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ASIA PACIFIC SOCIETY
OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
PROGRAMME BOOK
ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
O
W ELC OM E M ESSAGE
PROFESSOR GODFREY CHI-FUNG CHAN
Head, Department of Paediatrics and Adolescent Medicine
Li Ka Shing Faculty of Medicine, The University of Hong Kong
n behalf of the University of Hong
Kong, I’d like to welcome you to
Hong Kong, for the Summer School of
Asia Pacific Society of Human Genetics
that will take place from 26th to 28th,
August 2016. It’s an exciting time
for the Department of Paediatrics &
Adolescent Medicine at HKU, as we
organize the first summer school in
Hong Kong to promote education in
genetics for the junior faculties and
trainees.
The theme of the Summer School
of Asia Pacific Society is “Clinical
dysmorphology and genetic counselling
in the post-NGS era”. With the bloom of
next generation sequencing technology,
the Asia-Pacific community must
keep up with our knowledge in
genomic medicine. The program
will comprehensively cover the latest
advances in clinical genetics. Likewise,
tutored by experts from overseas, the
case discussion sessions will the most
valuable first-hand experience for our
participants. The “Post Summer School
Bioinformatics Workshop” will also
teach world-class bioinformatics and
data interpretation skills. We hope
this event can bring inspired people
together to meet, and stimulate global
interactions and collaborations in
genomics, in the beautiful geographic
location of Hong Kong.
We are pleased to have Prof. John Carey
(Editor in Chief of AJMG) and Prof.
Leslie Biesecker (Chief of the Medical
1
Genomics and Metabolic Genetics
Branch at the NHGRI, NIH) with
us. We are also thrilled to have world
leading experts such as Prof. David
Chitayat (Toronto Sickkids, Canada),
Prof. Kenjiro Kosaki (Keio University
School of Medicine, Tokyo, Japan)
and Prof. David Sillence (Westmead
Hospital, Sydney, Australia) as our
invited speakers. We are also grateful to
have Dr. Anne Tsai (Children’s Hospital
Colorado, Aurora, USA) to host the
case discussions, joined by numerous
other prominent speakers from the
region. Last but not least, I must thank
Dr Brian Chung, his dedicated team
and the Asia-Pacific Society of Human
Genetics for the excellent organization.
I have no doubt this is a rare opportunity
to bring education in genetics to South
East Asia, which becomes a lot more
accessible to our fellow neighbors.
Professor Godfrey Chi-Fung Chan
Tsao Yen-Chow Endowed Professor in
Paediatrics & Adolescent Medicine
Head, Department of Paediatrics and
Adolescent Medicine
Li Ka Shing Faculty of Medicine, The
University of Hong Kong
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
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O
W ELC OM E M ESSAGE
DR POH-SAN LAI
President, Asia-Pacific Society of Human Genetics
Associate Professor, Dept of Paediatrics, Yong Loo Lin School of
Medicine, National University of Singapore
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n behalf of the Asia Pacific
Society of Human Genetics, it
gives me great pleasure to welcome all
participants to this inaugural summer
school hosted at The University of
Hong Kong.
I am excited about this meeting as it
marks the first summer school organized
by the Society with the aim of providing
training and education in genetics and
genomics among trainees, fellows and
early career professionals in this field.
This year’s course focusses on clinical
genetics and genetic counselling. The
local organizing committee chaired
by Dr Brian Chung, has drawn up
an exciting programme with lectures
and discussion sessions by renowned
experts in this field. This three day
programme will introduce participants
to the latest approaches and tools for
the diagnosis and management of
patients with selected genetic disorders.
With genomic medicine and next-gen
sequencing (NGS) being increasingly
integrated into clinical care, it is timely
for those who are providing diagnostic,
management and counselling services
to be updated on the current trends and
challenges in this field. This course will
also provide opportunities for case study
presentations to facilitate interactive
discussions and learning experience on
how to reach a diagnosis for challenging
situations. I am also pleased that besides
this main programme, there will be a
post-summer school bioinformatics
workshop that is co-hosted with
Genome
Diagnostic,
Nijimegen,
Radbound University. This workshop
will provide hands-on training on NGS
data analysis and variant interpretation,
and underscores the importance of
bioinformatics technology in meeting
biomedical and clinical needs.
I invite all participants to enjoy the
stimulating environment over the next
few days and hope that you will gain
new knowledge, make new friends and
take away valuable insights that will
help you in your work back home.
Lastly, I thank everyone who made this
summer school possible, especially the
local organizing committee who had
worked hard on the programme for
many months, the international and
local faculty for sharing your unique
expertise and experience, University of
Hong Kong for hosting this course, and
all the sponsors who have contributed
towards helping us achieve this
educational outreach.
Welcome to the first summer school of
APSHG!
Best wishes,
Dr Poh-San Lai
10 August 2016
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
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I NVI T ED G UESTS
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SUMMER SCHOOL 2016
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I N VI T E D G U E ST S
JOHN C CAREY
KENJIRO KOSAKI
ӹӹ Professor of Pediatrics, University of Utah School of
Medicine, USA
ӹӹ Editor in Chief, American Journal of Medical
Genetics
ӹӹ Professor, Center for Medical Genetics, Keio
University School of Medicine, Japan
LESLIE G BIESECKER
DAVID SILLENCE
ӹӹ Chief & Senior Investigator, Medical Genomics
and Metabolic Genetics Branch; Head, Clinical
Genomics Section, National Human Genome
Research Institute, USA
ӹӹ Professor, Consultant Physician, Department of
Genetic Medicine, Westmead Hospital, Westmead,
Australia
DAVID CHITAYAT
ANNE CHUN-HUI TSAI
ӹӹ Staff Physician, Clinical and Metabolic Genetics,
The Hospital for Sick Children, Canada
ӹӹ Professor, Department of Paediatrics/ Obstetrics and
Gynecology/ Laboratory Medicine & Pathobiology/
Molecular & Medical Genetics; Medical Director,
MSc Program in Genetic Counseling, University of
Toronto, Canada
ӹӹ Head, The Prenatal Diagnosis and Medical Genetics
Program, Mount Sinai Hospital, Canada
ӹӹ Professor, Departments of Pediatrics and Genetics,
Section of Clinical Genetics and Metabolism,
University of Colorado School of Medicine and
Children’s Hospital Colorado, USA
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
A PSH G SUM MER S C H O O L
O R GA NIZ ING CO MMI TTE E
LOCAL ORGANIZING COMMITTEE AND
SPEAKERS FROM ASIA-PACIFIC REGION
CHAIRPERSON
Ms YWY Chu
Dr M Chopra
Dr ASY Kan
Dr NC Lee
Dr TY Tan
Dr MK Thong
Mr GKC Leung
Mr GTK Mok
Dr CCY Mak
Mr KS Yeung
Mr WHS Wong
Ms TMY Wong
Dr BHY Chung
COMMITTEE ADVISOR
Dr PS Lai
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Dr EMC
Cutiongco-De La Paz
Dr IFM Lo
Dr HM Luk
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
SEMINAR ROOM 3
THE HONG KONG JOCKEY CLUB BUILDING
FOR INTERDISCIPLINARY RESEARCH
THE UNIVERSITY OF HONG KONG
5 SASSOON ROAD
POKFULAM
HONG KONG SAR, CHINA
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P R OG R A MME A T A GL ANC E
VE N U E LAYOUT
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
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PROG RAM ME
ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
26TH AUG 2016 (FRI)
PROGRAMME
26TH AUG 2016 (FRI)
07:45-08:00
Registration
12:35-12:50
Q&A Session
08:00-08:30
Opening/ Welcome / Briefing
12:50-14:00
Lunch/
08:30-09:15
The Art of Facial Diagnosis in Syndrome
Recognition
14:00-14:30
Lessons in Genomic Dysmorphology
(Tiong Yang Tan)
14:30-14:45
Q&A session
14:45-16:00
Unknown Cases Session 1
(John Carey)
09:15-10:00
Consulting for Short Stature 2016 – Phenomic and
Genomic Partnerships in Diagnosis of Skeletal
Dysplasias
(David Sillence)
​APSHG Summer School Challenge
(Facilitated by Anne Tsai)
10:00-10:15
Q&A
16:00-16:30
Break
10:15-10:35
Break
16:30-17:45
Known Cases – Session 2
10:35-11:50
Known Cases – Session 1
(Facilitated By Anne Tsai)
17:45-18:15
Next-Gen Clinical Sequencing Facilitating
Molecular Diagnostic Analysis in Asia
(Poh-San Lai)
18:15-18:30
Q&A
11:50-12:35
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Approach to the Newborn with Disorders of Sex
Development
(David Chitayat)
(Facilitated by Anne Tsai)
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
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PROG RAM ME
ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
27TH AUG 2016 (SAT)
PROGRAMME
27TH AUG 2016 (SAT)
08:30-09:15
Mosaicism and the Molecular Taxonomy of
Human Disease
(Leslie Biesecker)
14:00-14:30
Impact of NGS on Clinical Diagnosis and
Counseling of Noonan Syndrome
(Nina Ni-Chung Lee)
09:15-10:00
Genetic Aspects of Arthrogryposis Multiplex
Congenita/fetal Akinesia
(David Chitayat)
14:30-14:45
Q&A Session
14:45-16:00
Known Cases – Session 3
(Facilitated by Anne Tsai)
16:00-16:30
Break
16:30-17:45
Known Cases - Session 4
(Facilitated by Anne Tsai)
17:45-18:15
Cross-cultural Genetic Counselling in Asian
Dysmorphology
(Meow Keong Thong)
18:15-18:30
Q&A Session
10:00-10:15
Q&A Session
10:15-10:35
Break
10:35-11:50
Unknown Cases – Session 2
(Facilitated by Anne Tsai)
11:50-12:35
Towards a Bayesian Framework for Sequence
Variant Interpretation
(Leslie Biesecker)
12:35-12:50
Q&A Session
12:50-14:00
"Lunch
Illumina Sponsor Presentation"
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
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P ROG RAM ME
ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
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28TH AUG 2016 (SUN)
08:30-09:15
The Basics of Writing Scientific Papers and Case
Reports
(John Carey)
09:15-10:00
Hypothesis-generating Research and Predictive
Medicine
(Leslie Biesecker)
10:00-10:15
Q&A Session
10:15-10:35
Break
10:35-11:05
Ethical Challenges in Clinical Genomic Medicine
(Eva Maria Cutiongco-de la Paz)
11:05-11:50
Consulting for Recurrent Fractures. is It
Osteogenesis Imperfecta? – A Phenomic and
Genomic Partnership
(David Sillence)
11:50-12:20
Why Do We Need to Do Clinical Genetic Research
in Asia?
(Brian Chung)
12:20-12:35
Q&A Session
12:35-13:45
Lunch
13:45-14:15
Facial Recognition Aids
(Nina Ni-Chung Lee, Brian Chung)
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PROGRAMME
28TH AUG 2016 (SUN)
14:15-15:15
Initiatives on Rare and Undiagnosed Diseases
in Japan: Exomes Are Better Than Clinicians in
Developing a Differential Diagnosis, But Not in
Making the Final Diagnosis
(Kenjiro Kosaki)
15:15-15:45
Dysmorphology Showcase
(Ivan Lo)
15:45-16:00
Q&A Session
16:00-16:20
Break
16:20-17:15
Forum Discussion
-Are Current Genetic Services Adequate in Your
National Healthcare Systems?
-How Are Incidental Findings from Clinical
Testing Managed?
(Hosted by Poh-San Lai and Eva Maria Cutiongcode la Paz)
17:15-17:30
Closing
18:30-20:45
Dinner Talk by John Carey:
Health Supervision in the Care of Children with
Genetic Syndromes
(Hosted by Hong Kong Society of Medical
Genetics)
The Federation of Medical Societies of Hong Kong,
Lecture Hall, 4/F, Duke of Windsor Social Service
Building, 15 Hennessy Road, Wanchai, Hong Kong
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
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K N OW N CA SE SE SSION 1
HEIDI HIU YEE CHENG (HONG KONG)
ӹӹ Diagnosis of Spondyloepimetaphyseal Dysplasia Congenita in Prenatal Skeletal
Dysplasia
SZE WING CHENG (HONG KONG)
ӹӹ A Rare Cause of Familial Short Stature
RAI-HSENG HSU (TAIWAN)
ӹӹ Hemihypertrophy and Scoliosis in a Six-year-old Girl
APRIL GRACE BERBOSO (PHILIPPINES)
ӹӹ A Case of Neurocristopathy in a Filipino Infant
ZHIJIANG HE (CHINA)
ӹӹ A 11 Months Old Girl with Rubinstein Taybi Syndrome: Case Report
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
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HEIDI HIU YEE CHENG
ӹӹ Department of Obstetrics and Gynaecology, Queen Mary Hospital,
HKSAR, China
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Eva Maria Cutiongco-de la Paz
DIAGNOSIS OF SPONDYLOEPIPHYSEAL DYSPLASIA
CONGENITA IN PRENATAL SKELETAL DYSPLASIA
A 29 year-old woman with good past
health, in her first pregnancy was referred
for fetal skeletal dysplasia. There was no
significant family history. Ultrasound at 12
weeks gestation showed thickened nuchal
translucency to 5.4mm. Chorionic villi
sampling showed normal karyotype and
microarray results. Ultrasound at 16 weeks
showed long bones one week behind.
