Short case report  1
Identification of a novel variant of SCARF2 in a Jordanian
family with a van den Ende-Gupta Syndrome and literature
review
Osama Odeha, Tawfiq Barqawia, Hussein Rashida, Safa Almashhdia
and Mohammad Shboulb
Clinical Dysmorphology XXX, XXX:000–000
a
Department of Medicine, Faculty of Medicine, The University of Jordan, Amman
and bDepartment of Medical Laboratory Sciences, Jordan University of Science
and Technology, Irbid, Jordan
List of key features
Blepharophimosis
Arachnodactyly
Camptodactyly
Wide nasal bridge
Cleft palate
Hypertelorism
Introduction
Van den Ende-Gupta Syndrome (VDEGS; MIM 600920)
is a rare autosomal recessive syndrome caused by homozy-
gous variants in the scavenger receptor class F member 2
(SCARF2) gene (Anastasio et al., 2010; Niederhoffer et al.,
2016). SCARF2 gene is mapped to 22q11.2 region, con-
sists of 11 exons and encodes the SCARF2. The function
of SCARF2 has not been fully elucidated. It is reported
that this protein belongs to the cell surface scavenger
receptors family involved in lipid scavenging and other
biologic processes, including pathogen clearance, endo-
cytosis, adhesion and antigen presentation. It is further
involved in the pathophysiology of several disorders,
such as pathogen infections, atherosclerosis, metabolic
disorders, neurodegeneration and cancer (Ishii et al.,
2002; PrabhuDas et al., 2014; Zani et al., 2015).
VDEGS is characterized by distinctive facial dysmor-
phism and skeletal abnormalities, such as blepharophi-
mosis, malar and maxillary hypoplasia, distinctive nose
such as narrow nose, hypoplastic alae nasi, a wide and
flat nasal bridge and columella malformation (Guerra
et al., 2005; Anastasio et al., 2010; Bedeschi et al., 2011;
Hildebrandt et al., 2021). Everted lower lip, cleft palate,
downslanting eyebrows, upslanting palpebral fissures,
arachnocamptodactyly, long slender bones of the hands
and feet with permanent contracture and deformity, bow-
ing of long bones, gracile ribs, valgus deformities of the
big toes, cerebellar enlargement and respiratory prob-
lems were also reported in some VDEGS cases (Guerra
et al., 2005; Anastasio et al., 2010; Bedeschi et al., 2011;
Hildebrandt et al., 2021). More than 40 VDEGS cases have
0962-8827 Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
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Correspondence to Mohammad Shboul, PhD, Department of Medical Laboratory
Sciences, Jordan University of Science and Technology, Irbid, Jordan
Tel: +962798012564; e-mail: maalshboul@just.edu.jo
Received 18 December 2021 Accepted 2 February 2022
been reported so far (Al-Qattan et al., 2018; Hildebrandt
et al., 2021). While VDEGS is predominantly caused by
SCARF2 variants, it seems that it could be heterogeneous
as more than 10 clinically diagnosed VDEGS cases were
found to be negative for SCARF2 variants (Niederhoffer
et al., 2016). Moreover, variable expressivity and addi-
tional infrequent phenotype have been reported in a
subset of patients with VDEGS, such as laryngeal abnor-
malities, hydronephrosis, ambiguous genitalia, cardiac
abnormalities, sclerocornea and other features (Carr et al.,
2007; Migliavacca et al., 2014; Niederhoffer et al., 2016;
Al-Qattan et al., 2018).
In this article, we report the clinical and molecular details
of three cases presenting with typical clinical features
of VDEGS from a consanguineous Jordanian family.
Molecular analysis of the SCARF2 gene revealed a novel
homozygous variant.
Subjects and methods
Three children (two females, one male) born to a
Jordanian family. The parents are healthy first-degree
cousins with additional three healthy children (two
females, one male). The family pedigree is illustrated in
Fig. 1a.
