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

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Developmental field: a group of cells or a region that responds as a coordinated unit to embryonic interaction; defects in developmental fields result in multiple malformations (e.g., formation of the lens depends on interaction with the optic cup). Many malformations are field defects.177

Syndrome: pattern of anomalies thought to be pathologically related. The term implies a single cause, not a field defect.

Disruption: a morphological defect resulting from the extrinsic breakdown of, or an interference with, an originally normal developmental process (e.g., amniotic bands). As these are usually nonrecurring events, counseling will indicate low risk for future family members.

Deformation: abnormal form, shape, or position of a part of the body caused by a mechanical process (e.g., intrauterine compression).

Association: statistically related association of anomalies not identified as a sequence or syndrome (e.g., CHARGE association).

A disturbance to a group of cells in a single developmental field may result in multiple malformations. A single structural defect or factor causing a cascade of secondary anomalies is referred to as a sequence, with a domino-type effect. A sequence implies heterogeneous causative factors. Pierre Robin syndrome (cleft palate, glossoptosis, micrognathia, and respiratory problems) may represent a sequence caused by abnormal descent of the tongue due to mandibular hypoplasia. This sequence has been reported in many syndromes, including Stickler, fetal alcohol, and chromosomal syndromes. In contrast, a syndrome implies a single cause, even if the etiological agent is not yet identified.

The term syndrome is used in many ways, often utilizing a variety of definitions. It may be attached to an assortment of signs and symptoms for which the etiology is known (e.g., Down’s syndrome, Marfan syndrome, trisomy 13), or it may be used to describe a group of findings for which the cause is poorly understood. The term disease is more frequently used with a group of signs and symptoms associated with progression or deterioration (e.g., diabetes). This separation is not always precise, and there are many examples of overlapping in which the term disease is used in a way that is more consistent with the definition of syndrome and vice versa. Although the etiology is known in some syndromes, the basic defect in many malformation syndromes remains unknown, with the name of the

syndrome based on a wide variety of things, such as the physician’s or patient’s name, the striking feature, and mythical designation. The number and types of abnormalities ascribed to many syndromes vary not only in the frequency with which the syndrome has been observed and reported in the literature but also in the underlying pleiotropic characteristics of the syndrome. The term phenotypic spectrum was used by Opitz et al.178 to describe the number of abnormalities reported for a given syndrome and their frequency in a controlled population. This approach helps to separate findings that are specific to the syndrome from those that are just a chance occurrence. A given anomaly may be clearly or questionably related to the syndrome or may be a chance occurrence; rarely, it may occur at a significantly lower frequency than would occur in a controlled population. This latter situation would suggest that the syndrome in some way protects the organism from a given abnormality. Various malignancies show increased correlations with a syndrome, whereas a few have the opposite relationship. For example, the association of Wilm’s tumor with aniridia is well appreciated, but patients with osteogenesis imperfecta may be more resistant to cancer.143

A weak recurring pattern is described as an association. This term implies that the defects occur with more frequency than would be expected by chance but do not show a pattern that can be clearly defined as a syndrome. The CHARGE association (ocular Coloboma, Heart defects, choanal Atresia, developmental or mental Retardation, and Genitourinary and Ear anomalies) is an example that may represent a variety of yet unidentified etiologies.180 If a definite etiology is established (e.g., a chromosomal abnormality) then, more precisely, that individual has a syndrome.

Cohen38–40 reported that new syndromes are described at a rate of approximately one or more per week. In a typical scenario, an infant with multiple anomalies is examined. An attempt is made to arrive at a specific diagnosis from classic textbooks.85,113,151,237 computer-based CD-ROM programs,9 London dysmorphology,142 online databases,149,176 and consultations with geneticists. If these investigations do not delineate a specific syndrome, the patient is presumed to represent an unknown genesis syndrome, in which the causes are unknown but the findings are thought to represent a unique pattern. The patient is then described in the literature, and the reaction of the scientific community is awaited.

At times, investigators have failed to recognize a previously described syndrome, and future correspondence will clarify the existing syndrome that the patient exhibits. Another possibility is that on seeing this constellation of findings, other physicians report additional cases, and this group of patients is classified into a category referred to as a recurring pattern syndrome. As more examples are observed, the validity of this new syndrome and the description of the spectrum of clinical manifestations increase. The etiology of the syndrome may not be appreciated at the time or even in the future, but if the specific cause is later described, these patients represent a known genesis syndrome and are subcategorized into such groups as (1) chromosomal defect, (2) enzyme deficiency, (3) environmental factor, (4) single gene syndrome, or (5) diseases or familial syndromes. The appreciation of developmental genes (e.g., Hox genes) has expanded the spectrum of possible genetic causation.

The study of many cases is required to establish whether any group of patients with similar but not identical findings represent different etiologies (heterogeneity) or the same cause with variable manifestations (pleiotropism).

