Syndromes and Genetics Flashcards
Prevalence of Noonan syndrome?
1 in 1000-2500
What gene is involved in pathogenesis of Noonan syndrome?
• DNA testing for several mutations in the RAS-MAPK signaling pathway will show mutations responsible for Noonan syndrome • Gene panels are available, 50% have muta- tions in the tyrosine phosphatase (PTPN11) gene on chromosome 12
AD inheritance
What are the developmental abn with noonan syndrome?
Mild ID (IQ range 64–127, median 102), speech differences
What behavioural abn are associated with noonan syndrom?
Stubbornness, mood disorders, rare autistic manifestations
What growth abn are associated with noonan syndrome?
Frequent failure to thrive, feeding difficulties, later proportionate and mild short stature (50%)
What neural abn are associated with noonan syndrome?
Motor delays, vision deficits, hearing loss (usually conductive)
Describe the connective tissue dysplasia associated with noonan syndrome?
Scoliosis, pectus (upper carinatum, lower excavatum), joint laxity, lax skin, bleeding diathesis
Describe the eye, cardiac, and urological abn associated with noonan syndrome
Eye (strabismus), cardiac (pulmonic stenosis, septal defects, hypertrophic cardiomyopa- thy), urogenital (obstructive uropathy, crypt- orchidism) defects
Describe the lymphatic abn associated with noonan syndrome
Pulmonary lymphangiectasia, chylothorax, non-immune hydrops
Describe tumours associated with noonan syndrome
Pheochromocytoma, ganglioneu- roma, juvenile myelomonocytic leukemia (often with PTPN11 gene rearrangements/ amplification)
Described the minor abn associated with noonan syndrome
• Short, webbed neck • Low posterior hairline • Ptosis, down-slanting palpebral fissures • Low-set or abnormal pinna (“jug-handle” ears) • Cubitus valgus, single palmar creases • Edema of the hands and feet
Describe the health supervision and preventative care with noonan syndrome
• Neonatal hearing screen, renal sonogram, ophthalmology, cardiology referrals • Monitor thyroid, renal functions; regular car- diac monitoring for aortic and valve changes • Cervical spine radiographs before sports, anesthesia
What abnormality does this infant have?
Short webbed neck of an infant with Noonan syndrome
What is the prevalence of Waardenburg Syndrome?
Prevalence: About 1 in 40–50,000 births, hav-
ing a 1.4% incidence in congenitally deaf
children
What gene mutations are involved in Waardenburg syndrome?
• Like Noonan syndrome, an array of different gene mutations (PAX3, MITF, EDN3, etc.) and subtypes have been described, all except some cases of type IV exhibiting autosomal dominant inheritance
Waardenburn syndrome involves abnormal neural crest development, accounting for…?
pigmentary changes and, in some cases, Hirschsprung disease
What developmental abn occur in Waardenburg syndrome?
Development: Mild cognitive delays that can
be related to the hearing loss
What neural abn are associated with Waardenburn syndrome?
• Neural: Sensorineural hearing loss, nonprogres-
sive, unilateral or bilateral, due to hypoplasia of
structures in the organ of Corti and semicircular
canals (evident on head computed tomography)
What eye abn are associated with Waardenburg syndrome?
• Eye: Iris pigmentary abnormality—hetero-
chromia (eyes of different colors), bicolored
iris, pale blue eyes with hypoplastic iridic
stroma, hypopigmented fundus, peripheral
retinal pigmentation
What hair abn are associated with Waardenburg syndrome?
• Hair: Hypopigmentation with poliosis (white
forelock), white hairs on other body regions,
premature graying
What facial abn are associated with Waardenburg syndrome?
• Face: Medial flare of bushy eyebrows, dysto -
pia canthorum (lateral displacement of inner
canthi), high and broad nasal bridge with
hypoplastic alae nasae
What other abn are associated with waardenburn syndrome?
• Cardiac, skeletal, and urogenital defects
occur in some
What health supervision and preventive care is warranted in waardenburg syndrome?
