Genetics - Fragile X and Turner Syndrome

Question 1

Fragile X Overview (6)

Answer 1

1. Mutation is common but the phenotype is subtle, especially early in life; Fragile X syndrome is associated with a range of intellectual impairments from learning problems to autism and anxiety.
2. The possibility of its presence can be considered in any child with mental retardation, developmental delay, or solely a learning disability or other behavioral problem, including even autism.
3. Affected children do not look strikingly abnormal.
4. Fragile X passed on from mother; X Chromosome dictates
5. BIG EARS, LONG NARROW FACE, anxiety, hypermobility
6. The disorder is linked to a fragile site on the long arm of the X chromosome at band q27.2
7. Affected individuals—1:4000 males; 1:8000 females

Question 2

Etiology/Incidence of Fragile X (6)

Answer 2

1. The amount of repeats of the CGG in a normal individual ranges from 5- 40, but 30 repeats is the most common.
2. Leads to gene silencing which in turn causes decreased or absent levels of fragile X mental retardation protein (FMRP).
3. Full mutation range occurs when there are greater than 200 CGG repeats in the coding of the protein or by a point mutation or deletion in the fragile X mental retardation gene.
4. Premutation occurs when the CGG repeat number is between 55 to 100 are unstable meiotically and produce FMRP that may be in lower amounts than normal.
5. The severity of cognitive impairment depends on the degree of the FMR1 methylation and gene silencing rather than the number of CGG repeats.
6. Different FMRP levels will have different clinical presentation since the methylation may differ

Question 3

Genetics of Fragile X (4)

Answer 3

1. Males are more severely affected than females since they only have one X chromosome
2. If a male has a methylated full mutation, they will have mild to moderate intellectual disability
3. Females with the full mutation typically have learning disabilities, but about 15% have intellectual disabilities
4. If the individual has premutation, they can have mild cognitive and/or behavioral deficits, primary ovarian insufficiency, and in older adult permutation carriers, especially males a fragile X-associated tremor /ataxia syndrome (FXTAS).

Question 4

Males and Females with Permutation (7)

Answer 4

A small number of female carrier of a permutation:

1. Some of the physical features of fragile X— Prominent ears or hypermobile finger joints
2. Emotional problems including anxiety, depression, obsessional thoughts, or schizotypy.

Males with a permutation have problems with

3. Executive functions
4. Social deficits
5. Attention problems
6. Obsessive-compulsive behavior.
7. Children with developmental delay, mental retardation or autism spectrum should undergo molecular testing for fragile X

Question 5

Fragile X Signs and Symptoms: Eyes (2)

Answer 5

1. Strabismus with refractive errors may be present.

2. Occasionally nystagmus and ptosis are found.

Question 6

Fragile X Signs and Symptoms: Face (3)

Answer 6

1. Long, narrow face
2. prominent jaw, with high arched palate
3. dental crowding and malocclusion

Question 7

Fragile X Signs and Symptoms: ENT, GI, GU (3)

Answer 7

1. ENT: protuberant ears by late childhood, chronic otitis media
2. GI: Gastroesophageal reflux
3. GU: Macro-orchidism occurs in more than 80% of adolescents and is less common in childhood.

Question 8

Fragile X Signs and Symptoms: Skin and Joints (3)

Answer 8

1. soft velvet skin
2. Joint hypermobility
   * Skin is hypermobile and there is joint hypermobility
   * The joint hypermobility becomes a major factor; MUST DO ROM with these children
3. Pes planus
4. Scoliosis
5. Clubfoot

Question 9

Fragile X Signs and Symptoms: Neuro and Musculoskeletal (6)

Answer 9

1. Seizures occur in 13% to 18% of affects males
2. 5% of females with the full mutation have seizures
3. Macrocephaly
4. Speech delay and echolalia
5. Perseverative speech
6. Poor gross motor coordination

Question 10

Fragile X Signs and Symptoms: behavior

Answer 10

1. Poor eye contact with excessive shyness and anxiety with hand flapping and biting
2. Tactile defensives
3. Attentional deficit with hyperactivity, hyperarousal to sensory stimuli, and ASD
   * A lot of ADHD in these families

Question 11

Fragile X Physical Exam Findings (9)

