Marfan’s syndrome

DEFINITION/OVERVIEW AND ETIOLOGY

This disorder was first described in France by A.B. Marfan in 1896.16 He described a family with four affected individuals with dolichostenomelia (very long extremities and bones). It was recognized as a connective tissue disorder in 1979,17 and the diagnostic criteria were published in 1996.18 Although it is now known to result from a mutation in the fibrillin (FBN1) gene,19 diagnosis remains clinical as this gene is large and most mutations are private. Fibrillin is a glycoprotein and is a major constituent of microfibrils and elastic fibers in the extracellular matrix.

The clinical diagnosis of Marfan’s syndrome requires criteria in at least two major systems (skeletal, ocular, cardiovascular, dura, or family history) and also the involvement of a third system (which can be major or minor and can also include pulmonary and skin findings). Affected individuals tend to have tall stature with long, thin extremities with scoliosis being a common complication (244). Major skeletal findings may include pectus carinatum, pectus excavatum requiring surgery, reduced upper segment to lower segment ratio or arm span to height ratio of >1.05, wrist and thumb signs, scoliosis >20° degrees or spondylolistesis, elbow extension of <170°, pes planus, or protusio acetabulae. Minor skeletal findings may include moderate pectus excavatum, joint hypermobility, a high arched palate with crowded teeth, and a characteristic facial appearance (dolichocephaly, malar hypoplasia, downslanting palpebral fissures, and enophthalmos). Ocular findings are discussed below. Cardiovascular findings may include a dilated ascending aorta, dissection of the ascending aorta, mitral valve prolapse, dilatation of the main pulmonary artery or descending aorta (which is unrelated to age), or calcification of the mitral annulus (which is also unrelated to age). Pulmonary findings that can be used to support the diagnosis include spontaneous pneumonthorax and/or apical blebs. Minor skin findings include striae atrophicae or recurrent and incisional hernias. Lumbosacral dural ectasia is considered a major criterion and a first-degree relative of the diagnosis.

The major cause of death is related to vascular complications and can occur at any age. The rate of cardiac complications has been reduced with the introduction of treatment with beta blockers. Health supervision guidelines have been established by the American Academy of Pediatrics.19

Marfan’s syndrome is inherited in an autosomal dominant (AD) manner. The fibrillin gene is located on chromosome 15. Again, although the gene has been identified, diagnosis is usually based on specific diagnostic criteria.18

CLINICAL PRESENTATION

The most characteristic ocular feature of Marfan’s syndrome is ectopia lentis (lens subluxation), which occurs in 60% of patients.20 The FBN1 fibrillin gene on chromosome 15 is defective. Fibrillin is a major component in multiple parts of the eye, including the lens zonules and lens capsule. These structures give support to the lens and also maintain its position behind the pupil and in front of the vitreous. Fibrillin fibers in the zonules and lens capsule are

abnormal, allowing for movement and subluxation of the lens.21–23 The defective

fibrillin is more prone to degradation by matrix metalloproteinases (MMPs) or proteolytic enzymes, which are present in the aqueous humor of the eye.24 Subluxation of the lens most commonly occurs superiorly and posteriorly (245). As subluxation increases, the lens can position itself such that the bottom edge straddles the visual axis. This location is most disturbing to the patient because looking through the superior aspect of the pupil through the subluxed lens usually requires a high myopic astigmatic correction, whereas the inferior (or reading) part of the pupil with the missing lens requires a high hyperopic correction. This biphasic correction is impractical to achieve in glasses or contact lenses. Even at the early stages of lens subluxation, high degrees of myopia and astigmatism are produced.

Subluxation into the vitreous, the pupil or the anterior chamber is less likely to occur in children. If the lens subluxates into the pupil, pupillary block glaucoma can occur which constitutes an ocular emergency. As the lens subluxates, the iris starts to tremble (also known as iridodenesis). This is best observed at the slitlamp. Atrophy of the dilator muscle of the iris can also occur, resulting in poor dilation.

