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

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common brain tumor in AS.157 Various other tumors have been reported, including embryonal carcinoma, hepatoblastoma, teratoma of the soft palate, angiosarcoma, lipoma, and palatal hemangioma.47,103,120,172,182 Robinow et al. grouped AS with the genetic hamartoses,157 and other diseases with central nervous system hamartomas might be considered in the differential diagnosis (tuberous sclerosis, neurofibromatosis, and von Hippel–Lindau disease).

Numerous other congenital abnormalities have been described in AS, including cleft lip and palate, costovertebral and vertebral abnormalities, and facial and skull asymmetry.

Inheritance

It is assumed that Aicardi’s syndrome is an X-linked disease with fetal demise in affected males. All reported cases have been sporadic except one.15 AS has been reported in several ethnic groups. Chromosomes in all patients have been normal with the exception of a case with an unbalanced X-autosomal translocation involving a breakpoint near Xp22. Two additional cases have had microdeletion at the Xp22 position of the X chromosome. This finding, however, has not been confirmed in other AS patients to date.47,132

Monozygotic twins discordant for Aicardi’s syndrome have been reported, prompting supposition that the affected twin was probably the consequence of a postzygotic mutation in early embryonic development.37 X inactivation has been studied, and unlike other X-linked dominant mutations, appears to be random in Aicardi’s syndrome.75

Treatment

Symptomatic treatment of seizure disorders is indicated. ACTH appears to have the most beneficial effect in seizure control. In some cases, removal of the choroid plexus papillomas may also lead to significant improvement.157 Monitoring for ophthalmic sequelae of the disease, including retinal detachments from colobomas, refractive errors, and ophthalmic signs of CNS tumors, is indicated. Barring any associated structural abnormality interfering with vision, such as a macular chorioretinal lacuna, retinal detachment, anisometropia, or optic nerve coloboma, vision is usually normal. Although optic nerve atrophy has not been reported with this entity,123 hydrocephalus

secondary to choroid plexus papillomas has been reported180 and could predispose children with AS to progressive optic nerve atrophy.

Prognosis

The prognosis for children with AS is extremely poor, with severe developmental delay and little to no development of language, poor to no ambulatory ability, and a shortened lifespan. Intractable seizures are common. Death may occur within the first 5 years, usually from secondary respiratory infections, but patients may survive into their early teens.159

ALPORT’S SYNDROME

Alport’s syndrome (AS), the most common type of hereditary nephritis syndrome, was first described during the early 1900s.3 It affects 1 in 5000 individuals.52 In AS, the hereditary nephritis is accompanied by high-tone sensorineural deafness and distinctive ocular signs.

Etiology

Alport’s syndrome is caused by a genetic defect in the type IV collagen (COL4A3, COL4A4, COL4A5), which makes up the basement membranes in many body systems.6 Marked variability is seen in the clinical presentation, natural history, histopathological abnormalities, and genetic patterns among patients with AS.

Clinical Features and Systemic Associations

Patients most commonly present in early childhood with asymptomatic, miscroscopic hematuria and recurrent episodes of gross hematuria that progress to renal failure in adulthood. In connection with one of the infectious diseases of childhood or a common cold in early childhood or adolescence, the affected individual will suddenly develop massive hematuria and/or proteinuria, often accompanied by cylindruria and leukocyturia. These urinary signs may vary in degree during the following months, and in some patients they may almost disappear.

However, they may become more pronounced again during the

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next episode of infectious disease or physical strain. Hypertension may occur in affected individuals and worsen as renal function deteriorates.84 In the X-linked form of AS (XL-AS), affected females have less obvious urinary findings and rarely develop uremia, whereas in the autosomal forms (AD-AS, AR-AS) males and females are equally affected.

Kidney biopsies obtained during the first decade of life may show changes by light microscopy. Later, the glomeruli develop mesangial proliferation and capillary wall thickening, leading to progressive glomerular sclerosis. Tubular atrophy, interstitial inflammation and fibrosis, and “foam” cells develop if the disease progresses.