• ENT and audiology team after diagnosis,
deaf community and physician team discus-
sion of cochlear implant and hearing aid
options
• Alertness for symptoms of cardiac, skeletal,
and GI defects
What is the prevalence of Treacher Collins Syndrome?
1 in 50, 000 births
What is the gene defect in Treacher Collins Syndrome?
Targeted DNA testing or whole exome
sequencing will show a mutation in the trea-
cle (TCOF1) gene in the chromosome
5q31.3q32 region
What is the inheritance pattern for treacher collins syndrome?
- Autosomal dominant inheritance pattern with 50% transmission risk in affected individuals
- Most severe cases are new mutations
What might treacher collins be mistake for?
• Confusion with the low genetic risk Goldenhar
syndrome/association may also occur if eye
and malar changes are not dramatic
What developmental abn are associated with treacher collins syndrome?
• Development: ID (5%), usually normal unless
compromised by unrecognized hearing loss
What growth abn are associated with treacher collins syndrome?
• Growth: Early failure to thrive because of
feeding difficulties, airway abnormalities
What neural abn are associated with treacher collins syndrome?
• Neural: Conductive deafness due to ear
anomalies
What craniofacial abn are associated with treacher collins syndrome?
• Craniofacial: Mandibulofacial dysostosis with
underdeveloped mandibular and zygomatic
bones causing small jaw and malar hypopla-
sia, projection of scalp hair onto lateral cheek
What ENT abn are associated with treacher collins syndrome?
• ENT: Choanal atresia, pharyngeal hypoplasia
with macro- or microstomia, cleft palate,
external and middle ear anomalies with canal
stenosis and ear tags
What is the prevalence of Craniosynostosis syndromes?
• Prevalence: 4–6 per 10,000 births if primary
and secondary synostosis are included; cra-
niosynostosis syndromes range from 1 in
25,000 (Saethre-Chotzen) to 1 in 100,000
births (Apert) or rarer
What is craniosynostosis?
• Craniosynostosis refers to premature fusion
of cranial sutures, often causing abnormal
head shape
• Can have primary (ossification defect) or sec -
ondary causes (failure of brain growth, rickets)
Is craniosynostosis a primary or syndromic pathology?
• Occurs as an isolated defect or as part of over
90 syndromes
What are the types of craniosynostosis?
– Scaphocephaly: Early fusion of sagittal
sutures, long and narrow head shape
– Anterior plagiocephaly: Early fusion of
one coronal suture, unilateral flattening of
the forehead
– Posterior plagiocephaly: Early closure of
one lambdoid suture
– Brachycephaly: Early bilateral coronal
suture fusion
– Trigonocephaly: Early fusion of metopic
sutures, keel-shaped forehead and
hypotelorism
– Turricephaly: Early fusion of coronal,
sphenofrontal, and frontoethmoidal
sutures, cone-shaped head
– Clover-leaf skull or Kleeblattschädel
anomaly
What syndromes involve craniosynostosis?
What mode of inheritance do these have?
• Syndromes involving craniosynostosis (coro-
nal synostosis most common, but any suture
can be involved)
– Apert syndrome: Craniosynostosis, hand
syndactyly
– Crouzon syndrome: Craniosynostosis, no
limb defects
– Pfeiffer syndrome: Craniosynostosis,
broad thumb and toes
– Saethre-Chotzen syndrome: Craniosynos-
tosis, often asymmetrical, brachydactyly
and syndactyly
– Carpenter syndrome: Tower or clover-leaf
skull due to multiple fused sutures, preax-
ial polydactyly, obesity
• All syndromes but Carpenter (autosomal reces-
sive) exhibit autosomal dominant inheritance.
What is the recurrance risk for isolated craniosynostosis?
• Isolated craniosynostosis, like other single
birth defects, exhibits multifactorial determi-
nation with 3–5% recurrence risk
What genetic defects are associated with craniosynostosis?
