Genetics Flashcards
1
Q
What is the inheritance pattern of Achondroplasia?
A
- Usually a spontaneous mutation (75%)
* If inherited, AD, completely penetrant inheritance pattern
2
Q
Features of Achondroplasia
A
• Disproportionate short stature (mean height 49-51 inches)
• Rhizomelic shortening, “trident” fingers
• Macrocephaly, frontal bossing, depressed nasal bridge, malar hypoplasia
○ 5% may have symptomatic hydrocephalus
• Fatal apnea (~10%) especially before age 2yrs
○ Misshaped and small foramen magnum
○ Vascular and cervicomedullary constriction
○ Restrictive pulmonary disease
○ OSA is very common
• Middle ear dysfunction – CHL
• Kyphosis
• Spinal stenosis is uniformly present
• Knee instability in toddlers, varus deformity (bowlegs)
• Orthodontic problems (crowding and overbite)
• Cognitive development and function is typically normal
○ ~10% with severe learning disabilities, ID or ASD
• Hypotonia, disproportionate limbs and joint hypermobility
3
Q
Developmental and anticipatory guidance for children with Achondroplasia
A
- Screening for hearing loss (hearing test annually) and language development
- Neurological history and physical with each visit, with consideration for CT/MRI
- Guidance around safe sleep habits and risk of SIDS
- Screening for OSA
- Gross motor and fine motor development
- Review weight gain and weight control
- Accessibility for the child’s needs (OT and device requirements)
- Psychosocial well being
- Avoidance of gymnastics or collision sports
4
Q
What oncogenic concerns are present for children with Beckwidth-Wiedemann?
A
Embryonal tumours
• Hepatoblastoma
• Wilm’s tumour
- Rhabdomyosarcoma
- Neuroblastoma
- Adrenocortical carcinoma
5
Q
What is the genetic basis for Beckwidth-Wiedemann?
A
Imprinting disorder on 11p15.5 (maternal copy is not expressed)
6
Q
Diagnostic Criteria for Beckwidth Wiedemann
A
3 major OR 2 major and 1 minor criteria OR proven genetic methylation error at 11p15.5 or heterozygous CDKN1C mutation and 1+ clinical finding
• Major features/findings: Macrosomia (Wt & Lt >97th), macroglossia, hemihyperplasia, omphalocele, embryonal tumour, visceromegaly, ear AbN (anterior linear crease, posterior helical pits), cleft palate (rare), cardiomyopathy (rare), FamHx+ (1+ family member)
• Minor features/findings:
Polyhydramnios/prematurity, neonatal hypoglycemia, vascular lesions (nevus simplex, hemangiomas), characteristic facies (midface retrusion, infraorbital crease), cardiomegaly/structural cardiac AbN, diastasis recti, advanced bone age
7
Q
What are anticipatory guidelines for Beckwidth-Wiedemann patients?
A
- Alphafetoprotein done every 3 months until age 4
* Abdominal ultrasound done every 3 months until age 8
8
Q
What is CHARGE Syndrome?
A
- Coloboma/Cranial nerve dysfunction (1, 7, 8, 9, 10)
- Heart defects
- Atresia of choanae
- Retardation of growth
- Genitourinary defects
- Ear defects
9
Q
What behavioural associations are seen with CHARGE syndrome?
A
- Obsessive compulsive disorder
- Attention deficit hyperactivity disorder
- Autism
- May see aggression and have self-abusive behaviors
10
Q
What is the recurrence risk of cleft palate?
A
- If inherited with a disorder, likely AD inheritance pattern
- 2-6% chance in unaffected parents after a single affected child
11
Q
What environmental risk factors are associated with cleft lip/palate?
A
- medications → phenytoin, valproate, topiramate, MTX (folic acid antagonist)
- cigarette smoking
- alcohol
- folate deficiency
12
Q
When is cleft lip/palate usually repaired?
