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Contents lists available at ScienceDirect

Obesity Research & Clinical Practice

journal homepage: www.elsevier.com/locate/orcp

Case Report

Chung–Jansen Syndrome with obesity

Harleen Kaur, Inusha Panigrahi ∗
Dept. of Pediatrics, APC, PGIMER, Chandigarh, India

a r t i c l e i n f o a b s t r a c t

Article history: Chung–Jansen Syndrome is a recently identified obesity syndrome, characteristic clinical features of
Received 11 December 2020 which are global developmental delay, intellectual disability, obesity and dysmorphism (DIDOD). We
Received in revised form 17 March 2021 present a child with the syndrome who also had hypothyroidism and renal involvement in form of small
Accepted 31 March 2021
kidneys on one side. The next generation sequencing done in the child showed a nonsense variant in the
PHIP gene leading to premature chain termination in the protein on bioinformatic analysis.
Keywords:
© 2021 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights
Brachydactyly
reserved.
CHUJANS
Intellectual disability
Obesity
Hypotonia
Pleckstrin

Introduction
Chung–Jansen Syndrome or CHUJANS (OMIM #617991) is a
rare genetic syndrome caused by the heterozygous mutation in
the PHIP gene located on the chromosome 6q14. A patient with
CHUJANS was described out of 100 severe intellectually disabled
children studied [1]. Ever since, the reported cases of PHIP muta-
tions have been increasing, most of which are de novo in nature and
having common clinical manifestations like intellectual disability,
behavioral problems, developmental delay, dysmorphic features,
obesity and hypotonia [2–4]. Here, in this report, we present a
patient of obesity and intellectual disability with heterozygous
nonsense variant in PHIP gene, identified by targeted next genera-
tion sequencing.
Case report
A 7 years old male, the only child of non-consanguineous
parents, was presented with abnormal weight gain, aggressive
behavior and hypothyroidism. He was born with normal vagi-
nal delivery with birth weight of 3.25 kg. Parents noticed that his
weight increased after 3 years age along with developmental delay.
There was no history of feeding problems in infancy and no history
of hearing loss. The examination revealed coarse facies, large ears
with thick helices and earlobes, round face, almond shaped eyes,
∗ Corresponding author at: Genetic Metabolic Unit, Dept.of Pediatrics, APC,
PGIMER, Chandigarh, India.
E-mail address: panigrahi.inusha@pgimer.edu.in (I. Panigrahi).
mild epicanthal folds, upturned nose, prominent philtrum, and full
lips (Fig. 1). He also had hypermetropia, astigmatism, brachydactyly
and clinodactyly of 5th finger, inverted nipples, and hypotonia.
While standing his feet were widely spaced with body slightly lean-
ing forward, and gait was wide based. He had obesity with weight
of 39.2 kg (+2.43 Z score) and height of 114 cm (−2.01 Z score) and
had BMI 30.2 kg/m2 . The parents also reported that the boy had
aggressive behavior, poor scholastic performance and intellectual
disability along with easy fatigability in the child.
Investigations showed delayed bone age (4 carpal epiphyses),
increased serum leptin of 64.57 ng/ml (N = 2.05–5.63 ng/ml), low
serum cortisol of 146.4 nmol/ml (N = 171–536 nmol/ml) and nor-
mal renal ultrasonography at 7 years of age. The thyroid profile
showed T3 of 2.02 units, T4 12.73 units and TSH of 3.63 units, on thy-
roxine therapy. The blood urea and serum creatinine were normal.
His lipid profile showed serum cholesterol, HDL, and triglyceride
levels of 177, 46.6 and 131 units respectively. The MRI brain was
normal. Evaluation of refraction showed hypermetropia with astig-
matism requiring spectacles. A repeat ultrasonography at 9 years
of age showed small right kidney with decreased corticomedullary
differentiation and lobulated left kidney. Currently, child is hav-
ing weight of 55 kg (+2.51 Z score), height of 116 cm (−3.38 Z) and
40.9 kg/m2 BMI (+3.55 Z) at 9 years of age. The hip X-ray showed
decreased joint space bilaterally and he was advised orthopedic
consultation. The targeted next-generation sequencing (NGS) test-
ing revealed a heterozygous variant in PHIP gene in Exon 25. The
identified variant was NM 017934.6(PHIP):c.2902C > T. This leads
to protein change NP 060404.4:p.Arg968* which causes loss of
function due to premature termination of protein 12 amino acids
downstream.

https://doi.org/10.1016/j.orcp.2021.03.015
1871-403X/© 2021 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Please cite this article as: Kaur H, Panigrahi I, Chung–Jansen Syndrome with obesity, Obes Res Clin Pract,
https://doi.org/10.1016/j.orcp.2021.03.015
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Table 1
Comparative analysis of present child and that reported by Jansen et al ear-
lier with same PHIP:p.Arg968* variant; OCD—obsessive compulsive disorder,
ADHD—attention deficit hyperactivity disorder.

