Mutiple mucosal neuromas, dysautonomia and abnormal intradermal histamine reaction

MUTIPLE MUCOSAL NEUROMAS, DYSAUTONOMIA INTRADERMAL HISTAMINE REACTION M. W. 1. M. Horstink’.2 Fested

H. H. J. Jaspar’

I;. J. M. Gabreds’

E. M. G. Joosten1,3

AND ABNORMAL

A. W. M. Gabsei;ls-

U. J. G. van Haelst4 J. J. Korten’

SUMMARY With reference to a patient a description is given of the syndrome of multiple mucosal neuromas - a syndrome which Seems to be caused by a disturbance in the development of neural crest derivatives. The syndrome was associated with a number of autonomic dysfunctions; this dysautonomia is correlated with the morphological findings in a sural nerve biopsy. The nerve was hypertrophic and showed few changes in the myelinated fibres; the unmyelinated fibres showed a chronic process of degeneration and regeneration, and small unmyelinated axons were found increased in number. It is suggested that the abnormal reaction to an intradermal histamine injection was due to the dysautonomia shown by this patient.

INTRODUCTION

In 1922 WAGENMANN described a lZyear-old boy with multiple painless greyish-yellow tumours on the conjunctivae and the tongue, which microscopic examination identified as neuormas: beneath the mucosal epithelium there were small tumours which consisted of disarranged bundles of myelinated nerve fibres separated by only scanty connective tissue; no ganglion cells were found. FROBOESE (1923) described the pathological anatomy of Wagenmann’s case and, after a detailed study of the litterature, concluded that true neuromas must have been involved because the tumours were made up of nerve parenchyma (myelinated axons) but contained no cell bodies as ganglioneuromas do. Since the publications of WAGENMANN and FROBOESE several cases have been reported in the litterature, in all of which essentially the same tumour structure was found although reports on the amount of fibrous tissue and the percentage of unmyelinated axons, if any, varied. The term ‘multiple mucosal neuromas’ was introduced in later publications (BAZEX and DUPRE, 1958). The tumours are up to about 5 mm in diameter, painless, of a greyish-yellow colour, and localized beneath the mucosa of the conjunctivae, nose, oral cavity, pharynx and larynx. They are usually symmetrically arranged in relation to the midline; the anterior dorsal area of the tongue is a typical site of predilection, and the same applies ‘Dept Neurology - 2 Dept. Child Neurology - a Dept Submicroscopic gy, Radboud Hospital, University of Nijmegen, The Netherlands. Clin. Neurol. Neurosurg.

1974 - 3/4

Morphology - 4 Dept Patholo-

213 to a lesser extent to the palpebrae.

The visible neuromas

cause

epithelium;

elevation

tumours

of the mucosal

can be present

In addition

are superficially

however,

invisible

localized

and

deep-seated

in large numbers (BAZEX and DUPRE 1958).

to the mucosal

neuromas

the patients show a number

normalities such as marfanoid

habitus, thick everted ‘negroid’

(medullary thyroid carcinoma,

phaeochromocytoma),

ed nerve fibres in the cornea, abnormalities

more

of Auerbach’s

lips, endocrine tumours

pes cavus, funnelchest, myelinat-

skin pigmentations, and Meissner’s

of other ab-

hypertrophic

plexuses

peripheral

and myopathy

nerves,

(JORGE and

BRACHETTO-BRIAN,1927; KOKE and BRALEY, 1940; v. EPPS, HYNDMANN and GREENE, 1940; BAZEX and DUPRE, 1958; CALMETTES,BAZEX, DEODATI, DUPRE and BEC, 1959: WILLIAMS and POLLOCK, 1966; MICHALOWSKI, 1967; CERNEA, CREPY, KUFFER and MASCARO, 1967; GORLIN, SEDANO,

VICKERS and CERVENKA, 1968; SCHIMKE, HART-

MANN, PROW and RIMOIN. 1968; JACOBI and KLEINE-NATROP, 1970; LEVY, HABIB. LYON, SCHWFISGUTH,LEMERLEand BOYER, 1970; BAUM, 1971; GORLIN and VICKERS, 1971). The first visible symptoms

months

in early childhood, on (BAZEX and DUPRE, 1958). The endocrine tumour

not appear until adolescence. STAM (1968), dysfunctions,

Particularly

there are indications

In this publication

HORSTINK,

to BARTLETT,BEAN and MANDEL-

according

of autosomal

from the age of two symptoms usually do

dominant

hereditary

transmission.

we are able to enlarge the syndrome with a number of autonomic

they have a typical

These morphological FtSTEN,

usually occur

findings GABREELS

morphological

substrate in the peripheral

are in extenso published

nerve. elsewhere (JOOSTEN,GABREELS-

and JASPAR, 1975).

