Not just skin deep: a case report of multiple endocrine neoplasia type 1.

Multiple endrocrine neoplasia (MEN) type 1 is characterized by mainly a triad of pancreatic, pituitary and parathyroid involvement. This is a case report of a 41-year-old male in whom recognition of collagenoma and gingival papule led to the identification of MEN type 1. Often the recognition of such dermatological manifestations help in the presymptomatic diagnosis of complex syndromes.

Introduction

Many a time the skin acts as a window to a variety of systemic illnesses. Multiple endrocrine neoplasia (MEN) type 1 is a complex hereditary disorder encompassing pancreatic and pituitary tumors and hyperplasia of the parathyroid glands and it has a variety of skin manifestations. This is a case report of a patient with MEN type 1 in whom the search for the systemic manifestations was lead by the recognition of the skin changes.

Case Report

A 41-year-old man was referred to the outpatient clinic of Dermatology, Medical College, Thiruvananthapuram, by surgical gastroenterologist for evaluation. He presented with asymptomatic skin lesions over the abdomen and front of neck of 3-year duration. For the last one and a half year he is having early morning fatigue, tremor, sweating and difficulty in holding objects. He was earlier diagnosed by a neurologist to have absence seizures and was put on anticonvulsants but there was no relief. He also gave a past history of two episodes of ureteric colic 6 years back. General examination was normal except for an increased arm span (height -165 cm, arm span - 179 cm) and an elevated blood pressure of 160/100 mm of Hg.

Dermatological examination revealed multiple discrete skin-colored soft as well as firm dome-shaped smooth papules of 0.5 cm diameter over the abdomen and lateral aspect of trunk [Figure 1]. A single 2 × 1 cm hyperpigmented macule with serrated margins was seen over the right side of chest [Figure 2]. Multiple discrete brownish macules as well as hyperpigmented and erythematous papules were seen over the anterior and lateral aspect of neck and pre-sternal area [Figure 2]. A single whitish papule of 0.5 cm was seen over the right lower gingival mucosa [Figure 3]. Examination of other systems was normal.

Figure 1

Papules on abdomen

Figure 2

Erythematous papule on chest,hyperpigmented macule on chest

Figure 3

Gingival papule

With these findings, the possibility of steatocystoma multiplex or neurofibroma or collagenoma with angiofibroma and café-au-lait macules was considered. In view of the late-onset cutaneous tumors and associated systemic symptoms, the patient was subjected to detailed investigations. The routine blood and urine examinations as well as liver and renal function tests were normal. Serum calcium level was 11mg% and serum phosphorus was decreased (1.9 mg%; normal value: 2.5 - 4.5 mg %). Random blood sugar was 51mg%. In view of the repeatedly low blood sugar values, serum insulin was measured. It was found that serum insulin was elevated (112.47 μIu/ ml; normal value: 2-25 μIu/ml) with an increased insulin/glucose ratio (2.205) and a slightly raised C-peptide level (4.16 mg/ml; normal value 1-3 mg/ml). The detection of hyper insulinemia prompted us to do a detailed endocrinological evaluation. Serum parathormone was elevated (151.4 pg/ml; normal value: 15-75 pg/ml) whereas the other hormones like thyroid hormones, cortisol, gastrin and prolactin were normal. Ultrasonographical examination of neck revealed a hypoechoic lesion of 5.3×11 mm seen posterior to the right lobe of thyroid suggestive of parathyroid adenoma. Visual field examination, OGD scopy and X-ray skull were normal. Plain CAT scan of the abdomen showed a tumor involving the body and tail of pancreas and multiple calculi were noted in the left kidney. CAT scan of head was normal but MRI brain showed a space-occupying lesion in the pituitary suggestive of pituitary adenoma [Figure 4].

Figure 4

MRI of Brain showing Pituitary tumour

Skin biopsy of the papules over the abdomen showed normal epidermis with increased dense connective tissue in the dermis which on subjecting to Van Gieson's stain- a mixture of Picric acid and Acid Fuchsin- took up red color confirming the diagnosis of collagenoma [Figure 5]. Erythematous papule on the pre-sternal area for which a provisional diagnosis of angiofibroma was made, showed hyperkeratosis, acanthosis and dilated blood vessels in the upper dermis with perivascular infiltrate which was more in favor of seborrhoeic keratosis rather than angiofibroma. Thus a final diagnosis of MEN type 1 was arrived at. The patient underwent parathyroidectomy and enucleation of the pancreatic tumor. The serum insulin level was normalized and his hypoglycemic symptoms disappeared after the surgical treatment.

