Received: 21 February 2020 Revised: 9 May 2020 Accepted: 17 May 2020

DOI: 10.1002/ajmg.a.61750

ORIGINAL ARTICLE

A study on facial features of children with Williams syndrome

in China based on three-dimensional anthropometric
measurement technology

Chai Ji | Dan Yao | Ming-Yan Li | Wei-Jun Chen | Sheng-Liang Lin |

Zheng-Yan Zhao

Department of Pediatric Health Care,

The Children's Hospital, Zhejiang University
School of Medicine, National Clinical Research
Center for Health, Zhejiang, Hangzhou, China
Correspondence
Zheng-Yan Zhao, The Children's Hospital,
Zhejiang University School of Medicine,
Department of Pediatric Health Care,
57 Zhugan Lane, Yanan Road, Hangzhou,
Zhejiang 310003, China.
Email: zhaozy@zju.edu.cn
Funding information
Natural Science Foundation of Zhejiang
Province, Grant/Award Number:
LQ20H090017
Abstract
To describe special facial features of children with Williams syndrome in China by
using method of three-dimensional craniofacial anthropometry. Using three-
dimensional stereo photogrammetric device, 14 craniofacial anthropometric mea-
surements were performed and five indices were calculated in 52 children with
Williams syndrome and 208 age and sex matched controls of Han Chinese ethnicity.
Except intercanthal width, mouth breadth, morphological face height, nasal height-
breadth index, nasal breadth-depth index, morphological ear index, the Williams syn-
drome group under 3 years old were smaller than the control group in the other
12 variables. Compared with the control group, the Williams syndrome group aged
3–5 years old had smaller biocular breadth, nasal length, nasorostral angle, bitragal
breadth, ear width, morphological ear index and face depth. The Williams syndrome
group aged above 6 years old had smaller biocular breadth, nasal breadth, bitragal
breadth, ear width, ear length and face depth than the control group. The craniofacial
variability index of the Williams syndrome group was greater than the control group.
Greater variation was found among children with Williams syndrome than normal in
China, specifically at eye, nose, ear and face shape, which demonstrate the usefulness
of three-dimensional stereo photogrammetric analysis in supporting accurate diag-
nose of the patient with Williams syndrome.

KEYWORDS

children, Williams syndrome, three-dimensions, facial feature

1 | I N T RO DU CT I O N 20,000–50,000 of live births (Strømme, Bjørnstad, & Ramstad, 2002)

Williams syndrome (WS), also known as Williams–Beuren syndrome
(WBS), is an infrequent genetic disorder characterized by a series of
typical physical and mental features. This disorder is mainly related to
a deletion of a number of genes on chromosome 7q11.23, and the
incidence ranges from 1:7500 to 1:25000 (Riby, Kirk, Hanley, &
Riby, 2014) due to inconsistent recognition of WS across different
countries and regions. The incidence reported by Stromme is 1 in
and the reported incidence in Hong Kong is 1 in 23,500 (Hirai
et al., 2016).
Almost every child with WS has special face, so they were called
an “elfin face” (Black & Carter, 1963; Jones & Smith, 1975; McNamara
Jr., 1984) when it was first recognized. “Elfin face” usually refers to
a small face, but the head measurements and a series of other
studies showed that the face of children with WS were not that small.
So many more physicians suggested that the designation of “elfin

Am J Med Genet. 2020;1–8. wileyonlinelibrary.com/journal/ajmga © 2020 Wiley Periodicals LLC 1

