Common Genetic Disorders in Child Neurology. Paula Goldenberg, MD, MSW, MSCE Medical Genetics Massachusetts General Hospital September 6, 2017

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1 Common Genetic Disorders in Child Neurology Paula Goldenberg, MD, MSW, MSCE Medical Genetics Massachusetts General Hospital September 6, 2017

2 Disclosure I am a scientific and clinical advisor for the International 22q11.2 Foundation Otherwise no conflicts to disclose

3 List common genetic conditions with chromosomal basis Objectives List common genetic syndromes that may be diagnosed with microarray testing Discuss common genetic disorders typically identified with molecular genetic testing

4 There is a lot of genetics in neurology, and neurologic features in genetic syndromes!

5 This meeting covers several other genetic conditions Neurometabolic Disorders Neuronal Ceroid Lipofuscinosis Tuberous Sclerosis Neurofibromatosis Neuromuscular Disorders Inherited Neuropathiies Mitochondrial Disorders Angelman syndrome 15q Duplication syndrome Cerebral dysgenesis Leukodystrophies and hypomyelinating disorders Ataxias Dystonias Autism

6 We will cover 12 common genetic syndromes Down syndrome Trisomy 13 Trisomy 18 Williams syndrome Smith-Magenis syndrome 22q11 deletion syndrome Prader-Willi syndrome Cri du Chat syndrome Fragile X Rett syndrome PTEN-associated autism Sotos syndrome

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8 Developmental delay, autism ACMG (2013): Tier 1: Microarray and Fragile X Tier 2: MECP2 in girls, or boys if phenotype is suggestive PTEN if HC >2.5 SD Brain MRI if specific indicators (microcephaly, regression, seizures, hx of stupor/coma) Genetic screening for patients with autism or developmental delay

9 Common Chromosomal Syndromes Down syndrome Trisomy 13 Trisomy 18

10 Chromosomal aneuploidy Missing or extra chromosome Best test for evaluating is a chromosome study not microarray Microarray may not detect trisomy vs. unbalanced Robertsonian translocation High recurrence risk if a parent has a balanced translocation

11 Down syndrome 1 in 700 births

12 Neurologic features of Down syndrome Hypotonia Developmental delay Intellectual disability Autism Epilepsy Early onset Alzheimer Dementia West syndrome: perhaps 5% have Down syndrome 1 Sleep apnea 1 Samaneechai O, et al. Treatment outcomes of West Syndrome in infants with Down syndrome. Pediatr Neurol Jan;48(1):42-7.

13 Acute Cognitive Regression Rarely reported Recent retrospective case series of 30 patients (age 11-30y) Onset age 20 years (mean 18y in girls 21y in boys) May be associated with a trigger event Change of school Awareness of disability Marriage of brother or sister Assault Illness or death of friend or family Overstimulation Mircher C, et al. Acute regression in young people with Down syndrome. Brain Sci 2017; epub

14 Clinical presentation Mood: Depression, anxiety Behavior: Apathy, catatonia, self-injury, aggression Thought: Delusion, stereotypy, inappropriate laughter ADLs: intact, partial regression, or total regression Language: intact, partial regression, or mutism Thyroid, EEG, and brain MRIs are typically normal Half did not recover, 43% partially recover, 10% fully recover Mircher C, et al. Acute regression in young people with Down syndrome. Brain Sci 2017; epub

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16 Trisomy 13 Patau Syndrome Approximately 1 in 16,000 births Increased with advanced maternal age Chromosome study to detect Robertsonian translocation Microphthalmia, coloboma Deafness Cleft lip and/or cleft palate Aplasia cutis VSD (80%)

17 Neurologic aspects of Trisomy 13 Holoprosencephaly Forebrain, olfactory, optic nerves Motor seizures with hypsarrhythmia pattern Apnea in early infancy Severe intellectual disability Microcephaly Hyper- or hypotonia

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19 Trisomy 18 Edwards Syndrome More common than trisomy 13 1 in 6,000 live births Increased risk with older mothers Chromosome study for translocations Polyhydramnios IUGR, feeding problems Hernias (inguinal, umbilical, diastasis recti) Limited hip abduction VSD

20 Trisomy 18 Neurologic conditions Choroid plexus cyst 5% have brain abnormalities cerebellar hypoplasia, agenesis of corpus callosum, microgyria, hydrocephalus myelomeningocele Hypotonia (infants)-->hypertonia Central apnea Seizures Intellectual disability Cereda A, Carey JC. The trisomy 18 syndrome. Orphanet J Rare Dis 2012; 7:81.