Answer 11

1. Macrocephaly
2. Prominent forehead with long thin face and prominent jaw, especially in adolescence
3. Macroorchidism in adolescent males; may be seen as early as age 5
4. Protuberant, large ears, long or wide
5. Soft, smooth skin
6. Heart murmur or apical midsystolic click
   * Mitral valve prolapse can lead to regurgitation
7. Serous otitis media
   * Ear fluid (like child with DS); must send to ENT for tubes otherwise they will get conductive hearing loss and hearing issues (same with DS)
8. Strabismus—40%
9. Joint laxity (especially fingers), hip subluxation, occasionally clubfoot

Question 12

Dif Dx of Fragile X (5)

Answer 12

1. Autism Spectrum Disorder
2. Mental retardation with nonspecificetiology
3. Klinefelter syndrome
4. Sotos (Cerebral Gigantism syndrome)
   * Very large heads and developmental delays; speech delays, unable to read, etc.
5. Attention deficit hyperactivity disorder

Question 13

Health Supervision of Children With Fragile X (7)

Answer 13

1. Strabismus check between 6 to 12 months
2. Mitral Valve prolapse check
   i. Need echo if click present
   ii. Antibiotic prophylaxis if mitral regurgitation
3. Review Personal support
4. Review family history and recommend genetic counseling; Psychosocial support to parents, child and family
5. Monitor for recurrent serous otitis
6. Treatment of the behavioral problems with the appropriate psychotropic medication and counseling
7. Genetic counseling—no spontaneous mutations have been found for fragile X syndrome; all family members should undergo genetic testing to identify transmitting males, carrier females, and affected individuals

Question 14

Primary Care of the Child with Fragile X (8)

Answer 14

1. Regular well-child examination with attention to:
2. Cardiac auscultation—if click or murmur heard, obtain echocardiogram, consider referral to cardiologist for possible mitral valve prolapse
   * Cardiology exam if you hear a click
   * If they need mitral valve replacement then first 6 months they need antibiotics
3. Otoscopic evaluation—serous otitis media
4. Ophthalmologic evaluation—strabismus (40%), myopia
   * Must see eye doctor because they have strabismus
5. Developmental evaluation—mild to severe delay
6. Anticipatory guidance
7. Enroll in Early Intervention; speech/language therapy and sensory/motor integration
   * Must have good IEP; always ask parents to bring them in
8. Ensure appropriate educational placement with necessary supports

Question 15

Turner Syndrome Overview (4)

Answer 15

1. Chromosomal anomaly as a result of multiple karyotypes including 45, X, 45,X/46XX mosaicism and a structurally abnormal X leading to developmental, cardiac, reproductive, genetic, and psychosocial issues.
   * Mosaicism is high in Turner Syndrome
   * A lot of genotypic to phenotypic variation
   * Generally the most severe types will be pure 45X monosomies
2. To make the diagnosis, the female must have the characteristic features of TS with the complete and partial absence of the second X sex chromosome with or without mosaicism of the cell line.
3. If the patient does not have the clinical features of TS but does have the 45,X cell populations, they do not have TS.
4. Typically the 45, X monosomy present with the most severe phenotype

Question 16

Etiology/Incidence of Turner Syndrome (2)

Answer 16

1. Nondisjunction during meiotic division, usually maternal; more than half have a mosaic chromosomal complement (45, XO/46/XX)
2. TS is present in one of 2500 live- born females; many affected embryos do not survive to term

Question 17

Signs and Symptoms of Turner Syndrome (12)

Answer 17

1. Female with unexplained growth failure or pubertal delay

Constellation of any of the following findings:

2. Edema of the hands or feet (particularlyinnewborn)
3. Nuchal folds (webbedneck)
4. Left sided cardiac anomalies, especially coarctation of aorta or hypoplastic left heart
5. Low hairline and high-archedpalate
6. Low set ears with small mandible; chronic otitis media
7. Short statures with growth velocity less than the 10th percentile for age
8. Markedly elevated FSH, Cubitus valgus, Nail hypoplasia
9. Multiple pigmented nevi ***
   * Unique to TS: multiple pigmented nevi
10. Short fourth metacarpal
11. Intrauterine growth restriction
12. Lack of development of secondary sexual characteristics

Question 18

Turner Syndrome Physical Exam (11)

