FEATURES OF THE WOLF-HIRSCHHORN SYNDROME (WHS) FROM INFANT TO YOUNG TEENAGER
Popescu D.E., Marian D., Zeleniuc M., Samoila Ch., Belengeanu V.
*Corresponding Author: Corresponding Author: Marian Diana, DMD, PhD, Ass. Prof, Department of Operative Dentistry, Faculty of Dental Medicine, “Vasile Goldiş” Western University of Arad, Liviu Rebreanu St, no.86, 310414 Arad, Romania; tel.: 0040744187899, e-mail: marian.diana@uvvg.ro
page: 75
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DISCUSSION
Wolf–Hirschhorn syndrome is a contiguous gene
deletion syndrome caused by haploinsufficiency of the
genes encompassed in the 4p16, with a minimal critical
region of 165kb [8]. The diagnosis is based on cardinal
clinical signs: facial dysmorphia with a highly evocative
appearance, growth retardation, hypotonia, intellectual
disability, seizures or EEG anomalies. Several patients
with chromosome 4p deletions have been described extensively
in literature, with more than 300 reported cases
worldwide in 2015 [13], but other cases have also been
reported so far. The incidence is estimated at 1/20,000-
1/50,000 births, with a female predilection of 2:1. The
distinctive cranio-facial features that facilitate suspicion
of the syndrome are considered as minimum criteria for
clinical diagnosis, as well as mild-to-severe mental retardation,
hypotonia, growth delay [14]. The syndrome has
great clinical and cytogenetic variability. The main clinical
features associated with WHS are microcephaly (90%),
intellectual disability (75%), low birth weight (77%),
short stature (25-66%), muscular hypotonia (90%), skeletal
anomalies (60%–70%), seizures (50-85%), congenital
heart defects (31-45%), and structural brain malformations
(25%) [15,16]. In addition, other manifestations were:
hearing loss (25%–50%), ophthalmologic abnormalities
such as iris coloboma, microphthalmia and strabismus
(25%–50%), and urinary tract abnormalities, such as renal
agenesis, oligomeganephronia, bladder exstrophy, cystic
renal dysplasia/hypoplasia, and obstructive uropathy), cardiac
(25%–50%) and eyelid ptosis can be seen in about
50% [13,14]. Intellectual disability of variable degrees, as
well as intellectual impairment, were noted in most of the
published cases. Intelligence ranged from moderately-toseverely
impaired [13, 16]. Most of the above-mentioned
clinical features were also seen in this case. Recent reports
have made comprehensive contributions to the Wolf-
Hirschhorn syndrome phenotype [13, 17, 18].
This case also has distinctive face features including
high forehead, hypertelorism, broad nose, smaller lower
part of the face, retrognathism, short philtrum with downturned
mouth.
Studies that used a 4p tiling BAC array CGH on
21 patients with WHS established that a portion of the
telomere, measuring 1.8 to 3 Mb, is the critical region
for the characteristic facial features for the syndrome [7].
Concerning the facial dysmorphia correlated with the patient’s
age, data from literature is contradictory. While
some reports in the literature specify that facial phenotype
is more nonspecific with age [14, 18, 19, 20], other reports
find that in adults the phenotype is similar to the one in
children [21, 22].
There are studies claiming that dental manifestations
such as delayed tooth eruption, bruxism, dental agenesis,
especially oligodontia and micrognathia, cone-shaped teeth,
enamel hypoplasia, worn teeth, dental attrition and discoloration
of permanent dentition, as well as congenital taurodontism
in the primary dentition, spacing, and over-retained mis-
shapen primary molars, are the manifestations with variable
expression in the clinical picture of the syndrome, possibly
due to the extent and the specific locus of the chromosomal
deletion [14 , 23, 24, 25 ]. This patient presents some of these
dental characteristics, such as delayed tooth eruption, bruxism,
enamel hypoplasia, dental agenesis. Data from literature
concluded that, in oligodontia, the main MSX1 gene placed
at 4.9Mb of telomere [26, 27, 9], and other genes located
outside the critical region, can be involved in this anomaly
[25] because oligodontia has also been found in patients with
deletions smaller than 2.7 Mb [7,25].
