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

according to the size and location of the AVM. Vascular accidents usually begin in the second or third decade. The most common manifestations of the midbrain vascular malformations are seizures and intracranial hemorrhage, occurring in about 10% to 80% of cases.2,3,33,105 Contralateral pyramidal deficits, mental disturbances, and contralateral homonymous hemianopia are common complications. Other complications include cranial nerve palsies, dorsal midbrain syndrome, internuclear ophthalmoplegia, nystagmus speech deficits, and mental retardation.

The cutaneous manifestations, present in half of patients, consist of a subtle nevus flammeus along the ipsilateral trigeminal distribution.105 AVMs of the ipsilateral pterygoid fossa, mandible, and maxilla may hemorrhage following dental extraction and facial surgery.

Inheritance

WMS is a rare sporadic syndrome with no hereditary component.

Natural History

The natural history of WMS is unpredictable. Rare patients develop intravascular thrombosis with central vein occlusion and subsequent neovascular glaucoma. The neurological complications include headaches, seizures, and subarachnoid hemorrhages. These complications are the primary cause of morbidity and mortality in WMS.

Treatment

No treatment is required for the retinal lesions. The condition is congenital and nonprogressive. Recognition of the association between the retinal and intracranial lesions may allow early identification of cerebral AVMs. With newer techniques of endovascular embolization, the ability to eliminate the intracranial AVMs without compromise of the cerebral circulation is possible. A multidisciplinary management approach is recommended.

MULTIPLE ENDOCRINE NEOPLASIA TYPE 2B (MEN 2B, THE MUCOSAL NEUROMA SYNDROME)

MEN 2B or the mucosal neuroma syndrome is a hamartoneoplastic syndrome characterized by medullary thyroid carcinomas (MTC), pheochromocytomas, mucosal neuromas, ganglioneuromas of the intestinal tract, and skeletal and ophthalmic abnormalities. MEN 2B patients have a Marfanoid body habitus with a characteristic dysmorphic facies.76

Incidence

The incidence of MEN 2B has not been documented accurately.

Etiology

The MEN 2B phenotype is caused by a mutation in the RET proto-oncogene. A mutation in codon 918 causes the substitution of threonine for methionine in the tyrosine kinase domain of the RET protein. Recent biochemical evidence suggests that this mutation alters the substrate specificity of intracellular signal transduction.

Ophthalmic Features

The mucosal neuromas are seen at the eyelid margins, causing an anteverted eyelid (Fig. 6-13). Slit lamp examination can reveal subconjunctival neuromas (Fig. 6-14) and medullated nerve fibers in the cornea (Fig. 6-15).

Clinical Assessment

Regular biochemical testing and imaging, with surgery when necessary, has shown to be effective in preventing mortality and morbidity in MEN 2 families.

Screening for MTC in a RET mutation-positive child of a known MEN 2B patient probably should start at age 1 year.97,107 However, normal calcitonin levels may be high in infants, and screening results may be difficult to interpret. In this situation some clinicians have advocated thyroidectomy on the basis of the MEN 2B phenotype alone. DNA testing for the MEN 2B mutation now provides greater certainty. In a family known to

FIGURE 6-13. Face of patient with multiple endocrine neoplasia (MEN) 2B. Note anteverted lids secondary to neuroma of the lids, Marfanoid facies, and neuromas of the lips.

have MEN 2B in which the causative mutation can be identified, DNA testing of unaffected family members at risk will free those who do not have the mutation from the need for biochemical screening and simplfy surgical decision making in those with the mutation. Increasingly, opinion is moving toward a recommendation for thyroidectomy in childhood on the basis of DNA testing alone. Because 50% of MEN2 cases are sporadic, DNA testing plays an important role in determining which apparently sporadic cases have heritable disease. Somatostatin receptor scintigraphy is a sensitive method for assessing MTC and pheochromocytoma metastases.56

FIGURE 6-16. Diffuse nodular neuromas of the tongue in MEN 2 B.

interior tongue (Fig. 6-16). Hyperplasia of the autonomic ganglia in the intestinal wall leads to disordered gut motility,12 which commonly presents in infancy or childhood as failure to thrive or alternating episodes of constipation and diarrhea. These abnormalities can be recognized on rectal biopsy. Generalized hypotonia (floppy baby) has been described in newborn infants.35 There may be a variety of skeletal abnormalities including pes cavus, slipped femoral epiphyses, pectus excavatum, bifid ribs13 and Marfanoid body habitus. Delayed puberty has been noted in a few girls with MEN 2B; the mechanism is unclear. Impotence in men is neurological in origin.

Inheritance

MEN 2B is inherited as an autosomal dominant gene, and 50% are de novo mutations.

Natural History

Oral neuromas are usually evident in childhood, with medullary thyroid carcinoma or pheochromocytoma becoming serious risks after adolescence. In MTC, total thyroidectomy is usually indicated as the lesion is often multicentric. Pheochromocytomas are often bilateral or even extrarenal. Severe constipation or diarrhea frequently develops before endocrine neoplasias are detected. An annual screening evaluation of all at-risk family members should be performed to identify and treat presymptomatic individuals.

Treatment

There is no medical treatment for MEN 2B. As mentioned earlier, thyroidectomy and adrenalectomy have been suggested even in presymptomatic patients.

Prognosis

The prognosis in MEN 2B depends on the early detection and treatment of the malignancies that occur.