244

244 Family with Marfan’s syndrome.

Microspherophakia, which is a lens that is shaped more spherically rather than the usual disc shape, occurs in 15% of patients. This condition results in high myopia. The cornea can be flat, larger than normal (megalocornea), or of normal diameter. Retinal detachment occurs more frequently and is thought to be secondary to an increased axial length; it can also occur following lens extraction.

MANAGEMENT/TREATMENT

Once a child has been identified as having Marfan’s syndrome, it is essential that they have regular eye exams to detect any myopia or astigmatism. Without prompt and adequate correction of these refractive errors, amblyopia may develop. If vision is good with optical correction, then there is no need to rush surgery. Once the lens starts to subluxate into the visual axis, and proper optical correction is impossible, surgery should be considered.

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245 Ectopia lentis in Marfan’s syndrome.

Surgery is also necessary for anterior or posterior subluxation that is causing corneal damage, pupillary block glaucoma, or uveitis.

Recent advances in surgical techniques have

et al. (2008) recently reported a series of 78 eyes using a microincision and an ocutome vitrectomy probe in order to remove a subluxed lens within the capsular bag.25 Hydrodelineation was used to lessen surgical trauma to the zonules. This technique resulted in a very low rate of retinal detachment. Glasses and contact lenses were then used for visual rehabilitation. Several small studies have used intraocular lens implantation for visual rehabilitation in children.26,27 Satisfactory results were obtained; however, the number of patients and the length of follow-up are too short to advocate this as the gold standard of care.

Homocystinuria

DEFINITION/OVERVIEW AND ETIOLOGY

Classic homocystinuria due to a deficiency of cystathionine beta synthase (CBS) was first described in 1962 by Carson and Neill.28 Soon after the clinical entity was described, the biochemical defect was identified and the natural history of the disease was described.29,30 The most easily recognized symptom, and often the only manifestation, is the ocular finding of ectopia lentis. Other clinical symptoms include lighter pigmentation than found with the rest of the family (i.e. hair, skin, irides) and a malar flush. Vascular instability is also a finding. Skeletal abnormalities including genu valgum, ankle vagus and pes planus, along with a tall, thin, ‘marfanoid’ habitus are also described. Arachnodactyly is rare. Platyspondyly, kyphoscoliosis, and compression fractures of the spine are also features of the disorder. Mental retardation is variable, depending on thromboses and vascular disease. Seizures may also be present and are probably also related to vascular accidents, as are psychiatric symptoms. Pyridoxine-responsive individuals have been identified and often have a somewhat milder clinical course.31

Homocystinuria is identified on expanded newborn screen as an elevated methionine level. Biochemical features include increased plasma homocysteine, homocystine, and methionine, increased urinary homocystine, and reduced CBS activity. CBS activity is tested in fibroblasts. Molecular genetic testing is available to identify mutations in the CBS gene. The disorder is inherited in an AR fashion. Management includes pyridoxine (vitamin B6) supplementation, a low protein/methionine diet, betaine treatment, and folate and B12 supplementation. The therapeutic goal is to keep plasma homocystine levels less than 11 µmol/L and to decrease plasma homocysteine levels. Aspirin therapy can also be used as an adjunct to prevent strokes.

Several other inborn errors of metabolism can present with homocystinuria. Methylene tetrahydrofolate reductase (MTHFR) deficiency and disorders of intracellular cobalamin metabolism have also been described. MTHFR deficiency was first described in 1972 and results

from the inability to interconvert methylene tetrahydrofolate to methyl tetrahydrofolate.32 Methyl tetrahydrofolate is necessary as a methyl donor for the conversion of homocysteine to methionine. Thus, plasma homocysteine is elevated while plasma methionine is decreased.

There is variability in symptoms and age of onset. The most common presentation in the pediatric population is developmental delay. Microcephaly is often noted. Neurologic involvement includes gait disturbances, seizures, and mental retardation. Ocular findings have not been described, and although subacute degeneration of the spinal cord has been described, it is not associated with megaloblastic anemia. Genetic testing is currently not available for MTHFR deficiency. It is inherited in an AR fashion.

