Ординатура / Офтальмология / Английские материалы / Handbook of Pediatric Eye and Systemic Disease_Wright, Spiegel, Thompson_2006
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SYSTEMIC FINDINGS
The white forelock is present in 30% to 40% of patients85 but may disappear with age or affect only a few hairs (see Fig. 4-9). It may be evident at birth, or soon afterward, or develop later. Young patients frequently dye the white hair, so a specific question must be asked. Premature graying in less than 10% or other pigmentation and changes of hair, lashes, or eyebrows have been noted. The nasal root is broad and may be associated with hypoplastic alar cartilage.85
An important characteristic is the sensorineural deafness, reported to occur more frequently in type II (75% of cases),93 which has been shown to manifest malformations of the organ of Corti and other inner ear structures.92,194 There are different combinations of hearing loss: unilateral or bilateral, severe or moderate, and total or partial.
OCULAR FINDINGS
Telecanthus (increased distance between medial canthi), usually with further displacement of lacrimal puncta, is the most striking adnexal finding in type I. Although the illusion of hypertelorism occurs in many patients, a true increase between the orbits exist in about 10%.182 Synophrys is frequent in both types but more so in type I.
Partial or complete heterochromia of one or both irides is seen in both types. The fundi may be albinotic.56,80 Strabismus has been noted in 10% of cases.56 Low-incidence anomalies include cataract, microphthalmia, and ptosis.80,85 Other ocular anomalies (e.g., cataracts, microphthalmia) have been reported occasionally.
GENETICS
Waardenburg syndrome is both a clinically and genetically heterogeneous disorder.85,195 It follows autosomal dominant inheritance for most, if not all, cases of type I, II and III, and is autosomal recessive for type IV, with variable penetrance and phenotypic expression of different clinical features. All four types show marked variability, even within families.195 Waardenburg syndrome type I is caused by “loss of function” mutations in the PAX3 gene on chromosome 2q37. PAX3 is a transcription factor expressed during embryonic development.
Recently, 11 mutational changes in the PAX3 gene were
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identified in patients with Waardenburg syndrome type I. Waardenburg syndrome type II is a genetically heterogeneous disorder, with about 15% of cases heterozygous for mutations in the microphthalmia-associated transcription factor (MITF) gene on 3p12, the human homologue of the mouse microphthalmia (mi) gene.173 Mutations in the PAX3 gene are associated not only with Waardenburg syndrome type I but also with type III.109 However, in type III, some but not all patients are homozygotes, whereas in type II they are heterozygotes. Type IV is caused by mutations in the genes for endothelin-3 (EDN3)65 or one of its receptors, endothelin beta-receptor (EDNRB) on chromosome 13.65,191 EDNRB mutations are dosage sensitive; heterozygosity predisposes to isolated Hirschprung disease with incomplete penetrance, whereas homozygosity results in more complex neurocristopathies associating with congenital aganglionic megalocolon and Waardenburg syndrome features.
Families with type IV have been found to have mutations in SOX10 that are likely to result in haploinsufficiency of the SOX10 product.128,186 MITF transactivates the gene for tyrosinase, a key enzyme for melanogenesis, and is critically involved in melanocyte differentiation. Absence of melanocytes affects pigmentation in the skin, hair, and eyes and hearing function in the cochlea. Therefore, hypopigmentation and hearing loss in Waardenburg syndrome type II are likely to be the results of an anomaly of melanocyte differentiation caused by MITF mutations. The molecular mechanism by which PAX3 mutations cause the auditory-pigmentary symptoms in type I and type III awaited explanation until Watanabe provided evidence that PAX3 directly regulates MITF. He suggested that the failure of this regulation due to PAX3 mutations causes the auditory-pigmentary symptoms in at least some individuals with type I.250 Because all these forms show marked variability even within families, at present it is not possible to predict severity, even when a mutation is detected. Clinical molecular testing, which entails direct DNA testing of PAX3, is available for Waardenburg type I, whereas only research studies are available for type II. Prenatal diagnosis by CVS or amniocentesis is possible when a specific mutation is known in advance. In the absence of molecular investigations, careful canthal and punctal measurements will help in the diagnosis. Family members may show different manifestations of the syndrome.
