E. Mass: A review of the oro-dento-facial characteristics of hereditary sensory and autonomic neuropathy type III (familial dysautonomia). Special Care in Dentistry, 32(1):15-20, 2012.

Abstract

A B S T R A C T
The oro-dento-facial features and dysfunction
of children with hereditary
sensory and autonomic neuropathy type
III, known as familial dysautonomia or
Riley–Day syndrome, was first described
in the scientific literature in 1949. They
include dental trauma; dental and soft
tissue self-mutilation; normal dental age;
normal sequence and timing of eruption
and exfoliation of teeth; smaller tooth
size; different and disproportional tooth
components; normal alveolar bone
height; small jaws, mild crowding, and
malocclusions. These persons have
craniofacial morphology that is different
from accepted norms but they resemble
norms of their ethnic origin. The subjects
can have gray, pale, shiny faces
with an asymmetric suffering expression;
frontal bossing, with eventual
hypertelorism and narrow lips; a lowcaries
rate; drooling, and
hypersalivation. They can have changes
in salivary composition and content,
which influences plaque and calculus
and increases the risk of gingival and
periodontal diseases. They also have difficulty
in controlling oral muscles; a
progressive decrease in number of
tongue fungiform papillae, accompanied
by lack of taste buds; and specific dysgeusia,
but a normal sense of smell.

Full text

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O R O - D E N T O - F A C I A L F E A T U R E S O F F A M I L I A L D Y S A U T O N O M I A
A R T I C L E
Spec Care Dentist 32(1) 2012 15
©2012 Special Care Dentistry Association and Wiley Periodicals, Inc.
doi: 10.1111/j.1754-4505.2011.00225.x
A B S T R A C T
The oro-dento-facial features and dys-
function of children with hereditary
sensory and autonomic neuropathy type
III, known as familial dysautonomia or
Riley–Day syndrome, was first described
in the scientific literature in 1949. They
include dental trauma; dental and soft
tissue self-mutilation; normal dental age;
normal sequence and timing of eruption
and exfoliation of teeth; smaller tooth
size; different and disproportional tooth
components; normal alveolar bone
height; small jaws, mild crowding, and
malocclusions. These persons have
craniofacial morphology that is different
from accepted norms but they resemble
norms of their ethnic origin. The sub-
jects can have gray, pale, shiny faces
with an asymmetric suffering expres-
sion; frontal bossing, with eventual
hypertelorism and narrow lips; a low-
caries rate; drooling, and
hypersalivation. They can have changes
in salivary composition and content,
which influences plaque and calculus
and increases the risk of gingival and
periodontal diseases. They also have dif-
ficulty in controlling oral muscles; a
progressive decrease in number of
tongue fungiform papillae, accompanied
by lack of taste buds; and specific dys-
geusia, but a normal sense of smell.
A review of the oro-dento-facial
characteristics of hereditary sensory
and autonomic neuropathy type III
(familial dysautonomia)
Eliyahu Mass, DMD
Pediatric Dentistry Clinic, Barzilai Medical Center, Ashkelon, Israel.
Corresponding author: e-mail: elimas@post.tau.ac.il
Spec Care Dentist 32(1): 15-20, 2012
FD is an autosomal recessive disorder
that exclusively affects children of the
Jewish Ashkenazi origin.4It is a progres-
sive degenerative disorder with
characteristic clinical features. Those fea-
tures include a myriad of signs and
symptoms, such as impaired pain percep-
tion, skeletal deformities, small stature,
failure to thrive, recurrent pneumonia,
and orthostatic hypotension.5The most
common cardiovascular side effects in
patients with FD is orthostatic hypoten-
sion without compensatory tachycardia.6,7
This means that upon standing up from a
supine position, individuals with FD
exhibit a precipitous drop in blood pres-
sure without compensatory increase in
heart rate. This inappropriate increase in
heart rate variability may cause arrhyth-
mia syncope and sudden death.8
Respiratory distress was found in
14% of patients with FD. Insensitivity to
hypoxia is common among patients with
FD. Hence, hypoxemia may induce
hypotension and bradyarrhythmia.8
Most lung damage occurs during
infancy and early childhood, when oral
coordination is extremely poor and the
diet consists mostly of liquids.9In older
patients, oral coordination problems may
persist and be apparent as a tendency to
drool and to aspirate food particles and
liquids.9–11The results of recurrent aspi-
rations and dysphagia may lead to
respiratory problems and failure to thrive
and, therefore, may support the recom-
mendation of gastrostomy.12
Smith et al.13were the first to notice
the absence of fungiform papillae (FP)
on the tongue and decreased deep
tendon reflexes. Most patients show
alacrima, vasomotor instability, hypoac-
tive or absent deep tendon reflexes,
relative indifference to pain and tempera-
ture, and taste impairment. With
increasing age, older patients tend to
have significant worsening of characteris-
tic clinical signs and symptoms.14
In 2001, Slaugenhaupt et al.15identi-
fied the responsible gene for FD, IkB
Introduction
Several types of hereditary sensory and autonomic neuropathies (HSANs) were classi-
fied in 1975.1At present, the Online Mendelian Inheritance in Man (OMIM) identifies
seven categories (HSAN types: 1, 2A, 1B, 2B, 3, 4, 5).2HSAN type III is classified as
MIM #223900 and is better known as Riley–Day syndrome, or as familial dysautono-
mia (FD). Riley et al.3first described the features of this disorder in 1949 in a report of
five Jewish patients.
KEY WORDS: familial dysautonomia,
hereditary sensory and autonomic
neuropathy, oral, dental

