Diabetes Mellitus as a Primary Manifestation of Multiple Endocrine Neoplasia Type 2B

Opmaak 1Introduction
The multiple endocrine neoplasia (MEN) type 2 is a familial syndrome transmitted as an autosomal dominant trait, associating various endocrine tumours. It has been subcategorized into two major syndromes called MEN 2A and MEN 2B. The MEN 2A accounting for over 75% of MEN 2 combines medullary thyroid carcinoma (MTC), phaeochromocytoma and hyperparathy- roidism (1-4). Several subvariants of MEN 2A have been described, such as familial medullary thyroid carcinoma (FMTC), MEN 2A with lichen amyloidosis and MEN 2A with Hirschsprung disease. MEN 2B, much less common but also more aggressive, associates CMT and phaeochromocytoma with multiple mucosal neuromas, ganglioneuromatosis of the gastrointestinal tract and a marfanoid habitus whereas hyperparathyroidism is absent (1-4, 5, 6). Although the identification of mucosal neuromas in a
child, especially on the distal part of the tongue, the lips and subconjonctival areas should alert the clinician to a diagnosis of MEN 2B, this phenotype could be unrecog - nized at first glance. The patient may present with symptoms related to phaeochromocytoma or ganglioneu- romatosis of the gastrointestinal tract (3, 5). The latter can cause diarrhoea, intestinal obstruction and colic-like childhood syndrome. Clinical presentation of phaeochro-
mocytoma is highly variable but usually consists of episodes of headaches, sweating, palpitations and hyper- tension. Hyperglycaemia can also be observed in phaeochromocytoma but is not a common inaugural symptom (7-13). We hereby report the history of a young patient in whom diabetes mellitus was the first clinical manifestation of phaeochromocytomas and who was eventually diagnosed with MEN 2B.
Case report
A 22-year-old man with a past history of pneumothorax and several operations for club feet was found to have diabetes mellitus two years before admission. His father who had a marfanoid appearance died at the age of 39 of rupture of an aneurysm. Diagnosis of diabetes mellitus was made by his GP on the basis of an oral glucose tol- erance test showing an increase in blood glucose from 92 to 248 mg/dl at 120 minutes. The patient was then treat- ed with metformin which was discontinued because of dizzy spells suggestive of hypoglycaemia. The patient was urgently referred to the emergency department of the hospital for acute dyspnoea due to a recurrence of pneumothorax. A Computed Tomography (CT) scan of the chest performed after aspiration disclosed bilateral adrenal masses (Fig. 1). History revealed attacks of epi- gastric, muscular and neck pain, that occurred after
Acta Chir Belg, 2008, 108, 732-737
Diabetes Mellitus as a Primary Manifestation of Multiple Endocrine Neoplasia Type 2B
J. E. Donckier*, A. Rosière**, F. Heureux*, L. Michel**
Departments of Internal Medicine and Endocrinology* and Surgery** University Hospital of Mont-Godinne, Université Catholique de Louvain, Yvoir, Belgium.
Key words. Diabetes mellitus ; multiple endocrine neoplasia type 2B ; phaeochromocytoma ; medullary thyroid carci- noma ; ganglioneuroma.
Abstract. A 22-year-old-man presenting with diabetes mellitus was found to suffer from multiple endocrine neoplasia type 2B (MEN B). The characteristic phenotype including mucosal neuromas, musculoskeletal abnormalities and a marfanoid habitus led us to suspect this diagnosis, which was confirmed by the genetic analysis showing the typical mutation in the RET proto-oncogene at codon 918. Subsequently, diagnoses of bilateral phaeochromocytoma and medullary thyroid carcinoma were made. The patient underwent first a laparoscopic removal of bilateral phaeochromo- cytoma and a radical thyroidectomy three months later. Both operations were uneventful. After operation, diabetes resolved, an effect partly explainable by an improvement of insulin sensitivity. Thus, clinicians should be aware of a diagnosis of MEN 2B in a young patient presenting with diabetes, a typical phenotype, symptoms of phaeochromocy- toma or a nodule in the thyroid.
