Selected Genetics

What is the most common genetic cause of intellectual disability?

Down syndrome.

What is different about Down syndrome compared to the other trisomies?

Only autosomal trisomy that is compatible with long-term life (nonlethal).

What is the incidence of Down syndrome?

1:740 live births.

What maternal factor is associated with Down syndrome?

Associated with increasing maternal age.

What chromosomal abnormality causes Down syndrome?

Trisomy of chromosome 21.

What is Down syndrome often caused by?

Due to a nondisjunction → usually in the ovum secondary to damage accumulated over time.

What happens to spindle fibers in Down syndrome nondisjunction?

The spindle fibers don’t pull apart the chromosomes as effectively.

What is the most commonly encountered risk factor for Down syndrome?

Advanced maternal age is the most commonly encountered risk factor for Down syndrome, esp after age 35.

What are the common craniofacial features of Down syndrome?

• Flat face

• upward slanted palpebral fissures

• small dysplastic ears

• epicanthal fold

• protruding tongue

• small nose with flat bridge

• third fontanelle.

What GI conditions are associated with Down syndrome?

• Duodenal atresia

• TEF

• Hirschsprung's disease

• annular pancreas

• imperforate anus.

What MSK features are associated with Down syndrome?

• Joint hyperflexibility

• Simian crease

• short neck / redundant skin

• sandal sign (in the toes)

• short pinky with clinodactyly.

What CNS features are associated with Down syndrome?

• Hypotonia (“floppy baby syndrome”)

• decreased Moro.

What other conditions are associated with Down syndrome?

• Refractive errors

• cataracts

• hearing loss

• epilepsy

• polycythemia

• ALL

• celiac disease.

What is seen in all Down syndrome patients?

Developmental delay in milestones.

What language difficulty is common in Down syndrome?

Particular difficulty with expressive language.

How are self-help skills affected in Down syndrome?

Self-help skills are significantly delayed relative to other children.

What psychiatric comorbidity is common in Down syndrome?

Psychiatric comorbidity is usually behavioral due to reduced cognition and amenable to pharmacotherapy.

What psychiatric conditions may also be seen in Down syndrome?

May also see depression, autism, and psychosis.

What is required for formal diagnosis of Down syndrome?

Formal diagnosis requires chromosomal analysis, although in many cases the diagnosis is made prenatally.

What is seen on first trimester screening for Down syndrome?

↑ fetal nuchal translucency.

What is the normal fetal nuchal translucency measurement?

Distance in normal fetus =

What does increased nuchal translucency suggest?

Much larger we need to start considering additional concerns with nuchal translucency

What markers are included in the quad or triple screen?

• aFP

• hCG

• estriol

• +/- inhibin A.

What marker pattern is seen in Down syndrome?

Inhibin A and hCG will be increased, aFP and estriol will be decreased.

What is the most accurate cause of inaccurate quad screen?

Incorrect dating.

What can chorionic villus sampling detect?

Can tell you if there’s 3 copies of chromosome 21.

When is chorionic villus sampling done?

Typically up to week 13.

When is amniocentesis used?

If concerns are caught later on, like after 13 weeks.

What are indications for further testing for Down syndrome?

• Suspicious results on ultrasound and/or marker screen

• advanced age greater than 35 years of age

• past history of baby with Down syndrome.

What happens to uE3 in Down syndrome?

↓.

What happens to AFP in Down syndrome?

↓.

What happens to b-hCG in Down syndrome?

↑.

What happens to Inhibin A in Down syndrome?

↑.

What is the mnemonic for Down syndrome marker pattern?

HIgh.

What is the management at birth for Down syndrome?

Routine newborn care.

What comorbidities should be addressed at birth in Down syndrome?

Address any comorbidities such as FPM, TE fistula, etcetera.

What other testing should be done in newborns with Down syndrome?

Thyroid function testing.

What cardiac evaluation is needed in Down syndrome?

Consultation with pediatric cardiology to investigate CHD.

What vision evaluation is needed in Down syndrome?

Consultation with pediatric ophthalmologist for vision screening.

What chromosomal abnormality causes Patau syndrome?

Trisomy of chromosome 13.

What causes Patau syndrome genetically?

Typically due to a non-disjunction but also may have Robertsonian translocation (20%).

What defects result from excess chromosomal material in Patau syndrome?

Defects of the midface, eye, and forebrain (plus others).

What is the prognosis of Patau syndrome?

Almost always incompatible with life.

What maternal factor is associated with Patau syndrome?

Associated with increasing maternal age.

What is the incidence of Patau syndrome?

1:15,000 livebirths.

What percentage of infants with Patau syndrome live after the first year?

Only 10% live after the 1st year.

What craniofacial features are seen in Patau syndrome (Trisomy 13)?

• Scalp defects (cutis aplasia)

• microphthalmia, hypotelorism

• cleft lip/palate

• microcephaly

• sloping forehead

• short neck

• holoprosencephaly (midline defect, one big brain, no separate hemispheres)

• low-set ears.

What extremity features are seen in Patau syndrome (Trisomy 13)?

• clinodactyly

• polydactyly

• hypoplastic nails

• capillary hemangiomas.

What other features are seen in Patau syndrome (Trisomy 13)?

• CHD

• missing or thin ribs

• renal anomalies

• cataract

• coloboma

• deafness

• severe developmental delay

• growth retardation.

What causes coloboma in Patau syndrome (Trisomy 13)?

Due to the failure of closure of the embryonic fissure in the eye, causing a keyhole appearance.

What is required for formal diagnosis of Patau syndrome?