PROTEUS SYNDROME

History

Initially described in 1979 by Cohen and Hayden,22 this disorder was set forth as a clinical entity in 1983 by Wiedemann,112 who utilized the term proteus (after the Greek god Proteus, the polymorphous), to capture the variable and changing phenotype of this condition. It has been suggested by Dr. Michael Cohen that John Merrick, the elephant man, most likely had the Proteus syndrome.20

Incidence

The disorder is rare, estimated to affect only several hundred patients in the United States and western Europe.6

Etiology

The etiology of Proteus syndrome is unknown. All cases have been sporadic in otherwise normal families. Recent reports have suggested that this disorder may be caused by somatic mutation during early development, resulting in mosaicism.21

Ophthalmic Features

Severe maldevelopment and malfunction of the retina lead to strabismus, nystagmus, and high myopia and retinal pigmentary abnormalities. In reviewing the literature, strabismus and epibulbar tumors were the most common abnormalities.26 In another patient with multiple meningiomas and craniofacial hyperostosis, the retina showed diffuse disorganization with nodular gliosis, retinal pigmentary abnormalities, chronic papilledema, and optic atrophy.38,114

Clinical Assessment

At the present time, there are insufficient data to recommend periodic screening for specific tumors in Proteus syndrome. Instead, clinicians should be vigilant for clinical signs of neoplasia (see following) and initiate prompt and thorough evaluation.5

Systemic Associations

Proteus syndrome causes postnatal overgrowth of multiple tissues in a mosaic pattern. Diagnostic criteria are listed in Table 6-13. The overgrowth can involve skin, subcutaneous tissue, connective tissue (including bone), the central nervous system, and viscera. Complications of Proteus syndrome include, among others, progressive skeletal deformities, invasive lipomas, invasive benign and malignant tumors, and deep vein thrombosis with pulmonary embolism. The hyperostosis of the external auditory canal is a highly specific finding. Approximately 50% of reported cases have had intellectual disability.5

TABLE 6-13. Diagnostic Criteria for Proteus Syndrome.

General criteria:

Mosiac distribution AND progressive course AND sporadic occurrence

Category A:

Connective tissue nevus (see Fig. 6-1)

Category B: Epidermal nevus

Disproportionate overgrowth of two of the following: limbs, skull, external auditory canal, vertebrae, or viscera (see Figs. 6-3, 6-4)

Specific tumors before end of second decade: bilateral ovarian cystadenomas or paranoid monomorphic adenoma

Category C:

Dysregulated adipose tissue (either lipoatrophy or lipomas) Vascular malformations: capillary, venous, or lymphatic

Facial phenotype: long face, dolichocephaly, downslanted palpebral fissures, low nasal bridge, wide or anteveterted nares, open mouth at rest

The diagnosis of Proteus syndrome requires all three general criteria plus either one criterion from category A, two criteria from category B, or three criteria from category C

Inheritance

The majority of cases have been sporadic.

Natural History and Prognosis

Proteus syndrome patients are frequently normal at birth, although birth weight is usually increased. A few patients have had the characteristic features in the newborn period, but they typically become obvious over the first year of age. Generally progressive throughout childhood, growth of the hamartomas and the generalized hypertrophy usually ceases after puberty. Moderate mental deficiency is seen in 50% of cases. Caring for a child with Proteus syndrome is a major challenge for parents and physicians. These challenges relate to medical and psychosocial consequences of Proteus syndrome. Morbidity is significant. Of 11 patients evaluated by Clark et al., 2 required amputation of a leg, 6 had fingers or toes removed, and 2 women underwent breast reconstruction. Spinal stenosis may develop because of vertebral anomalies or tumor infiltration.19

Cystic emphysematous pulmonary disease may be associated with severe morbidity and death. Affected individuals should be carefully monitored for the development of all types

of neoplasms because the full spectrum of this disorder is not known.

Treatment

There is no specific medical treatment for Proteus syndrome. As already described, surgical treatment of neoplasms is frequently required.

Future Research

Although progress is being made in the clinical understanding of Proteus syndrome, much remains to be done. Surgical treatments for tissue overgrowth and deformity with careful followup of outcome should allow delineation of effective strategies.

Because Proteus syndrome is sporadic and hypothesized to be caused by somatic mutation, efforts are underway to characterize differences in gene expression or genomic abnormalities in paired affected and unaffected tissues from Proteus patients. Characterization of the molecular defect should allow accurate diagnosis and better understanding of the underlying pathophysiology. Although the progressive nature of the condition complicates management, this attribute suggests that there is an active hyperproliferative process that may be amenable to direct pharmacological intervention.5

References

1.Altuna JC, Greenfield DS, Wand M, et al. Lantanprost in glaucoma associated with Sturge–Weber syndrome: benefits and side effects. J Glaucoma 1999;8:199–203.

2.Bech K, Jenesen OA. Racemose haemangioma of the retina. Acta Ophthalmol 1958;36:769–781.

3.Bech K, Jenesen OA. On the frequency of coexisting racemose hemangiomata of the retina and brain. Acta Psychiatr Scand 1961;36: 47–56.

4.Bellester R, Marchuk DA, O’Connell P, et al. The NF1 locus encoded a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 1990;63:851–859.

5.Biesecker LG. The multifaceted challenges of Proteus syndrome. JAMA 2001;285:2240–2243.

6.Biesecker LG, Peters KF, Darling TN, et al. Clinical differentiation between Proteus syndrome and hyperplasia: description of a distinct form of hemihyperplasia. Am J Med Genet 1998;79:311–318.