Chromosomal aberrationsDefinition :- ―Any deviation either in number or structure of the chromosomes is referred as chromosomal aberrations‖Types :-1) Structural aberrations.2) Numerical aberrations.
Terminologies: Diploid Hapliod Polyploidy : in multiple of ‗n‘ Aneuploidy : any number which is not exactly a multiple of ‗n‘ 2n - 1 ------ > Turners syndrome (45X)Or 2n + 1 ------ > Down‘s syndrome (47, trisomy 21)
Genesis of anuploidyNon-disjunction in meiosis. Or after formation of zygote.
Structural aberrations Stable:– - Deletions - Translocation - Insertion - Inversions - Isochromosomes Unstable:- - Dicentric - Ring chromosomesMay occur due toa) Ionizing radiationsb) Chemical agentsc) viruses
Deletion This Involves loss of a part of chromosome.1. Terminal deletion.2. Interstitial deletion.1. Terminal deletion. It involves a single break and the terminal part of the chromosome is lost.e.g. cri-du-chat syndrome
- Deletion of 5p arm- Cry of baby- Typical facial appearance- Microcephaly, hypertelorism,- Antimongoloid slant of palpebral fissure.- Low set ears, microganthia.
2) Interstitial deletion. It involves two breaks and the intervening portion of the chromosome is lost. Wilm‘s tumor with anirida. (11q13) Prader- will syndrome. (15q11-13) Angelman syndrome. (15q11-13)Microdeletion syndrome - Deletion of 3 – 4 Mb
Prader- will syndrome. (15q11-13)- Inherited from father- Short stature, hypotonia- Obesity- Small hands & feet- Mild to moderate mental retardation- HypogonadismAngelman syndrome. (15q11-13)- Inherited from mother- Severe mental retardation- Seizures & ataxic gaitDifference is due to genomic imprinting.
Translocation1) Robertsonian translocation- Involves two acrocentric chromosomes- D/G Translocation- Also called centric fusion- In 4% of down‘s cases- [50% from parents(balanced), 50% de novo in baby]
2) Reciprocal Translocation- Exchange of material distal to breaks- In non homologus chromosomes- No chromosome material is lost- Abnormal production of gamets- Spontaneous abortions/ baby with congenital malformations- Carrier couple- repeated abortions.
Insertion- Rare non-reciprocal type of translocation- Involves 3 breaks- 2 breaks to release fragment- 1 break to admit fragment.
Inversions Pericentric – involves both arms p & q Paracentric – either p or q Do not give abnormal phenotype Abnormal gamets may give abnormal progeny.
Isochromosomes- Abnormal split along the centromere- Seperation of arms- E.g. isochromosome X (Xq)- In some cases of Turners syndrome
Ring chromosomes- Two breaks at terminal ends- Fusion of the cut ends- 1/5th cases of turners syndrome
Factors playing role in chromosomalaberrations Maternal age > 35 yrs non-disjunction during meiosis 1 Radiation correlation between radiation and non-disjunction Chromosomal abnormalities balnced translocation in parents may produce aberrations in offsprings Autoimmune disorders - not clear High titer of thyroid autoantibodies in mother associated with Down‘s syndrome in their childrens
Numerical aberrations Autosomal :- Trisomy 21 / Down‘s syndrome Trisomy 18 / Edwards syndrome Trisomy 13 / Patau syndrome Sex chromosome related :- Turners syndrome / 45X Polysomy X syndrome / e.g. XXX, XXXX Klinfelters syndrome / 47 XXY
Autosomal Monosomies are fetal – Abortion. Trisomies are common.
Down’s syndrome / Trisomy 21 1866 – first identified by Langdon Down. 1959- Lejeune & associates demonstrated extra chromosome no.21 Mongolism Incidence- Approximately one in 1000 live births.
Clinical features Mental retardation – predominant feature IQ – 25-50 Small stature Hypotonia of muscles Brachycephaly with flat occiput Epicanthal fold—mongoloid slant Flat nose, low nasal bridge
Mouth is open with protruded tongue Highly arched palate with delayed dentition Hands are short and broad Cardiovascular defect in 1/10th cases.
Dermatoglyphics Simian crease- classical feature Wide gap between first and second toe.
Cytogenetics Trisomy 21 (47, +21), - 94 %, The frequency of trisomy increases with increasing maternal age. Robertsonian translocation involving chromosome 21- Approx. 3-4 %, not related to maternal age. Trisomy 21 mosaicism – 2 to 3 % cases
Risk of Down’s syndrome Maternal age Does the couple already have baby with down’s syndrome? What is karyotype of baby?(typical / translocation) Parent carrier of translocation?
Diagnosis Prenatal screening If no screening – It is recognized from the characteristic phenotypic features. Confirmed by Karyotype.( chorionic villous biopsy , amniocentesis)
ManagementCounseling May begin when a prenatal diagnosis is made. Discuss the wide range of variability in manifestation and prognosis. Medical and educational treatments and interventions should be discussed. Initial referrals for early intervention, informative publications, parent groups, and advocacy groups.
Management cont..1. Growth – Measurements should be plotted on the appropriate growth chart for children with DS. This will help in prevention of obesity and early diagnosis of celiac disease and hypothyroidism.2. Cardiac disease – All newborns should be evaluated by cardiac ECHO for CHD in consultation with pediatric cardiologist.3. Hearing – Screening to be done in the newborn period, every 6 months until 3 yrs of age and then annually.
4. Eye disorders - An eye exam should be performed in the newborn period or at least before 6 months of age to detect strabismus, nystagmus, and cataracts.5. Thyroid Function – Should be done in newborn period and should be repeated at six and 12 months , and then annually.6. Celiac Disease – Screening should begin at 2 yrs. Repeat screening if signs/Sx develop.
7. Hematology – CBC with differential at birth to evaluate for polycythemia as well as WBC.8. Atlanto-axial instability – X ray for evidence of AAI or sub- luxation at 3 to 5 years of age.9. Alzheimer‘s disease – Adult with a Down Syndrome has earlier onset of symptoms. When diagnosis is considered, thyroid disease and possible depression should be excluded.