However, mucosal neuromas around the eyelid or conjunctiva are unique to MEN2B, and can cause thickening and eversion of the eyelids as well as displacement of the eyelashes (59-61). tumorigenesis of MEN type 1 are unknown (58). The vast majority of MEN2 cases are associated with gain of function mutations in the RET protooncogene (59). Clinical presentation and relevance Although patients with both types of MEN syndromes are typically diagnosed based on non-ophthalmic findings and a strong known family history of disease, BIBR-1048 (Dabigatran etexilate) in new cases, a detailed ocular exam may direct the work-up and differential diagnosis. Visual field defects secondary to pituitary adenomas (see Pituitary Tumors) represent the majority of ocular findings in MEN1 (58). Patients with a diagnosis of MEN2A and MEN2B may demonstrate prominent corneal nerves. However, mucosal neuromas around the eyelid or conjunctiva are unique to MEN2B, and can cause thickening and eversion of the eyelids as well as displacement of the eyelashes (59-61). Additional features associated with MEN2 include prominent eyebrows and impaired pupillary dilation (61). Patients with these findings should be thoroughly evaluated by their primary care physicians and referred to endocrinology, given the mortality associated with these rare genetic syndromes. Treatment Given the heterogeneous clinical presentation of MEN syndromes, treatment is usually managed on a case-by-case basis and is beyond the scope of this review (57,61). Pediatric perspective Most patients with either type of MEN are diagnosed in adulthood, although there are reports of medullary thyroid carcinoma associated with MEN2 presenting in infancy (62). Given the autosomal dominant inheritance pattern of MEN, an extended family history and additional testing BIBR-1048 (Dabigatran etexilate) may be indicated when the index of suspicion for MEN is usually high. Wolfram syndrome Wolfram syndrome is a rare autosomal recessive condition characterized by the presence of DMs, diabetes insipidus, optic atrophy, and deafness (DIDMOAD). Additional endocrine associations include ACTH deficiency and growth hormone deficiency (52). DMs is usually the presenting feature, diagnosed around 6 years of age (63). The prevalence of cases with all four components of the acronym DIDMOAD is only between 14% and 58%, although the onset of each component varies over time. Accordingly, any pediatric patient diagnosed with urinary incontinence and diabetes should be evaluated for DIDMOAD, as the urinary incontinence may be an occult sign of diabetes insipidus. This slowly progressive disorder carries a poor prognosis, with a median age at death of 30 years, generally due to central apnea secondary to brainstem atrophy, as well as neuropsychiatric disease (64). Pathophysiology of ophthalmic manifestations Wolfram syndrome has been linked to BIBR-1048 (Dabigatran etexilate) mutations in the gene em WFS1 /em . This gene encodes wolframin, a protein that plays a regulatory role in calcium homeostasis in the endoplasmic reticulum (65). Immunohistochemical studies of the human Tfpi retina have exhibited wolframin expression in retinal ganglion cells, optic axons, and the optic nerve. Dysfunction of wolframin in these locations may explain the ophthalmologic findings associated with this syndrome (64,66). Clinical presentation and relevance Children with Wolfram syndrome present with bilateral optic nerve atrophy around 11 years of BIBR-1048 (Dabigatran etexilate) age. Initially, ocular manifestations are moderate and include loss of color and peripheral vision. However, visual symptoms progress to blindness within approximately eight years of diagnosis of atrophy (64). Progression of the disorder can be reliably correlated with retinal thinning (63). Less common ophthalmologic features include cataracts, retinal pigmentation, DR, glaucoma, abnormal pupillary reflexes, and nystagmus (64). Treatment To date, no known treatments exist for the ophthalmic complications of Wolfram syndrome. However, idebenone and docosahexaenoic acid have shown promise as potential management strategies to delay disease progression (63). However, given the spectrum of ophthalmic complications, as well as neurologic, neuropsychiatric, and endocrine manifestations, early diagnosis and supportive care is paramount. Pediatric perspective Wolfram syndrome is an exceedingly rare congenital disorder.