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ROLE OF THE OPHTHALMOLOGIST
The management of Waardenburg syndrome consists of early detection and treatment of deafness and significant ocular anomalies. Intelligence of patients is normal, and lifespan is unaffected except possibly for type IV. At present there are diagnostic molecular tests for type I and research tests for type II; therefore, the diagnosis remains, for the most part, a clinical one in which careful canthal and punctal measurements will help in the diagnosis. Family members may show different manifestations of the syndrome.
CHARGE ASSOCIATION
An association is a nonrandom collection of malformations that are not recognized as a clearly defined syndrome but that occur together more frequently than would be expected by chance. A number of chromosomal anomalies have been reported in patients manifesting many of the characteristic findings of CHARGE association; this makes the terminology confusing, and perhaps these cases should be referred to as CHARGE syndrome. Hall94 and Hittner et al.106 had noted certain malformations that seemed to occur together. In 1981, Pagon et al.180 suggested the mnemonic CHARGE to designate a certain heterogeneous group of anomalies (coloboma; heart defects; choanal atresia; retarded growth; development or central nervous anomalies; genital hypoplasia; and ear malformations or deafness) that may result from abnormal migration or interaction of cephalic neural crest cells.214,248
Ascertainment bias will affect the percentage of each anomaly in any series, but colobomas is one of the more common findings, perhaps because it is often one of the most conspicuous malformations and is noted early in infancy. Colobomas has been reported to occur in a high percentage (75%–95%) of cases in many series. The presence of three or four characteristics (CHARGE) in a patient with no other recognizable syndrome suggests the CHARGE association. Consideration of this diagnosis will remind the physician to carefully evaluate other systems.
SYSTEMIC FINDINGS
The most common systemic findings are heart defects (85%) (septal and other types), choanal atresia (79%) (unilateral or
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bilateral), retarded development or central nervous system anomalies (100%) (e.g., mental retardation, encephaly, microcephaly, and other structural abnormalities), genital hypoplasia (34%) (usually in boys), and ear anomalies (91%) (small or malformed external ears or sensorineural deafness) (62%). Many other systemic anomalies have also been reported, including microphthalmia, cleft palate, facial palsy, and swallowing difficulties.85,180 Autism has been noted in a few cases69 (Miller and Strömland, personal observation).
OCULAR FINDINGS
The typical colobomas may involve the iris, choroid, or optic nerve, and may be asymmetrical or unilateral, and associated with varying degrees of microphthalmia.29,106,207 High myopia or hyperopic refractive errors and nerve palsies have been noted.106 Strabismus, nystagmus, and amblyopia may be associated findings, possibly often secondary to asymmetry of involvement, although it is possible in cases of strabismus and nystagmus that the etiology may be central nervous system pathological changes.
GENETICS
Most cases are sporadic, but affected families have been described with suggested autosomal dominant or recessive modes of inheritance.53,85,106,180 Chromosomal anomalies have also been described multiple times, but no consistent locus has emerged. Recurrence risk is low. In a review of 47 cases, Tellier et al.230 noted a significantly higher mean paternal age at conception, which, together with concordance in monozygotic twins and the existence of rare familial cases, supported the role of genetic factors such as de novo dominant mutation or subtle submicroscopic deletion or chromosome rearrangement.
DEFORMATION SYNDROMES
Congenital deformations resulting from intrauterine restraint are common, usually disappear, and rarely have long-term consequences. They occur in about 2% of infants and may involve craniofacial structures. Congenital torticollis is one of the possible resultant deformations with an ophthalmologic implication, as it may suggest congenital superior oblique muscle palsy.
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Torticollis may result from plagiocephaly with mechanical effects on ocular motility (described earlier). Occasionally, fetal head constraint may cause craniosynostosis, particularly of sagittal, corneal, or metopic sutures.85
Deformations due to an abnormal uterine environment (e.g., breech or restricted area with a twin) may not cause significant increase in subsequent pregnancies unless the underlying problem continues. Deformational plagiocephaly is frequently a late gestational or postnatal deformity, but the important differential diagnosis is craniosynostosis because the treatment of these different etiologies is important.
