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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CASE PRESENTATION
The male proband at 11 months of age was referred to
Genetics for evaluation and testing for growth retardation
and hypotonia. Then again, at the age of 4, for assessing
the development, walking defects and absence of language,
and then, once more at the age of 16.
Clinical evaluation
We do not have any data regarding family history and
physical parameters at birth, since he was brought from
the orphanage for consultation at 11 months.
Growth parameters
Measurements of growth parameters are presented
in standard deviations (SD) for the ages when he was
examined:
At 11 months: G=5700g, T=65cm PC=42cm
SD: -3.54 for waist
SD: -4.4 for weight
SD: -3.25 for the cranial perimeter (PC)
At 4 years: G=12.3kg, T=91cm PC=47cm
SD: -2.68 for waist
SD: -2.46 for weight
SD: -2.27 for PC
At 16 years: G=47kg, T=148cm PC=51
SD: -2.94 for waist
SD: -1.54 for weight
SD: -2.75 for PC
Characteristically, there is severe delay of postnatal
development and microcephaly is present. Postnatal
growth and development are far behind for his age.
Facial Dysmorphism
Clinical features that are frequently associated with
WHS, such as high forehead, frontal bossing, high frontal
hairline, hypertelorism, high arched eyebrows, a wide
nasal bridge, short philtrum, micro-retrognathia, low set
years, were present in this case (Figure 1). All these facial
features were found upon consultation at the ages of
11 months, 4 years, and 16 years, as can be seen in the
patient’s photos (Figure 1).
Skeletal anomalies
Skeletal problems present in this case were scoliosis,
small hands and feet, brachydactyly, clinodactyly, tapering
fingers. There is slight cutaneous syndactyly between the
second and third toe (Figure 2). The dermatoglyphic pattern
was unusual because the thenar crease was absent and
there was a short hypoplastic mid-palmar crease. The fifth
finger had a single flexion crease on its volar surface (Figure
3b). X-ray examination of hands at 11 months (Figure 4a)
and 16 years (Figure 4b) revealed the relative shortness of
tubular bones, especially of distal and middle phalanges.
Neurological and behavioral development
The child also presented an episode of unprovoked,
generalized tonic-clonic seizures at 6 months, which were
controlled with anticonvulsants (phenobarbital). EEGs at
4 years of age were normal, in both the awake and drowsy
states, and no seizure activity was present. He achieved
independent walking by 26 months of age, and during
infancy he presented mild hypotonia. He pronounced his
first word at the age of 4. At the age of 16, his language is
very poor, limited to only six simple words. The adolescent
communicates with the family with the help of non-verbal
gestures and vocalizations. He can assist with dressing and
feeding himself, but otherwise depends on his maternal
assistant’s support.
Cognitive abilities were deficient and the Simon–Binnet
test determined a severe intellectual disability. On the
neurocognitive level, his developmental quotient (IQ) was
21, with the major delay occurring in speech. He could
not attend school due to lack of language but followed
cognitive stimulation therapies.
Other clinical examinations
Clinical and ultrasound examinations of other organs
and systems were normal.
Dental oral anomalies
The child has downturned corners of the large mouth
and a high-arched palate (Figure 3a).
At 11 months - absence of dental eruption;
At 4 years - the patient had delayed dental eruption,
with only 16 teeth;
At 16 years - dental examination was extremely difficult
due to the mental handicap. Because of poor oral
hygiene, multiple caries and residual roots are present, with
marbling of the lower frontal incisors. He also presents
enamel hypoplasia. The inflammatory periodontal index
clearly indicates the presence of gingivitis (Figure 5).
Through correlation with the orthopantomography,
the following aspects were highlighted (Figures 5, 6): the
right superior central incisor insufficiently erupted, rotated
mesially; both incisors with slight palatoversion; transposition
between the left lateral incisor and canine. In addition,
the patient has an open bite and the median line is deviated
to the right. Supplementary, we found agenesis of third
inferior molars on the orthopantomography (Figure 6).
