Trisomies and Microdups/dels Flashcards
What is the most common chromosomal aneuploidy occurring in humans? Most frequently occurring live-born aneuploidy?
T21
Describe the reason for the features seen in DS
Down syndrome critical regions are a few chromosomal regions associated with partial trisomy for a gene called Has21. The DSCR on 21q21.22 is responsible for many clinical features of DS.
What cardiac features are present in individuals with T21
Most common and leading cause associated with morbidity and mortality in pts, especially in the first 2yrs of life
CHDs in up to 50% of babies
most common: AVSD which is associated with mutations in CRELD1 then VSD
What can cause DS?
AMA
Sporadic trisomy (95%)
isochromosome: 2 long arms separate together instead of the long and short arms while in Robertsonian t (2-4% of pts; mostly 14;21)
1% caused by mosaicism
What percent of T21 fetuses are lost before term? What influences the chances of having a fetus with T21? Why is it the most common viable live chromosomal aneuploidy
50-75%
AMA
small number of genes on chromosome 21 (Hsa21) which is the smallest and least dense of the autosomes
What percent of babies with T21 have u/s findings? What would these findings be?
50%
Increased NT, absent nasal bone, cardiac anomalies (50%), echogenic bowel, EIF
What percentage of cases of T21 are attributed to mothers over 35? Under 35?
10%; 90%
under 35 is higher bc they have higher birth rates
What is the overall prevalence of T21? Risk at 35 to have a child with T21? at 40? at 45? at 50?
Overall: 1 in 800
at 35: 1 in 300
at 40: 1 in 100
at 45: 1 in 20
at 50: 1 in 5
What are the chances of having a child with T21 if mom is a carrier of Robertsonian t? If dad is?
15% if mom
1% if dad
How would a 21;21 translocation in a patient with T21 have occurred? If someone were to be a carrier of this translocation, what are the chances their children would have T21
de novo
100% of that person’s children would have T21
What is the most common Robertsonian translocation causing T21
14;21
What gastrointestinal features are present in individuals with T21
duodenal and small bowel stenosis and atresia
annular pancreas
imperforate anus
Hirschsprung disease (neural cells fail to migrate causing a segment of the rectum not being able to have normal peristalsis resulting in failure of normal defecation)
strong association with celiac disease
What hematologic features are present in individuals with T21
neutrophilia, thrombocytopenia, polycythemia (usually mild and will resolve in the first few weeks of life)
transient abnormal myelopoiesis/leukemia: detected during the first wk but resolved by 3mo; can also cause SAB
10x risk of developing leukemia
What neurologic features are present in individuals with T21
reduced brain volume, hypotonia, joint laxity, prone to decreased bone mass, increased risk of fractures, seizures (usually infantile spasms, tonic-clonic, myoclonic)
dementia in pts older than 45yo; 50-75% have dementia by 60yo
What endocrinological features are present in individuals with T21
hypothyroidism which can be congenital or acquired at any time during life
delayed puberty (primary hypogonadism)
What ocular and ENT features are present in individuals with T21
cataracts/iris anomalies/strabismus
anatomical structure of the ear predisposes pts to hearing deficits –> usually conductive hearing loss which is tx with pressure equalization tubes
What diagnostic tests can detect T21 and how
FISH: interphase nuclei most commonly used by using Hsa21 specific probes or the whole of Hsa21
karyotype: 3 Chrom 21’s
What referrals should you make for a pt with T21
Hearing and vision assessment
Thyroid function tests annually
Cardiac referral within first 6mo of life to correct CHDs
developmental pediatrician
pediatric pulmonologist
gastroenterologist
neurologist/neurosurgeon
orthopedic specialist
child psychiatrist
PT/OT/Speech
audiologist
What are the three potential etiologies for T18
Complete T18 (94%): nondisjunction during Me II, most often of maternal origin
Mosaic T18 (less than 5%)
Partial T18 (~2%): only a partial segment of 18q is present in triplicate, results from a balanced translocation or inversion carrier (18p trisomy DOES NOT result in T18 phenotype)
What is the recurrence risk for complete and partial T18
Complete: 0.5-1%
Partial: could be up to 20% depending on translocation
What is the average prevalence of T18? In which sex is it most present in?
1 in 2500
more often in females (3:2 ratio)
fetal loss is higher in males
Describe some of the neurologic and craniofacial findings in T18
Neuro: Neonatal hypotonia followed by hypertonia, Apnea
Seizures, Poor sucking, Delayed psychomotor development and ID
Craniofacial: Skull: Microcephaly, bitemporal narrowing, and prominent occiput.
Face: Triangular and asymmetric face with facial paralysis
Eyes: Microphthalmia, hypertelorism, epicanthus, short palpebral fissures, coloboma of iris, cataract, corneal clouding, hypoplastic supraorbital ridge, upward or downward slanting palpebral fissures, and abnormal retinal pigmentation.
Nose: Prominent nasal bridge with hypoplastic nasal root, upturned nares, and choanal atresia.
Oral cavity: Micro-retrognathia, microstomia, narrow arched palate, cleft lip, and cleft palate.
Ears: Microtia, preauricular appendages, low-set or retroverted ears, and dysplastic ears.
Describe some of the skeletal and cardiovascular features in T18
Severe growth retardation, Short neck, Short sternum, Broad chest, with or without widely spaced small nipples. Incomplete ossification of the clavicle, Hemivertebrae or fused vertebrae, scoliosis, Pectus excavatum , Narrow pelvis and limitation of the hip abduction, Hip dislocation, Arthrogryposis, Clenched hands with overriding fingers, camptodactyly, syndactyly, single palmar crease and clinodactyly of the fifth fingers, radial or thumb hypoplasia, and hypoplastic nails, Rocker-bottom feet with the prominent calcaneus, talipes equinovarus, dorsiflexed great toes
Cardiac defects are found in 90% of Edwards syndrome patients.
Ventricular or atrial septal defect, Patent ductus arteriosus, tetralogy of Fallot, overriding of the aorta, coarctation of the aorta, and hypoplastic left heart syndrome
Polyvalvular heart disease (involving two or more valves; the most common aortic and pulmonary valve
Describe some of the pulmonary and GI issues in pts with T18
Pulmonary hypoplasia, Tracheobronchomalacia, laryngomalacia, Obstructive and central apnea, Early-onset pulmonary hypertension
Omphalocele, Esophageal atresia with Tracheoesophageal fistula , Pyloric stenosis, Ileal atresia, Malrotation, Meckel diverticulum, Diastasis recti , Umbilical hernia
Describe some of the genitourinary and CNS malformations in pts with T18
Cryptorchidism, Hypospadias, micropenis, Clitoral hypertrophy, hypoplasia of the labia majora, ovarian dysgenesis, and bifid uterus; Horseshoe kidney, renal agenesis, hydronephrosis
Cerebellar hypoplasia, Meningoencephalocele, anencephaly, Hydrocephalus, Holoprosencephaly, Arnold-Chiari malformation, Hypoplasia of the corpus callosum
What tx options are available for pts with T18
Ethical issues exist around newborns due to the high mortality rate and difficulty predicting which infants will live beyond their first year of life
NICU management
Feeding management via nasogastric tube/gastrostomy
cardiac management via diuretics, digoxin for heart failure. palliative/corrective cardiac sx are recommended for complex CHDs
tx infections with standard approach
ortho management may be required particularly for scoliosis due to the hemivertebra
psychosocial support for families
What is the prognosis of fetuses with T18
40% due during labor and 1/3 are delivered pre term
avg survival is between 3d-2wks
What are the common complications seen in T18
Low birth weight followed by FTT
severe to profound developmental handicap is the rule; cognitive and motor delay is noted in most surviving pts
cardio-respiratory failure is the leading cause of death
Increased risk for neoplasms: Wilms’ tumor/nephroblastoma, hepatoblastoma, Hodgkin dz
What percent of babies with T18 have u/s findings? What would these findings be?
90%
IUGR, increased NT, hypoplastic nasal bone, clenched fists, CPC, rocker bottom feet, cardiac and renal anomalies
How can trisomy 13 occur
nondisjunction leading to a whole extra chromosome (~80%)
unbalanced translocation (~20%)
mosaicism (rare)
What is the expected prognosis of a fetus with T13
median survival is 7-10days
90% live less than a year
prognosis is better for pts with mosaicism and pts with unbalanced translocations
What percent of babies with T13 have u/s findings? What would these findings be
90%
midline facial defects, holoprosencephaly, cardiac defect, polydactyly, rocker bottom feet, clenched hands with overlapping fingers, increased NT
Describe the clinical features associated with T13
IUGR, microcephaly, midline facial defects (cyclopia, cleft lip, cleft palate); sloping forehead, small malformed ears, anophthalmia, microphthalmia, micrognathia, pre-auricular tags, alobar holoprosencephaly, postaxial polydactyly, congenital club foot, rocker bottom feet
VSD, ASD, tetralogy of Fallot, atrioventricular septal defect, double outlet right ventricle (but typically non lethal in infancy or childhood)
cryptorchidism, hypospadias, labia minora hypoplasia, bicornate uterus, omphalocele, incomplete rotation of the colon, Meckel diverticulum, polycystic kidneys, hydronephrosis, horseshoe kidney, severe psychomotor disorder, FTT, ID, seizures
How is Patau syndrome dx
prenatal u/s can help to detect malformations such as holoprosencephaly, or other central nervous system anomalies, facial anomalies, skeletal abnormalities, renal or cardiac defects, growth restriction
u/s after 17wks gestation is most sensitive in detecting abnormalities
karyotype, microarray
What tx are available for T13
Intensive tx is controversial due to the universally poor prognosis of pts despite tx
intubation or trach due to facial defects, cardiac sx to repair CHDs, herniorrhaphy, cleft lip repair, feeding tube placement, corrective orthopedic surgeries
specialized dietary feeds, seizure prophylaxis, prophylactic antibiotics for UTIs, the use of hearing aids
What aneuploidy is the most common cause of miscarriage
T16
What signs and symptoms are seen in triploidy
growth restriction, skull defects, macrocephaly, heart defects, abnormal brain development, adrenal gland defects, cystic kidneys, NTDs, widely spaced eyes, low nasal bridge, low-set malformed ears, small, jaw, absent/small eye, cleft lip, cleft palate, third and fourth finger syndactyly, 2-3 toe syndactyly, hands with unusual simian creases, liver defects, gallbladder defects, short neck, genital defects, twisted intestines
What does triploidy cause the pregnancy to develop? What can mom have bc of the condition?
