IMAGING CASE REPORT Apert Syndrome with Omphalocele

TE Herman and MJ Siegel Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, USA

Journal of Perinatology (2010) 30, 695–697; doi:10.1038/jp.2010.72 complete reconstruction at a later date. Because of choanal stenosis a tracheostomy tube was placed and a gastrosotomy tube was Case presentation placed for nutrition. A 2230 g female infant was born after a spontaneous vaginal Apert syndrome was originally described in 1906 by Eugene delivery at 33 weeks gestation to a gravid 1, para 1 38-year-old Apert from the Hopital des Enfant Malades in Paris; in an mother and a 42-year-old father. The pregnancy had been article De l’acrocephalosyndactylie, he created the word complicated by maternal Graves’ disease treated by Synthroid, and acrocephalosyndactyly to describe a condition that now bears by an abnormal fetal sonogram. The sonogram had demonstrated his name. Currently, Apert syndrome is also called an omphalocele. Intrauterine fetal chromosomal analysis acrocephalosyndactyly syndrome type I because subsequently other demonstrated normal chromosomes 46XX. At delivery, the infant similar conditions of digital abnormalities and craniosynostosis was in no respiratory distress but had striking brachycephaly, were described such as Pfeiffer syndrome, Saethre Chotzen proptosis with shallow orbits, low nasal bridge, a cleft soft palate, syndrome and Jackson-Weiss syndrome,1 and considered types of bilateral choanal stenosis and syndactyly of the toes and fingers. acrocephalosyndactyly using Apert’s neologism as a general A large midline omphalocele was also present. The infant was category. transferred to the neonatal intensive care unit and a skeletal survey Apert syndrome is characterized by a triad of craniosynostosis, (Figure 1) was obtained. A cranial computed tomography craniofacial dysmorphism and cutaneous and osseous syndactyly (Figure 2) and magnetic resonance imaging scan (Figure 3) were of the digits. The craniosynostosis is characteristic with tightly also obtained. fused coronal sutures, a constricted skull base and a wide, almost gaping sagittal defect or suture. In reality, the wide sagittal defect is not a normal suture and will ultimately prematurely fuse, Denouement and discussion but it does allow accommodation to brain growth often for up 3 The skeletal findings are those of Apert syndrome. Apert syndrome to 2 years of life. However, between 2 and 4 years of age this is a rare autosomal-dominant condition of craniosynostosis, gaping defect will close. As there are no normal sutures in Apert syndrome, some prefer the name sutural agenesis to craniofacial abnormalities and bilateral osseous and cutaneous 1 syndactyly.1 The diagnosis of Apert syndrome was confirmed by craniosynostosis to describe the skull findings of Apert syndrome. gene analysis confirming the canonical Apert mutation S252W in Characteristic craniofacial dysmorphism includes hypertelorism, the fibroblast growth factor receptor 2 (FGFR2) gene. This proptosis and midface hypoplasia. Choanal atresia and cleft palate are also very common occurring in B23 and 44% of mutation and the P253 mutation in the same gene account for 4 98.6% of all cases of Apert syndrome.2 The patient has a giant patients, respectively. Digital anomalies include at least fusion of omphalocele, or one containing most of the liver. To our the second through fourth digits symmetrically in the hands and knowledge, this is the first reported case of Apert syndrome with feet into a solid soft tissue mass. Symphalangism of the proximal an omphalocele. and middle phalanges and osseous fusion of the distal phalanges The patient will return at 2 months of age for cranioplasty and are also frequent. The thumb is usually not included in the syndactyly, but it is often radially displaced with shortened possible ventriculoperitoneal shunting. Hand reconstruction will 4 begin at 6 months of age. The omphalocele has been treated phalanges. conservatively with application of silver sulfadiazine cream to allow Among Eugene Apert’s original patients with this autosomal- the formation of an eschar to close the abdominal wall until dominant condition it was recognized that paternal age was a factor. The average age of fathers of children with Apert syndrome Correspondence: Dr T Herman, Mallinckrodt Institute of Radiology, St Louis Children’s is 34.1 with a 6 year s.d. The mutations in the FGFR2 gene are Hospital, Washington University School of Medicine, 510 South Kingshighway Boulevard, exclusively paternal in nature.1 St Louis, MO 63110, USA. E-mail: [email protected] In 1995, with isolation of the FGFR genes the genetic basis of Received 10 February 2010; revised 13 April 2010; accepted 25 April 2010 Apert syndrome and several of the other acrocephalosyndactyly Apert syndrome with omphalocele TE Herman and MJ Siegel 696