• Mutations in specific genes have been defined
for the major syndromes, often in fibroblast
growth factor receptor (FGFR) genes
In subsequent pregnancies, can craniosynostosis be detected?
• Specific gene testing or gene panels can pro -
vide a molecular diagnosis with options for
prenatal diagnosis in subsequent
pregnancies
What developmental abn are associated with craniosynostosis
surgical release of craniosynostosis can prevent ID, but IQ often in 70-74 range
What neural abn associated with craniosynostosis?
restriction of brain growth, increased ICP causes ID, visual, and hearing defects
What cranial abn are associated with craniosynostosis?
Abnormal shape for various suture fusions
• Plagiocephaly occurs with asymmetric syn-
ostosis; mild cases due to uterine constraint
must be distinguished
What facial abn are associated with craniosynostosis?
midface hypoplasia, palatal clefts, jaw changes
• Early airway obstruction may require
tracheostomy
What eye abn are associated with craniosynostosis?
• Eye: Shallow orbits, exophthalmos/ocular
proptosis, exposure keratitis due to sphenoi-
dal synostosis
What bone, heart and limb defects are associated with craniosynostosis?
Do limb defects give a clue for the cause?
• Cervical vertebral, cardiac, and limb defects
often occur
• Types of limb defects rather than the involved
suture(s) guide craniosynostosis syndrome
diagnosis
What health supervision and preventative care measures should be placed for patients with craniosynostosis?
• Most craniosynostosis conditions are evident
at birth and require immediate involvement of a craniofacial team to prevent cognitive and
sensory deficits
• Craniofacial surgery team evaluation, includ-
ing neurosurgery, ophthalmology, ENT, and
cleft palate expertise
• Monitoring of hearing, vision, and develop-
ment is critical in the more severe
syndromes
What is scaphocephaly?
– Scaphocephaly: Early fusion of sagittal
sutures, long and narrow head shape
What is anterior plagiocephaly?
– Anterior plagiocephaly: Early fusion of
one coronal suture, unilateral flattening of
the forehead
What is posterior plagiocephaly?
– Posterior plagiocephaly: Early closure of
one lambdoid suture
What is brachycephaly?
– Brachycephaly: Early bilateral coronal
suture fusion
What is trigonocephaly?
– Trigonocephaly: Early fusion of metopic
sutures, keel-shaped forehead and
hypotelorism
What is turricephaly?
– Turricephaly: Early fusion of coronal,
sphenofrontal, and frontoethmoidal
sutures, cone-shaped head
Prevalence of achondroplasia?
1 in 16,000 - 25,000
Most common type of short limb dwarfism, involving rhizomelic hypoplasia
• Skeletal radiologic survey to define affected
bone regions can tailor the differential of
skeletal dysplasia, often suggesting the diag-
nosis of achondroplasia by its typical spine
and hip changes
What genetic mutations and inheritance pattern is seen with achondroplasia?
• Specific mutation in fibroblast growth factor
receptor 3 (FGFR3) gene on chromosome
• Other mutations in this gene cause severe
thanatophoric dwarfism or milder hypo -
chondroplasia
• Autosomal dominant inheritance with a 50%
recurrence risk for affected individuals
• More than 80% of patients are due to new
mutations
what abn in lifespan are seen with achondroplasia?
• Lifespan: Sudden infant death in 5% and
depression common
What developmental abn are seen in achondroplasia?
• Development: Normal if complications like
hearing loss or cervical cord compression are
prevented, motor milestones often lag by
3–6 months because of macrocephaly and
early hypotonia
What growth abn are seen in achondroplasia?
• Growth: Short stature with males averaging 130 cm (~4 ft-2) and females 123 cm (4 ft)
what neural abn are associated with achondroplasia?
• Neural: Altered cerebrospinal fluid (CSF) cir-
culation, cord compression, conductive and
sensorineural hearing loss
what cranial abn are associated with achondroplasia?