CASE REPORT A 14-year-old girl was hospitalized in the Department of Child Neurology in view of conspicious emaciation. At the age of about 4 years the parents had noticed small tumours on the tip of the tongue; the lips had become thicker and the girl had changed from a plump little girl to a tall, thin child. In recent years the patient had often complained of fatigue and there had been unexplained febrile episodes lasting several days. So far she could remember, the patient had no overflow tears, and she was often disbelieved when she cried; onionskins, or soap in the eyes, produced no tears. There had been urine incontinence for years, with frequent micturition. Family: the maternal grandfather showed numerous caf&au-lait spots; a paternal aunt showed the same typical habitus as the patient.

PtlYSICAL

EXAMINATION

We observed a pale girl of marfanoid habitus: tall (height 162 cm -- P 75) and thin (weight 26 Kg P 2.5). with arachnodactyly, hypermobile joints, hardly any subcutaneous fat, pes cavus, funnelchest. Everted upper palpebrae, normal eye-lens, hypertrophic nerve fibres in the deeper layers of the cornea and dilatated lymph vessels along the limbus (slit-lamp examination). Moist cornea; no overflow tears. No pubic and axillary hair growth. Butterfly-shaped pattern of lentigines over the dorsum of the nose and the cheeks. Jaws: prognathism; lips thick and everted (fig. 1). Polypoid hypertrophy of the gingiva: irregular dental arch with tooth decay and diastema. The anterior dorsal area of the tongue showed a number of greyish-yellow painless tumours up to 5 mm in diameter (fig. 2), and an

Fig. 1. Shows the typical expression of the face. Note the thick. everted lips.

oblong tumour of the same colour was observed on the medial area of the right lower eyelid (fig. 3). Cutaneous evidence of neurofibromatosis was absent. The thyroid felt firm and enlarged, with lymphomas bilaterally palpable in the cervical region. Neurological examination revealed lively myotatic reflexes, normal skin reflexes, hypotonic atrophic muscles with very moderate muscular strength (no differences between proximal and distal muscles). Sensibility, olfactory and gustatory functions were intact. Flushing of the face was observed on one occasion. Findings with regard to the autonomic nervous system are presented in n&e I.

Laboratory,findings Blood: calcium, inorganic phosphate, alkaline phosphatase and CPK normal. Phosphate clearance normal. ~or~lo~~s; protein-bound iodine, cortisof and growth hormone normal. Serum cakcitonine: 19,690 U/ml (normal: 105-395 U/ml). Serum parathormone (after thyroidectomy): 720 U. (normal: up to 415 U.). Urine: excretion of metanephrines, WA, SHIAA, acid mucopolysaccharides and amino-acids normal. Hydroxyproline excretion: 328 &mole/24 hrs (normal: 573 Pmole/24 hrs). Chromosomes: normal. Intravenous histamine test normal.

215 Fig. 1. Close examination

of

the mouth.

Note the mucosal

neuromas

of

the

tooth

decay

trophic

gingiva.

and

tongue. hyper-

Fig. 3 shows a mucosal neuroma on the medial part of

the

conjunctiva

lower eyelid.

of

the

The eyelids are

slightly everted.

Autonomic deficit studies.

(nail scratching)

hyper-

15. Methacholine, 5 mg subcutaneously _~__ . ._ _ .-.- ---._ -.-.-.

.