2 JI ET AL.
face” for children with WS was not scientific and representative
(Burn, 1986; Mass & Belostoky, 1993). Currently the clinical diagnosis
of WS mainly relies on the evaluation of facial features, vascular mal-
formation, developmental delay and intellectual disability, then sug-
gests the suspected patient with WS to take genetic detection (Ji,
Yao, Chen, Li, & Zhao, 2014; Martens, 2013; Sugayama, Leone,
Chauffaille Mde, Okay, & Kim, 2007). Conventional facial features
used to distinguish WS include prominent ears, large earlobes, swollen
eyelids, strabismus, full cheeks, low nasal bridge, anterior-directed
nostrils, long philtrum, wide mouth with full lips, protruding and con-
stantly open mouth, dental malocclusion (American Academy of
Pediatrics, 2001; Chen, Ji, Yao, & Zhao, 2017; Järvinen, Korenberg, &
Bellugi, 2013). These facial features provide an initial clue for the
screening of this disease and are expected to become a breakthrough
point for noninvasive screening and diagnosis.
In the 1990s, with the quick development of computer-aided
detection and the technological improvement in facial measurement,
some scholars analyzed the facial features of eight children with WS
(aged 4–11 years) by collecting the data from their heads and faces.
Confined by a small sample size and the availability of few features in
respect of bone development, these data were insufficient to fully por-
tray the facial features of children with WS (Axelsson, Kjaer, Heiberg,
Bjørnland, & Storhaug, 2005; Mass & Belostoky, 1993). As the devel-
opment of soft tissue is more characteristic and observable, objective
description of facial soft tissues and organs has become a hot direction
for research. The molecular biology technique is not an ideal choice
as it cannot be used for wide population, and has caused delay
in the diagnosis of many diseased individuals. How to screen and iden-
tify patients with WS in a convenient, economic, and effective way
has become one of the problems that researchers are eager to solve.
Hammond et al. were among the first applying three-dimensional
(3D) imaging technology to the diagnosis and adjuvant treatment of
hereditary diseases with special facial features (Hammond et al., 2005).
In addition, Paul et al. comfirmed the special face by analyzing
286 Asian, African, Caucasian, and Latin American individuals with WS
using facial analysis technology (Kruszka et al., 2018).
This study used 3D stereo-photogrammetric device to obtain
3D images of facial surface of children with WS in China. This meth-
odology is characterized by its portability, high capture speed, high
accuracy, and had no side effects on the human body. All these
advantages make it possible to collect objective datasets of the chil-
dren's face images, which can aid in the recognition of children
with WS.
2 | METHOD
2.1 | Materials
2.1.1 | The WS group
From June 2009 to May 2016, the data of 52 patients, including
25 boys (aged 1.1 to 13.3 years) and 27 girls (aged 0.7 to 15 years),
diagnosed with WS due to deletion of genes on chromosome 7q11.23
by FISH, MPLA or CMA technique，were collected. They were gath-
ered from the outpatient or cardiovascular ward of the hospital or var-
ious special schools or welfare homes across the nation. They were all
Han Chinese, no minority. With the consent from parents and guard-
ians, their 3D facial data were collected. As children's faces vary with
age, children with WS enrolled in this study were divided into three
age groups, that is, under 3 years old (infants and toddlers), 3–5 years
old (preschool), and above 6 years old, respectively.
2.1.2 | The control group
Two hundred and eight control children of the same Han ethnicity
were selected for 3D facial data collection at 1:4 matching ratio. The
control group with under 3 years old was composed of healthy infants
and toddlers that had taken general physical examinations in various
community health centers. The 3–18 years old group were healthy
children and teenagers that had physical checkup in our outpatient
clinic. In order to eliminate the error and the interference of exces-
sively large and small human faces to data analysis, children whose
height and weight were above the 97th or under third percentiles on
the Chinese Centers for Disease Control (CDC) growth standard curve
were excluded, to ensure that the physical development of each child
in the same age group was at the normal level.
2.2 | Methods
The 3dMD face system, manufactured by 3dMD (www.3dmd.com/
3dMDface/), was used to obtain 3D facial models. Each scan results
in a triangulated surface mesh model of the subject's face with
4,000–20,000 vertices. All subjects gave informed consent, and each
subject's gender, birthday, height, weight, the history of disease and
facial surgery were recorded. Children, especially infants, often need
the researcher's help to present the correct facial posture. Without
the assistance, redundant data may appear which would have to be
removed after selecting the face region.
Research had shown the measurement error to be within as
little as 1/100 of an inch (Weinberg et al., 2006). Some researchers