A
- 3 months for lip repair (facilitates feeding)
* <12 months for palate (to help with speech and development)
13
Q
What long-term complications need to be considered for cleft lip/palate?
A
- hypernasal speech
- malposition of teeth
- recurrent otitis media and subsequent hearing loss
14
Q
Diagnostic Criteria for Marfan Syndrome
A
• In the absence of family history:
- Aortic Z-score ≥2 AND ectopia lentis
- Aortic Z-score ≥2 AND FBN-1 mutation associated with aortic aneurysm
- Aortic Z-score ≥ 2 AND systemic score ≥7 pts
- Ectopia lentis AND FBN-1 mutation associated with AA
• In the presence of family history:
- ectopia lentis AND fmhx of first degree relative
- systemic score ≥ 7 pts and fmhx of first degree relative
- Aortic Z-score ≥ 2 and fmhx of first degree relative
15
Q
What is the most common cardiac abnormality in Marfan Syndrome?
A
- Dilated ascending aorta
* MVP is 2nd most common
16
Q
How to differentiate between Marfan Syndrome and Homocystinuria?
A
- AD inheritance vs. AR (homocysteinuria)
- both have lens dislocations (ectopia lentis) but it is supratemporal in MS and “down and in” in homocystinuria
- joints are hypermobile in MS and rigid in homocystinuria
- Vasodilatory disease in MS and vaso-occlusive disease in homocystinuria
- There is no ID in Marfan Syndrome but may be profound in homocystinuria
17
Q
Clinical features of Marfan Syndrome
A
- Joint hypermobility
- Dolichocephaly, retrognathia, micrognathia
- Ectopia lentis
- Striae
- Long, thin and tall body habitus
- Anterior chest deformities (pectus excavatum or carinatum)
- Abnormal curvatures of the spine (most common thoracolumbar scoliosis)
- Thumb-sign, wrist sign
18
Q
Diagnostic criteria for Ehler’s Danlos
A
4 major features • Family history • Hyperextensible joints with frequent dislocations • Widened atrophic scars • Hyperextensible skin
19
Q
Genetic inheritance pattern for Ehler’s Danlos
A
- AD inheritance, but 50% de novo
- Genetic basis - COL5A1 (46%) or COL5A2 (4%)
- Skin biopsy - electron microscopy (suggestive, altered fibrillogenesis) or protein analysis by electrophoresis (type collagen) - not perfect
20
Q
Management of Ehler’s Danlos patients
A
• Non weight-bearing activity (for muscle strength & coordination) - e.g. swimming!
○ Avoid contact, fighting, running, football
• +/- NSAIDs, Deep stitches to allow healing, tape cuts to minimize stretch
○ Avoid ASA
• +/- Physiotherapy for motor delays
• Management of chronic pain & MH issues
• If MVP/Ao Dilation –> annual echo
21
Q
Genetic inheritance of Cornelia de Lange
A
Autosomal dominant inheritance pattern but 99% of cases are de novo
• Nipped B-like gene mutation
• chance of recurrence in a sibling 2-5%
22
Q
Clinical features of Cornelia de Lange
A
- Short stature
- Hypertonic
- Microcephaly, brachycephaly (flat posterior head), long philtrum, micrognathia, low set ears, SNHL, CHL due to AOM, synophrys, myopia, long curly lashes, ptosis, anteverted nostrils, depressed nasal bridge
- High arched palate, cleft palate/lip, widely spaced, late erupting teeth
- CVS - septal defects
- GI - GERD, pyloric stenosis , GI dysfunction
- GU - hypoplastic male genitalia, undescended testes
- Single palmar crease, 5th clinodactyly, oligodactyly (missing digits), syndactyly of 2nd and 3rd toes
- Skin - cutis marmorata, hirsutism, low posterior hairline
- Mental retardation - IQ 50
23
Q
What is the most common inherited cause of proximal RTA?
A
Cystinosis!
