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

B

FIGURE 4-14B. (continued).

of problems with upper airway obstruction in HSS, particularly in the neonatal period and in infancy. Obstruction may result from small nares and glossoptosis secondary to micrognathia and these may lead to cor pulmonale. Other low-incidence anomalies have also been reported.

OCULAR FINDINGS

Although Hallermann–Streiff syndrome is rare, most affected individuals require ophthalmologic care throughout their lives because of the severity and frequency of ocular findings, the most common of which is congenital cataracts, occurring in 80% to 90% of cases.22 One unusual characteristic of these cataracts is that they often spontaneously resorb.14,187,259 Microphthalmia is also a common finding (78%–83%). Nystag-

mus and strabismus are frequently seen as would be expected, many times secondary to ocular defects. Visual acuity is frequently reduced because of the ocular malformation, but glaucoma may be primary or secondary.108 Other ocular conditions reported in more than 10% of cases are uveitis, blue sclera, sparse eyebrows and eyelashes, fundus anomalies, downslanted palpebral fissures, iris atrophy, and congenital and corneal anomalies.12 Many other anomalies have been noted with low frequency.210

PATHOGENESIS

The pathophysiology of Hallermann–Streiff syndrome is unknown. François74 demonstrated connective tissue changes in elastin and postulated a primary disturbance in the metabolism of glycoproteins.

GENETICS

Almost all cases are sporadic, making the risk of recurrence very low. There are a few exceptions in the literature, such as occasional reports of an associated chromosomal anomaly28 and a few atypical cases with familial involvement.123 Some authors argue for autosomal dominant transmission with de novo mutation.22 Cohen34 gave a long review in which he pointed out that all cases have been sporadic; that the disorder has been both concordant and discordant in monozygotic twins; and that an affected female with two normal children was reported by Ponte.187 Cohen stated: “I cannot accept any of the familial cases recorded to date.”

ROLE OF THE OPHTHALMOLOGIST

Ophthalmologic consultation should be obtained immediately after diagnosis, and these patients should be monitored for the rest of their lives.206 If the cataracts are advanced, early surgery may be indicated, followed by appropriate optical correction and amblyopia therapy, if indicated. Because the eyes are microphthalmic and surgery is frequently performed when patients are young, early insertion of intraocular lenses would be very risky. The frequency of secondary or primary glaucoma necessitates close monitoring of intraocular pressure. Other ocular findings (e.g., strabismus, uveitis, and nystagmus) should be treated as usual.

MÖBIUS SEQUENCE

Möbius syndrome/sequence is known to ophthalmologists because of the apparent combination of facial palsy (seventh nerve) and abducens palsy (sixth nerve) with or without limb or other systemic anomalies. This description, although frequently found in textbooks, oversimplifies the ocular motility findings and implies a well-defined syndrome, which is not the case.

The association of cranial nerve palsies with craniofacial and limb malformations is well recognized in the literature, occurring in a number of syndromes, although the differentiation between many of these syndromes is not distinct. Recognizing the overlapping of these entities, Hall96 grouped them under the collective heading of “oromandibular limb hypogenesis syndromes” (OMLH), and included Möbius syndrome and other conditions Observed limb anomalies range from mild changes, such as syndactyly of digits, to amputation defects of the limb.85,204 Because the proximal limb structures are characteristically normal or near normal, Temtamy and McKusick231 referred to this group of syndromes as “terminal transverse defects with orofacial malformations” (TTV-OFM). The term sequence is preferred because multiple etiologies appear to cause the embryologic developmental error.

SYSTEMIC ANOMALIES

The severity of limb deformities, especially involving the feet, are believed by some231 to be somewhat specific. The craniofacial anomalies vary greatly and include micrognathia, tongue malformations, facial and oral clefts, oligodontia, and paresis of other cranial nerves. Cranial nerve palsies may occur in any of these entities but become the distinguishing criteria for Möbius sequence (Fig. 4-15). Although the associations of restricted horizontal movements of the eye and facial nerve palsy had been noted in the late 1800s, Möbius164,165 created a separate diagnostic entity, which ultimately bore his name.

Facial nerve paresis and abduction deficiency are usually bilateral, but unilateral involvement has also been reported. Asymmetry, especially of the facial nerve paresis, is often noted. Systemic findings are common, and it is the patients with severe systemic findings and cranial nerve palsies in whom syndrome delineation is confusing and frequently somewhat arbitrary. Deficiency of the sternal head of the pectoralis major muscle

FIGURE 4-15. Möbius syndrome: note masklike facies. Patient also has marked limitation of abduction and Poland syndrome (deficiency in sternal head of pectoralis major plus ipsilateral hand anomaly).

