Genetics - Williams and Marfan Syndrome

Question 1

Williams Syndrome (4)

Answer 1

1. Caused by a microdeletion of chromosome 7
2. Present at birth and affects boys and girls equally.
   * Usually doesn’t get picked up until later in childhood when you can tell there is developmental delay
3. As routine genetic amniocentesis does not typically detect chromosome microdeletions, children with WS usually come to the attention of pediatricians during infancy or childhood.
4. Increased awareness of the clinical features and establishment of a reliable diagnostic test have revealed WS to be one of the more commonly recognized genetic disorders in childhood.

Question 2

Williams Syndrome: Microdeletion of chromosome 7 (7)

Answer 2

1. equal among boys and girls
2. Dysmorphic facies
3. Cardiovascular disease: 80%– Supravalvar aortic stenosis
4. Mental retardation 75%
5. Idiopathic hypercalcemia
6. Cognitive disorder
7. Impaired visual-spatial cognition

Question 3

Williams Syndrome: Characteristic facies (8)

Answer 3

1. Small upturned nose
2. Long philtrum (upper lip length)
3. Wide mouth
4. Full lips
5. Small chin
6. Puffiness around the eyes.
7. Blue and green-eyed children with Williams syndrome can have a prominent “starburst” or white lacy pattern on their iris.
8. Facial features become more apparent with age.

Question 4

Characteristics of Patients With Williams Syndrome (11)

Answer 4

1. Ocular and visual—50% with strabismus
2. Auditory – 50% with SOM
   a. Hypersensitivity to sound; Mother will say that the child wakes up or cries very easily
3. Microdontia – 90%
4. Malocclusion-90%
5. Hypertension-85%
6. Kidney abnormality- 50%
7. Feeding difficulty-20%
8. Soft lax skin-70%
9. Joint hypermobility-90%
10. Hypercalcemia-20%
11. Early puberty-50%

Question 5

Children with WS (2)

Answer 5

1. Majority of children with WS have cardiovascular anomalies.
2. Most common cardiovascular defect is supravalvar aortic stenosis
   a. Requires repair of aortic valve
   b. Often progressive condition that may require surgical repair

Question 6

Williams Syndrome Signs and Symptoms (16)

Answer 6

1. Bitemporal narrowing
2. Epicanthal folds
3. Strabismus
4. Full cheeks
5. Short nose or anteversion of the nose
6. Prominent ear lobes
7. Broad brow
8. Periorbital fullness
9. Stellate lacy iris pattern Full nasal tip
10. Long philtrum
11. Small, widely spaced teeth
12. Wide mouth
13. Malar hypoplasia (flat cheeks bones)
14. Prominent lips
15. Malocclusion
16. Small jaw

Question 7

Williams Syndrome: Behavior and Neurodevelopmental Problems (6)

Answer 7

1. Older children
   a. Strength in language and auditory memory, with a significant weakness in visual-spatial cognition.
2. Behavioral problems
   a. Hypersensitivity to sound
   b. Sleep problems
   c. Attention-deficit/hyperactivity disorder
   d. Anxiety.
   e. Overfriendliness and an empathetic nature are commonly observed.

Question 8

Williams Syndrome and Hypercalcemia (5)

Answer 8

1. Idiopathic infantile hypercalcemia; Usually resolves during childhood
2. Causes extreme irritability, vomiting, constipation, and muscle cramps associated with this condition.
3. Symptomatic hypercalcemia usually resolves during childhood, but lifelong abnormalities of calcium and vitamin D metabolism may persist.
4. Hypercalciuria is common and predisposes to nephrocalcinosis.
5. Cause of the abnormality in calcium metabolism is unknown.

Question 9

Primary care management with Williams Syndrome (24)

Answer 9

1. Complete physical and neurological
2. Growth parameters on Williams syndrome growth chart
3. Cardiology evaluation
4. GU system evaluation
5. Calcium determination
6. Thyroid
7. Ophthalmologic evaluation
8. Multidiscipline developmental evaluation with EIP and special education placement
9. FISH to determine the ELN deletion; To look at chromosome 7
10. No multivitamins due to deleterious effects of vitamin D
11. Periodic cardiovascular evaluation
12. Screen for hypertension
13. Review feeding
14. Hearing assessment
15. Constipation screening
16. Anesthesia consult for surgery: associated with administration of anesthesia and death in these patient
17. Ultrasound of kidney
18. Dental care
19. Thyroid functions every four years
20. Serum creatinine every 4 years
21. Prinary calcium creatinine ratio every two years
22. Total calcium if asymptomatic every 2 years
23. Orthopedic evaluation
24. Ophthalmology care to evaluate for myopia

Question 10

Parental Counseling in Caring for Children with Williams Syndrome (9)

Answer 10

1. Multidisciplinary approach
2. Educational and vocational; Need extra time with fine motor skills such as writing + Money concepts can be a struggle (difficulties managing money)
   * Need high levels of supervision in job and home due to distractibility and social disinhibition
3. Minimize distraction
4. Manage sensitivity to sound
5. Use obsessive thinking positively
6. More anxiety but avoid allowing them to be carried away
7. May have underlying feelings of sadness and low self esteem need training
8. Social skills training
9. Music therapy may be helpful—Very musically inclined

Question 11

Marfan Syndrome Definition

Answer 11

Inherited disorder of connective tissue; affects the skeletal, cardiovascular, and ocular systems