Genetic defect in cystinosin (cystine-transporting protein) that also leads to dysregulation of vesicle trafficking, lysosomal biogenesis, mTOR signaling, and autophagy
Cystine accumulation → enhanced cell death via apoptosis, mitochondrial dysfunction, oxidative stress, and inflammation
24
Q
Clinical features of cystinosis
A
- Proximal tubular acidosis
- Systemic metabolic disorder
- Accumulation of cystine crystals in the cornea (the eye is the first apparently affected organ next to the kidneys)
- Skeletal deformities (e.g., genua valga, scoliosis, stress fractures)
- Functional disabilities (e.g., bone pain, walking impairment) later in life
- Severe early-onset hypophosphatemic rickets
- Hypothyroidism
- Cysteamine toxicity with copper deficiency
- Cystine crystal laden macrophages are known to be present in the bone marrow
- Premature skin ageing with the subcutaneous infiltration of a palpable amorphous material, thinning of the epidermis, and presence of teleangiectasia, and dome-shaped, skin-colored papules over the nose, and chin
- High incidence of a Chiari 1 malformation or cerebellar tonsillar ectopy
25
Treatment/Management for cystinosis
• Nutritional support - prevention of rickets and improvement of growth, free access to water, Na, K, HCO3, phosphate, vitamin D, Cu, carnitine
• Hormonal replacement therapy
○ Growth hormone
○ Levothyroxine for hypothyroidism
○ Insulin
• ACE-i for proteinuria
• Cystine-depleting therapy
○ Cysteamine must be given every 6 hours, does not prevent Fanconi's or corneal crystals
○ Procysbi (q12 hours but difficult to take re: timing and eating restrictions)
• Renal replacement therapy in ESRD
• After kidney transplantation, cysteamine should be administered as soon as possible as it does not interfere with the reabsorption of immunosuppressive agents
• Corneal cystine crystal deposition - treated with cysteamine hydrochloride topical aqueous solutions (eye drops)
26
What are the clinical features of DiGeorge Syndrome?
* C - cardiac abnormalities - tetrology of fallot, critical pulmonary stenosis, conotruncal defects
* A - abnormal facies (hyperthelorism, low set ears, long tubular nose with hypoplastic alae, shortened philtrum)
* T - thymus hypoplasia
* C - cleft lip/palate
* H - hypocalcemia
* 22 - 22q11.2 deletion
27
What should be done in the immediate management of DiGeorge Syndrome patients?
* Echocardiogram
* CXR (for thymus)
* serum calcium, phosphate, TSH, free T4, PTH
* swallowing and nutritional assessment
* no live vaccines until immune system can be formally assessed
* Genetic testing via FISH specific for 22q11.2
28
Genetic inheritance for Duchenne's Muscular Dystrophy?
* Abnormal gene at the Xp21 locus
| * X-linked (though some women may be affected via Lyon hypothesis)
29
Classic features of Duchenne's Muscular Dystrophy?
* Gower's sign
* Proximal muscle weakness
* Calf muscle hypertrophy
* Delayed gross motor skills
* High CK
* Respiratory weakness and recurrent infections
* If advanced/progressive - chronic CO2 retention
* Intellectual disability
* Cardiomyopathy
* Scoliosis
30
Diagnostic test for Duchenne's Muscular Dystrophy?
• Primary test: PCR for dystrophin gene mutation
- If positive, may defer muscle biopsy
- If negative, definitive test is muscle biopsy
31
A child with Duchenne's Muscular Dystrophy requires elective surgery. What must be done pre-op?
This child is at risk of malignant hyperthermia. The surgical and anesthesia team must be alerted and preparations made regarding induction drugs (i.e. avoidance of succinylcholine and inhalational anesthetics) and availability of Dantrolene
32
What is the inheritance pattern of Hyperhidrotic ectodermal dysplasia?
Generally X-linked recessive, but AD and AR forms also exist
33
Clinical features of Ectodermal dysplasia?
