Apert syndrome

Apert syndrome is a form of acrocephalosyndactyly, a congenital disorder characterized by malformations of the skull, face, hands and feet. It is classified as a branchial arch syndrome, affecting the first branchial (or pharyngeal) arch, the precursor of the maxilla and mandible. Disturbances in the development of the branchial arches in fetal development create lasting and widespread effects.

In 1906, Eugène Apert, a French physician, described nine people sharing similar attributes and characteristics. Linguistically, “acro” is Greek for “peak,” referring to the “peaked” head that is common in the syndrome. “Cephalo”, also from Greek, is a combining form meaning “head”. “Syndactyly” refers to webbing of fingers and toes.

In embryology, the hands and feet have selective cells that die, called selective cell death or apoptosis, causing separation of the digits. In the case of acrocephalosyndactyly, selective cell death does not occur and skin, and rarely bone, between the fingers and toes fuses.

The cranial bones are affected as well, similar to Crouzon syndrome and Pfeiffer syndrome. Craniosynostosis occurs when the fetal skull and facial bones fuse too soon in utero, disrupting normal bone growth. Fusion of different sutures leads to different patterns of growth on the skull. Examples include: trigonocephaly (fusion of the metopic suture), brachycephaly (fusion of the coronal suture), dolichocephaly (fusion of the sagittal suture), plagiocephaly (fusion of coronal and lambdoidal sutures unilaterally), and oxycephaly or turricephaly (fusion of coronal and lambdoid sutures).

Apert syndrome occurs in approximately 1 per 160,000 to 1 per 200,000 live births.

Signs and symptoms
The cranial malformations are the most apparent effects of acrocephalosyndactyly. Craniosynostosis occurs, with brachiocephaly being the common pattern of growth. Another common characteristic is a high, prominent forehead with a flat posterior skull. Due to the premature closing of the coronal sutures, increased cranial pressure can develop, leading to mental deficiency. A flat or concave face may develop as a result of deficient growth in the mid-facial bones, leading to a conditir prognathism. Other features of acrocephalosyndactyly may include shallow bony orbits and broadly spaced eyes. Low-set ears are also a typical characteristic of branchial arch syndromes.

The major attribute of the syndrome is syndactyly of the hands and feet. Commonly there is fusion of fingers or toes with an equal number on both sides of the body. Those with Aperts syndrome may also show Synonychia, the fusion of two or more nails of the digits. It is typical for the middle 3 fingers to be fused together. The thumb and big toe may be broad and malformed. Apert syndrome is progressive with age as the joints continue to grow, but remain immovable.

Causes
Acrocephalosyndactyly may be an autosomal dominant disorder. Males and females are affected equally; however research is yet to determine an exact cause. Nonetheless, almost all cases are sporadic, signifying fresh mutations or environmental insult to the genome. The offspring of a parent with Apert syndrome has a 50% chance of inheriting the condition. In 1995, A.O.M. Wilkie published a paper showing evidence that acrocephalosyndactyly is caused by a defect on the fibroblast growth factor receptor 2 gene, on chromosome 10.

Apert syndrome is an autosomal dominant disorder; approximately two-thirds of the cases are due to a C to G mutation at the position 755 in the FGFR2 gene, which causes a Ser to Trp change in the protein. This is a male-specific mutation hotspot: in a study of 57 cases, the mutation always occurred on the paternally derived allele. On the basis of the observed birth prevalence of the disease (1 in 70,000), the apparent rate of C to G mutations at this site is about .00005, which is 200 to 800 fold higher than the usual rate for mutations at CG dinucleotides. Moreover, the incidence rises sharply with the age of the father. Goriely et al. (2003) analyzed the allelic distribution of mutations in sperm samples from men of different ages and concluded that the simplest explanation for the data is that the C to G mutation gives the cell an advantage in the male germline.

Treatments
Surgery is needed to prevent the closing of the coronal sutures from damaging brain development. In particular, the LeFort III or monobloc midface distraction osteogenesis which detaches the midface or the entire upper face, respectively, from the rest of the skull are performed in order to reposition it in the correct plane. These surgeries are performed by both plastic and oral and maxillofacial (OMS) surgeons, often in collaboration. Another surgery is needed to address syndactyly of hands and feet.

Dental significance
Common relevant features of acrocephalosyndactyly are a high-arched palate, pseudomandibular prognathism (appearing as mandibular prognathism), a narrow palate, and crowding of the teeth.