From Eskisehir Osmangazi University Medical School, Department of Ophthalmology, Meselik, Eskisehir, Turkey.
Address correspondence to Nilgun Yildirim, MD, Eskisehir Osmangazi University Medical School, Department of Ophthalmology, Meselik, 26480 Eskisehir, Turkiye.
Multiple endocrine neoplasia is defined as the occurrence of tumors in two or more endocrine glands and is categorized as type 1, type 2a, and type 2b. Type 1 includes adenomas in the parathyroid, pancreas, thyroid and adrenal glands associated with subcutaneous lipomas. Type 2 includes pheochromocytoma, medullary thyroid carcinoma, parathyroid tumors, and hyperplasia. Type 2a is characterized by medullary carcinoma, pheochromocytoma, and parathyroid disease, whereas type 2b is characterized by medullary thyroid carcinoma, pheochromocytoma, and multiple mucosal neuromas. Multiple endocrine neoplasia type 2b occurs at a significantly earlier age than type 2a and is inherited in an autosomal dominant pattern.1
The diagnosis of multiple endocrine neoplasia is often delayed and the disease is fatal in most cases due to metastatic medullary thyroid carcinoma. Early diagnosis is important to prevent fatal results. Ocular involvement in multiple endocrine neoplasia is a well-known entity and sometimes may be the first sign of the disease. Hence, ophthalmologists must consider multiple endocrine neoplasia if prominent ophthalmic findings are present, including thickened corneal nerves, conjunctival and eyelid neuromas, thickened lower and upper eyelids, impaired pupillary dilation, keratoconjunctivitis sicca, nasal displacement of the lacrimal puncta, prominent orbital ridges, and heavy eyebrows. Also, systemic findings including a marfanoid habitus, history of diarrhea, constipation, or both, thickened lips, nodules on the anterior aspect of the tongue, cafe-au-lait spots, and nodules on the cheek mucosa can be detected. Recently, maxillofacial and orthopedic changes have also been reported to be typical for multiple endocrine neoplasia.2,3
We describe the ocular findings of a child with multiple endocrine neoplasia type 2b whose diagnosis was first made at an early stage by recognizing the prominent corneal nerves and ocular findings.
A 16-year-old girl was admitted to the Department of Ophthalmology because of severe bilateral conjunctival hyperemia and stinging lasting for more than 1 year. She had been previously examined in a different hospital by an ophthalmologist and prescribed artificial tear drops and vasoconstrictive eye drops. However, stinging of the cornea did not resolve and she was referred to our hospital for future investigation. Her medical history was otherwise unremarkable.
On ophthalmologic examination, best-corrected visual acuity was 20/20 in both eyes. Intraocular pressures obtained by Goldmann applanation tonometer were within the normal range. Dilated fundus examination revealed nothing abnormal. Slit-lamp biomicroscopic examination showed extremely thickened peripheral corneal nerves extending to the mid-corneal region (Fig. 1A). Both eyes displayed multiple, subconjunctival plexiform neuromas (Fig. 1B) and the limbus was irregularly thickened. Both upper and lower eyelids were thickened and a nodular neuroma was detected on the left upper conjunctival eyelid margin (Fig. 2A). Schirmer test scores were 7 mm in the right eye and 6 mm in the left eye. Break-up time was 15 seconds in the left eye and 10 seconds in the right eye. Other ophthalmic findings were unremarkable. The patient was referred to the Department of Pediatric Endocrinology for suspected multiple endocrine neoplasia.
Figure 1. (A) the Patient’s Left Eye Showing Extremely Thickened Peripheral Corneal Nerves Extending to the Mid-Corneal Region (arrow Head). (B) the Patient’s Right Eye Showing Subconjunctival Plexiform Neuromas (arrow Heads).
Figure 2. (A) Left Upper Eyelid of the Patient Showing a Nodular Neuroma on the Conjunctival Eyelid Margin. (B) Multiple Mucosal Neuromas on the Anterior Aspect of the Tongue (arrow Heads).
On physical examination, a 2 × 3 cm nodule was detected within the thyroid gland. Medullary thyroid carcinoma was diagnosed by fine needle aspiration biopsy and thyroidectomy ensued. Further investigation with abdominal computed tomography revealed a pheochromocytoma (3 × 4.5 × 2 cm) of the right adrenal gland, which was removed surgically. There were multiple mucosal neuromas on the anterior aspect of the tongue (Fig. 2B) and pes cavus were also found. The patient was diagnosed as having multiple endocrine neoplasia type 2b. Her family members were also examined but none were found to be affected.