placenta may be immature, large and filled with cysts (molar pregnancy); mosaic will survive longer but with ID, DD, seizures, short stature, obesity, other abnormalities
pregnant mother sometimes has HTN, edema, and albuminuria (AKA Preeclampsia)
What are the ways in which triploidy can occur
Type 1: (fertilization of an egg by two sperms (most common); fertilization of an egg by a diploid sperm) diandry, associated with moderate growth delay, normal or microcephalic head and enlarged placenta with a partial mole
Type 2: (fertilization of a diploid egg by a single sperm) digyny, associated with severe limb and trunk growth delays, macrocephaly, uneven development of body parts with a molar placenta
What is a molar pregnancy and what risks does it carry
molar pregnancy is a rare complication caused by unusual growth of trophoblasts
placental tissue swells and appears to form fluid-filled cysts and there is no fetus
women who have had a molar pregnancy need to be followed bc remnants can grow and carry a small risk of developing into a cancer called choriocarcinoma; aim is to ensure if it does develop to catch it early and tx it; f/u is usually between 6mo-2yrs
What is a partial molar pregnancy
placenta might have both regular and irregular tissue
might be a fetus, but the fetus usually miscarries early in the pregnancy
occurs due to diandric triploidy
How often does triploidy occur in pregnancies? In what sex are they most common
1-3%
2/3 of triploid pregnancies are male
What type of technology can triploidy NOT be picked up on
CMA
Counting method-based NIPT
What does the extra X chromosome contribute to the phenotype of KS
responsible for testicular hyalinization (tissue degeneration into a glass-like substance) and fibrosis leading to primary gonadal failure
hypogonadism
SHOX gene in PAR leads to tall stature, long limbs, reduced upper/lower segment ratio
What tx/management is available for pts with KS
PT/OT/adaptive tx like orthotics
supplemental testosterone tx for hypogonadism
screening for ASD
calcium and vitamin D supplementation
TESE
What percentage of pts with KS will likely have metabolic syndrome
44% due to hypogonadism and obesity (insulin resistance, type 2 diabetes, dyslipidemia, fatty liver dz, peripheral vascular dz, thromboembolic dz)
What is TESE
Testicular sperm extraction: small pockets of gonadal tissue producing sperm may be identified, extracted, and injected by intracytoplasmic sperm injection into an ovum for fertilization
What cancer risks are associated with KS
Breast cancer (50x greater risk than other men), extragonadal germ cell tumors, non-Hodgkin lymphoma
no routine screening is warranted
What percentage of men of infertile men are XXY? What percent have full 47,XXY
~3%; ~85%, rest are mosaic or another form
What is the most common sex chromosomal abnormality found in females
Turner
What percentage of individuals with Turner syndrome have the classic chromosomal karyotype? Other chromosomal causes (mosaicism/nonfunctional X)?
50% have monosomy X (45,XO)
50% have a mosaic chromosomal component (45,X with moasicism)
What are some of the etiologies for non-classic Turner syndrome
Isochromosome Xq, where there are two copies of the long arm of the chrom that are connected head to head
Ring chromosome: where a part of the ends of short and long arms of the X chromosome is missing
Xp or Xq deletion: deletion of part of the short arm of the X
chromosome takes place
RARELY Turner can result from the deletion which is inherited, rather than the sporadic nature of the other etiologies
SHOX: associated with the short stature in the condition
What is the prevalence of Turner syndrome? Why is the prevalence going down
1 in 2000-2500
birth rate is decreasing bc some mothers carrying fetuses choose to terminate the pregnancy
Describe the prenatal features and newborn features associated with Turner syndrome
increased NT, nuchal cystic hygroma, coarctation of the aorta/left-sided heat anomalies, brachycephaly, horseshoe kidney, polyhydramnios, oligohydramnios, or fetal hydrops
Newborn: congenital lymphedema of the hands and feet, webbed neck, nail dysplasia, narrow and high arched palate, short fourth metacarpals/metatarsals
Describe the adult features associated with Turner syndrome
short stature, “shield” chest with widely spaced nipples, webbed neck, low anterior hairline, deformities of the forearm and wrist
normal intelligence, increased risk of learning disabilities, delayed puberty, primary amenorrhea, premature ovarian failure, streak gonads, cardiac malformations, aortic dissection, hearing loss, horseshoe kidneys, nearsightedness or farsightedness, strabismus, amblyopia, epicanthal folds, ptosis, hypertelorism, red-green color blindness, hypothyroidism, celiac dz, IBD, increased risk for gonadoblastoma
What are streak gonads
ovaries mainly consisting of connective tissue and no follicles or only a few atretic follices
What is the next step if an initial karyotype is normal in a pt with clinically suspected Turner syndrome
second karyotype should be performed using a different tissue like skin, buccal mucosa cells, or bladder epithelial cells
What tx is available for Turner syndrome
pts respond well to growth hormone therapy and should be started on tx with growth hormone once their height falls below 5% for age
if pts develop scoliosis, they should be referred to an orthopedic sx
evaluation by cardiologist w EKG for prolonged QT interval, echo or MRI to look at cardiac anomalies; QT prolonging drugs should be avoided; if coarctation of aorta is present, needs sx to correct it; blood pressure should be controlled using beta blockers as first line tx, followed by ACE inhibitors
may need special education in school
audiology exam q3-5yrs
serum FSH and AMH should be measured around 10-11 to assess for ovarian function; estrogen replacement therapy from 11-12yrs
renal u/s necessary at time of dx
cryopreservation of ovarian tissue or oocytes recommended after 12yo
screening for celiac, autoimmune thyroiditis, liver dz, metabolic syndrome, Vit D deficiency, and gonadoblastoma
Who with Tuner syndrome should be screened for Y chromosome material? If it’s present, what should you do?
those who have marker chromosome elements on karyotype or those who develop virilization
gonads should be removed, otherwise it increases the risk of gonadoblastoma
What consultations should someone with Turner syndrome have
endocrinology, cardiology, gynecology, audiology, ophthalmology, orthopedic sx (if they develop scoliosis), nephrology (if they have renal anomalies)
What is the only viable monosomy?
Turner
What percentage of Turner babies miscarry?
98%
How does Jacobs syndrome occur and what is the other form of it
most commonly arises in me II in the father
less common form is 46,XY/47,XYY mosaicism
What are the features associated with Jacobs syndrome
tall stature, mild learning disabilities, delayed speech, flat feet, macrodontia, underbites, macrocephaly, hypotonia, clinodactyly, hypertelorism, developmental delay, behavioral issues, increased incidence of asthma and ASD
most boys go through puberty normally and many men are fertile despite the increased risk of sperm abnormalities
What tx/management is available for those with Jacobs syndrome
speech therapy and behavioral interventions, OT if hypotonia is present, comprehensive eval from reproductive endocrinologist (IVF or ICSI available, many who do so are able to father children successfully)
What clinical features are associated with Triple X syndrome
epicanthal folds, hypertelorism, hypotonia, clinodactyly, tall stature, delays in attaining developmental milestones, delayed speech and language, learning difficulties, anxiety, ADHD, normal sexual and fertility development
How does triple X occur?
studies suggest that the risk of the condition increases with maternal age
in most children, the extra X chromosome comes from the mother
What tx/management is recommended for pts with triple X syndrome
early intervention for infants, evaluate muscle tone and strength, speech/OT/PT
What causes Wolf-Hirschhorn syndrome? Who does it affect?
occurs more frequently in females than in males
deletion in the short arm of chrom 4p (4p16.3).
deletions more than 3-5Mb are associated with a higher risk of CHDs and cleft palate
How is Wolf-Hirschhorn syndrome dx?
