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

GENETICS

Gripp et al.90 found a pro250-to-arg (P250R) amino acid substitution in FGFR3 in 4 of 37 patients with synostotic anterior plagiocephaly. This same mutation was identified in patients with Muenke nonsyndromic coronal synostosis as well as in individuals with Saethre–Chotzen syndrome. In 3 mutation-positive patients with full parental studies, a parent with an extremely mild phenotype was found to carry the same mutation. None of the 6 patients with nonsynostotic plagiocephaly and none of the 4 patients with additional suture synostosis had the FGFR3 mutation.

HYPERTELORISM

Hypertelorism is an anatomic description that indicates an increased distance between the orbits (greater than 2 standard deviations from normal values). Hypertelorism is thought to be the consequence of arrest in development of the greater wings of the sphenoid, making them smaller than the lesser wings and thus fixing the orbits in the widely separated fetal position. The most accurate diagnoses involve radiologic methods. The exact location for measuring the intraorbital distance may vary among different investigators, but there are appropriate established norms for the various locations.17 A less accurate clinical determination is to measure the interpupillary distance (previously described in the introduction of the chapter).

Soft tissue variations may result in a false diagnosis of hypertelorism. The most common cause of pseudohypertelorism is an increased distance between the medial canthi (i.e., telecanthus). If the abnormality is confined to the soft tissue, the term primary telecanthus is sometimes used. Patients with increased intraorbital distance and proportional increased intercanthal distances are at times referred to as having secondary telecanthus. Therefore, secondary telecanthus is not “pseudo”- hypertelorism, as there is a true increase in the orbital distance. A combination of telecanthus and lateral displacement of the lacrimal puncta occurs in some patients (Fig. 4-9); this is seen most commonly in Waardenburg syndrome but also is seen in a few other syndromes, such as blepharonasofacial syndrome.192

Hypertelorism, a nonspecific finding in many dysmorphic individuals, is associated with a large, heterogeneous group of

FIGURE 4-9. Waardenburg syndrome with forelock and primary telecanthus.

etiologies, such as craniofacial syndromes, teratogenic deformities, and disruptions.41 Hypertelorism is a characteristic finding of a variety of chromosomal aberrations.85 No single specific ocular abnormality is associated with the various types of hypertelorism, but dysfunction of the lacrimal excretory system caused by disturbed midline anatomy exists in many patients without regard to etiology of the hypertelorism. Lacrimal duct probings are not always successful because of these anatomic changes, and more complex diagnostic evaluations of the lacrimal system are needed.

Strabismus, usually exotropia, is frequently present if the hypertelorism is severe. If the bony orbits are abnormal in more respects than in their horizontal position (e.g., craniosynostosis), other motility disturbances also may be present.

GENETICS

The recurrence risk is determined by the etiology of the hypertelorism. For example, if the cause is associated with Crouzon syndrome, the recurrence risk would be 50%, whereas frontonasal dysplasia usually occurs sporadically and thus has a low recurrence risk.

nant and autosomal recessive modes of inheritance have been suggested, without completely convincing evidence in either case. Autosomal recessive inheritance was suggested by the inbred kindred reported by Moreno,169 who reviewed the conflicting literature on the genetics of this anomaly. An X-linked dominant form has also been suggested as a possibility.76

Hypotelorism

Hypotelorism, like hypertelorism, is an anatomic description and not a syndrome diagnosis. The intrapupillary distance must be considered in relationship to the head size so that relative hypotelorism in a microcephalic head would have a different implication than true hypotelorism in a head with normal circumference. Hypotelorism may occur with isolated median cleft lip and a few other craniofacial anomalies with a normal brain,85 but many times it is an indication of abnormal brain development such as holoprosencephaly.

ROLE OF THE OPHTHALMOLOGIST

In the examination of a child with hypotelorism, it is most important for the ophthalmologists to be aware of possible central nervous system anomalies and to refer the patient for further medical evaluation. If there are any ocular developmental anomalies, the child should be treated in the standard way.