Answer 18

1. Check BP and peripheral pulses
   a. Look for cardiac or renal causes if elevated
   b. BP in coarctation will be lower in legs than in arms
2. Check for serous otitis media and otitis media every visit
3. Hearing loss is more common in Turner’s syndrome may be sensorineural or conductive
4. If dysmorphic, consider plastic surgery for neck, face or ears
5. Obesity is a problem in Turner syndrome
6. Glucose intolerance occurs more frequently in persons with Turner syndrome
7. Short female with broad chest Wide-spaced nipples
8. Webbed neck
9. Congenital lymphedema that can persist
10. Associated findings:
    a. Gonadal dysgenesis (90%),
    b. Renal anomalies (60%)
    c. Cardiac defects (20%)
    d. Most commonly coarctation of the aorta
    e. Hearing loss (50%).
11. Natural history: Infertility, normal lifespan, mean IQ 90, short stature.
    a. No intellectual deficits

Question 19

Incidence of clinical findings in TS (6)

Answer 19

1. Short stature >100%
   a. Consider karyotype in child with short stature if parents aren’t short
2. Gonadal dysgenesis >90%
3. Edema of hand and feet >80%
4. Broad chest >80%
5. Wide spaced inverted nipple >80%
6. Narrow maxilla including palate/micrognathia >80%

Question 20

Clinical Abnormalities in Child With Turner Syndrome: Cardiac (6)

Answer 20

1. Bicuspid aortic valve
2. Coarctation of aorta
3. Aortic valve stenosis
4. Hypoplastic Left heart
5. MVP
6. Dissecting aortic aneurysm (rare)

Question 21

Clinical Abnormalities in Child With Turner Syndrome: Kidney (4)

Answer 21

a. Horseshoe kidney
b. Duplicated renal pelvis
c. Ectopic or malrotated kidney
d. Vascular kidney

Question 22

Primary Care Management of Turner Syndrome: Genetic and Renal (2)

Answer 22

Genetic Testing
1. Cytogenetic testing for Karyotype 45 XO

Renal ultrasound to detect renal anomalies
2. Renal anomalies, which are found in 30% to 50% of females with a horseshoe kidney being the most common

Question 23

Primary Care Management of Turner Syndrome: Hearing and Endocrine (6)

Answer 23

Evaluation for hearing loss. As adult risk of sensorineural loss is 60%

Endocrine and GYN

1. Annually from age 4 onward, T4, TSH due to high rate of autoimmune thyroid disease
2. Abdominal and pelvic ultrasound - gonadal dysgenesis
3. Plasma gonadotropin studies to detect low levels of normal female hormones
4. To increase adult height, growth hormone therapy
5. Hormone (estrogen) replacement therapy beginning about 12-13 years of age (Bondy)

Question 24

Primary Care Management of Turner Syndrome: Sleep, psychosocial, cardiac (4)

Answer 24

1. Risk of sleep apnea is up to 50% *** significant

Psychosocial support

2. Assistance in school if there are learning disabilities; intelligence in normal
3. Support Groups
4. Referral to cardiology for cardiac anomaly diagnosis and treatment
   a. Cardiac echocardiogram or MRI for:
   i. Coarctation of aorta (20%)
   ii. Bicuspid aortic valve (50%)

Question 25

Primary Care Management of Turner Syndrome: Optho, ENT, dental (3)

Answer 25

1. Referral to ophthalmology– Strabismus and hyperopia (farsightedness) each occur in 25–35% of these children (Bondy)
2. Referral to ENT if recurrent otitis – Abnormal relationship between the between the Eustachian tube and middle ear since the cranial base is different.
3. Dental – Referral to orthodontist due to narrowed maxilla and wide, micrognathic mandible as well as pediatric dentist

Question 26

Primary Care Management of Turner Syndrome: Ortho and gastro (2)

Answer 26

1. Orthopedics: Referral to orthopedics if scoliosis

2. Gastroenterology: Screen for celiac disease, which runs from 4-6% in patients with Turner syndrome

Question 27

Education needs for children with TS: 0-4 years old (2)

Answer 27

1. Evaluation for hip dislocation

2. Eye exam by pediatric ophthalmologist (if age ≥ 1)

Question 28

Education needs for children with TS: 4-10 years old (2)

Answer 28

1. Thyroid function tests (T4, TSH) and celiac screen (TTG Ab) Educational/ psychosocial evaluations
2. Orthodontic evaluation (if age ≥ 7)

Question 29

Education needs for children with TS: 10 and older (3)

Answer 29

1. Thyroid function tests (T4, TSH) and celiac screen (TTG Ab)
2. Educational and psychosocial evaluations Orthodontic evaluation
3. Evaluation of ovarian function/estrogen replacement LFTs, FBG, lipids, CBC, Cr, BUN BMD (if age ≥ 18 yr.)