FISH and CMA
EEG can pick up abnormal brain activity in 90% of pts
What clinical features are associated with Wolf-Hirschhorn syndrome
IUGR, distinctive facies (“greek warrior helmet”; broad nasal bridge continuing to the forehead, microcephaly, high forehead with prominent glabella (area of skin btwn eyebrows and above nose), high arched eyebrows, hypertelorism, epicanthus, poorly formed ears with pits/tags, short philtrum, downturned mouth, micrognathia, cleft lip/palate), kyphosis, scoliosis, accessory/fused ribs, clubfeet, split hand, hypotonia, severe DD, feeding difficulties, FTT, ID (mod to severe), seizure often triggered by fever, thinning of the corpus callosum, CHDs, recurrent respiratory infections and ear infections due to antibody deficiency, half of male pts with hypospadias and cryptorchidism
How is Wolf-Hirschhorn syndrome tx?
symptomatic and requires multidisciplinary management including rehab programs, appropriate seizure tx and feeding therapies)
most individuals survive into adulthood
What is the etiology of cri du chat syndrome
partial or complete del of chromosome 5p (dels occur de novo); occurs from chromosomal breakage during gamete formation females more commonly affected
80-90% are paternal in origin
10-15% result from unbalanced parental t’s
80-90% result from terminal dels of chrom 5
3-5% are due to an interstitial del
What parts of the chromosome are responsible for the features in cri du chat syndrome
critical region is 5p15.2, individuals with a del that does not include this region do not show a typical phenotype and in some cases are even normal
5p15.3: responsible for characteristic cry
5p15.2: responsible for the other significant clinical features
What clinical features are associated with cri du chat syndrome
microcephaly, moon face, hypertelorism, prominent epicanthic folds, large nasal bridge, downturned corners of the mouth, short philtrum, premature grey hair, abnormal transverse flexion creases
hypotonia in neonatal period with later hypertonia
prominent microcephaly
prominent supraorbital arch, dental malocclusions
hypersensitivity to sound, cardiac disorders/CHDs, cutaneous hemangioma, renal pathology
high palate, mandibular microretrognathia, hypoplasia of the enamel, chronic periodontitis
hyperactivity, self-injurious behavior, repetitive movements, gentle personality, obsessive attachment to objects
How is cri du chat syndrome dx
karyotype; if negative, FISH, CGH, qPCR
What tx is available for pts for cri du chat syndrome
pts benefit from rehab, especially with early intervention
PT to help with any difficulty in swallowing and suction
psychomotricity, speech therapy
audiometric exam should occur in all children bc of SNHL
What is the expected prognosis of pts with cri du chat syndrome
morbidity and mortality decrease after the first few yrs of life
75% of deaths occur during the first mo, about 90% occur during the first yr
early dx is the most important factor in prognosis of the dz; also size, and placement of deletion
Describe the features associated with 1p36 del syndrome
microbrachycephaly, large and late-closing anterior fontanel, straight eyebrows, deep set eyes, broad and depressed nasal bridge, midface retrusion, posteriorly rotated low set abnormal ears, long philtrum, pointed chin, brachydactyly, camptodactyly and short feet
congenital hypotonia, feeding difficulties, delay in motor development and fine motor skills, delayed or absent speech, prenatal-onset growth deficiency, structural brain abnormalities, seizures, CHDs, eye/vision problems, hearing loss, skeletal abnormalities, abnormalities of the external genitalia
What is the etiology of 1p36 del syndrome
breakpoints ranging from 1p36.3 to 1p36.33
50% of cases are due to a de novo terminal 1p36 del and 29% due to an interstitial del
remaining are due to complex chromosomal rearrangements
How can 1p36 del syndrome be dx? What evals should they undergo
FISH, CMA
eval for CHDs (echo and electrocardiogram); brain abnormalities with MRI, seizures with EEG; neurodevelopmental assessment; standard exams for eye/vision problems, hearing loss, skeletal and renal abnormalities
What is the prognosis for pts with 1p36 del syndrome
severity varies between affected individuals
pts with remain dependent on others for most activities of daily living and will require medical support throughout their lifetime
survive well into adult life
What laboratory features would you expect to see in pts with 22q11.2 del syndrome
hypoparathyroidism, hypothyroidism, growth hormone deficiency, cytopenias (thrombocytopenia, hemolytic anemia, and neutropenia)
What is the etiology of 22q11.2 del syndrome
identification of a heterozygous 2.54Mb deletion at 22q11.2 in ~85% of pts; extends from the flanking low copy number repeats A-D including TBX1 (90% de novo, 10% inherited)
~5% have a heterozygous 1.5Mb del from LCRs A-B; 2% have a del from A-C; 5% have smaller dels from B-D or C-D (these are also called nested deletions and are typically inherited from a parent (60%))
phenotype of significantly smaller/larger dels within this region may be clinically distinct from 22q11.2DS; PVs in a single gene in this region are NOT causative of 22q11.2DS
How is 22q11.2 del syndrome dx
CMA or targeted del analysis
before 04, CMA platforms did not include coverage for this region and ppl may not have been dx
targeted del analysis= FISH, MLPA, and qPCR; not appropriate for an individual whose deletion was not detected by CMA; MLPA can be used to detect the different deletion sizes by LCR
Describe the clinical features associated with 22q11.2 del syndrome
Heart: CHDs in 64% (conotruncal defects- VSDs, tetralogy of Fallot); major cause of mortality (~87% of deaths), die prematurely with sudden death
Palate: 67% w palatal abnormality, most common- velopharyngeal incompetence, submucosal cleft palate, bifid uvula
Feeding: 36% w significant feeding issues, severe dysphagia, dysmotility in pharyngoesophageal area from 3rd and 4th pharyngeal arches, constipation
Immune: immunodeficiency from thymic hypoplasia and impaired T cell production (function as well); children with significant deficiencies typically improve in first yr of life; C4+ lymphopenia associated with TBX dels; recurrent sinusitis, otitis media, lower respiratory infections
Autoimmune: idiopathic thrombocytopenia purpura seen 200x more frequently than general pop
Parathyroid: under function is most severe in neonatal period
Growth: most adults are of normal stature, children in less than 5th percentile for height; obesity
Eyes: hooded lids, posterior embryotoxon, tortuous retinal vessels, strabismus
Other craniofacial features: cupped, microtic, protuberant ears; preauricular pits or tags, hearing loss, stridor, laryngomalacia, vascular ring; facial features may NOT be present in persons of AA descent
CNS: hypotonia in infancy, microcephaly, seizures associated with hypocalcemia; significantly reduced brain volumes
Psychosocial development/cognitive function: delays in motor milestones and emergence of language, significantly delayed mental development
Psychiatric illness: disinhibition and impulsiveness, shyness, ADHD, anxiety, ASD; 60% of adults with psychiatric disorders, 25% with schizophrenia; increased risk for early Parkinson dz
Musculoskeletal: 91-100% with occipital-cervical anomaly (flattening of skull, open arch at first cervical vertebra), club foot, polydactyly, shoulder deformities, overfolded toes
Genitourinary: unilateral hydronephrosis, renal agenesis, multicystic dysplastic kidney; boys more likely to have abnormalitiy than girls- cryptorchidism and hypospadias, girls with vaginal agenesis and uterine agenesis
Other: abnormal lung lobation, dental carries, malignancies (hepatoblastoma, RCC, thyroid carcinoma, melanoma, leukemia, Wilms tumor, neuroblastoma)
What conditions are under the 22q11.2 del syndrome classification? When is DiGeorge used?
encompasses the phenotypes of DiGeorge, Velocardiofacial syndrome, conotruncal anomaly face syndrome, some cases of AD Opitz G/BBB syndrome, and Cayler cardiofacial syndrome
DiGeorge is only used if someone has the clinical features of 22q11.2 but no deletion detection
What is the most frequent microdeletion syndrome
22q11.2 syndrome
What evals does someone need following 22q11.2 syndrome dx
cardiology, ENT, gastro, immunology, hematology, endocrine, ophthalmology, audiology, neurology, speech and language assessment, psychiatry, musculoskeletal, nephrology
What are the recommended tx for a pt with 22q11.2 syndrome
sx/tx for cardiac anomalies
sx for palatal anomalies
tx for feeding difficulties
tx infections aggressively, tx for autoimmune dz
calcium supplementation
standard tx for growth hormone deficiency, ocular anomalies, seizures, PT/OT/speech therapy, psych illnesses, enamel hypoplasia
hearing aids
restriction of activity for cervical spine abnormalities
sx/tx for renal anomalies
What should pts with 22q11.2 syndrome avoid
infants with lymphocyte abnormalities should not be immunized with live vaccines
carbonated drinks and alcohol consumption may exacerbate hypocalcemia
caffeine intake may contribute to anxiety
How should a high risk pregnancy for DiGeorge syndrome be managed
level II u/s with fetal echo to evaluate for: CHDs, airway, palate, swallowing, and gastro issues leading to polyhydramnios (congenital diaphragmatic hernia, tracheoesophageal fistula, subglottic stenosis, vascular ring, laryngeal web, cleft palate); renal anomalies, skeletal issues like club foot and craniosynostosis; umbilical and inguinal hernia
How is the dx of Williams syndrome established
identification of a heterozygous 1.5-1.8Mb del at chromosome 7q11.23
CMA or FISH (can be used in situations where CMA is not available)
What clinical features are seen in Williams syndrome
50% of infants are small for GA
mild ID in ~75% of individuals (strength in verbal short term mem but extreme weakness in visuospatial cognition)
overfriendliness, social disinhibition, excessive empathy, attention problems, specific phobias, repetitive behavior and specific interests (less than 10% live independently)
sleep disorders occur in 65%
elastin arteriopathy is the major cause of morbidity and mortality (SVAS is most common and may worsen over time especially in first 5yrs of life; 1/3 will require sx correction); elevate left heart pressure, cardiac hypertrophy and cardiac failure (has been implicated as a cause of sudden death)
increased sensitivity to sound is common, dental findings, sensory defensiveness, chronic abdominal pain, hypercalcemia in infancy (but may recur in adults); most often symptomatic (vomiting, irritability, constipation) in first 2yrs of life
urinary frequency, renal artery stenosis, bladder capacity is reduced
hypotonia, lax joints, scoliosis is common, ataxia, dysmetria, tremor, reduced brain size, reduced gray matter volume
hoarse or low-pitched voice, hair grays prematurely, poor weight gain, prenatal growth deficiency, poor linear growth, obesity and overweight, precocious puberty; hypothyroidism
stellate/lacy iris pattern in the eye, malar flattening, full cheeks, long face and neck, sloping shoulders
What are the genotype-phenotype correlations in Williams syndrome
1.55Mb (90-95% of individuals; contains 25 genes)
1.84Mb (5-10% of individuals; contains 27 genes)
dels within the WBSCR may be of maternal OR paternal origin; microcephaly has been correlated with maternal origin of the WBSCR del in others
What initial evals should be conducted following a Williams syndrome dx
plot growth parameters, complete physical and neuro exam
developmental assessment
neuropsychiatric eval
eval by cardiologist, measure BP, echo and ECG
ophthalmologic eval
audiologic eval
dental eval
gastro/nutrition/feeding team eval
u/s of bladder and kidneys
orthopedics/PT/OT
serum concentration of calcium or ionized calcium; urine calcium to creatinine or spot urine sample
thyroid function tests
What should pts with Williams syndrome avoid? How should pregnancies with Williams syndrome be managed?