Structural scan showed normal bone
mineralization and metaphyses, bilateral
club feet, normal thoracic circumference,
short long bones with 4 weeks behind date.
Ultrasound repeated at 24 weeks gestation
showed further shortening of long bone 5
weeks behind, with thoracic circumference
at 10th centile. Subsequent ultrasound
showed further shortening of long bones.
Ultrasound at 34 weeks of gestation showed
baby with small for gestational age but
with satisfactory interval growth. Thoracic
circumference became <2.5th centile with
short long bones 10 weeks behind date.
Further molecular studies with SLC26A2
sequencing and FGFR3 gene were normal.
Baby was delivered at 38 weeks gestation
by emergency lower segment Caesarean
section in Private with birth weight 2.34kg.
Apgar score was 8 at 1 minutes and 9 and
5 minutes. Baby had rhizomelic shortening
of limbs, bilateral clubfeet, macrocephaly
and small chest. Head circumference was at
50th-75th percentile with both body height
and weight less than 3rd percentile. Baby
had poor feeding due to micrognathia,
with malar hypoplasia and short neck.
Baby also failed hearing test. X-ray showed
juxta truncal abnormalities such as inverted
T distribution with platyspondyly and
deficient pubic bone.
Sequencing of COL2A1 gene has been
recently performed and showed a de
novo heterozygous missense mutation
c.1357G>T, p.G453C, which has not
been reported for type II collagenopthies.
However, substitution of Gly435 by
other amino acids have previously
been reported as pathogenic mutation
for
spondyloepiphyseal
dysplasia
congenita (SEDC), achondrogenesis and
hypochondrogenesis. Therefore the change
from Glycine to Cysteine is considered to
be pathogenic. Overall, clinical phenotype
and condition of the proband in our case is
compatible with SEDC.
KEYWORDS
ӹӹ spondyloepiphyseal dysplasia congenita, SEDC, skeletal dysplasia, prenatal
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SZE WING CHENG
ӹӹ Clinical Genetic Service, Department Of Health, HKSAR, China
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Brian Chung
A RARE CAUSE OF FAMILIAL SHORT STATURE
Short stature is a common paediatric
complaint, which is defined as the height
that is 3 or more standard deviations below
the mean height for age. It can be divided
into proportional and disproportional short
stature. For disproportional short stature, it
is usually due to skeletal dysplasia.
The acromelic dysplasia is a rare group of
skeletal dysplasia. It includes three rare
disorders: Weill-Marchesani syndrome
(WMS), Geleophysic dysplasia (GD) and
Acromicric dysplasia (AD) all characterized
by short stature, short hands, stiff joints,
skin thickening, facial anomalies, normal
intelligence and abnormal skeletal
symptoms. The three disorders have their
unique features. WMS can be differentiated
from GD and AD by the presence of
dislocation of microspherophakia, an
eye lens (crystalline) that is smaller than
normal and has a rounded shape. GD is
clinically diagnosed in an individual with
the above mentioned shared features in
addition to progressive cardiac valvular
abnormalities, characteristics ‘happy’ face,
hepatomegaly and tracheal stenosis. AD
is characterized by characteristics face,
special radiological findings and hoarse
voice. Mutations in Fibrillin-1 (FBN1) gene
have been identified in AD, GD and WMS
patients. Acromelic dysplasia is extremely
rare condition and only six Chinese cases
had been reported in literature.
We reported a family of three with acromelic
short stature. FBN1 genetic study showed
all have heterozygous missense mutation
c.5284G>A (p.Gly1762Ser) in exon 42 of
FBN1 gene was detected. This mutation was
previously reported in the literature to be
associated with GD. The family members
exhibited the features in between AD
and GD. This suggests pleiotropic nature
of specific FBN1 mutation in acromelic
dysplasia.
LEARNING POINTS
ӹӹ Rare causes of disproportional short stature
ӹӹ The approach of familial short stature
ӹӹ Pleiotropic nature of FBN1 mutation in acromelic dysplasia
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RAI-HSENG HSU
ӹӹ Department of Pediatrics and Medical Genetics, National Taiwan
University Hospital, Taipei, Taiwan
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Anne Tsai
HEMIHYPERTROPHY AND SCOLIOSIS IN A SIX-YEAR-OLD
GIRL
O
vergrowth syndromes comprise a
heterogeneous group of disorders
that lead to excessive tissue proliferation,
including somatic and visceral growth.
Several classifications have been developed
in an attempt to facilitate the diagnosis of
these syndromes, but these attempts have
been hindered by the syndromes’ several
overlapping clinical manifestations.
Here, we report the case of a 6-year-old girl
who presented with progressive left upper
back and upper extremity hypertrophy
since birth. A lump over the left upper
back was also noted. The size was enlarged
as the patient grew. On exam, she had
scoliosis with left upper back and extremity
showing overgrowth out of proportion
to the right sides, and there was a mass
lesion over the left upper back. Laboratory
analyses revealed normal results. Magnetic
resonance imaging of the upper extremities
without contrast enhancement showed
diffuse left upper limb enlargement. For
diagnostic and therapeutic purposes, she
underwent liposuction and tumor excision.
Pathological examination revealed a
fibrolipoma. The analysis of the 11p15
region showed normal methylation status
at both KvDMR and H19. Genetic testing
on paraffin-embedded tissue revealed
Glu542Lys mutation in PIK3CA gene. The
percentage of mutation ranges from 6.5%
to 7%. The diagnosis of CLOVES syndrome
was confirmed with clinical and genetic
findings.
Major progress such as the identification of
genetic causes has recently enhanced the
delineation of the clinical manifestations,
knowledge
of
the
underlying
pathophysiological
mechanisms,
and
phenotype-genotype correlations. As a
consequence, the possibilities for distinction
between the different overgrowth disorders
have increased.
LEARNING POINTS
ӹӹ Differential diagnosis of hemihypertrophy
ӹӹ Testing for somatic mutation
ӹӹ Management of cloves syndrome
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APRIL GRACE DION-BERBOSO
ӹӹ Institute of Human Genetics, National Institutes of Health,
University of the Philippines, Manila, Philippines
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Ho Ming Luk
A CASE OF NEUROCRISTOPATHY IN A FILIPINO INFANT
April Grace Dion-Berboso, MD1, Maria
Melanie Liberty B. Alcausin, MD1 2
We report on a Filipino newborn male infant
who presented with signs and symptoms
of progressive abdominal enlargement,
bowel
obstruction,
and
recurrent
hypoventilation. We made the diagnosis
of Haddad syndrome based on a high
index of clinical suspicion. We confirmed
the disorder by sequence analysis of the
PHOX2B gene which showed a 27-repeat
heterozygous expansion of the polyalaninecoding region. Haddad syndrome is a rare
congenital disorder in which congenital
central hypoventilation syndrome (CCHS)
1
Institute of Human Genetics, National Institutes of Health
Philippines, University of the Philippines, Manila
2Department of Pediatrics, University of the Philippines-Philippine
General Hospital
occurs with Hirschsprung’s disease. The
PHOX2B gene is mapped in chromosome
4p12 and encodes a transcription factor
which is important for normal autonomic
nervous system development. Mutations on
this gene predispose to a range of autonomic
aberrations and loss of ventilatory drive
during sleep, resulting in reduced CO2
and O2 sensitivity. The performance
of PHOX2B gene mutation analysis is
important in patient management and
genetic counseling. A positive finding
warrants parental testing to determine if the
mutation is segregating in the family or is a
novel mutation. Early diagnosis is necessary
to avoid respiratory, neurocognitive, and
cardiovascular complications.
LEARNING POINTS
ӹӹ The faces of subjects with CCHS are generally shorter and flatter resulting in the
characteristic box-shaped face and an inferior inflection of the lateral 1/3 of the upper
vermillion border (liptrait). This happens because mutations in the PHOX2B gene
are also expressed in the dorsal rhombencephalon, a region that gives rise to facial
structures.
ӹӹ The performance of PHOX2B gene mutation analysis is important in patient
management and genetic counseling.
ӹӹ An early diagnosis and confirmation by genetic testing is vital for the proper
management of affected patients and prevention of complications.
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ZHIJIANG HE
ӹӹ Department of Pediatrics, Hong Kong University - ShenZhen
Hospital, ShenZhen, GuangDong, China
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Tiong Yang Tan
A 11 MONTHS OLD GIRL WITH RUBINSTEIN TAYBI
SYNDROME: CASE REPORT
RSTS is an extremely rare multiple
congenital anomaly/intellectual disability
syndrome. RSTS is characterized by typical
facial features, microcephaly, broad thumbs
and first toes, intellectual disability and
postnatal growth retardation. Several organs
and systems may be affected. Our patient
is an 11months old Chinese girl born in
Mainland with development delay, mental
retardation and special facial deformities.
She raise her head stable at 5months; turn
over at 7month; grasp objects initiative at
7month; can’t seat erect until 9month, can’t
crawl and mimic bye-bye at 11month.Her
anterior suture was very wide and down
to forehead; Thumbs and big toe were big;
sharp and small forehead; small of eye
and mouth, absence of uvula; muscle tone
is litter higher; mild strephexopodia. She
was admitted in our neonatal word after 17
hours of birth because of decrease of milk
intake; She was admitted in general ward
when she was 1 month 17days because of
bronchitis.
Although, it cannot yet be confirmed, RSTS
is the most likely diagnosis. All clinical
features are compatible with this syndrome;
however, the diagnosis is currently based on
only clinical findings. His family refused to
do more chromosomal microarray and gene
investigations. RSTS gene most frequently
involved is cyclic-AMP-regulated enhancer
binding protein (CREBBP) on chromosome
16p13.3; alterations in the E1A-binding
protein p300 (EP300) on chromosome
22q13 have also been detected. A diagnosis
of RTS is essentially clinical because the
characteristic cytogenetic or molecular
abnormality can be detected only in 55%
of patients, leaving the diagnosis in the
remaining 45% to be based on clinical
features alone.
In conclusion, RSTS is an extremely rare
condition for which some clinical aspects
have been clearly identified, but a lot of
studies are ongoing and needed. Multicenter
studies are needed to expand our knowledge
on the clinical phenotype, identify specific
genotype-phenotype correlations, evaluate
the presence of somatic mosaicisms to
better define mild phenotypes, and identify
new candidate genes. The ultimate goal
of these studies is to extend our current
knowledge concerning this syndrome and
to define new international guidelines for
diagnosis, care and treatment of patients
with RSTS.
KEYWORDS
ӹӹ Rubinstein Taybi syndrome; intellectual disability; dysmorphic facial features;
genotype-phenotype
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K N OW N CA SE SE SSION 2
I-FAN CHANG (TAIWAN)
ӹӹ Nail Hypoplasia, Neurological Deficits and Multiple Anomalies in Two Siblings
TECK WAH TING (SINGAPORE)
ӹӹ Coffin Siris Syndrome: a Case of Global Developmental Delay with Coarse
Facial Features
SARAH JOSEPHI-TAYLOR (AUSTRIALIA)
ӹӹ Incontinentia Pigmenti in a Male Infant: a Case Report
SHIYI XIONG (CHINA)
ӹӹ A Rare Genetic Syndrome with Mesomelic Limb Shortening and Distinct
Facial Features
PUI TAK YU (HONG KONG)
ӹӹ A Case of Dysmorphic Child with Short Stature and Progressive Joint
Contracture
NAWAL MAKHSEED (KUWAIT)
ӹӹ Mutation in the Snap29 Gene Causes Cednik Syndrome in Two Siblings of a
Consanguineous Arab Family: to Highlights the Power of Wes Particularly in
Clinically Challenging Cases.
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
I-FAN CHANG
ӹӹ Department of Pediatrics and Medical Genetics, National Taiwan
University Hospital, Taipei, Taiwan
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Ho Ming Luk
NAIL HYPOPLASIA, NEUROLOGICAL DEFICITS AND
MULTIPLE ANOMALIES IN TWO SIBLINGS
The two siblings, aged 2 and 3 years,
were noted to have coarse face,
brachytelephalangy, hypoplastic terminal
phalanges, nails hypoplasia, seizure,
and severe neurological deficits. Facial
dysmorphism including long face, arched
eyebrows, upslanting and long palpebral
fissure, broad nasal bridge, tented upper
lip, high arch palate, bifid uvula, and
coarse face were noted. Elder brother
was also noted to have imperforate anus,
Hirschsprung disease, bilateral hearing
loss, optic neuropathy with strabismus,
neurogenic bladder with renal dysplasia
at birth. Now he is on tracheostomy due
to mixed type apnea and gastrostomy
due to feeding difficulties. Younger sister
was noted to have right lung hypoplasia,
left hearing loss, right hydronephrosis
and nephromegaly with suspicion of
ureteropelvic junction obstruction. Due to
tracheomalacia with frequent apnea and
desaturation, she needs BiPAP support.