Case reports
Diabetes Mellitus and MEN 2B 733
meals or defecation. Intestinal transit was however reported as normal with two motions a day. A diagnosis of phaeochromocytoma was then suspected. On clinical examination, the patient had a tall stature (182 cm for a weight of 44 kg), a marfanoid habitus (Fig. 2) and increased joint laxity. Heart rate was 85/min and blood pressure 120/70 mmHg. Neuromas were found on the distal part of the tongue as well as on the conjunctive of both eyes (Fig. 3). Palpation of the neck revealed a goitre and a nodule in the right lobe of the thyroid. There was no lymphadenopathy. The heart, lungs and abdomen were normal. The patient could only walk on his toes because of a limitation of foot flexing resulting from pre- vious operations. A slit lamp examination of the eyes demonstrated enlarged corneal nerves. A 24-hour contin- uous blood pressure monitoring showed mean blood pressure values of 116/68 mmHg. Laboratory findings showed normal C-reactive protein, full blood count, renal function, electrolytes and liver enzymes. Calcium, phosphorus and parathormone levels were within the normal range. Thyroid function tests were normal but calcitonin was increased at 1480 pg/ml (normal 0-10). Chromogranin was also raised at 218 U/l (normal < 23). Supine aldosterone and renin activity were normal at 0.286 nmol/l (normal 0.038-0.44) and 0.82 ng/ml/h (nor- mal 0.2-2.8) respectively. DHEA sulfate was normal at 4.4 µM (normal 2.5-12). Urine free cortisol was 177 µg/day (normal 20-90). 24-hour urinary cate- chomamine levels were as follows : adrenaline 41 µg/day (normal 1.7-22.4), noradrenaline 270.3 µg/day (normal
Fig. 1 Abdominal computed tomography (CT) scan showing bilateral phaeochromocytoma (left). The 123I-metaiodobenzylguanidine (MIBG) scintigraphy confirmed bilateral adrenal hotspots consistent with the diagnosis of phaeochromocytoma (right).
Fig. 2 Appearance of the patient. As commonly observed in MEN 2B, he exhibits a marfanoid habitus with a tall stature, long limbs and a long thin face with prognathism.
734 J. E. Donckier et al.
12.1-85.5), dopamine 262 µg/day (normal 50-600), metadrenaline 4108 µg/day (normal 52-341), normeta- drenaline 9884 µg/day (normal 88-444), and vanillyl- mandelic acid 20.4 mg/day (normal 1.2-6.5). A glucose tolerance test showed an increase in blood glucose from 99 mg/dl to 240 mg/dl at 120 minutes and of plasma insulin from 6.53 to 93.4 µU/ml, which was consistent with a diagnosis of diabetes. Glycated haemoglobin was 6.1%. The other investigations consisted in 123I- metaiodobenzylguanidine (MIBG) scintigraphy which showed intense hotspots in both adrenals (Fig. 1) and a thyroid isotope scan which revealed a goitre and a cold nodule in the right lobe. Neck ultrasound confirmed this nodule whose dimensions were 15 15 24 mm and which was associated with several other small nodules in both lobes. Altogether, a diagnosis of MEN 2B associat- ing MTC and bilateral phaeochromocytomas was made. This diagnosis was confirmed by a genetic analysis showing the typical mutation in the RET proto- oncogene, with a methionine to threonine substitution at codon 918. After being given terazocin, an alpha- adrenergic blocking agent, the patient underwent a laparoscopic removal of bilateral phaeochromocytoma,
which was uneventful. The endoscopic approach to the adrenals was transperitoneal via a supracolonic access to the retroperitoneal space. The patient was operated in the lateral decubitus, the operated side up. The position was changed between the removals of the left and the right phaeochromocytomas. Pathological examination revealed a 5 cm phaeochromocytoma in the left adrenal and three nodules of 1.5 cm in diameter also containing typical lesions of phaeochromocytoma in the right adre- nal. A fourth 6 mm nodule composed of chromaffin cells was finally found next to the left adrenal cortex. Replacement therapy with cortisol and 9-alpha fludro- cortisone was then initiated. Three months later, a radical thyroidectomy was performed. Pathological findings confirmed MTC, located in three nodules, one in the right lobe (2.5 cm in diameter), two in the left (1.7 and 1 cm in diameter). Replacement therapy with thyroid hormones was also given. Three months after operation, calcitonin has decreased to 72 pg/ml and 24-hour catecholamine excretion is normalized. The patient feels better and has gained 8 kilograms. Paroxysmal symp- toms have completely resolved. A new glucose tolerance test now shows an increase in blood glucose from 84 to
Fig. 3 The patient has facial features of MEN 2B, including mucosal neuromas on the anterior third of the tongue, the lips and the inner eye- lid (A and B). Lips are thickened and bumpy and the upper eyelids everted. Slit lamp examination reveals corneal nerve hypertrophy (C).