avoid vitamin D
should be monitored for the development of pregnancy induced HTN, arrhythmias, and heart failure; regular urinalyses in late gestation due to increased risk for UTI
What are some genetic counseling considerations that need to take place when thinking about Williams syndrome
in ~25% of families, the unaffected parent in whom the del originated has an inversion on chrom 7 involving 7q11.23
~6% of the general pop also has this inversion polymorphism
What causes Smith Magenis syndrome? How is it dx?
heterozygous del of 17p11.2 (70% with 3.5Mb deletion; 20% with larger or smaller deletions)
heterozygous PV in RAI1 (sequence analysis then del dup)
CMA typically is performed first (visible del can be detected by routine karyotype but it is not uncommon for the del to be overlooked)
What are the facial characteristics and neurologic features associated with Smith Magenis syndrome
brachycephaly, synophrys, deep set eyes, midface retrusion, micrognathia in infancy (facial features becomes more recognizable in early childhood)
hypotonia, hyporeflexia, peripheral neuropathy, relative insensitivity to pain, mild intention tremor of upper extremity, “inverted champagne bottle appearance” with pes cavus or pes planus deformity, broad-based gait, toe walking, DD, mild- moderate ID, infrequent crying, decreased babbling, relative strength in long term memort
What behavioral features are associated with Smith Magenis syndrome
sleep disturbance, maladaptive and self-injurious behaviors (nail yanking (onychotillomania), skin picking, insertion of foreign objects into body orifices (polyembolokoilamania)), stereotypies (self-hugging behaviors, teeth grinding, body rocking, “lick and flip” behavior), significant social impairment , head banging, frequent outbursts/temper tantrums, attention-seeking behaviors, impulsivity, inattention with or without hyperactivity, oppositional behaviors, aggression, rapid mood shifts, anxiety, toileting difficulties, inverted circadian rhythm, fragmented and shortened sleep cycles
degree of sleep disturbance remains one of the strongest predictors of maladaptive behaviors
caution must be taken when evaluating individuals with SMS for maltreatment or abuse
What growth/feeding features, oral/dental features, musculoskeletal features, hearing features, endocrine, and malignancy features are seen in pts with Smith Magenis syndrome
food foraging at night, obesity
high prevalence of dental anomalies, specifically tooth agenesis
hands and feet remain small
hearing loss, hyperacusis, or oversensitivity to certain frequencies/sounds
puberty typically occurs in the normal time frame
dry skin
SMS due to a heterozygous 17p11.2 deletion often results in haploinsufficiency of FLCN that is associated with Birt Hogg Dube syndrome (adult onset hereditary cancer syndrome characterized by cutaneous fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax, and renal tumors)
What is the prognosis of Smith Magenis syndrome? What are some phenotype/genotype correlations
life expectancy does not differ from those with other cognitive impairment (near normal)
In those with PVs in RAI1: higher rates of onychotillomania and polyembolokoilamania, risk of obesity, but do not have short stature or other organ system involvement
What recommended surveillance should someone with Smith Magenis syndrome undergo
neurologic (monitoring of seizures); multidisciplinary team to develop an IEP; behavior assessment for attention, aggressive, or self injurious behavior; measurement of growth parameters; fasting lipid profile; otolaryngologic for assessment and management of otitis media and other sinus abnormalities; audiologic eval to monitor for conductive or SNHL annually; monitoring for scoliosis; ophthalmologic eval; routine urinalysis for UTIs; thyroid function w T4 and TSH; repeat qualitative immunoglobulins with vaccine titers; complications of BHD in persons with FLCN deletion should be tx as typical
How is Prader Willi syndrome dx
identification of abnormal DNA methylation within the PWCR
del of the paternally inherited 15q11.2-q13
uniparental disomy of the maternal chromosome (UPD 15)
imprinting defect of the paternal chrom either due to an imprinting center del or epimutation
How is Prader Willi syndrome dx
First tier testing
begin with DNA methylation analysis (methylation specific PCR, identification of maternal-only imprinting but CANNOT identify the cause of the abnormal DNA methylation) and oligo small nucleotide polymorphism combination array (OSA) (detects del/dups, small imprinting center dels; WILL identify individuals with UPD 15 due to isodisomy and segmental isodisomy)
Second tier testing
DNA polymorphism testing of the proband and parents is recommended to identify UPD 15 due to heterodisomy or abnormal DNA methylation
Other third tier options
MS-MLPA can establish the dx by identification of maternal only imprinting; CANNOT distinguish UPD 15 from an imprinting defect by epimutation
DNA sequence analysis can identify imprinting defects due to imprinting center deletions but is not often used
FISH has limited specific probes, does NOT query the whole PWCR, determine the size of the deletion, provide info about the rest of the chroms; identify UPD 15 or imprinting defects; may only be used to clarify recurrence risk
What is the breakdown of the causes for Prader Willi syndrome
15q del 60-70%
UPD 15 complete isodisomy 4-5%
UPD 15 segmental isodisomy 17-23%
UPD 15 heterodisomy ~8-11%
imprinting center deletion <0.5%
imprinting defect by epimutation ~2-4%
What are features associated with Prader Willi syndrome
perinatal findings: decreased fetal movements, small for GA, prenatal hypotonia
decreased movement and lethargy w decreased spontaneous arousal, weak cry, poor reflexes, poor suck, dysphagia, lethargy, poor appetite, poor weight gain in early infancy, feeding difficulties, early motor milestones at ~ 2x the normal age, language milestones are delayed and speech is impaired, mild ID, multiple severe learning disabilities
hypogonadism, genital hypoplasia, incomplete pubertal development, infertility, hypoplastic scrotum with poorly rugated scrotal skin, decreased pigmentation, unilateral/bilateral cryptorchidism, advanced bone age, reduced GH secretion, short stature, hands and feet grow slowly
hypothalamic pituitary dysfunction, hypothyroidism by 2yo, corticotropin deficiency, and abnormal oxytocin neurons, up to 25% with type II diabetes by 20yo, hyperphagia causing lack of satiety leading to hoarding/foraging for food, eating of inedible objects, stealing of food or money to buy food; obesity results from hyperphagic behaviors and decreased total caloric requirements
delayed gastric emptying, rare vomiting increasing the risk of gastric necrosis with significant hyperphagia, anxiety, tantrums, rigidity/resistance to change, OCD, early onset ADHD, psychosis by young adulthood
diminished pain perception, characteristic facial features, hypopigmentation of hair, eyes, and skin (due to del of OCA2 on 15q), skin and mucosal picking, strabismus, myopia, reduced REM, altered sleep patterns, narcolepsy, scoliosis presumed to be related to hypotonia, generalized seizures, decreased saliva flow, increased dental caries, dental crowding and enamel hypoplasia,
What is the lifespan for those with Prader Willi syndrome
respiratory failure/other febrile illnesses are the most frequent cause of death in children
cardiac dz and failure, pulmonary thromboembolism, obesity-related complications, and gastric causes are most common in adults
choking is common; due to disordered pharyngeal and esophageal swallowing and lack of attempt to clear residue or coughing is common
What are some genotype phenotype correlations in Prader Willi syndrome
post term delivery and AMA is more common with UPD 15
individuals with UPD 15 are less likely to have the typical facial appearance, hypopigmentation, or skill with jigsaw puzzles is somewhat higher verbal IQ than those with 15q del
those with UPD 15 are more likely to have psychosis and ASD
What txs are recommended for Prader Willi syndrome
poor infantile feeding- special feeding techniques (special nipples or gavage feeding by nasogastric tube)
hypogonadism- consider hCG tx in infancy for cryptorchidism, orchiopexy as needed; HRT at puberty and beyond
endocrine manifestations- GH tx normalizes height, increased lean body mass, decreased fat mass, and increased mobility which are beneficial to weight management; tx for precocious puberty, type 2 diabetes, hypothyroidism, and/or central adrenal insufficiency
hyperphagia/obesity- well-balanced, low calorie diet, regular exercise, and close supervision to minimize food stealing and prevent obesity
acute gastro manifestations- vomiting and/or loss of appetite could signal life threatening illness
neurobehavioral manifestations- ABA therapy in childhood helps ameliorate some of the common behavioral issues; standard pharmacologic therapy
dermatologic manifestations- consider meds for skin picking if not managed w distraction or covering lesions
ophthalmologic- tx of strabismus
sleep issues- individualized tx depending on cause which may include tonsillectomy and adenoidectomy and/or CPAP/BiPAPA
Skeletal- calcium and vitamin D supplementation; GH therapy, bisphosphonate therapy for low bone density
seizures- ASM
decreased saliva production- manage w products developed for tx of dry mouth such as special toothpastes, gels, mouthwash, and gum
What surveillance is recommended for Prader Willi syndrome
monitor developmental progress and educational needs
monitor testicular positioning as cryptorchidism may recur after orchidopexy
hemoglobin A1C/ glucose tolerance test for DM
Free T4 and TSH levels for hypothyroidism; assess for central adrenal insufficiency
monitor height, weight, and BMI
assess for presence of behavioral findings and OCD features, psychosis, radical behavioral changes
skin exam for sores, cutaneous infection
ophthalmologic exam for strabismus and/or refractive errors
assess for snoring, frequent nocturnal awakening, eval for respiratory status during sleep with sleep study,
clinical exam for scoliosis
bone density exam by DXA scan
assess for new seizures
dental eval
What should pts with Prader Willi syndrome avoid
unsupervised access to food since hyperphagia may result in rapid ingestion and fatal choking, silent aspiration, and exposure to spoiled food
emetics are typically ineffective for induction of vomiting after ingestion of uncooked/spoiled food items
antidiarrheal meds can cause severe colonic distention, necrosis, and rupture
What is the recurrence risk to sibs for Prader Willi syndrome? What parental testing should be offered?