GENETICS

Hypotelorism is an etiologically heterogeneous entity. The recurrence risk of hypotelorism with or without holoprosencephaly depends on the etiology. Many cases are sporadic, but there are a few conditions that have some recurrence risk. Relatives should be examined for mild forms of hypotelorism, bifid nose, pituitary deficiency, and dental anomalies.

HOLOPROSENCEPHALY

Holoprosencephaly, which occurs with a frequency of 1 in 16,000 live births and about 1 in 200 spontaneous abortions, is a spectrum of central nervous system malformations involving midline structures. It is an etiologically heterogeneous entity, including teratogenic causes such as maternal diabetes.

DeMeyer et al.58 outlined the facial dysmorphism that they proposed predicted different types of holoprosencephaly. At one extreme is cyclopia with a single median eye sometimes associated with a proboscis. There may be varying degree of doubling of the ocular structures in this severe developmental anomaly. Less severe malformations of the face and brain may be associated with iris coloboma.36,37 Occasionally, holoprosencephaly is not accompanied by characteristic facial features, but significant hypotelorism implies central nervous system malformations and usually mental retardation, and the child should be worked up with that possibility in mind. In Aicardi’s syndrome, hypotelorism, costovertebral defects, mental deficiency, arrhinencephaly, agenesis/dysgenesis of the corpus callosum, seizures, and other central nervous systems anomalies are associated with choroidoretinal lacunae.63 Flexion spasms in the infant represent the usual mode of clinical presentation in the Aicardi syndrome. This group of findings is confined almost exclusively to girls, suggesting X-linked dominant inheritance with lethality in hemizygous males. All cases would, on this hypothesis, be new mutations. There are many recognized syndromes and chromosomal anomalies with holoprosencephaly.36,37,119,163

PATHOGENESIS

Holoprosencephaly indicates a midline cleavage anomaly of the embryonic forebrain. As it is seen in cases of known chromosomal, genetic, and teratogenic factors, this seems to best fit into the category of a developmental field defect.

Sulik and Johnston226 suggested that these complex facial and central nervous system anomalies can be traced to a defect in development that occurs near the third week of gestation. They were able to produce this defect by administering alcohol in a mouse model.

GENETICS

The recurrence risk of holoprosencephaly depends on the etiology. Relatives should be examined for mild forms of hypotelorism, bifid nose, pituitary deficiency, and dental anomalies. Holoprosencephaly can be chromosomal, multifactorial, or monogenic in origin and may be associated with other midline malformations. Autosomal dominant holoprosencephaly is a rare but well-documented entity. The transmitting parent may

be normal or have a single central maxillary incisor as the only manifestation of a midline abnormality. At least 12 genetic loci have been associated with holoprosencephaly, including the sonic hedgehog gene (SHH) at 7q36.246 Sporadic cases account for two-thirds of cases, and the recurrence risk after an isolated case is predicted to be 13% to 14%.175

MANDIBULOFACIAL DYSOSTOSIS (TREACHER COLLINS, FRANCESCHETTI–ZWAHLEN–KLEIN SYNDROMES)

Mandibulofacial dysostosis (MFD) has many names depending on the medical specialty or the country of origin in which it is reported. Although this syndrome was first described in the literature in the 1800s by Berry,20 detailed descriptions of the major manifestations were later published.71,239 It occurs in 1 in 25,000 to 1 in 50,000 births with more than 50% new mutations and some relationship incidence related to paternal age.115

SYSTEMIC FINDINGS

The disorder shows an unusually wide range of expressivity and involves structures primarily derived from the first branchial arch, groove, and pouch. The complete form is characterized by

(1)coloboma or notching of the outer part of the lower eyelid;

(2)lack of development of the malar bone and mandible; (3) antimongoloid slant of the palpebral fissures; (4) large mouth (macrostomia), abnormal (highly arched) palate, and anomalies of dentition; (5) malformations of the external and middle ear;

(6)atypical hairline with projections toward the check; and (7) blind fistulas between the ears and angles of the mouth (see Fig. 4-1). The condition is almost always bilateral. Incomplete and abortive cases are common. The abnormalities are bilateral and usually quite symmetrical contrasted with hemifacial microsomia. Intelligence is usually normal.

