PEDIATRIC DENTISTRY / Copyright © 1979 by The AmericanAcademy of Pedodontics / Vol. 1, No. 2 / Printed in U.S.A.

Multiple endocrineneoplasia, Type 2B,with medullarythyroid carcinoma: adiagnostic potentialfor dentistry*Gayle Nelson, D.D.S.Thomas Aceto, Jr., M.D.Michael Keppen, M.D.Loyd Wagner, M.D.

Multiple endocrine neoplasia (MEN) Type 2B is designation that has been proposed for the combina-tion of medullary thyroid carcinoma (MTC), parathy-roid adenoma, pheochromocytoma, mucosal neuro-mas, and somatic abnormalities. ~ The neural lesionsproduced a characteristic diffuse or nodular involve-ment of the tongue, lips, and buccal mucosa. Becauseof these multiple neuromas on the mucosal surfaces,this entity also became known as "multiple mucosalneuroma syndrome.’’2 Early recognition of the orallesions and peculiar facies present a pathognomonicpattern for this disease. It is a pattern which shouldalert the dental clinician to a potentially lethal set ofsequelae.

Three forms of MEN have been defined. They areType 1, Type 2A, and Type 2B which is also calledType 3 by some authorities. 3 Type 1 involves thepituitary and adrenal glands.3 Type 2A includes MTC,pheochromocytoma, and parathyroid adenoma.5 Inaddition to the same involvement as Type 2A, Type2B (or Type 3) also includes the entities of mucosal-neuromas, peculiar facies, and other somatic abnor-malities.6

The mucosal neuromas, which are microscopicallycomposed of enlarged tortuous nerves, constitute a

* The authors would like to acknowledge Dr. Edmond McGreevy,Dr. L. Gilbert Thatcher, and Dr. Donald Mehrens who assisted inthe preparation of the manuscript and served as consultants in themanagement of this case.

valuable clinical marker of the syndrome since theyare present in childhood and generally antedate clini-cal presentation of the thyroid and adrenal neoplasms.They produce characteristic enlargement of the lipsand nodularity of the tongue, and, although they areasymptomatic and benign, they cause psychologic up-set because of unsightliness and may require surgicalcorrection of the deformity. ~ Other areas of mucousmembrane which lend themselves to clinical exami-nation by the dentist would include the conjunctiva.Such mucosal neuromas are likewise found in thisarea.7 (Fig. 1).

Clinical characteristics include marfanoid habituswith long limbs, scoliosis, chest deformities, pes cavus,and hyperextensible joints. These patients presentalso with thickened, anteverted eyelids; nasal muco-sal neuromas; and a peculiar facies, which has beendescribed as "coarse-appearing" (Fig. 2).

The manifestations in the oral cavity include mul-tiple neuromas on the anterior one-third of the tongue,upper and lower lips, the buccal mucosa adjacent tothe oral commissures, and occasionally the palate andmandible. A complete review of 51 cases with charac-teristic oral findings has been reported in literature.~

The absence of a palpable thyroid mass in personswith the other clinical signs and symptoms is notreason enough to discount the almost certain presenceof a MTC. Thus, in an effort to aid in early detectionand minimal metastases, these patients should be eval-uated immediately.

Report of a Case

D.H., a 15-year-old male, was referred to the De-partment of Pediatrics and Adolscent Medicine at theUniversity of South Dakota in late 1976 by this pedi-atric dentist who recognized peculiar facies and orallesions (Figs. 2 and 3).

Constipation, the first manifestation of chronic dis-ease, had begun at age four months. The patient washospitalized on five separate occasions between 1963and 1969 for chronic constipation. A barium enema in1965 was interpreted as normal; however, in 1969 abarium enema revealed dilatation of the colon. At thelaparotomy in 1969, the colon was found to be diffuselythickened with nodular growths. A total colectomyand ileoprocto-anastomosis was performed.

The Armed Forces Institute of Pathology diagnosedganglioneuromatosis from histologic section.

Following the colectomy, the patient experiencedepisodes of abdominal distention and discomfort

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Fig. 1.

Fig. 2.

which simulated small bowel obstruction. He was hos-pitalized five times from 1969 to 1971 for this problem,twice undergoing laparotomy for lysis of adhesions.The patient gave no history of flushing, excessivesweating, or "spells." He had experienced nocturnalenuresis since the time of the colectomy.