* Complete or partial absence of eccrine/sweat glands
* Malformed, dagger-like teeth
* Dry, thin, hypopigmented skin
* Saddle-nose (depressed nasal bridge)
* Friable or absent hair
34
Clinical manifestations for Fetal Alcohol Syndrome (3)
1) abnormal facial features
- smooth, long philtrum
- short palpebral fissures
- thin lip vermillion
2) CNS dysfunction i.e. intellectual disability, agenesis of corpus callosum, holoprosencephaly
3) pre-/post-natal growth deficiency (<10th %ile)
35
What is the most common form of inherited mental retardation?
Fragile X Syndrome
36
What is the molecular basis behind Fragile X?
Trinucleotide repeat expansion (CGG) in the FMR1 gene (Fragile site Mental Retardation gene). X-linked dominant
- normal 5-44 CGG repeats
- intermediate “grey zone” 45-54 CGG repeats
- pre-mutation carrier 55-200 CGG repeats
- full mutation > 200 CGG repeats
98% of cases caused by expanded trinucleotide repeat
- Incomplete penetrance
- 50% of females have learning disability or mild MR
- But 100% penetrance of full FXS in males
37
Clinical features of Fragile X syndrome
* Intellectual disability, Autistic features (20-30%), ADHD, Anxiety
* Tall, slim body habitus with joint laxity/hyperextensibilty
* Club foot
* DDH
* Coarse facies, long & narrow face, large prominent cupped ears, prominent jaw, dental crowding, high-arched palate
* Macro-orchidism
* MVP (50%)
* Pectus excavatum
* Strabismus and visual disturbances
* Feeding difficulties
* Enuresis
38
Are children with premutation repeats symptomatic?
Yes!
• Female reproductive Sx:
- Premature ovarian failure (POF <40yo)
- Early menopause (<45yo): 30% of females
• FXTAS (Fragile X associated Tremor-Ataxia Syndrome), seen >50yo
• Neurodevelopmental disorder: ADHD, autism, dev delay & mild features FXS (appearance)
39
What are the indications for Fragile X testing?
* any child with developmental delay, borderline IQ, ID
* any child with autism without a specific etiology
* consider if suspected Sotos syndrome, PWS
* family history of primary ovarian insufficiency, FXTAS, learning problems/MR
* siblings of a child with fragile X (BOTH male and female if any symptoms at all)
NOT indicated for isolated ADHD
40
What is the number 1 cause of hypogonadism and infertility in males?
Klinefelter Syndrome (XXY)
41
Genetic inheritance pattern for Klinefelter Syndrome
* 50% caused by paternal nondysjunction in meiosis I
* otherwise sporadic
* Recurrence risk <1%
42
Clinical features of Klinefelter Syndrome
* Tall, long torso, long limbed
* Hypogonadism, hypospadias
* Feminine appearance to chest (gynecomastia) and hips
* Sparse body hair and facial hair
* Lower muscle mass
* Decreased bone mineral density
* Impaired cognition with expressive language delay
* Anxiety, withdrawn, shy
43
What long-term health concerns are there for Klinefelter Syndrome?
• Fertility
○ infertility, azoospermia
○ mosaics 46XY/47XXY males occasionally fertile • Hypercoagulable state
○ DVT and PE risk in adults
• Malignancy risk
○ male breast cancer 20x higher over XY men
○ Higher risk of: ALL, HL, NHL, hCG secereting tumours (germ cell)
• Decreased energy, endurance, poor coordination
• Autoimmune disorders – SLE, RA, thyroid, type 2 diabetes
44
Is McCune Albright a cause of central or peripheral precocious puberty?
Peripheral
Somatic gene mutation, thus has variable expression
45
Clinical features of McCune Albright
1) Precocious puberty with potential for other endocrine disorders (GH, LH, FSH, TSH, ACTH)
2) Skeletal dysplasia
3) Cafe au lait macules
46
What chromosomal disorders predispose children to cancer?
