Chromosomal Disorders

Definitions Gene: smallest unit of a single characteristic Chromosome: structural elements i n the cell nucleus that carry the genes and convey genetic information Each cell (except RBO) contain all of the chromosomes from both parents in the n ucleus 23 pairs of chromosomes come from each parent Autosome: one of the 22 pai rs of chromosomes that is not responsible for determining the sex of the child S ex Chromosome: X and Y chromosomes responsible for sex determination

Chromosomal Defects Abnormal Number Monosomy: one less than the diploid number (45) Trisomy: one more than the diplo id number (47) Mosaicism: some cells have the correct number of chromosomes and some have more or less than the correct number of chromosomes Abnormal Structure Deletion: loss of a chromosomal segment Translocation: the occurrence of a chrom osomal segment at an abnormal site either on another chromosome or in the wrong position on the same chromosome

Prenatal Diagnosis Maternal Serum Alpha-fetoprotein (MSAFP) Done at 16 18 wks gestation High MSAFP: incorrect dates; multiple gestation; neu ral tube defects, abdominal wall defects; renal anomalies; esophageal or intesti nal obstructions Low MSAFP: incorrect dates; chromosomal defect (esp. Trisomy 21 ) Ultrasound

 Amniocentesis Usually done at 16 18 wks gestation Fluid analysis may require up to 2-3 wks Can usually determine: fetal sex, metabolic disorders, chromosomal abnormalities Chorionic Villus Sampling (CVS) Usually done at 8 10 wks gestation Fetal cell analysis usually takes 24 48 hours

Newborn Care History Family History: any similar relatives, frequency of spontaneous abortions Prenat al History: fetal activity, maternal exposures, uterine malformations

Newborn Assessment Face: configuration, spacing of feature, location of features Head: size and sha pe of skull, fontanel Eyes: structure, location, color of iris Ears: low set or correct location, skin tags Nose: number of nares, location, flattened bridge Or al: size and shape of tongue, mouth, jaw Neck: webbing, extra folds Hands & Feet : broad, square, polydactyly, abnormal creasures, contractures, overriding finge rs or toes

Family Support Crisis Grief loss of perfect child Genetic counseling Identify the normal

Trisomy 21 a.k.a. Downs Syndrome Caused by an extra chromosome 21 Normal Karyotype Trisomy 21 ( 47,XY,+21)

Trisomy 21 Incidence 1 : 650 1000 live births, parental age related 75 % abort spontaneously Sex rati o: 3 males / 2 females Most common autosomal chromosomal disorder causing mental retardation Risk Factors maternal age Parental carrier of translocation Prenatal Testing Triple screen (alpha-fetal protein decreased, estriol decreased, beta-HCG increa sed) If positive, amnio or CVS may be indicated

Clinical Presentation Size: small, 20% are premature Skull: short and round with a flat occiput, separat ed sutures Eyes: slant upward and outward Prominent epicanthal fold Moon-shaped fac e Brushfields spots Cheeks: red Palate: narrow and short Nose: short with flat bridge Tongue: protrudes, tongue thrusting Skin loose around lateral and dorsal aspects o f neck Hands: fingers are short, hands are square, thumbs are low set, separated more than usual from second finger, 5th finger is short and curves inward, singl e/bilateral simean crease Ears: low-set, posteriorly rotated ears

Clinical Presentation Umbilicus: herniated Feet: wide space between great toe and 2nd toe, deep crease b etween great toe and the 2nd toe, flat feet Heart: VSD Duodenal atresia Muscular hy potonia Retarded psychomotor development Hyperlaxity of ligaments Velvety, loose adhering mottled skin in infancy, coarse skin in adolescence Mouth frequently open/frequently open mouth Visual and/or hearing impairment

Prognosis Congestive heart failure d/t CHD Upper respiratory tract infections Developmenta lly delayed Mildly to severely mentally retarded: IQ ranges from 25 70 Increased risk for thyroid problems and leukemia

Trisomy 18 a.k.a. Edwards Syndrome, Trisomy E, Trisomy 16 18 Caused by an extra chromosome 1 8 Normal Karyotype Edwards Syndrome (47,XY, +18)

Trisomy 18 Incidence 1 : 6000 8000 live births F > M (4 : 1) Most die in embryonic or fetal life Risk factors Increased paternal and maternal age Prenatal screening Good indicator is if in maternal serum during mid trimester have low human chori onic gonadotrophin and low unconjugated estriol Ultrasound If anomalies seen, am nio or CVS may be indicated

3 Types of Trisomy 18 Full Form Every cell in the body has 3 chromosome 18 instead of 2 Severe form Mosaic Form Some cells have 3 chromosome 18 and others have 2 Less severe form Partial Form In some cells there may be an extra copy of part of chromosome 18 Severity depen dent on anomalies

Clinical Presentation Prenatal hx: feeble fetal activity, polyhydramnios, small placenta, single umbili cal artery Post-dates SGA Weight: low birth weight in term infant Weak cry Response t o sound decreased Ears: low set and/or abnormal shape Mouth: micrognathia, microstomia, cleft lip, cleft palate Mental retardation Heart: VSD, PDA, ASD Feet: rocker bottom, big toe shortened and dorsiflexed, clubfeet Cr ossed legs Diastasis recti Pectus carinatum GU defects: horseshoe kidneys, hydronep hrosis, polycystic kidneys