His weight and height were above the fiftieth per-

centile in 1969. Both parameters were at the thirdpercentile in 1977. The conjunctiva! surfaces of theupper and lower eyelids exhibited neuromas (Fig. 1).Corneal nerves were thickened on slit lamp examina-tion.

Family history was negative for coarse-appearingfacies, thyroid cancer, or sudden deaths.

Oral findingsThe lips were diffusely enlarged and appeared ev-

erted and patulous (Fig. 2). There were palpablemasses in both the upper and lower lips. The mostprominent and unsightly mass was in the midline ofthe upper lip. There were flattened, plate-like projec-tions just adjacent to the labial commissure, bilat-erally. The anterior one-third of the tongue presentedwith regularly shaped, round, raised lesions whichresembled the size of typical circumvallate papillae,i.e., 0.3 X 0.5 mm in diameter with sessile base at-tached. The tongue appeared to be long and narrow,having normal functional movements. On the otherhand, the lips were flaccid and exhibited little mus-cular tonus. Multiple diastemata between the perma-nent teeth and anterior protrusion of maxillary andmandibular dental arches were present (Fig. 4).

This middle and lower face protrusion is reflectedin the cephalometric tracing of a lateral radiograph ofthe head. The sella-nasion-A point of the maxilla(SNA) is 86 degrees, with 81 degrees being the normalrange. The sella-nasion-B point of the mandible (SNB)is 80 degrees, with 78 degrees being normal. The incisallabial inclination of the anterior teeth is reflected inthe inter-incisive angle. This measures 107 degreescompared to a more obtuse angle of 128 degrees beingnormal. Cephalometric measurements have not beendocumented in previous cases.

Fig. 3.

MEN 2B-MTC DIAGNOSIS126 Nelson et al.

Fig. 4.

Permanent teeth exhibited a marked delay in theexfoliation schedule. At age 15, only 12 permanentteeth were erupted, and 12 primary teeth remained toexfoliate.

The gingival tissue was not hypertrophied; however,it was inflamed and tended to bleed easily. Oral hy-giene was excellent. The patient complained of dis-comfort throughout the course of physiologic toothexfoliation.

No thyroid nodules or cervical adenopathy werenoted. No cafe-au-lait spots, diffuse pigmentation, orneurofibromas were found on the trunk or extremities.

Thyrocalcitonin levels were markedly elevated. Thishormone is made by the c-cells of the thyroid medulla.An increase in thyrocalcitonin levels is seen in c-cellhyperplasia and MTC.

With the data obtained, the patient was referred tothe Mayo Clinic in August, 1977, for confirmation ofdiagnosis. There the patient underwent total thyroid-ectomy with a modified radical neck dissection. A 12-g gland with multiple, palpable nodules was removed.Medullary carcinoma with amyloid stroma was seenon microscopic sections. Metastatic involvement waspresent in multiple jugular and tracheoesophagealnodes and in one mediastinal node. A parathyroidadenoma was identified and removed.

Discussion

The characteristics of patients with MEN, Type 2B,can be easily overlooked in the routine clinical exam-ination. Patulous, nodular lips, nodular lesions on thetongue, anteverted eyelids, and peculiar facies led theclinician to the possibility of MEN Type 2B. Earlyrecognition of this syndrome will contribute to earlydiagnosis of MTC and pheochromocytoma. Many in-

stitutions are stressing the need for a prophylacticthyroidectomy.

In the study of Carney et al.,815 of 17 patients withgastrointestinal problems of MEN syndrome, such asconstipation, diarrhea, and cramping, had obvious orallesions at birth or in early childhood. In two of thesepatients, the oral lesions were present for 26 years ormore before other symptoms of the disease appeared.It is important to reemphasize that GI problems suchas constipation, cramping, diarrhea, etc., combinedwith distinctive oral lesions are signs of the MENsyndrome.

Little has been written about the cephalometricassessment of these patients. An anterior position ofboth mandibular and maxillary segments relative tothe cranial base was noted here. The anterior mandib-ular and maxillary permanent teeth were flared andexhibited multiple diastemata. This could be attrib-uted to a muscular imbalance between the musculartongue and flaccid lips.

