Chromosomal abnormalities Lecturer: prof. Pavlyshyn H.A., MD

Chromosomes Normal cells of humans contain 46chromosomes; occurring in pairs and numbered from 1 (the largest) to 22 (the smallest); The chromosomes may be divided into two major types: the 44 autosomes and the 2 sex chromosomes. Autosomes are indistinguishable in males and females, who are genetically distinguished on the basis of their complement of sex chromosomes. Males have an X and a Y chromosome, and females have two X chromosomes.

What are chromosomes? Chromosomes are tiny, string-like structures in cells of the body that contain the genes. Each person normally has 23 pairs of chromosomes, or 46 in all. This is a normal karyotype of human chromosomes. A karyotype is a picture of chromosomes lined up to look at and compare.

Chromosomal abnormalities Generally 5-6/1000 the incidence of chromosomal abnormalities. These abnormalities are caused by errors in the number or structure of chromosomes. Many children with a chromosomal abnormality have mental and/or physical birth defects. Some chromosomal abnormalities result in miscarriage or stillbirth. 50% of spontanous abortion are chromosomal abnormal.

Chromosomal Disorders The defects are classified as abnormalities of number or structure and content (autosomes, sex chromosomes) Numerical defects - are abnormalities of the euploid number of chromosomes (46), Examples: trisomy 21 (Down syndrom), trisomy 18, trisomy 13, Klinefelter syndrome (47,XXY) Turner syndrome (45, X)

Chromosomal Disorders The defects are classified as abnormalities of number or structure and content (autosomes, sex chromosomes) Structural defects - result from chromosome breakage and rearrangement. Possibilities include unbalanced translocation, deletion, duplication, inversion, isochromosome and centric fragment. Examples: cri du chat syndrome (5q deletion), Wilms tumor with aniridia (11 q deletion), Prader-Willi syndrome

Single Chromosome Disorders Deletion - portions of the chromosome are lost (genetic material is missing); 2. Duplication - genetic material is present twice; 3. Inversion - parts of the chromosome are flipped (genetic material is “flipped”)

Two Chromosome Disorders (Both types are called “translocation”) Insertion Genetic material is added from another chromosome when cells go through meiosis, parts of the chromosomes stick together and switch Translocation Material is swapped with another chromosome

Chromosomal Disorders Chromosomal non-disjunction: when cells go through meiosis the chromosomes don’t separate correctly and either too many or not enough are passed on.

Chromosomal Disorders Mosaicism – refer to the presence of two or more cell lines with different chromosome compositions in an individual. Mosaicism occurs as a result of chromosomal non-disjunction after fertilization (when cells go through meiosis the chromosomes don’t separate correctly and either too many or not enough are passed on). The genetic changes is not carried by parents, so the risk for recurrence of a child with mosaicism is usually negligible.

When to suspect it Unexplained infertility Multiple abortion >2 Prior case of defective baby Presence of congenital anomalies (mental retardation, multiple congenital abnormalities, dysmorphic features) 45% have minor single anomalies 9% 3 minor anomalies 1.5% HAVE major anomaly 2 or more major anomalies may represent genetic syndrome or chromosomal abnormalities

Classification of chromosomes diseases Sex linked (Klinefelter syndrome, Turner syndrome, Trisomy X); Autosomal inheritance

Down Syndrome (Trisomy 21) is the most common autosomal trisomy compatible with life Types of defects Trisomy 21 (95 %); Some cases result from translocation More rarely, mosacism (about 2%) Karyotype = 47,XX+21 or 47,XY+21

Risk correlate with maternal age <25 y/o 1/1600 35 to 39 y/o 1/270 30 to 34 y/o 1/800 > 40 y/o 1/80

DOWN SYNDROME Clinical features Characteristic appearance with dysmorphic features; General. Hypotonia with tendency to keep mouth open and protrude the tongue; Excessive mobility, flexibility of joints. Relatively small, short stature with awkward gait.