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22 Common conditions found on microarray testing Cri du Chat syndrome (5p deletion) Williams syndrome Smith-Magenis syndrome 22q11 deletion syndrome Prader-Willi syndrome

23 5p deletion syndrome Cri-du-Chat syndrome 1:15,000-50,000 newborns 85% de novo (80% paternal) 15% due to paternal translocation Low birth weight, slow growth (52-70%) Cat-like cry Laryngeal abnormality Mild to profound intellectual disability Hypotonia Ophthalmologic features 46%: refraction errors, strabismus, cataracts, optic nerve abnormalities ADHD

24 Severity depends on deletion location on chromosome 5p

25 You Tube audio of the high pitched cry Gid- Cri du Chat

26 7q11.23 deletion Williams syndrome 1 in ,000 Most are de novo There are some familial cases Features are not obvious in newborns Failure to thrive Supravalvular aortic stenosis, branch PA stenosis, PS, septal defects, renal artery stenosis Friendliness, empathy Cocktail party personality Hypercalcemia CV collapse with anesthesia Including those that don t have heart defects Recommend cardiac anesthesiologist

27 Neurologic and Psychiatric features of Williams syndrome Anxiety Phobias, fears Generalized anxiety ADHD Mild to severe intellectual disability Visuospatial deficits Relative strength with verbal skills Love of Music (Berkshires Music Academy: 1 st year 85% had Williams) Hyperacusis 50% need treatment for anxiety or ADHD

28 17p11.2 deletion Smith-Magenis Syndrome 1 in 25,000 De novo deletion One mother mosaic for deletion RAI1 mutation (in deletion region) Can be mistaken for Down syndrome in infants Retinoic Acid Inhibitor 1 accounts for some but not all SMS findings Often small deletions causing frameshift SCA2 is caused by CAG repeats of RAI1 (allelic)

29 Smith-Magenis syndrome Neurologic and Psychiatric Features Infantile hypotonia Mild to profound ID Hoarse voice Delayed sleep onset, frequent night waking, sleepiness during the day Circadian disturbance Self-injury Head banging Wrist biting Onychotillomania Polyembolokoilamania Aggression Insensitivity to pain Seizures (25%) and abnormal EEGs (50%) Ventriculomegaly (>50%)

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31 22q11 deletion syndrome 1:2,000-4,000 births Possibly 1:1,000 pregnancies de novo (90%) or familial (10%) 5% atypical deletions (negative FISH) Wide phenotype No genotype-phenotype correlation Conotruncal cardiac defects (75%) Hypoparathyroidism (50-60%, usually in infancy) Cleft palate, cleft lip, VPI Thymic hypoplasia

32 22q11 deletion syndrome Neurologic and psychiatric aspects Average borderline IQ with wide distribution Nonverbal learning disability Hypotonia Seizures Asymmetric crying facies (absent depressor angularis oris) Cayler cardiofacial syndrome Cranial nerve dysfunction and aspiration Polymicrogyria Anxiety and Depression Risk of psychosis: approx 25% At the same time, many young adults go to college and graduate school

33 Patient 1: 4mo Right Handed Extensive right frontal, parietal and temporal polymicrogyria T2 Axial T1 Coronal T1 Sagittal FLAIR Sagittal Right hemisphere

34 Patient 2: 16m Bilateral frontal, left parietal, and left temporal involvement T1 axial T1 axial T2 Coronal T1 Sagittal Left Hemisphere

35 22q11 deletion syndrome Consider microarray for a patient with unilateral or bilateral PMG Seizures in infancy if hypocalcemic consider 22q11 deletion syndrome Asymmetric crying facies: consider microarray testing

36 15q11.2 Prader-Willi syndrome 1 in 10,000-30,000 Paternal deletion 65-75% Maternal UPD 20-30% Imprinting Center defect rare For some defects need to rule out balanced translocation in parents Phases of feeding concerns Normal prenatal growth Newborns: low muscle tone, poor suck, tube feeding years: increased interest in food, crossing percentiles 8y-adulthood: intense and relentless food seeking (locked food access) Some adults become able to detect satiety

37 Easiest option! Do methylation PCR and send patients to genetics if positive

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39 Features of PWS Hyperphagia: Food-seeking behavior, with hoarding or foraging for food, eating of inedibles, and stealing of food or money to buy food, are common Ghrelin levels are low Short stature, small hands and feet, growth hormone deficiency