• Cranial: Macrocephaly, platybasia, narrow
foramen magnum, maxillary hypoplasia
what facial abn are seen with achondroplasia?
• Face: Frontal bossing, myopia, shallow nasal
bridge, myopia, chronic otitis media
What respiratory abn are seen with achondroplasia?
• Respiratory issues: Due to small chest, upper
airway obstruction, and sleep-disordered
breathing
what skeletal abn are associated with achondroplasia?
• Skeleton: Rhizomelic limbs causing extra
skin folds, cervical spine fusion,
kyphoscoliosis, joint laxity leading to
arthritis and injuries, splayed fingers (trident
hands)
what genital abn are associated with achondroplasia?
• Genital: Uterine fibroids, menorrhagia, nar-
row pelvis requiring cesarean delivery
What heath supervision and preventive care should be in place for pts with achondroplasia?
• Monitor for feeding difficulties and apnea
• Infantile respiratory and sleep evaluations,
anesthesia precautions
• Childhood ophthalmology, ENT, and ortho-
pedic follow-up
• Somatosensory potentials to measure trans-
mission through foramen magnum, and check
for cord compression
• Flexion-extension radiography to assess cer-
vical instability/respiratory obstruction
• Management controversies include use of
decompressive surgery for cervical cord com-
pression, limb- lengthening procedures, and
growth hormone therapy as many have poor
response
Prevalence of Marfan syndrome?
1 in 1000 - 2500
Marfan syndrome is grouped by McKusick as?
Heritable disorders of connective tissue
What mutation is involved in Marfan syndrome?
• Criteria developed for clinical diagnosis are
less important now that targeted DNA testing
will demonstrate mutations in the fibrillin-1
(FBN1) gene on chromosome 15
What are practical clinical criteria for Marfan syndrome?
• Practical clinical criteria involve one major
finding (eye or heart) along with several
minor findings (e.g., Marfanoid
habitus, arachnodactyly maneuvers, skin
changes)
What mode of inheritance is Marfan syndrome?
• Marfan syndrome exhibits autosomal domi-
nant inheritance with an equal sex ratio and
variable expression
What lifespan abn is assocaited with Marfan syndrome?
• Lifespan: The major cause of death is aortic
dissection, preventable by beta-blocker or
losartan therapy
What development abn are associated with marfan syndrome?
• Development: Normal with occasional verbal
performance discrepancy and visual attention
problems
What growth abn are associated with Marfan syndrome?
Tall stature, low upper to lower segment ratio, thin and fragile habitus
what neural abn are associated with marfan syndrome?
dural ectasia, sacral meningocele, anterior or posterior disc herniation
what cranial abn are assocaited with marfan syndrome?
dolichocephaly, prominent supraorbital ridges, temporomandibular joint disease
what eye defects are associated with marfan syndrome?
ectopic lentis, myopia, retinal detachment
what cardiac abn are associated with marfan syndrome?
aortic enlargement, mitral valve dysfunction and prolapse, arrhythmias, aneurysms of the aorta or pulmonary artery
what pulmonary abn are associated with marfan syndrome?
reduced vital capacity, spontaneous pneumothorax, emphysema
what skeletal abn are associated with marfan syndrome?
scoliosis, spondylolisthesis, flat feet, joint laxity
What is arachnodactyly (assoc with marfan syndrome)?
evidenced by ability to perform the Walker-Murdoch (overlap of thumb-5th finger when encircling the wrist) and Steinburg (protruding thumb beyond ulnar hand border with clenched fist) signs
what epidermal abn are associated with marfan syndrome?
atrophic striae (stretch marks), recurrent incisional hernias
what hematologic abn are associated with marfan syndrome?
clotting tendency, renal vein thrombosis
What health supervision and prevantive cares should be in place for pts with marfan syndrome?
