFR2 gene (S252F; 176943.0017).

In a series of 260 cases of Apert syndrome, Oldridge et al. (1999) found that 172 carried the S252W mutation and 85 had the P253R mutation, indicating that the molecular mechanism of Apert syndrome is exquisitely specific. Two patients had an Alu-element insertion in or near exon 9 (176943.0025).

Lajeunie et al. (1999) identified the S252W and P253R mutations in 23 (64%) and 12 (33%) of 36 Apert syndrome patients, respectively. One affected fetus had the S252F mutation.

Moloney et al. (1996) found that 74 of 118 patients with Apert syndrome had the FGFR2 S252W mutation and 44 had the P253R mutation. Using sequence analysis of the neighboring introns flanking the mutation-prone exon and a novel PCR-based assay, ARMS (amplification refractory mutation system), to determine the phase of the mutant allele and nearby polymorphisms in 57 informative families, Moloney et al. (1996) determined that the mutant allele was paternal in origin in all cases. The authors noted that a paternal bias for point mutations is evident in a number of disorders, but that the extreme skewing in favor of paternal mutations observed in Apert syndrome is unusual. A paternal age effect was noted. The data suggested a stronger paternal age effect for the S252W mutation, which involves a CpG dinucleotide, than for the P253R mutation, which does not.

Glaser et al. (2003) used allele-specific peptide nucleic acid PCR assays to determine FGFR2 mutation frequency in the sperm of 148 men aged 21 to 80 years. The number of sperm with FGFR2 mutations increased in the oldest age groups among men who did not have a child with Apert syndrome. These older men were also more likely to have both mutations in their sperm. However, this age-related increase in mutation frequency was not sufficient to explain the Apert syndrome birth frequency. In contrast, the mutation frequency observed in men who were younger and had children with Apert syndrome was significantly greater, suggesting selection for sperm with specific mutations. Glaser et al. (2003) concluded that contributing factors to the paternal age effect may include selection and a higher number of mutant sperm in a subset of men ascertained because they had a child with Apert syndrome. No age-related increase in the frequency of these mutations was observed in leukocytes. Selection and/or quality control mechanisms, including DNA repair and apoptosis, may contribute to the cell type differences in mutation frequency.

Genotype/Phenotype Correlations

Park et al. (1995) reported 36 patients with Apert syndrome, 35 of whom were found to carry either the S252W or P253R mutation in the FGFR2 gene, with a frequency of 71% and 26% for these 2 mutations, respectively. A study of 29 different clinical features demonstrated no statistically significant differences between the 2 subgroups defined by the 2 major mutations.

Slaney et al. (1996) found differential effects of the 2 FGFR2 mutations on syndactyly and cleft palate in Apert syndrome. Among 70 unrelated patients with Apert syndrome, 45 had the S252W mutation and 25 had the P253R mutation. The syndactyly in both the hands and the feet was more severe in patients with the P253R mutation. In contrast, cleft palate was significantly more common in patients with the S252W mutation. No convincing differences were found in the prevalence of other malformations associated with Apert syndrome.

Lajeunie et al. (1999) found considerable clinical variability among 36 patients with Apert syndrome confirmed by genetic analysis. Two patients had no clinical or radiologic evidence of craniosynostosis. In 2 other patients with atypical forms of syndactyly and cranial abnormalities, the detection of a specific mutation was helpful in making the diagnosis.

Among 21 Apert syndrome patients who underwent craniofacial surgery, von Gernet et al. (2000) found that the postsurgical craniofacial appearance was better in patients with the P253R mutation, whereas these patients showed a more pronounced severity of the syndactyly. Six patients had the P253R mutation and 15 had the S252W mutation.


Dodson et al. (1970) described deletion-translocation of the short arm of a chromosome 2 to the long arm of a chromosome 11 or 12 in a patient with Apert syndrome. They found reports of chromosomal abnormalities in 3 other cases of Apert syndrome.

Population Genetics

Blank (1960) estimated the frequency of Apert syndrome to be 1 in 160,000 births.

Cohen et al. (1992) studied the birth prevalence of Apert syndrome in Denmark, Italy, Spain, and 4 areas of the United States. A total of 57 cases gave a birth prevalence calculated to be approximately 15.5 per million births, which is twice the rate determined in earlier studies. The mutation rate was calculated to be 7.8 x 10(-6) per gene per generation. Apert syndrome accounted for about 4.5% of all cases of craniosynostosis. Czeizel et al. (1993) reported a validated birth prevalence of Apert syndrome in Hungary to be 9.9 per million live births. The mutation rate was calculated to be 4.6 x 10(-5) per gene per generation. Data on 14 other 'sentinel' anomalies observed between 1980 and 1989 were given.

Tolarova et al. (1997) reported that the California Birth Defects Monitoring Program, from 1983 through 1993, identified 33 infants with Apert syndrome. The sample was enlarged with an additional 22 cases from the Center for Craniofacial Anomalies at the University of California, San Francisco. Birth prevalence calculated from the 31 cases was 12.4 per million live births. The calculated mutation rate was 6.2 x 10(-6) per gene per generation. Asians had the highest prevalence (22.3 per million live births) and Hispanics the lowest (7.6 per million). In a population-based subsample of 31 affected infants, there was an almost equal number of affected males and females, but in the San Francisco sample there were more affected females (sex ratio 0.79). For all cases, the mean age of mothers was 28.9 years, and of fathers 34.1 years. Almost half of the fathers were older than 35 years when the child was born; for more than 20% of cases, both parents were older than 35 years.

Animal Model

Hill et al. (2013) used 2- and 3-dimensional imaging to evaluate postnatal brain and skull development between days P0 and P2 in mice carrying the P253R FGFR2 mutation (176943.0011). Postnatal day 2 roughly corresponds to 10 months of age in human infants. At P0, the mutant brain was 1% larger and the mutant skull was 2% smaller compared to unaffected littermates. At P2, heterozygous mutant mice had 9% smaller skulls than controls, although the size reduction was not uniformly distributed. The facial skeleton, including the palate, was reduced by 11%, whereas the neurocranium was reduced by 3%, and the skull showed increased height in the posterior neurocranium compared to controls. The brain size in mutant mice at P2 was not different from control mice overall, but there was shortening of the corpus callosum as well as increased mediolateral and decreased rostrocaudal growth of the cerebrum. The findings were similar to those observed in human infants with Apert syndrome. The results suggested that size and form of the brain and skull show different patterns of growth in mutant and control mice during the postnatal period. However, the change in the skull-brain relationship from P0 to P2 implies that each tissue affected by the mutation retains a degree of independence, rather than one tissue directing the development of the other.


Vogt (1933) described cases presenting the hand and foot malformations characteristic of Apert disease together with the facial characteristics of Crouzon disease, caused by a very hypoplastic maxilla. The syndactyly was less severe than in Apert disease and the thumbs and little fingers were usually free. Nager and de Reynier (1948) gave this deformity the name of Vogt cephalodactyly, while other authors called it Apert-Crouzon disease, indicating the similarity to both abnormalities. Temtamy and McKusick (1969) called it ACS II in an earlier classification. There were no reported instances of hereditary transmission of this specific phenotype, but this could be due simply to low reproductive fitness.


Wheaton (1894) may have provided the first description of Apert syndrome (Mantilla-Capacho et al., 2005).