A cleft palate exists in about 35% of patients, with an additional 30% to 40% of patients showing more minor palatal anomalies.85 The temporal orbital wall is affected with secondary hypoplasia and malposition of soft tissues. Consistent bony abnormalities include absence or severe hypoplasia of the zygomatic process of the temporal bone and deformities of the

encounter a classical case and then find other family members with mild previously unrecognized manifestations. The risk of recurrence for future children and offspring is 50%. The paternal age was noted to be older in the estimated 50% to 60% of new mutations.115 There seems to be no sex or racial predilection.203

There is variable expression within families; some patients are mildly affected, and others are so severely affected that they die shortly after birth.203 The gene locus for the Treacher Collins syndrome was finally mapped to chromosome 5Q32–q33.3 by Jabs and coworkers,111 and Dixon and coworkers62; and the Treacher Collins Syndrome Collaborative Group238 isolated the locus for the TCOF1 gene in 1996. Although TREACLE was the initial designation for the gene for Treacher Collins syndrome, it is now used to designate the protein product. Dixon61 reviewed the clinical and molecular features of Treacher Collins syndrome. A total of 51 mutations in the TCOF1 gene had been identified to date, all of which result in introduction of premature termination codons into the reading frame, suggesting haploinsufficiency as the molecular mechanism underlying the disorder. Splendore et al.218 screened 28 families with a clinical diagnosis of Treacher Collins syndrome for mutations in the 25 coding exons of TCOF1 and their adjacent splice junctions through SSCP and direct sequencing. Pathogenic mutations were detected in 26 patients, yielding the highest detection rate reported so far for this disease (93%).

When a specific mutation is known in advance, prenatal diagnosis is possible by CVS or amniocentesis. Otherwise, ultrasound imaging in the second trimester can be used to view the fetal profile for micrognathia and maxillary hypoplasia, features suggestive of the disorder. Additionally, presence of polyhydramnios with no visible stomach bubble can be an indicator of reduced fetal swallowing due to marked micrognathia.

ROLE OF THE OPHTHALMOLOGIST

Most of these patients require no ophthalmologic treatment other than routine management of strabismus, if it exists, and correction of the refractive error (although it may be somewhat difficult to fit eyeglasses because of the ear deformity). A few patients have tearing secondary to malformed positions of the palpebral fissures and other lacrimal anomalies that require treatment.13 The primary treatment for severe cases consists of recon-

struction of the hypoplastic facial bones and surgical correction of the ear deformities.

The management of mandibulofacial dysostosis also includes early recognition of hearing deficits and cosmetic correction of any major facial defects. Patients are usually of normal intelligence. Because some patients have narrow airways, extreme care is recommended during endotracheal intubation.

NAGER SYNDROME (PREAXIAL

ACROFACIAL DYSOSTOSIS)

Patients with Nager syndrome resemble those with mandibulofacial dysostosis with the additional finding of limb deformities. The mandibulofacial dysostosis is characterized mainly by severe micrognathia and malar hypoplasia. The limb deformities consist of absence of the radius, radioulnar synostosis, and hypoplasia or absence of the thumbs. This syndrome is usually sporadic, and there are reported systemic findings of small stature, malformation of the thumbs, radial deformities, and kidney malformations.85 McDonald and Gorski150 presented a summary of 76 previously reported cases and added 2 new cases. They favored inheritance as a pleiotropic disorder with markedly variable penetrance and expressivity, but granted that the occurrence of affected sibs with normal parents suggested genetic heterogeneity with the existence of an autosomal recessive form. They found 5 families with normal parents and 2 affected siblings. Zori et al262 suggested that the gene for this disorder may reside on chromosome 9, at q32.

OCULO-AURICULO-VERTEBRAL SPECTRUM (HEMIFACIAL MICROSOMIA, GOLDENHAR’S SYNDROME, FACIAL MICROSOMIA)

Hemifacial microsomia encompasses a heterogeneous spectrum of conditions characterized by malformations involving the ear, oral, and mandibular structures. There are no absolute minimum criteria for diagnosis, and the incidence of this syndrome complex is unknown. Goldenhar’s syndrome is considered by many to be a variant in the group and is estimated to