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