Clinical Presentation Hands: clenched and with flexed fingers (usually where index finger overlaps 3rd and 4th fingers),flexion contraction of the two middle digits, underdeveloped or absent thumb, simian crease, arches on seven or more fingers, nails underdevelo ped Syndactyly Eyes: ptosis of one or both eyelids, epicanthal folds Head: abnormally prominent occiput, microcephaly Hernias: umbilical, inguinal Redun dant skin folds esp. over the back of the neck Males: cryptorchidism

Prognosis 20 30% die during the first month 90% die by age one 1% chance of surviving to 1 0 yrs High mortality rate is caused by congenital heart malformations, gastroint estinal and genitourinary anomalies, feeding difficulties, and associated centra l nervous system defects that produce central apnea. Although they function with severe handicaps, all older children with Trisomy 18 smile, laugh, interact, re late to their families, and achieve some psychomotor maturation. Mosaic cases ma y show milder phenotypic expression and prolonged survival.

Care Management No treatment beyond supportive care NG or GT feedings Orthopedic management Card iac management Genetic counseling Parental support Apnea monitoring / O2 if need ed

Trisomy 13 a.k.a. Pataus Syndrome, 13+ Syndrome, 13 15 D Syndrome, Trisomy Syndrome Caused b y an extra chromosome 13 Normal Karyotype Trisomy 13 (47,XX,+13)

Trisomy 13 Incidence 1 : 5000 live births Male = Female Risk Factors Increases with maternal and paternal age Increases with increased parity Parenta l carrier of balanced translocation Prenatal Screening Ultrasound If anomalies seen, amnio or CVS may be indicated

Clinical Presentation Severe mental and psychomotor retardation Ears: malformed, low-set Hands: flexion d eformities; polydactyly, simian crease, clenched hands Heart: VSD, PDA, ASD, rota tional anomalies (dextrocardia) Eyes: microphthalmos, colobomas of iris, cataract s, retinal dysplasia, close set (may fuse into one) Nose: broad and flattened Mouth: cleft lip and palate Hernias: umbilical hernia, in guinal hernia Kidneys: polycystic Skin: cutaneous hemangiomas Head: dermal sinus on scalp, microcephaly Brain: gross defects, grand mal seizures, myoclonic jerks, s eizures, holoprosencephaly

Clinical Presentation Skin loose around lateral and dorsal aspects of neck Single umbilical artery Apnea G enitalia Female: bicornate/septate uterus Male: cryptorchidism Mouth: cleft lip, cleft palate Spine: meningomyelocele Feet: rocker bottom Low-birth weight Omphalocele GI XR or US may reveal abnormal rotation of internal organs

Prognosis 82% die within the first month 5 - 10% survive the first year Survival to adulth ood rare Common disorders if survive beyond 1 month of age Severe mental retardation Feeding disabilities GE reflux Slow post natal gr Apnea Kidney defects Seizures Developmental disabilities Scoliosis

Care Management No treatment beyond supportive care Parental support

Turners Syndrome a.k.a. TS, Monosomy X, Gonadal Dysgenesis, Bonnevie-Ullrich Syndrome, XO Syndrom e Is the absence of one set of genes from the short arm of one X chromosome Normal Karyotype Turners Syndrome (45,X)

Turners Syndrome Incidence 1 : 2000-3000 live-born females Females only affected 98% of pregnancies with TS spontaneously abort 10% of pregnancies that spontaneously abort have TS Risk Factors Increased paternal age Mother with mosaic or deletional Turners Syndrome SHOX gene association SHOX gene provides instructions for making a protein that regulates activity of other genes

Clinical Presentation Short stature; mean birth weight 2.9 kg; average height: 47 Webbed neck Low posterior hairline Micrognathia Ears: low-set, sometimes malformed, prone to otitis media Wi dely spaced hypoplastic nipples on a shield-shaped chest Increased carrying angle at the elbow Heart: coarctation of the aorta, aortic vavular stenosis, bicuspid aortic valve, aortic dissection Eye: ptosis, strabismus, amblyopia, cataracts, ep icanthal folds, dry eyes, red-green color blindness Congenital hip dislocation Abn ormal growth patterns Congenital lymphedema of hands and feet

Clinical Presentation Absent or retarded development of secondary sexual characteristics that normally appear at puberty Absent menstruation Absence of normal vaginal moisture infertilit y Gonadal dysplasia Horseshoe kidney Unilateral renal agenesis Intelligence: not at risk for mental retardation, better verbal then visuospatial abilities Broad nasa l bridge

Prognosis Females are basically normal despite failure of sexual development At risk for Middle ear infections Scoliosis Arthritis Cataracts Hashimotos thyroid abnormalities High blood pressure Obesity Diabetes mellitus Osteoporosis Keloid formation

Care Management Early Supportive care Surgery to correct treatable defects Late Growth hormone therapy Estrogen replacement therapy Counseling and psychiatric s upport 2 5% have some ovarian function and can menstruate and become pregnant Ot hers can have children using donor eggs and in-vitro fertilization

VATER Association VATER = Vertebral anomalies Anal atresia Tracheo-Esophageal fistula, Radial and renal dysplasia Incidence Unknown Etiology Unknown

Clinical Presentation Three or more of the following defects must be present: Vertebral anomalies Anal atresia with or without fistula TEF with EA Radial dysp lasia, including thumb or radial hypoplasia, polydactyly, and syndactyly Renal a nomaly Single umbilical artery

 Prognosis FTT Possibility of normal life after slow mental development during infancy Care Management Supportive care Surgery: surgical correction of anomalies