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16 Spec Care Dentist 32(1) 2012 Oro-dento-facial features of familial dysautonomia
O R O - D E N T O - F A C I A L F E A T U R E S O F F A M I L I A L D Y S A U T O N O M I A
Kinase-associated protein gene
(IKBKAP). Since then, the incidence of
FD has declined as a result of the ability
to institute accurate population screening
of the carrier state and prenatal diagnosis
during pregnancy.16Survival rate was
improved in recent years due to early
access to centralized and more advanced
treatment.17
There are two specific geographic loca-
tions with a higher prevalence of FD. One
is in Israel and the other, with a larger
prevalence, is in the U.S. The average inci-
dence of FD cases among Ashkenazi Jews
in Israel, between 1977 and 1981, was 1 in
3,703 or 27 in 100,000.18
The oro-dental complex is one of the
systems affected by the disease.19In some
cases, impaired dental or oral functions
may present life-threatening episodes.19
Therefore, to improve the quality of life
of patients with FD and reduce the risk of
unnecessary complications, it is impera-
tive for medical and dental practitioners
to be familiar with this complex.
FD serves as an adequate model to
advance the knowledge regarding the
influence of sensory and autonomic neu-
ropathy on the upper part of the
gastro-intestinal tract. The purpose of
this review is to describe the anatomical,
physiological, pathological, and func-
tional manifestations at the level of the
oral, dental, and facial tissues in patients
with FD.
General oral and dental
status
Oral and dental features were not sys-
tematically evaluated in FD until 1965.20
From birth throughout life, patients with
FD have diverse, frequent, very severe
systemic problems. These life-threatening
events lead parents and medical profes-
sionals to have little concern for the oral
condition and function. The same applies
to many patients even when they grow
older. The first comprehensive descrip-
tion of dental and oral findings, based on
a screening of 22 patients compared with
44 matched, paired controls, was pub-
lished in 1992.21The main findings were
high rates of dental trauma (59%) and
orodental self-mutilation (32%). Dental
age was found to be within normal
range, and dental arch measurements
implied proportionally small jaws and
crowding of teeth. The low-caries rate
was linked to hypersalivation and/or a
possible change in the salivary composi-
tion and content. Plaque accumulation
was increased in all patients, causing
build-up of calculus and consequently
gingival and periodontal diseases
(Figure 1).
Observable salivary drooling was
attributed to difficulty in controlling the
oral muscles, difficulty in swallowing,
and probable hypersalivation, especially
in young patients.21
The primary and permanent teeth
of patients with FD erupt and exfoliate
in a normal sequence and timing.
Examination of dental panoramic radi-
ographs of patients with FD revealed, in
most cases, normal dental age, which
corresponds to match-paired healthy
children, with a similar chronological age
and which showed no association with
skeletal age.21
Sporadic subjective evaluations of the
jaws of patients with FD describe them
as proportionally small with malocclu-
sion and crowding.4,20,22–24Compared to
normal standards and based on arch
measurements and the amount of crowd-
ing of the teeth examined on study
models of patients with FD, only one
study21confirmed those observations.
These findings, in addition to the lack of
coordination of the oral and peri-oral
muscle activity, have indicated that most
patients with FD have moderate to severe
malocclusions of the kind that hinder
normal mastication, swallowing, and
speech.21A cephalometric evaluation of
craniofacial morphology of children with
FD further confirmed these
observations.25
Craniofacial morphology
In addition to short stature and skeletal
deformities, the craniofacial morphology
of patients with FD is significantly differ-
ent, in some parameters, from the
“classical” accepted norms, but resembles
Figure 1. Accumulation of plaque and calculus in a 22-year-old patient with FD, due to lack of func-
tion. Note the loss of the anterior teeth, which have been extracted by the patient during
dysautonomic crises.