* Trisomy 21
* Klinefelters Syndrome
* Noonan Syndrome
* Trisomy 8
* Monosomy 5 or 7
47
What conditions of genetic fragility predispose children to cancer?
* Ataxia-telangiectasia
* Bloom syndrome
* Fanconi anemia
* Xeroderma pigmentosa
* Rothmund-Thompson syndrome
* Werner syndrome (premature aging)
* Dysplastic nevus syndrome
48
What immunodeficiency syndromes predispose children to cancer?
* Wiskott-Aldrich
* SCID
* X-linked agammaglobulinemia
49
When should a sacral dimple be investigated for myelomeningocele?
* When located >2.5 cm cephalad from anal verge
* When the gluteal crease has branching/bifurcation
* When there are abnormal cutaneous markings i.e. abnormal hair growth or tufting, skin tags, hemangiomas, SC mass or lumps, abnormal pigmentation
* When it is larger than 0.5 cm in size
50
How much folic acid should a pregnant woman be advised to take during her pregnancy?
Low risk: 0.4-1.0 mg/day
| High risk: 5.0 mg/day
51
What makes a woman high risk for developing a neural tube defect?
* Personal hx/fmhx of neural tube defect i.e. spina bifida
* Previous child with NTD
* Diet poor in folate rich foods
* Medications such as antiepileptics like Phenytoin
* Insulin-dependent diabetes
Advise to take at least 3 months prior to conception and continuing 10-12 weeks postconception. Would also recommend taking through pregnancy and into a minimum of 4-6 wks into breastfeeding
52
What is the risk of recurrence for birthing a child with a neural tube defect?
• Risk of recurrence after 1 affected child is 3-4%
○ Canadian numbers: recurrence risk for women who have had a pregnancy which resulted in an infant with a NTD is 2% to 5% in high risk populations
• Increases to 10% with 2 prior affected children
53
Diagnostic Criteria for Neurofibromatosis Type 1
At least 2 features from "CAFE SPOT"
• Clinical rather than genetic diagnosis
* Cafe au lait macules (≥6 over 5 mm if prepubertal and over 15 mm if post-pubertal)
* Axillary freckling
* ≥2 neuro-F-ibromas or one plexiform neurofibroma
* Eye hamartomas (≥2 lisch nodules)
* Skeletal abnormalities (sphenoid dysplasia, tibial pseudarthrosis)
* Positive family history of first degree relative
* Optic glioma "Tumour"
54
Inheritance pattern for NF1?
Autosomal Dominant
55
Surveillance guidelines for NF1
* Initial ophthalmological exam at diagnosis followed by yearly exams
* Dermatological exam
* Developmental exam
* MRI if symptomatic i.e. seizures
56
Clinical features of Noonan Syndrome
```
• "Noonan facies"
○ High forehead, low posterior hairline
○ Eyes: Hypertelorism, epicanthal folds, ptosis, blue-green irises, down-slanting palpebral fissures, myopia, nystagmus
○ Nose: low nasal bridge, upturned nose,
○ Short webbed neck
○ Low-set ears
○ Mouth: dental malocculusion
• Short stature
• Shield chest
• Pectus carinatum
• Scoliosis
• Hypertrophic cardiomyopathy, ASD, VSD
• Lymphadema
• Cryptorchidism, small penis
• Delayed puberty
• Failure to thrive
• Multiple skeletal and hematologic abnormalities
• Nevi, lentigines, café-au-lait spots
```
57
What other syndromes are associated with Noonan Syndrome?
* NF1
* LEOPARD syndrome: lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, deafness
58
What is PHACES?
* P - posterior fossa abnormalities i.e. Dandy-Walker variants
* H - hemangioma (large, segmental)
* A - arterial abnormalties (risk of strokes
* C - cardiac defects i.e. coarctation, aortic arch anomalies, VSD
* E - eyes i.e. coloboma, microphthalmos, optic nerve atrophy, glaucoma
* S - sternal defects i.e. clefting, supraumbilical raphe
59
What is the genetic phenomenon involved in Angelman Syndrome and Prader Willi Syndrome? How do you distinguish between the two?