Genetic evaluations including karyotype
and array CGH were negative. CoffinSiris syndrome panel (ARID1A, ARID1B,
SMARCA4, SMARCB1, and SMARCE1)
revealed a novel heterozygous variant of
ARID1B gene (c.5143G>A; p.Ala1715Thr).
Further whole exome sequencing on this
family revealed a compound heterozygous
missense mutation on PIGV gene. Both
brother and sister had marked unexplained
elevation of alkaline phosphatase 3131 and
1302 (U/L) respectively. In conjunction
with hyperphosphatasia, the diagnosis
of Hyperphosphatasia with mental
retardation syndrome 1 (Mabry syndrome)
was confirmed. Hyperphosphatasia with
mental retardation syndrome and CoffinSiris syndrome had similar clinical pictures.
Hyperphosphatasia
differentiates
the
phenotypes. Whole exome sequencing is a
powerful tool for further delineation of the
causative genes.
LEARNING POINTS
ӹӹ The differential diagnosis of fifth finger hypoplasia/ fingernail hypoplasia
ӹӹ The differential diagnosis of Coffin-Siris syndrome
ӹӹ Whole exome sequencing for unknown disease in pediatric patients
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LEARNING POINTS
TING TECK WAH
ӹӹ Genetics Service, Department of Paediatrics, KK Women’s and Children’s Hospital,
Singapore
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Ho Ming Luk
COFFIN SIRIS SYNDROME: A CASE OF GLOBAL
DEVELOPMENTAL DELAY WITH COARSE FACIAL FEATURES
Patient is a Chinese female and the only
child of non-consanguineous parents with
no family history of developmental delay.
Antenatal scans were normal. She was
delivered at term via caesarean section. She
achieved head control at 6 months old and
sat unsupported since 15 months old. She
could cruise with support at 2 years old.
She started to walk at 3 years old. She had
severe speech delay with no word expressed
at 7 years old. She was not toilet trained
yet to initiate social interaction with her
classmates when she was 7 years old. When
she was examined at 8 years old, her height
was 123.5 cm (25th-50th percentile), weight
was 26.5 kg (25-50th percentile).She had
coarse facial features with thick and arched
eye brows, thick lips, and low nasal bridge.
She was hypotonic with normal deep
tendon reflexes bilaterally. Examination of
the heart, lung and abdomen was normal.
Her joints were normal. Her digits were
normal.
Urine glycosaminoglycan analysis was done
in view of her coarse facial features showed
increased excretion of glycosaminoglycan
and a faint keratan sulphate band.
Mucopolysaccharidoses type 4 (Morquio
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
ӹӹ Mucopolysaccharidosis (especially type I, II and VII) should be considered when
assessing a child with global developmental delay and coarse facial features. It is
important to look for associated features such as hepatosplenomegaly, joint stiffness/
laxity, skeletal dysplasia, corneal clouding and cardiac valve thickening. Urine
glycosaminoglycan analysis is a screening investigation.
ӹӹ Coffin-Siris syndrome (CSS) is another possible differential diagnosis when assessing
a child with global developmental delay and coarse facial features. Lack of fifth digit
abnormality does not exclude CSS.
ӹӹ Speech development is most severely delayed in patients with ARID1B mutations with
most of them spoke their first words after 3 years old.
Syndrome) was suspected. But this is
unlikely because she has no joint laxity and
no signs of skeletal dysplasia on examination
and on x-rays. She is also not small for
her age and there is no corneal clouding.
Moreover, neurodevelopment is usually not
affected in Morquio Syndrome. Karyotype
from peripheral blood was normal. MRI
brain showed agenesis of corpus callosum.
Chromosomal microarray was normal.
Whole exome sequencing revealed a
mutation at c.3304C>T p.Arg1102* of
ARID1B gene. It is a de novo heterozygous
pathogenic mutation previous reported
in ClinVar and dbSNP. This patient is
diagnosed to have Coffin-Siris Syndrome
(CSS) based on her clinical features (global
developmental delay with severe speech
delay, coarse facial features, thick lips, and
thick eye brows) and molecular genetics
findings of a stopgain mutation in ARID1B
gene. She belongs to ‘classic’ CSS group
based on her facial features. There is another
group called ‘variant’ CSS group who has
more refined facial features, thin eyebrows
and thin vermillion border of the lips.
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
SARAH JOSEPHI-TAYLOR
ӹӹ Department of Clinical Genetics, Royal North Shore Hospital,
Sydney, Australia
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Anne Tsai
LEARNING POINTS
ӹӹ Consideration of a usually embryonically lethal X-linked dominant condition in a
46,XY male, due to somatic mosaicism.
ӹӹ Challenges in prognostication as limited case reports of similar in the literature.
ӹӹ Counselling regarding patients own transmission to future generations.
INCONTINENTIA PIGMENTI IN A MALE INFANT:
A CASE REPORT
Sarah Josephi-Taylor1 2, Yemima Berman2
BACKGROUND
Incontinentia Pigmenti (IP) is an
X-linked
dominant
genodermatosis
(OMIM: #380300) caused by a common
deletion in the IKBKG gene. The cardinal
features of IP are cutaneous, although
neuroectodermal features are prominent
and confer greater disease morbidity.
There is a strong female preponderance as
it is embryonically lethal in males. Male
survival has been documented in cases of
Klinefelter syndrome, somatic mosaicism
or hypomorphic IKBKG mutations.
CASE SUMMARY
EA, a male infant born at 32 weeks due
to maternal pre-eclampsia, developed an
erythematous rash over his trunk and
limbs in the first 72 hours of life. The rash
evolved to multiple vesicles and pustules
of various sizes in a linear distribution,
over his trunk, scalp and three limbs. EA
remained clinically stable and afebrile. Viral
PCR was negative. Anti-staphylococcal
cover was commenced for an S. aureus
supra-infection. Bloods revealed only
1
Department of Clinical Genetics, Royal North Shore Hospital,
Sydney, Australia.
2School of Women’s and Children’s Health, University of New South
Wales.
35
an eosinophilia. Biopsy of affected skin
demonstrated an eosinophilic spongiform
process, the differentials of which included
erythema toxicum neonatorum and
IP. Dermatologists clinically favoured
IP and our team was consulted. After
discussion with the family, we arranged for
a karyotype and testing for the common
11.7kb IKBKG deletion in DNA extracted
from both skin and lymphocytes. The
karyotype was normal 46,XY. The common
IKBKG deletion was detected in DNA from
both skin and lymphocytes. The mutation
was detected at a higher level in skin than
lymphocytes, but still at levels lower than
is seen in females, consistent with somatic
mosaicism.
CONCLUSION
There are only a few reports of males with
IP in the literature. Counselling the family
regarding prognostication was challenging,
as previous cases of male IP frequently
had Klinefelter syndrome, which was a
confounder for intellectual outcomes. EA
is being managed as per the guidelines
for females with IP, which includes
regular ophthalmology review for neovascularisation risks, dental review and
developmental assessment.
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SUMMER SCHOOL 2016
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
SHIYI XIONG
ӹӹ Fetal medicine Unit & Prenatal Diagnosis Center, Shanghai
First Maternity and Infant Hospital, Tongji University School of
Medicine, Shanghai, China
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Ivan Lo
A RARE GENETIC SYNDROME WITH MESOMELIC LIMB
SHORTENING AND DISTINCT FACIAL FEATURES
BACKGROUND
Here we report the first Chinese patient
with autosomal Robinow syndrome (RS),
presenting with the mesomelic upper limb
shortening and the typical facial features.
Our report suggests that the facial features
of RS in this ethnic background are not
different from those in other ethnicities.
CASE SUMMARY
Mesomelic upper limb shortening and
distinctive facial features were noticed
at birth to the proband born to a healthy
nonconsanguineous Chinese couple. She
remained undiagnosed until she was 4.5
years old, when her mother raised concerns
about recurrence at 20 weeks’ gestation
in a subsequent pregnancy. Physcial
examination and skeletal radiographs
were consistent with autosomal dominant
Robinow syndrome. A novel de novo
heterozygous
pathogenic
mutation
c.249C>G (p.Cys83Trp) in the WNT5A
gene was identified, confirming the
diagnosis.
CONCLUSION
Robinow syndrome was diagnosed on the
basis of the typical clinical and radiological
features
including
hypertelorism,
mesomelic limb shortening, radial head
dislocation and genital hypoplasia. A de
novo Pathogenic heterozygous WNT5A
variant confirmed the clinical diagnosis.
KEYWORDS
Hypertelorism; Mesomelic limb shortening;
Radial head dislocation; Brachydactly;
Bilobed tongue; Genital hypoplasia
LEARNING POINTS
ӹӹ Robinow syndrome is a genetically heterogeneous disorder characterized by distinct
facial features (often described as ‘fetal facie’), mesomelic limb shortening, hypoplasia
of the external genitalia and dental abnormalities.
ӹӹ Robinow syndrome can be diagnosed by typical clinical features combined with NGSbased gene sequencing.
ӹӹ This is the first Robinow case reported in Chinese population. This might be of its low
prevalence and under recognized by pediatricians.
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
PUI-TAK YU
ӹӹ Clinical Genetic Service, Department of Health, Hong Kong SAR, China
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Brian Chung
A CASE OF DYSMORPHIC CHILD WITH SHORT STATURE
AND PROGRESSIVE JOINT CONTRACTURE
Myhre syndrome is a clinically recognizable
syndrome
with
multiple
system
involvement. .It was first described in 1981
(Myhre et al.,1981), in 2 unrelated patients.
The condition was further reported by
Soljak et al. (1983). Children with Myhre
syndrome usually have low birth weight and
short, typical facial features includes short
palpebral fissure, hypoplastic maxilla, short
philtrum, narrow mouth, prognathism,
small ear. Joint limitation, thick skin and
muscular body build was characteristic
findings. Skeletal abnormalities include
thickening of the skull bones, flattened
bones of the spine (platyspondyly),
broad ribs, hypoplastic iliac wings, and
brachydactyly. They may also experience
arthropathy with stiffness and limited
mobility. Myhre syndrome may also have
autistic features and developmental delay
especially in gross motor, cognitive and
speech. They may also have hearing loss,
which can be sensorineural or conductive
type. Other uncommon features includes
cleft palate, cleft lip, eye abnormalities, and
in males, cryptorchidism.
Myhre syndrome is caused by gain of
function mutations in the SMAD4 gene.
The SMAD4 gene provides instructions for
making a protein involved in transforming
growth factor beta (TGF-β) pathway.
SMAD4 protein interacts with other
proteins to control the activity of particular
genes. Thus, changes in SMAD4 binding
or availability may result in abnormal
signaling in many cell types, which affects
development of several body systems and
leads to the signs and symptoms of Myhre
syndrome.
Here, we report the first case of molecularly
confirmed Myhre syndrome in Hong Kong
Chinese that presented with short stature,
dysmorphism, skeletal abnormalities and
arthropathy. Literature review on Myhre
syndrome was also performed.
LEARNING POINTS
ӹӹ Myhre syndrome should be considered in cases with short stature, muscular body build
and joint contracture
ӹӹ Differential diagnosis of Myhre syndrome
ӹӹ Follow up of Myhre syndrome should look for laryngotracheal stenosis, eye, hearing
impairtment and pubertal abnormalities
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SUMMER SCHOOL 2016
HONG KONG
ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
NAWAL MAKHSEED
ӹӹ Pediatric Department, Al-Jahra Hospital, Ministry of health, Kuwait
ӹӹ Email: [email protected]
MUTATION IN THE SNAP29 GENE CAUSES CEDNIK
SYNDROME IN TWO SIBLINGS OF A CONSANGUINEOUS
ARAB FAMILY: TO HIGHLIGHTS THE POWER OF WES
PARTICULARLY IN CLINICALLY CHALLENGING CASES.
We report two siblings of a consanguineous
Arab family from Syria with two affected
girls. The proband presented after birth with
mild facial dysmorphism, microcephaly
significant hypotonia, alternating squint,
poor visual attention, failure to thrive
(weight below -3SD) and diffuse ichthyosis.