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those of patients of the same ethnic
origin (Jews of Eastern European
origin).25However, despite the overall
resemblance, the mandible is retro-
gnathic and has a steep plane angle and
its growth axis is more horizontal. The
incisors are more retropositioned and
retroclined than those of their healthy
counterparts.25These findings may affect
the treatment decisions of orthodontists
and the airway management techniques
of healthcare providers and anesthesiolo-
gists. In most healthy individuals,
skeletal deformities do not affect normal
functions of mastication and swallowing,
due to a compensatory mechanism that
helps to bridge those discrepancies.
Based on the characteristic features of
FD, it has been suggested25that the oral
and peri-oral soft tissues comprising
tongue, lips, and cheeks are affected by
the neuropathy, and therefore, do not
allow for this normal dento-alveolar
compensatory mechanism. The alveolar
bone height does not differ from that of
healthy controls.26
Tooth and crown compo-
nent dimensions
Tooth size and proportions of the partic-
ular crown components (enamel, dentin,
pulp) are derived from the neural crest
development.27Given that dysfunction of
the neural crest is known to be present
in patients with FD, tooth size is signifi-
cantly smaller than normal; the enamel is
thicker on the occlusal table, whereas the
pulp chamber is smaller and dispropor-
tional to the tooth size.28It is, therefore,
reasonable to conclude that neural crest
dysfunction is the reason for distorted
tooth dimensions rather than a general-
ized growth arrest as observed in other
hereditary syndromes such as Down or
Crouzon.28To compare the extent of the
effect of tooth components in FD and
Down Syndrome (DS), Zilberman et al.29
suggested that the reduction in crown
width in both syndromes is the result of
reduced proliferation during tooth germ
formation. However, the differences in
enamel and dentin thickness suggested
that ameloblasts and odontoblasts were
affected differently in the later phases of
cell function. In FD, cell function was
stimulated, resulting in thicker enamel
and dentin, whereas in DS, cell function
was reduced, resulting in thin enamel
and dentin.29In another study,30prenatal
and postnatal enamel development and
postnatal calcification were examined in
maxillary second primary molars from
children with FD. The postnatal enamel
was also scanned histologically for mani-
festation of growth insults. Maxillary
primary second molars in children with
FD showed thicker prenatal enamel for-
mation and better mineralization,
compared to molars from healthy indi-
viduals and other syndromes. All primary
molars in children with FD histologically
showed a large number of postnatal trau-
matic lines within the enamel, indicating
severe systemic traumatic episodes
during the first year of life.30
There is no similarity to amelogene-
sis imperfecta or to dentinogenesis
imperfecta. Ankylosed or congenitally
missing teeth were not reported.
Soft tissues
Tongue, lips, and cheeks
The absence or severe decrease in
number of FP of the tongue is considered
to be one of the “cardinal” criteria for the
diagnosis of FD (Figure 2). This is
accompanied by lack of taste buds, which
are normally located at the bottom of the
pit of the papilla.4,5,13,31–34After portray-
ing the tongue in FD, Smith et al.13
reported the absence of taste bud papil-
lae.35Later, Brunt and McKusick4stated
that the presence of this abnormality is a
“sine qua non for the diagnosis,” basing
their statement on the fact that FP were
absent in all of their patients. Based on a
delayed diagnosis of two patients with
FD, Gadoth et al.36suggested that the
reduction in number and size of the FP
is a progressive degenerative process.
The tongue, lips, and cheeks are the
most frequent sites of oro-dental self-
mutilation in patients with FD.19
Repetitive compulsive chewing of those
tissues, especially during dysautonomic
crises, produces either tumor-like lesions
or superficial ulcers and loss of tissue.
Because of their impaired pain percep-
tion or complete insensitivity to pain,
patients are unaware of these injuries
and show no signs of discomfort. In tod-
dlers, tongue-sucking and thrusting
against erupting sharp edges of emerging
primary teeth may cause ulcerations.19
Similar injuries have been described on
the ventral part of the tongue of healthy
infants and are known as Riga–Fede dis-
ease, traumatic eosinophilic granuloma,
or traumatic ulcerative granuloma with
stromal eosinophilia.19The wounds usu-
ally heal spontaneously (Figure 3).
Signs of previous injury, such as a scar,
deformity, or tissue loss, may be noted on
routine examination (Figure 4).19
Gingiva
Oral hygiene is very poor in patients
with FD, with a hygiene index two-to-
three times higher than in healthy
MassSpec Care Dentist 32(1) 2012 17
O R O - D E N T O - F A C I A L F E A T U R E S O F F A M I L I A L D Y S A U T O N O M I A
Figure 2. Absence or progressive reduction of
fungiform papillae of the tongue of a 12-year-
old boy.
Figure 3. Tongue with Riga–Fede disease;
patient was suspected to suffer from FD and
was sent for examination. Two weeks later, the
lesion healed spontaneously.

