Disorders Flashcards
Marfan syndrome
First defined in 1896 by Antoine Marfan, various features added until 1949 when it was found to be AD from single locus
Phenotype: tall stature, ocular: ectopia lentis (50-60%), mitral regurgitation , aortic dilation and dissection,
Dx based on skeletal, cardio, ocular in 1975
Bentall procedure or composite graft developed in 1968 - as prophylactic as opposed to a response (hospital mortality went from 50% to <2%)
Tx: prophylactic Beta adrenergic blockade, prophylactic valve sparing aortic surgery
Marfan syndrome
Risk factors for aortic dissection: aortic root diameter, rate of change of diameter, FHx of dissection, thickness of aortic wall
Progressive and can be congenital
Missense mutations tend to be more severe
Other mutations in FBN1
Can cause familial atypical skeletal, aortic aneurysm, ectopia lentis, tall stature conditions Sprintzen-Goldberg syndrome MASS Scheuerman kyphosis Stiff skin syndrome Geleophysic dysplasia (dwarfism) Acromicric dysplasia Weill-Marchesani syndrome
As the clinical history improves, new aspects of natural history emerge
Other features of Marfan
Dural ectasia: ballooning of the dural sac surrounding the spinal cord, can cause pain and leg weakness, confusion with pelvic masses
Hepatic cysts and hemangiomas, renal cysts that are benign
Pneumothorax
Restrictive lung disease
Later onset problems with Marfan
Cardiomyopathy, cataract, glaucoma, degenerative arthritis, osteoporosis, back pain and neurologic complications (dural ectasia), pneumothorax, restrictive lung disease and sleep apnea, psychologic (Damocles syndrome) and dealing with chronic illness
Losartan, atenolol-medications
22q11.2
1965 - Angelo digeorge first described association of neonatal hyperparathyroidism, immunodeficiency, congenital heart disease (added later)
Affect neural crest cell migration (3rd and 4th pharyngeal pouch) causing structural abnormalities: 1. Outflow tract of the heart (conotruncal cardiac anomalies), 2. Thymic hypoplasia (immunodeficiency), 3. Hypoplasia of the parathyroid glands (hypocalcemia)
Also can have cleft palate, a Jejunal web
22q11 (velocardialfacial syndrome)
Characterized by: palatal abnormalities, cardiac anomalies (often conotruncal), mild dysmorphic features
22q11.2 detection
MLPA and microarrays are preferred (both size the deletion), arrays do not require an elevated index of suspicion. Methods still include FISH
-a contiguous gene deletion syndrome, Haploinsufficiency of ~50 genes resulting in a multi system disorder with significant morbidity
Most deletions de novo (90%), when familial often a surprise
De novo 22q11.2 deletions are a result of:
Non allelic homologous recombination
Due to presence of low copy repeats that flank the region and result in aberrant interchromosomal exchanges resulting in either a deletion or a duplication
LCRs: also known as segmental dups, define the breakpoints, used to describe the size of the resultant deletion. Typical deletion extends from LCR A to D but can have atypical nested smaller deletions
FISH probes are located between A to B and TBX 1 gene
22q11.2 most common microdeletion syndrome
~1/1000 to 1/2000 live births, incidence may be higher due to variable expressivity
2nd most common cause of congenital heart anomalies (after Downs): 22q identified in 52% of patient’s with interrupted aortic arch Type B, 34% patients with truncus arteriosus, 16% with ToF (more commonly associated with 22q than Down)
Most common cause of syndromic palatal anomalies including CL/P, Pierre Robin, submucosal CP/ bifold uvula, velopharyngeal dysfunction (nasal regurge, hypernasal speech), commonly result in polyhydramnios!
Also common cause of major developmental disabilities, accounting for 2-3% of individuals with such delays
22q11.2 -Indications for diagnostic testing by age
Childhood: conotruncal cardiac anomalies, palatal defects/delayed speech, immunodeficiency, hypocalcemia, DD/LD, facies, autoimmune disease
Adulthood: behavioural problems, psychiatric illness, previously affected child
Overall prevalence of medical problems varies by age
And focus of problems shifts over time for families and clinicians
Diagnosis is often missed especially in adolescents, adults and non caucasians
Not specific to a sex, race or ethnic group
22q11.2 mortality
Is low
~4% patients succumbed to complications associated with the deletion, most related to complex CHD, median age of death is 4 mo
Adults may be prone to premature death
22q11.2 major frequent associations
Immunodeficiency, cardiac anomalies, palatal defects, Endocrine abnormalities, renal anomalies, GI differences, Developmental/ behavioural problems
22q11.2 immunodeficiency
77% have immunodeficiency
Including thymic aplasia/ hypoplasia resulting in:
-impaired T cell production (67%) -> chronic infection
-humoral defects (23%)-> poor vaccine response
-IgA deficiency (6%)
-autoimmune disease: idiopathic thrombocytopenia, juvenile rheumatoid arthritis, autoimmune thyroid disease, autoimmune hemolytic anemia, vitiligo
Absent thymus on U/S is now a prenatal marker
Newborn screen for SCID (ex: T cell lymphopenia) can pick up 22q.
