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Case report: multiple endocrine neoplasia type 2B misdiagnosed as familial dysautonomia E. MASS*, M. LAPIDOT**, N. GADOTH*** ABSTRACT. Background Familial dysautonomia (FD) is a rare autosomal recessive disorder of the peripheral nervous system, affecting exclusively Jewish children of Ashkenazi extraction. The typical clinical features consist of somatic abnormalities: failure to thrive, characteristic facies, excessive sweating, labile blood pressure, recurrent aspiration pneumonias, lack of tears, and diminished and later absent deep tendon reflexes with generalized reduction of pain sensation. Oro-dental features include a lack of tongue fungiform papillae, impairment of taste, oro-dental self-mutilation, dental crowding, excessive plaque and calculus accumulation, salivary over production and low caries experience. Case report A child with multiple endocrine neoplasia type 2B (MEN 2B) received, at the age of 11 months, an incorrect diagnosis of familial dysautonomia (FD). At the age of 6 years, a paediatric dentist experienced with FD noticed a normal number and shape of tongue fungiform papillae, while expecting to find a smooth tongue lacking those structures. The presence of numerous submucosal neuromata initiated a meticulous neurological and endocrine work-up, which established the diagnosis of MEN 2B. This led to an early detection and appropriate treatment of asymptomatic medullary thyroid carcinoma (MTC). KEYWORDS: MEN 2B, Familial dysautonomia, Tongue, Submucosal neuromata.
Background Familial dysautonomia (FD) is a rare autosomal recessive disorder of the peripheral nervous system, affecting exclusively Jewish children of Ashkenazi extraction. The typical clinical features consist of somatic abnormalities such as failure to thrive, characteristic facies, excessive sweating, labile blood pressure, recurrent aspiration pneumonias, lack of tears, diminished and later absent deep tendon reflexes with generalized reduction of pain sensation. There are also a number of characteristic oro-dental features, such as lack of tongue fungiform papillae, impairment of taste, oro-dental self-mutilation, dental crowding, excessive plaque and calculus accumulation, salivary over production, and low caries experience [Mass et al., 1992; Mass and Gadoth, 1994; Gadoth, 1995; Mass et al., 1996; Gadoth et al., 1997]. *Department of Paediatric Dentistry, Goldschleger School of Dental Medicine **Institute of Adult Endocrinology, Rabin Medical Center, Beilinson Campus, Petah Tiqva ***Department of Neurology, Meir General Hospital, Kfar Saba, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel E-mail:
[email protected]
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Oral multiple mucosal neuromata are the hallmark of multiple endocrine neoplasia type 2B (MEN 2B), which consists of medullary thyroid carcinoma (MTC) and pheochromocytoma. Children affected by MEN 2B may suffer from ‘dysautonomic’ symptoms in the form of bouts of facial flushing, drooling, diarrhoea and constipation [Edwards and Reid, 1998]. The present case report describes a child with minor ‘dysautonomic’ features who received a diagnosis of FD at an early age by paediatricians specializing with FD. Some years later, a paediatric dentist who provided dental care for children in FD noticed the presence of tongue submucosal neuromata which led with to the correct diagnosis of MEN 2B.
Case report A 16-year-old Jewish Ashkenazi right handed male was diagnosed with familial dysautonomia at the age of 11 months at a special center for this disease. At 2.5 years of age he was first seen by one of the authors (EM) who had been providing dental care for a relatively large number of children with FD. The unrelated parents and two older siblings were healthy. 1
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FIG. 1 - a) Photograph of anterior dorsal surface of the tongue with large sessile confluent nodules characteristic of submucosal neuromata (arrow). Note numerous normal appearing fungiform papillae (arrowhead); b) intraoral photograph showing submucosal neuromata are present in the labial vestibulum and anterior to the incisive papilla (arrows).
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During infancy failure to thrive, numerous breath holding spells and attacks of facial flushing were reported. Later, consistent drooling, peculiar asymmetrical facial appearance and frequent bouts of vomiting were noted. The initial dental treatment session was due to a traumatic injury of the maxillary primary incisors. The child had asymmetrical coarse facial appearance with thick lips and high arched palate which seemed at that time to be different from the oral and facial features of other children with FD. The characteristic facial features of FD consisted of frightened apprehensive facial expression, sweaty and pale facial skin, asymmetrical facial features, thin lips, shallow cheeks, hypertelorism, concomitant strabismus and dry and reddish appearing corneas secondary to poor tearing, the ‘dysautonomic face’ [Rotem, 1989]. This was discussed with the mother who insisted that the diagnosis of FD had been confirmed in several centers. At the age of 6 the patient underwent a second dental assessment by the same paediatric dentist. He was of normal height and weight but appeared ‘marfanoid’. The anterior surface of the tongue was covered with multiple sessile confluent nodules, which were also present on the anterior maxillary frenulum and incisive papilla. There were numerous normal shaped fungiform papillae (Figs. 1a and 1b). These findings were exceptional for FD, but suggestive of MEN. The complete neurological examination was essentially normal. In particular, the oro-dental, somatic and corneal pain perception, tearing, taste, sweating, deep tendon reflexes, pulse and blood pressure were all normal. These findings were considered incompatible with the diagnosis of FD. 2
Light and electron microscopy of a biopsy obtained from one of the tongue nodules (by professor HH Goebel, Mainz, Germany), disclosed the presence of classical neuromata. Once the presence of submucosal neuromata was confirmed, an appropriate evaluation for MEN 2B yielded high levels of calcitonin, which suggested the presence of medullary thyroid carcinoma and was followed by total thyroidectomy. Pheochromocytoma was not present. A metastatic cervical lymph node was removed 2 years later, followed by several neck dissections thereafter. Recently, a new cervical metastasis was found and excised. All metastatic nodes were confirmed histologically as medullary thyroid carcinoma. Gastrointestinal workup disclosed the presence of megacolon, which was defined as pseudo Hirschprung’s disease. Genetic studies revealed a MET 918 THR mutation at the RET gene locus. Genetic testing for FD was negative.