DOWN SYNDROME Clinical features Central Nervous System Mental retardation (mean IQ< 50) Developmental delay Hypotonia Alzheimer-like dementia Signs of hypothyroidism Leukemia

DOWN SYNDROME Craniofacial Microcephaly, brachycephaly with relatively flat occiput Flat facial profile Short, up slanting palpebral fissures Small nose with flat nasal bridge; Brushfield, speckled spots of the iris Inner epicanthal folds Small mandible, small mouth with protruding tongue Small ears with abnormal shape Late closure of fontanels;

DOWN DISEASE Flat facial profile Small nose with flat nasal bridge; Short, broad hands Stubby fingers Flat facial profile Small nose with flat nasal bridge; Inner epicanthal folds Short, up slanting palpebral fissures

“Happy children” Down Syndrome Rough skin Mentally retarded Small round face Protruding tongue Impotency in males Short lifespan “Happy children”

The palm of patient with Down syndrome crease simian

Cardiac – CHD: PDA, VSD, ASD, Atrioventricular Septal Defect (AV-Canal) ;

DOWN SYNDROME PRINCIPAL FEATURES IN NEONATE Hypotonia 80% Poor Moro reflex 85% Hyperflexibiliry of joints 80% Excess skin on back of neck 80% Flat facial profile 90% Slanted palpebral fissures 80% Anomalous auricles 60% Dysplasia of pelvis 70% Dysplasia of mid phalanx fifth finger 60% Simian crease 45%

Down syndrome With early intervention and special education, many learn to read and write and participate in various childhood activities.

Trisomy 18 Edwards syndrome Incidence 1/8000 Sever Mental retardation and many physical birth defects >90% dead in 1st year

Trisomy 18 severe birth defects + mental retardation

Trisomy 18 chromosome Edwards syndrome Polyhydramnios, Small placenta Intrauterine growth retardation; Craniofacial dysmorphism (strawberry-shaped head) Microcephaly; Micrognathia (small mandible); Small face with prominent occiput

Edwards syndrome(18+) Fixed finger contractures Overlap of second finger on third, fourth finger on fifth Fixed finger contractures

Trisomy 18 Edwards syndrome Weak cry Small sternum, small nipples and pelvis Hypoplasia of skeletal muscle, subcutaneous and adipose tissue. CHD, VSD, PDA and horseshoe kidney, omphalocele

Small sternum, small nipples

Hypogonadism - small penis, cryptorchidism Edwards syndrome(18+) Hypogonadism - small penis, cryptorchidism Rocker-bottom feet

Trisomy 13 Patau syndrome(13+) severe birth defects mental retardation

Trisomy 13 Patau syndrome(13+) IUGR – intrauterine growth retardation Open scalp lesion, scalp defect (cutis aplasia) Cleft palate (may be bilateral) Microcephaly Malformed ears Microphthalmos, coloboma of the eyes

Patau syndrome (13+) variable defect in facial development Microcephaly Cleft palate

Polydactyly of feet

Trisomy 13 Patau syndrome(13+) CNS malformations, midline brain defect, holoprosencephaly CHD - variety of cardiac defect (VSD, ASD, TGV

Newborn boy with diagnosed Patau syndrome (cleft lip and palate, polydactyly of left hand, atrial septal defect) Boy 5 yrs old with Patau syndrome (congenital deafness and blindness)

Patau syndrome (13+) PROGNOSIS 50% of patients die before 1 month of age 70 % - die before age 6 month, 90 % - die before age 1 year

Sex chromosome disorders involve abnormalities in the number or structure of the X or Y chromosome Turner syndrome Affects 1 in 2500 newborn girls; One X chromosome is either missing or abnormal; In 55% of girls who have Turner-syndrom there is a 45, X karyotype; In 25 % of patients – the structure of one of the X chromosomes is altered (deletion, duplication). in 15 % of patients – mosacism;