DISRUPTION SYNDROMES
Disruptions are breakdowns or interference in an originally normal development. One cause of disruption anomalies could be disturbance of the vascular supply of the embryo in an area destined to form craniofacial sutures. Another cause is aberrant bands from premature amniotic rupture (see following).
RECURRENCE RISK
The recurrence risk for disruption-type anomalies is low because most are chance occurrences.
AMNIOTIC BAND SYNDROME (AMNIOTIC RUPTURE SEQUENCE, ADAM COMPLEX, STREETER BANDS)
Premature amniotic rupture of the sac, resulting in amniotic bands, may produce deformities, disruptions (breakdown in normal development), and malformations.81,153,179,235 These aberrant bands can produce severely malformed structures.
The collection of fetal malformations resulting from the entanglement or attachment of amniotic remnants following rupture of the amniotic sac is referred to as the amniotic band syndrome (ABS), among other names (listed in heading). The diagnosis is frequently difficult to make because of the wide spectrum of potential deformities that might be produced depending on the number and location of the bands and the timing of their formation.
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Amniotic bands have been noted in 2% of malformed infants, and are estimated to occur at a frequency of 1 in 10,000 live births,8 but may be more common in abortuses.85 With few exceptions of possible familial occurrence and relation to amniocentesis, most cases appear to be sporadic and thus recurrence risk is very low. The sex distribution is usually equal, although male predominance has been reported. Amniotic bands have been proposed to be an occasional cause of isolated lid and ocular defects, but this relationship is difficult to establish unless other characteristic systemic anomalies are also present or if actual bands are visible at the time of birth (a rare occurrence).
Modern techniques in ultrasonography and the subsequent utilization of this procedure in many pregnancies have resulted in reports of intraamniotic membranes in a number of patients, even though the procedure was performed for routine indications in cases with no identifiable risk factors. Some infants were found to have malformations consistent with amniotic band syndrome at the time of birth, but other infants with these unusual sonographic findings were found to be normal at birth, which has raised the question of occurrence of “innocent” amniotic bands. Herbert et al.99 reported one case in which intraamniotic strandlike structures were observed on ultrasonography that were later found on the placenta at time of delivery.
SYSTEMIC FINDINGS
The anomalies are rarely alike in affected individuals, but there is often a pattern of malformations that include one or more of the following: (1) facial clefts that do not conform to normal embryologic patterns; (2) skull defects, including asymmetrical encephaloceles; (3) constrictive anomalies of limbs, which in their most severe forms may cause amputations; (4) umbilical cord abnormalities; (5) compression-related defects; and (6) visceral malformations. A variety of infrequent findings have also been reported in the literature.105,153,155,179,235
OCULAR FINDINGS
Observed ocular anomalies include lid colobomas (frequently with adjacent corneal opacities) and contiguous facial clefts, hypertelorism, palpebral fissure changes, microphthalmia or
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FIGURE 4-17. Amniotic band syndrome: note facial clefts and skin indentation (secondary to intrauterine bands) involving face and lids, causing secondary corneal opacity. Child has typical ring constriction and amputation anomalies of hands and feet caused by bands.
anophthalmia, and strabismus19,24,153 (Fig. 4-17). A unilateral coloboma of the globe, perhaps the most interesting finding, has been reported occasionally.18,156,236 A lacuna-type defect of the retina has been reported in patients with ABS.98
PATHOGENESIS
Malformations may result from distortion and cleavage of formed structures or interference of normal embryologic development. The cause of the eye malformation often appears to be consistent with the proposed mechanism of action of the bands. Corneal leukomas are usually located adjacent to lid defects and facial clefts. In some cases, a fissure in the skin, similar to the constriction defects in the extremities, was noted next to lid or corneal defects. When distortion is severe in the involved orbital area, microphthalmos or anophthalmia may result.
GENETICS
Some cases are possibly autosomal recessive, but for the majority the cause for amnion disruption remains unknown.
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PSYCHOSOCIAL CONSIDERATIONS
Craniofacial malformations may occur alone, coupled with facial malformations, or part of a broader pattern of malformations. In any of these instances, the psychosocial impact for the family can be considerable. The birth of a dysmorphic or malformed infant often precipitates a major family crisis that can disrupt the usual pathways for parent–infant bonding. Parental reaction and adjustment depend on many factors including cultural background, social factors, attitudes, and established coping patterns.