• Cardiology and ophthalmology evaluations
when diagnosis suspected
• Monitoring of aortic root size at intervals dic-
tated by symptom severity (6 months to
3–4 years), often accompanied by beta-
blockers or losartan therapy
• Activity and physical therapy to strengthen mus-
cles with frequent prohibition of collision sports
Prevalence of Ehlers-Danlos Syndrome?
• Prevalence: Listed as 1 in 5000 births for all
types but much more common if patients with
more subtle joint laxity/hypermobility and
skin elasticity are included
• 20% of women, 10% of men are hypermobile
defined by scores > 4–5 on the 9-point
Beighton scale
Early recognition or diagnosis of Ehlers Danlos is good because?
• Early recognition of hypermobility can guide
activities that prevent adolescent injury and
early arthritis
• Diagnosis allows treatment of associated
autonomic imbalance (tachycardia, chronic
fatigue, bowel issues)
Associated autonomic imbalance in Ehlers-Danlos lead to?
• Associated autonomic imbalance (dysauto-
nomia) leads to treatable postural orthostatic
tachycardia (POTS), low bowel motility/irri-
table bowel syndrome (IBS), and mast cell
activation disorder (MCAD)
Non-specific diagnosis such as […] are often due to Ehlers-Danlos with dysautonomia
fibromyalgia,
chronic fatigue syndrome, and serum-nega-
tive rheumatoid arthritis
Diagnostic criteria for Ehlers Danlos?
• Diagnostic criteria less important in era of
genomic testing, but a practical approach
could include:
– For classical or hypermobile EDS:
◦ Major criteria: Joint hypermobility and
skin elasticity/scarring
◦ Minor criteria: Smooth/velvety skin and
joint subluxation/injury
– For vascular EDS:
◦ Major criteria of typical “tight, chiseled
face,” arterial aneurysm/dissection and/
or bowel rupture
◦ Minor criteria of translucent skin, mus-
cle/joint rupture
Lifespan abn assoc with Ehlers Danlos?
• Lifespan: Generally normal with the excep-
tion of vascular EDS
Developmental abn assoc w/ Ehlers Danlos?
• Development: Early motor delays, normal
cognitive function, anxiety, depression from
chronic pain
Growth abn assoc w/ Ehlers Danlos?
• Growth: Early colic and failure to thrive due
to low bowel motility/IBS; eosinophilic
esophagitis (MCAD)
CNS abn assoc w/ Ehlers Danlos?
• Central nervous system: Migraines, chronic
daily headaches, Chiari deformation, fragile
dura contributing to CSF leaks
peripheral nervous abn assoc w/ Ehlers Danlos?
• Peripheral nerves: Carpal-tunnel syndrome,
chronic regional pain syndromes
Joint abn assoc w/ Ehlers Danlos?
• Joints: Hypermobile with subluxations, liga-
ment/tendon tears, osteoarthritis, plica bands,
areas of dead bone
Skin abn assoc w/ Ehlers Danlos?
• Skin: Elastic, thin and translucent, easy bruis-
ing, striae, white-surfaced and keloid scars,
slow healing
Face abn assoc w/ Ehlers Danlos?
• Face: Distinctive only in some with vascular
EDS—bulging eyes, thin nose and lips due to
tight skin
Eye, GI and skeletal abn assoc w/ Ehlers Danlos?
• Eye (myopia, retinal detachment); mouth
(dental, temporomandibular joint [TMJ]
issues); GI (IBS, low motility); cardiovascu-
lar (tachycardia, valvular prolapse, aneu-
rysm); skeletal (kyphoscoliosis, flat feet,
herniated disc) defects
what allergy and pulmonary abn assoc w/ Ehlers Danlos?
• Allergy/pulmonary: Frequent asthma/short-
ness of breath, food and medication intoler-
ances, transient rashes/hives, anaphylaxis,
spontaneous pneumothorax
Urogenital abn assoc w/ Ehler Danlos?
• Urogenital: Pelvic congestion with menor-
rhagia, endometriosis, ovarian cysts; hyper-
active bladder with increased urinary tract
infections, bladder and uterine prolapse
Health supervision and preventive care in Ehlers Danlos?