14. a. Histamine 1: 3000intradermally in physiological saline b. Physiological saline intradermally

13. Dermographia

8. Respiratory response to hypoxia and capnia (2 % and over) 9. Cold appliit#oo (ii cubes, shower;) 10. oesoph& motility 1 I. DiSital Mood Row (Whitney method) a. body temperature b. cold (water at IG’C) c. heat (water at 38” C) 12. rrr (0.05 U insulin/kg)

5. Valsalva manoeuvre 6. Eyeball pressure Carotid sinlls massage I. a. &se&~ perspiration (Meeco etectrolytic water analyaer; Warndorff 1972) b. Acetylcholine 0.2 mg/O.2 ml intradermally c. Body heating (sauna, bromophenol powder)

_..~___

impairment of pilomotor fibres glossopharyngeal/vagus nerve intact vasoconstriction reflex vasoconstriction no reflex vasodilatation pancreas innervation disturbed? (cf. familial dysautonomia) local capillary vasodilatation, arterial vasoconstriction via axonal artery reflexes no manifest axon reflex reaction at 14 a) not resulting from non-specific stimulation sweat, salivary and Iacrimal glands intact

no or minimal pilomotor reaction contrast radiographs normal reduced (2 vol. %/mm) blood flow: zero no increased blood flow delayed restoration of glucose level, initial value not being approximated until after 4 hours sharply defined red line surrounded by white zone of 3-4 mm width; no flare wheal and red zone of 2-3 mm width; no flare no reaction salivation

normal chemoreceptor

lacrimation,

normal excitabilhy sweat glands no overhow secretion of the thermoregulatory exocrine sweat glands

maximum: 37.2 mg/sq cm/hour no sweat secretion limbs; minimal sweat secretion trunk; normal sweat secretion forehead: axillary hyperhydrosis hyperventilation

sweating,

normal rest activity sweat glands

0.50 mgisq cm/hour

system

pressoreceptor system intact vagus nerve intact

1IS/SS,puke 83 recumbent upright 1lo/SO, pulse 92 normal overshoot bradycardia

miosis

e. light reflex

hypotension

mydriasis mydriasis mild mydriasis

4. 0rthostatic

..--___.

Cannon-type parasympathetic denervation hypersensitivity pupillary dilator muscle intact postganglionic sympathetic intact pain afferents, central and peripheral s> mpathetic system intact Edinger-Westphat nucleus and parasympathetic innervation functionary intact pressoreceptor system intact

CONCLUSlON

-_____----~.

miosis (2 mm)

___----.(partial) parasympathetic denervation parasympathetic innervatian intact

,< 5 mm in 5 minutes probably normal

RESULT --

b. 2% Ephedrine c. 5 % cocaine hydrochloride d. ciliospinal reflex

1. Lacrimation (Schirmer test) 2. Salivation (moistening blotting-paper) 3. Pupillary reactions to : a. 2.5 % methacholine

TEST

TARLE I

G

t3

217

Fig. 4. Sural nerve. The small 0.4 I”. Magn.: 21600.

unmyelinated

axons

are indicated

(‘X’).

The diameters

are about

LEG within normal limits. IQ weak mediocre level (: 90 Hawik). Skeletal A’-W.Y.Y: epiphyseal lines of the long bones not yet closed. Pneumoencephalogram normal. IVP and colon-contrast normal. S~~ina/jluid: cells, protein, glucose, pyruvate and lactate: normal. EMG: myopathic features with numerous rapid polyphasic units in the proximal muscles and strikingly low voltages. ENG: conduction time of peripheral motoneuron normal. Conduction time sural nerve (I 8 cm) : 3.5 msec. (normal: 3.8 msec.). Normal voltage.

Morphological,findings T’hyroirl. Microscopy: medullary thyroid carcinoma. Electron microscopy (2 ‘4 osmium fixation. embedding in Epon): the carcinoma contains two cell types: perifollicular cells with numerous secretory granules, and groups of cells containing no or few granules, the groups being surrounded by a basement membrane. Glossal ~W?IOW. Microscopy (HE staining): tissue fragment lined with short crests of epithelium of

