Ординатура / Офтальмология / Английские материалы / Handbook of Pediatric Eye and Systemic Disease_Wright, Spiegel, Thompson_2006

PATHOGENESIS

The causes of craniosynostosis are known to be heterogeneous. The premature closure of the suture may result from a number of pathogenic mechanisms and has been reported in chromosomal, monogenetic, and teratogenic syndromes; in nutritional deficiency; and in other syndromes of unknown genesis.39

Most cranial and facial sutures do not close until adulthood, but a few synostose spontaneously early in development (premaxial, maxiofacial, axillary, and metopic). The reason for this predictably age-related synostosis is unknown, but it has been proposed to be related to the functional environment of a particular suture and the need for adaptive skeletal change in the craniofacial area.137,138,140,211

RECURRENCE RISK

Simple cases of craniosynostosis are often sporadic occurrences. Syndromic types frequently show autosomal dominant inheritance (Crouzon or Apert, Pfeiffer, and Saethre–Chotzen syndromes), although a few show autosomal recessive (Carpenter’s syndrome) or other forms of inheritance.

ROLE OF THE OPHTHALMOLOGIST

The ophthalmologist is an indispensable member of the craniofacial team for this group of patients. Initially, examination of the optic nerve status as an indicator of intracranial pressure is most crucial. This evaluation, along with determination of whether there is vision-threatening corneal exposure, will determine whether emergency surgical intervention by the craniofacial team is necessary. Subsequently, the identification and treatment of strabismus, amblyopia, refractive errors, dacryocystitis, and mild corneal exposure may require frequent ophthalmologic visits. An ophthalmologist’s consultation will be a factor in determining the time and extent of reconstructive craniofacial surgery. Major strides forward in the field of reconstructive surgery for the craniosynostosis group of patients has led to functional and cosmetic improvement for many and has resulted in increased knowledge of the pathophysiology of craniofacial structures.21,232

Ocular complications after major reconstructive surgery are potentially serious. Direct or indirect damage to the neurological pathways to the eye can result in permanent visual loss. For-

tunately, blindness has been a rare complication. In a combined report of 793 cases,253 2 patients sustained permanent visual loss; in another study of 75 cases,54 only 2 patients had severe visual complications. Choy et al.30 reported their complications in reconstructive surgery, and Diamond et al.,60 Morax,168 and Choy et al.31 reported ocular alignment changes after surgery. The cause of serious complications was not uniform in the few reported cases, although postoperative hematoma and nerve decompression was reported in some cases.

Changes in lid position may occur after midface surgery, requiring secondary ptosis surgery. Because the levator muscle is often normal from a neuromuscular standpoint, resection may have a greater effect than one would predict if the ptosis were congenital. Because lacrimal system dysfunction is common postoperatively and is related to an increased incidence of lacrimal excretory system anatomic anomalies or damage due to reconstructive surgery, the timing of lacrimal surgery depends on the severity of symptoms (particularly recurrent infection) and the potential effect of future surgery on the anatomy. Preoperative tearing is best treated after reconstructive surgery unless recurrent severe dacryocystitis exists that cannot be medically treated. This issue must be discussed with the craniofacial team to arrive at an appropriate decision.54,253

Apert Syndrome

Apert syndrome is characterized by craniosynostosis midface hypoplasia and syndactyly of extremities (Fig. 4-6). Its transmission is believed to be autosomal dominant, but most cases are sporadic and caused by high neonatal mortality and reduced fitness of affected individuals.42

Blank23 estimated a frequency of 1 in 160,000 population, but Cohen45 believed the prevalence may be higher. Prenatal diagnosis is possible.135

SYSTEMIC FINDINGS

Craniosynostosis of the coronal suture is characteristic with associated findings of midface deficiency, high-arched palate, syndactyly of the hands and feet involving digits two through four,45 and central nervous system anomalies. The cranial base is malformed, and frequently there is bulging of the bregma. A trilobulated shaped skull (cloverleaf) has also been reported. The nasal bridge is depressed, and the nose is humped. Fused cervical ver-

FIGURE 4-7. Apert syndrome. Ocular motility showing a small exotropia in primary position with a large exotropia looking up and esotropia looking down. Both inferior oblique muscles are overacting.

along with a characteristic V-pattern strabismus (Fig. 4-7). Abnormal origins, size, or insertion of ocular muscles may be present.52,143 Infrequent findings include an albinotic appearance of the fundus, congenital glaucoma, and keratoconus.85,145