She has a red nodular lesion of her right
lower limb which was diagnosed as
angiokeratoma by skin biopsy. She had
bilateral developmental hip dysplasia
required the Pavlic-Harness device for 6
months. MRI brain showed white matter
changes and hypoplastic/dysplastic corpus
callosum. Over time she continued to have
truncal hypotonia with progressive upper
and lower limbs spasticity with exaggerated
deep tendon reflexes. She has showed very
mild gross motor progression; she was
only able to roll and sits for a short period
without support. She has no speech. Her
younger sister had antenatal finding of
ventriculomegaly, and she showed similar
clinical manifestation since birth but
without angiokeratoma. Weight is below
-3SD, and head circumference below
-2SD). Her brain MRI showed abnormal
thin corpus callosum with absence of its
posterior part and dilated post horns of
both lateral ventricles. Three maternal
uncles died in Syria during childhood
with similar clinical presentation. The first
patient had full metabolic investigations, all
were normal. The first patient was suspected
to have Sjogren-Larsson syndrome,
but analysis of the ALDH3A2 gene was
negative. Using Whole Exome Sequencing
(WES), identified a homozygous (c.223del,
p.Val75Serfs*28) mutation in the SNAP29.
This was confirmed in her younger sister.
OUR REPORT HIGHLIGHTS:
ӹӹ The power of WES in diagnosing clinically challenging cases particularly in
consanguineous population
ӹӹ CEDNIK syndrome is one of the new causes of ichthyosis and our cases showed
angiokeratoma that was not reported before.
ӹӹ CEDNIK syndrome causes facial dysmorphismwith progressive neurodegenerative
disorder
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SUMMER SCHOOL 2016
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
K N OW N CA SE SE SSION 3
ANNIE CHIU (HONG KONG)
ӹӹ Nutritional Transformation of Dysmorphism in a Case of Costello Syndrome
CLARA CHUNG (AUSTRALIA)
ӹӹ Just Moyamoya or Something More?
MARY ANNE CHIONG (PHILIPPINES)
ӹӹ Kartagener Syndrome Occurring Simultaneously in a Filipino Child with 5p(Cri du Chat) Syndrome – a Case Report
DI MILNES (AUSTRALIA)
ӹӹ The Utility of Clinical Examination in Guiding Genetic Testing
SHU MO (CHINA)
ӹӹ Case Report: SHORT Syndrome
PREMALA MUTHUKUMARASAMY (MALAYSIA)
ӹӹ A Genetic Disorder of Obesity and Progressive Blindness
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SUMMER SCHOOL 2016
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
ANNIE TG CHIU
ӹӹ Department of Paediatrics and Adolescent Medicine, Queen Mary
Hospital, Hospital Authority, Hong Kong
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Ni-Chung Lee
NUTRITIONAL TRANSFORMATION OF DYSMORPHISM IN A
CASE OF COSTELLO SYNDROME
Costello syndrome is a RASopathy mapped
to the HRAS gene of chromosome 11. Like
other RASopathies, it is characterized
by classic facial gestalt, multisystem
involvement including cardiomyopathy and
intellectual disability, and abnormal growth.
In particular, it is marked by prenatal
overgrowth and postnatal failure to thrive,
which is contributed to by decreased intake,
oromotor dysfunction, gastroesophageal
reflux as well as dysregulated central control
of body weight.
We present a child with Costello syndrome
whose failure to thrive was out of proportion
even for his diagnosis, with a body weight
of 3.6kg only (i.e. equivalent to his birth
weight) at 7 months of age. As a result of
his suboptimal nutritional status, his facial
dysmorphic features were obscured, and
in the absence of obvious multisystemic
involvement at the time he eluded clinical
recognition of the syndrome. It was only
with optimization of his nutritional status
and the achievement of a body weight of
5.2kg at 9 months that his dysmorphic
features became more apparent, affirming
the molecular diagnosis from exome
sequencing. The difficulty in recognizing
his dysmorphic features in an emaciated
state was shared by a facial dysmorphism
recognition software (FACE2GENE),
which failed to list RASopathy amongst its
differential diagnosis based on the child’s
picture at 7 months, but put it as the 6th
differential diagnosis based on his picture
at 9 months.
The case illustrated how drastic failure to
thrive can be in Costello syndrome, as well
as how nutritional status can appear to
obscure and transform dysmorphic features
in a child. It also highlights the importance
of serial dysmorphic evaluation in difficult
cases.
LEARNING POINTS
ӹӹ Clinical features of Costello Syndrome and RASopathies
ӹӹ Nutritional status as a potential confounder in the interpretation of dysmorphism
ӹӹ Importance of serial evaluation in children with uncertain diagnosis
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
CLARA CHUNG
ӹӹ Department of Medical Genetics, Sydney Children’s Hospital,
Australia
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Ni-Chung Lee
JUST MOYAMOYA OR SOMETHING MORE?
INTRODUCTION
Moyamoya angiopathy can be found in
isolation (Moyamoya disease) or associated
with a number of different syndromal
diagnoses (Moyamoya syndrome). One
such associated syndrome is Noonan
Syndrome. We present a case of a child
with Moyamoya syndrome associated with
Noonan-like syndrome due to a mutation
in CBL gene who had no ‘classic’ features
of Noonan/Noonan-like syndrome and a
number of red herrings.
PATIENT INFORMATION
AM was a 3 year old boy who was the
only child to a non-consanguineous
Armenian couple. There was no significant
family history. He presented at the age
of 2 with a transient ischaemic attack
(TIA). Subsequent investigations revealed
Moyamoya angiopathy as the reason for
his TIA. He had global developmental
delay and a left conductive hearing loss.
He had a period of thrombocytopenia
as an infant, which was diagnosed as
idiopathic thrombocytopenic purpura. He
had otherwise been well. On examination,
his weight was on the 75th centile and
his height was on the 25th centile. He has
subtle dysmorphic features and significant
splenomegaly. He had no neurocutaneous
stigmata.
DIAGNOSTIC
OUTCOME
ASSESSMENT
&
Initially, he did not appear to fit with a
syndromal diagnosis. He had no cardiac
lesions. However, a RASopathy panel was
performed on him as he had some features
that have been described in this group
of disorders. This panel found a known
pathogenic mutation in CBL. Mutations in
CBL have recently been described to cause
Noonan-like syndrome and has also been
associated with juvenile myelomonocytic
leukaemia (JMML). This led to concerns
being raised about his unexplained
splenomegaly. He was subsequently
reviewed by the oncologist and will continue
to be monitored for possible development
of a haematological malignancy such as
JMML. Ultimately, this diagnosis has
led to a change in the management and
surveillance in this patient.
LEARNING POINTS
ӹӹ Clinical features of Costello Syndrome and RASopathies
ӹӹ Nutritional status as a potential confounder in the interpretation of dysmorphism
ӹӹ Importance of serial evaluation in children with uncertain diagnosis
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
MARY ANNE D. CHIONG
ӹӹ Department of Pediatrics, University of Santo Tomas, Manila,
Philippines
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Maya Chopra
KARTAGENER SYNDROME OCCURRING SIMULTANEOUSLY
IN A FILIPINO CHILD WITH 5P- (CRI DU CHAT) SYNDROME
– A CASE REPORT
Hazel Ann B. David1, Clara R. Rivera1 and
Mary Anne D. Chiong1 2
Kartagener syndrome (KS) is a genetic
disorder caused by defects in the structure
and function of cilia that leads to abnormal
mucociliary clearance and cause diseases
of the sinus and pulmonary regions. It is
characterized by the triad of bronchiectasis,
sinusitis and situs inversus totalis. The
most common gene affected is DNAH5
which encodes for ciliary dynein axonemal
heavy chain. This gene resides in the same
chromosome region affected in Cri du
chat syndrome, the terminal short arm of
chromosome 5 (5p).
Here, we report a 7 month old Filipino
female who presented with clinical and
cytogenetic characteristics of Cri du
Chat Syndrome (CdCS) as well as situs
1
Department of Pediatrics, University of Santo Tomas, Manila,
Philippines
2Institute of Human Genetics, NIH, Manila, Philippines
inversus totalis, recurrent respiratory
infections and bronchiectasis. Our patient
had a partial deletion on chromosome
5p13-5p15.3 causing the consequential
deletion of one allele of DNAH5 which
resides on chromosome 5p15.2. Since the
immunoflourescent staining done showed
complete absence of DNAH5 and the
transmission electron microscopy of nasal
cilia also confirmed the absence of the outer
dynein arms, we conclude that there was a
mutation in the remaining allele of DNAH5
leading to the clinical manifestations of
Kartagener syndrome.
Therefore in patients with CdCS who present
with chronic or recurrent respiratory
infections and or laterality defects,
screening for ciliary dyskinesia should be
initiated since Kartagener syndrome and
CdCS share a common genetic link through
changes on chromosome 5.
LEARNING POINTS
ӹӹ 5P deletions with unmasked recessive conditions
ӹӹ Patients with cdcs who have recurrent pulmonary infections or laterality defect should
be screened for ciliary dyskinesia
ӹӹ Search for a genetic link if 2 syndromes are seen in one patient
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DI MILNES
ӹӹ Genetic Health Queensland, Royal Brisbane and Women’s Hospital,
Brisbane, Queensland, Australia
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Ni-Chung Lee
THE UTILITY OF CLINICAL EXAMINATION IN GUIDING
GENETIC TESTING
Di Milnes1, Chirag Patel1
Tietz syndrome (TS) is an autosomal
dominant
disorder
of
congenital
sensorineural hearing loss and generalised
hypopigmentation due to a heterozygous
mutation in the MITF (microphthalmiaassociated transcription factor) gene.
The MITF gene encodes a transcription
factor involved in the development of
pigmentary cells in the retina, inner ear and
skin. Mutations in MITF are responsible
for Waardenburg syndrome type 2a and
variants: WS2 with ocular albinism (WS2/
OA) and TS. One proposed model for the
variation in pigmentation seen in WS2/
OA and TS is digenic inheritance of a
MITF mutation with a second mutation of
a downstream target. Two candidate genes
have been reported in families with WS2/OA:
TYR and TYRP1. Molecular and phenotypic
characterisation of families with WS2/OA
1Genetic Health Queensland, Royal Brisbane and Women’s Hospital,
Brisbane, Queensland, Australia
or with TS will aid further delineation of
the pigmentation pathways. We present
a family of four children, three of whom
have congenital profound sensorineural
hearing loss in association with striking
blue irides, iris transillumination defects,
fundal hypopigmentation and variable
skin pigmentation consistent with TS.
In addition, the proband presented with
bilateral colobomas, in the absence of
microphthalmia. Biallelic MITF mutations
have been previously reported in patients
with
colobomatous
microphthalmia,
macrocephaly, albinism and deafness
(COMMAD syndrome). Genetic testing of
the proband, using a commercially available
pigmentation panel, detected a pathogenic
heterozygous mutation in the MITF gene
together with a number of variants in
candidate pigmentation genes, including
an OCA2 and TYRP1 variant. Family
studies from both affected and unaffected
individuals will be presented.
LEARNING POINTS
ӹӹ Causes of syndromic hearing loss
ӹӹ Clinical examination in guiding genetic testing
ӹӹ The potential role of modifiers in the variability of expression of a disorder
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
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SHU MO
ӹӹ Department of Paediatrics, The University of Hong Kong Shenzhen
Hospital, Shenzhen, China
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Ho Ming Luk
CASE REPORT: SHORT SYNDROME
SHORT syndrome is defined by its acronym:
short stature (S), hyperextensibility of
joints and/or inguinal hernia (H), ocular
depression (O), Rieger abnormality (R)
and teething delay (T). It’s a rare disorder
that affects many parts of the body. Recent
researches showed that PIK3R1 mutations
are responsible for SHORT syndrome.
SHORT syndrome, include: triangular face,
prominent forehead, deep-set eyes, thin
nasal alea, small chin, large low-set ears,
thin lip and downturned mouth. Another
feature of the boy is lack of fatty tissue under
the skin (lipoatrophy). The lipoatrophy is
generalized, with BMI less than the third
percentile.
Our patient is a 2y4m boy when he saw the
doctor for the first time for his short stature.
He is the second child in his family. His
mother, father and sister are normal height.
The patient was born at gestational age of
32 weeks, birth weight 1.95kg. His mother
was good health during pregnancy. Now
his height is 82cm (<3rd percentile), weight
9.3kg (<3rd percentile), body mass index
(BMI) 13.8 (<3rd percentile). He has mild
hyperextensibility of joints and teething
delay (total eight teeth).
The patient also has speech delay, however
there was no intellectual deficiency. He
can speak at 2y11m, and has been in
kindergarten from then on.
The patient has typical facial features of
53
The ophthalmological
normal.
examination
is
Investigations show that his triglyceride,
thyroid function, calcium, blood sugar and
oral glucose tolerance test (OGTT) are all
normal. Bone age, echocardiogram and
head CT scan are normal too. Gene test
identify the mutation in PIK3R1, which are
the major cause of SHORT syndrome.
