THE MANY FACES OF ORAL-FACIAL-DIGITAL SYNDROME
Sukarova-Angelovska E, Angelkova N, Palcevska-Kocevska S, Kocova M
*Corresponding Author: Assistant Profesor Elena Sukarova-Angelovska, Pediatric Clinic, Faculty of
Medicine, Vodnjanska 17, 1000 Skopje, Republic of Macedonia; Tel.: +389-70-358582; Fax: +389-2-
243301; E-mail: ESukarova@doctor.com
page: 37
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DISCUSSION
The group of OFD syndromes presents mainly
with malformations of the face, oral cavity and lower
parts of the limbs (hands and feet). Other organs
may also be affected, including kidney, brain, heart,
eye, genitalia. Thus, the number of subgroups keeps
growing, with the new published cases. Considering
the broad spectrum of anomalies of various organs,
it has been proposed that OFD syndromes belong to
the group of ciliopathies [4].
There is no defi nite consent about the classifi cation
of OFD. Modes for classifi cation of OFD syndromes
were proposed by different authors, mostly
based on the additional malformations and survival:
oral-facial-skeletal syndromes [11]; orocardiodigital
variant [12]; CAVE, cerebroacrovisceral early lethal
[13]. Fenton and Watt-Smith [2] proposed only two
types of OFD (autosomal recessive and X-linked),
based on the inheritance pattern. However, inheritance
cannot always be determined. The spectrum
of appearance and extensivity of the features could
be variable, thus it is diffi cult to delineate between
the described subgroups. Overlapping of the features
between groups is common; therefore classifi
cation of a specifi c patient is sometimes diffi cult.
Appearance of a new feature added to the syndrome
is also common.
There are some point markers for delineation
between subgroups of OFD and related syndromes
[3,14]; however, diagnostic doubt can be seen in
many reports [15-17]. Phenotypic variations were
also present in our patients.
Patient 1 had many clinical characteristics of
OFDII, according to the generally accepted classifi
cation [3]. Minor polydactyly of the hands and
feet together with the oral fi ndings (notch of the lip,
tongue nodules and hamartoma) point to OFDV, but
our patient’s mental retardation was much more severe
than that described for this subtype. A previously
undescribed feature in this patient was preaxial
polydactyly of the feet. Similar minor limb manifestation
was described by Levy et al. [18], clarifi ed
as Mohr syndrome. Abnormal eye movements and
rotatory nystagmus can distinguish type III from the
other types. However, limb anomalies are presented
only by postaxial polydactyly of the feet in this type
as reported so far. On the other hand, rotatory nystagmus
has been described in some cases of OFDII.
Therefore, patient 1 fi ts into this group (Table 1).
The degree of polydactyly is not always in concordance
with the degree of mental retardation (as in
our patient); however, it is in concordance with cerebral
changes. Unfortunately, KTM was not performed
in our patient.
The phenotypic appearance of patient 2 is suggestive
of an OFDVI because of the presence of
Y shaped metacarpals, central polydactyly of the
feet, cerebellar anomalies and specifi c facial appearance
with hypertelorism. Some authors [16,19]
found central polydactyly with forked metacarpal in
OFDII but others [20,21] consider forked metacarpal a cardinal feature of OFDVI. Central nervous system
(CNS) malformations, rarely present in other types
of OFD syndromes, are most consistent with OFDI
and OFDVI [22]. Although a female, this patient is
unlikely to have OFDI because of the lack of skin
millia and specifi c family history: the mother did
not have any oral or kidney anomalies; the four sisters
of the patient were also normal.
The features of patient 3 may be consistent with
most of the OFD syndromes. The family history:
mentally retarded sister and miscarriages (possible
aborted male fetuses) may point to the diagnosis of
X-linked dominant OFDI syndrome. However, the
older sister did not have the features of OFD syndrome,
and the mother at the age of 38 years did not
have renal cysts. Also, the baby did not have pseudocleft
of the upper lip or millia. Tachypnoea that
was not permanent, but frequent event can point
to the diagnosis of OFDVI, in which tachypnoea
together with postaxial polydactyly of fi ngers and
bifi d hallux have been described. Other syndromes
such as Joubert syndrome [23] also have episodes of
tachypnoea, however, they were described to have
only postaxial polydactyly of the hands and feet,
which was not present in our patient.
The complex and apparently lethal condition of
patient 4 represents a form with the main features
of OFD syndromes: lobed tongue with medial cleft
and hamartoma, postaxial polysyndactyly of hands
and feet. In addition, the newborn had mesomelic
limb shortening, so it could be OFDIV. In the differential
diagnosis of this case other syndromes were
considered. The diagnosis of Majewski syndrome
was excluded because of the absence of short ribs.
The typical breathing pattern for Joubert syndrome
(tachypnoea) was absent, although the baby had episodes
of apnea. The diagnosis of Hall-Pallister syndrome
[24] was excluded because of the absence of
the hamartoma of the brain and anal anomalies present
in this condition. We cannot fully exclude the
diagnosis of the lethal form of Smith-Lemli-Opitz
syndrome [25], since there are many overlapping
features, i.e., unlobulated lungs, ambiguous gentialia,
etc. The phenotypic similarity of these two syndromes
was pointed by Verloes et al. [26].
The subgroup OFDIV seems to be very heterogeneous
[27], ranging from minor orofacial and
skeletal changes, to major malformations of many
organs. For example, cardiac malformations have
been described in several types of OFD syndrome [16,19,28]. Ades et al. [29] reported a fetus with
severe malformations of the kidneys, heart, hepatic
ducts, lung and ambiguous genitalia. Cases of OFD
with multiple skeletal and visceral involvement
were also described [5,17,20,27,30-34]. Although
there is heterogeneity between these reports, we
suggest classifying all severe forms as a separate
subgroup of OFD with multiple system involvement
with mainly unfavorable outcome (Table 2).
Reports of cases with OFD syndromes show a
wide variety of facial changes, from minor notches
of the lip to complete oral clefts; from bifi d tongue
tip to lobulated and hamartomaus tongue; from hypoplastic
nasal wings to bulbous or broad nose. These
features may construct a specifi c pattern with variable
appearance in different subgroups. The diagnosis
of a specifi c OFD syndrome cannot be made only
by the examination of the facial changes. However,
some facial features, i.e., hypertelorism for types I,
III and VI, broad nose for type II, alar hypoplasia
and millia for type I, small teeth for type III, micrognathia
for type IV, although not specifi c, may
help clinical clarifi cation between subtypes of OFD
syndromes until a molecular diagnostic tool will be
available.
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