Clinical reports
Case 1: Patient (III.1) is a 22-year-old female patient
presenting with asymmetrical face, blepharophimosis,
hypertelorism, downslanting eyebrows, flat and wide
nasal bridge, narrow nose, prominent nasal tip, malar
hypoplasia, everted lower lip, prominent ears and hal-
lux valgus as well as arachnodactyly and camptodactyly
(Fig.  1a). She looks short and had scoliosis which was
corrected surgically. She further complains of finger con-
tractures that have not improved causing difficulties and
function restriction. The patient has normal intelligence
and no motor developmental delay. Ophthalmologic
examination showed decreased visual acuity and audio-
logic testing showed hearing loss. Further investigations
DOI: 10.1097/MCD.0000000000000415
2  Clinical Dysmorphology  XXX, Vol XXX No 00

Fig. 1.

The family pedigree and patient characteristics. (a) Family pedigree. Square and circle denote male and female, respectively. Filled and unfilled
symbols indicate affected and unaffected individuals, probands are indicated by arrow. (b–l) Phenotypic features of the affected individuals. Case
1 (III.1): (b) blepharophimosis, malar hypoplasia and wide nasal bridge, (c,d) arachnocamptodactyly of the fingers and (e) hallux valgus and long
halluces. Case 2 (III.5): (f) wide nasal bridge, blepharophimosis, hypertelorism and asymmetric narrow nose, (g) large prominent ears, (h) arachno-
dactyly of the fingers and (i) hallux valgus. Case 3 (III.6): (j) wide nasal bridge, blepharophimosis, (k) large prominent ears, (l) arachnodactyly of the
fingers.

showed no cardiac anomalies. Detailed clinical pictures
are illustrated in Fig. 1b–e.
Case 2: The second patient (III.5) is a 14-year-old boy
with dysmorphic features similar to his sisters includ-
ing prominent ears, blepharophimosis, flat and wide
nasal bridge, asymmetric narrow nose, prominent
nasal tip, everted lower lip, cleft palate, prominent
ears, micrognathia and malar hypoplasia (Fig.  1a).
Neurologic, cardiac and renal examinations were nor-
mal. He exhibited inspiratory and expiratory stridor
in the neonatal period. An otolaryngologic evaluation
revealed laryngomalacia and congenital tracheal ste-
nosis. Physical examination showed camptodactyly,
crowded teeth, macrocephaly and a curved penis.
Arachnodactyly of the hands and feet and large hal-
luces were also noted bilaterally. Motor and mental
development were normal. Ophthalmologic exami-
nation showed decreased visual acuity and audiologic
evaluation documented hearing difficulties. Detailed
clinical pictures are illustrated in Fig. 1f–i).
Case 3: The last-born child in the family (III.6) is a 5-year-
old girl who had blepharophimosis, hypertelorism, malar
hypoplasia, everted lower lip, prominent ears, mild exter-
nal deformity, decreased visual acuity, bulbous nasal tip
and digit anomalies similar to her brother and sister but less
severe (Fig. 1a). Neurologic, cardiac and pulmonary exami-
nations were normal. Motor and mental development were
normal. Detailed clinical pictures are illustrated in Fig. 1j–l.
Mutation analysis
After informed consent was obtained from the family,
blood samples were collected from the patients and all
family members (Fig. 1, II:1, II:2 and III:1–6). Genomic
DNAs were extracted using standard protocols. This
study was approved by the local ethics committee of the
University of Jordan.
Genetic analysis was carried out by PCR and Sanger
sequencing of the exon and intron boundaries of the
SCARF2 gene. Primers were designed using the Primer 3

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Fig. 2.
Genotyping and amino acids conservation. (a) The genotyping result of SCARF2 (NM_153334.7): c.220G>T (p.Glu74Ter) variant in all family
members. All three affected children are homozygous and parents and unaffected siblings are heterozygous for the nonsense variant. The letter ‘G’
and ‘T’ represent wild-type and mutant alleles, respectively. (b) Conservation analysis shows that the Glu residue at 74 in SCARF2 is conserved
across human, chimpanzee, cattle, mouse, rat, chicken, fish and frog.
software (http://frodo.wi.mit.edu/primer3/) and are avail-
able upon request. Capillary sequencing was performed
in a 3730 DNA Analyzer (Applied Biosystems, Foster
City, California, USA), and the data were analyzed using
Sequencing Analysis software.