had evaluated measurement accuracy and developed software to
make 3dMDface a stronger tool with which to study anthropometry
(Aldridge, Boyadjiev, Capone, DeLeon, & Richtsmeier, 2005).
2.2.1 | Preprocessing the face model
The face region was isolated and segmented. As there were often
missing data on top of the head and in the nostrils and ears, such
noise data points were cleaned and the holes filled. Spikes generated
by vertices leaping from the surface were reduced using a Gaussian
filter function. Posture positioning helped extract facial feature points
more accurately.
JI ET AL.
2.2.2 | Set 21 facial feature landmarks
The nasion, endocanthion (left and right), exocanthion (left and right),
alare (left and right), subnasale, pronasale, cheilion (left and right), sup-
eraurale (left and right), subaurale (left and right), postaurale (left and
right), tragion (left and right), gnathion, and lip center (Figure 1). Using
these points, we computed distance measurements, facial indices and
the CVI. Distance was measured in the unit of millimeters.
Anthropometric measurements and calculated indices:
1. Intercanthal width (endocanthion–endocanthion) (en-en): between
the landmarks at the inner commissures of the right and left palpe-
bral fissures.
2. Biocular width (exocanthion–exocanthion) (ex-ex): between the
right and left landmarks of the exocanthions at the outer commis-
sures of the palpebral fissures.
3. Nose height (subnasale–pronasale) (sn-pn): between the mid-
points at the base of the columella and the highest point at the
top of the columella.
4. Nose width (alare–alare) (al-al): between the most lateral points
of the nasal alare.
5. Nose length (nasion–subnasale) (n-sn): between the nasion land-
mark at the root of the nose and the midpoint at the base of the
columella.
6. Mouth width (cheilion–cheilion) (ch-ch): between the right and
left cheilion landmarks.
7. Face height (nasion–gnathion) (n-gn): between the nasion point at
the root of the nose and the chin point.
8. Upper face depth (tragion–nasion) (t-n): between the tragion point,
located just above the tragus of the ear, and the nasion landmark.
F I G U R E 1 Portrait and profile views of 21 landmarks. (a) Normal
child. (b) Child with WS [Color figure can be viewed at
wileyonlinelibrary.com]
3
9. Middle face depth (tragion–subnasale) (t-sn): between the tragion
point and the subnasal landmark, the midpoint at the base of the
columella.
10. Lower face depth (tragion–gnathion) (t-gn): between the tragion
landmark and the chin point.
11. Bitragal width (tragion–tragion) (t–t): between the right and left
tragion landmarks.
12. Ear length (superaurale–subaurale) (spa-sba): between the level
of the highest point on the free margin of the auricle and
the level of the lowest point on the free margin of the ear lobe.
We measured the both ears length and calculated the average
value.
13. Ear width (tragion–postaurale) (t-poa): between the most anterior
point and most posterior point of the ear. We measured the both
ears width and calculated the average value.
14. Nasorostral angle (NRA): < nasion, pronasale, subnasale>.
15. Physiognomic upper facial index (PUFI): n-gn / t–t × 100.
16. Length–breadth index of the nose (LBIN): n-sn / al-al × 100.
17. Height–breadth index of the nose (HBIN): al-al / sn-pn × 100.
18. Morphological ear index (MEI): t-poa / spa-sba × 100.
Craniofacial variability index (CVI): The CVI can assist in the eval-
uation of facial anatomy and defines the range of the normal distribu-
tion of craniofacial morphology (Roelfsema, Hop, van Adrichem, &
Wladimiroff, 2007; Ward, Jamison, & Farkas, 1998). It was calculated
in the following steps: means and standard deviations (SDs) were com-
puted for each of the gender categories and age; each measurement
was then converted to z-scores; z-score = (measurement−age-specific
mean value)/SD; the individual's variability index was calculated by
taking the SD of the z-scores for the 18 variables.
Each human face was located accurately using landmarks auto-
matically extracted with manual adjustment. Landmarks on each face
were located twice, and the coordinates of the two points averaged,
to reduce measurement error.
All photo-shooting works of children were carried out under the
consent granted by themselves or by their parents or guardians by
signing an informed consent form and were subject to supervision of
the Ethics Committee of the Children's Hospital Affiliated to Zhejiang
University School of Medicine.
2.3 | Statistical method
The quantitative data in respect of three-dimensional face imaging
was expressed as mean ± SD and the qualitative data was expressed
as the number of cases (percentage). The quantitative data of these
two groups were then compared by applying the t-test for two inde-
pendent samples and the qualitative data were analyzed by chi-square
test. Benjamini-Hochberg method was used to calculated false discov-
ery rate (FDR). Multivariate analysis of variance (ANOVO) were used
to compare the overall difference. Statistical analysis was performed
using SAS 9.2 statistical software and adjusted p < .05 indicates statis-
tical significance.
4 JI ET AL.