GENETICS

Two very specific changes in adjacent amino acids in the fibroblast growth factor receptor 2 (FGFR2) gene: Pro250Arg and Ser252Trp account for 97% of all mutations in Apert syndrome. The Ser252Trp mutation is more common, seen in 71% of Apert syndrome patients compared to the Pro253Arg mutation, which is seen in 26%. Cleft palate is more common in patients with Ser252Trp, whereas the degree of syndactyly is more prominent in the patients with Pro253Arg.183,184,215 In Apert syndrome, the clinical manifestations within a family usually show little variability. Apert syndrome shows full penetrance, meaning that all individuals carrying a mutation for Apert syndrome will exhibit some phenotypic manifestation, even if fairly subtle. Affected individuals have a 50% chance of passing the disease-causing mutation to each one of their children. An advanced paternal age effect in new mutations has been conclusively demonstrated

at the molecular level in Apert syndrome.167 Germline mosaicism (where the mutation is confined to a percentage of the gonadal cells) has been observed. The limited number of different mutations in Apert syndrome (Ser252Trp, Pro253Arg) greatly facilitate diagnostic confirmation in addition to rendering feasible prenatal diagnosis via amniocentesis or chorionic villi sampling (CVS) in an at-risk pregnancy.

Pfeiffer’s Syndrome

SYSTEMIC

Pfeiffer’s syndrome is similar to Apert syndrome (see page 714), but also is characterized by very shallow orbits (already part of Apert) and short broad thumbs and toes. Corneal exposure is an important problem in these children.

Pfeiffer’s syndrome is both clinically and molecularly heterogeneous. Cohen35,47 has proposed three clinical subtypes with varying degrees of severity. This separation is often not clinically distinct in any patient but does allow a way of determining general prognosis.

Pfeiffer’s syndrome types 2 and 3 are more common than type 1. Patients with Pfeiffer’s syndrome type 1 can exhibit a spectrum of craniofacial involvement ranging from moderate to severe midfacial hypoplasia. Skeletal features encompass broad and medially deviated thumbs and great toes; variable degrees of brachydactyly can occur as well. Associated findings may include hearing loss or hydrocephalus. Intellect is usually normal. Overall, Pfeiffer’s syndrome type 1 has a more favorable prognosis than types 2 and 3.

Craniofacial involvement in Pfeiffer’s syndrome type 2 is more severe that in type 1, with cloverleaf skull and extreme proptosis (often to the point of inability to close eyelids). Not surprisingly, developmental delay and mental retardation are common. Skeletal findings are similar to type 1 with broad and medially deviated thumbs and great toes and a variable degree of brachydactyly. Additionally, ankylosis of the elbows and knees can occur. Associated findings have included choanal stenosis or atresia, laryngotracheal abnormalities, hydrocephalus, seizures, and increased risk for early death.

Pfeiffer’s type 3 is almost identical to type 2; however, the skull shape is turribrachycephalic. The cognitive, skeletal features, and associated findings are those of type 9.

GENETICS

Inheritance is autosomal dominant with complete penetrance and variable expressivity. Mutations causing Pfeiffer’s syndrome have been found on FGFR1 and FGFR2. A single common missense mutation, Pro250Arg, has been associated in five unrelated families with a relatively mild form of Pfeiffer’s syndrome type 1.170,199 Multiple mutations are known in FGFR2 and have been associated with a variety of phenotypes including Pfeiffer’s. Rutland et al.208 and Schell et al.211 suggested that genotype– phenotype correlations can be drawn between the mutation in FGFR1 and those on FGFR2. Severe craniosynostosis and midfacial hypoplasia, more pronounced proptosis, and perhaps broader thumbs are more likely to be associated with mutations on FGFR2 than with the single mutation in FGFR1. In about 45% of Pfeiffer’s syndrome patients, no mutation has been identified. With familial Pfeiffer’s syndrome, when a specific mutation is known in advance, prenatal diagnosis is possible by CVS or amniocentesis. Ultrasonographic examination may show cloverleaf skull in type 2.

Table 4-1 compares the clinical features of FGFR craniosynostosis syndromes, and Table 4-2 summarizes the molecular basis.

Carpenter’s Syndrome

Carpenter’s syndrome, also known as acrocephalopolysyndactyly type II, is a variation of Apert syndrome characterized by preaxial polydactyly on the side of the thumb or big toe, syndactyly, brachycephaly, synostosis, obesity, hypogonadism, mental retardation, shallow orbits, proptosis, and laterally placed intercanthi.43,201

TABLE 4-1. Distinguishing Clinical Features in the FGFR-Related

Craniosynostosis Syndromes.

GENETICS

Inheritance is autosomal recessive and the molecular basis is unknown to date. In all cases, examination of the parents has been normal.

