ARTICLE
Auteur(s) : Aslı Altaykan1, Sibel Ersoy-Evans1,
Serap Emre2, Diclehan Orhan3, Şafak
Güçer3, Gül Erkin1
1Hacettepe University Faculty of Medicine, Department
of Dermatology, Ankara, Turkey
2Hacettepe University Faculty of Medicine, Department of
Medical Biology, Ankara, Turkey
3Hacettepe University Faculty of Medicine, Department of
Pediatrics, Pediatric Pathology Unit, Ankara, Turkey
accepté le 28 Mars 2007
Multiple endocrine neoplasia (MEN) is a genetic endocrine syndrome
with 4 well-known subtypes. Type 2B, which is the least common of
all, is transmitted in an autosomal dominant fashion. Its estimated
occurrence is 1/600,000 [1]. MEN type 2B is characterized by
medullary thyroid carcinoma (MTC), unilateral or bilateral
pheochromocytoma, ganglioneuromatosis, mucosal neuromas, and
typical facies with thick lips, low-set ears, down-slanted
palpebrae, and a marfanoid habitus [2]. Such patients may also have
café au lait spots and lentigines [3].Lichen nitidus is a
distinctive eruption of unknown etiology, which is also very rare
(3.4/10,000 blacks) [4]. It is known to be associated with atopic
dermatitis, Crohn’s disease, and juvenile chronic arthritis [4].
Genetic inheritance had not been identified, but familial cases
were reported [5]. It is characterized by widespread, tiny,
flat-topped shiny papules with a predilection for the arms and
wrists, lower abdomen, breasts, and genital region [4]. We observed
lichen nitidus in a patient with MEN type 2B, an extremely rare
comorbidity with a prevalence we calculated to be 1/200,000,000.In
95% of MEN type 2B cases, a single point mutation at codon 918
(M918T) has been identified [6]. Our patient was found to have the
germline mutation at codon 918 of exon 16 in the RET
proto-oncogene. To the best of our knowledge, we report the first
case of MEN type 2B associated with lichen nitidus, who also had
the most common mutation de novo.
Case report
A 19-year-old girl presented to our department with a widespread
eruption with mild pruritus that had been present for about a year.
It was learned that she had undergone total thyroidectomy 6 years
earlier for MTC and she had been on L-thyroxine since then. There
was no history of other drug intake. Family history was
unremarkable and her parents were not related. Dermatological
examination showed multiple skin-colored, shiny, flat-topped
papules scattered over the trunk and extremities (figure 1A).
Histopathological examination of one of the lesions from the trunk
revealed a focal, band-like infiltrate composed of lymphocytes and
histiocytes in the papillary dermis. This infiltrate expanded the
dermal papilla, as evidenced by the typical claw-clutching-a-ball
sign formed by rete ridges extending downward surrounding the
infiltrate (figure
1B). Overlying epidermis was thinned and parakeratosis was
observed. Additionally, basal vacuolar alteration and dyskeratotic
cells in the epidermis were noted. Staining for amyloid was
negative. These histopathological findings were interpreted as
lichen nitidus.
Physical examination was remarkable for typical facies with a
long, thin face, thick lips, down-slanted palpebrae, and low-set
ears. She had a marfanoid appearance with a slender figure, long
arms, and long fingers. Additionally, multiple papules and nodules
over the tip of her tongue (figure 2), buccal mucosa
and gingiva, as well as her inner eyelids were noted. As the
patient declined biopsy, those lesions were clinically diagnosed as
neuromas. Opthalmological examination revealed prominent and
thickened corneal nerves. Adrenomedullary disease screening by
measurement of urinary metanephrines and fractionated
catecholamines (epinephrine, norepinephrine, dopamine) revealed no
other abnormalities. The patient had no gastrointestinal symptoms
and she declined to have a gastrointestinal system
investigation.
Subsequently, she was recommended topical methylprednisolone
aceponate ointment twice daily and an emollient with urea. Since no
improvement was observed after 3 months of treatment, topical
therapy was discontinued and she was given broadband UVB
phototherapy, which controlled her pruritus and led to a 50%
improvement in her rash after 36 sessions.
DNA analysis
Informed consent for genetic analysis was obtained from the patient
and DNA analysis was performed from both peripheral leukocytes and
paraffin embedded tissue samples of the MTC. DNA was isolated from
peripheral leukocytes by the ammonium acetate salting out procedure
[7] and from the paraffin block as previously described [8].