3 | RESULTS
There was no statistically difference detected by chi-square test
between the WS group and the control group compared for age and
sex (p > .05). No statistically difference was detected in 18 variables
between boys and girls (p > .05). The overall features of the faces
were statistically different between the WS group and the control
group in different age groups. (p < .001).
(5) Frontal and Profile Face Morphology: The WS group had
greater physiognomic upper facial index than the control group but
did not differ in terms of morphological face height. Its upper, middle,
and lower face depths were all smaller compared with the control
group. But in under 3 years old, the WS group had smaller morpholog-
ical face height than the control group (t = 2.71, p = .014) and did not
differ in physiognomic upper facial index (p > .05).

3.2 | Craniofacial variability index (CVI)

3.1 | The WS group compared with the control
group
(1) Eyes: All the WS groups had an evidently smaller biocular breadth
than the control groups (p < .001) (Tables 1–4). There was no differ-
ence between the two groups in terms of the intercanthal width
except in the group under 3 years old (t = 3.36, p = .003).
(2) Nose: Compared with the control group, the WS group was
smaller in nasal height, nasal breadth, nasal length, and nasorostral
angle (for nasal height, t = 2.15, p = .049; for nasal breadth, t = 2.41,
p = .028; for nasal length, t = 2.40, p = .028; and for nasorostral angle,
t = 2.89，p = 0.008) but was no difference in nasal height-breadth
index and nasal breadth-depth index (p > .05). This difference faded
with age. There was no difference between the WS group and the
control group in terms of nose variables above 6 years old (p > .05).
(3) Mouth: The mouth breadth of the WS group was no differ-
ence from that of the control group in different age groups (p > .05).
(4) Ears: Compared with the control group, the WS group was
smaller in ear length, ear width and bitragal breadth but was no differ-
ence in terms of morphological ear index (p > .05). Small changes were
found by different age groups. There was statistically difference in
morphological ear index between 3–5 years old groups and no differ-
ence in ear width between under 3 years old groups.
The CVI of the WS group (1.25 ± 0.38) was greater than that of the
control group (0.83 ± 0.37), showing a statistically significant differ-
ence (p < .001), but the CVI between boys and girls inside the WS
group had no statistically difference (25 boys: 1.29 ± 0.50; 27 girls:
1.21 ± 0.21; t = 0.77, p = 0.445).
4 | DI SCU SSION
3D surface imaging systems, which can generate high-density face
models and allow us to take accurate measurements, is a good way to
get relatively objective data about the facial variation in children with
WS. Our study found that children with WS had shorter biocular
breadth than the control children at any age. They were also shorter in
intercanthal width under 3 years old. Children with WS in their infancy
and toddler are more likely to have periorbital fullness, epicanthus, and
depressed nasal root, creating an illusion of wide interpupillary dis-
tance when observed by medical staff. These symptoms accompanied
by evident growth retardation and development delay lead some
young children with WS to be falsely diagnosed with the most com-
mon chromosomal disorder—Down's syndrome. However, measure-
ments suggested that children with WS had shorter interpupillary

T A B L E 1 Summery of facial features

Variable WS group (n = 52) Control group (n = 208) t value Adjusted p value
difference between WS group with
ex_ex 80.58 ± 7.70 87.60 ± 8.89 5.22 <.001 normal group (distance: mm)
sub_pro 11.93 ± 2.99 12.81 ± 2.56 2.15 .049
al_al 28.80 ± 4.00 30.32 ± 4.08 2.41 .028
n_sub 34.84 ± 6.49 36.90 ± 5.27 2.40 .028
tr_n 96.09 ± 9.54 102.08 ± 9.61 4.02 <.001
tr_sub 98.40 ± 10.38 104.08 ± 10.70 3.45 .002
tr_gn 105.66 ± 11.85 112.61 ± 13.36 3.43 .002
t_t 121.32 ± 9.86 132.13 ± 11.15 6.39 <.001
spa_spa 46.58 ± 4.71 48.86 ± 5.19 2.89 .008
t_poa 25.56 ± 2.31 27.58 ± 2.80 4.80 <.001
NRA 39.70 ± 7.75 42.73 ± 6.51 2.89 .008
PUFI 69.30 ± 5.67 65.40 ± 4.27 −5.49 <.001
F value p value
Multivariate ANOVA 12.88 <.001

Note: NRA and PUFI are not distances.

