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

cysts have been reported in siblings.51 Oral anomalies include a cleft lip and pseudocleft lip, lip pits, and cleft palate. The ears are typically low set and posteriorly rotated. Dolichocephaly has been noted, as well as premature graying of the hair. The differential diagnosis for this disorder includes Treacher Collins, branchio-oculo-renal syndrome, CHARGE association, Van der Woude’s syndrome, Goltz–Gorlin syndrome, and Delleman syndrome.

Inheritance

An autosomal dominant inheritance has been reported, although most reported cases have been sporadic.55,107 Although branchio- oculo-facial syndrome (BOF) and branchio-oto-renal syndrome (BOR) are thought to be distinct syndromes,116 one father–son pair has been reported,108 and we have observed a child with microphthalmia, a feature “distinctive” for BOF, but without the distinctive skin findings of BOF (Fig. 8-3).

CHARGE ASSOCIATION SYNDROME

The acronym CHARGE proposed by Pagon et al.146 refers to a nonrandom clustering of malformations first described by Hall,68 including ocular coloboma, heart malformation, atresia of choanae, retarded growth and development and/or central nervous system malformations, genital hypoplasia and/or hypogonadism, and ear abnormalities and/or deafness. In addition, facial palsy, esophageal and laryngeal abnormalities, renal malformations, and facial clefts have been observed with higher frequency in patients with CHARGE association.46,68,184

Etiology

The cause and exact prevalence of the CHARGE association remains unknown (Fig. 8-4A,B).68 However, the combination of malformations observed in CHARGE association strongly evokes a polytopic developmental field defect involving the neural crest cells. The total clinical spectrum of CHARGE association is still waiting to be determined.

Clinical Features and Systemic Associations

Colobomas found in the CHARGE association are indistinguishable from colobomas found in other genetic diseases (Fig. 8-4B). They range from iris colobomas and small choroidal colobomas with no visual impairments to colobomas with severe micropthalmos and poor to no vision. In the original report of CHARGE association by Roberta Pagon and associates,146 the severity of the coloboma or visual impairment did not correlate with the severity of the other CNS anamolies and developmental delay. A review of 180 cases of CHARGE from the literature71 documented ocular colobomas in 81.7% of cases. A majority of these were posterior colobomas of the choroid and/or optic nerve. When iris colobomas were present, they were usually accompanied by choroidal and optic nerve colobomas.162 Colobomas are typically bilateral, but can be quite asymmetrical (personal observation). The large number of posterior colobomas highlights the need for careful dilated fundus examination in any child suspected of having CHARGE association, even when there is no outward sign of poor vision or eye malformation. The differential of bilateral colobomas includes an autosomal recessive isolated genetic disease, as well as trisomy 13, cat-eye syndrome, and 4p syndrome (Wolf–Hirschorn syndrome).

Microphthalmia was observed in 49 of 129 cases reviewed.71 Other ocular abnormalities reported include optic nerve hypoplasia,162 persistent hypoplastic primary vitreous (PHPV), lacrimal canalicular atresia,11 congenital glaucoma due to maldevelopment of the anterior chamber angle,192 eyelid coloboma,162 and bilateral Marcus-Gunn jaw winking phenomenon.201

Congenital heart defects were found in 85% of patients with CHARGE association in one large study.184 There are conflicting data in the literature with regard to the frequency of specific cardiac malformations in CHARGE association. Tellier et al.184 found that the most common malformations were atrial and ventricular septal defects, followed by patent ductus arteriosus (PDA), conotruncal heart defects, and outflow anomalies. Aortic arch anomalies were rare. However, another review reported that the most common malformations were conotruncal anomalies followed by aortic arch anomalies,114 a pattern similar to DiGeorge sequence.

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Choanal atresia is present in about 58% of the patients with CHARGE association. The atresia is unilateral or bilateral, and both bony and membranous.89

Growth deficiency is usually postnatal and affects all the body in a symmetrical fashion. Head circumference is proportional to length.146,184 Growth hormone deficiency has been reported in a few patients.184 Growth deficiency couples with failure to gain weight. The linear growth and weight curve of patients with CHARGE association usually shifts below the 3rd percentile during the first 6 to 9 months of age.146

Mental development is affected in most patients with CHARGE association. Mental retardation may range from mild to profound.89 Axial hypotonia was found to be common (93%) in one large study.114 In an extensive review, Lin et al.117 found CNS malformations to be common in CHARGE association. These malformations may be due to aberrant development, migration, or interaction of the cephalic neural crest.199 The following CNS malformations have been noted in patients with CHARGE association: holoprosencephaly, arhinencephalia, agenesis of corpus callosum and septum pellucidum, various forebrain and hindbrain defects, and various cranial nerve palsies (VI, VII, VIII, IX, and X).117,184

Genital hypoplasia is more prone to be recognized and reported in males than females. Hypogonadism in males with CHARGE association include micropenis, cryptorchidism, and rarely hypospadius. Central gonadotropin deficiency may account for some of these abnormalities.184