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
PREMALA MUTHUKUMARASAMY
ӹӹ Department of Paediatrics, University Malaya Medical Centre,
Kuala Lumpur, Malaysia
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Eva Maria Cutiongco-de la Paz
A GENETIC DISORDER OF OBESITY AND PROGRESSIVE
BLINDNESS
Premala Muthukumarasamy1,
Keong Thong1
Meow-
A seven year old girl of Malaysian Chinese
descent presented with progressive loss of
vision, obesity and learning difficulty. Her
parents are of consanguineous marriage
and she was born term with good Apgar
scores after an uneventful supervised
pregnancy with a birth weight, length and
head circumference within the 25th-50th
centiles. Clinically, she had truncal obesity
with her height and weight on the 75th
centiles, acanthosis nigricans and nystagmus
with cone rod dystrophy. Cardiorespiratory,
abdominal and neurological examinations
were unremarkable. A genetic mutation
analysis
revealed
a
homozygous
deleterious mutation detected in the
ALMS1 gene defined as c.6169_6170dupat;
p.leu2058phefs*17. This mutation confirms
a diagnosis of Alstrom syndrome.
1Department of Paediatrics, University Malaya Medical Centre,
Kuala Lumpur, Malaysia
Both Bardet- Biedl and Alstrom syndromes
are autosomal recessive conditions
characterised by obesity and progressive
loss of vision with cone rod dystrophy on
retinal examination. However, Bardet-Biedl
syndrome (BBS) is further characterised by
learning difficulties, postaxial polydactyly,
renal and genital abnormalities whereas
the features of Alstrom syndrome include
sensorineural hearing loss, short stature,
type 2 diabetes mellitus and dilated
cardiomyopathy. To date, mutations in
more than 16 different genes have been
known to cause BBS whereas ALMS1 is the
only gene in which mutation is known to
cause Alstrom syndrome.
We describe features of BBS in our patient
with Alstrom syndrome, illustrating the
significant overlap in phenotype of these 2
distinct syndromes. A genetic diagnosis is
crucial for management, long term care and
genetic counseling.
LEARNING POINTS
ӹӹ Both BBS and alstrom syndrome are characterised by separate features that require
long term follow up and care.
ӹӹ There is a significant overlap in phenotypic features of these 2 autosomal reccessive
conditions.
ӹӹ Genetic mutation analysis of the ALMS1 gene should be considered in a patient with
clinical features of BBS.
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HONG KONG
ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
K N OW N CA SE SE SSION 4
TAWFEG BEN-OMRAN (QATAR)
ӹӹ A Family with Two Coexisting Genetic Disorders: a Diagnostic Dilemma in
Dysmorphic Syndromes
MONETTE FANER (PHILIPPINES)
ӹӹ Persistent Hemihyperplasia in a Thirteen-year Old: a Case Report
CUT NURUL HAFIFAH (INDONESIA)
ӹӹ Facial Asymmetry, Coloboma Iris, and Intractable Hypocalcemia in a Newborn
ANTHONY PAK YIN LIU (HONG KONG)
PO LAM SO (HONG KONG)
ӹӹ The Phenotypic Variability of Igf1r Deletion- from Lethal Hydrops to Normal
Phenotype in the Same Family
MA-AM JOY TUMULAK (PHILIPPINES)
ӹӹ A Case Report of an 11- Year Old Filipino Female with Dysmorphic Features
and Clenched Fist
57
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
TAWFEG BEN-OMRAN
ӹӹ Clinical and Metabolic Genetics, Department of Pediatrics, Hamad
Medical Corporation, Doha-Qatar
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Poh-San Lai
A FAMILY WITH TWO COEXISTING GENETIC DISORDERS: A
DIAGNOSTIC DILEMMA IN DYSMORPHIC SYNDROMES
We report a consanguineous Arab family
from Qatar with four abnormal children.
The proband presented with overlapping
clinical features suggestive of a novel
syndrome including congenital cataract,
facial dysmorphism and intellectual
disability. He was eventually diagnosed
with both Nance-Horan syndrome (NHS)
and milder dystroglycanopathy phenotype
using Whole Exome Sequencing (WES).
However, the other three siblings presented
with a milder spectrum of clinical features
and were eventually diagnosed with milder
dystroglycanopathy
phenotype
using
WES. Our report highlights the power of
WES particularly in clinically challenging
cases. In addition, this report emphasizes
the importance of considering X-linked
conditions in consanguineous family
as well as contemplating the possibility
of two genetic disorders in one patient.
Furthermore, this case provides a unique
example of the implications of having two
coexistence genetic disorders on patient
care and genetic counseling of the family.
LEARNING POINTS
ӹӹ This family exemplifies the challenges in establishing an accurate diagnosis in the
presence of two genetic conditions in one patient and absence of healthy siblings.
ӹӹ It is important to emphasize considering the possibility of two syndromes in the same
child in consanguineous families.
ӹӹ We recommend performing WES as a first line test to reach the final diagnosis
particularly in neurogenetic disorders in populations with high rates of consanguinity.
59
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
MONETTE FANER
ӹӹ Section of Clinical Genetics, Department of Pediatrics, University
of the Philippines Manila – Philippine General Hospital, Philippines
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Anne Tsai
LEARNING POINTS
ӹӹ Beckwith-wiedemann syndrome phenotype can vary significantly, from a child with
hemihyperplasia and macroglossia to some cases which may be fatal in the intrauterine,
neonatal, or early childhood period.
ӹӹ Diagnosis of Beckwith-Wiedemann syndrome in adolescents may be established
by a detailed history and physical examination, and from assessing early childhood
photographs.
ӹӹ Establishing the diagnosis is important for initiating early tumor surveillance and
management.
PERSISTENT HEMIHYPERPLASIA IN A THIRTEEN-YEAR
OLD: A CASE REPORT
BACKGROUND
Hemihyperplasia is defined as asymmetric
regional body overgrowth because of an
underlying abnormality of cell proliferation.
It may be isolated or may be part of a variety
of syndromes, and is associated with tumor
development. This case discusses the
approach to an adolescent presenting with
persistent hemihyperplasia.
CASE SUMMARY
The patient is a thirteen-year old male
who consulted with the chief complaint of
asymmetric limbs, right bigger than the left.
He was born term via Caesarian section for
large for gestational age (birthweight >10lbs)
to a then 35-year old G3P2 (2002) mother
with history of increased amniotic fluid
volume in the third trimester. At birth, he
was noted to have asymmetry of the limbs,
right side bigger than the left, and enlarged
tongue. No further work-ups were done,
and the enlarged tongue gradually resolved.
The persistence of the limb asymmetry
prompted consult. Physical examination
revealed normal anthropometrics for
age, right malar area more prominent
61
than the left, bilateral ear pits and creases,
undescended left testis, right upper limb
hypertrophy, right lower limb hypertrophy,
bilaterally widened space between first and
second toes, café-au-lait spot on proximal
3rd of the right upper arm, and bilateral leg
length 89.5cm (mean). Ultrasound showed
large right kidneys (8.5-9.3cm) with intact
morphology. Based on the clinical features
and laboratory findings, he was diagnosed
to have Beckwith-Wiedemann Syndrome.
Further work-ups to look for associated
malformations were advised, and referral to
subspecialties were facilitated.
CONCLUSION
Beckwith-Wiedemann
Syndrome
phenotype can vary significantly, from
a child with hemihyperplasia and
macroglossia to some cases which may be
fatal in the intrauterine, neonatal, or early
childhood period. Diagnosis of BeckwithWiedemann Syndrome in adolescents may
be established by a detailed history and
physical examination, and from assessing
early childhood photographs. Establishing
the diagnosis is important for initiating
early tumor surveillance and management.
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SUMMER SCHOOL 2016
HONG KONG
ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
CUT NURUL HAFIFAH
ӹӹ Department of Paediatrics, Faculty of Medicine, Universitas
Indonesia, Jakarta, Indonesia
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Tiong Yang Tan
FACIAL ASYMMETRY, COLOBOMA IRIS, AND INTRACTABLE
HYPOCALCEMIA IN A NEWBORN
BACKGROUND
CHARGE syndrome is a rare clinical entity
in which mutation of CHD7 was found
to be the genetic basis for two-third of
cases. Here we report a case of a newborn
with suspected CHARGE syndrome and
intractable hypocalcemia, an uncommon
manifestation in this syndrome.
CASE SUMMARY
A 1 day-old boy was referred to our hospital
due to multiple anomalies. He had right
side facial asymmetry, small right ear, right
eye lagophtalmus, coloboma of iris, retina,
and optical nerve. He also had swallowing
difficulties and poor feeding. Based on
the clinical features, we look for possible
diagnosis using a database search in the
internet. This patient has 3 major criteria of
CHARGE syndrome, thus the patient was
clinically diagnosed as CHARGE syndrome.
Nevertheless these features may overlap with
the clinical features of DiGeorge syndrome.
At 6th day of age, he had recurrent tetany
due to intractable hypocalcemia. Further
evaluation of hypocalcemia showed low
level of vitamin D and normal PTH
level. He was given calcium 75 mg/kg/
day and vitamin D supplementation 1000
IU/day, yet the hypocalcemia persisted.
63
Hypocalcemia in patient with DiGeorge
syndrome was due to hypoparathyroidism,
but this may not be the cause in patient with
CHARGE syndrome. Instead, mutation of
the calcium sensing receptor (CaSR) on
exon 7 (c.2968A>G) resulted in an altered
set point for PTH secretion in patient with
CHARGE syndrome. Evaluation renal
calcium excretion in our patient showed
normal urine calcium and abdominal
ultrasonography showed enlarged left
kidney pelvices without nephrocalcinosis.
Overlapping features of CHARGE
syndrome and DiGeorge syndrome
suggest a common neural crest defect and
a mechanism that is partly explained by
TBX1, a major candidate gene involved in
22q11.2 deletion syndrome. This gene may
be a functional target of CHD7. To confirm
our diagnosis we send a DNA sample to a
genetic laboratory in Michigan, USA.
CONCLUSION
Despite lack of diagnostic facilities,
diagnosis made based on clinical features
was possible in our settings. Intractable
hypocalcemia in our patient with unknown
cause may suggest that there is another
cause of hypocalcemia other than the
reported mechanism of hypocalcemia in
these syndromes.
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SUMMER SCHOOL 2016
HONG KONG
ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
LEARNING POINTS
ӹӹ The importance and implication of phenotypic variability when conducting clinical
counselling
PO LAM SO
ӹӹ Department of Obstetrics and Gynecology, Tuen Mun Hospital,
Hong Kong
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Anne Tsai
THE PHENOTYPIC VARIABILITY OF IGF1R DELETIONFROM LETHAL HYDROPS TO NORMAL PHENOTYPE IN THE
SAME FAMILY
BACKGROUND
IGF-1 (insulin-like growth factor type
1) is well known to be fundamental in
intrauterine and postnatal growth. IGF1R
(insulin-like growth factor 1 receptor)
deletion has been reported to be associated
Silver Russell Syndrome (SRS) like features
with growth retardation. All the cases in the
literature are postnatal cases. Prenatal case
with lethal outcome has not been reported.
We report a family IGF1R deletion that
having diverse clinical phenotype ranging
from lethal hydrops to growth retardation.
CASE SUMMARY
A 37 years old pregnant woman was
referred to prenatal counseling clinic as
her 4 years old daughter had speech delay
and failure to thrive. The affected child had
intrauterine growth restriction since 26
weeks of gestation that born at 38 weeks
with birth weight of 1.8kg. After birth,
there was no catch up in growth that all
her height and weight were remained at
<3% centile. She had mild frontal bossing
and triangular face. There was no body
asymmetry or clinodactyly. Developmental
assessment at the age of 2 suggested she had
mild speech delay. Array CGH showed a
microdeletion of the 15q chromosome, on
the sub-terminal region 15q26.3 (chr15:
99,395,233-99,498,237) of about 103.2kb
65
involving the exon 2 to 20 of IGF1R gene.
The same deletion was maternal inherited
that mother had short stature of 148cm
(at 3th percentile) but without other
SRS features. Concerning on her current
fetus, intrauterine growth restriction was
developed since 20 weeks of gestation,
together with fetal anemia and hydropic
changes. No other structural lesion being
detected. Other investigation included
maternal serum parvovirus B19 serology
was negative. Hematological examination of
fetal blood showed pancytopenia. Prenatal
invasive testing by amniocentesis at 20
weeks was performed that showed same
partial IGF1R deletion. After thorough
counseling, the couple decided termination
of pregnancy. Postmortem examination of
the fetus revealed scaphocephaly, low setting
ears, pectus excavatum and hypocellularity
of bone marrow.
CONCLUSION
We have reported the first case of prenatal
diagnosed IGF1R deletion that present
as severe intrauterine growth retardation
and hydropic change. This family also
demonstrates the variable intra-familial
expressivity of IGF1R deletion that make
the genetic counseling for prenatal case
extreme challenging.
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
ANTHONY PAK-YIN LIU
ӹӹ Department of Paeidatrics and Adolescent Medcine, LKS Faculty
of Medicine, Queen Mary Hospital, The University of Hong Kong,
Hong Kong
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Ho Ming Luk
We describe the atypical disease course
of a 9-year-old Chinese girl with known
Familial Adenomatous Polyposis (FAP). The
patient first presented at the age of 3 years
with abdominal distension and anorexia.