Generally parents with malformed infants go through an identifiable sequence of complex emotional reactions, although the amount of time required to work through the problems of each stage varies. The initial period is usually one of overwhelming shock. Some parents do not react with shock, but tend to intellectualize the problem and focus on the facts relating to their infant’s condition. A second stage of disbelief follows, in which most parents practice denial, the intensity of which varies considerably. Feelings of sadness and anger follow the stage of disbelief. A gradual lessening of sadness, anger, and anxiety gives way to a new stage of equilibrium in which the parents become increasingly comfortable with their situation and develop confidence in their ability to care for their infant. This new equilibrium takes a variable amount of time to reach. During the period leading up to it, parents deal with the responsibility for their child’s problems and achieve an adequate adaptation. Some parents may remain in a state of chronic sorrow for a protracted period of time.
Parents attach great importance to the approach and the general attitude of family, friends, and the medical and nursing staff. Kindness, sensitivity, and empathy make deep and lasting impressions. Parents often have little or no experience with their child’s diagnosis, and may feel extremely isolated, as if they are the only ones to have a child with this particular condition. It can be extremely helpful to provide the family with resources through which they can network with other families. This assistance is helpful in “demystifying” the condition, and talking to other parents helps provide emotional support in addition to offering a venue for exchange of practical information. A parent who has had to grapple with a similar circumstance can provide critical validation of another parent’s feelings. Following is a list of national and international resources that typically provide networking services; disorder-specific information written for
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families; newsletters which address a myriad of topics including medical management issues and recent advances in medical research; and listings of local and national meetings and educational conferences, to name a few. It can be useful for families to contact one or several organizations to be placed on their mailing list, as this is an easy way for families to stay informed of any research advances or relevant studies.
•AboutFace International
123 Edward Street, Suite 1003 Toronto, Ontario
M5G 1E2 Canada Phone: 800-665-FACE
Email: info@aboutfaceinternational.org Web: www.aboutfaceinternational.org
•American Cleft Palate-Craniofacial Association 104 South Estes Drive, Suite 204
Chapel Hill, NC 27514 Phone: 919-933-9044 Fax: 919-933-9604 Email: cleftline@aol.com Web: www.cleftline.org
•Australian Cranio-Facial Unit Women’s and Children’s Hospital 72 King William Road
North Adelaide, SA 5006 Australia
Phone: 61-8-82047235 Fax: 61-8-82047080
Email: dstone@wch.sa.gov.au Web: www.wch.sa.gov.au/acfu
•Children’s Craniofacial Association P.O. Box 280297
Dallas, TX 75243-4522
Phone: 800-535-3643; 972-994-9902 Fax: 972-240-7607
Email: DNKM90A@prodigy.com Web: www.masterlink.com/children
•Crouzon Support Network P.O. Box 1272
Edmonds, WA 98020 Email: penny@crouzon.org Web: www.crouzon.org
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•Let’s Face It P.O. Box 29972
Bellingham, WA 98228-1972 Phone: 360-676-7325
Email: letsfaceit@faceit.org Web: www.faceit.org
CONCLUSIONS
With identification of more human genes involved with various malformations or malformation syndromes, more information about DNA and protein interactions will emerge from genetic and biochemical experimentation. Additional extracellular components, such as hormones, growth factors, and cytokines that modulate skull development, will also undoubtedly be discovered, yielding a wealth of contributing factors to study.
Acknowledgments. This work was supported in part by core grant EY 1792 from the National Eye Institute, Bethesda,
Maryland, by an unrestricted research grant from Research to Prevent Blindness, Inc., New York, New York, and by the Lions of Illinois Foundation, Maywood, Illinois.
References
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4.Aleksic S, Budzilovich G, Choy A, et al. Congenital ophthalmoplegia in oculoauriculovertebral dysplasia: hemifacial microsomia (Goldenhar–Gorlin syndrome). Neurology 1979;26:638–644.
5.Aleksic S, Budzilovich G, Greco MA, et al. Intracranial lipomas, hydrocephalus and other CNS anomalies in oculoauriculo-vertebral dysplasia (Goldenhar–Gorlin syndrome). Child’s Brain 1984;11:285– 297.
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