Figure 1 (a) Frontal and (b) lateral radiographs of the chest and abdomen. A large omphalocele (O) is present. A nasogastric tube is in place. Otherwise the study is normal. (c) Frontal and (d) lateral radiographs of the skull. On the frontal film, there is a wide sagittal suture (arrows) and harlequin or laterally pointed orbits (curved arrows). On the lateral film, the coronal suture is seen to be sclerotic and closed (arrowhead.) The skull is short and high with a flat midface. (e) Frontal left hand. The right hand had an identical appearance. The proximal phalanges are labeled PP, the middle phalanges MP and the distal phalanges DP followed by the number of the digit. The single thumb phalange is labeled ThP. There is cutaneous syndactyly of the second through fifth digits. Symphalangism or fusion of the second and fourth middle phalanges and proximal phalanges is present. The middle phalange of the third digit is abnormally broad and short. The fifth middle and distal phalanges are not ossified. There is no osseous fusion of the distal phalanges. There is a single large broad phalange in the thumb. (f) Frontal left foot. The right foot had an identical appearance. There is complete soft tissue syndactyly of all digits. There is a single abnormally large and broad great toe phalange. The proximal phalanges of digits 2, 3 and 4 are not ossified and the middle phalange of digit 5 is not ossified. There is no osseous syndactyly.

syndromes and skeletal dysplasias was revealed. Two mutations in with shovel-shaped incisors.3 The humeri are usually short, the FGFR2 gene account for 98.6% of all cases of Apert syndrome.2 subluxed with ﬂattened humeral heads with very poor motion of These two mutations are the S252W and P253R mutations. the humeral glenoid joint.5 Fusion of the calcaneus and cuboid Mutations in the FGFR3 gene account for 99% of cases of the most bone is also a characteristic ﬁnding. well known skeletal dysplasias, achondroplasia and thanatophoric Although omphalocele has to our knowledge not been described dwarf. Different FGFR2 mutations are found in Jackson-Weiss in Apert syndrome, many other malformations have been syndrome and Pfeiffer syndrome, which also has nonsense occasionally described in patients with Apert syndrome. Central mutations in the FGFR1 gene. The phenotype of patients with nervous system malformations include abnormal corpus callosum, S252W and P253R are very similar except that cleft palate is more and limbic system, megencephaly, congenital heart disease and common in the S252W mutation patients and urogenital genitourinary abnormalities. Urogenital abnormalities occur anomalies are more common in the P253R mutation.4 in B10% of the affected patients.3 However, gastrointestinal Other frequent craniofacial abnormalities in patients with Apert abnormalities are rarer, with cases of imperforate anus and syndrome include malocclusion, and ectopic and delayed teeth malrotation reported.1

Journal of Perinatology Apert syndrome with omphalocele TE Herman and MJ Siegel 697

Figure 2 (a) Frontal and (b) lateral three-dimensional reformatted images of the skull. A gaping wide sagittal suture (SS) is present, as well as midface hypoplasia with harlequin eyes.

Figure 3 (a) Midline sagittal T1-weighted image of the brain and (b) sagittal T1-weighted image of the brain through right orbit. There is a hypoplastic corpus callosum (curved arrow) and a bulging globe of the eye (arrow).

Conﬂict of interest 2 Passos-Bueno MR, Richier Costa A, Seritie AL, Kneppers A. Presence of the Apert The authors declare no conﬂict of interest. canonical S252W FGFR2 mutation in a patient without severe syndactyly. J Med Genet 1998; 35: 677–679. 3 Kreiborg S, Cohen MM. The infant Apert skull. NeurosurgClinNAm1991; 2: 551–554. 4 Park WJ, Theda C, Maestri NE, Meyers GA, Fryburg JS, Dufresne C et al. Analysis of References phenotypic features and FGFR2 mutations in Apert syndrome. Am J Hum Genet 1995; 1 Perlyn CA, Nichols C, Woo A, Becker D, Kane AA. Le Premier Siecle: one hundred 57: 321–328. years of progress in the treatment of Apert syndrome. J Craniofac Surg 2009; 20: 5 Beligere N, Harris V, Pruzansky S. Progressive bony dysplasia in Apert syndrome. 801–806. Radiology 1981; 139: 593–597.

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