15q del: proband should have karyotype and FISH (<1% risk); father should have karyotype and FISH (to identify cryptic t or paracentric inversion of 15q11.2) (up to 25% risk)
UPD15: proband w karyotype; if normal, then karyotype; if proband has marker chromosome, then karyotype in both parents; if proband has 15/15 t, then karyotype mom (risk ranges from less than 1% to 100% for rob t)
imprinting center defect: proband doesn’t need any additional testing (less than 1% risk); father should have DNA methylation and OSA (or MLPA) (50% risk to sib)
imprinting defect by epimutation: no additional testing necessary, <1% risk to sibs
What testing should be done in pregnancies where no family hx of PWS exists
if a 15q11.2 del is suspected on CVS/Amnio, OSA is indicated; parent of origin studies should be performed after confirmation of a del to determine if the del is maternally derived (AS) or paternally derived (PWS)
if trisomy 15 or mosaic trisomy 15 is detected on testing of CVS and if amnio shows 46 chroms, possibility of trisomy rescue leading to loss of a paternal chromosome 15 (UPD 15) should be considered
if an inherited or de novo t involving chrom 15 is present or if a supernumerary OSA (to rule out del) and parent of origin or DNA methylation studies (to r/o UPD) are indicated
NIPT has a high false positive rate and will NOT distinguish an AS del from a PWS del and will not detect UPD and imprinting defects
What is the deletion mechanism associated with Prader Willi syndrome
accounts for 60-70% of individuals with PWS
multiple tandem repeats flank the common breakpoints; these low copy repeat sequences are subject to nonhomologous paring during meiosis, leading to dels, dups, triplications, and inverted dups of chrom 15
How can Angelman syndrome be caused?
abnormal methylation at 15q11.2-q13 due to:
del of mat inherited 15q11.2-q13
pat UPD 15
mat imprinting defect on chrom (only paternal contribution)
mat UBE3A PV
How can the dx of Angelman syndrome be established?
DNA methylation analysis first- identifies 80% of individuals with AS (CANNOT distinguish between AS resulting from a del, UPD, or imprinting defect). If normal:
sequence then del dup of UBE3A
based on lab findings, in an individual who is found to have the del on CMA, FISH, or karyotype, perform DNA methylation to determine if the del is on the maternally derived chrom 15 (less than 1% of affected individuals have a chromosome rearrangement in the 15q11.2-q13 region)
Using the following dx techniques, what CANNOT be picked up for the dx of Angelman syndrome: DNA methylation, MS-MLPA, FISH, CMA, UPD analysis, AS imprinting center deletion analysis, UBE3A sequence analysis
Del of 15q11.2-q13 CANNOT be picked up by UPD analysis or UBE3A sequence/del dup
UPD CANNOT be picked up with FISH
Imprinting defects CANNOT be picked up with FISH, CMA, or UPD
Describe the clinical features seen in pts with Angelman syndrome
seizures by 5yo; generalized, somewhat specific EEG changes, most common are myoclonic, atonic, generalized tonic-clonic, and atypical absence; brain MRI with mild atrophy and mild dysmyelination; NONCONVULSIVE STATUS EPILEPTICUS: can be associated with loss of developmental skills and diminished awareness and may last several hrs or days; NONEPILEPTIC MYOCLONUS can include jerking, tic like, or twitching movements
sleep problems- early and frequent awakenings, dyssomnias (cant fall asleep or maintain it), fragmented and irregular sleep wake cycles, disruptive night laughter/seizures; constipation, GERD, scoliosis
behavioral features- frequent laughter and smiling, apparent happy demeanor, excitability, hand-flapping movements, hypermotoric behavior, constantly keeping hands/toys in mouth, hyperactivity, aggressive and self-injurious behavior (pinching, biting, grabbing, slapping, hitting); frustrations communicating preferences and wants, seeking sensory stimulation and social attention, avoidance of undesired situations
jerky, robot-like, stiff gait, legs kept wide based, “puppet like arms”; 10% of children are non ambulatory; severe language and cognitive impairment (appropriate and consistent used of 1-2 words is rare); communicate by pointing, reaching, using gestures
sucking difficulties, hypotonia, cyclic vomiting, hyperphagia, microcephaly, characteristic facial features (flat occiput, occipital groove, wide mouth, widely spaced teeth, protruding tongue, and prognathia; lighter hair, skin and eyes; strabismus; scoliosis, normal pubertal development and fertility
What is the prognosis of Angelman syndrome
generally good physical health and life span appears to be nearly normal
independent living is not possible for adults with Angelman syndrome
What phenotype-genotype correlations exist in Angelman syndrome
15q11.2-q13 del results in the most severe phenotype with microcephaly, seizures, motor difficulties, and language impairment; also have a lower BMI compared to individuals with UPD or imprinting defect
those with UBE3A PVs (truncating more severe than missense) and with imprinting defects may be less clinically affected than those with UPD
individuals who are mosaic for the nondeletion imprinting defect have the most advanced speech skills (Still only ~60 words)
What evaluations should someone with Angelman syndrome undergo following dx
neuro exam including brain MRI, EEG
developmental and behavioral assessment
gastro/nutrition/feeding team eval
ophthalmology exam
orthopedics/PT/OT for mobility issues
How should pts with Angelman syndrome be tx
ASM; some with uncontrollable seizures benefit from ketogenic or low glycemic diet
make accommodations for a safe environment for the pt and their family in the home; sleep is safe but confining bedrooms to accommodate disruptive nighttime wakefulness may be necessary (can also give melatonin to help)
OT/PT/speech; special adaptive chairs may be required for extremely ataxic children
upright positioning and motility drugs for GERD
newborns may require feeding therapy to prevent FTT and deal with feeding issues
may need surgical rod stabilization/lumbar jackets for scoliosis
What are children with Angelman syndrome at risk for
overtreatment bc their movement abnormalities can be mistaken for seizures and their EEG abnormalities can persist despite seizures being controlled
What is the recurrence risk to sibs for Angelman syndrome? What parental testing should be offered?