(Poland anomaly), at times associated with an ipsilateral hand deformity (Poland syndrome), is another interesting malformation that has been reported in a number of cases but most frequently occurs in patients with Möbius-like syndromes.

Autosomal spectrum disorder (ASD) was reported previously by Gillberg and Steffenburg79 and has been reaffirmed in a multidiscipline study.112,162.

OCULAR FINDINGS

Sixth nerve paresis is the classic description of the major strabismus finding in Möbius sequence, but a closer look at the motility description in many patients shows variable horizontal limitations of movement with occasional vertical involvement.

Miller et al.161 and Miller and Strömland162 described various patterns of strabismus. (1) Bilateral limitation of abduction with no observable fissure change or significant limitation of adduc-

tion. This type represents the patients with classic Möbius syndrome described in the literature. Esotropia may be present in the primary position. (2) Bilateral marked limitation of both abduction and adduction. These patients appear to have a horizontal gaze paresis, and a subset of patients will demonstrate greater adduction on convergence than on horizontal versions.104,162,220 There may be no ocular motility deviation in the primary position. Changes in fissures are difficult to assess due to limited horizontal movement. A number of patients described in the literature as having a sixth nerve palsy and partial third nerve palsy with normal vertical movements seem to fit better in this group of apparent gaze palsy patterns, because a partial third nerve palsy involving only the medial recti seems improbable. (3) Bilateral limitation of abduction, limitation of adduction, and retraction on adduction (Duane type). The clinical ocular motility pattern of a few patients clearly resembled that of a typical patient designated as having Duane’s syndrome. (4) Asymmetrical or unilateral ocular motility disturbances. This pattern was noted in a very small number of cases in the literature. (5) Both horizontal and significant vertical limitation of movement. This finding was also uncommon. The motility disturbances were frequently bizarre and asymmetrical, resembling more of a congenital fibrosis pattern than cranial nerve palsies, although some cases in the literature are mentioned as demonstrating involvement of both third and sixth cranial nerves.220,258 A few patients have been described in the literature as showing complete ophthalmoplegia, and they may be similar to our group number 5.134 Other ocular malformations are rare, although coloboma, heterochromia cyclitis, and nystagmus have been

reported.49,77,110,231

PATHOGENESIS

Most cases of Möbius sequence have no known cause, although two known teratogens (misoprostol, thalidomide) have been associated with some cases. One concept101,231 is that these conditions fall into a formal genesis syndrome, “i.e., syndromes that have similar mechanisms of production of anomalies but are etiologically heterogeneous.”178

Vascular disruption has been proposed as another mechanism for the production of the constellation of malformations seen in the Möbius sequence.16,55,139 The cause of these vascular interruptions may be multiple: environmental, genetic, or local

accidents in development, but the final result is ischemia, edema, and hypoxia to the embryonic tissues or cranial nerve nuclei supplied by that vessel. Hyperthermia has been implicated in a few cases.81 The vascular disruption theory has been strengthened by some of the pathological findings at autopsy234,257 and on imaging studies.129,260 There is some evidence that there is a zone of vulnerability in the developing brainstem.136

Abbott et al.1 reported eight cases of Möbius syndrome with a marked decrease of horizontal saccades with limited abduction and adduction. Abnormal innervation has occasionally been suggested as a possible etiology for this set of clinical findings.103,161 The use of the abortifacient drug misoprostol in early pregnancy has been associated with children having characteristics of Möbius sequence when abortion attempt has been unsuc-

cessful after an attempted self-induced abortion.70,83,84

GENETICS

Although instances of occasional families showing autosomal recessive or dominant inheritance have been described, many of these families may represent other entities. Most cases of Möbius syndrome appear to occur sporadically.85 Unless a positive family history exists, the recurrence risk has been estimated by Baraister10 to be about 2%. To date, three Möbius syndrome loci have been mapped: MSB1 to 13q12.2–q13, MSB2 to 3q21–q22, and MSB3 to 10q21.3–q22.1. Therefore, in familial cases, linkage studies are possible.127,216,242,261

ROLE OF THE OPHTHALMOLOGIST

The ophthalmologic symptoms are primarily related to strabismus and occasionally to corneal exposure due to the seventh nerve paresis. Because these patients have multiple systemic problems, they should not be on the same therapeutic timetable as the child with typical comitant congenital esotropia without other malformations. Epicanthus and facial configuration may accentuate a relatively small-angle squint. The esotropia may improve with age. Patients with marked limitation of abduction and adduction frequently have little deviation in the primary position of gaze, thus requiring no surgical intervention for strabismus. Further weakening of the medial recti (if there is associated limitation of adduction) should be approached with caution. If a large esotropia exists in the primary position, medial

rectus recessions and recess-resect surgeries have reportedly improved the cosmetic appearance in the primary position in some patients.1,202