JI ET AL. 5

T A B L E 2 Facial features comparison

Variable WS group (n = 16) Control group (n = 64) t value Adjusted p value
between WS group and normal group
under 3 years old (distance: mm) en_en 28.95 ± 2.72 31.04 ± 2.10 3.36 .003
ex_ex 73.76 ± 5.56 79.24 ± 4.12 4.42 <.001
sub_pro 9.34 ± 1.13 10.91 ± 2.16 2.81 .013
al_al 25.83 ± 1.71 27.00 ± 2.76 1.61 .133
n_sub 27.75 ± 3.49 31.52 ± 2.39 5.12 <.001
ch_ch 30.95 ± 3.00 30.93 ± 3.41 −0.02 .984
gn_n 72.21 ± 6.33 76.26 ± 5.07 2.71 .014
tr_n 85.71 ± 4.99 91.70 ± 4.45 4.70 <.001
tr_sub 86.61 ± 4.76 92.46 ± 4.49 4.60 <.001
tr_gn 92.30 ± 6.29 98.31 ± 5.63 3.74 .001
t_t 111.17 ± 6.78 120.00 ± 5.39 5.55 <.001
spa_spa 41.76 ± 3.76 44.16 ± 3.04 2.69 .014
t_poa 24.45 ± 2.19 25.71 ± 2.12 2.10 .058
NRA 31.32 ± 3.82 36.31 ± 3.34 5.20 <.001
PUFI 64.99 ± 4.55 63.56 ± 3.25 −1.44 .172
LBIN 107.36 ± 10.71 118.87 ± 24.82 1.81 .103
HBIN 280.32 ± 37.15 256.98 ± 51.88 −1.69 .122
MEI 58.81 ± 5.73 58.29 ± 3.96 −0.43 .712
F value p value
Multivariate ANOVA 3.99 <.001

Note: NRA, PUFI, LBIN, HBIN and MEI are not distances.

T A B L E 3 Facial features comparison

Variable WS group (n = 15) Control group (n = 60) t value Adjusted P value
between WS group and normal group
3–5 years old (distance: mm) en_en 31.26 ± 2.82 32.03 ± 2.90 0.93 .430
ex_ex 79.46 ± 5.41 85.72 ± 4.29 4.78 <.001
sub_pro 11.60 ± 1.35 12.59 ± 2.25 1.64 .147
al_al 27.69 ± 2.13 29.39 ± 3.17 1.96 .088
n_sub 34.14 ± 3.53 36.22 ± 2.95 2.34 .040
ch_ch 37.47 ± 3.16 34.96 ± 5.73 −1.63 .147
gn_n 82.84 ± 6.84 84.89 ± 7.46 0.96 .430
tr_n 96.07 ± 5.74 101.34 ± 4.28 3.97 .001
tr_sub 98.23 ± 5.89 102.94 ± 4.42 3.44 .005
tr_gn 105.34 ± 6.71 110.68 ± 5.69 3.14 .007
t_t 120.84 ± 7.11 132.01 ± 5.33 6.77 <.001
spa_spa 48.52 ± 3.78 48.73 ± 3.49 0.21 .884
t_poa 26.18 ± 2.25 28.14 ± 2.65 2.63 .021
NRA 38.98 ± 3.99 41.79 ± 3.63 2.63 .021
PUFI 68.52 ± 3.48 64.27 ± 4.67 −3.30 .005
LBIN 123.61 ± 12.46 124.87 ± 20.51 0.23 .884
HBIN 241.17 ± 28.47 239.89 ± 43.23 −0.11 .914
MEI 54.03 ± 3.23 57.83 ± 4.61 3.00 .010
F value p value
Multivariate ANOVA 9.56 <.001

Note: NRA, PUFI, LBIN, HBIN and MEI are not distances.
6 JI ET AL.

T A B L E 4 Facial features comparison

Variable WS group (n = 21) Control group (n = 84) t value Adjusted p value
between WS group and normal group
en_en 35.67 ± 3.24 35.48 ± 4.51 −0.19 .901 above 6 years old (distance: mm)
ex_ex 86.58 ± 5.62 95.33 ± 7.36 5.08 <.001
sub_pro 14.13 ± 3.17 14.41 ± 1.95 0.51 .733
al_al 31.87 ± 4.19 33.52 ± 3.01 2.08 .081
n_sub 40.75 ± 3.49 41.50 ± 3.85 0.81 .580
ch_ch 42.52 ± 4.56 42.79 ± 5.35 0.21 .901
gn_n 94.66 ± 7.96 95.65 ± 7.54 0.53 .733
tr_n 104.01 ± 6.20 110.51 ± 6.84 3.96 <.001
tr_sub 107.50 ± 5.96 113.76 ± 7.52 3.54 .002
tr_gn 116.07 ± 6.34 124.87 ± 9.25 4.11 <.001
t_t 129.40 ± 5.19 141.46 ± 8.13 6.46 <.001
spa_spa 48.87 ± 3.00 52.54 ± 4.56 3.50 .002
t_poa 25.96 ± 2.24 28.60 ± 2.69 4.16 <.001
NRA 46.60 ± 4.96 48.30 ± 4.91 1.42 .261
PUFI 73.14 ± 5.23 67.62 ± 3.66 −5.64 <.001
LBIN 130.34 ± 24.39 124.27 ± 11.50 −1.67 .177
HBIN 235.45 ± 52.80 235.97 ± 32.44 0.06 .955
MEI 53.27 ± 5.40 54.70 ± 5.84 1.02 .465
F value p value
Multivariate ANOVA 8.89 <.001