Prenatal diagnostics of Turner syndrome Blister hyhrome of neck area and edema of fetus

XO SYNDROME (Turner Syndrome) Short Female, Broad Chest with Wide Space of Nipples, Congenital Lymph edema Dysmorphic features – lymphedema of hands and feet at birth, shield-shaped chest, webbing of the neck, appearance of short neck low posterior hairline, Cubitus valgus (increased carrying angle) Short stature (height adult – 135 cm) Multiple pigmented nevi

Webbing Neck Lymphedema Криловидна складка на шиї Webbing Neck Lymphedema

Functional and structural abnormalities Turner syndrome Functional and structural abnormalities GONADAL dysgenesis is present in 100% of patients, is associated with primary amenorrhea and lack of pubertal development due to absence of ovarian hormones. Females are unable to become pregnant GONADOBLASTOMA (tumor of abdominally located gonads with Y-containing cells) in patients who have a cells line with Y chromosome.

Congenital anomaly of uterus and testis

continue RENAL anomalies (40 %) include duplication of the collecting system and horseshoe kidney. CHD (20 %) – AS, CA, bicuspid aortic valve. Dissecting aortic aneurysm in young adulthood may be a serious complication. Thorax. Broad chest with widely spaced nipples that may be hypoplastic; often mild pectus excavatum;

Tendency to become obese Turner syndrome Short stature Tendency to become obese

PROGNOSIS Depends on the type and severity of malformations Life span probably normal in most cases

Klinefelter syndrome Hypogenitalism and Hypogonadism. Long Legs, Dull Mentality, and/or Behaviorals 80 % - children with Klinefelter syndrome have a male karyotype with an extra chromosome X-47,XXY 20% - have multiple sex chromosome aneuploidies (48,XXXY; 48,XXYY; 49,XXXXY), mosaicism (46,XY/47,XXY); 20% of aspermic adult male (blocked spermatogenesis

XXY SYNDROME, KLINEFELTER SYNDROME

Klinefelter syndrome Puberty occurs at the normal age, but the testes remain small. Patients develop secondary sex characters late; 50% develop gynecomastia. They have taller stature. Because many patients with Klinefelter syndrome are phenotypically normal until puberty, the syndrome often goes undiagnosed until they reach adulthood, when their infertility aids in their clinical identification. Patients with 46,XY/47,XXY have a better prognosis for testicular function.

XXY syndrome. A, 9 year XXY child: note is small penis, long legs. B, 16 year untreated XXY adolescent; note the gynecomaslia and scoliosis. C, 21 year untreated XXY adult; note the obesity and hypovirilization.

Klinefelter syndrome Their intelligence shows variability and ranges from above to below average. Persons with KS can show behavioral problems, learning disabilities, and deficits in language. Problems with self-esteem are often the case with adolescents and adults. Substance abuse, depression, and anxiety have been reported in adolescents with Klinefelter syndrome. Those who have higher X chromosome counts show impaired cognition. It has been estimated that each additional X chromosome reduces the IQ by 10-15 points, when comparing these persons with their normal siblings. The main effect is seen in language skills and social domains.

Deletion 5p syndrome (cri-du-chat , cat’s cry syndrome) The cause of this syndrome is a deletion of part of the short arm of chromosome 5. ABNORMALITIES Low birth weight (less than 2.5 kg)-72% Slow growth-100% Cat-like cry-100% Mental deficiency-100% Hypotonia-78%

Deletion 5p syndrome (cri-du-chat , cat’s cry syndrome) Cat-like cry in infancy, microcephaly, downward slant of the palpebral fissures

Deletion 5p syndrome (cri-du-chat , cat’s cry syndrome) Clinical features Beginning in the newborn period and continuing through the first few months of life Children affected with this disorder have a striking cat-like cry that is caused by laryngeal hypoplasia.

Prenatal diagnostic of chromosomal diseases