Results
Pedigree analysis of the family suggested an autosomal
recessive pattern of inheritance. Sequencing analysis
revealed a nonsense variant (c.220G>T; p.Glu74Ter) in
exon 2 of the SCARF2 gene. Genotyping results, as shown
in Fig. 2a, confirmed the homozygous state of the variant
in the affected children. Parents and unaffected siblings
were found to be heterozygous. The identified variant is
predicted to cause premature termination of the protein
at residue 74 (p.Glu74Ter), which will likely result in loss
of function. Moreover, due to the introduction of a pre-
mature stop codon, this aberrant mRNA transcript could
be degraded by the nonsense-mediated mRNA decay
(NMD) mechanism or formation of a truncated protein
that lacks 797 amino acids. This variant is also located
in a region that is highly conserved among vertebrates
(Fig. 2c). Furthermore, the identified variant seems to be
a novel variant, as it has not been previously reported in
the literature, or population or public databases, such as
single nucleotide polymorphism database, exome aggre-
gation consortium browser and the 1000 genomes pro-
ject. Based on American College of Medical Genetics and
Genomics (ACMG) guidelines, this variant was classified
as pathogenic for an autosomal recessive VDEGS.
Discussion
VDEGS is a very rare autosomal recessive syndrome with
approximately 40 patients depicted to date. VDEGS is
caused by variants in the SCARF2 gene. In this study, we
evaluated a consanguineous Jordanian family with three
affected children with a remarkably similar phenotype
that resembles VDEGS in all aspects. The syndrome is
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Identification of a novel variant of SCARF2 gene Odeh et al. 3
characterized by craniofacial features such as blepharo-
phimosis, malar hypoplasia, In this study, we report max-
illary hypoplasia, triangular face, nasal anomalies (one or
more of the following phenotype: flat nasal bridge, narrow
or beaked nose, nasal tip abnormalities and infrequently
pseudocleft of the columella), downslanting eyebrows
and everted lower lip (Guerra et al., 2005; Anastasio et
al., 2010; Bedeschi et al., 2011; Jerome-Majewska, 2016;
Hildebrandt et al., 2021). The disease causes various
skeletal abnormalities, such as arachnodactyly, campto-
dactyly, bowing of long bones, gracile ribs, valgus deform-
ities of the big toes, flexion contractures of elbows and
knees and a hooked clavicle as well as digit abnormalities
(Guerra et al., 2005; Anastasio et al., 2010; Bedeschi et al.,
2011; Jerome-Majewska, 2016; Hildebrandt et al., 2021).
Laryngeal abnormalities and cerebellar enlargement
have also been described (Carr et al., 2007; Migliavacca et
al., 2014). Joint laxity, recurrent patellar dislocations and
short distal ulnae have been recently reported as part of
the clinical spectrum of VDEGS (Al-Qattan et al., 2018).
VDEGS has multiple clinical features that overlap with
different diseases. Due to the region involved in VDEGS
being the same as the region involved in DiGeorge syn-
drome, the two diseases share multiple clinical features,
such as hypoplastic mandible, palatal abnormalities, a bul-
bous nasal tip and sclerocornea (Migliavacca et al., 2014).
VDEGS also shares many clinical features with another
rare disease called Marden-Walker syndrome (MIM
248700) but is distinguished mainly by the absence of
intellectual disability and failure to thrive (Niederhoffer
et al., 2016). Teebi–Shaltout syndrome (MIM 272950)
is another extremely rare autosomal recessive disease
sharing many features with VDEGS, such as blepharo-
phimosis and a bulbous nose with hypoplastic alae nasi
(Anastasio et al., 2010). Several clinical manifestations
were found to overlap with the congenital heart defects
and skeletal malformations syndrome (CHDSKM; MIM
617602). These features include blepharophimosis and
4  Clinical Dysmorphology  XXX, Vol XXX No 00
maxillary hypoplasia, everted lower lip, hallux valgus,
camptodactyly, arachnodactyly (Chen et al., 2020). This
disease is dominantly inherited and associated with
ABL1 gene variants (Wang et al., 2017; Chen et al., 2020).