Note: NRA, PUFI, LBIN, HBIN and MEI are not distances.

distance than control children and this trait was particularly evident
under 3 years old. In fact, abnormal interpupillary distance is a highly
frequent clinical manifestation in many chromosomal disorders and
should be measured objectively rather than judged subjectively. Due
to technical limitations, objective measurement of the periorbital full-
ness remains a problem. It requires the further refinement of eye fea-
tures before they can be used as basis for identification.
Wide mouth with full lips in children with WS has always been
recognized as one of the highly frequent facial manifestations. Chil-
dren with WS enrolled in this study visually exhibit typical mouth fea-
tures but showed no statistically significant difference from control
children across all age groups in terms of mouth breadth. Considering
low cognitive ability and over-friendly behaviors, children with WS
displayed rich facial expressions during the photo moment, including
deliberately compressing their lips or opening or closing their mouths.
Nevertheless, the 3dMDface system captured facial images at an
ultra-fast speed of 1.5 ms and the pictures collected exhibited basi-
cally qualified natural expressions. By analysis, this phenomenon may
be attributed to the sharp contrast between the relatively narrow face
commonly existing in children with WS and their normal mouth
breadth, which result to visually wider mouth. Hence in subsequent
studies, it will be necessary to take into account mouth movements of
children with WS, and add the lip thickness index for the purpose of
better analyzing and evaluating the mouth shape in an objective
manner.
When describing the nose of children with WS in prior studies,
low nasal bridge, short nose, anterior-directed nostrils, and/or chubby
nose tip are commonly used. In our study, we found that children
with WS had smaller nose, lower nasal bridge, and anterior-directed
nostrils compared with the control children but differ little in terms of
their proportions. The feature of chubby nose was not found in these
young patients. We found that children with WS had shorter and
lower nose than the control children in the infancy and toddler period.
They had the normal nasal height in the 3–5 years old group and to
the normal nasal shape in the above 6 years old group. These features
indicated that the nose of children with WS gradually closed to normal
as age increased. Nose growing from small to normal level with age
was also one of the notable features distinguishing children with WS
from children with Down's syndrome.
Common descriptions about ear features in children with WS are
prominent ears and large earlobes. Our study found that the ears of
children with WS were smaller than those of the normal group but dif-
fer little in terms of their morphological proportion. For the size of the
earlobe, no objective indicator could be accurately embodied in this
study. Our findings indicated that the ear width and bitragal breadth
were smaller in children with WS above 3 years old than the normal
groups. These two indicators were the comparatively stable and mea-
surable items and be used clinically to distinguish children with WS
from normal children.
Many facial descriptions of children with WS are mainly bitemporal
narrowness, full cheeks, and small jaws. Small jaw is an easy feature
to judge, but the concepts of bitemporal narrowness and full cheek are
less understandable for many medical staffs. Our study found that
infants and toddlers with WS were small in face shape but had normal
JI ET AL.
facial proportion and less distinct bitemporal narrowness, and these
facial features tended to become evident in children with WS above
3 years old. Also, the prevalence of widely spaced small teeth and dental
malocclusion distincted their facial features as age increases in children
with WS (Axelsson, 2005; Sinha, Tamang, & Chakraborty, 2014).
CVI is a comprehensive assessment of facial features. The higher
the CVI, the more incongruent the facial variability is. In our study, we
found the CVI in the WS group was greater than that of the control
group, which confirmed that children with WS had very different