• Very special connective tissue panel that you have to order; not pure microarray that you order but rather special connective tissue panel
• Tests for defect in fibrinogen gene with Marfan Syndrome

Question 12

Marfans Etiology/Incidence (3)

Answer 12

1. Autosomal dominant inheritance of defective fibrillin gene (FBN1 mapped to chromosome 15 [15q21.1])
2. 15% sporadic mutation
3. Incidence is 1:5000

Question 13

Marfans Criteria: Ghent Diagnostic (4)

Answer 13

Ghent diagnostic criteria for Marfan syndrome was revised and includes the any one of the following:

1. Aortic root ≥2 z score and ectopia lentis
2. Aortic root ≥2 z score and FBN1 mutation
3. Aortic root ≥2 z score and systemic score ≥7
4. Ectopia lentis and FBN1 mutation known to be associated with

Question 14

Marfans Criteria: Family History + (3)

Answer 14

1. Positive family history of Marfan syndrome and ectopia lentis
2. Positive family history of Marfan syndrome and systemic score ≥7
3. Positive family history of Marfan syndrome and aortic root ≥3 z score in those <20 y of age or ≥2z score in an adult (>20 years of age).

Question 15

Marfans Criteria: Systemic Scores (12)

Answer 15

1. Wrist and thumb sign (3)
2. Wrist or thumb sign (1); If you can wrap your fingers around and overlap with your thumb
3. pectus carinatum (2)
4. pectus excavatum or chest asymmetry (1)
5. hindfoot deformity (eg, valgus) (2)
6. pes planus (1)
7. pneumothorax (2)
8. dural ectasia (2)
9. Protrusio acetabulae (2)
10. Reduced upper-to-lower segment ratio and increased arm-span-to-height ratio (1)
11. Scoliosis or thoracolumbar kyphosis (1)
12. Reduced elbow extension (1)

Question 16

Marfans Criteria: Craniofacial Features (6)

Answer 16

3 of the following craniofacial features

1. Dolichocephaly,
2. Downward-slanting palpebral fissures
3. Enophthalmos, retrognathia, and malar hypoplasia (1)
4. Skin striae (1)
5. Myopia (1)
6. Mitral valve prolapse (1) 1)(Tinkle, Saal, and the Committee and Genetics 2013)

Question 17

Marfan Ocular System (4)

Answer 17

Major criterion
1. Ectopia lentis

Minor criterion

2. Abnormal flat cornea
3. Increased axial length of globe
4. Hypoplastic iris causing decreased miosis

Question 18

Marfan Syndrome: US to LS ratio (7)

Answer 18

1. Upper segment head to symphysis pubis to lower segment (type 2)
2. US to LS in infants is 1.7 to 1.8 to 1
3. As child approaches adolescent .9 to l.0:1
4. Upper: lower segment ratio is low in Marfan syndrome
5. Abnormal in bony dysplasia
6. After spinal irradiation
7. Long arms and legs
   * Entire arm span could be greater than total length of body

Question 19

Natural History of Marfan Syndrome (5)

Answer 19

1. Patients with aortic root dilation >2 standard deviations (SDs) above the mean should be treated with atenolol and followed with a yearly echocardiogram.
2. Significant aortic root dilation requires surgical repair.
3. With corrective surgery, mean age of survival approaches normal life span
4. Significantly lower in patients with untreated vascular complications
5. Intellectually normal but higher rate of ADHD

Question 20

Marfan Syndrome Diagnostic Evaluation (6)

Answer 20

1. Genetic testing to evaluate for the defects in FBN1
2. Positive family history of Marfan syndrome
3. Cardiac evaluation
4. Ocular evaluation—slit-lamp examination for ectopic lentis
5. Skeletal evaluation—scoliosis screening; trunk/extremities ratio
   a. Higher rates of scoliosis
6. Differential: Urine screening for amino acids at birth to evaluate for homocystinuria
   a. Homoecystine will be high in Marfans

Question 21

Marfans Differential Dx (8)

Answer 21

1. Mitral valve prolapse syndrome
2. Loeys-Dietz syndrome
   a. Dislocated lenses
3. Homocystinuria
4. Vascular type of Ehlers-Danlos syndrome
5. Stickler syndrome
   a. Associated with cleft palate
6. Fragile X
7. Familial thoracic aortic aneurysm
8. Congenital contractual arachnodactyly
   a. Longer tapering fingers with contractures; can’t completely extend them

Question 22

Management of Patient with Marfan Syndrome (10)

Answer 22

1. Refer to cardiology for periodic echocardiogram to detect dissecting aortic aneurysm, mitral valve prolapse
2. Surgical graft repair of the ascending aorta and aortic valve has been successful
3. Propranolol to reduce effect of ventricular ejection on ascending aorta
4. Refer to ophthalmology for treatment of myopia, lens subluxation, cataracts, glaucoma, and retinal detachment
5. Refer to endocrinology for hormonal treatment to curtail height– valuable psychological effect;
6. Management of scoliosis and kyphosis; prevention of secondary problems of feet
7. Psychosocial support for patient and family and genetic counseling
8. Ensure mainstream or inclusive school placement with any necessary supports, physical activity limitations if cardiovascular involvement
9. Avoidance of wind instruments, sky diving, scuba diving, mountaineering in patients with emphysematous lung disease - Symptoms of pneumothorax
10. Sleep apnea due to palatal problems