Hearing loss in patients with AS is progressive, symmetrical, and sensorineural. The degree of hearing loss varies from subtle to profound. The onset of hearing loss is usually before the age of 10 years and is more severe in males in XL-AS.8 The molecular composition of the basement membranes of the cochlea is specific, and changes in the component proteins can lead to sensorineural hearing loss. COL4A3, COL4A4, and COL4A5 are found in the basilar membrane parts of the spiral ligament and in the stria vascularis. Although the mechanism of hearing loss is not known, there is focal thinning and thickening in the glomerulus of the kidney with eventual basement membrane splitting. Extrapolating to the spiral sulcus of the ear, loss of integrity of the basement membrane might affect adhesion of the tectorial and basilar membrane and its junction with the spiral ligament, affecting translation of mechanical energy.36

The most common ophthalmic manifestations of Alport’s syndrome are bilateral anterior lenticonus and perimacular retinal flecks,65 reported in 24% to 37% of patients.66,147,149,185 They are more likely found in affected adults than children,186 presumably as a result of gradual accumulation of abnormal collagen.58

Anterior lenticonus is associated with Alport’s syndrome in more than 90% of cases.99 It is not present at birth, but appears during the second to third decade of life.63,86,101,183 Electron microscopy shows a thinned basal lamina with basement membrane disruptions.99,177 Spontaneous and traumatic ruptures of the anterior lens capsule have occurred.142,177 Anterior and posterior subcapsular cataracts have been reported as frequent findings in AS,63 but glucocorticoid medications are also commonly used by affected patients and may contribute to cataract formation.147 Posterior lenticonus has been reported to occur

infrequently in patients with anterior lenticonus and Alport’s syndrome.131

Perimacular yellow flecks are the most common retinal finding, presumably caused by a toxic effect to or primary degeneration of the retinal pigment epithelium or Bruch’s membrane.76 Reddish macular patches and loss of the foveal reflex have been described.147

Reports of electrophysiological studies have largely been normal,58,59,76,86,149,165 although abnormal electroretinography, electro-oculography, and/or fluorescein angiography have all been reported in affected patients.188

Corneal findings in AS include corneal arcus,63,147 posterior polymorphous dystrophy,76,183,185 and recurrent nontraumatic corneal erosions.18,153

Correlation between the type of mutation causing the disease and type or incidence of ocular finding has not been made,147,188 and variation of ocular findings within pedigrees is common.147

Other features described in AS include thrombocytopenia, macrothrombocytopathia, hypoparathyroidism, polyneuropathy, ichthyosis, and thyroid abnormalities.8

Inheritance

Seventy-five percent of cases are transmitted through X-linked dominant inheritance, although autosomal dominant (15%) and recessive (10%) inheritance patterns have also been reported.50 Accurate familial study is mandatory in patients with AS, as the identification of the different patterns of inheritance greatly affects genetic counseling.

The majority of AS patients have XL-AS, involving mutations in the COL4A5 gene located on the long arm of X chromosome (Xq22.3). Mutation of the COL4A3 and COL4A4 genes located on the long arm of chromosome 2 (2q36–2q37) causes AR-AS. Recently a dominant form of AS (AD-AS) was linked to the COL4A3/COL4A4 locus.193 Cochat et al. in 1988 described the association of diffuse leiomyomatosis with a subtype of XL-AS.30 Later, Zhou et al. in 1993 demonstrated that the leiomyomatosis-nephropathy syndrome represents a contiguous gene syndrome due to deletions that disrupt the COL4A5 and COL4A6 genes, two adjacent genes on the X chromosome.208 Although the diagnosis of AS still relies heavily on histological studies, routine application of molecular genetic diagnosis will probably be available in the near future.

