View larger version (58K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Prominent corneal nerves in the cornea of the proband, a 20-year-old man with asymptomatic multiple endocrine neoplasia 2A, show sclerotic scatter (A) and transillumination (B).

The patient and his father were evaluated for the MEN syndromes. Genetic testing in both revealed a mutation in the RET proto-oncogene at exon 14 (V804M) specific for MEN type 2A. Results of further evaluation of the son for MTC, hyperparathyroidism, and pheochromocytoma were negative. He had a prophylactic total thyroidectomy in June 2007. On histologic examination, there was no evidence of MTC or C-cell hyperplasia. The father also had a total thyroidectomy with lymph node dissection in October 2007. Two foci of MTC were found in the thyroid, together with tumor deposits locally in the soft tissue and level VI metastasis in the lymph node.

Screening of additional family members revealed a 65-year-old paternal great aunt of the proband with a remote history of carcinoid tumor found on incidental appendectomy. Although she tested positive for the V804M mutation in September 2007, results of thyroid ultrasound and fine-needle aspiration as well as calcitonin and resting metanephrine levels were normal. Results of ophthalmic examination were normal. She had a prophylactic thyroidectomy in January 2008. On pathological examination, there was no evidence of MTC. Screening of remaining family members was attempted (Figure 2); however, this was only partially successful because several were not able to be contacted while others declined to be tested for the mutation.

View larger version (24K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 2. Family pedigree of 2 related patients with prominent corneal nerves associated with a mutation in codon 804 (RET) on chromosome 10q11. The pedigree is incomplete because several members could not be contacted while others declined to be tested. MTC indicates medullary thyroid carcinoma; ?MTC, MTC status unknown; PCN, prominent corneal nerves; ?PCN, corneal nerve status unknown.

Comment
Corneal nerves are occasionally identifiable on careful biomicroscopic examination of the normal cornea and are seen commonly in a number of corneal conditions. In an otherwise normal cornea, the finding of prominent corneal nerves as exemplified in these 2 patients should arouse suspicion of an underlying MEN syndrome.

The prominent corneal nerves in the index case were observed and attributed to lattice corneal dystrophy, although the usual error is to confuse them with ghost stromal blood vessels.

Multiple endocrine neoplasia was first There are now 3 subtypes of the syndrome, MEN 2A and 2B and familial MTC. The incidence of MEN 2 is 1 in 30 000. Inheritance is autosomal dominant. The MEN 2 syndromes are caused by mutations in the RET proto-oncogene on chromosome 10q11. By different mechanisms, these mutations ultimately result in the activation of an intracellular tyrosine kinase domain that is involved in growth factor signaling.

The MEN 2A subtype accounts for 60% to 90% of MEN type 2. The incidence of MTC in this subtype is as high as 95%, with the possibility of multiple and/or multifocal tumors. The incidence of parathyroid tumors is 20% to 30% and of pheochromocytomas is 50%. The MEN 2A subtype differs from MEN 2B in that patients do not display the characteristic mucocutaneous neuromas, marfanoid habitus, and other skeletal abnormalities.

The treatment of patients who carry a mutation for one of the MEN syndromes requires an evaluation for all of the life-threatening manifestations, specifically MTC and pheochromocytoma.¹ This would include determination of baseline calcitonin and carcinoembryonic antigen levels (MTC), 24-hour urine catecholamines, metanephrines and vanillylmandelic acid or plasma-free metanephrines (pheochromocytoma), serum calcium, and parathyroid hormone levels (parathyroid tumors). Based on laboratory testing, further imaging may be necessary. Management of thyroid cancer has been stratified based on codon mutation.²

Prominent corneal nerves are a well-known manifestation of MEN 2B and have been described in patients with MEN 2A.^3-4 Among patients with MEN-2 disease, this specific codon mutation (V804M) has been associated with MTC but the association with prominent corneal nerves had not been noted until the study of a kindred with familial medullary carcinoma by Kasprzak et al in 2001.⁴ This particular mutation has highly variable expression of invasive MTC.⁵

While this kindred and the one described herein are in many respects similar, the diagnosis in the proband from the first kindred was made only on presentation of advanced thyroid carcinoma despite the presence of prominent corneal nerves noted some 15 years earlier.⁴ The corneal findings in the proband of our kindred led to identification of the syndrome and the decision to perform a prophylactic thyroidectomy. Because patients with MEN 2A do not exhibit the other classic phenotypic features of MEN 2B, it is essential that the clinical significance of prominent corneal nerves is recognized and acted on. Based on this case series, given that there were no other concerning features on history or examination of the index case, it is reasonable to consider genetic testing in all patients with prominent corneal nerves. However, as this study shows, not all individuals with this mutation will show evidence of prominent corneal nerves. To detect those with systemic manifestations of the MEN 2A syndrome, screening of family members is indicated regardless of the finding of normal corneas.

The astute ophthalmologist can play a potentially life-saving role in the early detection and rapid referral of patients with this finding. Regrettably, the prominent corneal nerves were not discovered in the father of the proband until his son's presentation. He had already developed metastatic MTC.

AUTHOR INFORMATION
Correspondence: Dr O’Day, Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, 2311 Pierce Ave, Nashville, TN 37232-8808 (denis.m.oday{at}vanderbilt.edu).

Author Contributions: Dr O’Day had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: None reported.

Funding/Support: This study was supported by an unrestricted grant from Research to Prevent Blindness.

Additional Contributions: Susan W. Caro, RNC, MSN, APNG, assisted in the production of the family pedigree figure.