15q del (65-75%): mother should have karyotype and FISH (<1% risk if all normal); if mom has a chromosomal rearrangement, risk can be up to 50%
UPD15: karyotype in both parents; if proband has 15/15 t, then karyotype dad (risk ranges from less than 1% (both parents normal) to 100% for rob t)
imprinting center defect: mother should have targeted IC del testing (<1% risk if normal, if mom is a carrier for the del, 50% risk to sib); if no del in the imprinting center in the proband, there is a <1% rr
PV in UBE3A: mom should have targeted testing for UBE3A PV; if mom is heterozygous, 50% risk for each sib (since ~30% of UBE3A PVs are inherited); <1% if no PV is found in mom
What is the relationship between IVF, fertility, and Angelman syndrome
IVF and ICSI have been demonstrated to increase the chance of certain imprinting disorders
association between fertility issues and Angelman syndrome
What is the molecular pathogenesis of Angelman syndrome
UBE3A has a large 5’ CpG island; DNA methylation does NOT differ between the mat and pat alleles; imprinted expression of UBE3A is regulated indirectly through a paternally expressed antisense transcript, which can block paternal UBE3A expression
What does WAGR stand for
Wilms tumor, aniridia, genitourinary anomalies, intellectual disability
What clinical features are associated with WAGR
Most affected pts have two or more clinical features at birth (although some may be hard to detect/don’t show in a pt)
congenital aniridia, cataracts, glaucoma, limbal insufficiency, optic nerve hypoplasia, corneal opacification, visual impairment
risk for end stage renal dz when presenting with Wilms tumor (45-60% of pts); bilateral synchronous kidney tumors are the most common (4-7%) and present <5yo
can also have genitourinary anomalies, neurological abnormalities, variable ID or behavioral abnormalities
What is the etiology of WAGR
contiguous gene deletion syndrome involving an interstitial de novo 11p13 micro del of variable size
most cases are sporadic although rarely is inherited AD
What pathognomonic feature of WAGR syndrome should prompt genetic testing
Congenital aniridia in infants to detect the specific deletion or other genetic etiology
What management/tx is available for pts with WAGR
supportive measures for visual impairment and light sensitivity
medical/sx intervention for cataracts, glaucoma, corneal complications
sx, chemo, radiation can be recommended for the tx of tumors
require lifelong oncological and ophthalmologic monitoring
may need transplant for renal dz
What sex is more affected by Jacobsen syndrome
Females (2:1 ratio)
What are the clinical features associated with Jacobsen syndrome
craniofacial dysmorphism (skull deformities, hypertelorism, ptosis, colomboma, downslanting palpebral fissues, epicanthal folds, V-shaped mouth, small low set posteriorly rotated ears), craniosynostosis, eye abnormalities, CHDs, ID, behavioral problems (ADHD, ASD), seizures, Paris-Trousseau bleeding disorder, structural kidney defects, urogenital anomalies (cryptorchidism, chronic constipation, pyloric stenosis), immunodeficiency
What is the etiology of Jacobsen syndrome
del of one copy of the long arm of chrom 11 (11q)
most dels are terminal; interstitial dels in this region and terminal dels less than 7Mb can cause a partial phenotype
How is Jacobsen syndrome dx? What % are de novo
confirmed by CMA and/or FISH
90% de novo, 10% inherited from a parent with a balanced t or from a parent carrying a terminal del of 11q
What is the recommended management/tx for Jacobsen syndrome
evals by pediatrician, pediatric cardiologist, neurologist, hematologist, allergy/immunologist, endocrinologist, and ophthalmologist
might need neurosx, urology, and nephrology consults
psychological/psychiatric care may be warranted; may require heart sx in the neonatal period; special attention needs to be made for hematological problems
What is the prognosis of Jacobsen syndrome
early dx can lead to lifesaving interventions (prophylactic platelet transfusions at times of risk to prevent bleeding, prophylactic antibiotic/IVIG infusions to prevent life-threatening infections, early medical or sx intervention for complex CHDs, brain imaging to identify potential life threatening brain aneurysms
What are the clinical features associated with hereditary neuropathy with liability to pressure palsies
dz onset in the 20s-30s; some pts are asymptomatic and never dx
sudden onset of focal sensory loss and muscle weakness triggered by mechanical stresses to the nerve (compression, repetitive movement, stretching of the affected limbs); foot drop, hand numbness, arm weakness, sensory loss in index finger and thumb; absent deep tendon reflexes, pes cavus, diffuse pain, severe fatigue, severe limb paralysis
50% have incomplete recovery and suffer from recurrent focal sensory and motor deficits
What is the etiology of hereditary neuropathy with liability to pressure palsies
PV in PMP22 (20% of pts); 1.4Mb del of 17p11.2 (80% of pts)
What management/tx is recommended for pts with hereditary neuropathy with liability to pressure palsies
those with foot drop or wrist drop may benefit from an ankle-foot orthosis, wrist splint
activities that involve prolonged sitting with crossed legs, leaning on elbows and repetitive movements of the wrists, as well as rapid weight loss should be avoided
What is the prognosis for pts with hereditary neuropathy with liability to pressure palsies
not life threatening, does not appear to affect longevity
can still suffer from pain and fatigue
What are the clinical features associated with Miller Dieker syndrome
LISSENCEPHALY
severe developmental delay, epilepsy, feeding problems, generalized agyria
What is the etiology of Miller Dieker syndrome
del of 17p13.3 including LIS1 gene
What is the management/tx available for Miller Dieker syndrome
management is symptomatic
nasogastric tubes and gastrostomies
seizure control is important
How is the dx of 16p11.2 del syndrome established
identification of a heterozygous 593kb del at 16p11.2
CMA (how most individuals are identified), exome/genome sequencing with CNV calling (these extra algorithms need to be used to detect the recurrent deletion), targeted del analysis (FISH, qPCR, MLPA)
What clinical features are associated with 16p11.2 del syndrome
one of the most common neurodevelopmental disorders
developmental delay (severity varies); most affected individuals DO NOT have ID although have learning difficulties, increased risk for psychiatric disorders (ADHD, Anxiety, OCD); childhood apraxia of speech, dysarthria, some degree of language impairment, obesity which generally emerges in childhood; almost all have behavioral traits shared with ASD (repetitive movements, problems with social communication, seizures in ~25%; neuroimaging findings (Chiari I malformation; cerebellar tonsillar ectopia; platybasia), pervasive increase in brain volume throughout the brain
How are pts with 16p11.2 del syndrome tx
initiation of weight management and nutrition counseling for obesity
standard tx for psychiatric/behavioral issues, epilepsy, dystonia, Chiari I malformations, scoliosis, Type II diabetes, hearing, CHDs
consider low doses of carbamzepine or phenytoin for paroxysmal kinesignenic dyskinesia
What is the de novo rate for pts with 16p11.2 del syndrome
93%; 7% have a parent that had the deletion, may have more subtle neurodevelopmental and behavioral manifestations
What is the etiology of Koolen de Vries syndrome
17q21.31 del
presence of a PV in KANSL1
What are the clinical features associated with Koolen de Vries syndrome
hypotonia, poor suck, feeding difficulties, tracheo/laryngomalacia, global psychomotor developmental delay, oral hypotonia, apraxia, mild to moderate ID, severely delayed speech development, epilepsy, facial dysmorphism (blepharophimosis, ptosis, pear shaped nose with bulbous nasal tip, large/protruding ears), short stature, pectus excavatum, spine anomalies, dislocation of the hip, long slender fingers, slender lower limbs, heart defects (bicuspid aortic valve, atrial and VSDs), kidney and urologic anomalies, cryptorchidism
Cheerful disposition
How is Koolen de Vries syndrome dx
CMA, multigene panel, comprehensive genomic testing
if normal CMA results, targeted sanger of the KANSL 1 gene can be considered based on clinical findings
What is the management/tx for Koolen de Vries syndrome
routine exams by PCP
cardiac, kidney, and urologic evals
intensive motor speech tx, language development requires focused intervention and augmentative (Sign language) or alternative (communication device) support until oral speech and language develops
derm for multiple nevi
How is Sotos syndrome dx
identification of a PV in NSD1 or 5q35 del encompassing NSD1 (1.9Mb del) on molecular testing (typically seen in most Japanese pts)
sequence then del dup (45-80%) and/or CMA (15-50%)
epigenetic signature analysis/methylation assay: distinctive epigenetic signature in peripheral blood has been identified in individuals with Sotos syndrome; should be considered to clarify the dx
What are the clinical features associated with Sotos syndrome
facial gestalt is evident at birth: dolichocephalic, broad forehead, sparse hair
delay of early developmental milestones, some degree of intellectual impairment
overgrowth of prenatal onset, considerably taller than their peers (bc of increased limb length), macrocephaly
ASD, phobias, aggression, 20% with cardiac anomalies (PDA, ASD, VSD)
cranial ventricular dilatation, cerebral atrophy
pes planus and joint laxity
MATERNAL PREECLAMPSIA OCCURS IN ~15% OF PREGNANCIES WITH SOTOS SYNDROME
jaundice, hypotonia, poor feeding
scoliosis, seizures
tumors: sacrococcygeal teratoma, neuroblastoma, presacral ganglioma, ALL, small cell lung cancer, astrocytoma, Wilms tumor
What are genotype phenotype correlations in Sotos syndrome
those with a 5q35 microdel have less overgrowth and more severe learning disability
How is Sotos syndrome tx
referral to the appropriate specialist for cardiac anomalies, renal anomalies, scoliosis, and seizures
when brain MRI is performed and ventricles are dilatated, shunting is not typically necessary
How is Sotos syndrome managed
cardiac referral; echo; BP check
examine spine for curvature