Polymerase chain reaction (PCR) amplifications were carried out in
a final volume of 50 μl using the primers 5’ AGGGATAGGGCCTGGGCTT-3’
and 5’- TAACCTCCACCCCAAGAG-3’ for the first 40 cycles. For the
second 40 cycles, 2 μl of the PCR product was used as a template
with the nested primers 5’-AGAGTTAGAGTAACTTCAATGTC-3’ and 5’-
TAACCTCCTCCACCCCAAGAGA-3’ [9]. The fragment sizes of the PCR
products were 192 bp and 151 bp, and the annealing temperatures
were 58 °C and 55 °C, respectively. PCR products were
purified with the PCR DNA Purification Kit. They were sequenced in
the forward and reverse directions. Cycle sequencing was performed
with an ABI PRISM Big Dye Terminator Cycle Sequencing Kit according
to the manufacturer’s instructions. Sequences were analyzed with an
ABI PRISM 3130 DNA Analyzer. Direct sequencing confirmed a T-to-C
transition at codon 918.
Discussion
Although it is well-known that MEN type 2B is an autosomal
dominantly inherited disease, half of the cases are due to de novo
mutations in the RET proto-oncogene [10]. The RET proto-oncogene,
localized on chromosome 10q, comprises 21 exons and encodes a
receptor tyrosine kinase that is thought to play a role in the
development of neural crest. It is expressed in the tumors of
neural crest derivatives, including pheochromocytoma,
neuroblastoma, and MTC [11, 12]. Most of the mutations in the RET
proto-oncogene have been described in exon 16 at codon 918. This
single point mutation in the tyrosine kinase domain of RET has been
found to be associated with both inherited and de novo MEN type 2B.
In one study, this mutation was found in 82 (95.3%) of the 86
Caucasian patients with MEN type 2B syndrome [10]. However, new
mutations involving codon 883 of exon 15 have recently been
described [13]. Moreover, an individual with the presence of 2
germline mutations at codons 804 and 806 has been identified [14].
The present case had a germline mutation in exon 16 at codon 918
(M918T).
MEN syndromes were described in the last century and
subsequently classified into 2 major categories: type 1 and type 2.
MEN type 2 syndrome has been further subdivided into 2 major
variants, namely MEN type 2A and MEN type 2B. MEN type 2A is
characterized by MTC, hyperparathyroidism, and pheochromocytoma.
Although MEN type 2B is the least common [15], it can be easily
recognized by its distinctive appearance. Mucosal neuromas, which
usually present by the age 3, and are localized on the distal
portion of the tongue, lips, subconjunctival areas, and throughout
the gastrointestinal tract (ganglioneuromatosis) are the hallmark
of this syndrome. These neuromas play a part in typical facies,
with marked thickened irregular lips, and thickened, sometimes
everted eyelids [2, 16]. Marfanoid habitus with a tall and slender
build, long limbs, and a long thin face with prognathism, but
without palatal and lens abnormalities, is another specific feature
of this syndrome. All MEN type 2B patients develop MTC, which
presents at an early age with a poor prognosis. Unilateral or
bilateral pheochromocytoma also occurs in approximately half of the
individuals with this disorder [17]. Corneal nerve hypertrophy,
when present, is a characteristic ocular manifestation of this
syndrome. Other features include bony abnormalities such as pectus
excavatum, pes cavus, talipes equinovarus, and scoliosis [15]. Our
patient had a history of MTC, and showed features of marfanoid
habitus, mucosal neuromas, and corneal nerve thickening, as well as
typical facies with thick lips.
Skin lesions are not common in MEN syndromes; however, in
several MEN type 2A families, itchy skin lesions, which were
histopathologically consistent with lichen amyloidosis, have been
described [18]. On the other hand, skin lesions associated with MEN
type 2B are not very well-known. As far as we know, only café au
lait spots and lentigines have been reported [3]. Recently, a case
of MEN type 2B, with subcutaneous metastasis of pheochromocytoma,
was described [19]. We report another skin finding, lichen nitidus,
in a patient with MEN type 2B syndrome. The histopathology in our
case with focal parakeratosis, a dense dermal infiltrate composed
of lymphocytes and histiocytes, focal nature of the infiltrate, and
epidermal flattening, was highly suggestive of lichen nitidus.
Typical histopathological findings and a negative staining for
amyloid aided in differentiating our case from lichen planus and
lichen amyloidosis, respectively. Lichen nitidus is a focal,
asymptomatic, chronic inflammatory reaction with unknown etiology,
which in most cases resolves spontaneously within a few months to a
year. Isolated reports associated with atopic dermatitis, Crohn’s
disease, and juvenile chronic arthritis have been described [4].
Intervention is warranted when the patient is disturbed by the rash
due to pruritus or cosmetic appearance. Treatment options include
topical or oral corticosteroids, phototherapy, astemizole, and oral
retinoids [20-22]. Our patient did not respond to topical
methylprednisolone aceponate ointment, but showed some improvement
with broadband UVB phototherapy.
MEN type 2B is a rare hereditary disease, and to the best of our
knowledge, there have been no reported cases of MEN type 2B
patients diagnosed with concurrent lichen nitidus, another rare
disease. For this reason, our case was most interesting and
suggests that further data are necessary to discern whether the
occurrence of lichen nitidus in our MEN type 2B patient was an
isolated coincidence, or if there is a causative link between the
two.
Acknowledgements
Financial support: none. Conflict of interest: none.
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