One problem confronting less experienced physicians is that textbook descriptions frequently characterize and illustrate only the classic cases or severely affected patients, and more minimally affected individuals may not be recognized. Figure 4-1 shows examples of mildly, moderately, and severely affected children with mandibulofacial dysostosis, a dominantly inherited condition with high penetrance but variable expressivity. Frequently, other family members with the syndrome are not identified until a diagnosis is made in a severely affected child.

Children with congenital malformations and syndromes involving craniofacial structures are at a significant risk for ocular anomalies. The number of syndromes and isolated malformations is great, and the spectrum of eye problems is vast. Therefore, the development of an approach to the dysmorphic child is more productive than an attempt to memorize all ocular pathological changes reported in the literature. It is useful to consider these ocular findings in two general categories.

1. Ocular complications secondary to abnormal size, shape, or position of bony and soft tissue changes in orbital structures.

These complications may occur during development (disruption or deformation) or may be acquired after birth. These derived changes can be anticipated from the malformations present in the

surrounding tissues. They are not necessarily specific to a syndrome but are the result of a type of deformity or mechanical factors. The same anomaly may occur in separate syndromes.

There are numerous common examples of secondary complications. Abnormalities in orbital size or position may result in many commonly listed and often severe ocular findings. For example, in craniosynostosis the resultant shallow orbits may result in corneal exposure or ulceration and motility disturbances. If the craniosynostosis causes extensive cranial suture closure, increased intracranial pressure may ensue with papilledema and optic atrophy.

2. Intrinsic ocular pathology. Examples include primary malformations associated with craniofacial syndromes, such as myopia and retinal pathological changes in Stickler syndrome, anterior segment developmental anomalies seen in fetal alcohol syndrome and many chromosomal anomalies, and Duane’s syndrome, associated with many craniofacial malformation syndromes.

OPHTHALMOLOGIC EXAMINATION

Most ophthalmic findings are detected during the routine complete eye examination. The modifications of the examination consist of a more detailed search for milder forms of the “anticipated pathology,” the recording of negative findings, and baseline measurements of anatomic relationships. These additions aid in a retrospective review of ocular manifestations in a particular syndrome, studies of the natural history with and without surgical intervention, and in devising coordinated treatment plans for a patient who is frequently being cared for by practitioners in multiple specialties of medicine.

Cycloplegic refraction and careful examination of the lids, palpebral fissures, anterior segment, pupils, and fundus, as well as special study of the optic disc, are routine and mandatory.

FIGURE 4-1A–C. Mandibulofacial dysostosis (Treacher Collins syndrome) in three children with different degrees of severity of the syndrome: (A) lid colobomas; (B) lower lid notching with absent cilia nasally, severe microtia with hearing deficit; (C) severe midface hypoplasia, facial clefts, lower lid coloboma, severe external ear malformations, and hearing loss.

Motility evaluation should include measurements in the primary position and all fields of gaze, with particular attention to the presence or absence of A- or V-pattern deviations and limitations of versions and ductions. Intraocular pressure measurements, visual field examination, exophthalmometry, corneal sensitivity tests, color vision tests, and tests of binocular vision should be performed when possible and desirable. When visual or structural abnormalities are noted, less routine tests, such as fluorescein angiography, visualization of the lacrimal system by radiologic techniques and electrophysiology, visual field analysis, and other tests may be appropriate. When abnormalities are numerous or serious ophthalmic disease is strongly suspected, examination under anesthesia may be necessary if the patient cannot cooperate. Before such a procedure is undertaken, however, consultation with other medical personnel should be conducted to anticipate anesthesia or sedation complications or to combine procedures that are scheduled to be completed. Patients with multiple craniofacial malformations are frequently at increased risk for complications and must be monitored more closely.

Some evaluations should be performed in patients with craniofacial anomalies that are not usually part of a routine eye examination, including measurements and documentation of certain anatomic relationships: (1) inner and outer canthal distances, (2) interpupillary distance, (3) palpebral fissure size, (4) position of the lacrimal puncta, (5) obliquity of the palpebral fissure, and (6) asymmetry of orbits and orbital structures. These measurements serve two purposes. First, they prevent errors of recording false impressions such as pseudohypertelorism caused by soft tissue changes in the canthal area such as telecanthus. In addition, they provide useful data for the study of the syndrome characteristics and serve as a baseline if reconstructive surgery is performed. With greater success in surgical correction of severe craniofacial anomalies, there has been renewed interest in the study of growth patterns of abnormal facial structures, necessitating detailed documentation of normal and abnormal findings. Accurate normal values are necessary for these comparisons (Fig. 4-2).85,95,107,113

If proptosis or exophthalmos is observed, careful measurements should be obtained. The instrument used to measure proptosis either reflects the personal preference of the examiner or is the one most readily available but should be standard for each examination. Because many patients are children, a simple type may be the most useful.