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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 2 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 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 3 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 4 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG I NVI T ED G UESTS 5 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 6 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 7 Dr EMC Cutiongco-De La Paz Dr IFM Lo Dr HM Luk 8 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 9 P R OG R A MME A T A GL ANC E VE N U E LAYOUT 10 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 11 Approach to the Newborn with Disorders of Sex Development (David Chitayat) (Facilitated by Anne Tsai) 12 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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" 13 14 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG P ROG RAM ME ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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) 15 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 16 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 17 18 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 19 20 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 21 22 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 23 24 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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. 25 26 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 27 28 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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. 29 30 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 31 32 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 33 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. 34 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. 36 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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. 37 38 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 39 40 ASIA PACIFIC SOCIETY OF HUMAN GENETICS 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 41 42 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 43 44 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 45 46 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 47 48 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 49 50 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 51 52 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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. 54 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. 55 56 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 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 58 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 60 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. 62 ASIA PACIFIC SOCIETY OF HUMAN GENETICS 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. 64 ASIA PACIFIC SOCIETY OF HUMAN GENETICS 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. 66 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. 68 ASIA PACIFIC SOCIETY OF HUMAN GENETICS 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 70 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 72 ASIA PACIFIC SOCIETY OF HUMAN GENETICS 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). 74 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 76 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. 78 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 79 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 80 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 81 82 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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. 83 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. 84 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 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 85 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 86 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 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 87 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. 88 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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? 89 90 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 91 92 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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) 93 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. 94 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 95 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. 96 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 97 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. 98 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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. 99 100 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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. 101 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. 102 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 106 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 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 107 108 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 109 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 110 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG T H E T A IPING SHA N M EDI C AL HERITA GE TR A I L 111 112 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG T H E T A IPING SHA N M EDI C AL HERITA GE TR A I L 113 114 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG T H E T A IPING SHA N M EDI C AL HERITA GE TR A I L 115 116 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 117 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 118 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG A C K N OWLEDGEMEN T 119 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG A C K N OW L E D G E M E N T 120 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG A C K N OWLEDGEMEN T 121 121 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 123 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 124 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 125 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 126 ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG ASIA PACIFIC SOCIETY OF HUMAN GENETICS SUMMER SCHOOL 2016 HONG KONG 127