40 Prader Willi Syndrome Neurologic and Psychiatric features Delayed milestones (sit 12m, walk 24 mo, delayed language) Moderate ID 20% Mild intellectual disability 40%, borderline/low avg 20% Sleep: Central and obstructive sleep apnea, altered sleep architecture, REM Behavior problems 70%-90% (suggestive of ASD in 19%) Temper tantrums Stubbornness Controlling and manipulative behavior Compulsivity Difficulty with change in routine ADHD Psychosis in 10-20% and more common in those with UPD Seizures 10-20%

41 Common Molecular Syndromes Fragile X Rett Syndrome PTEN Sotos Syndrome

42 FMR1 Fragile X syndrome 1: Males 1: Females >200 CGG repeats of FMR1 Question: Can Fragile X be diagnosed with sequencing FMR1? Testing with PCR or Southern Blot Only a small minority have mutations Males with full mutation Intellectual Disability (Moderate to Severe) Autism Seizures ADHD Females with full mutation Are fertile May have learning disability 1/3 have intellectual disability Anxiety

43 Complicated Discussions Intermediate can expand to premutation (mother to child) Premutation Premature ovarian insufficiency Fragile X Ataxia Tremor syndrome Can expand to full mutation (mother to child) Fragile X carrier screening of preconception/pregnant women more commonly currently Women with premutation/infertility What if you make a diagnosis and parents say they are not having more children?

44 Why test parents? Recurrence Risk: accidents happen Often additional family members with Fragile X may be diagnosed 176 probands with Fragile X in Clinic 227 with full mutation (219 male, 8 female) 558 with premutation (59 male, 499 female) On average 5 more family members identified Family members can have preconception testing or pregnancy options Visootsak J, et al. Climbing the branches of a family tree: diagnosis of Fragile X syndrome. J Pediatr 2014;164(6):

45 MECP2, Rett syndrome 1 in 8500 females, by age 15y >99% de novo Rarely mother may carry the mutation with skewed X- inactivation X-linked dominant Liveborn males have severe neonatal encephalopathy Death in early childhood (age 2y) Classic Rett (females) Normal development to 6-18 months Developmental stagnation Regression of language and motor skills Repetitive, stereotypic hand motions Fits of screaming and crying Autistic features Panic attacks Bruxism Episodic apnea and/or hyperpnea Gait ataxia Tremors Seizures (90%) Postnatal microcephaly

46 Variant/Atypical Rett Most severe form: no period of grossly normal development occurs Congenital hypotonia and infantile spasms Milder form: girls have less dramatic regression, milder ID Gradual regression that begins after the third year, lose purposeful hand use, and develop seizures retain some speech and the ability to walk Variant/Atypical Rett can be associated with MECP2, FOXG1 and CDKL5 mutations

47 Rett syndrome 1.5% of patients with negative testing for Angelman can have MECP2 mutations Adulthood: long QT and ECG abnormalities,?increased risk of sudden death

48 Frontal and profile views of subject two with a PTEN mutation (D252G) at 3.5 years of age showing macrocephaly. M G Butler et al. J Med Genet 2005;42: by BMJ Publishing Group Ltd

49 PTEN-associated autism with macrocephaly Possibly 1% of children with autism have PTEN mutations De novo or familial Prevalence 1.5 in 10,000? Head circumference average 4 SD above the mean Allelic with Bannayan-Riley-Ruvalcaba Syndrome Cowden syndrome: an adult cancer risk syndrome Due to this condition being allelic with Cowden syndrome: periodic screening for breast, thyroid, renal and endometrial cancers starting at age 18

50 Sotos syndrome NSD1 1 in 10,000-14,000 Macrocephaly with prenatal onset Large hands and feet Advanced bone age Sotos-like syndrome associated with NFIX

51 Sotos syndrome Neurologic and psychiatric findings IQ mean 78 Delayed milestones: sit at 9m, walk at 17m, some words 25m Autism Seizures Behavior problems: social skill problems, aggressiveness, tantrums Immaturity MRI findings can include ventriculomegaly, complete or partial agenesis of the corpus callosum, supratentorial extra cerebral fluid spaces including the posterior fossa

52 Broad review of 12 high-yield, common syndromes Chromosomal Down syndrome Trisomy 13 and 18 Copy number variants (all deletions) Cri-du-chat Williams syndrome Smith-Magenis Prader-Willi 22q11 deletion Molecular Fragile X Rett PTEN Sotos

53 Many thanks for your kind attention!