• Usual diagnosis as teen or young adult—car-
diology, orthopedic, GI, allergy/mast cell
referrals with monitoring for joint pain/injury,
tachycardia, fatigue, anxiety, constipation/
diarrhea, reflux, allergy, skin reactivity
• Evaluate for head and neck pain, especially
posterior, and consider upright head magnetic
resonance imaging (MRI) study for Chiari
• Encourage swimming and light weight lifting
rather than running
• POTS treated with hydration, salt, high pro-
tein diet, medications (beta-blockers, mido-
drine, fludrocortisone)
• Mast cell activation treated by allergists with
antihistamine protocols (triple-drug therapy:
cetirizine/ranitidine/montelukast)
Prevalance of osteogenesis imperfecta?
Prevalence: 1 in 20,000 births if all types are
included
What are the overall types of osteogenesis imperfecta?
Four major types are recognized with cranio-
facial changes, deafness, bowed limbs, and
fractures—type II is an outlier with lethal
dwarfing limb and chest changes
What genetic defects are involed in osteogenesis imperfecta?
What mode of inheritance?
• Heterozygous mutations in the genes for the
alpha-1 and alpha-2 chains of collagen I
(COL1A1, COL1A2)
• Autosomal dominant inheritance patterns
• Targeted COL1 gene testing will provide the
diagnosis in over 80% of cases
Describe type 1 osteogenesis imperfecta?
Type I: Near normal growth with blue-gray
sclerae, multiple fractures, and later hearing loss
Describe type 2 osteogenesis imperfecta?
Type II: Extremely severe with usual death in
the perinatal period and rare survival for
months; poorly mineralized cranium and long
bones with large fontanel, hydrocephalus,
hypotonia, short and bowed limbs distorted
by multiple fractures in utero and callus
formation
Describe type III osteogenesis imperfecta?
Type III: Prenatal growth deficiency, multiple
fractures at birth, limb bowing, severe kypho-
scoliosis leading to respiratory compromise;
dentinogenesis imperfecta is severe, bluish
sclerae less after infancy
Describe type IV osteogenesis imperfecta?
• Type IV: Short stature with limb deformities;
femoral bowing in infancy that improves;
dental changes
• Other types have been added, including a
type VI with vertebral fractures and lack of
COL1 mutations
Developmental abn for type 1 osteogeneis imperfecta?
• Development: Usually normal since hearing
loss occurs late (third decade)
Growth abn associated with type 1 osteogenesis imperfecta?
Growth: Prenatal deficiency and short stature
with significant limb fractures
Neural abn assoc with type 1 osteogenesis imperfecta?
Neural: Hearing impairment due to otosclerosis
cranial abn assoc with type 1 osteogenesis imperfecta?
Cranial: Macrocephaly, Wormian bones, mal-
occlusion of jaw
facial abn assoc with type 1 osteogeneis imperfecta?
Blue-gray sclera, dentin/pulp hypopla-
sia, translucent blue-gray teeth, caries
How common are fractures in type 1 osteogenesis imperfecta?
Fractures (92% overall): 8% at birth, 23%
infancy, 45% preschool, 17% school, less
after puberty
connective tissue abn assoc w/ type 1 osteogenesis imperfecta?
Connective tissue: Lower limb bowing,
kyphoscoliosis, easy bruising, inguinal and
umbilical hernias
What health supervision and preventative care should be undertaken in pts with type 1 osteogenesis imperfecta?
• Neonatal skeletal radiologic survey to ascer-
tain fractures and extent of deformities
• Orthopedic care with later hearing screening
• Endocrine consultation may help with
bisphosphonate therapy
• Vitamin D and calcium supplementation if
hypophosphatasia with large fontanel, frac-
tures, and similar dental problems is excluded
Prevalence of beckwith-wiedemann syndrome (BWS)?
Prevalence: 1 in 12,000 births and probably
higher, with some cases having only
macroglossia