Crouzon Syndrome

Crouzon syndrome occurs in approximately 1 in 25,000 births.46 The coronal suture is most frequently involved, but different combinations of sutures have been reported in 75% of cases.125,126 Craniofacial findings in Crouzon syndrome are similar to those for Apert syndrome and other types of craniosynostosis, but the prevalence of various malformations and the family history are different, and there are no anomalies of the hands or feet (although a radiographic metacarpal-phalangeal profile may reveal shortening.171 About 5% of individuals have acanthosis nigricans, which can appear after the neonatal period. This finding is associated with a specific mutation in the FGFR3 gene. Progressive hydrocephalus occurs in approximately 30% of affected individuals, often with tonsillar herniation.

OCULAR FINDINGS

Proptosis occurs in most patients and may be severe, with visionthreatening corneal exposure necessitating reconstructive surgery earlier than usual. Optic atrophy and blindness are also more frequent than in other types of craniosynostosis syndromes. Low-frequency anomalies reported include keratoconus, iris and corneal malformations, glaucoma, and ectopia lentis.85

Abnormal location and position of ocular muscles have been reported frequently in both Crouzon and Apert syndromes. These findings may be due to a bias of the type of patients more frequently referred to an ophthalmologist, or they may represent a true increased prevalence in these particular forms of craniosynostosis.

GENETICS

Crouzon syndrome has a clear autosomal dominant mode of inheritance, with about 67% of cases being familial.44 Variability of expression characterizes Crouzon syndrome. Most of the mutations associated with Crouzon syndrome are located in FGFR2. With the milder phenotype that can be seen in Crouzon syndrome, inheritance of the mutant gene from an affected parent is common. To date, about a half dozen mutations found in patients and families with Crouzon are identical to those that cause Pfeiffer’s syndrome, and one 9-bp deletion overlaps with an 18-bp deletion in Pfeiffer’s syndrome (see Table 4-2). When a specific mutation is known in advance, prenatal diagnosis is possible by CVS or amniocentesis.

PLAGIOCEPHALY

Plagiocephaly is defined as asymmetry of the skull caused by unilateral or asymmetrical involvement of the cranial sutures or a deformation defect from compression on the head.26,33 Female preponderance is noted in both types of plagiocephaly.26 Figure 4-8A shows a patient with plagiocephaly. Frequently, the asymmetry is best observed by looking down on a patient’s head (Fig. 4-8B).

SYSTEMIC FINDINGS

Plagiocephaly is sometimes divided into a frontal type involving a corneal suture or an occipital type involving the lambdoidal suture. Unilateral coronal synostosis is estimated to occur in 1 per 10,000 births, 10 times more frequently than lambdoidal synostosis.26 Deformational plagiocephaly is more frequent, but many of these infants are not referred to craniofacial centers because of the natural history of improvement of this form of plagiocephaly. The following discussion concerns

the frontal type of plagiocephaly, which is the most common and of greatest concern to the ophthalmologist.

In the synostotic form, the orbit is elevated on the affected side and the nasal root is also deviated on that side. Usually the ear is supraplaced, the forehead flattened, and the palpebral fissure more flattened on the involved side. Craniofacial growth will be altered. The most reliable diagnostic tests are standard radiographs or CT scans. Primary radiographic findings may be unreliable in the first few months of life26 and may need to be repeated if deformity remains or progresses, even when the initial early radiographic evaluation did not disclose any abnormality. Three-dimensional CT scans, although expensive, give more information on the degree of deformity or orbital dysmorphology.148,241

OCULAR FINDINGS

Affected patients have a high incidence of vertical strabismus. The strabismus pattern depends on the type and degree of plagiocephaly. These children may show an abnormal head position with either the synostotic or deformation forms. With the deformation type, the head tilt is often more to the affected side, whereas with the synostosed form the tilt is to the opposite side, often with a hypertropia secondary to a superior oblique muscle palsy187 on the side of the abnormal orbit as well as a classic upslanted overacting inferior oblique muscle. Surgery similar to that for a routine superior oblique palsy may be indicated. These patients should be examined carefully because they may exhibit other types of patterns or motility disturbances.

It is possible that other ocular symptoms or signs ascribed to craniosynostosis may exist that are limited to the affected side. However, because an adequate number of sutures are opened in most cases, there usually is no optic nerve damage or increased intraocular pressure. There are exceptions to this rule, however.

ROLE OF THE OPHTHALMOLOGIST

The diagnosis and treatment of any form of strabismus is usually the most important task in synostotic plagiocephaly. Torticollis with deformation plagiocephaly is treated with physical therapy and head helmets. Although the differentiation between these forms appears clear in some cases, the relationship of the head position to the observed strabismus is not clear.