CT scan of the abdomen showed multifocal
liver masses with grossly elevated alphafetoprotein. Multiple pulmonary metastasis
were present and biopsy confirmed the
diagnosis of hepatoblastoma. Family
history was remarkable for her mother
suffering from FAP (APC c.2695dup,
p.Thr899Ansfs*13) associated metastatic
colonic adenocarcinoma. The patient
received
neoadjuvant
chemotherapy
followed by surgical resection of residual
hepatic tumors and achieved clinical
remission. Blood test confirmed the presence
of the same germline APC mutation
inherited from her mother. Genetic
counselling was offered and surveillance
endoscopy planned. Nevertheless, the
patient, at the age of 8-years, presented to
us with per-rectal bleeding. Colonoscopy
showed solitary half-circumference tumor
at the splenic flexure with histology
confirming adenocarcinoma. Staging scan
confirmed the absence of metastasis and
the patient underwent total colectomy with
ileorectal anastomosis followed by adjuvant
chemotherapy. Pathology review confirmed
the diagnosis of moderately differentiated
67
adenocarcinoma alongside with 4 tubular
adenoma with moderate dysplasia. In view
of the unusually early development of
colonic adenocarcinoma, repeat mutation
analysis by next generation sequencing
(409 key tumor-suppressor genes and
oncogenes studied) was performed. In
addition to the known APC mutation, a
heterozygous mutation was detected in
MSH6 (c.4068_4071dup, p.Lys1358Aspfs).
The mutation resulted in frameshift and
stop codon 1 position downstream, it was
reported in ClinVar (SCV000108202) and
was considered to be likely benign. The same
MSH6 variant was not detected in testing
of our patient’s father. Further investigation
by immunohistochemistry showed no loss
of staining for all four MMR proteins in
the tumor sample, and no microsatelliteinstability could be demonstrated in the
tumor or surrounding tissue; thus supporting
the benign nature of the MSH6 variant.
Although the reason behind such atypical
course of our patient remains uncertain, this
scenario highlights the importance of clinical
judgement on top of the value of expert
guidelines. The application of personalized,
genomic medicine might allow us to tailormake a surveillance schedule for each patient,
whilst challenging the role of standardized,
evidence-based recommendations.
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SUMMER SCHOOL 2016
HONG KONG
ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
MA-AM JOY R. TUMULAK
ӹӹ Institute of Human Genetics, National Institutes of Health,
University of the Philippines Manila, Philipinnes
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Anita Kan
A CASE REPORT OF AN 11- YEAR OLD FILIPINO FEMALE
WITH DYSMORPHIC FEATURES AND CLENCHED FIST
Trisomy 18 is a relatively common genetic
disorder. Affected newborns usually
die within two weeks after birth. This is
especially true in the Philippines, where
there are no documented cases of Trisomy
18 who survived longer. Here, we present a
case of an 11 year-old Filipino female who
was diagnosed with Trisomy 18 at birth. A
documentation of the physical and mental
development of patients who survive years
would be helpful in formulating guidelines
for the care and management of Trisomy 18
patients. Caution should also be exercised
when counseling families about the
features, symptoms, and prognosis of their
child with Trisomy 18.
LEARNING POINTS
ӹӹ Features typically seen in neonates with trisomy 18, may not be seen in older patients.
ӹӹ Caution should be exercised when counseling families about the features, symptoms,
and prognosis of their child with trisomy 18.
ӹӹ Early intervention, such as physical therapy and rehabilitation, is important in a good
quality life of these patients.
69
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
UN K N OW N SE SSION 1
MARY ANN ABACAN (PHILIPPINES)
MUZHIRAH HANIFFA (MALAYSIA)
EDBERT JASPER JOVER (PHILIPPINES)
ӹӹ A Case Report on a 10-month-old Boy of Filipino Descent with Multiple
Congenital Anomalies
WINNIE ONG (MALAYSIA)
ӹӹ An Unknown Diagnosis Associating Facial Dysmorphism, Macrocephaly,
Bilateral Cataract and Intellectual Impairment in a Malaysian Chinese Girl
KAVITHA RETHANAVELU (MALAYSIA)
SARAH WYNN (HONG KONG)
SHIYI XIONG (CHINA)
ӹӹ Radio-humeral Synostosis and Hypoplastic Thumbs and Halluces with Absent
Nails: a New Syndrome?
TAWFEG BEN-OMRAN (QATAR)
ӹӹ Peters’ Anomaly, Growth Retardation, and Sparse Hair in Two Sisters: a New
Autosomal Recessive Syndrome?
71
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SUMMER SCHOOL 2016
HONG KONG
ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
MARY ANN ABACAN
ӹӹ Institute of Human Genetics, National Institutes of Health - University of the Philippines
Manila
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Ivan Lo
LEARNING POINTS/
POSSIBLE DIFFERENTIAL DIAGNOSIS AND CAUSATIVE GENES
ӹӹ Schinzel-Giedion Midface Retraction Syndrome – on the basis of the hypertrichosis,
prominent forehead, hypertelorism, open fontanelle
ӹӹ Hajdu-Cheney Syndrome – on the basis of hirsutism, “coarse face” but there is absence
of skeletal affectation
UNKNOWN CASE
INTRODUCTION
This is an unknown case of a 2-year and
10-month old child who presented with
developmental delay, hirsutism and coarse
facial features.
PATIENT INFORMATION
The patient is HR, a 2-year and 10-month
old girl who was seen at clinic for evaluation
of her dysmorphic features. HR is the only
child of a healthy non-consanguineous
couple of Filipino descent. She was born
to a then 25-year old primigravid, preterm
(8 months AOG) via spontaneous vaginal
delivery. The prenatal course was generally
unremarkable. At birth, HR had poor cry
and respiratory distress. She was admitted at
the NICU and treated for RDS and neonatal
sepsis. She was hirsute and had edema of the
face. At 5 months of age, she was noted to
have developmental delays but was advised
to observe this until 1 year of age. On
systems review, there are no concerns with
her vision, she has episodes of spasticity
and cyanosis (seizure equivalents?), she has
regular bowel movement and no episodes
of vomiting. Presently (at 2 years and 10
months), she has global developmental
delay. HR is not taking any medications and
continues to go to physical therapy sessions.
73
Her parents noted some improvement in
her development.
CLINICAL FINDING
HR is proportionately small for age, had
mild hirsutism, an open and flat anterior
fontanelle (1 x 1 cm), frontal bossing (left
more prominent than the right), prominent
metopic ridge and wide forehead. She had
mild coarsening of her features, bushy
eyebrows and an infraorbital crease. She
had prominent cheeks and retrognathia.
She did not have any hepatosplenomegaly
but her abdomen was globular. She had an
absent vaginal opening and hypoplastic
labia.
DIAGNOSTIC ASSESSMENT
The following are the diagnostic
examinations and their results: Cranial CT
Scan (May 2013) showed mild to moderate
non-communicating hydrocephalus with
obstruction at the 3rd and 4th ventricle;
abdominal ultrasound (3 April 2013)
showed an unremarkable right hepatic
lobe, gallbladder, spleen and kidneys;
non-visualized left lobe of the liver and
pancreas; normal FT4 and TSH (18 June
2014), normal chromosomal analysis,
normal echocardiogram and an abnormal
OAE bilateral (29 Sept 2014).
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
MUZHIRAH HANIFFA
ӹӹ Kuala Lumpur Hospital Genetics, Kuala Lumpur, Malaysia
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Anne Tsai
15 year old boy initially referred to
genetic team with suspected progressive
pseudorheumatoid dysplasia
WISP3 gene testing done came back
negative
He presented at 2 yrs of age with bilateral
pes cavus, which were not present at birth
He had op done for this, but not fully
corrected.
Since late childhood, he started developing
joint swelling and deformities
He developed progressive joint deformities
with contractures involving his shoulders,
elbows, hips, knees, ankles, wrists and small
joints of hands and feet. Pain associated
with movement and not present at rest.
13 y/o: developed right hip pain-MRI done
showed right hip erosion with osteoporosis.
75
He was treated as seronegative rheumatoid
arthritis. Investigated for tuberculosis
but was negative, however completed
treatment.
Parents are first cousins and he has 3 other
brothers and parents who are all normal on
examination.
He has no learning difficulties.
His problems are:
1. Severe generalised osteoporosis
2. Short stature
3. Skeletal and bony anomalies
4. Seronegative inflammatory markers
5. Mutiple fractures- right carpal
bone,lumbar vertebra, midtarsal bone
6. Delayed puberty
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
EDBERT JASPER M. JOVER
ӹӹ College of Medicine, University of the Philippines Manila,
Philippines
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Anita Kan
A CASE REPORT ON A 10-MONTH-OLD BOY OF FILIPINO
DESCENT WITH MULTIPLE CONGENITAL ANOMALIES
This is a case of a 10-month-old boy, born
full-term to G1P0 mother of Filipino
descent who was diagnosed with Multiple
Congenital Anomalies (MCA). Specifically,
he was noted at birth to have midline
clefts, hydrocephalus, and amniotic bands.
Chromosomal analysis noted 46,XY
normal male karyotype. Parents reported
no teratogenic exposures during pregnancy.
Since the family history is unremarkable
for any known syndromes or history of
birth defects, differential diagnosis includes
77
amnion rupture sequence and chromosomal
abnormality. Given the unknown diagnosis,
genetic counseling is a challenge because of
the psychosocial impact of cultural beliefs
on the parents and on the family as a whole
in terms of understanding the probable
cause for their child’s condition. This case
report attempts to illustrate the importance
of providing genetic counseling, despite the
uncertainty of the diagnosis, in the context
of Filipino culture.
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ASIA PACIFIC SOCIETY OF HUMAN GENETICS
SUMMER SCHOOL 2016
HONG KONG
WINNIE PEITEE ONG
view of her sagging cheeks, delayed fontanelle closure, high myopia and lax abdominal
skin and joints, we wondered if she could belong to a cutis laxa group of disorder, though
phenotypically there was no exact match.
ӹӹ Department of Genetics, Hospital Kuala Lumpur, Kuala Lumpur,
Malaysia
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Ho Ming Luk
AN UNKNOWN DIAGNOSIS ASSOCIATING FACIAL
DYSMORPHISM, MACROCEPHALY, BILATERAL CATARACT
AND INTELLECTUAL IMPAIRMENT IN A MALAYSIAN
CHINESE GIRL
We present a 12 year-old girl who remains a
diagnostic challenge. She is the youngest of
3 children of non-consanguineous parents;
there is no significant family history. She
was born term following an uneventful
pregnancy, with normal birth weight and
length, and relative macrocephaly. Her
initial neonatal period was stormy with
severe Group B Streptococcal pneumonia
and clinical sepsis requiring ventilatory
and inotropic support, and subsequently
needed home oxygen for 6 months.
Initial assessment also revealed some
dysmorphism and hypotonia and early
suspicions included Weaver syndrome and
Marshall-Smith syndrome. She had poor
focusing in early infancy with nystagmus.
Ophthalmological evaluations revealed
high myopia and later, bilateral cataract,
for which intraocular lens were inserted.
Echocardiogram revealed a small atrial
septal defect. She also had precocious teeth
eruption and a large anterior fontanelle
with delayed closure and postnatal onset
macrocephaly. Over the years, the other
main concern was global developmental
delay especially expressive speech delay,
evolving to moderate-severe learning
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difficulties, compounded by short attention
span. Hearing assessment was normal.
Clinical examination showed her to be
macrocephalic with OFC >98th centile,
with weight and height at 50th and 25th
centile respectively. She was dysmorphic
with prominent forehead, long and
downslanting palpebral fissures, thick bushy
eyebrows, long eyelashes, bluish sclerae,
roving nystagmus, bilateral infraorbital
creases, depressed infrazygomatic arch,
sagging cheeks, dimple on chin, large ears,
slightly lax skin over abdomen, deep-set
nails and hyperlaxity of small joints of
hands and elbows. She also had frequent
echolalia. To date, genetic and metabolic
investigations were normal including
karyotype, microarray, thyroid function,
VLCFA, TIEF, PTEN gene analysis, urine
GAGs, ultrasound KUB. MRI brain
showed mild dilatation of lateral and third
ventricles. Bone age was not advanced
and skeletal X-rays did not show features
of Lenz-Majewski syndrome. Her clinical
evolution made Weaver and MarshallSmith syndrome less likely. Although her
eyes were reminiscent of Kabuki syndrome,
most other features were not typical. In
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KAVITHA RETHANAVELU
ӹӹ Hospital Kuala Lumpur Genetics
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Ho Ming Luk
6 years old /Chinese /girl
With underlying Tetrology of Fallot, subtle
dysmorphic features, global developmental
delay and cerebellar vermis hypoplasia
was referred to our genetic clinic to work
out is her condition is associated with any
syndrome.
We initially thought that she may have Di
George syndrome, however FISH for 22q11
deletion deletion was normal. We also
proceed with MRI scan which showed that
the child has cerebellar vermis hypoplasia.
