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Home , 1p36 deletion syndrome, Angelman syndrome, Cri du chat syndrome

Genomic Technologies Objectives

& • Understand the benefits and limitations of Recognition commercially-available • Recognize presenting features of common genetic

By Samantha Leib, MD, FAAP Pediatrician • Improve comfort level managing and Department of and Genomic Medicine monitoring patients with genetic conditions Saint Peter’s University Hospital in the primary care setting

Understanding the Basics

1 Genomic Technologies

2 3 Reasons to Diagnose

• Comprehensive information regarding the diagnosis or probable diagnosis

• Medical management Prenatal Screening

• Anticipatory guidance and surveillance

• Risk and recurrence assessments for the patient and other family members

Non-invasive Prenatal Testing (NIPT) What is NIPT? • The use of NIPT to screen for the presence of fetal • Non-invasive prenatal testing became feasible with the development of massive parallel sequencing (MPS) and counting of • Cell-free fetal DNA (cffDNA) cfDNA fragments. • Fetal DNA that circulates freely in the mother’s • Most current tests for this purpose use whole bloodstream (2-6% of total) MPS in order to quantitatively compare the • Originates from apoptosis amount of, for example, 21 DNA of trophoblasts that make up the placenta due to molecules in a maternal sample with that of an maternal immune system euploid reference sample. interaction

• Other tests use targeted sequencing, mapping only • cffDNA is significantly smaller the chromosome regions of interest, or use a than maternal DNA and can qualitative SNP-based approach. be distinguished by size

4 How does it actually work?

• Maternal blood sample obtained

• PCR to replicate DNA to analyze

• Massively parallel sequencing (next- generation sequencing)

• Amount of fetal DNA compared with reference DNA with expected amount

Common Screens Screening Limitations MaterniT21 Plus: Harmony Screens for: • These screening tools do not provide a definitive 21 Trisomy 21 genetics risk in all individuals. Trisomy 18 Trisomy 18 Trisomy 13 Trisomy 13 • Cell-free fetal DNA does not replace the accuracy Sex chromosome aneuploidy Sex chromosome aneuploidy and precision of prenatal diagnosis with CVS or 22q syndrome (DiGeorge) amniocentesis. 5p (Cri-du-chat syndrome) 15q (Prader-Willi/Angelman • A patient with a positive test result should be syndromes) referred for and offered invasive 4p (Wolf-Hirschhorn syndrome) prenatal testing for confirmatory diagnosis. 8q (Langer-Giedion syndrome) 11q () • A negative test result does not ensure an unaffected pregnancy.

5 Average Cost

1. : $600 2. Microarray: $750 - $2,500 Syndrome Recognition 3. NIPT: $100 - $400 4. panels: $1,000 - $3,000 5. Whole exome: $2,500 - $5,000

6 Facts: • Affects an estimated 1 in 7,500 to 10,000 people

• Occurs equally in both males and females

• Autosomal dominant condition

• Majority are de novo deletions

• Caused by a deletion from a specific region on

Clinical Features Clinical Features Distinctive Facies: Unique Personality: • Broad forehead, bitemporal • Overfriendliness narrowing, periorbital fullness • Empathy • A stellate/lacy iris pattern, , • Generalized anxiety short nose with a broad nasal tip, • Specific phobias malar flattening • ADHD • Long philtrum, wide mouth with full lips, , micrognathia, and Intellect/Cognitive Profile: large ear lobes (seen at all ages) • Developmental delays • Strengths in verbal short-term memory and • Young children have epicanthal folds, full cheeks, and widely spaced teeth language (affinity towards music) • Weakness in visuospatial construction • Adults have long face and neck, • Most have some degree of resulting in a gaunt appearance

7 Clinical Features Clinical Features

Cardiovascular disease: Growth Abnormalities: • Any artery may be narrowed (elastin arteriopathy) • FTT in infancy • Most commonly supravalvar aortic stenosis (75%) • Short stature • Peripheral pulmonic stenosis common in infancy (PPS) Endocrine Abnormalities: • Hypercalcemia Connective Tissue Abnormalities: • Hypothyroidism • Joint limitation or laxity • Early puberty • Hernias • DM • Soft/lax skin • Rectal prolapse