Characteristically, ear malformations in the CHARGE association include asymmetry and ears that are short, wide, and low set with small or absent lobes, ear tags, and malformed pinnae.40 Asymmetrical or bilateral hearing loss is present in more than two-thirds of patients with CHARGE association. Both middle ear anomalies (ossicular malformation) and internal ear anomalies (semicircular canal hypoplasia) are common. Deafness can be mild to profound, sensorineural, or mixed sensorineural and conductive, and may progress over time.41

Other systemic findings include skeletal and GI anomalies. Skeletal anomalies of the vertebrae and ribs have been found in about one-half of patients with CHARGE association. Intestinal malformations include esophageal atresia, tracheoesophageal fistula, renal anomalies, velopharyngeal incompetence, and DiGeorge sequence.184 On prenatal echography, the combination

of intrauterine growth retardation, CNS anomalies, congenital heart disease, esophageal atresia, and renal anomalies may raise a suspicion for CHARGE association. These signs, however, could be observed in several other multiple congenital anomaly syndromes, such as VATER association.

Inheritance

The CHARGE association is usually a sporadic event of unknown cause.170 However, some affected patients have had abnormal chromosomes, including a microdeletion of 22q11 (DiGeorge sequence). Because CHARGE association shares phenotypic features with recognized chromosomal syndromes such as trisomy 13, the cat-eye syndrome, and the 4p syndrome, molecular and chromosome analysis should be performed in all patients with CHARGE association.29

Prognosis

Although the prognosis of CHARGE patients is poor, the clinical spectrum of this condition is variable. The presence of midline anomalies and esophageal and bilateral choanal atresia are frequently combined and carry a poor prognosis.100,117 Severe phenotypic expression of CHARGE association in males has been noted in one large study.184

COCKAYNE’S SYNDROME

In 1936, E.A. Cockayne described two children with dwarfism, retinal atrophy, and deafness.31 Cockayne’s syndrome (CS) is a rare autosomal recessive disorder with postnatal growth failure, characteristic facies, atypical retinopathy, deafness, mental deterioration, UV light sensitivity, and premature aging. CS is a progressive disorder with an underlying leukodystrophy.128

Etiology

A defect in DNA metabolism has been documented in fibroblasts of CS patients that involves increased sensitivity of cells to UV light, decreased RNA synthesis following UV exposure, and abnormal excision repair.17 The two genes involved in CS (CSI, CSII) are required for transcription-coupled repair (TCR),

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a subpathway of nucleotide excision repair. Alterations of these two genes are likely to be responsible for the two forms of CS.

Clinical Features

Pigmentary degeneration of the retina is one of the hallmarks of CS.31 The fundus findings described in the original monograph were markedly narrowed arterioles with sparing of the veins, an absent macular reflex, and blackish dots concentrated in the posterior pole. Since then, the most common and pervasive ophthalmic abnormality described has been pigmentary retinopathy, with 55% of the diagnosed children being affected.128 The pigmentary retinopathy is progressive, and normal fundus findings early in life may not exclude the diagnosis of Cockayne’s syndrome. Other ophthalmic abnormalities reported in Cockayne’s syndrome include decreased lacrimation, corneal infiltrates and opacities, band keratopathy, miotic pupils, iris hypoplasia, microphthalmos, cataracts, and optic atrophy or hypoplasia.128

Ocular pathology has been reported in one case.111 Lipofuscin deposition was noted in the retinal pigment epithelium. The outer segments of the photoreceptors disintegrated, with loss of cells from the ganglion cell and outer nuclear layers. Marked thinning of the nerve fiber bundles was noted over the optic nervehead, with both axonal loss and partial demyelination. In the cornea, there were pigment-laden macrophages.

Systemic Associations

Growth and development usually proceed at a normal rate in early infancy. Profound growth failure, however, begins after 2 years of age. Weight is more affected than length, which has led to the term cachectic dwarfism for describing CS patients128 (Fig. 8-5).

All patients with CS eventually develop neurological dysfunction, including the cerebellar signs of gait ataxia, tremor, incoordination and dysarthric speech, as well as peripheral neuropathy, autonomic dysfunction, and seizures.127,128 Almost all patients with CS over 2 years of age have microcephaly. Cerebral imaging may demonstrate cerebral atrophy with calcifications in various parts of the brain. Cerebral histopathology of patients with CS commonly demonstrates a patchy “tigroid”

FIGURE 8-5. Ten-year-old girl with Cockayne’s syndrome. Note the short stature, cachectic habitus, abnormal standing posture, flexion deformity of the joints, barrel-shaped chest deformity, deep-set eyes, and thin hair. (Courtesy of Dr. R.S. Wilroy, Memphis, TN.)

demyelination of the subcortical white matter with macroscopic and microscopic calcifications and neurofibrillary tangles.178,181 Despite their mental deficiencies, patients with CS are described as friendly, interactive, happy, and social.