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Treatment

There is no effective treatment for the glomerulonephritis. Peritoneal and hemodialysis may be necessary. Renal transplantation for AS is usually very successful. However, certain mutations within the type IV collagen genes carry an increased risk of developing specific antiglomerular basement membrane (anti-GBM) nephritis after renal transplantation. Anti-GBM nephritis of the allograft almost always results in graft loss.109,125

Prognosis

Dual sensory loss in AS patients creates an urgent need for appropriate vision and care and rehabilitation. Because of the high risk for developmental delay and decreased social integration, early intervention should be considered in the treatment plan. A multidisciplinary approach by the health care management team will enhance the quality of life and positive outcomes for AS patients.121

ALSTRÖM SYNDROME

A syndrome of retinal degeneration combined with obesity, diabetes mellitus, and sensorineural hearing loss was described in 1959 by C.H. Alström. It has since come to be known as a distinct syndrome, Alström syndrome.4 As of 1997, 37 definite cases had been reported in the literature.164

Etiology

The etiology of Alström syndrome is unknown.

Clinical Features

Presentation is typically of an infant or young child with profound vision loss and nystagmus. Severe photophobia and nystagmus are common by 4 months of age and almost uniformly present by 1 year of age. Although the fundus is typically normal at birth, a narrowing of the retinal vessels can be seen early on with patchy diffuse atrophy of the retinal pigment epithelium and/or increased pigment in the midperiphery and a macular sheen. There is typically no “bull’s-eye” maculopathy early on,

as is commonly seen in Bardet–Biedl syndrome.164 Also, bone spicule formation is not noted until the second or third decade. Posterior subcapsular cataracts have been reported in 100% of patients with Alström syndrome.168

Reported ophthalmic histopathological findings are consistent with diabetes, and include iris and ciliary body lacy vacuolization and asteriod hyalosis.168 No sign of chorioretinal fusion or optic nerve atrophy has been seen in patients with Alström syndrome, in contrast to patients with retinitis pigmentosa. Large, superficial optic nerve drusen were found. Histopathology was indistinguishable from that of other secondary or pseudoretinitis pigmentosa syndromes.168

ERG is absent or attenuated, with rod function better preserved than cone function until later in childhood, when all visual function is extinguished.187 This condition has created some confusion with Leber’s congenital amaurosis. RussellEggitt and associates previously reported seven patients with infantile cardiomyopathy and atypical Leber’s amaurosis in 1989,163 who were subsequently found to have Alström syndrome.104 The diagnosis of Alström syndrome should be considered in infantile cone and rod retinal dystrophy, particularly if the weight is above the 90th percentile, or if there is infantile cardiomyopathy.

Natural History

See Prognosis.

Systemic Associations

Infantile obesity, infantile cardiomyopathy, and hypogenitalism are typical. Sensorineural deafness is common by 7 years of age.164 Normal secondary sexual characteristics are found, although gynecomastia and reduced fertility are typically seen later on. Noninsulin-dependent diabetes mellitus (NIDDM) occurs in the second or third decades. Polydactyly and mental retardation, central features of Bardet–Biedel syndrome, are not seen in Alström syndrome.

Because of a potentially fatal infantile cardiomyopathy at 2 weeks to 7 months of age, infants suspected of having Alström syndrome should be referred for cardiac evaluation in an urgent fashion.164 Once the diagnosis is suspected, workup should begin for signs of renal or hepatic failure, hypothyroidism,

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growth hormone deficiency, hyperuricemia, hypercholesterolemia, hypertriglyceridemia, and kyphoscoliosis.

Inheritance

Alström syndrome probably has an autosomal-recessive pattern of inheritance. A large French Canadian kindred with an autosomal recessive pattern of inheritance has revealed a locus on 2p13, although a second locus may be associated with the Alström phenotype.35 A mouse model candidate has a defective gene on mouse chromosome 7, with homologous human region

11p15.135,136

Treatment

There is no known treatment for the vision loss secondary to Alström syndrome. Management of the endocrine, cardiac, and kidney disease is critical, although a shortened lifespan is expected.

