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2000-07-24-05 Apert syndrome © Silva www.thefetus.net/

Apert syndrome

Updated 2006-01-18 by Juliana Leite, MD

Original text 2000-07-24 Philippe Jeanty, MD, PhD & Sandra R Silva, MD

Synonymes: acrocephalosyndactyly type 1, Apert-Crouzon disease

Definition: Apert syndrome is a rare developmental deformity characterized by craniofacial and limb malformations accompanied by variable degrees of mental retardation in 50% of the cases. In 1894, Wheaton did the first description and subsequently, in 1906, Apert summarized the disorder, presenting nine cases.

Incindence: The occurrence of Apert syndrome is estimated at 0.0625 to 0.1:10,000 live births. The male/female ratio is 1.

Etiology: Apert syndrome is an autosomal disorder with dominant inheritance. Most of the cases are sporadic, resulting from fresh mutations. Association with advanced paternal age has been described.

Sonographic findings: brachycephaly and acrocephaly, high forehead, flat occiput, craniosynostosis usually involving the coronal sutures, flat face, and hypertelorism. Other ultrasound findings that are present are agenesis of the corpus callosum, mild ventriculomegaly and fusion of the cervical vertebrae at the level of C5-C6. In the extremities we can find syndactyly “mitten hand” (osseous and cutaneous) usually involving the second, third, and fourth fingers. There is a broad thumb and hallux. Polyhydramnios (caused by the decreased fetal swallowing) and variable degrees of mental retardation have also been found, and their occurrence and intensity seem to be correlated to the severity of central nervous system anomalies. The prenatal diagnosis by ultrasound and fetoscopy has been reported in all trimesters of pregnancy. Increased nuchal fold at the first trimester might be a sonographic marker for the disorder.

Diagnosis:The most typical findings in Apert syndrome are craniosynostosis (by synostosis of the coronal sutures), bilateral symmetric syndactyly of the limbs (mitten-like hands and feet), and midfacial hypoplasia. Additional features, which appear with variable frequency, include:


● Skeletal anomalies: short and broad head, high cranial vault (acrocephaly), prominent forehead (frontal bossing) hypertelorism and proptosis, depressed nasal bridge with parrot-beaked nose, hypoplastic maxilla, prognathism.
● Cardiac anomalies: pulmonic stenosis, overriding aorta, ventricular septal defects.
● Central nervous system anomalies: hydrocephaly, malformation of the corpus callosum and limbic structures, gyral abnormalities, hypoplasia of the white matter, and heterotopic gray matter.

Figure 1: Craniosynostosis with narrowing of the skull at the level of the coronal suture

Figure 2: Exaggerated frontal bossing.

Genetic anomalies: The most common mutations associated with Apert syndrome are substitution S252W and P253R, which occur in the fibroblast growth factor receptor 2 genes. Genetic molecular studies are recommended for the fetus (by chorionic villi sampling or amniocentesis) and for parents when Apert syndrome is suspected, in particular in those families affected for the first time. The development of molecular techniques for the definitive diagnosis of this condition in prenatal cases was made possible by the finding of the FGFR2 gene mutations.

Differential diagnosis: Genetic syndromes also characterized by the presence of craniosynostosis such as Crouzon, Pfeiffer, Carpenter, and Saethre-Chotzen may be included in the differential diagnosis. Molecular genetic studies can exclude these disorders.

Recurrence risk: When resulting from a fresh mutation, the recurrence risk is improbable. If one of the parents carries the disorder, the recurrence risk is 50%.

Management: If diagnosed before viability, termination of pregnancy can be offered. After viability, standard obstetrical management is not altered. Delivery in a tertiary center is recommended.

 

References

1. Esser T, Rogalla P, Bamberg C, Kalache KD. Application of the three-dimensional maximum mode in prenatal diagnosis of Apert syndrome. Am J Obstet Gynecol 2005;193(5):1743-745
2. Ferreira JC, Bernstein PS, Jabs EW, Glickstein JS, Marion RW, Baergen RN, Gross SJ. Second-trimester molecular prenatal diagnosis of sporadic Apert syndrome following suspicious ultrasound findings. Ultrasound Obstet Gynecol 1999;14:426-430
3. Skidmore DL, Pai AP, Toi A, Steele L, Chitayat D. Prenatal diagnosis of Apert syndrome: report of two cases. Prenat Diagn 2003:23(12):1009-13
4. Parent P, Le Guern H, Munck MR, Thoma M. Apert syndrome, an antenatal ultrasound detected case. Genet. Counsel., 1994, 5(3): 297-301
5. Kaufmann K, Baldinger S, Pratt L. Ultrasound detection of Apert syndrome: a case report and literature review. Am J Perinat., 1997, 14(7): 427-430
6. Jones KL. Apert syndrome in Smith"s recognizable patterns of human malformation, W.B. Saunders Company. 1997, 418-419
7. Blank CE. Apert"s syndrome (a type of acrocephalosyndactyly). Observations on a British series of thirty-nine cases.  Ann. Hum. Genet., 1960, 24: 151-164
8. Tunte W, Lenz W. Zur haufigkeit und mutations-rate des Apertsyndroms. Hum. Genet.(Berlin), 1967, 4: 101-111
9. Erikson JD, Cohen MM Jr. A study of parental age effects on the occurrence of fresh mutations for the Apert syndrome. Ann. Hum. Genet., 1974, 38: 89-96
10. Park WJ, Theda C, Maestri NE, Meyers GA, Frigurg JS, Dufresne C, Cohen MM Jr, Jabs EW. Analysis of phenotypic features and FGFR2 mutations in Apert syndrome. Am.J. Hum.Genet., 1995, 57: 321-328

 

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