218 varying width, which tend towards squamous metaplasia and local parakeratosis. The underlying connective tissue comprises many large, transversely and lon~tudinaily cut, decussate nerve bundles which are partly mye~inated. Sporadic ganglion cells. The nerve fasciculi are partty ensheated by a perineurium. In addition, some coarsely fibrous collagenous connective tissue interspersed with the nerve fibres, particularly in the upper layers. Von Gieson staining: no abnormalities of elastine fihrcs. Bodian staining: numerous axons in transversely and longitudinally running bundles. Sural nerve. Microscopy (H. E. staining): increased nerve diameter, obvious even macroscopically. Density of myelinated fibres greatly reduced: a fair amount of collagenous connective tissue and mucoid (i.e. metachromatically staining ground substance) is seen among the myelinated fibres. Enzyme hist~hemistry, conventional histology and teased preparations: myehnated fibres of normal aspect without signs of degeneration or regeneration. The reaction to NAVH and beta-rieo sporadically reveals a highly active structure, in view of its shape and location probably an unmyelinated axon. Schwann cells clearly increased in number, but no microscopic evidence of well-defined onion-bulbs. Electron microscopy (2 “/, osmium fixation after prior fixation in glutaraldehyde, embedded in Epon): myelinated fibres sporadically show Wailer’s degeneration and (exclusively around small mydinated fibres) frequently small onion-bulbs. The l~nmyelinated axons reguhuty show degenerative changes and a conspicuous relative increase in sometimes very small unmye~i~tted axons. (fig. 4). Quantitative studies showed a decrease in the density of myelinated fibres, but the transverse fascicular area was so increased that the total number of myelinated fibres in the nerve fell within the normal range. The histogram of the myelinated fibres showed a normal distribution, The densityof the unmyelinated axons was low-normal (and with correction for the increased nerve volume it was certainly normal, possibie even increased). The histogram of the unmyeIinated axons showed an increase in very small axons which, together with the signs of degeneration of unmyelinated axons, is suggestive of a process of degeneration and regeneration. (fig. 5) DISCUSSION

The patient described above fully answers the description of the Muli~ple Mucosai neuromas syndrome (LMMNsyndrome’). The flushing which this patient showed, is frequently observed in cases of meduilary thyroid carcinoma (WILLIANS and POLLCCK 1966). The patient showed a marfanoid habitus but the typical ophthalmological symptoms described by Marfan were absent, as were the sometimes reported increase in excretion of acid-mucopolysaccharides and increased hydroxyproline excretion. The decreased hydroxyproline excretion in our patient was consistent with the hypercalcitoninaemia, which is known to lead to diminished bone resorption and which also caused the (reactive) hyperparathyroidism. The latter explains the fact that the patient had normal skeletal X-ray pictures. The symptoms of the MMN syndrome manifest themselves specifically as symptoms of disturbances of neural crest derivatives. The neural crest is known to give rise to the melanoblasts of the skin, parts of the cranial skeleton and odontoblasts, the sensory part of the peripheral nervous system and also parts of the autonomic (peripheral) nervous system. ( H~RSTADLUS, 1950; WESTON, 1970). Pearse (PEARSE, 1969) described a group of endocrine cells with several common characteristics and with a common ancestor: the neural crest. After a number of these characteristics he designated these cells APUD cells (Amino-acid Precursor (i.e. dopa and SHTP) Uptake and Decarboxylation). The perifollicular C-cells of the thyroid and the adrenal medullary cells come under this heading. In the MMN syndrome we encounter several neural crest derivatives : neuromas, nerve fibres in the cornea, phaeochromocytoma, medullary thyroid

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Fig. 5 shows at the left side the histogram of the myelinated fibres; at the right side the histogram of the unmyelinated axons is shown, (horizontal lines indicate normal values). The number of the fibres (resp. axons) of a certain diameter is given as a percentage of the total number of ftbres (resp. axons) in the sural nerve. The fig. shows an increase in very small axons.

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abnormalities

and autonomic

nervous

system

The MMN syndrome has been related to other syndromes, e.g. Von Recklinghausen’s disease. Reports on the MMN syndrome variously refer to neuroma, neurofibroma and plexiform neuroma, but the pathological anatomical descriptions are always in agreement and essentially the same as the description of FROBOESE (1923). After detailed studies, FROBOESE (1923) BAZEX and DUPRE (1958), WILLIAMSand POLLOCK (1966) and GORLIN and VICKERS (1971) concluded, however, that a special type of tumour is involved in the MMN syndrome which is not a normal neurofibroma. Our

220 studies

confirm

this conclusion

and/or

unmyelinated

but which resembles characteristics syndrome.