Disorders of intracellular cobalamin metabolism have recently been described.33,34 Several complementation groups have been identified. The most common of the disorders is cobalamin C deficiency; however, there are at least nine identified complementation groups which can be differentiated by biochemical phenotype. Complementation groups cblA, B, and D (variant 2) have the findings of methylmalonic acidemia/aciduria. cblC, D, and F have, in addition to methylmalonic acidemia/aciduria, hyperhomocysteinemia and homocystinuria. Complementation groups cblD (variant 1), E, and G have hyperhomocysteinemia and homocystinuria. All of these have low methionine, which differentiates them from CBS deficiency. Clinically, megaloblastic anemia is a defining feature. Other clinical findings include failure to thrive, mental retardation, seizures, behavioral problems, and psychiatric disturbances. Ophthalmic findings are seen in cblC, cblE, and cblG.

After the disorder is suspected, diagnostic testing includes urine organic acid analysis, plasma amino acid analysis, total homocysteine levels, urine homocystine levels, and plasma vitamin B12 levels. Genetic testing is available for CBS deficiency, cblC (MMACHCmethylmalonic aciduria and homocystinuria type C protein), cblE (MTRR-methionine synthase reductase) and cblG (MTRmethionine synthase). All are inherited in an AR fashion.

Treatment includes hydroxycobalamin injections, betaine, pyridoxine, folate or folinic

acid, and methionine supplementation. Carnitine supplementation is used if methylmalonic acidemia is present. Dietary protein restriction is implemented, particularly for those with methylmalonic aciduria. Even with treatment, prognosis is poor, with most patients dying young or being severely handicapped.33

CLINICAL PRESENTATION

The hallmark ophthalmic feature of homocystinuria is lens dislocation or ectopia lentis. It is present in 90% of patients and has been detected as early as 3 years of age.35 The zonules in patients with homocystinuria undergo degeneration.36 Normal zonular structure maintains the suspended lens behind the iris and in front of the vitreous body. Abnormal zonules interrupt this suspension and predispose a lens to dislocation. Typically, it is bilateral and inferior. Dislocation anteriorly has been documented with rates of 18– 50%.37 Dislocation into the anterior chamber can traumatize the cornea and cause opacification and a bullous keratopathy. The most significant complication of anterior dislocation is pupillary block glaucoma, which is a true ophthalmic emergency. Pupillary block causes a sharp rise in the intraocular pressure (IOP), along with corneal edema and pain. If left untreated, the high pressure will cause central retinal artery occlusion, and eventual optic atrophy with visual acuity and field loss.

Iris atrophy has been reported and is likely secondary to iris ischemia from recurrent episodes of pupillary block glaucoma. Nonvisually significant cystoid retinal degeneration has been found, which worsened with age.38 Anterior staphyloma, an extreme thinning of the cornea, is unusual, but has been reported both preand postoperatively.39 Myopia is common.

The important ophthalmic feature associated with cblC, cblE and cblG is a pigmentary degenerative retinopathy that primarily affects the macula (central vision), resulting in poor vision and nystagmus. Systemic treatment appears to have little effect on the retinal disease.

MANAGEMENT/TREATMENT

Treatment falls into two main categories: preventative treatment and the treatment of ocular complications.

Preventative

The ophthalmic benefit of treatment with pyridoxine and/or a diet low in methionine and supplementation with cystine remains unclear. A clear-cut benefit without development of ectopia lentis was demonstrated in 14 patients treated over a mean follow-up of 8.2 years.38 Other studies suggest that therapy may benefit pyridoxine responders, but showed no statistical benefit with pryridoxine unresponsive patients.

Cyloplegic refraction to detect and treat myopia is imperative. Early conservative prophylactic treatment methods (surgical or laser iridectomy) have failed to prevent lens dislocation into the anterior chamber.37

Ocular complications

Once dislocation of the lens into the anterior chamber has occurred, surgical treatment is necessary. Nonsurgical lens manipulation with pupillary dilatation, manual lens repositioning, and pupillary constriction fails in the long term. With newer microinstrumentation, lensectomies are safer with lower complication rates. The risk of postoperative retinal detachment has declined with newer microsurgical techniques. Prophylaxis for thromboembolic events should always be considered with general anesthesia. Most patients are visually rehabilitated with spectacle correction. If the child’s mental capacity and dexterity are good, contact lenses can be considered.