Genetic Abnormalities

Question 1

Epidemiology of Downs Syndrome?

Answer 1

One of the most common genetic disorders, affecting 1 in 650-1,000

Question 2

describe the common genetic abnormalities in the 3 main types of Downs Syndrome?

Answer 2

The underlying genetic defect is trisomy 21 in 94% of cases.
Mosaicism (2.4%) and translocations (3.3%) also occur.

USMLE:
95% of cases due to meiotic nondisjunction of homologous chromosomes (associated with advanced maternal age)

4% of cases due to Robertsonian translocation. (chromosomes 14 and 21)

1% of cases due to mosaicism (no maternal association; post-fertilization mitotic error).

Question 3

what are the risk factors for Downs?

Answer 3

Family history.
Age of mother:
1:385 risk at 35 years
1:106 at 40 years
1:30 at 45 years

from USMLE:
1:1500 in women 45 years old).

Question 4

what is a Robersonian Translocation?

Answer 4

Robertsonian translocation (ROB) is a rare form of chromosomal rearrangement that in humans occurs in the five acrocentric chromosome pairs, namely 13, 14, 15, 21, and 22. Other translocations occur but do not lead to a viable fetus.

A Robertsonian translocation is a type of nonreciprocal translocation involving two homologous (paired) or non-homologous chromosomes (i.e. two different chromosomes, not belonging to a homologous pair). A feature of chromosomes that are commonly found to undergo such translocations is that they possess an acrocentric centromere, partitioning the chromosome into a large arm containing the vast majority of genes, and a short arm with a much smaller proportion of genetic content. During a Robertsonian translocation, the participating chromosomes break at their centromeres and the long arms fuse to form a single, large chromosome with a single centromere. The short arms also join to form a smaller reciprocal product, which typically contains nonessential genes and is usually lost within a few cell divisions.

Question 5

what are the neonatal features of Downs Syndrome at birth?

Head

Answer 5

Head:
Brachycephaly.
Oblique palpebral fissures.
Epicanthic folds.
Ring of iris speckles - Brushfield's spots.
Ears set low, folded or stenotic meatus.
Flat nasal bridge.

Question 6

what are the neonatal features of Downs Syndrome at birth?

mouth & neck

Answer 6

Mouth:
Protruding tongue (small narrow palate).
High arched palate.

Neck:
Loose skin on nape of nec

Question 7

what are the neonatal features of Downs Syndrome at birth?

Hands and Feet

Answer 7

Hands:
Single palmar crease.
Short little finger.
In-curved little finger.
Short broad hands.

Feet:
Gap between hallux and second toes.

Question 8

Cardiological Disorders associated with Downs Syndrome?

Answer 8

The most common cardiac abnormalities are:

Atrioventricular canal defects.
Ventricular septal defect.
Isolated secundum atrial septal defects.
Isolated persistent patent ductus arteriosus.
Fallot's tetralogy.

Adult patients, without known congenital heart disease, may develop mitral valve prolapse or aortic regurgitation. A second assessment in early adulthood may be appropriate.

Question 9

ENT disorders associated with Downs Syndrome?

Answer 9

90% of patients with Down’s syndrome may have conductive, sensorineural, or mixed hearing loss.[1]
They are more susceptible to otitis media, sinusitis and pharyngitis.
Obstructive sleep apnoea may develop.

Question 10

Opthamological Disorders associated with Downs Syndrome?

Answer 10

Most commonly:

Cataracts.
Refractive errors.
Strabismus.
Nystagmus.
Congenital glaucoma.
Keratoconus.

Question 11

Gastro Disorders associated with Downs Syndrome?

Answer 11

Oesophageal atresia or tracheo-oesophageal fistula.
Duodenal atresia.
Pyloric stenosis.
Meckel’s diverticulum.
Hirschsprung’s disease.
Imperforate anus.
Gastro-oesophageal reflux.
Dental problems - delayed and unusual patterns of eruption, missing teeth.
Coeliac disease occurs frequently enough for screening to be recommended.

Question 12

Orthopedic Disorders associated with Downs Syndrome?

Answer 12

Atlanto-axial instability*.
Hyperflexibility.
Scoliosis.
Hip dislocation after two years.
Patellar subluxation or dislocation.
Foot deformities.

Question 13

Neurological Disorders associated with Downs Syndrome?

Answer 13

Learning difficulties (these range from severe, to those with ‘low normal’ IQ).
Behavioural problems.
Seizures occur in 5-10%.
In older patients an Alzheimer’s-type picture develops in >60% of those over 60 years of age.

Question 14

hematological Dosorders associated with Downs syndrome?

Answer 14

Patients have approximately 12 x greater risk of infections (eg, pneumonia) due to impaired cellular immunity.

They also have increased risk of acute myeloblastic leukaemia (AML), acute lymphoblastic leukaemia (ALL) and acute megakaryoblastic leukaemia (AMegL).

Polycythaemia and transient myeloproliferative disorder (a self-limiting type of leukaemia which regresses spontaneously by the age of 2 months) may occur in newborns.

Question 15

what are the 2 main types of screening used in screening for Downs syndrome?

what no of weeks of pregnancy is each one done?

Answer 15

There are two methods of screening for Down’s syndrome: serum screening and ultrasound screening (nuchal translucency).

Question 16

what does the serum screening for Downs syndrome show?

PAPP-A
Beta-hCG
AFP
Inhibin A

Answer 16

Serum markers for Down’s syndrome[5]
These include:

PAPP-A: produced by placental syncytiotrophoblasts; levels reduced in pregnancies affected by Down’s syndrome.

Beta-hCG: produced by placental syncytiotrophoblasts; raised levels in pregnancies affected by Down’s syndrome.

AFP: produced by fetal yolk sac and liver; reduced levels in pregnancies affected by Down’s syndrome.

uE3: produced by placenta and fetal adrenals; reduced levels in pregnancies affected by Down’s syndrome.

Inhibin-A: produced by placenta; raised levels in pregnancies affected by Down’s syndrome.

Question 17

what does the Nuchal Translucency tell us?

When is it done to screen for Downs Syndrome?

Answer 17

Fetal nuchal translucency (FNT) screening uses ultrasound to measure the size of the nuchal pad at the nape of the fetal neck. It should be performed between 11 weeks + 2 days and 14 weeks + 1 day.
Increased nuchal translucency reflects fetal heart failure, and is typically seen in any serious anomaly of the heart and great arteries, and strongly associated with a chromosomal abnormality.

Question 18

When is Chorionic Villus sampling done? (no of weeks pregnant)

When is Amniocentesis done ? (no of weeks pregnant)

what is the risk of miscarriage for the above?

Answer 18

chorionic villus sampling (if less than 13 weeks of gestation)

amniocentesis (if beyond 15 weeks of gestation).

These procedures carry a risk of miscarriage (0.5-1% excess miscarriage risk for amniocentesis; 1-2% for chorionic villus sampling).

Question 19

what screening can be done if the mother is gone 14 weeks?

Answer 19

QUAD test

If a woman books later in pregnancy (when nuchal translucency is not as accurate, or if it is not technically possible to measure it) the quadruple test can be taken between 14 + 2 to 20 + 0 weeks of gestation.

This measures free beta-hCG, alpha fetoprotein (AFP), inhibin-A and unconjugated estriol (uE3)