Yearly Surveillance Interval/Age Test/Measurement Williams Syndrome Serum calcium determination every Infancy 4-6 months until age 2 years •Medical evaluation Video link •Vision screening to monitor for refractive errors and strabismus •Hearing evaluation •Monitoring of blood pressure in both arms Annual •Measurement of calcium/creatinine ratio in a random spot urine and urinalysis •Cardiology evaluation at least yearly for the first 5 years, every 2-3 years thereafter Every 2 years •Serum concentration of calcium Every 3 years •Thyroid function and TSH level •Renal and bladder ultrasound Every 10 years examination •Oral glucose tolerance test (OGTT) starting at age 30 years to evaluate for diabetes mellitus 1 •Evaluation for mitral valve prolapse, In adults aortic insufficiency, and arterial stenoses •Evaluation for (from Gene Reviews)

8 Clinical Features Growth: • Long limbs Facts: • Decreased upper-to-lower segment ratio • Affects 1 in 500 to 1,000 newborn males • Increased arm span • Mean height at 75% • Diagnosis is confirmed by chromosomal analysis Hypogonadism with Hypogenitalism: • Childhood-, , • Paternal meiosis I errors account for 50%- small penis/testes 60% of 47,XXY males with the remainder • Adolescence/adulthood-testes remain small; due to maternal meiosis I or II errors or to a virilization is incomplete with gynecomastia occurring in 1/3 of adolescents postzygotic error • Facial hair is sparse • It’s the most common cause of • Testosterone levels decrease in late hypogonadism and in men adolescence and early adulthood (< ½ of normal) • Infertility

9 Clinical Features Clinical Features Occasional Complications: Performance: • Elbow dysplasia • IQ between 85-90; verbal IQ is usually higher than performance IQ • Taurodontism • Problems with reading and spelling • Diabetes • Autoimmune diseases • Immature behavior, introverted personality, poor judgment, difficulty forming peer relationships • Varicose veins & hypostatic anterior leg ulcerations • 20-50% will have a fine-to-moderate intention tremor • Chronic bronchitis/emphysema/asthma • Mediastinal germ cell tumors • Breast cancer (risk is significantly increased over the general male population, approaching the risk in normal women)

Management

• Any evidence of delayed milestones deserve prompt referral to early intervention and a developmental specialist • Any evidence of learning problems should be pursued with a comprehensive Development educational evaluation • Evidence of behavioral/emotional problems should prompt referral to a behavioral/psychological specialist

• Obtain baseline testosterone, FSH, and LH levels ~11-13 yo • Treatment with testosterone replacement therapy beginning at age 11-12 years Endocrine (if testosterone is decreased or gonadotropins increased for maturational age); this will permit more typical adolescent development and prevent many features of adult Klinefelter syndrome that are secondary to testosterone insufficiency • Monitor testosterone levels into adulthood

• There’s an increased risk for extragonadal, usually mediastinal germ cell tumors; age of susceptibility is early adolescence to age 30 • Increased risk of breast cancer (approaching that of women); 20-fold increase Neoplasia over the normal male population; monthly self-examination and annual clinical breast examinations are recommended; the value of periodic mammography has not been established

10 Clinical Features • Happy demeanor that includes Facts: frequent laughing, smiling and excitability • Angelman syndrome affects an estimated 1 in 12,000 to 20,000 people • Newborns: typically have a • The gene involved is UBE3A on normal phenotype; developmental delays seen • Mechanism could be a deletion, around 6-12 months , or an imprinting defect • Speech impairment, with minimal • 50% familial, 50% de novo to no use of words; receptive • Seen in all races language and nonverbal communication skills better than expressive language skills

Clinical Features Other Findings • Flat occiput • Uplifted, flexed arm position • Protruding tongue especially during ambulation • Movement or balance disorder, usually of gait • Tongue thrusting; • Wide-based gait with and/or tremulous movement of limbs; average child suck/swallow disorders pronated or valgus- positioned ankles • Feeding problems and/or with AS walks between 2.5 -6 yo; jerky, robot-like, • Increased sensitivity to heat during infancy stiff gait with uplifted, flexed, and pronated forearms • Attraction to/fascination with • Wide mouth and widely water; fascination with crinkly • Hypermotoric behaviors spaced teeth items • Frequent • Abnormal food-related behaviors • Absolute or relative by age 2 • Strabismus • Hypopigmented skin, light • Hyperactivity hair and eye color • • Seizures, usually starting before age 3 (compared to family); seen • Constipation only in those with deletion • Abnormal sleep-wake cycles and diminished need for • Hyperactive lower-extremity sleep deep-tendon reflexes • Obesity