facial features than normal children. Some studies found that there
was a certain correlation between CVI and age though the correlation
coefficient was small, and the difference between genders was statis-
tically significant (Farkas et al., 2005; Zhuang, Landsittel, Benson,
Roberge, & Shaffer, 2010). However, we found no difference between
boys and girls with WS. This insignificant gender difference in WS
may be attributed to the small sample size.
The pathological mechanism behind facial dysplasia is not yet
known. It is thought to be related to the deletion genes that regulate
elastin, and among them, the GTF2IRD1 is the most studied (Tassabehji
et al., 2005). The establishment of animal models had provided clues for
better analysis of genes and phenotypic characteristics (Osborne, 2010;
Palmer et al., 2007; Palmer et al., 2010). Since most experimental sub-
jects were chosen from mice, but human facial growth is more compli-
cated. The correlation between genes and facial development in human
needs further study.
There are some limitations in this study. First, due to the small
sample size, different age groups could not be grouped by gender.
Second, the variables of periorbital fullness and mouth characteristics
were too less to reflect the characteristics of WS. More landmarks
and measurements should be added to obtain more data about these
facial features. In the future, we plan to expand the sample size,
increase the measurement data, control the measurement error, and
obtain more meaningful objective basis.
In conclusion, this study used 3D anthropometric measurement
technology to confirm that the peculiar facial features caused by WS
was evidently expressed in the infancy and early childhood in Chinese
Han population. It provided objective basis to help clinicians to under-
stand and get acquainted with such diseases more quickly, and bring
to these children and their parents a chance for timely diagnosis,
treatment and intervention.
CONF LICT OF IN TE RE ST
The authors declare that the research was conducted in the absence
of any commercial or financial relationships.
AUTHOR CONTRIBUTIONS
Zheng-Yan Zhao and Chai Ji: Conception and designed the research;
Chai Ji, Dao Yao and Ming-Yan Li: interviewed respondents and
entered data; Sheng-Liang Lin, Wi-Jun Chen and Ming-Yan Lin: ana-
lyzed the data and performed the statistical analyses; Chai Ji and
Zheng-Yan Zhao: wrote and revised the manuscript. All authors:
approved the final content of the manuscript. None of the authors
declared a conflict of interest.
7
DATA AVAILABILITY STAT EMEN T
Data sharing is not applicable to this article as no new data were cre-
ated or analyzed in this study.
OR CID
Zheng-Yan Zhao https://orcid.org/0000-0003-2368-0486
RE FE RE NCE S
American Academy of Pediatrics. (2001). Health care supervision for chil-
dren with Williams syndrome. Pediatrics, 107, 1192–1204.
Aldridge, K., Boyadjiev, S. A., Capone, G. T., DeLeon, V. B., &
Richtsmeier, J. T. (2005). Precision and error of three-dimensional phe-
notypic measures acquired from 3dMD photogrammetric images.
American Journal of Medical Genetics. Part A, 138a, 247–253.
Axelsson, S. (2005). Variability of the cranial and dental phenotype in
Williams syndrome. Swedish Dental Journal Supplement, 170, 3–67.
Axelsson, S., Kjaer, I., Heiberg, A., Bjørnland, T., & Storhaug, K. (2005).
Neurocranial morphology and growth in Williams syndrome. European
Journal of Orthodontics, 27, 32–47.
Black, J. A., & Carter, R. E. (1963). Association between aortic stenosis and
facies of severe infantile hypercalcaemia. Lancet, 2, 745–749.
Burn, J. (1986). Williams syndrome. Journal of Medical Genetics, 23,
389–395.
Chen, W. J., Ji, C., Yao, D., & Zhao, Z. Y. (2017). Thyroid evaluation of chil-
dren and adolescents with Williams syndrome in Zhejiang Province.
Journal of Pediatric Endocrinology & Metabolism, 30, 1271–1276.
Farkas, L. G., Katic, M. J., Forrest, C. R., Alt, K. W., Bagic, I., Baltadjiev, G.,
… Yahia, E. (2005). International anthropometric study of facial mor-
phology in various ethnic groups/races. The Journal of Craniofacial Sur-
gery, 16, 615–646.
Hammond, P., Hutton, T. J., Allanson, J. E., Buxton, B., Campbell, L. E.,
