Lectures by Ibnlatef

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Down's syndrome
Down's syndrome (trisomy 21):
 This is the most common autosomal trisomy and the most common genetic cause of
severe learning difficulties.
 The incidence in live-born infants is about 1 in 650.
Cytogenetics:
 The extra chromosome 21 may result from non-disjunction, translocation, mosaicism.
Non-disjunction (94%):
 Most cases result from an error at meiosis the pair of
chromosome 21s fails to separate.
 So that one gamete has two chromosome 21s and one has
none fertilization of the gamete with two chromosome 21s
gives rise to a zygote with trisomy 21 parental
chromosomes do not need to be examined.
 Increased maternal age lead to non-disjunction especially
after 40 years old.
Translocation (5%):
 When the extra chromosome 21 is joined onto another
chromosome (usually chromosome 14, but occasionally
chromosome 15, 22 or 21), this is known as an unbalanced
Robertsonian translocation.
 An affected child has 46 chromosomes, but three copies of
chromosome 21 material.
 In this situation, parental chromosomal analysis is essential
since one of the parents carries a balanced translocation in
25% of cases.
 Translocation carriers have 45 chromosomes, one of which
consists of the two joined chromosomes.
 The risk of recurrence is 10-15% if the mother is the
translocation carrier and about 2.5% if the father is the carrier.
Ibnlatef Notes Pediatrics

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 If a parent carries the rare 21:21 translocation, all the offspring will have Down's
syndrome.
 If neither parent carries a translocation (75% of cases), the risk of recurrence is <1%.
Mosaicism (1%):
 In mosaicism some of the cells are normal and some have trisomy 21.
 This usually arises after the formation of the zygote, by non-disjunction at mitosis.
 The phenotype may be milder in mosaicism.
Causes:
 The cause of the extra full or partial chromosome is still unknown.
 Maternal age is the only factor that has been linked to an increased chance of having a
baby with Down syndrome resulting from nondisjunction or mosaicism.
 However, due to higher birth rates in younger women, 80% of children with Down
syndrome are born to women under 35 years of age.
 There is no definitive scientific research that indicates that Down syndrome is caused
by environmental factors or the parents' activities before or during pregnancy.
 The additional partial or full copy of the 21st chromosome which causes Down
syndrome can originate from either the father or the mother.
 Approximately 5% of the cases have been traced to the father.
Clinical features:
 Typical craniofacial appearance:
o Round face and flat nasal bridge.
o Upslanted palpebral fissures.
o Brushfield spots in iris (pigmented spots).

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o Epicanthic folds (a fold of skin running across the inner edge of the palpebral
fissure).
o Small mouth and protruding tongue, Small ears.
o Flat occiput and third fontanelle.
 Other anomalies:
o Short neck.
o Single palmar creases (present in 6-7% of normal population).
o Incurved fifth finger.
o Wide 'sandal' gap between toes.
o Hypotonia.
o Congenital heart defects (40%).
o Duodenal atresia.
o Hirschsprung's disease.
 Later medical problems:
o Delayed motor milestones.
o Moderate to severe learning difficulties.
o Small stature.
o Increased susceptibility to infections (due to hypotonia, especially in respiratory
tract).
o Hearing impairment from secretory otitis media.
o Visual impairment from cataracts, squints, myopia.
o Increased risk of leukemia and solid tumors.
o Risk of atlantoaxial instability.
o Hypothyroidism and coeliac disease.
o Epilepsy.
o Alzheimer's disease.
Diagnosing Down's syndrome:
 Screening during pregnancy:
o Combined test  Blood test + nuchal translucency ultrasound
scan (nuchal translucency is a collection of fluid at the back of
the baby's neck) between 11 and 14 weeks of pregnancy.
o Blood test that can be offered between 14 and 20 weeks of
pregnancy, this blood test is less accurate than combined test.
 Diagnosis during pregnancy:
o Chorionic villus sampling (CVS)  usually done from week 11 of pregnancy.
o Amniocentesis  usually carried out from week 15 of pregnancy
 Diagnosis after birth:
o Based on baby's appearance.
o Sample of child's blood can be taken and analyzed to look for the extra copy of
chromosome 21.