Prognosis

There is a rapid and progressive loss of visual function to less than 20/200 by 10 years of age and to no light perception by 20 years of age. In the final stages of the disease, affected individuals exhibit progressive chronic nephropathy with eventual renal failure, which is the most frequent cause of death.62 The oldest surviving patient reported in the literature is 36 years of age.164

BRACHMANN–DE LANGE SYNDROME

Brachmann–de Lange syndrome (BDLS), often referred to as Cornelia de Lange syndrome or de Lange syndrome, is a phenotypically variable multisystem disorder involving congenital malformations, growth retardation, and neurodevelopmental delay. Although the first reported case in the literature was Brachmann’s in 1916, Cornelia de Lange in 1933 suggested that these manifestations comprised a new malformation syndrome.43,194 The incidence has been estimated at 1 in 10,000 live births, but is difficult to estimate because mild cases may go undiagnosed.64,139

Etiology

The etiology of BDLS is unknown.

Clinical Features

Brachmann–de Lange syndrome (BDLS) in its severe form is easily recognizable by the experienced examiner. The characteristic face, preand postnatal growth deficiency, feeding dysfunction, limb anomalies (when present), psychomotor delay, and distinctive behavioral pattern are diagnostic in a newborn or young infant.

Ocular features did not figure prominently in the original descriptions of BDLS. However, in 1990, Levin and associates reported a series of 22 children with BDLS detailing the ophthalmic findings.110 Of the 21 children in this series with available histories, 17 (81%) had required previous ophthalmic care, highlighting the importance of ophthalmic features in this disease. The most common ophthalmic feature in CDLS is hypertrichosis of the eyebrows and eyelashes with synophrys. The synophrys is typically in a “V” configuration over the nasal bridge. Other tendencies include antimongoloid slant, hypertelorism, ptosis, nystagmus, high myopia, strabismus, amblyopia, and photophobia. Absent upper lacrimal puncta and canaliculi have been reported with BDLS.196 A significant percentage of children with BDLS have a history of recurrent conjunctivitis, blepharitis, hordeola, and nasolacrimal duct obstructions. Treatment of high myopia and amblyopia with glasses and/or patching can prove difficult in patients with BDLS because of their defensive behavioral tendencies. Diagnostic examinations can also be challenging.

The facial features are perhaps the most diagnostic of all physical signs (Fig. 8-2). Microcephaly and brachycephaly, “penciled” eyebrows, synophrys, long eyelashes, anteverted nostrils, long philtrum, thin lips, crescent-shaped mouth, and widely spaced teeth are all typical features.83 Hypertrichosis, including generalized hirsutism, as well as a low posterior hairline, and hair tufts on the neck or lower back are common.

By far, the two most common areas of involvement in BDLS are the gastrointestinal (GI) tract and the heart. GI abnormalities include gastrointestinal (GE) reflux and various forms of obstructions. Persistent vomiting and feeding problems result in failure to thrive.194 Heart defects are widely variable from minor

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FIGURE 8-2. Five-year-old girl with Brachmann–de Lange syndrome. Note synophrys, epiphora secondary to nasolacrimal duct anomaly, short nose, anteverted nares, long philtrum, and thin upper lip. (Courtesy of Dr. J.C. Ward, Memphis, TN.)

to severe in their clinical consequences. Respiratory problems are usually limited to recurrent upper respiratory infections and pneumonias. Many respiratory difficulties are probably complicated or initiated by undetected GE reflux. Genitourinary anomalies are common in BDLS and include genital hypoplasia, hydronephrosis, and renal dysplasia or hypoplasia.54

Limb abnormalities usually associated with BDLS include oligodactyly or severe deficiencies of the arms. Relatively small hands and feet are frequently a striking feature.12

Significant speech delay has been noted in the majority of children with BDLS. The majority of the speech delay is attributed to hearing loss due to stenotic external auditory canals, and/or frequent ear infections.85

The BDLS has a range of severity from perinatal lethality with multiple congenital anomalies to almost imperceptible cases compatible with normal reproduction and normal intelligence.139 The majority of patients with BDLS have severe mental retardation, with IQs generally ranging from 30 to 50.88