Clayton-Smith, J., … Tassabehji, M. (2005). Discriminating power of
localized three-dimensional facial morphology. American Journal of
Human Genetics, 77, 999–1010.
Hirai, M., Muramatsu, Y., Mizuno, S., Kurahashi, N., Kurahashi, H., &
Nakamura, M. (2016). Typical visual search performance and atypical
gaze behaviors in response to faces in Williams syndrome. Journal of
Neurodevelopmental Disorders, 8, 38.
Järvinen, A., Korenberg, J. R., & Bellugi, U. (2013). The social phenotype
of Williams syndrome. Current Opinion in Neurobiology, 23,
414–422.
Ji, C., Yao, D., Chen, W., Li, M., & Zhao, Z. (2014). Adaptive behavior in
Chinese children with Williams syndrome. BMC Pediatrics, 14, 90.
Jones, K. L., & Smith, D. W. (1975). The Williams elfin facies syndrome. A
new perspective. The Journal of Pediatrics, 86, 718–723.
Kruszka, P., Porras, A. R., de Souza, D. H., Moresco, A., Huckstadt, V.,
Gill, A. D., … Muenke, M. (2018). Williams-Beuren syndrome in diverse
populations. American Journal of Medical Genetics. Part A, 176,
1128–1136.
Martens, M. (2013). Developmental and cognitive troubles in Williams
syndrome. Handbook of Clinical Neurology, 111, 291–293.
Mass, E., & Belostoky, L. (1993). Craniofacial morphology of children
with Williams syndrome. The Cleft Palate-Craniofacial Journal, 30,
343–349.
McNamara, J. A., Jr. (1984). A method of cephalometric evaluation. Ameri-
can Journal of Orthodontics, 86, 449–469.
Osborne, L. R. (2010). Animal models of Williams syndrome. American
Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 154c,
209–219.
Palmer, S. J., Santucci, N., Widagdo, J., Bontempo, S. J., Taylor, K. M.,
Tay, E. S., … Hardeman, E. C. (2010). Negative autoregulation of
GTF2IRD1 in Williams-Beuren syndrome via a novel DNA binding
mechanism. The Journal of Biological Chemistry, 285, 4715–4724.
8 JI ET AL.
Palmer, S. J., Tay, E. S., Santucci, N., Cuc Bach, T. T., Hook, J.,
Lemckert, F. A., … Hardeman, E. C. (2007). Expression of Gtf2ird1, the
Williams syndrome-associated gene, during mouse development. Gene
Expression Patterns, 7, 396–404.
Riby, D. M., Kirk, H., Hanley, M., & Riby, L. M. (2014). Stranger danger
awareness in Williams syndrome. Journal of Intellectual Disability
Research, 58, 572–582.
Roelfsema, N. M., Hop, W. C., van Adrichem, L. N., & Wladimiroff, J. W.
(2007). Craniofacial variability index in utero: A three-dimensional
ultrasound study. Ultrasound in Obstetrics & Gynecology, 29, 258–264.
Sinha, P., Tamang, B. K., & Chakraborty, S. (2014). Craniofacial anthropom-
etry in newborns of Sikkimese origin. The Journal of Laryngology and
Otology, 128, 527–530.
Strømme, P., Bjørnstad, P. G., & Ramstad, K. (2002). Prevalence estimation
of Williams syndrome. Journal of Child Neurology, 17, 269–271.
Sugayama, S. M., Leone, C., Chauffaille Mde, L., Okay, T. S., & Kim, C. A.
(2007). Williams syndrome: Development of a new scoring system for
~ Paulo, Brazil), 62, 159–166.
clinical diagnosis. Clinics (Sao
Tassabehji, M., Hammond, P., Karmiloff-Smith, A., Thompson, P.,
Thorgeirsson, S. S., Durkin, M. E., … Donnai, D. (2005). GTF2IRD1 in cra-
niofacial development of humans and mice. Science, 310, 1184–1187.
Ward, R. E., Jamison, P. L., & Farkas, L. G. (1998). Craniofacial variability
index: A simple measure of normal and abnormal variation in the head
and face. American Journal of Medical Genetics, 80, 232–240.
Weinberg, S. M., Naidoo, S., Govier, D. P., Martin, R. A., Kane, A. A., &
Marazita, M. L. (2006). Anthropometric precision and accuracy of digi-
tal three-dimensional photogrammetry: Comparing the Genex and
3dMD imaging systems with one another and with direct anthropome-
try. The Journal of Craniofacial Surgery, 17, 477–483.
Zhuang, Z., Landsittel, D., Benson, S., Roberge, R., & Shaffer, R. (2010).
Facial anthropometric differences among gender, ethnicity, and age
groups. The Annals of Occupational Hygiene, 54, 391–402.
How to cite this article: Ji C, Yao D, Li M-Y, Chen W-J,
Lin S-L, Zhao Z-Y. A study on facial features of children with
Williams syndrome in China based on three-dimensional
anthropometric measurement technology. Am J Med Genet
Part A. 2020;1–8. https://doi.org/10.1002/ajmg.a.61750