Prominent ocular findings such as thickened corneal nerves have been described in all patients with multiple endocrine neoplasia, and it has been reported that thickened corneal nerves can be seen in children as young as 2 years of age.4 The histopathology of the enlarged corneal nerves has been studied and an increased number of Schwann cells and axons have been found.5 In addition, myelination of the corneal nerves as the cause of enlargement has also been suggested.6,7 Riley and Robertson5 showed that these myelinated corneal nerves finished near the limbus. Thickened corneal nerves may be the first manifestation of certain systemic diseases, such as multiple endocrine neoplasia type 2a, multiple endocrine neoplasia type 2b, leprosy, neurofibromatosis, pheochromocytoma, primary amyloidosis, ectodermal dysplasia, Refsum’s syndrome, and congenital ichthyosis. They also appear in certain corneal diseases, such as keratoconus, herpes simplex, herpes zoster, and Fuchs’ bullous keratopathy.8–10
Prominent nerves are also present in the subconjunctival regions of patients with multiple endocrine neoplasia type 2b. They form plexiform bundles that lead to formation of flat neuromas, which appear as nodules. They can also be seen in the perilimbal region accompanied by dilated perilimbal conjunctival blood vessels.
Medullary thyroid gland carcinoma and multiple mucosal neuromas associated with prominent ocular findings have been found in all patients with multiple endocrine neoplasia type 2b described in the literature. Pheochromocytoma and other systemic findings have been reported in varying degrees. Multiple endocrine neoplasia type 2b is often diagnosed at an advanced stage on the basis of elevated catecholamines or calcitonin present in pheochromocytoma and medullary thyroid carcinoma, and this delay in diagnosis may lead to fatal results. In particular, the thickened corneal nerves in corneal stroma may be the first hint of multiple endocrine neoplasia type 2b (or possibly types 2a or 3). Therefore, ophthalmologists must consider multiple endocrine neoplasia type 2b whenever they detect extremely thickened corneal nerves to ensure early diagnosis and treatment.
- Carney JA, Sizemore GW, Hayles AV. C-cell disease of the thyroid gland in multiple endocrine neoplasia, type 2b. Cancer. 1979;44:2173–2183. doi:10.1002/1097-0142(197912)44:6<2173::AID-CNCR2820440630>3.0.CO;2-0 [CrossRef]
- Carney JA, Bianco AJ Jr, Sizemore GW, Hayles AB. Multiple endocrine neoplasia with skeletal manifestations. J Bone Joint Surg Am. 1981;63:405–410.
- Schenberg ME, Zajac JD, Lim-Tio S, Collier NA, Brooks AMV, Reade PC. Multiple endocrine neoplasia type 2b: case report and review. Int J Oral Maxillofac Surg. 1992;21:110–114. doi:10.1016/S0901-5027(05)80545-4 [CrossRef]
- Robertson DM, Sizemore GW, Gordon H. Thickened corneal nerves as a manifestation of multiple endocrine neoplasia. Trans Am Acad Ophthalmol Otol. 1975;79:OP-772–OP-787.
- Riley FC Jr, Robertson DM. Ocular histopathology in multiple endocrine neoplasia type 2b. Am J Ophthalmol. 1981;91:57–64.
- Baum JL, Adler ME. Pheochromocytoma, medullary thyroid carcinoma, multiple mucosal neuroma: a variant of the syndrome. Arch Ophthalmol. 1972;87:574–584.
- Koke MP, Braley AE. Bilateral plexiform neuromata of the conjunctiva and medullated corneal nerves. Am J Ophthalmol. 1940;23:179.
- Arffa RC, Grayson M. Grayson’s Diseases of the Cornea. St. Louis: Mosby; 1991.
- Kane LA, Tsai MS, Gharib H, et al. . Familial medullary thyroid cancer and prominent corneal nerves: clinical and genetic analysis. J Clin Endocrinol Metab. 1995;80:289–293. doi:10.1210/jc.80.1.289 [CrossRef]
- Mensher JH. Corneal nerves. Surv Ophthalmol. 1974;19:1–18.