On the profile teleradiography, the CS5 stage of maturation
of the cervical vertebrae can be observed. CS5 stage
is reached at an average age of 14.6 +/- 1.1 years, according
to Yan Gua and al [12]. CS5 stage is the penultimate
stage of cervical vertebra maturation and the last CS6 stage
appears at an average age of 15.6 +/- 1 year, according to
the same authors. This aspect leads us to the conclusion
that skeletal development is delayed, the information being
consistent with the information obtained from other
studies. The curvature of the cervical vertebrae may suggest
hyperkyphosis, but more investigations are needed
for confirmation.
Interpretation of teleradiographic analysis reveals the
following aspects:
1. Facial typology. The facial pattern represents the
reduced total facial height (total facial angle - reduced).
2. Mandibular growth. The lower facial floor is reduced.
The direction of mandibular growth is with
anterior rotation (counterclockwise).
3. Mandible shape. Mandibular body (horizontal ramus)
is short. The posterior vertical dimension is
reduced.
4. Skeletal relationships: Facial depth shows sagittal
deficiency (retrognathism) within one standard deviation.
The jaw shows a sagittal deficiency (maxillary
hypoplasia) within one standard deviation.
5. Dental report shows the upper molar in the correct
sagittal position, open interincisal angle (palatoversion
of upper incisors), and lower incisors in
infraocclusion, retropositioned in slight lingual
eversion.
The cephalometric analysis (Table 1) is important in
acknowledging the alterations of the craniofacial features
and for evaluating the growth pattern. The analysis can be
used to monitor changes over time and for the orthodontics
in an eventual treatment. The cephalometric data was
analyzed using the Heb.Uni. software program (Table 2).
Chromosome Analysis and
Fluorescent In Situ Hybridization (FISH)
Conventional cytogenetic analysis was performed
at 11 months. The cytogenetic study was carried out using
peripheral blood lymphocytes with GTG banding,
according to the standard procedures at 550 band resolution,
and 30 metaphases were analyzed and karyotyped as
per ISCN guidelines (2016). We used an Olympus BX51
fluorescent microscope (Olympus Life Science Europa
GmbH, Hamburg, Germany) for the analysis, the Andor
iXon3 897 CCD camera and the standard MetaSystems
karyotype (MetaSystems GmbH, Altussheim, Germany).
Image analysis and karyotyping was performed using the
ISIS analysis system (Metasystems, Germany). We found a
low rate of cells with abnormal aspect in the sample. This
cytogenetic evaluation revealed a mosaic karyotype. Out of
the 30 metaphases analyzed, only 2 showed a 4p deletion
and 28 normal cells were observed. The karyotype was
46,XY,del (4)(p16.3) [6.6%]/46,XY[93.4%].
The patient was re-evaluated cytogenetically at the
age of 4. Additionally, we performed Fluorescent In Situ
Hybridization (FISH), using the same microscope and
camera as for cytogenetic evaluation. A commercial Wolf-
Hirschhorn syndrome probe was used following the manufacturer’s
instructions (Vysis, Abbott laboratories, IL).
FISH was carried out using Vysis Inc Wolf-Hirschhorn
Region Probe LSI WHS Spectrum Orange (4p16.3), CEP
4 Spectrum Green on one slide (Figures 8 a, b).
Due to the “happy” facial aspect, we performed a
differential diagnosis for Williams syndrome with a FISH
probe specific Vysis Williams Region Probe (7q11.23 LSI
ELN Spectrum Orange and 7q31 D7S486, D7S522 Spectrum
Green).
FISH analysis was performed on interphase cells,
as well as on metaphase cells from lymphocytes cultured
from peripheral blood, using the commercially available
probes Vysis Wolf-Hirschhorn Region Probe LSI WHS
Spectrum Orange (4p16.3), CEP 4 Spectrum Green on
one slide. 200 interphase cells were evaluated on the first
slide and a 65% percent mosaic 4p16.3 deletion was revealed
with the nuclear in situ hybridization (nuc ish)
p16.3(WHSx1)[130]/(WHSx2)[70] (Figure 8 a, b). Also,
the FISH analysis ruled out the Williams syndrome.
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