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controls. Yet their gingival index was
found to be significantly higher only in
the permanent dentition.21Indeed, this
finding is not surprising, because correla-
tion of plaque accumulation and
periodontal disease is more common in
adults than in children.37,38
Facial appearance
It is believed that everyone who comes
across enough patients with FD will iden-
tify these patients simply upon visual
inspection. Furthermore, just the sight of
the face may disclose the presence of the
disease.39Moses et al.5described the
facial appearance in general terms. It was
later delineated as pale, gray, and shiny
(due to continuous sweating), with suf-
fering expression; frontal bossing,
sometimes with hypertelorism and
narrow lips, especially the upper lip upon
smiling.39An attempt to relate the typical
facial appearance by delineating the
underlying bony structure revealed a sim-
ilarity to the ethnic group in which FD is
most often diagnosed.25
By describing the “dysautonomic
face,” Rotem indicated typical “asymmet-
ric facial appearance with pale, chalky
skin, thin lips, mild hypertelorism, and
frequent divergent strabismus.”39Like the
others, this description was subjective,
although, after looking at many patients
with FD, one can accept the delineation
of a typical “pale, shiny, suffering expres-
sion, with narrow lips and pronounced
asymmetry” (personal observation).
Taste and smell
Taste and smell abnormalities have been
found to exist in persons with FD. The
review articles4,5,40on patients with FD
include ageusia in the list of characteristic
symptoms of the disorder. However, these
were based on data obtained from two sep-
arate, crude studies published in 196441,42
and a description of “a global loss of
taste.”43A study44of psychological–cogni-
tive and reflex-like facial–behavioral
responses to taste and smell confirmed the
presence of a specific dysgeusia rather
than general ageusia, but proved the sense
of smell to be normal. The patients with
FD were better able to taste than those
reported in earlier studies,44and were sim-
ilar to controls in their ability to identify
the taste of sour stimuli and to estimate
the stimulus intensity and appeal. When
taste was impaired, it did not correlate
with the severity of the disease.44
Saliva
The unusual low-caries rate in subjects
with FD has been attributed to the pres-
ence of “hypersalivation” or to “possible
change in the salivary composition and
content, caused by chronic autonomic
denervation.”21The salivary glands may
be partially denervated, resulting in the
presence of denervation supersensitivity
and consequently also to drooling.
Denervation supersensitivity has been
shown in the pupil and in the cardiovas-
cular system of patients with FD.45,46
Such a mechanism may lead to aberra-
tions in salivary flow rate and/or
composition. Indeed, submandibular/
sublingual gland hyperactivity was
described as a “new abnormality” in
FD.47,48At the acinar level, this hyperac-
tivity was expressed with increased fluid,
electrolyte and protein output, and, at
the ductal level, with increased ion secre-
tion and absorption rate. These changes
were thought to be the result of progres-
sive autonomic neuropathy, leading to
denervation supersensitivity and ongoing
parasympathetic denervation characteris-
tics in patients with FD.47
Whole unstimulated and stimulated
saliva samples were collected from caries-
free children with FD and from healthy
age- and ethnicity-matched, caries-free
and caries-affected children.49This was
done to explore the possibility that, in
addition to increased salivary flow, chil-
dren with FD have alterations in their
salivary components, which may suggest
an explanation for their low-caries rate.
The electrolyte and protein content of the
unstimulated saliva and the microbial
count and buffering capacity of the stim-
ulated saliva were determined. The
results of this investigation suggested that
the reduced caries activity in FD may be
associated with high-salivary flow rate,
whereas in healthy children, low-caries
rate may be associated with high-salivary
calcium concentration.49
Miscellaneous
According to Axelrod,9gastroesophageal
reflux (67%) and frequent recurrent vom-
iting (40%) crises are among the clinical
features found in patients with FD.
Figure 4. Scars and missing tissues of the lower lip, due to repeated compulsive biting during
dysautonomic crises.