Uniparental disomy - process in which a gene region on either the maternally or paternally contributed chromosome is silenced, resulting in expression by only one parent
Angel-M-an - mom's genes are silent, paternal uniparental disomy
P-rader Willi - papa's genes are silent, maternal uniparental disomy
60
Clinical presentation of Prader Willi?
```
• Infantile
○ Almond shaped eyes
○ Hypotonia with poor feeding
○ Hypogonadism (small penis, cryptorchidism)
• Child
○ Aggressive behaviour or short temper
○ Voracious appetite
○ Obesity
○ Cognitive impairment
○ Generally small unless treated with growth hormone
```
61
Clinical presentation of Angelman Syndrome?
* Severe ID, marked delay of motor milestones
* Movement or balance disorder
* Absent speech or fewer than six words
* Any combination of frequent laughing/smiling, apparent happy demeanor, easily excitable personality often with uplifted hand-flapping
* Craniofacial features: blond hair (65%), decreased pigmentation of the choroid and iris, the latter resulting in pale blue eyes (88%), maxillary hypoplasia, deep-set eyes, a large mouth with tongue protrusion and widely spaced teeth; prognathia.
* Ataxia and jerky arm movements - puppet gait (100%)
* Drooling; excessive chewing/mouthing behavior
* Seizures
* Hypotonia and occasionally hyperreflexia
* Left hand preference
* Increased sensitivity to heat
* Abnormal sleep-wake cycles
62
Classic Triad of Prune-Belly (Eagle-Barrett) Syndrome
1) deficient or weakened abdominal musculature
2) urinary tract dysmorphism (hypotonic bladder - good storage, low-pressure VUR - incomplete/bad emptying)
3) bilateral cryptorchidism
63
What surveillance measures should be done for children with Prune-Belly Syndrome?
* annual renal ultrasonogram
* physical exam and assessment of somatic growth
* regular blood pressure checks
* annual urinalysis and determination of serum levels of electrolytes
64
What condition is linked to MeCP2 gene mutations?
Rett Syndrome
65
Clinical findings in Rett Syndrome
* Developmental regression
* Loss of purposeful hand movements with hand-wringing movements
* Apparent microcephaly (halting of growth rather than shrinking)
* Autism-like features
* Seizures
* Particular sighing pattern of respirations with periodic apnea
* Ataxia
* Apraxia
* Inconsolable crying
* Bruxism
66
Long-term health surveillance measures for children with Rett Syndrome
* Monitor for poor intake and growth failure
* Bowel dysmotility, constipation, and functional megacolon
* Gallbladder dysfunction, including gallstones
* Intermittent esotropia is common
* Scoliosis
* Osteopenia (poor intake, lack of mobility)
67
Clinical features of Russell-Silver Syndrome
* Short Stature (prenatal onset)
* Skeletal Asymmetry
* Small Incurved Fifth Finger
* Triangular face with frontal prominence and delayed closure of AF
* Mild global delay and speech delay
68
Genetic mechanism behind Russell Silver Syndrome
* Genetically heterogeneous
| * Maternal uniparental disomy (Chromosome 7)
69
Describe the clinical features of a child with Smith-Lemli-Opitz?