Discussion Familial dysautonomia is a rare autosomal recessive disorder with characteristic clinical and oro-dental features. Being exclusively expressed in Jewish children of Ashkenazi origin its occurrence in this particular population is not so rare, with a gene frequency of 1:32 [Gadoth, 1995]. Prior to the recent discovery of the genetic defect responsible for FD [Cuajungco et al., 2003], the diagnosis was based on clinical features only. The tongue has served as an easy diagnostic tool as the lack of fungiform papillae was considered unique and pathognomonic [Gadoth et al., 1982]. The presence of normal fungiform papillae, normal skin EUROPEAN JOURNAL OF PAEDIATRIC
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MISDIAGNOSIS OF MEN 2B AS FAMILIAL DYSAUTONOMIA
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sensation, deep tendon reflexes and tearing and the negative genetic testing for familial dysautonomia in our patient was sufficient to discard this diagnosis. The association of ‘marfanoid features’, drooling, intestinal ganglioneuromatosis causing pseudoHirschprung’s disease, MTC, and pheochromocytoma (not found in our patient) are compatible with the diagnosis of MEN 2B. This diagnosis was further confirmed by the presence of the MET 918 THR mutation at the RET gene locus. The presence of mucosal neuromata should always alert the paediatric dental clinician to the possibility of MEN 2B and should initiate an extensive search for associated neoplasms such as MTC and pheochromocytoma. Elevated calcitonin is a useful clue for the diagnosis of MTC as this hormone is secreted by the tumor. The detection of MEN 2B in subjects with the RET mutation at the codon 918 may be life saving. The MTC in subjects with this mutation has an early onset and an aggressive course [Dralle et al., 1998]. Recently it has been recommended that prophylactic thyroidectomy in these patients should be performed as early as 6 months [Leboulleux et al., 2002; Kahraman et al., 2003]. Indeed, in spite of the fact that the diagnosis in our patient was reached relatively early, the child had already metastatic MTC and the course thereafter was far from favorable. The misdiagnosis of FD in this patient is somewhat surprising. It was based on minor ‘dysautonomic’ clinical signs and symptoms, disregarding the presence of normal tongue fungiform papillae and uncharacteristic facies and body stature. The Ashkenazi ethnic background probably contributed to the incorrect diagnosis. The establishment of the correct diagnosis in this patient by a dentist experienced with the oro-dental features and phenotypic characteristics of FD provided a chance for early and probably life saving treatment of a malignant disease at a presymptomatic stage.
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References Cuajungco MP, Leyne M, Mull J, Gill SP, Lu W, Zagzag D et al. Tissue-specific reduction in splicing efficiency of IKBKAP due to the major mutation associated with familial dysautonomia. Am J Hum Genet 2003 Mar;72(3):749-58. Dralle H, Gimm O, Simon D, Frank-Raue K, Gortz G, Niederle B et al. Prophylactic thyroidectomy in 75 children and adolescents with hereditary medullary thyroid carcinoma: German and Austrian experience. World J Surg 1998 Jul;22(7):744-50; discussion 750-1. Edwards M, Reid JS. Multiple endocrine neoplasia syndrome type IIb: a case report. Int J Paediatr Dent 1998 Mar;8(1):55-60. Gadoth N. Familial Dysautonomia: Hereditary Autonomic and Sensory Neuropathy Type III. In: Korczyn AD, ed. Handbook of Autonomic and Sensory Nervous System Dysfunction. New York: Marcel Dekker Publisher; 1995. pp. 95-115. Gadoth N, Mass E, Gordon CR, Steiner JE. Taste and smell in familial dysautonomia. Dev Med Child Neurol 1997 Jun;39(6):393-7. Gadoth N, Margalith D, Schlien N, Svetliza E, Litwin A. Presence of fungiform papillae in classic dysautonomia. Johns Hopkins Med J 1982 Dec;151(6):298-301. Kahraman T, de Groot JW, Rouwe C, Hofstra RM, Links TP, Sijmons RH, Plukker JT. Acceptable age for prophylactic surgery in children with multiple endocrine neoplasia type 2a. Eur J Surg Oncol 2003 May;29(4):331-5. Leboulleux S, Travagli JP, Caillou B, Laplanche A, Bidart JM, Schlumberger M, Baudin E. Medullary thyroid carcinoma as part of a multiple endocrine neoplasia type 2B syndrome: influence of the stage on the clinical course. Cancer 2002 Jan 1;94(1):44-50. Mass E, Sarnat H, Ram D, Gadoth N. Dental and oral findings in patients with familial dysautonomia. Oral Surg Oral Med Oral Pathol 1992 Sep;74(3):305-11. Mass E, Gadoth N. Oro-dental self-mutilation in familial dysautonomia. J Oral Pathol Med 1994 Jul;23(6):273-6. Mass E, Wolff A, Gadoth N. Increased major salivary gland secretion in familial dysautonomia. Dev Med Child Neurol 1996 Feb;38(2):133-8. Rotem Y. Dysautonomic face. Harefuah 1989 Feb 15;116(4):237-8.
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