Oral

axons,

: the mucosal a picture

which

more an amputation

of Von

Recklinghausen’s

manifestations

neuromas

are consisting

is not normally neuroma.

disease

seen in neurofibromab

Moreover, are

usually

the typical absent

are rare in Von Recklinghausen’s

PIERCE and JACKSON, 1955), and no mucosal

neuromas

of myelinated

were found

clinical

in the

disease

MM~

(BAI)~I\~,

in a series of 223

cases of this disease (CROWE’, 1956). In the cases described by RAPPAPOK.~ and CAMDEN (1953). SCHIMKE rt al. (1968) and LJUNGBERC;, CEDERQUIS~and v. SYXJ~NIrz ( 1967), however, the MMNsyndrome seems to be associated with Von Recklinghausen’s disease (neurotibromatosis and caf&au-lait spots), but in these cases there is no mention of microscopical descriptions of both the neuromas and the neurofibromas. Although the clinical features of the two conditions are quite disparate, their possible concomitance nevertheless suggests some relationship between the two. In Von Recklinghausen’s disease, neural crest derivatives are encountered too: the Schwann cell, skin pigmentations and sometimes phaeochromocytoma. The two conditions seem to be linked by the neural crest. Much more known is the occurrence of the endocrine tumours without other symptoms of the MMN syndrome ( L. JUNGRERC;et al., 1967; SIPPL~. 1961: SAPIRA, AL-rMAN, VAN DYK and SHAPIRO, 1965), the association of phaeochromocytoma with medullary thyroid carcinoma can be regarded as a special type of a neural crest syndrome. We have been unable to find incontrovertible evidence in the literature of the occurrence of mucosal neuromas without associated endocrine tumours or typical habitus; the oldest publications make no mention of endocrine tumours, but do not specify their absence either (WAGENMAN. 1922; JORGE and BRACHETTO-BRIAN, 1927). One of Gorlin’s patients (GORLIN and VICKERS, 1971) did not show evidence of endocrine tumours, but this patient ~35 only 14 years old at that moment. A more or less typical habitus is invariably mentioned. It seems reasonable to suggest that the neural crest can express itself in clinical pathology as two syndromes : one endocrine and one neurocutaneous. in addition to the abnormalities reported also in the literature, our patient showed a number of dysfunctions of the autonomic nervous system, e.g. ‘overflow-anhydrosis’ of the thermoregulatory sweat glands, suggestive of a disturbance in the sympathetic sudomotor innervation (GUTTMANN, 1940). Our study showed that the sweat glands themselves were intact. The axillary hyperhydrosis in a reaction of the adrenergic apocrine glands to mental stress, as was the hydrosis on the forehead (EVANS, 1957). The same pattern of sweat secretion is found in Parkinson patients (APPENZELLER and Goss, 1971). The disorders of sweat secretion probably also play a role in the patient’s febrile episodes, as did the disturbed thermoregulation. The diminished lacrimation and the miosis following metacholine instillation suggest parasympathetic denervation, which is only partial in this patient, The urinary incontinence is also found, jointly with orthostatic hypotension and anhydrosis, in the syndrome of SHY and DRAGER (I 960); in our patient, too, the urinary incontinence suggested a disorder of autonomic bladder innervation. The findings concerning digital blood flow suggested a Raynaud syndrome, which

221 is also characterized response

to cold;

vasodilatation,

by low flow at normal but in Raynaud

which is quite absent

autonomic

functional

there

in our patient.

patient indicate disturbed sympathetic constriction and absent vasodilatation. The

temperature

syndrome

disorders

vasomotor impress

and reflex vasoconstriction is usually

In any case the findings activity

with

us as possible

in

also unmistakable increased

expressions

in our vasoof ab-

normalities of the unmyelinated axons, as found in the sural nerve biopsy. S~HIMKE (1968) and LEVY et al. (1970) likewise described abnormalities of autonomic

et al.