Formal diagnosis requires chromosomal analysis, although in many cases the diagnosis is made prenatally.

What may ultrasound demonstrate in Patau syndrome?

Ultrasound may demonstrate small for gestational age or intrauterine growth restriction, increased nuclear translucency.

What is included in the 2nd trimester screening for Patau syndrome?

Quad screen or triple screen (aFP, hCG, estriol, +/- inhibin A).

When is chorionic villi sampling done for Patau syndrome?

Chorionic villi sampling done 10 to 13 weeks of gestation for mothers with suspicious results on ultrasound or marker screen, advanced age especially over 35 years of age, past history of a baby with trisomy.

When can amniocentesis be performed for Patau syndrome?

Amniocentesis can be performed after 15 weeks gestation.

What happens to uE3 in Patau syndrome?

↔.

What happens to AFP in Patau syndrome?

↑.

What happens to b-hCG in Patau syndrome?

↔.

What happens to Inhibin A in Patau syndrome?

↔.

What is the mnemonic for Patau syndrome marker pattern?

Patau – AFPatau high.

What is the preterm management for Patau syndrome?

If suspected prenatally, mother should deliver at a specialized center.

What is the neonatal management for Patau syndrome?

If diagnosis is suspected only after birth, obtain immediate cytogenic profile.

Who should be consulted in Patau syndrome?

Consult neonatology.

What should be discussed with parents in Patau syndrome?

Discuss severity of condition with parents.

What counseling should be advised for parents in Patau syndrome?

Parents should be advised to obtain genetic counseling and planning future pregnancies

What chromosomal abnormality causes Edward syndrome?

Trisomy of chromosome 18.

What causes Edward syndrome genetically?

Typically due to nondisjunction but may also have Robertsonian translocation.

What is the prognosis of Edward syndrome?

Almost always incompatible with life.

What sex predominance may be seen in Edward syndrome?

May have a female predominance.

What maternal factor is associated with Edward syndrome?

Associated with increasing maternal age.

What is the incidence of Edward syndrome?

1 in 8000 live births.

What craniofacial features are seen in Edward syndrome?

• Tight palpebral fissures

• narrow nose

• hypoplastic alae (flares of nose)

• microcephaly

• hypertelorism (wide-spaced eyes)

• micrognathia (jaw is undersized)

• narrowed by frontal diameter

• low-set, malformed ears.

What extremity features are seen in Edward syndrome?

• Rocker bottom feet

• clinodactyly

• clenched hand

• hypoplastic nails.

What other features are seen in Edward syndrome?

• Omphalocele

• CHD

• multiorgan defects

• hypertonia

• short sternum

• Polyhydramnios in utero

• severe developmental delay

• growth delay.

What percentage of infants with Edward syndrome live past age 1?

Only 5% live past the age of 1 year.

What happens to uE3 in Edward syndrome?

↓.

What happens to AFP in Edward syndrome?

↓.

What happens to b-hCG in Edward syndrome?

↓.

What happens to Inhibin A in Edward syndrome?

↓.

What is the mnemonic for Edward syndrome marker pattern?

Edward’s – HE are low.

What is required for formal diagnosis of Edward syndrome?

Formal diagnosis requires chromosomal analysis, although in many cases the diagnosis is made prenatally.

What fetal abnormalities may be seen on ultrasound in Edward syndrome?

• Abnormal positioning of fingers

• increased nuchal translucency

• abnormal head shape

• intrauterine growth restriction

• omphalocele.

What is the difference between omphalocele and gastroschisis?

Omphalocele is usually midline and associated with Edward’s syndrome, intestines protrude out and are protected by a membrane

What is included in the 2nd trimester screening for Edward syndrome?

Quad screen or triple screen (aFP, hCG, estriol, +/- inhibin A).

When is chorionic villi sampling done for Edward syndrome?

Chorionic villi sampling done 10 to 13 weeks of gestation for mothers with suspicious ultrasound or marker screen, advanced age especially over 35 years, past history of a baby with trisomy.

When is amniocentesis performed for Edward syndrome?

Amniocentesis performed after 15 weeks gestation.

What is the preterm management for Edward syndrome?

If suspected prenatally, mother should deliver at a specialized center.

What is the neonatal management for Edward syndrome?

If diagnosis is suspected only after birth, obtain immediate cytogenic profile.

Who should be consulted in Edward syndrome?

Consult neonatology.

What should be discussed with parents in Edward syndrome?

Discuss severity of condition with parents.

What counseling should be advised for parents in Edward syndrome?

Parents should be advised to obtain genetic counseling and planning future pregnancies

What type of chromosomal aneuploidy is seen in Turner syndrome?

Sex chromosomal aneuploidy seen in females (45, X0).

What clinical features are associated with Turner syndrome?

• short stature

• primary amenorrhea

• delay of the large

• multiple system effects.

Is Turner syndrome associated with advanced maternal age?

Sporadic

In Turner syndrome, which parent is more likely to contribute the nondisjunction?

More likely to be due to the father in this case.

What is the incidence of Turner syndrome?

Incidence: 1:2500.

What percentage of Turner syndrome conceptions spontaneously abort?

95% of these conceptions spontaneously abort.

What general features are seen in Turner syndrome?

Short stature, congenital lymphedema.

What craniofacial features are seen in Turner syndrome?

• Neck webbing

• low posterior hairline

• low set ears.

What MSK features are seen in Turner syndrome?

• Congenital hip dislocation

• shield chest, scoliosis

• Madelung deformity

• osteoporosis.