urinalysis, urine culture for infections
ophthalmologic exam, hearing test if concerns
CANCER SCREENING NOT RECOMMENDED (only 3% of pts)
What is the de novo rate for Sotos syndrome
5% have an affected parent; 95% are de novo
intrafamilial clinical variability has been reported
What are the clinical features associated with Cat eye syndrome
very wide clinical spectrum ranging from normal to severe multisystemic dz
preauricular skin pits/tags, iris coloboma (50%), external ears may be low set and severely reduced, hypertelorism, flat nasal bridge, small mandible, cleft lip/palate, anal atresia, congenital total pulmonary venous return anomaly/TOF, agenesis of kidney(s), hydronephrosis, supernumerary kidneys, renal hypoplasia, spinal defects, limb malformations, biliary atresia, intestinal malrotation, Hirschsprung dz, mild ID
What is the etiology of Cat eye syndrome
most pts harbor a small supernumerary biosatellited marker chrom that results in partial tetrasomy of 22pter-22q11
1/3 of cases is present in the mosaic state
rarely caused by trisomy 22, intrachromosomal triplication of the 22q11 region
How can Cat eye syndrome be dectected
Karyotype and FISH (for low level mosaicism, need specific probes)
What is the management/tx of a pt with Cat eye syndrome
sx correction for anal atresia and severe cardiac manifestations
bacterial infections should be anticipated and tx vigorously
screen for hearing and visual impairment
early intervention and educational support can be beneficial
What is the prognosis for someone with Cat eye syndrome
some pts die from severe malformations in early infancy
life expectancy is generally not reduced for the rest
Describe the clinical features associated with Pallister Killian syndrome
facial dysmorphism (coarse face w flat profile, high forehead with temporo-frontal balding, sparseness of eyebrows and lashes, shallow supraorbital ridges, hypertelorism, flat and broad nasal bridge, short nose with upturned nares, large mouth with downturned corners and prominent upper lip, macroglossia and pointed chin with age)
hypotonia, contractures, diaphragmatic and anal defects, VSDs in 25%, severe ID, pigmentary skin anomalies, deafness, seizures
What is the etiology of Pallister Killian syndrome
pts have mosaicism for a supernumerary isochrom 12p, resulting in four copies of the short arm of chrom 12
mostly of mat origin
karyotype is 47,XX or XY,i(12)(p10)/46,XX or XY
What antenatal presentations (on u/s) can be present in a fetus with Pallister Killian
diaphragmatic hernia, polyhydramnios, hydrops fetalis, cardiac malformations, short limbs
How is Pallister Killian syndrome dx
additional chrom is usually absent from routine blood lymphocytes exam, requires skin bx and fibroblast chrom exam (usually present in 30-100% of fibroblast metaphases)
interphase FISH on a buccal may allow for a prelim dx
What is the prognosis for Pallister Killian syndrome
prognosis is usually poor. Death may occur perinatally, mainly due to diaphragmatic hernias, or during the first yrs of life in ~1/2 of pts
intellectual deficit is mostly profound and almost always accompanied with seizures. Manifestations progress with age; some pts with a low level mosaicism are less severely affected
What is the etiology of Potocki-Lupski syndrome
17p11.2 duplication
What are the clinical features associated with Potocki-Lupski syndrome
hypotonia, poor feeding, FTT, DD (cognitive and language deficits), mild to moderate ID, behavioral problems, anxiety, ADHD, ASD, BPD, dilated aortic root, ASD/VSD, obstructive and central sleep apnea
What is hereditary motor and sensory neuropathies
CMT
nerve length dependent disorder characterized by slowly progressive foot deformities (pes cavus), sensory loss, weakness in the lower extremities, reduced or absent deep tendon reflexes
exhibit symptoms in first-second decade of life, insidious onset of weakness that begins in the lower extremities and later involves the upper extremities
What is the etiology for hereditary motor and sensory neuropathies
80-90% are due to CNVs in PMP22 and PVs in GJB2, MPZ, MFN2
18-50% of cases remain unsolved
CMT1A (most common neuropathy): caused by 1.5Mb dup of 17p11.2 including PMP22 (leads to gene dosage effect, given the sensitivity of nervous tissue to the gain or loss of a copy of the PMP22 gene; results from unequal mitotic crossing over facilitated in the MALE germline)
What are the most common inheritance for hereditary motor and sensory neuropathies
AD CMT is the most common, then XLR, AR are rare
How is CMT categorized based on nerve conduction
Based on median nerve conduction velocity (NCV), CMT is broadly categorized into demyelinating (CMT1), axonal (CMT2) types. Frequency ranges from 37.5-84% for CMT1 and 12-35.9% for CMT2
How is CMT classified based on age of onset? What are the typical features associated?
Early infantile (less than 2yo), childhood (2-10), juvenile (10-20); adult (20-50), late adult (later than 50)
CMT1 accounts for 1/2 of cases: demyelinating pathology, AD, early onset, distal motor weakness, moderate slowing of nerve conduction velocity; CMT1a caused by PV in PMP22, CMTb caused by PV in MPZ
CMT2 accounts for 15-30% of cases: axonal pathology, AD, onset in the 2nd-3rd decade, distal motor weakness, normal or slightly slowed NCV, PV in MFN2
CMTX accounts for 10-15% of cases: both demyelinating and axonal pathology, XLR, onset in 1st-2nd decade, generally more severe in males than females, gait impairment, mild slowing of NCVs, PVs in Cx32 gene
What clinical features can be present in pts with hereditary motor and sensory neuropathies
difficulty walking, running; tripping, falling, delayed motor milestones
symmetrical weakness of the feet and legs, atrophy of weak muscles, reduction/loss of tendon reflexes, skeletal deformities, foot drop/high-stepping gait, hand weakness, musculoskeletal pain, pes cavus, hammer toes, atrophy of the lower legs, scoliosis, ptosis, optic atrophy, early cataracts, glaucoma, age-related macular degeneration, deafness, vocal cord palsy, features of dysautonomia (urinary urgency/incontinence, hyperhidrosis, etc.)
How is the dx of hereditary motor and sensory neuropathies confirmed
EMG and NCV testing for confirming the dx of neuropathy and distinguish between demyelinating and axonal types of CMT
valuable for screening asymptomatic relatives of the index pt
CMT large panel testing should be performed. If not, sequential genetic testing based on motor NCVs should be done
MLPA is the recommended analytical platform; NGS is the preferred technique for establishing the genetic dx in CMT once CNVs or mutations in common genes are excluded.
What is the tx and management for hereditary motor and sensory neuropathies
Refer to neurologists, physiatrists, orthopedic surgeons, podiatrists, PT/OT
need evals for DM, thyroid dysfunction, nutritional deficiencies that affect peripheral nerve function
slit lamp for cataracts, intraocular tension recording for glaucoma, laryngoscopy for vocal cord mobility, and audiometry for hearing loss, spirometry and polysomnography (eval for restrictive lung dz, obstructive sleep apnea, restless leg syndrome)
musculoskeletal pain alleviated with tylenol, NSAIDs; neuropathic pain may respond to tricyclic antidepressants, carbamazepine, gabapentin; fatigue managed w modafinil
PT, corrective sx for foot deformities, scoliosis, hip dysplasia; referral to orthopedic sx for progressive pes cavus, ankle contractures, hip dysplasia, scoliosis
How is the disability of pts with CMT scored? What is the prognosis for these pts?
CMTNS: composite of 9 items that incorporates motor and sensory signs and symptoms, electrophysiological parameters
(0) is the best (mild), (36) is the worst (severe) disability
rate of progression varies among different forms; life expectancy is usually unaffected but condition can be severe if onset is early
How is the dx of MECP2 duplication syndrome established
heterozygous whole gene dup of MECP2
CMA to detect genome wide large dup/dels
ID multigene panel including dup analysis of MECP2 and other genes of interest
What are the clinical features associated with MECP2 duplication syndrome
Mainly affects males, females are often ASYMPTOMATIC due to extreme or total X-inactivation
gastro: feeding difficulties from hypotonia, GERD, FTT, excessive drooling, constipation
development: severely delayed motor developmental milestones, walking also severely delayed; speech development is severely delayed, the majority do not develop speech; moderate to severe ID
spasticity, mild contractures, seizures (most are resistant to tx; onset and severity correlate with neurologic deterioration, characterized by loss of speech, hand use, and/or ambulation)
recurrent respiratory infections, brachycephaly, midface retrusion, large ears depressed nasal bridge, normal growth
What is the recommended tx for MECP2 duplication syndrome
feeding therapy for FTT/Poor weight gain
monitor for constipation
orthopedics/PT/OT speech
ASM by neurologist
tx infections immediately w appropriate antibiotics
What are some genetic counseling considerations for MECP2 duplication syndrome
in a family with more than one affected individual, the mother of an affected male is either an obligate heterozygote for interstitial MECP2 dup or a carrier for a balanced t involving Xq28
X inactivation analysis of amnio cells is not informative bc the pattern in amniotic cells may not correlate with X inactivation in the fetal body and brain
Syndromes associated with a del on the end of a chrom are more likely to occur when…
there is a ring chromosome (both ends of a chrom have dels)
How is the clinical dx of BWS established
established in a proband who has 2 tier 1 findings OR one tier 1 and one tier 2 clinical finding
molecular dx: established in at least one tier 1 or tier 2 clinical finding AND either
1. a constitutional epigenetic or genomic alteration leading to an abnormal methylation pattern at 11p15.5
2. CNV of chromosome 11p15.5
3. heterozygous BWS PV in CDKN1C
Which individuals with BWS should undergo tumor surveillance even in the absence of BWS clinical findings
individuals with constitutional 11p15 (epi)genomic alterations
What is the BWS critical region?