* Narrow forehead, epicanthal folds, ptosis, short mandible, short nose, anteverted nares, and low-set ears
* 2-3 toe syndactyly
* Post-axial polydactyly
* Ambiguous genitalia (short penis , hypoplastic scrotum , undescended testes)
* Moderate to severe intellectual disability
* Feeding problems: hypotonia, oral-motor incoordination, dysmotility, hypomotility, GERD, constipation, and formula intolerance
* Pyloric stenosis and Hirschsprung's disease
* Cardiac - endocardial cushion defect, HLH, ASD, PDA, and membranous VSD
* CNS: microcephaly, abnormalities of myelination, ventricular dilatation, malformations of the corpus callosum and/or cerebellum, Dandy-Walker malformation holoprosencephaly
* Congenital cataracts, opsoclonus, nystagmus, sclerocornea, iris coloboma, glaucoma, optic atrophy, microophthalmia
* Genitourinary anomalies i.e. hypospadias, cryptorchidism, micropenis, hypoplastic scrotum, bifid scrotum, microurethra, UPJ obstruction, hydronephrosis, renal cystic dysplasia, renal duplication, renal agenesis, reflux
* Adrenal insufficiency
70
What non-genetic test confirms diagnosis of Smith-Lemli-Opitz?
High serum 7DHC and low total cholesterol
71
What is the classic presentation for Sturge Weber Syndrome?
* Facial capillary malforation (Port-wine stain)
* Glaucoma
* Leptomeningial angioma (mostly occipital & posterior parietal)
All are related to abnormal blood vessels/vasculature
- GNAQ gene (NOT hereditary) leads to anomalous embryonic vascular bed dev’t
Presentation: Seizures, hemiparesis, stroke-like episodes, headaches, developmental delay
72
Name features of Trisomy 13
13 - Patau Syndrome
```
Midline defects:
• Holoprosencephaly
• Cleft lip and palate
• Ocular hypotelorism
• Low set, malformed ears
• Cerebral malformation
• Microcephaly
• Cardiac malformations
• Scalp defects
• Hypoplastic/absent ribs
• Flexed fingers with postaxial polydactyly
```
73
Classic presentation for Trisomy 18
```
18 - Edward Syndrome
• Rocker-bottom feet
• Low birthweight
• Closed fists with index finger overlapping the 3rd digit and the 5th digit overlapping the 4th
• Narrow hips with limited abduction
• Short sternum
• Microcephaly
• Prominent occiput
• Cardiac and renal malformations
• Intellectual disability
```
74
Name characteristic features seen in a child with Trisomy 21
* Facial dysmorphism: low set ears, epicanthal folds, short upturned nose, retrognathia, micrognathia
* Single palmar crease
* Widening between first and sescond toes (sandal-toe)
* Septal defect (ASD, VSD, AVSD)
* Risk of transient erythroblastopenia of childhood and subsequent ALL
* Developmental delay, anxiety, ADHD
* Greater risk of hypothyroidism, T1DM
* Cervical vertebral instability
* Hirshsprung's disease, celiac disease, duodenal atresia
* Congential cataracts, strabismus, myopia
75
What is the risk of recurrence in a family that has one child affected by T21?
* If sporadic: <1-1.5%
* If associated with Robertsonian translocation: 100% recurrence risk for a chromosomally abnormal child, otherwise, 5-13% if a female child has t(14;21), (lower if male has the translocation)
76
Prenatal testing strategies for detection/screening of T21?