This syndrome follows a strong autosomal dominantinheritance pattern. With this in mind, the clinicianshould thoroughly examine siblings and other imme-diate family members for potential occult involve-ment.

The patient discussed experienced slowing of growthand short stature rather than the usually tall, marfan-oid appearance. Many factors may have influenced hisgrowth failure; among them are intestinal malabsorp-tion and excess thyrocalcitonin.

The preoperative clinical evaluation of this patientdemonstrated no objective anatomic evidence forMTC or metastases. The decision to remove this pa-tient's thyroid was made because of the very highincidence of MTC in patients with distinctive pheno-typic features of the syndrome of MEN Type 2B dueto the increased thyrocalcitonin levels. MTC is thesingle most important cause of mortality in the MENType 2B syndrome.

No chemotherapy or suppressive protocols havebeen used on this individual since the cells involved inthis type of carcinoma do not respond well to chemo-therapy.

Summary

(1) Because of the craniofacial anomalies in thissyndrome, the dentist should be able to diagnose MENType 2B. It is important that the dentist be aware ofthis syndrome, since these patients have potentiallylethal endocrine neoplasia.

(2) Oral lesions of ganglioneuromatosis or unex-plained GI problems such as constipation, diarrhea,etc., should prompt consideration of MEN Type 2B inthe diagnosis.

(3) Total thyroidectomy should be considered for all

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patients with the syndrome since MTC is potentiallypreventable if removed in the early stage of c-celldisease.

References

1. Carney, J. A., Sizemore, G. W., and Lovestedt, S. A.: "MucosalGanglioneuromatosis, Medullary Thyroid Carcinoma and Phe-ochromocytoma: Multiple Endocrine Neoplasia, Type 2B," OralSurg, 739-752, 1976.

2. Smith, D. W.: Recognizable Patterns of Human Malformation,2nd ed., Philadelphia: W. B. Saunders Company, 1976.

3. Khairi, M. R. A., Dexter, R. N., Burzynski, N. J., and Johnston,C. C., Jr.: "Mucosal Neuroma, Pheochromocytoma and Medul-lary Thyroid Carcinoma: Multiple Endocrine Neoplasia Type3," Medicine (Baltimore), 54:89-112, 1975.

4. Sipple, J. H.: "The Association of Pheochromocytoma withCarcinoma of the Thyroid Gland," Am J Med, 163-166, 1961.

5. Williams, E. D.: "A Review of 17 Cases of Carcinoma of theThyroid and Pheochromocytoma," J Clin Pathol, 18:288-292,1965.

6. Steiner, A. L., Goodman, A. D., and Powers, S. R.: "Study of aKindred with Pheochromocytoma, Medullary Thyroid Carci-noma, Hyperparathyroidism and Cushing's Disease: MultipleEndocrine Neoplasia, Type 2," Medicine (Baltimore), 47:371-409, 1968.

7. Williams, E. D., and Pollock, D. J.: "Multiple Mucosal Neuro-mata with Endocrine Tumors: A Syndrome Allied to von Reck-linghausen's Disease," J Pathol Bacterial, 91:71-80, 1966.

8. Carney, J. A., Go, V. L. W., Sizemore, G. W., and Hayles, A. B.:"Alimentary-Tract Ganglioneuromatosis: A Major Componentof the Syndrome of Multiple Endocrine Neoplasia, Type 2B," NEnglJMed, 295:739-752, 1976.

Dr. Gayle V. Nelson, Assistant ClinicalProfessor of Pediatrics at the Univer-sity of South Dakota and NebraskaMedical Schools, is primarily in privatepractice of pediatric dentistry in SiouxFalls, South Dakota. Requests for re-prints should be addressed to: Dr. G.V. Nelson, 101 So. Cleveland, SiouxFalls, South Dakota 57103.

Dr. Michael Keppen is resident in In-ternal Medicine, University of Okla-homa, Oklahoma City, Oklahoma.

Dr. Thomas Aceto, Jr., is Professorand Chairman of Pediatrics—Adoles-cent Medicine, University of South Da-kota Medical School, Sioux Falls,South Dakota.

Dr. Loyd Wagner is Clinical AssistantProfessor, Department of LaboratoryMedicine, University of South DakotaMedical School, Sioux Falls, South Da-kota.

MEN 2B-MTC DIAGNOSIS128 Nelson et al.