Over the years under our follow up she was
found to be doing better developmently.
Finally we also sent array CGH.
BIRTH HX: No consanguity; Antenatal
uneventful; Born full SVD, Apgar score 8, 9;
Cried at birth however admited to nicu for
unable to maintain saturation and was then
diagnosed to have TOF (Tetrology ff Fallot);
Requiring admission for 1 month and was
given propranolol however she was never
intubated or ventilated.
PAST MEDICAL HX: Under went BT shunt
operation at 8 months old and is being
planned for second stage cardiac surgery
next year.
independent; Toilet trained; Gross motor:
walking with wide base gait, frequently falls,
only started standing at 3 and half years old,
walking at 4 years old; Speech: can only say
mama, papa, good receptive speech and able
to sign to indicate need. Hearing assessment
was normal; Fine motor: can hold pencil
and copy alphabet; Otherwise we’ll and
attending special school positive progression
of developmental milestones
IMMUNIZATION: completed Malaysian
immunization shedule
On examination: Mild cyanosis; Flat nasal
bridge; Left eye divergent squint; Thin upper
lip; High arch palate; Normal dentation;
Low posterior hair line; Pettus excavatum;
Clinidactaly and long and tapered fingers;
Brachycephaly; No joint laxity; Mild web
neck; Mild facial asymmetry; Good eye
contact; Spine normal; Waikiki with wide
base gait; No tremors; No dystonia; No neuro
cutaneous changes; Thoracotomy scar seen;
Apex beat not displaced; Cvs s1s2 with pan
systolic murmur heard lt lower sternly edge;
Continuous murmur hears lt infraclavicular
region; Tone normal, reflexes normal plantar
down going bilaterally; Power 5/5 all 4 limbs
DEVELOPMENTALLY: Social :self care
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SARAH WYNN
ӹӹ Central Health, Hong Kong
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Anita Kan
UNKNOWN CASE: GIRL, AGED 3YEARS 10MONTHS
Born to a 34-year-old mother after an
uneventful pregnancy by a natural delivery.
She has met all her developmental
milestones at the appropriate time: rolled
at 12 weeks, commando crawling at 18
weeks; walked at 12 months; first words at
10 months and over 100 words by the age of
18 months. She has good eye contact and is
very social.
Cyanotic episode at 2 days old overnight
while in hospital nursery, heart scan showed
no anomalies, no further complications.
She started rocking at 6 months, around the
time she could support her own weight on
all fours the rocking was initially isolated
to the cot and only at nap and night time
sleep times. Head-bashing then started at
around 10-12 months when she grew large
enough to reach the headboard of her cot
while rocking on all fours. By 20 months
had developed a bald spot on the front of
her head.
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Night-time cot rocking is often accompanied
by singing, humming or muttering of long
lists of words. The head-bashing causes a
frequent severe swollen lump in the middle
of her forehead just above the bridge of
her nose. At 2 years an EEG was normal
however MRI detected an intercranial bleed
which was determined to be an old bleed.
A further MRI with contrast was done in
addition to an MRA which ruled out an
aneurysm.
She was diagnosed by a pediatric
opthalmologist) with severe myopia (-6/-7)
and prescribed glasses to be worn full-time.
She has an insatiable appetite. She is
constantly hungry, will steal food and even
after eating will cry for more food. Her diet
is wheat free and dairy free.
Due to her insatiable appetite Prader Willi
Syndrome was considered but array CGH
and uniparental disomy (UPD) testing both
came back normal.
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SHIYI XIONG
ӹӹ Fetal medicine Unit & Prenatal Diagnosis Center, Shanghai
First Maternity and Infant Hospital, Tongji University School of
Medicine, Shanghai, China
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Ivan Lo
RADIO-HUMERAL SYNOSTOSIS AND HYPOPLASTIC
THUMBS AND HALLUCES WITH ABSENT NAILS: A NEW
SYNDROME?
BACKGROUND
Here we report an orphan Chinese patient
with, radio-humeral synostosis, hypoplastic
thumbs and hallux and absent thumb and
great toenails.
CASE SUMMARY
The proband was an orphan who had
been referred from an orphanage for
management advice because a diagnosis of
fibrodysplasia ossifcans progressive (FOP)
had been raised in the past. There was little
documented history. He was presumed to
be 16 month at presentation. He was noted
to have distinctive facial features, bilateral
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radio humeral synostosis confirmed
radiographically and hypoplasia of his great
toes and thumbs which had absent nails.
CONCLUSION
This patient’s clinical course do not fit with a
diagnosis of FOP. Although absent toenails
and thumbnails have been described in a
number of syndromes, they have not been
reported in association with radiohumeral
synostosis and the facial phenotype of this
boy.
KEY WORDS
Hypertelorism, radio-humeral synostosis,
thumb nails absent
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TAWFEG BEN-OMRAN
ӹӹ Clinical and Metabolic Genetics, Department of Pediatrics, Hamad
Medical Corporation, Doha-Qatar
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Poh-San Lai
PETERS’ ANOMALY, GROWTH RETARDATION, AND SPARSE
HAIR IN TWO SISTERS: A NEW AUTOSOMAL RECESSIVE
SYNDROME?
We report on two Yemeni sisters with a
very similar phenotype characterized by
Peters’ anomaly, growth retardation, sparse
hair, and normal intelligence. Additional
common features include sparse outer
third of eye brows, long nose with narrow
and high nasal bridge, bulbous nasal tip,
brachydactyly with hypoplastic nails, and
joint hypermobility. The younger sister
has also jejunal atresia and small atrial
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septal defect. Parents are first cousins. We
sequenced B3GALTL gene and did not
observe any pathogenic sequence variation.
In addition, whole exome sequencing
(WES) failed to identify any candidate
genes to account for their phenotype. We
propose this condition in the two sisters is a
unique clinical entity and likely constitutes
a previously undescribed autosomal
recessive syndrome.
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UN K N OW N SE SSION 2
YULIA ARIANI ASWIN (INDONESIA)
ӹӹ A Case Report of a Child with an Unknown Multiple Congenital Anomaly
Associated with Loss of Heterozygosity
BARBRA CAVAN (PHILIPPINES)
ӹӹ UNKNOWN CASE: A 9 Year Old Boy with Macrocephaly and Supernumerary
Teeth
GILBERT T. CHUA (HONG KONG)
ӹӹ GMT Syndrome – a Novel Primary Immunodeficiency Disease?
KRISTIN
GRACE
(PHILIPPINES)
GUERRERO-GONZALEZ
ӹӹ Postnatal Onset of Growth Deficiency, Coarse Facial Features, and Loose Skin
in a 7-month Old Infant
KITIWAN ROJNUEANGNIT (THAILAND)
ӹӹ A Newborn with Left Lung Agenesis, Congenital Heart Defect and Preaxial
Polydactyly: Case Report
NYDIA RENA BENITA SIHOMBING (INDONESIA)
ӹӹ A Patient with Multiple Congenital Anomalies and Developmental Delay
THIPWIMOL TIM-AROON (THAILAND)
ӹӹ A Case Report: Any Possible Single Gene Disorders Presenting with Praderwilli-like Phenotypes in Neonate?
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YULIA ARIANI ASWIN
ӹӹ Department of Medical Biology, Faculty of Medicine Universitas
Indonesia, Jakarta, Indonesia
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Maya Chopra
A CASE REPORT OF A CHILD WITH AN UNKNOWN
MULTIPLE CONGENITAL ANOMALY ASSOCIATED WITH
LOSS OF HETEROZYGOSITY
Multiple congenital anomaly (MCA)
has become an increasing problem in
worldwide, since it significantly contributes
to infant mortality rate (IMR) and caused
many morbidities during neonatal until
childhood period. Prevention has to be
done to decrease the insidence through
prenatal diagnosis, hence a proper postnatal
definitive diagnosis should be established
as a reference. Microaray system is one of
the leading technique in order to detect
copy number variaions (CNV’s) and loss
of heterozygosities (LOH’s) which may
responsible to phenotype. This report is
aimed to demonstrate a case of MCA with
normal G-banding result, no pathologic
CNV’s, with wide area of LOH’s contain
several genes which may responsible to
the phenotype. An 8 year old girl was
brought by parents to hospital with a chief
complains dyspnea and looks cyanosis
since 1 month prior to admission. She was
born spontaneously, fullterm, no cyanosis,
with distinctive face. Birth weight was
2800 gram. Her growth was retarded, but
her development was normal. There is no
hystory of seizure. Patient was a student
in 3rd grade of elementary school, with
an average level of intelligence. Physical
examination reveals tachypnea and
cyanosis. There was pansystolic mur-mur
without gallop. Clubbing fingers were
noticed.
There are several dysmorfic
feature such as frontal bossing, wide frontal,
depressed nasal bridge, hypertelorism,
downslanting palpebrae, asymetric face
(hemi hypoplasia), midfacial hypoplasia,
strabismus. No chromosomal aberation
was found. Microarray examination
showed benign duplication regions at
chromosome 21, 22 and 7. Benign deletion
regions were found at chromosome
21 and 6. There are 2 large regions of
heterozygosity (ROH) more then 5 Mb in
size, which are located at chromosome 1
and 3. Those regions consist of 29 genes,
which might responsible to the phenotype.
Unrecognized multiple congenital anomaly
with normal chromosome results needs
further evaluation using mycroarray
system. Although CNV’s calling give
normal result, SNP calling might shows
important finding. In this case microarray
examinations showed 2 large regions of
heterozygosity consist of 29 genes which
might responsible to the phenotype.
KEYWORDS
ӹӹ case report, unknown multiple congenital anomaly, SNP-array, loss of heterozygosity
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BARBRA CAVAN
ӹӹ Department of Pediatrics, Cebu Doctors’ University Hospital, Philipinnes
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Ni-Chung Lee
UNKNOWN CASE: A 9 YEAR OLD BOY WITH
MACROCEPHALY AND SUPERNUMERARY TEETH
This 9 y/o boy from Dumanjug, Cebu
Province, Philippines was referred for
evaluation of a possible syndromic cause.
He is the youngest of 4 male siblings, and
was born to non-consanguineous Filipino
parents (31 y/o G5P3 (3013) mother and 34
y/o father). Prenatal ultrasounds at 4 and 7
months AOG both showed a big fetal head.
The plan then was for CS delivery.
He was born term, via primary CS and
noted to have fair cry. Birth weight was 4.6
kg, while length and head circumference
measurements were bigger than usual.
He was on mixed feeding with good suck.
Upon discharge, they were advised to see a
neurologist.
At 1 month old, he had 4 neonatal teeth.
When he was 9 months, he was seen by a
pediatric neurologist who did a cranial
ultrasound. It showed mild communicating
hydrocephalus, probably ex-vacuo type.
The parents were advised regarding the
risk for seizure. No follow up done and
no seizures developed. Developmental
milestones were normal.
At 5 y/o, endocrine work-up was done for
his tall stature. This included bone aging,
hormone levels (thyroid, cortisol, 17-OHP)
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and urine metabolic screen and all came
back normal. Brain MRI showed prominent
ventricles and prominent peripheral
sulci which could mean non-specific
parenchymal volume loss.
At the age of 7, the child had facial swelling.
Aside from caries, his dental X-ray showed
supernumerary teeth. Surgical removal of
some teeth has been done twice.
Anthropometrics on examination were:
Wt=40 kg (z score: 1.68), Ht= 150 cm (z
score: 2.31), and head circumference=
61 cm (>97th percentile). BMI=30.2 (z
score: 0.80). Arm span/height ratio: 0.97.
The head is large with a long face, coarse
facial features, prominent mandible, thick
upturned upper lip with supernumerary
teeth on the upper gums, anteverted nares,
flat chest, irregularly irregular heart rate,
grossly male genitalia, (+)lordosis, dry
skin, scars on the dorsum of the feet from
previous skin infections. Hand length and
foot length on the 97th percentile. Neuro
exam was normal.
Karyotype: 46, XY.
2D echo showed evidence of rheumatic
heart disease.
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GILBERT T. CHUA
DISCUSSION
ӹӹ What will be the next step of investigation to look for the underlying genetic
abnormalities?
ӹӹ Department of Paediatrics and Adolescent Medicine, Queen Mary
Hospital, Hong Kong SAR
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Maya Chopra
GMT SYNDROME – A NOVEL PRIMARY
IMMUNODEFICIENCY DISEASE?
We present a 6 year old boy with recurrent
infections, T cell dysfunction, selective IgM
deficiency, growth hormone deficiency,
dysmorphism, autism spectrum disorder
(ASD) and developmental delay.
He was born at full term with birth history of
congenital pneumonia. He later developed
recurrent acute bronchiolitis and pneumonia
throughout infancy and childhood caused
by viruses and encapsulated bacteria
leading to bronchiectasis. Nasal ciliary
function test and sweat test were normal
excluding primary ciliary dyskinesia and
cystic fibrosis respectively. Immunological
workup revealed selectively low IgM;
low CD3, CD4, CD8, NK cells levels; and
impaired lymphocyte proliferation.