In this study, we report three affected siblings with clini-
cal features typical of VDEGS. The three children share
common features similar to previously reported cases,
such as asymmetrical face blepharophimosis, hyper-
telorism, downslanting eyebrows, flat and wide nasal
bridge, prominent nasal tip, malar hypoplasia, prominent
ears as well as arachnodactyly and camptodactyly. These
phenotypes were milder in the little girl. Other features,
including asymmetric narrow nose, crowded teeth, cleft
palate, macrocephaly, laryngomalacia, tracheal stenosis
and a curved penis were only observed in the affected boy.
Compared to all published VDEGS cases, the affected
individuals in this study showed hearing loss, decreased
visual acuity, laryngeal abnormalities and scoliosis, which
are infrequently seen in VDEGS cases. Moreover, the
curved penis and the tracheal stenosis have never been
reported in published cases.
All three patients were found to have a homozygous non-
sense substitution variant (c.220G>T; p.Glu74Ter) in the
SCRF2 gene and parents were found to be heterozygous.
The identified variant is highly conserved among verte-
brates and is predicted to cause premature termination.
The resulted aberrant mRNA transcript could likely be
degraded by the NMD mechanism or the formation of a
truncated protein resulting in loss of function (Maquat,
2004). The identified variant seems to be novel, as it has
not been previously reported in the literature, or popula-
tion or public databases. According to the ACMG guide-
lines (Richards et al., 2015), this mutation is classified as
pathogenic (class 5: PVS1, PM2, PP1, PP3 and PP4).
Mutations in the SCARF2 gene are known to be the cause
of this syndrome. More than 40 cases with VDEGS have
been reported so far (Al-Qattan et al., 2018; Hildebrandt et
al., 2021). However, previous studies demonstrated that
many patients who showed clinical features consistent
with VDEGS were negative for SCARF2 gene mutations
suggesting that this syndrome might show genetic het-
erogeneity (Schweitzer et al., 2003; Leal and Silva, 2009;
Bedeschi et al., 2011). A recent study identified variants
in the ABL1 gene in many cases that had negative testing
for the SCARF2 gene (Hildebrandt et al., 2021). However,
the phenotypic overlap between CHDSKM and VDEGS
could lead to misdiagnosis, but absence of the congenital
heart defect and aortic root dilation distinguishes the lat-
ter. It has also been proposed that different phenotypes
of VDEGS are produced depending on the severity of the
loss of function in the SCARF2 gene (Migliavacca et al.,
2014). The clinical heterogeneity can also be explained
by other unidentified genes especially for cases that are
negative for both SCARF2 and ABL1 genes.
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Conclusion
We report a novel homozygous nonsense variant
(c.220G>T; p.Glu74Ter) in three individuals from a
consanguineous Jordanian family. Parents and nonaf-
fected siblings are heterozygous. This variant is a loss
of function and could be responsible for the severe
phenotype in our patients. The affected patients in
this article further support the existence of this syn-
drome of blepharophimosis, arachnodactyly and camp-
todactyly with normal intelligence, as a distinct entity.
Furthermore, the curved penis had not been previ-
ously described in cases of VDEGS.
These findings expanded the mutational spectrum of
the SCARF2 gene. Additional functional and expression
studies are needed to confirm the pathogenicity and the
effect of the identified variant at the protein level.
We believe that patients diagnosed with this syndrome
might benefit from further evaluation regarding these
anomalies. Moreover, our results might be helpful in
genetic counselling for families with clinical phenotypes
of this syndrome.
Acknowledgements
We wish to thank the family for their collaboration.
Informed consent has been obtained from patients that
grants permission for the publication of images as part of
this work.
Conflicts of interest
There are no conflicts of interest.
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