nerves in the MMN syndrome: they found hypertrophic Auerbach and Meissner, and also hypertrophic peripheral Because of the absence of pain disorder and the presence we concluded that the abnormal unmyelinated axons had the autonomic nervous system. Dysautonomias are also observed in certain degenerative

nerves in the plexuses of nerves. of autonomic dysfunction, to be axons belon@ng to affections

of the nervous

system (SHY and DRAGER, 1960; BANNISTER and OPPENHEIMER, 1972); occasionally they have been described as paracarcinomatous conditions (IVY, 1961; CHIAPPA and YOUNG, 1973; THOMAS and SHIELD, 1970), but the findings correspond with those in our patient. The same applies

in these patients do not to Riley-Day’s familial

and FINEGOLD, 1971) and the Adie syndrome and LUCAS, 1965). And in our patient there was no more generalized neuropathy of the type seen in diabetes or amyloidosis either. The above considerations would seem to warrant the conclusion that our patient suffered from a distinct type of dysautonomia with a separate pathological anatomical substrate in the peripheral nerve, and probably occurring solely in the context of the MMN syndrome. It is difftcult to explain the absence of a flare following intradermal histamine

dysautonomia (PETAJAN,

(PEARSON, BUDZILOVICH

DANFORTH,

D’AUESIO

injection. Defects in the peripheral pain fibres which mediate the axonal reflex (DUNER and PERNOW, 1952) were not clinically demonstrable in our patient. However, it is apparent

from the nerve biopsy that a chronic

process of degeneration

and regenera-

tion was present in the unmyelinated axons. Since this failed to produce disturbances in pain sense, however, involvement of pain fibres seems improbable; and it is unlikely that the axonal reflex was negative due to pain fibre disorder. Apart from the pain fibres, however, other factors play a role: in familial dysautonomia there is an identical reaction to histamine, which sometimes recovers in response to a metacholine infusion. Familial phaeochromocytoma, which sometimes presents itself as familial dysautonomia (SMITH and DANCE, 1964) is in that case characterized by absence of a flare, which returns after excision of the phaeochromocytoma. Resection of the sympathetic ganglia greatly enhances the flare phenomenon after histamjne injection on the operated side ( DUNER and PERNOW, 1952). These observations indicate an autonomic contribution to the influence on the axonal reflex : the above data can be reduced to an increased ‘sympathetic tonus’ of the skin vessels, which precludes vasodilatation in response to histamine. The absence of reflex vasodilatation in response to heat. in our patient, possibly

222 also fits into this picture. autonomia

and absence

In the literature we found

some more patients with dys-

of flare but with a normal

wheal (PETAJAN et ~1.. 1965;

YOUNG, ASBURY, ADAMS and CORBETT, 1969; WICHSER, VIJAYAN and DREYFUS, 1972) just as in our patient; on the other hand we also found some patients with dysautonomia

(sudomotor

response

and/or

vasomotor

disorders)

(THOMASHEFSKY, HORWITZ and

which

show

FEINGOLD, 1972;

a normal

histamine

ANDERSEN, LINDB~RG,

MODIGH and RESKE-NIELSEN,1972; APPENZELLER and KORNFELD, 1973). In all these patients,

however,

striction

and absent vasodilatation.

Another

we are not exactly

possible explanation

informed

whether they also show vasocon-

for our patient has been suggested by BAUM ( 197 I ) :

in a patient with the MMN syndrome

(and decreased tear function!)

he found the same

histamine response as we did, and he explained

this on the basis of increased hista-

minase activity due to the medullary

of the thyroid (BAYLIN, BEAVENand

ENGELMAN, 1970). is not abolished

This theory

by

carcinoma

raises the question

histaminase,

while

the reflex

that the absence of the flare is correlated,with vasodilatation. function,

It is very probable

had a dysautonomia

why the local

histamine

effect

effect

therefore

think

is.

We

the dysautonomia

that Baum’s

which

precludes

patient, which showed decreased tear

too.

ACKNOWLEDGEMENT We are indebted

to S. L. H. Notermans

STADHOUDERS(Inst. of Electron matology)

(Dept

Microscopy)

for their help in the preparation

of. electroneurophysiology)

A. M.

and J. A. WARND~RFF (Inst. of Der-

of this manuscript.

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