Normal newborn calcium is 8.8-11.3 mg/dl, if < think 22q
22q11.2 deletion - cardiac anomalies
In 76% ToF/ ToFPA (20%) most common VSDs (14%) Interrupted aortic arch type B (13%) Truncheons arteriosus, aortic arch anomalies (vascular ring), ASD, others
Not all lesions are identifiable on fetal echo
Significant morbidity
Many cardiac lesions require neonatal surgery, may not be identifiable by pulse ox etc
Early diagnosis of CHD markedly increases neurological prognosis and reduces overall healthcare costs
22q 11.2 - palatal anomalies
77%
Include:
-velopharyngeal dysfunction (45%), submucosal CP/ Bifid uvula (20%) {neither identifiable on prenatal US
- overt cleft palate (11%)
-CL/P (1%)
- Only prenatal clue may be polyhydramnios!
22q11.2 - Endocrine anomalies
Hypocalcemia, hypoparathyroidism
Generally presents: tetany, seizures, significant feeding difficulty, laryngeal stridor
Neonatal seizures, likely mediated by neonatal hypocalcemia, May increase risk for severe cognitive defects
Often transient, recurrence during times of stress
Thyroid disease, short stature, growth hormone deficiency +/- pituitary anomalies, IUGR (may be prenatal clue)
22q11.2 deletion GI and GU abnormalities
GI (35%) : esophageal dysmotility, GERD, intestinal malrotation, lifetime constipation, hirschprungs disease, umbilical hernia, esophageal atresia, imperforate anus
GU (36%) : renal agenesis/dysplastic kidneys/ duplicated collecting system/ hydronephrosis, cryptorchidism/hypospadias/absent uterus, iguinal hernia
Rare but other important associations with 22q11.2
ENT, GI and skeletal: laryngeal web, esophageal atresia, T E fistula, choanal atresia, SNHL and conductive HL, cervical and thoracic vertebral anomalies and scoliosis
Unprovoked seizures (not due to hypocalcemia) (15%), polymicrogyria, myleomeningocele, hepatoblastoma, Wilms tumours, renal cell carcinoma, thyroid carcinoma, leukaemia, melanoma, neuroblastoma
Diaphragmatic hernia, post axial polydactyly, club foot, radial ray defects
Craniosynostosis,
Other rare features 22q11 deletion
Hemifacial microsomia/ auricular anomalies:
-microtia/anotia, preauricular tags or pits, helical differences, protuberant ears
Eye findings:
-microphthalmia/anophathalmia, ptosis, scleracornea, retinal coloboma, hypertelorism, tortuous retinal vessels, hooded eyelids, upslanting palpebral fissures
Can have severe micrognathia with glossoptosis/ Pierre robin: requiring mandibular distraction or tracheostomy
Nasal differences with or whiteout cleft, nasal dimple or crease, prominent nasal root, bulbous nasal tip, hypoplastic nevi, hemangioma
Asymmetric crying face in ~14%
Intellectual deficits and psychiatric illness with 22q11.2 deletion
ID >95%:
-ADHD, ASD, anxiety, OCD, oppositional defiant disorder
psychiatric illness (25% in children, 60% in adults) - schizophrenia (25%), depression, anxiety, OCD
Young children with 22q
Delays in achieving motor milestones (age of walking ~18 mo)
Delays in emergence of language (age of speaking ~30 mo, some as old as 7) but then becomes a strength
ASD in >10%
All benefit from early intervention especially in speech therapy or sign language
~30% fall in low IQ scale less than 70 often due to an insult in brain due to cardiac event or stroke
~65% have non verbal learning disability, trouble with math and reason and abstract concepts
Treatment for 22q
Emphasis on monitoring and treatment of hypocalcemia/thyroid dysfunction:
-ionized calcium, PTH, TSH especially during stress
As needed:
-specialized educational interventions, speech therapy and palatal evaluation/surgery, treat psychiatric illness, emphasis on early dx and effective treatment, both from a physical and cognitive perspective
Emphasis on multi system nature
Pregnancy is a biological stressor: risk for new onset hypocalcemia, adult CHD risks, seizure disorders, autoimmune disorders
Important GC ing got 22q
Somatic mosaicism
Germline mosaicism ( likely small chance)
Dual diagnosis - co occurring conditions
Unmasking of AR conditions
Nested B-D or C-D missed by FISH
Overlapping phenotype due to TBX1 mutation
Phenocopies/ differential diagnosis :
CHARGE/CHD7 mutation, Goldenhar, SLO, Kabuki, Alagille, Jacobsen.
Not related to maternal age