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Investigations:
 Laboratory studies:
o Complete blood count with differential.
o Bone marrow examination  to rule out leukemia.
o Thyroid-stimulating hormone (TSH) and thyroxine (T4)  to rule out
hypothyroidism.
o Papanicolaou smears  every 1-3 years in sexually active women.
o Cytogenetic studies (karyotyping)  for diagnosis of trisomy 21.
o FISH  for rapid diagnosis of trisomy 2.
o Assessment of mosaicism for trisomy 21  lymphocyte preparations, buccal
mucosa cellular preparations, FISH, scoring frequency of trisomic cells.
o Immunoglobulin G.
o Maternal serum biochemical markers.
 Imaging studies:
o Echocardiography  in every newborn suspected of having trisomy 21 to identify
congenital heart disease.
o Ultrasonography.
 Postnatal diagnostic tests that may be warranted include the following:
o Auditory brainstem response (ABR), or brainstem auditory evoked response (BAER).
o Pediatric ophthalmic examination.
o Growth charts specifically for children with Down syndrome.
o Rigorous dental hygiene and dental evaluation.
Diagnostic considerations:
 The presence of 8 or more of the characteristic clinical findings leads to a definite
diagnosis of Down syndrome.
 Chromosomal analysis is always recommended and of utmost importance in doubtful
cases.
 In addition to the differential diagnosis, other problems to be considered include the
following:
o 49,XXXXY chromosome and other high-order multiple X chromosome disorders.
o Congenital hypothyroidism.
o Mosaic trisomy 21 syndrome.
o Partial trisomy 21 (or 21q duplication).
o Robertsonian trisomy 21.
o Zellweger syndrome or other peroxisomal disorders.
 Differential Diagnosis  Trisomy 18.

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Management:
 There are no medical treatments for intellectual disability associated with Down
syndrome, but improved medical care has greatly enhanced quality of life and
increased life expectancy.
 Elements of medical care include the following:
o Genetic counseling.
o Standard immunizations and well child care.
o Management of specific manifestations of Down syndrome and associated
conditions (endocrine, infectious, cardiac, respiratory, neurologic, psychiatric,
dermatologic, or dental disorders).
o Early intervention programs.
 Special considerations in adolescents are as follows:
o Ongoing monitoring measures, including annual audiologic evaluation and annual
ophthalmologic evaluation.
o Ongoing management of manifestations of the syndrome and associated
conditions.
o Discussion of issues related to the transition to adulthood.
 Surgical management of associated conditions:
o Timely surgical treatment of cardiac anomalies.
o Surgical repair for GI anomalies (duodenal atresia and Hirschsprung disease).
o Stabilize the upper segment of the cervical spine if neurologic deficits are clinically
significant.
o Careful anesthetic airway management is needed because of the associated risk of
cervical spine instability.
o Congenital cataracts must be extracted soon after birth and subsequent correction
with glasses or contact lenses provided.
o Adenotonsillectomy may be performed to manage obstructive sleep apnea.
Complications:
 Heart problems:
o Around half of children with Down's are born with a congenital heart defect.
o The most common defect to affect children with Down's a septal defect.
o It can cause a build-up of blood in one or more of the heart's chambers, which
causes the heart to work harder to pump blood through the four chambers.
 Gut problems:
o Many people with Down's have some sort of problem with their digestive system.
o Constipation, diarrhoea and indigestion are all common, as are more serious
problems such as small bowel obstruction, which stops food passing from the
stomach into the large bowel.

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o Some children also develop coeliac disease and reflux.
o Conditions such as imperforate anus or Hirschsprung's disease are rare, but slightly
more common in children with Down's syndrome.
 Hearing problems:
o Most people with Down's syndrome have problems with their hearing.
o This is often temporary, but it can sometimes be permanent.
o Glue ear (a build-up of fluid in the middle ear) is a common cause of temporary
hearing problems in people with Down's syndrome.
o Glue ear can be treated with minor surgery, which involves placing small tubes
called grommets in the ear to help drain away the fluid.
 Vision problems:
o Short-sightedness, long-sightedness.
o Squint, nystagmus.
o Eye infections (conjunctivitis, uveitis or blepharitis).
o Cataracts, keratoconus, glaucoma.
 Thyroid problems:
o Around one in 10 people with Down's syndrome have problems with their thyroid
gland.
o Most people with Down's syndrome who have a problem with their thyroid
have hypothyroidism.
o Thyroid problems will usually be picked up during blood tests and can often be
treated with medication to replace the lack of thyroid hormone in the body.
 Increased risk of infections:
o People with Down's syndrome are more likely to develop infections, such as the
lung infection pneumonia, because their immune system has not developed
properly.
o To reduce the risk of infections, routine childhood vaccinations will be
recommended.
o If child develops a bacterial infection, a course of antibiotics will usually be
prescribed to treat it.
 Dementia:
o There is a tendency for people with Down's syndrome to develop dementia at a
younger age than in the general population, usually from about 40 years of age
onwards, although it's not inevitable that everyone with Down’s syndrome will
develop it.
o Possible signs of dementia include problems with short-term memory and
understanding, confusion, and disorientation.
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