• First- trimester screening:
○ nuchal translucency ultrasonography
○ maternal serum human chorionic gonadotropin (B-hCG)
○ pregnancy-associated plasma protein A (PAPP-A)
• Second-trimester screening: Quad screen
○ measurement of maternal serum hCG
○ unconjugated estriol
○ AFP
○ inhibin levels
77
Diagnostic tests for T21
```
• Prenatally
○ Amniocentesis
○ Chorionic villus sampling
○ NIPT
• Karyotype
```
78
Diagnostic Criteria for Tuberous Sclerosis
Definite TSC – 2 major features OR 1 major + 2 minor
Probable TSC – 1 major feature + 1 minor
Possible/suspect TSC – 1 major feature OR 2+ minor features
Major Features "CASSSH FURRL"
1. Cortical tuber
2. Ash leaf spots – 3+ hypomelanotic macule, 5+mm
3. Subependymal nodule (SEN)
4. Subependymal giant cell astrocytoma (SEGA)
5. Shagreen patch (connective tissue nevus)
6. Multiple retina nodular hamartomas
7. Facial angiofibromas (3+) or forehead plaque
8. Nontraumatic ungual or periungual fibromas (2+)
9. Cardiac rhabdomyoma, single or multiple
10. Renal angiomyolipoma
11. Lymphangioleiomyomatosis (LAM)
Minor Features
1. 3+ dental enamel pits
2. Gingival fibromas (2+)
3. Non renal hamartomas
4. Retinal achromic patch
5. Confetti skin lesions (numerous 1-3mm hypopigmented macules, scattered, arms & legs)
6. Multiple renal cysts
7. (Bone cysts)
8. (Hamartomatous rectal polyps)
79
Anticipatory guidelines for Tuberous Sclerosis
• Medical genetics consult
• Annual derm exam with Woods Lamp
• ECHO at presentation and q 1-3 years until regression, ECG q 3-5 years
• Renal Monitoring:
○ MRI abdomen (prev US abdo) q1-3yr
○ GFR & BP annually (min)
○ renal CT/MRI if large or numerous renal tumors detected on ultrasound
• Neurological issues
○ CT or MRI at diagnosis, q1-3 yrs if no symptoms or annually to monitor size of tumours
○ EEG: Baseline & if seizures develop
○ Annual clinical monitoring for TAND (TSC-associated neuropsychiatric disorder)
• Ophthalmology at diagnosis and annually
• Pulmonary evaluation
○ If lung cysts: PFTs annually & HRCT q2-3yr
• Topical rapamycin inhibitor (sirolimus or rapamycin) can improve the appearance of facial angiofibromas, ungual fibromas and hypomelanotic macules
• Targeted Treatment = mTOR inhibitors for fibromas or SEGAs
• Dental: q6mo
• Early developmental evaluation
80
What conditions are associated with Tuberous Sclerosis?
* Infantile spasms (Hypsarrhythmias)
* Autism
* ADHD
81
Clinical manifestations of Turner Syndrome?
* Redundant skin at the neck (webbed neck), lymphedema of hands and feet, shield chest - broad, widely spaced nipples, pectus excavatum, low hairline, high-arched palate, low set ears
* Short stature
* Increased carrying angle at elbow
* Bicuspid aortic valve or coarctation of aorta
* Premature ovarian failure (gonadal dysgenesis)
* Primary amenorrhea
* Horseshoe kidney
* Increased risk of diabetes, hypothyroidism, celiac disease
* Congenital hip dislocation
* Scoliosis
82
What does VACTERL stand for?
* vertebral abnormalities
* anorectal abnormalities
* cardiac abnormalities
* transesophageal fistula
* renal abnormalities
* limb abnormalities
83
Clinical features of Waardenberg Syndrome
• Congenital SNHL (60%) – non progressive, UL or BL, usually profound
• Pigmentary changes (iris, hair, skin)
○ White forelock (45%) or early greying (<30yo)
○ Eyes: Complete heterochromia iridium (i.e. irides of different colour) vs. partial/segmental heterochromia (2 colours in same eye) vs. hypoplastic or brilliant blue irides
○ Congenital leukoderma (skin hypopigmentation) often of face, trunk, limbs
• Dystopia canthorum (lateral displacement of inner canthi)
• Facial features: High nasal root, medial eyebrow flare
84
Clinical features of Williams Syndrome
* Elfin facies - broad forehead, stellate iris pattern, flat nasal bridge, smooth, long philtrum, pointed chin, epicanthal folds
* Widely spaced, small teeth
* "cocktail personality" - indiscriminately, warm and talkative
* Anxiety developing later in life, ADHD
* Supravalvular aortic stenosis
* Hypercalcemia (with associated risk of renal stones)
* Hypothyroidism
* Mild intellectual disability
85
Longterm complications that need monitoring in Williams Syndrome (5)
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Hypertension
Hypercalcemia, renal calculi
Developmental/Intellectual disability
Anxiety
Short stature
GERD and feeding intolerance
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