A
B
C
149 mg/dl at 120 minutes and of plasma insulin from 12.3 to 28 µU/ml which indicates a simple glucose intolerance. To assess a possible bowel involvement, we performed more recently a barium enema, which demonstrated severe diverticulosis of the left colon (Fig. 4).
Discussion
We here report the case of a patient in whom diabetes mellitus was the first clinical manifestation of bilateral phaeochromocytomas that occurred in the setting of a MEN 2B syndrome. Although diabetes was reported in phaeochromocytoma with a prevalence of 36-50% (2, 7- 9), it occurs less commonly as a primary symptom of the tumour. The mechanisms underlying the development of diabetes are complex and result from the metabolic actions of catecholamines circulating at high concentra- tions (7, 12, 13). Adrenaline appears to be more potent than noradrenaline in producing hyperglycaemia. Its plasma concentrations have been significantly and inde- pendently related to the presence of diabetes in patients with phaeochromocytoma. A first action of adrenaline, considered as a main cause of diabetes is an impairment of insulin secretion which is a2-receptor mediated (14, 15). In the liver, adrenaline activates b2-receptors to
Diabetes Mellitus and MEN 2B 735
enhance both glycogenolysis and gluconeogenesis (16). Finally, adrenaline limits glucose utilization in muscle through direct b2-adrenergic effects (17). In our patient, it is difficult to establish which mechanism was predomi- nant. Both adrenaline and noradrenaline were secreted in excess. During an oral glucose tolerance test performed before operation, plasma insulin increased significantly but insufficiently to prevent glucose levels to reach a dia- betic threshold. After removal of tumours, diabetes resolved and the oral glucose tolerance test only showed mild glucose intolerance. The increase in insulin secre- tion was less pronounced than before operation, which could suggest improved insulin sensitivity. Such an inter- pretation is supported by a previous study showing in 10 patients with phaeochromocytomas (5 with diabetes and 5 without) a decrease in fasting hyperinsulinaemia after operation (10). In addition, using the technique of the euglycaemic hyperinsulinaemic clamp, the authors observed after operation a significant improvement of insulin sensitivity. This study, however, does not exclude that defects in insulin secretion also contributed to alter- ations in glucose metabolism, a view supported by other authors (14, 15). A diagnosis of MEN 2B was made in our patient at
the age of 20. This is relatively late because patients with MEN 2B usually present in the first to the second decade of life (5). However, in a recent series of 21 patients with MEN 2B, the age at diagnosis could range from 1 to 31 years (6). Conversely, MEN 2A appears more often in the second and the third decade (5). The clinical diagno- sis of MEN 2B was confirmed in our patient by the genetic analysis showing the typical RET mutation at codon 918. This specific mutation is found in over 95% of MEN 2B (3, 18) although other mutations (at codons 883, 922, 804/806 and 804/904) have been reported less frequently (3, 6). Interestingly, 50% of MEN 2B are due to de novo mutations (19). In this case, the absence of family history associated with a rare syndrome and the lack of experience of primary care physicians could account for a delay in diagnosis. A study reported a median delay in diagnosis of 26 months (range 0- 18 years) from onset of a MEN 2B complaint to the cor- rect diagnosis (20). Our patient is likely to have inherit- ed the syndrome from his father as the latter had also a marfanoid appearance and died very early of rupture of an aneurism. Sex distribution is usually thought to be equal in MEN 2B. Nevertheless, Carlson et al demon- strated in a series of 25 sporadic cases that all of them were formed from mutations on the paternally derived chromosome, suggesting that a RET allele might be more susceptible to mutation when inherited from the father (19). The characteristic phenotype of our patient (his mar-
fanoid habitus, mucosal neuromas, increased joint laxity and abnormalities of feet) in association with MTC and