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MassSpec Care Dentist 32(1) 2012 19
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Oro-pharyngeal incoordination may cause
aspiration of liquids and food particles, as
well as exfoliated primary or traumati-
cally avulsed teeth. In those cases,
surgical intervention (fundoplication) is
performed, resulting in reduced or absent
masticatory function, because nutrition is
supplied through the tube.21On the other
hand, lack of function may cause plaque
and calculus accumulation, leading to
gingival and periodontal diseases.21
Conclusions
Characteristic oro-dento-facial features of
sensory and autonomic neuropathy are
typically represented in patients with
familial dysautonomia. They include
high rates of dental trauma and self-
mutilation; proportionally small jaws,
crowding of the teeth and moderate to
severe malocclusion; and different cran-
iofacial morphology from accepted
classical norms. The subjects also have
proportionally smaller teeth and different
measurements of crown components
(enamel, dentin, pulp), normal dental
age and alveolar bone height. Other fea-
tures include hypersalivation, drooling,
plaque accumulation, calculus, and peri-
odontal diseases; absence or severe
decrease in number of FP of the tongue;
characteristic “dysautonomic face”
(asymmetry; pale, chalky skin; thin lips;
mild hypertelorism; divergent strabis-
mus); specific dysgeusia; lack of tears;
and a low-caries rate (Table 1).
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Table 1. Oro-dento-facial features of patients with familial dysautonomia.
Oro-dento-facial features DescriptionReference
Dental trauma59% of patients21
Oro-dental self mutilation32% to 36.8% of patients 19, 21
Jaw measurementsProportionally small jaws compared to those of healthy counterparts21, 25
Malocclusion
Crowding; pronounced retrognathism in the mandible and a steep mandibular plane angle; retroposi-
tioned and retroclined incisors
21, 25
Craniofacial morphology
Significantly different from the classically accepted norms; skeletal features resemble those of the FD
ethnic group (Ashkenazi Jews)
25
Tooth size Small (e.g., reduced crown width)29
Tooth components (enamel,
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Disproportional (e.g., increased enamel height in 2nd primary and 1st permanent molars) 28, 29, 30
Upper primary second molars show better mineralization and thicker prenatal enamel formation in com-
parison to healthy and other syndromes. All FD primary molars show large number of postnatal
traumatic lines, implicating severe traumatic episodes during the first year of life.
Dental ageWithin normal range21
Alveolar bone heightNo difference from healthy controls 26
Saliva
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Periodontal tissuesPlaque accumulation, calculus, and periodontal diseases21
TongueAbsence or progressive degeneration of fungiform papillae; common site of self-mutilation 13, 19, 36
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21

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