CHROMOSOMAL DISORDERS Down and Cri Du Chat syndromes Victoria Kvon 512-II pediatrics Ministry of Public Health of the Republic of Uzbekistan Tashkent Pediatric. - презентация

1 CHROMOSOMAL DISORDERS Down and Cri Du Chat syndromes Victoria Kvon 512-II pediatrics Ministry of Public Health of the Republic of Uzbekistan Tashkent Pediatric Medical Institute

2 Chromosomal Disorders 50% of 1 st trimester miscarriages 5% of stillbirths 0.5% of liveborns – Down syndrometrisomy 21 – Fragile X syndrome Somatic cell abnormalities in cancers

3 Cytogenic Technology Peripheral blood lymphocyte culture – Phytohemagglutinin – Hypotonic swelling Banding---Giemsa – 350 – 550 bands/N (haploid set) – 850 in prometaphase – G-bands (dark): AT-rich, fewer transcribed genes, LINES – R-bands (light): GC-rich, more transcribed genes, SINES (Alu)

4 Metaphase spread

5 Prometaphase spread

6 Banding nomenclature

7 Chromosome morphology

8 Ideogram of human chromosome

9 Human karyotype

10 Fluorescence in situ hybridization FISH

11 Locus-specific probes Ch 15 centromere (green) Ch 15 PWS critical region (red)

12 Centromeric probes Trisomy 9 leukemia

13 Centromeric probes (Ch 13 red, Ch18 pink, Ch 21 green, X yellow, Y white) 2x 13 (red), 21 (green) but 3X 18 (pink) and 2x X (yellow) plus Y (white) 48,XXY,+18

14 Trisomy 21 Down syndrome

15 Genetics 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

16 Three different patterns of chromosomes can cause Down syndrome Non-disjunction 94% people have three separate copies of chromosome 21 - trisomy 21 4% have the extra copy of chromosome 21 because of a Robertsonian translocation 1% have mosaicism with normal and trisomy 21 cell lines (and usually have much milder features because of the presence of the normal cells); - occurs postzygotically

17 Trisomy 21: 47,XX,+21 three separate copies of chromosome 21

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20 Clinical Features Head and neck Brachycephaly Up-slanting palpebral fissures Epicanthal folds Brushfield spots Flat nasal bridge Folded or dysplastic ears Open mouth Protruding tongue Short neck Excessive skin at the nape of neck Extremities Short broad hands Short fifth finger Incurved fifth finger Transverse palmer crease Space between first and second toe Hyper flexibility of joints

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22 Neonatal features Flat facial profile Poor Moro reflex Excessive skin at the nape of neck Slanted palpebral fissures Hypotonia Hyper flexibility of joints Dysplasia of pelvis Anomalous ears Dysplasia of midphalanx of fifth finger Transverse palmer crease

23 Brushfield spots

24 Mental Retardation Almost all DS babies have MR. Mildly to moderately retarded. Starts in the first year of life. Average age of sitting(11 mon), and walking (26 mon) is twice the typical age. First words at 18 months. IQ declines through the first 10 years of age, reaching a plateau in adolescence that continues into adulthood.

25 Heart Disease 50 % of Down Syndrome pts have heart disease Atrioventricular septal defect VSD Secundum ASD PDA Tetrology of Fallot Mitral valve prolapse AR, MR

26 GI abnormalities 5% of cases Duodenal atresia or stenosis, sometimes assoc with annular pancreas in 2.5 % of cases Imperforate anus Esophageal atresia with TE fistula is less common Hirschsprungs disease Strong assoc with celiac disease b/w 5 – 16 %, 5 – 16 fold increase as compared to general population

27 Growth BW, length and HC are less in DS Reduced growth rate Prevalence of obesity is greater in DS Weight is less than expected for length in infants with DS, and then increases disproportion ally so that they are obese by age 3-4 yrs

28 Hearing loss Unilateral or bilateral Conductive, sensorineural or mixed Otitis media is a frequent problem

29 Hematologic disorders The risk of leukemia is 1 to 1.5 percent. 65% of newborn have polycythemia resulting in hypoglycemia. Risk of AML and ALL is also much higher than the general population. Transient leukemia – exclusively affects NB. - It is asymptomatic with spontaneous resolution in 2-3 months. - Vesiculopustular skin eruptions are common and resolve with disorder.

30 Endocrine disorder Thyroid disease – Hypothyroidism occurs more frequently than hyperthyroidism. Diabetes – The risk of type 1 diabetes is three times greater than that of the general population.

31 Reproduction Women with DS are fertile and may become pregnant. Nearly all males with DS are infertile. The mechanism is impairment of spermatogenesis

32 Diagnosis Prenatal screening If no screening – It is recognized from the characteristic phenotypic features. Confirmed by Karyotype.

33 Cri du Chat(CdC) syndrome

34 CdC cytogenetics Arises from a partial terminal or interstitial deletion of the short arm of chromosome 5 (5p). – De novo deletion – Parental translocation – Other rare cytogenetic aberrations

35 CdC cytogenetics Multigenic Researchers have found two critical regions for CdC – Cat-like cry localized at 5p15.3 – Facial dysmorphisms and psychomotor/mental retardation localized at 5p15.2

36 Cri-du-chat is French for cry of the cat, referring to the distinctive, high-pitched, catlike cry made by children afflicted by this disorder. Becomes less noticeable as the child gets older, making it difficult for doctors to diagnose cri-du-chat after age two. Partial deletion of the 5 pair chromosome.

37 CdC- Phenotype Facial Dysmorphisms – Including microcephaly, round face, hypertelorism, epicanthal folds, low- set ears, and micrognathia.

38 CdC phenotype Microcephaly Normal brain size Brain in Cri du Chat Low set ears

39 CdC phenotype Severe psychomotor and mental retardation Other health problems associated with CdC: – Poor-suck, hypotonia, respitory and heart defects, growth retardation, and cleft palate and/or lip. – CdC patients are generally very sociable, but may exhibit maladaptive behaviors such as inattentiveness, hyperactivity, temper-tantrums, and self injury.

40 Diagnosis and treatment No methods of treating disease directly Several ways to treat medical problems associated with Cri du Chat – Physical therapy – Speech therapy – Behavioral management Prenatal Diagnosis Amniocentesis Chorionic villus sampling (CVS) In vitro fertilization Postnatal Diagnosis Cat-like cry Karyotyping FISH analysis

41 Take care, be patient and attentive to your lovely baby!