BWS associated with abnormal regulation of gene transcription in TWO imprinted domains on chrom 11p15.5
BWS critical region includes: imprinting center 1, which regulates expression of IGF2 and H19; imprinting center 2, which regulates expression of CDKN1C, KCNQ10T1, and KCNQ1
What are the molecular alterations that can cause BWS
Loss of methylation of IC2 on the MATERNAL chrome (~50%)
Gain of methylation of IC1 on the MATERNAL chrome (~5%)
Paternal UPD of 11p15.5 (~20%)
heterozygous PV on MATERNAL CDKN1C allele (~5%)
can also be caused by translocations, inversions, and dups but these causes are VERY rare (~1%)
20% have an unknown etiology
What genetic testing options should be explored for suspected BWS? What is important to keep in mind about the phenotypic presentation and genetic testing?
children with milder/atypical phenotypes may have mosaic pathogenic BWS causing alterations but may still be at increased risk for developing tumors associated with BWS
testing frequently performed on peripheral blood sample but may need to obtain tissue from an affected region to have a higher likelihood of detecting an alteration
testing can include DNA methylation studies, signle gene testing, CNV analysis for sequences within 11p15.5, CMA, karyotype, and multigene panels
- DNA methylation of both IC2 and IC1 SIMULTANEOUSLY- methylation of both suggests UPD
- single gene testing of CDKN1C should be considered in familial cases, in individuals with BWS and midline anomalies, or in individuals whom a strong clinical suspicion exists but no alternate detectible genetic explanation exists
- CMA: high density SNP array can be used to detect smaller genetic changes including del/dups, segmental paternal UPD, and genome wide UPD
- karyotype: could be considered to test for an inversion or translocation involving 11p15.5
What are some prenatal/perinatal features of BWS
Polyhydramnios, premature birth, and fetal macrosomia; long umbilical cord, enlarged placenta, increased risk for mortality as a result of complications of prematurity, macroglossia, hypoglycemia, and rarely, cardiomyopathy
Describe the growth/craniofacial features associated with BWS
Overgrowth is defined by length/height and/or weight that is >90th or >97th centile, or >2 SDs above the mean for age and sex
adult height typically remains at the upper range of normal
hemihyperplasia: may affect segmental regions of the body or selected organs and tissues; typically characterized by overgrowth of muscle tissue but can be associated with bone overgrowth as well; may be limited to one side of the body (ipsilateral) or involve opposite sides of the body (contralateral)
macroglossia in 90% at birth; can occasionally obstruct breathing in neonates, may also interfere with feeding but typically does not require sx intervention
cleft palate is RARE; ear findings can be unilateral or bilateral; ear lobe creases and ear pits
facies: infraorbital creases, midface retrusion, thin vermilion of the upper lip, and prominent jaw
What are the endocrine, GI, Neoplasia, skin, and renal associations with BWS
Endocrine: neonatal hypoglycemia (most episodes mild and transient, resolve in 72hrs; can last more than that bc of hyperinsulinism (increased insulin secretion and/or action at the time of hypoglycemia)), hypothyroidism
GI: omphalocele, umbilical hernia (may need sx repair), diastasis recti are common
Neoplasia: increased risk for Wilms tumor (risk highest in first 7yrs of life), hepatoblastoma (risk highest in first 3-4yrs of life), neuroblastoma, rhabdomyosarcoma, and adrenocortical carcinoma
Renal: kidney abnormalities, hypercalciuria even in the absence of renal abnormalities
Skin: infantile hemangiomas of the skin and intra abdominal organs; rare hearing loss
What is the general risk of tumors for pts with BWS through loss of methylation at IC2? What cancers are they at highest risk for
general risk: 2.6%
hepatoblastoma: 0.7%
Wilms tumor: 0.2%
What is the general risk of tumors for pts with BWS through gain of methylation at IC1? What cancers are they at highest risk for
general risk: 28%
Wilms tumor: 24%
rare to have hepatoblastoma
What is the general risk of tumors for pts with BWS through paternal UPD? What cancers are they at highest risk for
general risk: 16%
Wilms tumor: 7.9%
hepatoblastoma: 3.5%
neuroblastoma: 1.4%
adrenocortical carcinoma: 1.1%
What is the general risk of tumors for pts with BWS through heterozygous CDKN1C PV? What cancers are they at highest risk for
general risk: 5.6%
neuroblastoma: 4.2%
no increased risk for Wilms or hepatoblastoma
What is the general risk of tumors for pts with BWS with normal molecular testing but classic BWS phenotype? What cancers are they at highest risk for
general risk: 6.2%
Wilms tumor: 4.1%
hepatoblastoma: 0.3%
What are some features of BWS by loss of methylation at IC2 that are distinct from the other etiologies
lower risk for tumor development overall
omphalocele; hemihyperplasia
female monozygotic twinning discordant for BWS
hx of subfertility/use of ART to achieve pregnancy
What are some features of BWS by gain of methylation at IC1 that are distinct from the other etiologies
one of the highest risks for Wilms tumor
hemihyperplasia
+ FH in those with deletion of IC1
What are some features of BWS by paternal UPD that are distinct from the other etiologies
one of the highest risks for Wilms tumor and hepatoblastoma
more commonly associated w hemihyperplasia when paternal UPD is mosaic
severe BWS phenotype
What are some features of BWS by heterozygous CDKN1C PV that are distinct from the other etiologies
associated with neuroblastoma
most commonly associated with + FH of BWS
cleft palate, omphalocele
What are some features of BWS by duplication of 11p15 that are distinct from the other etiologies
developmental delay
if affects KCNQ1, EKG and echo is recommended
What are the treatment recommendations for individuals with BWS
Hypoglycemia: oral feeding, tx with glucose supplementation
hyperinsulinism: standard tx per endo; partial pancreatectomy can be considered if persistent hypoglycemia exists/they are unresponsive to tx
cleft palate: standard sx tx
macroglossia: feeding/respiratory support for those with issues; can consider tongue reduction sx in infancy/early childhood
speech delays: speech therapy
omphalocele: sx by pediatric surgeon
hemihyperplasia of upper limbs does not require intervention, of the lower limbs could do shoe lifts to even out legs
standard tx for neoplasia, hypercalciuria, CHDs, hearing loss, developmental delays
What kind of tumor surveillance should pts with BWS undergo
In North America, proactive tumor screening is often recommended when the risk of tumor development exceeds 1%
abdominal u/s w views of liver, adrenal glands, and kidneys q3mo until 4yo for Wilms tumor, adrenocortical carcinoma, abdominal neuroblastoma
renal u/s only q3mo from 4yo-7yo to screen for Wilms tumor
serum AFP levels q3mo until 4yo to search for underlying tumor
physical exam by pediatrician, geneticist, or pediatric oncologist 2x/yr
for those with heterozygous PVs in CDKN1C
abdominal u/s, urine vanillylmandelic acid and homovanillic acid, and chest radiograph q3mo until 6yo then q6mo until 10yo
If BWS is associated with multilocus imprinting disturbances (MLID), what should be reviewed?
mat hx should be reviewed with respect to potential recurrent pregnancy loss or other adverse outcomes that could indicate a mat effect gene abnormality
PVs in mat effect genes are associated with an increased risk for reproductive complications such as preeclampsia, RPL, and molar pregnancy as well as the risk for having children with imprinting disorders
What is the recurrence risk for someone who has a heterozygous CDKN1C PV
If the proband is female, the recurrence risk for BWS is 50%
If the proband is male, the recurrence risk is low, but there have been too few cases to generate a risk figure
What is the relationship between BWS and monozygotic twins
monozygotic twins clinically discordant for BWS (usually females) have been shown to also be discordant for loss of methylation at IC2 in skin fibroblasts but variable concordant in blood cells, probably as a result of shared fetal circulation
male monozygotic twins are much less frequently observed and demonstrate additional molecular findings including UPD for 11p15 and gain of methylation at IC1
What prenatal testing is available for BWS? What are some considerations during high risk pregnancies for this condition? If there is a negative FH but omphalocele is present?
DNA from amniotic fluid provides the most reliable tissue source for evaluating fetal methylation status; tissue from CVS does not yield reliable results
for ALL pregnancies at increased risk for BWS:
AFP may be high due to omphalocele
U/s exam can be done at 19/20wks then 25-32wks to assess growth parameters that may become advanced for GA late in the second tri and to detect AWDs, organomegaly, kidney anomalies, cleft palate, etc.
neg FH: consider molecular genetic testing for methylation in amniocytes, then CDKN1C PV in nothing is detected on methylation test; CMA for structural rearrangements if the previous two are negative; serial u/s for growth
What imprinted genes cause which features in BWS
IGF2: Wilms tumor
H19: may function as a tumor suppressor
CDKN1C: tumor suppressor gene and potential negative regulator of fetal growth
KCNQ1: implicated in two cardiac arrhythmias (Romano Ward/Long QT and Jervell Lange)
IC1: regulates IGR2 and H19 expression (normally methylated on dad and not on mom)
IC2: regulates CDKN1C and KNCQ1 (normally methylated on mom and not on dad)
When does imprinting occur
based on parental origin but happens during gametogenesis; gametes are formed w imprinting patterns which remain during fertilization, embryo development, and life but are RESET in primordial germ cells producing gametes for the next gen
What are some prenatal considerations when thinking about trisomy rescue and UPD
trisomy rescue can result in confined placental mosaicism or mosaic trisomy bc some of the cells still have three copies, but others have 2
this can result in a positive NIPT/CVS result for trisomy; to assess risk for UPD or mosaic trisomy, cyto testing on amnio or blood sample after birth