11 Management Angelman Syndrome

• Evaluation for GER in infants and young children; dietary eval to Video link assure optimal nutritional status • Baseline MRI and EEG • Management of seizures • Musculoskeletal exam for scoliosis and gait impairment; orthopedic referral as needed Initial Evaluation • Ophthalmology exam for strabismus, evidence of ocular albinism, and visual acuity • Developmental evaluation focused on: 1. Nonverbal language ability and related educational and teaching strategies (ST) 2. to enable optimal ambulation

• Annual exam; check for scoliosis • Assure proper nutrition and monitor for the development of obesity Yearly Surveillance • Treatment for manifestations: like constipation, behavioral problems, orthopedic problems, sleep disturbances

12 Facts: • Defined as loss or abnormality of the second in at least one cell line in a phenotypic female; mosaicism occurs (~ 50%) • Occurs in about 1 in 2,500 newborn girls worldwide • ~99% of 45, X pregnancies spontaneously abort • Diagnosis by karyotype • Short stature and are the cardinal features

13 Clinical Features Clinical Features

Birth and Neonatal Period: Infancy: • Growth: often borderline small for gestational age • Growth: length usually close to and parallel to the 3rd • Lymphadema percentile • Cardiac abnormalities: e.g. coarctation of aorta, • Feeding difficulties aortic stenosis, bicuspid aortic valve • Poor sleeping pattern

Clinical Features Clinical Features

School: Preschool: • Growth: height gradually falls away from 3rd percentile • Short stature: height velocity usually low/normal • Middle ear disease • High activity levels • Obesity • Behavioral difficulties with exaggerated fearfulness • Specific learning difficulties (math, visuospatial tasks) • Recurrent middle ear infections; otitis media with • Social vulnerability effusion; variable conductive hearing loss; sensorineural deafness in a minority • Foot problems (toenail involution, cellulitis) • Renal anomalies

14 Clinical Features Management Adolescence: • Examine hips for dysplasia • Growth: impaired pubertal growth spurt even with estrogen Health Supervision • Review newborn hearing screen • Cardiology consultation induction • Renal US Birth to Newborns • Discuss the possibilities of feeding problems (due to impaired oral • Ovarian failure: absent/incomplete puberty motor function • Hypertension • Genetics/Endocrine consultations

• Increased prevalence of immune disorders (celiac, thyroiditis, IBD) • Assess weight gain • Measure BP, check pulses; compare leg and arm systolic BP • Learning disabilities (coarct) Infancy • Perform ophthalmologic evaluation • Social vulnerability • Check ears; evaluate child’s hearing at 6 mos and 12 mos of age • Foot problems • Monitor developmental milestones Young Adulthood: (same as above plus) • Monitor growth (the age GH is initiated varies, but can be started as early as 2 to 3 years of age if height below the 5th • Long term estrogen replacement percentile or decreasing growth velocity)----Use Turner Syndrome-specific growth curves • Fertility problems • Check BP/pulses 1 to 5 years • Evaluate hearing, and check for OM, serous otitis every visit • Osteoporosis • Evaluate renal status as indicated • Test thyroid function every 1 to 2 years; in absence of clinical signs, • Sensorineural deafness can start around 4 yo • Aortic dilatation/dissection • Assess for developmental delays and learning difficulties • Hypertension

Management

• Monitor growth; in addition to GH, the endocrinologist may add oxandrolone • Check BP and pulses • Evaluate hearing, check for OM, serous otitis every visit 5 to 13 years • Evaluate dentition for malocclusion • Continue TFT’s at 1-2 year intervals • Check for scoliosis (lordosis, kyphosis) yearly • Monitor for school problems • Counsel regarding optimizing bone density (Vit D/Ca)

