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Down’s Syndrome

An error in number of chromosomes is called Aneuploidy. Among all the aneuploidies , trisomy of the 21st chromosome or Down’s syndrome is the most common autosomal aneuploidy with an extra 21 chromosome due to nondisjunction.

How common –Down’s syndrome ( DSynd ) is the most common chromosomal disorder It is estimated to affect approximately in 1 in 700 live births ( Kanamori et al 2000 ) DSynd is the most commonly identified genetic form of mental retardation and the leading cause of specific birth defects and medical conditions ( Sherman et al ) CDC ( USA ) reports that between 1979 and 2003 the number of babies born with DSynd increased by about 30 % Most common figure in literature quotes that DSynd occurs in 1 out of 600-800 births DSynd happens in people of all races and socio economic status No sex preponderance.

Trisomy happens due to non-separation or non-disjunction ( NDJ ) of chromosome 
( Ch21 ) during gametogenesis – leading to disomic gametes with two copies of a particular chromosome being formed which upon fertilization by a haploid gamete from opposite sex leads to the formation and implantation of trisomic fetus Three subtypes have been described

Trisomy 21st -most common ~ 95 % extra chromosome 21 in every cell usually not hereditary non-disjunction slightly higher risk than general population of 2nd child being affected

Transloaction seen in about 4 % the extra 21st chromosome is translocated or joined on to another chromosome affected people are indistinguishable from those with trisomy 21 but they have 46 chromosomes and non 47 and 1 chromosome is larger as it carries the extra 21 hereditary potential

 

mosaicism implies that some cells have an extra 21 chromosome while others have the usual two severity of the illness would depend upon proportion of cells affected

It is most likely that the risk factors are multi-factorial and include both genetic and environmental factors All the risk factors are not completely understood Among the maternal risk factors -advanced maternal age ( 35 or older ) at the time of conception is the most significant risk factor Altered recombination patterns is the only other factor which has been shown to associate increased susceptibility of maternal non-disjunction Maternal genetic factors as polymorphism of certain genes probably make them susceptible for NDJ errors Paternal error probably constitute 5-10 % of the total incidences of DSynd Environmental factors as
○ maternal cigarette smoking
○ use of oral contraceptives
○ peri-conceptional maternal alcohol consumption
○ exposure to radiation
○ low socioeconomic status

Tests can be screening tests and diagnostic Diagnosis can be made before or after birth Various strategies / tests can be used for diagnosis as
◘ nuchal translucency ( in simple terms the fluid at the back of the baby’s neck ) and biochemistry in 1 st trimester

Features suggestive of DSynd include increased nuchal fold thickness , small or no nasal bones and large ventricle

◘ triple / quadruple testing – those at high risk are offered -
◘ chorionic villi sampling ( CVS ) – done between 11-14 weeks
◘ amniocentesis from around 15 weeks
Both lead to a slight increased risk of miscarriage

Triple test involves measurement of serum markers – alpha- fetoprotein ( AFP ) , human chorionic gonadotrophin ( hCG ) and estriol ( uE3 )

Adding the hormone inhibin A makes it a Quad test
 All pregnant women in England are offered a screening test for Down’s syndrome , Edward’s syndrome and Patau’s syndrome between 10-14 weeks of pregnancy ( NHS UK )
 Several other methods exist to help with the screening/ diagnosis as
♦ FISH of interphase nuclei
♦ QF-PCR 
♦ PSQ – paralogue sequence quantification 
♦ digital PCR and next generation sequencing ( NGS )

Currently the combination of age related risk markers and triple/ quadruple testing gives a detection rate of 85-95 %. This effectively implies that screening for DSynd can be achieved in the 1st trimester of pregnancy with a detection rate of about 95 % and a false positive rate of less than 3 %


 

slanting eyes small chin rounded face with flattish profile flat nasal bridge head often smaller than average due to underdevelopment of the facial bones back of the head may be slightly flattened small mouth with a flattish roof tongue may protrude due to the small mouth and the weakness of tongue and jaw muscles macroglossia and scrotal ( fissured ) tongue Brushfield spots in iris abnormal outer ears big toe abnormal pattern of fingerprint and short fingers

Differentials –Zellweger syndrome 9qter deletion or other chromosomal abnormalities Aymè- Gripp syndrome

 

intellectual disability / learning difficulties increased risk of early onset Alzheimer disease ( AD ) after age 50 increased risk of dementia epilepsy ( 6 % of children and in 80 % of those with advanced AD ) cord compression from subluxation / dislocation of atlanto-axial joint

 

congenital heart disease ( 50 % of neonates ) most common is atrioventricular septal defect ( up to 40 % ) persistent ductus arteriosus ( PDA ) tetralogy of Fallot pulmonary arterial hypertension ( complication of CHD ) mitral valve prolapse and aortic regurgitation in adults ( 50 % ) increased risk infective endocarditis ( adults )

 

Hirschsprung disease oesophageal or duodenal web / atresia other defects as tracheoesophageal fistula , imperforate anus , pyloric stenosis , Meckel diverticulum chronic constipation GORD Coeliac disease

 

hearing impairment in 50 % ( lifelong audiological surveillance is essential ) visual problems as refractive errors , strabismus , nystagmus ,conjunctivitis , acquired cataracts , keratoconus , glaucoma , retinitis pigmentosa , blindness

 

skin becomes thicker , drier and rough generalised xerosis associated with keratosis pilaris early skin ageing and photosensitivity other changes include cutis marmorate , xerosis , palmoplantar hyperkeratosis , cheilitis , seborrhoeic dermatitis , folliculitis , tinea pedis , onychomycosis , crusty scabies , atopic dermatitis , alopecia areata , vitiligo , psoriasis ( severe form ) , pityriasis rubra pilaris , syringoma , elastosis perforans serpiginosa and skin verticis girata

 

no medical cure for DSynd problems can be 
♦ clinical ( multimorbidity )
♦ functional ( for e.g LD )
♦ social ( need for care , support ) survival rate has improved remarkably in the past decades due to factors as
♦ cardiac surgery ( repair of congenital defects )
♦ vaccinations and antibiotics
♦ thyroid hormones
♦ leukaemia therapies
♦ anticonvulsant drugs number of individuals with DSynd who survive beyond 60 has increased and now 80 % of affected individuals survive into adolescence

 

women have reduced fertility if conceived children are at an increased of having DSynd- approximately 50 % of their children will have DSynd and are also at ↑ ed risk of other congenital malformations men with DSynd are generally considered sterile

Discussion – no medical cure for DSynd problems can be 
♦ clinical ( multimorbidity )
♦ functional ( for e.g LD )
♦ social ( need for care , support ) survival rate has improved remarkably in the past decades due to factors as
♦ cardiac surgery ( repair of congenital defects )
♦ vaccinations and antibiotics
♦ thyroid hormones
♦ leukaemia therapies
♦ anticonvulsant drugs number of individuals with DSynd who survive beyond 60 has increased and now 80 % of affected individuals survive into adolescence.

women have reduced fertility if conceived children are at an increased of having DSynd- approximately 50 % of their children will have DSynd and are also at ↑ ed risk of other congenital malformations men with DSynd are generally considered sterile

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