Information/feature Index patient Individual 2 in

Jansen et al. [3]

Gender Male Male

Age 7 years 11 years
Growth
Birth weight 3250 gm Unknown
Height −2.01 SD +0.5 SD
Weight +2.43 SD +1 SD
BMI 30.2 18.7
Head circumference – +0.2 SD
Obesity Yes No
Developmental delay Yes Yes
Age at walking 24 months 18 months
Age at talking/speech 12 months 9 months
Neurological
ID Yes Yes (Mild)
Behavioral Problems Yes (aggressive Yes (complex OCD,
behavior, poor complex ADHD,
scholastic very social, soft
performance) emotional)
Hypotonia Yes No
Brain abnormalities No Yes (slightly large
cerebellum)
Fatigue Yes No
Facial
Coarse facies Yes Not mentioned
Round face Yes No
High forehead No Yes
Full eyebrows/ No Yes
Fig. 1. Photograph of the face of the child showing coarse facies, large ears with synophrys
thick helices and earlobes, round face, almond shaped eyes, mild epicanthal folds, Almond shaped eyes Yes Yes
upturned nose, prominent philtrum and full lips (Picture taken with informed consent Epicanthal folds Yes (over right eye) Yes
for publication). Ptosis No Yes
Large ears Yes No
Thick helices and Yes Yes
Materials and methods earlobes
Upturned nose Yes Yes
The child was one of the cases of obesity evaluated in the Long philtrum No (prominent Yes
philtrum)
Genetic Clinic for likely genetic cause. The possibility of genetic obe-
Thin lips No Yes
sity syndrome including Simpson–Golabi–Behmel syndrome and Extremities
Bardet–Biedl syndrome was kept, to diagnose and rule out other Tapering fingers No Yes
syndromes, targeted next generation sequencing (NGS) was per- Clinodactyly of 5th Yes Yes
formed. The variant filtering and annotation on NGS was done as finger
Brachydactyly Yes Not mentioned
per ACMG guidelines [5].The informed consent for publication of Delayed bone age Yes (4 carpal Not mentioned
photographs was taken from the parents. epiphysis)
Others
Genital abnormality No Yes (bilateral
Discussion cryptorchidism)
Vision problems Yes Yes (strabismus,
Common obesity syndromes include Prader Willi syndrome and (hypermetropia, hypermetropia)
Bardet Biedl syndrome. The implicated gene for CHUJANS is PHIP astigmatism)
Skin pigmentation No Yes (several CALs)
(OMIM *612870) Pleckstrin homology domain-interacting protein abnormalities
present on chromosome 6q14, first ascertained in intellectual dis- Renal abnormalities Yes (small right Not mentioned
ability patient few years earlier [1]. Previously, PHIP was reported kidney, decreased
to be translated into different isoforms through alternative splic- corticomedullary
differentiation)
ing due to use of different naming. PHIP (PHIP1, long isoform) is
Inverted nipples Yes Not mentioned
1821 amino acid long protein also known as DCAF14 (DDB1 and
CUL4-associated factor 14) plays a key role in the ubiquitin ligase
pathway, as substrate receptor that helps in the binding of ubiqui- significance, 18 and 33 were of likely pathogenic and pathogenic
tin complex to its target protein and monitor a variety of cellular clinical significance respectively (ClinVar, accessed on 18 July
pathways such as cell cycle, cell survival, genomic integrity, gene 2020). The phenotype of both missense and loss of function vari-
transcription and embryonic development [2–4,6]. The gene is also ants have no significant difference. In previously reported cases
involved in regulation of pancreatic beta cell growth through IGF1 of PHIP gene mutation or CHUJANS, majority of them were hav-
and in insulin signaling and thus obesity occurs with disruption in ing delayed attainment of developmental milestones, intellectual
function of the PHIP gene or the encoded protein [6]. disability and learning problems, behavioral problems, dysmorphic
The ClinVar entry for PHIP gene showed a total of 70 reported features and hypotonia, additional ophthalmologic problems were
variants out of which, 13 are frameshift, 15 are missense, 17 also common [2–4]. Management of obesity has to be done as per
are nonsense and 3 are splice site variants. In totality 2 variants standard guidelines including diet restriction, and maintaining glu-
were of benign, 2 were of likely benign, 15 were of uncertain cose homeostasis.

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H. Kaur, I. Panigrahi
The variant identified in the child with obesity is of uncertain
significance in PHIP gene which is associated with developmental
delay, intellectual disability, obesity and dysmorphism. The same
variant is one of the 7 examples of allelic variants of PHIP gene
on OMIM (*612870.0005) (OMIM, accessed on 18 July 2020). The
p.Arg968Ter variant is a loss of function variant of PHIP gene that
is involved in the same phenotypic features, indicated by pres-
ence of already existing loss of function variants in the gene like
NP 060404.4:p.Gln1191Ter and many others. The same variant is
also reported in ClinVar and dbSNP as variant of uncertain signifi-
cance by single submitter previously in 2018 [3].
Comparative table lists the phenotypic feature if index child as
compared to individual 2 of Jansen et al. 2018 having same muta-
tion showed that out of 27 comparable features, 9 are same in both
patients, 12 differ and 6 are not mentioned in comparative patient,
the differences between patients can be due to ethnic variations
in facial phenotypes (Table 1). Café au lait spots were not evident
in current child due to possibly a darker skin tone. However the
facies of index child matches more to individual 15 of Jansen et al.
2018 [3]. Clinical variability is well known in autosomal dominant
disorders with familial or de novo variant. The variant in the index
case has a minor allele frequency of 0.0008% and 0.02% in gnomAD
and 1000 genome databases respectively. In-silico predictions of
the variant by CADD, Mutation Taster and PANTHER were done and
found to be deleterious, disease causing and probably damaging.
Conclusion
We hypothesize that Arg968* mutation in PHIP gene might
be causative of the characteristic phenotype and is causing the
Chung–Jansen Syndrome in the index child, as the child is having
the clinical manifestations of CHUJANS as previously reported. In
addition the child also had hypothyroidism and renal involvement
with small right kidney and decreased corticomedullary differenti-
ation. This adds to the variability of the clinical phenotype resulting
from the same variant.
Obesity Research & Clinical Practice xxx (xxxx) xxx–xxx
Funding source
None.
Conflicts of interest
None.
Statement of ethics
Informed consent for publication of details was taken from the
parents.
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