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Break-up time was 15 s OD and 5 s OS; basal tear secretion
was 1 mm OD and 4 mm OS. Orthoptic findings were unremark-
able. The patient was diagnosed as having MEN type 2b. The di-
agnosis was confirmed by genetic analysis. A molecular genetic
study of the RET proto-oncogene showed a heterozygous ATG to
ACG mutation in codon 918 of exon 16, which is present in 95%
of patients with MEN type 2b [4].
some 10 [5]. It encodes the Ret receptor tyrosine kinase,
a transmembrane protein expressed in neuroendocrine
cells that transduces signals for growth and differentia-
tion. Recently, maxillofacial and orthopedic changes
have also been found to be typical for MEN type 2b,
such as a broadened nasal bridge, a markedly enlarged
and bifurcated inferior alveolar channel and shortened
roots of the lower incisor teeth, slipped captor femoral
epiphysis, pes cavus, talipes equinovarus, kyphosis, sco- Discussion
liosis, lordosis, increased joint laxity and weakness of
the proximal muscles of the extremities [3, 12]. If the MEN type 2b syndrome is characterized by medullary
disease is discovered late, patients usually die of meta- thyroid gland carcinoma and typical mucosal neuromas
static thyroid carcinoma.
found in all patients described in the literature. Pheo-
chromocytoma, marfanoid habitus and other features are
variably expressed. In all cases described in the litera-
ture, thickened corneal nerves were found, no matter
how old the patients were. Robertson et al. [11] de-
scribed two families with MEN 2b. In one of the families
thickened corneal nerves were found in two children
aged 2 and 4 years, too young for marfanoid habitus to
be determined. In the 4-year-old a medullary thyroid
gland carcinoma could already be detected. The 2-year-
old showed elevated calcitonin levels, and total thyroid-
ectomy revealed C-cell hyperplasia.
Although our patient had been seen by ophthalmolo-
gists long before any other symptoms were apparent, the
diagnosis of MEN 2b was first established when a med-
ullary thyroid gland carcinoma and a pheochromocytoma
occurred on one side.
Among the other signs, greatly thickened corneal
nerves formed an irregular lace pattern across the entire
cornea. The enlargement of corneal nerves may be
caused by the increase in the number of axons found by
Riley et al. [10] in histopathologic sections of the cornea.
An increased number of Schwann cells may also contrib-
ute to the large size of the corneal nerves [10]. Myelin-
ation of corneal nerves as the cause for increased visibil-
ity has also been suggested [1, 7]. In histopathologic sec-
tions Riley et al. [10] found the myelination of the corne-
al nerves to terminate near the corneoscleral limbus.
Thickened corneal nerves rarely occur in other diseases;
however, they have been described to appear occasional-
Case report
A 34-year-old white male was referred to the Department of Oph-
thalmology for ophthalmologic examination by the Department of
Clinical Biochemistry. He complained of strong bilateral conjunc-
tival hyperemia in the morning, which had first appeared in child-
hood and had increased ever since. He was seeing an ophthalmol-
ogist occasionally and was prescribed vasoconstrictant eye drops,
which decreased the redness immediately. His ophthalmologic his-
tory was otherwise unremarkable.
At the age of 22 years, a medullary thyroid carcinoma was di-
agnosed, and thyroidectomy ensued. Further investigation dis-
closed a pheochromocytoma of the left adrenal, which was re-
moved surgically. Five years later a pheochromocytoma of the
other adrenal was diagnosed and removed surgically. Since then
he had been receiving hydrocortisone 30 mg, fludrocortisone
0.1 mg and levothyroxine 150 µg per day. Two years ago, he was
referred to the Department of Clinical Biochemistry for further
follow-up. Calcitonin levels were found to be 123 pg/ml (normal:
<100 pg/ml); serum tests concerning catecholamines were nega-
tive.
The patient's father had died at the age of 31 from myocardial
infarction. No links with endocrine neoplasias were found. The
mother and sister of the patient had been examined elsewhere. The
mother had been diagnosed as having a goiter, but no thyroid ma-
lignancy had been found. All other findings, including a pentagas-
trin-stimulated calcitonin test, were reported to have been unre-
markable. Neither the mother nor sister was available for ophthal-
mologic examination.
The patient had no further close relatives.
On examination, uncorrected visual acuity was 20/20 in both
eyes, intraocular pressure was normal and ophthalmoscopic find-
ings were unremarkable. Slit-lamp examination showed thickened
upper and lower eyelids (Fig. 1). Extremely thickened corneal ly in patients with MEN 2a, MEN 3, neurofibromatosis,
nerves in the superficial and midcorneal stroma could be recog-
pheochromocytoma, congenital ichthyosis, leprosy and
nized (Fig. 2). Both eyes displayed multiple small plexiform and
medullary C-cell carcinoma without known mutations
nodular subconjunctival tumors (Fig. 3a,b). The conjunctiva at the
for MEN 2a and 2b. Corneal nerves also appear more
corneoscleral limbus was irregularly thickened and appeared al-
visible in some corneal diseases, such as herpes simplex,
herpes zoster, posterior polymorphous dystrophy, Fuchs'
bullous keratopathy and keratoconus [6, 8].
most chemotic (Fig. 3a). Only the left cornea showed an arcus li-
poides.
Enlarged, prominent nerves are also common in the
subconjunctival region of patients suffering from MEN
2b, leading to a swelling of the overlying conjunctiva, as
we found in the perilimbal conjunctiva. These nerves can
also occur in bundles as relatively flat neuromas, appear-
ing as nodules. Perilimbal neuromas are often associated
with dilated perilimbal conjunctival blood vessels, lead-
Fig. 1 The patient's right eye, showing a thickened upper and
lower eyelid
Fig. 2a, b Thickened corneal nerves of both eyes
Fig. 3a, b Both eyes of the patient, showing subconjunctival nod-
ular tumors
Fig. 4a, b Both eyes of the patient, showing plexiform subcon-
junctival tumors
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