WILDERVANCK SYNDROME (CERVICO- OCULO-ACOUSTIC SYNDROME)

Wildervanck255 noted the combination of hearing loss, Klippel–Feil deformity, and an eye motility disturbance (Duane’s retraction syndrome) in a case report. He further described the triad in 1960 in a group of 21 patients and called this combination of findings the cervico-oculo-acoustic syndrome.254

SYSTEMIC FINDINGS

The first characteristic of the triad noted in Wildervanck syndrome is hearing loss, usually secondary to a congenital inner ear anomaly, although mixed forms have been described.50 Regular and computed tomography of otologic structures have demonstrated frequent abnormalities of the middle ear structures and semicircular canals.66,212,256 The hearing loss is primarily bilateral, but unilateral cases occur.66

The secondary characteristic of the triad is Klippel–Feil anomaly of the spine consisting of fusion of one or more cervical (occasionally thoracic) vertebrae, resulting in a short webbed neck (Fig. 4-16). Movement is restricted in all directions. Other spinal anomalies have also been described.56,75 There may be asymmetry of the face and other low-incidence anomalies.75 This syndrome (at least profound childhood deafness and Klippel–Feil malformation) may be responsible for at least 1% of deafness among females.

OCULAR FINDINGS

The third characteristic of the triad is Duane’s syndrome, either bilateral or unilateral, with a spectrum of horizontal limitation patterns.154,196

Epibulbar dermoids have been noted in a number of cases121 and low-incidence anomalies such as subluxation of lens223 and pseudopapilledema120 have been reported. Paradoxical lacrimation, Klippel–Feil anomaly, and Duane’s syndrome have been reported together.25

A

FIGURE 4-16A,B. Wildervanck syndrome: patient has short, webbed neck due to Klippel–Feil anomaly of spine. Additionally, she has a bilateral neurosensory deafness and unilateral Duane syndrome. (A) Frontal view. (B) Side view.

PATHOGENESIS

The developmental defect causing Wildervanck syndrome is unknown. Although this syndrome has certain distinct characteristics (female preponderance, familial pattern), there is considerable overlap with other conditions. In the Fraser and MacGillivray75 review of the literature, dermoids were noted in four cases. The authors concluded that intermediate forms exist between cervico-oculo-acoustic syndrome and other first-arch

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FIGURE 4-16B. (continued).

conditions such as Goldenhar’s syndrome. However, the familial pattern and strong preponderance of females in Wildervanck syndrome are significantly different findings from those of hemifacial microsomia.

The early effects of thalidomide intake (days 21 to 25 of gestation) produce a high incidence of Duane’s syndrome with external or internal ear anomalies, paradoxical lacrimation, facial nerve palsy, and a few lipodermoids; all findings are reported also in Wildervanck syndrome, which suggests that the timing of the developmental insult is an important factor in producing this group of malformations.155 In thalidomide embry-

opathy, spinal anomalies are not as prominent as in Wildervanck and Goldenhar syndromes.

GENETICS

Genetic counseling is difficult because of the confusion about the inheritance pattern. Although the frequency of the isolated forms of Duane’s syndrome is higher in females (60%–70%), there is an almost complete predominance of females in Wildervanck syndrome, leading some authors to suggest an X-linked dominant inheritance with lethality in males. Often patients manifest only part of the syndrome, and Kirkham122 postulated autosomal dominant inheritance with incomplete penetrance and variable expressivity with partial sex limitation. He reviewed 112 cases of Duane syndrome and noted 12 cases with perceptive deafness, 5 with Klippel–Feil anomaly, and only 2 with the complete triad. Wildervanck255 also observed variable expressivity of this syndrome and suggested that only two characteristics of the triad are needed to make the diagnosis. Interestingly, 1 patient in his original report had epibulbar dermoids. Wildervanck, in an extensive 1978 review of the subject, concluded that polygenic inheritance with limitation to females is most likely.254

WAARDENBURG SYNDROME (KLEIN–WAARDENBURG SYNDROME)

A detailed description was given by Waardenburg245 of a previously described syndrome characterized by developmental anomalies of the eyelids, nasal root, and eyebrows, along with other findings of heterochromia iridis, white forelock, and sensorineural deafness. On the basis of clinical and genetic criteria, four types of Waardenburg syndrome are recognized. The primary differentiating aspect is the presence (type I) or absence (type II) of the lateral displacement of the medial canthus and lacrimal puncta.7 Waardenburg syndrome type III (Klein–Waar- denburg) is similar to type I, but is also characterized by musculoskelatal anomalies (an ortho-osteomyomo dysplasia of the upper limbs, or with abnormalities of the arms). Waardenburg type IV (Shah–Waardenburg syndrome) is the association of Waardenburg syndrome with congenital aganglionic megacolon (Hirschsprung disease).65