A study from Romania describes 7 cases of Wolf-
Hirschhorn syndrome with variable manifestations in
phenotype, which were confirmed by genetic analyses:
karyotype and/or Multiplex ligation-dependent probe amplification
(MLPA) [28]. The dentition aspects were present
in only 3 cases. Trying to establish a correlation between
the extent of deletion and dental anomalies, it results from
the above-mentioned report that a more severe anodontia
occurs with a greater deletion, just as the study of Limeres
et al [25] mentions, that the minimal region associated with
oligodontia in their cohort is in the interval of 2.3–5.5 Mb.
Regarding the cephalometric analysis, based on the
measurement of various soft tissues and dento-skeletal
landmarks, in order to assess the facial proportions and
establish the growth pattern, we did not find any references
in literature.
Severe speech delay is the outstanding clinical symptom
in this case, also observed in the other reports [29]. It
is cited that intellect is deficient, and speech is usually limited,
or even absent, and communication is only reserved
for simple tasks [30, 31]. A study on patients, aged 4-17
years, has found that cognitive impairment can be mild
to severe, with an average IQ = 44.1 [29]. Our case was
assessed with IQ = 21, i.e., severe intellectual disability.
Since it was not possible to communicate with the boy, it
is possible that the declining IQ score resulted from the
absence of language.
The study of Fisch et al. [32] compared the cognitive
appearance between a group of 19 children with WHS and
a control group of 26 children with other subtelomeric
deletions -11q25 Jacobsen syndrome, 2q37 deletion and
deletion/duplication due to inversion 8p21-23. The conclusion
was that mental retardation is much more severe
in patients with WHS, compared to the control group. As
for social skills, they are better in patients with WHS, as
in our case [32].
If a correlation was found for some of the cases, the
literature also presented atypical situations regarding the
genotype-phenotype relationship [5,33].
Regarding the relationship between the LETM1 (Leucine
Zipper And EF-Hand Containing Transmembrane 1)
gene and seizures, the literature data is contradictory. In a
study, 6 out of 8 subjects with 4p terminal deletions that
keep the LETM1 gene have had convulsions, whereas other
7 cases with interstitial deletion, including the LETM1
gene, did not present convulsions [28]. As for seizures, our
patient presented these manifestations in only one episode
at the age of 6 months. However, the literature mentions
that seizures tend to disappear with age [15].
The cases of WHS syndrome with cytogenetic mosaic
aspect were rare and the authors underlined that the patient
phenotype had only a few manifestations [34, 35, 36, 37].
This case with 4p deletion in mosaic has a more complex
clinical aspect compared to literature reports. The deletion
is in general telomeric but may be interstitial in the 4p
chromosome. It has been suggested that the clinical phenotype
is correlated with the amount of deletion and can be
grouped into 3 major subgroups correlated with the severity:
mild form, where the deletion is <3.5 Mb, associated with
minimal manifestations (mild intellectual disability, possible
fluent language, and usually independent walking by the age
of 2-3 years;); medium, the phenotype described as “classical”,
with a deletion between 5 and 18 Mb, characterized
by specific facial phenotype, severe intellectual disability,
delay or absence of speech, late walking, malformations;
and the severe form, where the deletion is over 22 Mb,
with very severe intellectual delay, facial anomalies, severe
scoliosis, psychotic behavior, and multiple anomalies [11].
Other syndromes with similar aspects that involve
growth retardation, intellectual disability and facial dysmorphism
are Williams, Cris Du Chat, or Angelman syndrome.
We made the differential diagnosis with the Williams
syndrome based on the happy face and good social
behavior, which was infirmed through the FISH analysis.
The Cris Du Chat syndrome can also have overlapping
features with WHS, such as poor growth, intellectual deficit
and microcephaly, but the hallmarks of this syndrome
are distinctive facial features and a high -pitched, shrill
cry [38]. During teenage years it could be confused with
Angelman syndrome, due to severe speech impairment,
but Angelman presents specific movement and balance
problems (ataxia) [39].
One limitation of the study was that there are no molecular
genetic investigations of this case, which are important
in their own way, as some genes of the microdeletion
in the short arm of chromosome 4 have been associated
with specific features that define certain aspects of the
Wolf Hirschhorn phenotype. Surely, an Array GH analysis
would have precisely indicated the size of microdeletion
in the 4p chromosome with haploinsufficiency of genes in
this region, thus detecting the genotype–phenotype correlation
in the syndrome, but the Array GH analysis fails
to detect the state of chromosomal mosaicism.
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