He was also found to have isolated short
stature since 9 month-old. Clonidine
stimulation test and glucagon stimulation
tests confirmed growth hormone deficiency.
Further clinical evaluation showed soft
dysmorphic features, including prominent
occiput, frontal bossing, sparse hair and
eyebrows, flat nasal bridge and single palmar
creases. X-ray of the knees was normal,
excluding
cartilage-hair
hypoplasia.
Neurodevelopmental assessment revealed
that he has global developmental delay and
mild ASD.
Regarding the family history, both parents
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were healthy non-consanguineous Chinese
couple. He has a younger brother who also
has ASD, but without recurrent infections
or similar dysmorphic features. Array CGH
of his younger brother showed a variance of
unknown significance at 11q14.1 with 167
kb copy loss.
Such clinical phenotype of our index
patient has never been described in the
literature, including growth hormone
deficiency, selective IgM deficiency and
T cell dysfunction. We proceeded with
exome sequencing to search for potential
pathognomonic
genes.
Inheritance
models including autosomal recessive
(AR), X-linked hemizygous, compound
heterozygous recessive, and de-novo
heterozygous
autosomal
dominant
mutations were considered in this analysis.
Total of 1137 genetic variants were found,
but none of them were related to primary
immunodeficiencies or growth hormone
deficiency. We propose this is potentially a
newly described disease – GMT syndrome.
Currently, our patient is managed with
inhaled bronchodilators and corticosteroid,
regular intravenous immunoglobulin and
subcutaneous growth hormone injections.
Trainings have also been offered from
allied health with regards to his global
developmental delay and autism spectrum
disorder.
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KRISTIN GRACE GUERREROGONZALEZ
ӹӹ Department of Pediatrics, University of the Philippines Manila –
Philippine General Hospital, Philipinnes
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Tiong Yang Tan
CONCLUSION
Costello Syndrome involves multiple organ systems and is diagnosed based on clinical
findings however it has overlapping features with Cardiofaciocutaneous (CFC) syndrome
and Noonan syndrome. Molecular genetic testing of mutations in the HRAS for Costello
syndrome; BRAF, and less commonly KRAS, MEK1 and MEK2 for CFC syndrome;
PTPN11 and less frequently KRAS, SOS1, RAF1 and NRAS for Noonan syndrome allows
for confirmation of the condition.
KEYWORDS
ӹӹ case report, unknown multiple congenital anomaly, SNP-array, loss of heterozygosity
POSTNATAL ONSET OF GROWTH DEFICIENCY, COARSE
FACIAL FEATURES, AND LOOSE SKIN IN A 7-MONTH OLD
INFANT
BACKGROUND
Costello syndrome is a rare autosomal
dominant disorder characterized by
feeding difficulties, developmental delay,
failure to thrive, characteristic craniofacial
coarse appearance (macrocephaly, coarse
features, thick lips), loose skin, thin deepset nails, increased incidence of cardiac
and neurologic abnormalities as well as
increased occurrence of malignancies. It
is caused by pathogenic mutations in the
oncogene HRAS. Management includes
treatment of manifestations, complications
and surveillance.
CASE SUMMARY
A 7 month old male infant presented at
the clinic with developmental delay, failure
to thrive, and coarse facial features. He
was delivered preterm to a 26 year old
G2P1 (1001) with maternal history of
polyhydramnios on sonographic evaluation.
He was born preterm at approximately
35 weeks, large for gestational age with
a birthweight of 3.6kg (above the 97th
percentile) and was noted to have weak
cry and poor activity, managed as a case
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of sepsis and eventually discharged well
at 10 days of life. He was noted to have
feeding difficulties and developmental
delays. He is the second child of a healthy
nonconsanguineous Filipino couple with
no other similar history and features in
the family. On physical examination he
was noted to be proportionately small for
age (weight of 4.24kg and length of 57.3cm
both below the third percentile, head
circumference of 42cm which was also at
the 3rd percentile.) He had fine hair, coarse
facial features, epicanthal folds, infraorbital
creases, thick lobes, low nasal bridge, thick
lips, macroglossia, chest deformity (pectus
carinatum), hyperplastic nipples, loose
skin, thin deep set nails, deep plantar and
palmar creases. He was also hypotonic and
had nystagmus. Echocardiography revealed
mild pulmonic stenosis. Ultrasound of
the abdomen showed normal findings.
Cranial imaging was also requested to
evaluate for possible associated structural
anomalies. Clinical features were consistent
with Costello syndrome. The patient was
subsequently referred to a developmental
pediatrician, cardiologist, and neurologist
for evaluation and comanagement.
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KEYWORDS
ӹӹ lung agenesis, preaxial polydactyly, heart defect, tracheal stenosis, hemivertebra
KITIWAN ROJNUEANGNIT
ӹӹ Pediatrics department, Faculty of medicine, Thammasat University, Thailand
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Tiong Yang Tan
A NEWBORN WITH LEFT LUNG AGENESIS, CONGENITAL
HEART DEFECT AND PREAXIAL POLYDACTYLY:
CASE REPORT
Lung agenesis, an uncommon defect,
is comprised of the absence of lung
parenchyma, bronchus and pulmonary
vasculature. It can be isolated or associated
with syndromes. Our patient presented
with the combination of lung agenesis
and multiple congenital anomalies which
was a unique and rare presentation. The
patient was born by a 34-year-old insulindependent gestational diabetic mother at
term with the birth weight, length and head
circumference at the 50th percentile. The
Apgar scores were 9 and 10, respectively.
Within 1 hour of his life, he developed
cyanosis during early feeding, therefore left
lung agenesis was diagnosed, accompanied
by left preaxial polydactyly; congenital
heart defect including ventricular septal
defect, right-sided aortic arch, absence of
left subclavian artery and abnormal venous
drainage; hemivertebra; tracheal stenosis;
left facial palsy; and bilateral 2nd and 3rd
toe cutaneous syndactyly.
A specific causative gene has not yet
been identified. Interestingly, there were
only 8 cases reported around the world.
Currently, the whole exome sequencing
technique may identify the causative gene,
so the patient DNA was sent to the research
group in Miami, Florida USA, who has had
another 4 cases. Other differential diagnosis
are included Holt-Oram syndrome, which
presents with cardiovascular defects,
mostly septal defects, thumb anomalies,
and vertebral defects. Lung agenesis is
an uncommon finding; yet, there was
a case of TBX5 mutation causing lung
agenesis accompanied with thumb
and cardiac abnormalities. VACTERL
association (Vertebral defects, Anal atresia,
Tracheoesophageal fistula with tracheal
atresia, Cardiac defects, Renal dysplasia,
Radial abnormalities and Limb defects)
may present with anomalies such as in this
patient. The etiology is unknown: diabetic
mother is one of the risk factors.
Although, it cannot yet be confirmed,
LACHT syndrome (Lung Agenesis,
Congenital Heart defects and Thumb
anomalies) is the most likely diagnosis.
All clinical features are compatible with
this syndrome; however, the diagnosis is
currently based on only clinical findings.
In conclusion, although we were unable to
give a definite diagnosis for this patient;
nonetheless, a bright part is that we
established a new network of knowledge
with other researchers which may lead to
useful discoveries in the future.
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NYDIA RENA BENITA SIHOMBING
ӹӹ Faculty Of Medicine, Diponegoro University, Emarang, Central Java, Indonesia
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Ni-Chung Lee
A PATIENT WITH MULTIPLE CONGENITAL ANOMALIES
AND DEVELOPMENTAL DELAY
The etiology and pathogenesis of children
with multiple congenital anomalies and
intellectual
disability/developmental
delay in Indonesia are often unable to be
elucidated. Consequently, it affected not
only the patient but also the parents, since
confusion and lack of knowledge may lead
to inadequate care.
This report concerns a two months
old male baby, who was referred by a
pediatrician with a diagnosis of multiple
congenital anomalies. He is the second
child of healthy, non-consanguineous
parents. History taking and pedigree
construction were collected. Physical
and dysmorphologies examinations were
conducted. Conventional karyotyping was
performed and genomic DNA of the patient
was extracted for further investigations.
Dysmorphology database software were
used to find possible differential diagnosis
of the syndrome.
Family history was unremarkable. Prenatal
history revealed bleeding during 8 weeks
of pregnancy. The patient had history of
bronchopneumonia and tricuspid valve
regurgitation.
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Dysmorphologies
found
including
macrocephaly, down slanting palpebral
fissure, telecanthus, macrotia, depressed
nasal bridge, small and upturned nose,
anteverted nostrils, cupid bow mouth,
micrognatia, abnormal palmar creases,
broad great toes and clinodactyly of first foot
finger. There were also contracture on upper
extremities and wide spaced nipple, while
genital examination was unremarkable.
Chromosome analysis of the patient
revealed 46,XY with no chromosomal
rearrangements. The working assessment
was suspected Robinow syndrome.
Follow up for Robinow gene testing
suggested no mutations found on DVL1,
ROR2, or WNT5A gene. At present, the
patient has developmental delay. He is now
14 months old. The patient is able to roll
over and babble. He is recently admitted
to the hospital because of dyspnea. Further
investigations to other possible differential
diagnosis is warranted. As the diagnosis
established, the gene abnormality is
expected to be found. Therefore, the mode
of inheritance could be determined in order
to conduct genetic counseling.
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THIPWIMOL TIM-AROON
ӹӹ Division Of Medical Genetics, Department Of Pediatrics, Faculty Of Medicine
Ramathibodi Hospital, Mahidol University, Bangkok Thailand
ӹӹ Email: [email protected]
ӹӹ Summer School Tutor: Dr Ho Ming Luk
A CASE REPORT: ANY POSSIBLE SINGLE GENE DISORDERS
PRESENTING WITH PRADER-WILLI-LIKE PHENOTYPES IN
NEONATE?
Prader-Willi syndrome (PWS) is rare
genetic disorder presenting with neonatal
hypotonia, recognized dysmorphic features
(almond-shaped eyes, light skin and hair,
downturn lips, bitemporal narrowing),
intellectual disability, and unique eating
behavior (poor feeding in newborn period
and hyperphagia in childhood and adult
period). Many reports described several
causes of genetic disorders with PraderWilli (PW)-like phenotypes including
unbalanced chromosome rearrangement,
microdeletion/duplication
syndrome,
and maternal uniparental disomy of
chromosome 14. We describe a female
newborn infant with significant hypotonia,
poor weight gain and minor dysmorphic
features mimicking PWS. The patient
has normal karyotype, negative SNRPN
methylation test and unremarkable single
nucleotide polymorphism (SNP) array
result. We hypothesized that single gene
disorders, which have not been reported,
could be a possible cause of PW-like
phenotypes. Whole exome sequencing
should be considered in our patient.
KEYWORDS
ӹӹ Prader-Willi-Like Phenotypes, Facial Dysmorphism, Neonatal Hypotonia, AlmondShaped Eyes, Poor Feeding, SNRPN Methylation Test, Array CGH
LEARNING POINT
ӹӹ Differential diagnosis of neonatal hypotonia mimicking PWS.
ӹӹ A patient with unidentified causes of possible genetic diseases needs to follow up for
more clues.
ӹӹ Do not jump to diagnosis only because of recognition patterns of diseases, we may get
wrong.
103
104
105
18 (Cat A)
11.5
9
18
23 (Cat B)
18 (passive)
Hong Kong College of Paediatricians
Hong Kong College of Pathologists
Hong Kong College of Physicians
Hong Kong College of Psychiatrists
Hong Kong College of Radiologists
College of Surgeons of Hong Kong
C NE C R ED I T S
TO BE CONFIRMED
10 (Cat 2.2)
MAX. POINTS
8
23 (non O&G)
10 (Cat 5.2)
Hong Kong College of Otorhinolaryngologists
COLLEGE
College of Ophthalmologists of HK
Hong Kong College of Obstetricians and Gynaecologists
Hong Kong College of Family Physicians
12
23 (Cat B)
Hong Kong College of Dental Surgeons
Hong Kong College of Emergency Medicine
15 (Non-anaes)
MAX. POINTS
Hong Kong College of Anaesthesiologists
COLLEGE
CM E /C N E A CCR ED I TA TI O NS
2.5
5
5
5.5
5.5
5.5
6
7
6
2
7
6
3.5
5.5
5
5.5
2
5.5
6
3
29 AUG 2016 30 AUG 2016
3
7
5
6
7
7
29 AUG 2016 30 AUG 2016
ASIA PACIFIC SOCIETY OF HUMAN GENETICS
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POS T S UM MER SC H O O L
B I OI N FO RM ATICS
W O RK SHO P 2016
29TH AUGUST 2016 TO 30TH AUGUST 2016
ROOM 314
3/F, WILLIAM M.W. MONG BLOCK
21 SASSOON ROAD
POKFULAM
HONG KONG
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108
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