Fig. 4 Barium enema showing severe diverticulosis of the left colon
736 J. E. Donckier et al.
bilateral phaeochromocytomas led to the diagnosis of MEN 2B. MTC has been reported to occur in all cases of MEN 2B whereas phaeochromocytomas develop in approximately 50% of patients (21). In a recent series of 22 patients with MEN 2B identified between 1973 and 2006 from the database of The University of Texas MD Anderson Cancer Center, the frequency of extrathyroidal manifestations were 45% for phaeochromocytomas, 100% mucosal neuromas, 45% for musculoskeletal abnormalities, 73% for gastrointestinal dysmobility and 41% for enlarged corneal nerves (20). In this series, phaeochromocytomas were diagnosed later than MTC, the age at the time of diagnosis ranging from 19 to 33 years for phaeochromocytoma and from 6 to 25 years for MTC. Only two patients had a synchronous diagno- sis of phaeochromocytoma and MTC, just like in our patient. Surprisingly, intestinal symptoms were missing in our patient, his bowel movement being normal. Intestinal involvement is however a common feature of MEN 2B (5, 20, 22). It is characterized by diffuse intes- tinal ganglioneuromatosis, which can occur anywhere in the gastrointestinal tract and lead to a loss of normal bowel tone, diverticulosis, colonic distension and mega- colon (22). Symptoms often start in infancy or early childhood. At this time, patients may document a failure to thrive, poor feeding or constipation whereas adults more often report either constipation or diarrhoea. Clinical presentation may be more severe, including abdominal pain and vomiting, some patients even requir- ing surgery such as partial colectomy (20). Fortunately, investigations performed in our patient only revealed a diverticulosis, that has remained uncomplicated so far. Regarding the surgical strategy, our patient underwent
a laparoscopic removal of phaeochromocytomas before MTC, which we found the wisest attitude to avoid a potential intraoperative catecholamine crisis. Therefore, in all cases of MEN 2B, a systematic screening for the presence of phaeochromocytoma should be recommend- ed before thyroidectomy as well as a regular screening thereafter. An appropriate pharmacological preparation is also mandatory, which in the present case was fully satis- factory with the alpha-adrenergic blocker terazocin. Administration of a beta-adrenergic blocking agent (only after alpha-blockade) may be sometimes a useful adjunct. Some authors also advocate the safety of calcium block- ers. The surgical approach can be a laparoscopic adrena- lectomy. In our experience, this technique proved to be safe and effective in terms of intra- and postoperative morbidity (23, 24). In MEN 2B, we would favour unilat- eral adrenalectomy when only one gland is affected in order to delay steroid replacement therapy. A close fol- low-up of the patient is then needed. However, it is note- worthy that other authors recommend an initial bilateral adrenalectomy because of the high incidence of bilateral lesions even at a cellular level and to avoid further opera-
tions and metastases (25). Few phaeochromocytomas (approximately 10%) are malignant in MEN 2B (5). This is quite different from MTC, which is extremely aggres- sive in the syndrome. Indeed, among MEN 2 variants, the aggressiveness of MTC has been classified in decreasing order as following : MEN 2B > MEN 2A > FMTC (1, 26). Therefore, prophylactic thyroidectomy has been recommended once a RET mutation is detected and should be performed, even in infancy before 6 months of age (1, 20). A central and bilateral lateral neck dissection is also usually recommended unless the diagnosis is made in the first few years of life (1, 20). In conclusion, we report a case of MEN 2B presenting
with diabetes as a primary manifestation of the syn- drome. The association of diabetes with a characteristic phenotype including mucosal neuromas, musculoskele- tal abnormalities and a marfanoid habitus should prompt the clinician to search for a diagnosis of MEN 2B. Once the diagnosis established, the patient should be screened for the presence of phaeochromocytoma and MTC.
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