To Be Your Local Expert – a General Pediatrician’S Story

To Be Your Local Expert – A General Pediatrician’s Story

DDC Clinic mission: To enhance the quality of life for people with special needs caused by rare genetic disorders

What Does It Take to Be Your Local Expert? “Through My Window …”

- “Research Clinic Opens in Ohio for Genetic Maladies That Haunt Amish Families” By FRANCIS X. CLINES June 20, 2002 “You Have a Lot to Learn!”

Chicken breast disease – Amish Normaline myopathy • Autosomal recessive • Onset with neonatal tremors and hypotonia • Contractures • Chest deformity • Respiratory failure To be your local expert is not simply a desire or a choice, it is a call of duty! Cohen Syndrome – Overview

• Genetics: autosomal recessive • First reported by Dr. Michael Cohen in 1968 • Gene related to the disease: COH1 (VPS13B) on chromosome 8q22 • Incidence: Over 1000 patients are diagnosed worldwide, and over 200 patients are reported • A disease with multiple system involvements 7th Cohen Syndrome Family Gathering in June 2014

Cohen Syndrome – Clinical Manifestations

• Psychomotor retardation • Microcephaly • Characteristic facial features • Childhood hypotonia and joint laxity • Progressive retinochoroidal dystrophy and myopia • Truncal obesity • Neutropenia • Cheerful disposition • Any earlier signs or symptoms? Cohen Syndrome – Fetal Movements in 65 Patients Cohen Syndrome – Facial Features

• Thick hair and low hairline • High -arched and waved-shaped eyelids • Long and thick eyelashes, thick eyebrows • High and narrow palate • Short philtrum and prominent upper central incisors, resulting in open-mouth appearance Cartilage-hair Hypoplasia Dwarfism (CHH)

• First reported in 1965 by McKusick et al • Genetics: autosomal recessive • Related gene: ribonuclease mitochondrial RNA-processing (RMRP) gene • Common clinical features • Short stature • Metaphyseal dysplasia • Fine sparse hair • Hirschsprung disease • Immunodeficiency • Hematologic malignancies • A huge phenotypic variation Amish Brittle Hair Syndrome

• First described in early 1970s • The disease related gene identified on 2005: TTDN1 or C7ORF11 on chromosome 7p14 • Genetics: autosomal recessive • Other names: nonphotosensitive trichothiodystrophy, hair-brain syndrome, BIDS syndrome • Clinical features (brittle hair, intellectual impairment, decreased fertility and short stature)

Cockayne Syndrome

 Genetics: autosomal recessive  Related genes: ERCC6 and ERCC8  Severe in Amish, notable at birth  Severe microcephaly, failure to thrive photosensitivity, congenital cataracts and sensorineural hearing loss MOPD (Microcephalic Osteodysplastic Primordial Dwarfism) Type I

He et al. Science 2011;332:238-240 Microcephalic osteodysplastic primordial dwarfism type 1

Published by AAAS TMCO1 Defect Syndrome

 Autosomal recessive disorder  Characterized by distinctive craniofacial dysmorphism, skeletal anomalies, mental retardation and frequent sinus infections  “TMCO1 defect syndrome” is proposed as name of the disease

Xin B et al. PNAS 2010;107:258-263

 Another novel condition we described recently  An acronym (first 3 letters of gene SAMHD1 as well) is used to name the disease  Stenosis  Aneurysm  Moyamoya  Stroke  Synonym: Aicardi– Goutières syndrome (AGS)  The gene may be associated with stroke

Xin B et al. PNAS 2011;108:5372-5377

• Fetal movement: less active in Cohen syndrome and TMCO1 defect syndrome • Umbilical cord: thinner in SAMS association • Birth weight • SAMS association – low end of normal • Cockayne syndrome – even smaller • MOPD type I – very small, often less than 3 lb • Newborn hearing screening • Often fail – Cockayne syndrome and GM3 deficiency How Does the Baby Cry?

• Cohen syndrome – high-pitched, weak cry, “like kitten” • NBIA (Hallervorden-Spatz disease or syndrome) – “like laughing” • SIDDT (sudden infant death with dysgenesis of the testes) syndrome - an unusual staccato cry, “like a goat” • Cockayne syndrome – “quiet cry”, “seldom cry” • GM3 synthase deficiency – “cried his/her head off” Don’t Forget to Challenge Your Authorities!

History or diagnosis Suspect History of meningitis SAMS association

Early onset of stroke A severely irritable baby, febrile GM3 synthase deficiency or afebrile, a sepsis work-up negative Cui-du-chat syndrome Cohen syndrome Rett syndrome Misdiagnosed? Autism Misdiagnosed? Learn Some Pennsylvania Dutch – It Can’t Hurt!

• Look at ears - • Hold still – • Open your mouth, bigger!

Bilingualism delays onset of dementia (4.5 years) (Alladi et al, Neurology 81:1938, 2013) What is Genetics? Final Thoughts

“These special children are not just interesting medical problems, subjects of grants, and research. Nor should they be called burdens to their families and communities. They are children who need our help and, if we allow them to, they will teach us compassion,… they will teach us to love. If we come to know these children as we should, they will make us better scientists, better physicians, and thoughtful people” Dr. Holmes Morton