• Examine for pigmented nevi • Check BP and pulses • Evaluate hearing, check for OM, serous otitis • Lipid profile • Check for scoliosis, kyphosis, lordosis • Refer to cardiologist for complete evaluation • TFT’s every 1-2 years • Evaluate the adolescent for the development of secondary sex characteristics. Measure LH and FSH to assess gonadal function. Initiate Estrogen therapy when ready. 13 to 21 years • Referral to Pediatric Endocrinology for hormone replacement • Evaluate for lymphadema • Monitor school function and behavior • Discuss social adaptation; tend to be socially immature • Present information of reproductive options to bearing children (adoption, medically assisted reproduction) • If patient has sufficient ovarian function to ovulate, refer for genetic counseling; at risk for having a fetus with chromosome abnormalities and having

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Facts: • It is the most commonly inherited form of mental retardation

• Occurs in approximately 1 in 4,000 males and 1 in 8,000 (heterozygous) females

• Due to an abnormality in the FMR-1 gene; FMR-1 harbors an unstable CGG trinucleotide repeat

• Full , which cause Fragile X are the consequence of expansion of the repeats in a CGG number that exceeds 200

Clinical Features Clinical Features Physical Cognitive/Developmental Profile • Prominent forehead • Moderate to severe MR • Long, narrow face • Average IQ is 40 in a completely methylated full • In females with a full mutation, cognitive profile similar to males, but more variability (esp. IQ scores) • Prominent jaw • Language delay; may not speak until 2-3 yo • Large, protuberant ears • Abnormal speech (tachylalia and tacyphemia) • Palate frequently arched • Fine and gross motor delays • Dental crowding and malocclusion Behavior Profile • Strabismus, refractive errors, nystagmus, • ADHD (impulsivity/distractibility) ptosis • Anxiety • OCD-like behaviors • Macro-orchidism (>80% of adolescent and • Emotional lability adult males) • Features of autism (hand-flapping, biting, perseverative speech, poor eye contact, sensory • Connective tissue dysplasia; soft velvet-like defensiveness, lack of interest in social interaction) skin, joint hypermobility, scoliosis • Autism is present in 30% of people with a full mutation; Fragile X is found in 2-6% of people with autism • Mitral valve prolapse • Seizures Psychiatric Profile • Tall initially, then growth slows in adolescence; • Oppositional defiant disorder • OCD and 25% of adult men have a height ≤ 5% • Mood lability (aggressive and self-injurious behaviors)

16 Management

Health supervision • Monitor for feeding difficulties; assess for GER • Examine for orthopedic abnormalities (hip dysplasia, ) • Monitor head-growth velocity • Monitor growth and development; look for hypotonia Birth to 1 year • Refer for services like early intervention as needed

• Eye exam • Monitor for orthopedic problems related to connective tissue dysplasia • Check for inguinal hernias • Assess the child’s history for seizures or staring episodes; EEG if indicated • Monitor for OM’s; yearly audiology exams • Communication skills as well as other developmental 1 to 5 years milestones should be monitored closely; affected children require services for speech, motor and cognitive development • Monitor behavior, emotional, and psychological status; follow for signs of autism • OSA • Cardiac exam

Management Be Available…

• Monitor for macro-orchidism and measure testicular volume with an orchidometer; check for hernias (occurs in 15%) • Girls should be followed for • Offer support; offer resources (online/organizations) • Monitor developmental progress; make certain cognitive, speech and language, and motor needs are addressed 5 to 12 years • Monitor for ADHD; address problems with behavior modification and/or in combination with medication management • Discuss how to tell family members and friends • Monitor for obsessive-compulsive behaviors, anxiety, aggression, depression about the condition • Make sure support services at school are in place • Enuresis is common • Monitor for scoliosis • Review recurrence risk for subsequent pregnancies;

• Assess for seizures, esp. atypical seizures discuss options like prenatal and preimplantation • Monitor for cardiac murmur or click 13 to 21 years (same • Pursue behavioral/psychological intervention if indicated genetic diagnosis as above plus) • Discuss the availability and need for vocational training and group home placement if appropriate • Facilitate transition to adult medical care • Refer for formal genetic counseling to address these issues

17 Suggested Resources Thank You! • Genetics Home Reference . https://ghr.nlm.nih.gov/

• Gene Reviews . https://www.ncbi.nlm.nih.gov/books/NBK1116/

• Clinical practice guidelines from the American Academy of

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