Figure 5

Van Gieson's stained section of skin coloured papule over abdomen consistent with Collagenoma, 40× magnification

MEN type 1 is a complex hereditary disorder encompassing pancreatic and pituitary tumors and hyperplasia of the parathyroid glands. Hyperparathyroidism is the most frequently expressed endocrinopathy in the syndrome which may also include on or more of the following: pancreatic tumors like insulinomas and gastrinomas, pituitary tumors like pinealomas, acromegaly, cushing's syndrome, thyroid tumors, carcinoids and hyperprolactinemia.[1] The term MEN was introduced by Steiner et al in 1968 to describe disorders with a combination of endocrine tumors. These are complex genetic syndromes caused by activation or inactivation of different types of genes known to be involved in the regulation of cell proliferation and they include MEN 1, MEN 2, von Hippel - Lindau syndrome, Neurofibromatosis type 1 and Carney complex. Steiner and his colleagues also reported that the syndrome could be divided into two classes, MEN 1, (pituitary, pancreatic and parathyroid involvement) and MEN 2 (thyroid, medullary cancer, adrenal medullary and parathyroid disease).[2]

Wermer in 1954 first described the classical triad of pancreatic, pituitary and parathyroid tumors which is now known as MEN 1. Hence MEN 1 is also known as Wermer's syndrome. It is inherited in an autosomal dominant pattern and is caused by inactivating mutation of the tumor suppressor gene MEN 1 on chromosome 11q13 which encodes a peptide called menin. Its prevalence is 1 in 30,000. Among cases showing biochemical expression of MEN 1, 90-97% exhibit primary hyperparathyroidism; pancreatic tumors are manifested in 30-80%, and pituitary tumors are manifested in 15-50%.[1] The cutaneous lesions seen in MEN 1 include angiofibromas (88%), collagenomas (72%), café-au-lait macules (38%), lipomas (34%), confetti-like hypopigmented macules (6%) and gingival papules (6%). Collagenomas are skin-colored to slightly hypopigmented firm, round to oval papules and nodules of 0.2-2cm diameter, mostly located on upper part of trunk and neck and show an increased amount of collagen and normal or decreased elastic fibers on histopathological examination.Other conditions where collagenomas are seen include Tuberous sclerosis, Birt-Hogg-Dubé syndrome, Down syndrome, Chronic myelocytic leukaemia, Syphilis, Cowden's syndrome, Proteus syndrome and Encephalocraniocutaneous lipomatosis.[3]

The constellation of these cutaneous findings like collagenomas, angiofibromas and gingival papules do not establish the diagnosis of MEN 1 as they are also seen in other genodermatoses like tuberous sclerosis (TSC) and Birt - Hogg - Dubé syndrome (BHDS). Figure 5 shows the overlapping clinical features seen in these three disordersBHDS is an uncommon autosomal dominant genodermatosis characterized by a triad of skin tumors - fibrofolliculomas, trichodiscomas and acrochordons - together with an increased risk of renal tumors and spontaneous pneumothoraces. BHDS should be considered, along with tuberous sclerosis and multiple endocrine neoplasia type 1 in the differential diagnosis of multiple facial angiofibromas and collagenomas, particulary when the onset is in adulthood.[4] Angiofibromas seen in MEN 1 are clinically and histologically indistinguishable from those observed in TSC.[5] However, angiofibromas in patients with MEN 1 tend to be smaller and fewer in number than in those with severe TSC. In the former, they also tend to appear on the upper lip and its vermilion border, regions usually spared in patients with TSC.[6] So a thorough search should be made for other associated cutaneous tumors and systemic involvement before arriving at a final diagnosis.

Angiofibromas and collagenomas (single or multiple) have 50-65% sensitivity and 92-100% specificity for MEN 1. The combination criteria of multiple angiofibromas (more than three) and any number of collagenomas had the highest sensitivity (75%) and specificity (95%). This criterion has greater sensitivity than pituitary or adrenal disease and is comparable to hyperparathyroidism in some studies of patients with MEN 1 with gastrinoma.[7] These cutaneous tumors also help in the presymptomatic diagnosis of MEN 1 because, even though the symptoms of endocrine tumors are delayed until the fourth decade, the cutaneous tumors make their first appearance in the teenage years itself. In addition, symptoms of hormone dysregulation may mimic non-endocrine diseases including neurologic or psychiatric disorders. Depression often associated with hyperparathyroidism and hypercortisolism.[89] Confusion and abnormal behavior characterize hypoglycemic episodes in patients with insulinomas and they are often unrecognized or mistaken for seizures or psychiatric disorders.[10]