Chromosomal Disorders


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A short documentation on chromosomal disorders

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Chromosomal Disorders

  1. 1. CHROMOSOMES Choromosomes are condensation of DNA material in the nucleus of a cell. Each human cell contains 23 pairs of chromosomes(except in the gonads). There are two types of chromosomes: Autosomes- Chromosome 1-22 Sex chromosome- X chromosome and Y chromosome STRUCTURE OF A CHROMOSOME: NORMAL HUMAN KARYOTYPE:
  2. 2. CHROMOSOMAL ABNORMALITIES Numerical Abnormalities: Monosomy e.g. Turner’s syndrome Trisomy e.g. Down’s syndrome, Edward’s syndrome, Patau’s syndrome Structural Abnormalities Deletion Duplication
  3. 3. TURNER SYNDROME (45 X0 GONADAL DYSGENESIS) KARYOTYPE: 45 X0 INCIDENCE: 1:3000 newborns INHERITANCE: Sporadic, meiotic or mitotic nondisjunction GENITALIA: Female CLINICAL FEATURES:  The disorders maybe recognizable at birth - *lymphedema of the dorsum of hands&feet, loose skin folds at the nape of neck.  Short stature, short neck with webbing, low posterior hairline  Facies - Anomalous ears, prominent narrow & high arched palate, small mandible &epicanthal fold  Broad shield-like chest & widely spaced nipples  Increased carrying angle at elbow  Knee anomalies e.g medial tibialexostosis  Short 4th metacarpals & metatarsals  At puberty, sexual maturation fails to occur  Adult stature <145 cm  Pigmented naevi, keloid, abnormal nails, puffiness of dorsum of fingers  Mentally normal unless ring chromosome is present  Associated congenital defects are common Kidney – horse-shoe kidney, double or cleft renal pelvis Heart – coarctation of aorta Ears – perceptive hearing defect Congenital lymphedema – usually recedes in early infancy*
  4. 4. HORMONE PROFILE  Low plasma estradiol  High plasma LH & FSH concentration DIAGNOSIS  Hormone profile  Karyotype/Barr body (absent)
  5. 5. MANAGEMENT  Height monitoring, cardiac evaluation, BP measurement , ECHO at baseline & every year is recommended.  Growth hormone therapy: 0.375mg/kg/week daily SC Oxandrolone 0.06mg/kg/day early in childhood if diagnosed  Ovarian hormone replacement – to elicit increase in height and development of secondary sex characteristics. 100µg/kg/day ETHINYL ESTRADIOL at 12-13 yrs of age. Dose is gradually increased over 2-3 yrs& subsequently cyclical therapy estrogen-progesterone combination is started  Prophylactic GONADECTOMY in Turner syndrome with Y chromosome is recommended – due to chances of developing gonadoblastoma
  6. 6. KLINFELTER’S SYNDROME Klinefelter syndrome is a chromosomal condition that affects male physical and cognitive development. Incidence 1:500-1000 newborn Genotype: 47, XXY CLINICAL FEATURES Delayed/ incomplete puberty Gynaecomastia Reduced facial and body hair Infertility Crytorchidism Hypospadias Micropenis Taller than counterparts High risk of breast cancer and SLE Learning disabilities and delayed speech and language development
  7. 7. TREATMENT Early identification and anticipatory guidance are extremely helpful, although Klinefelter syndrome is rarely diagnosed in prepubertal males. Treatment should address 3 major facets of the disease: hypogonadism, gynecomastia, and psychosocial problems. Androgen therapy Testosterone replacement should begin at puberty, around age 12 years, and the dose should increase until it is sufficient to maintain age-appropriate serum
  8. 8. concentrations of testosterone, estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). Androgen therapy is used to correct androgen deficiency, to provide appropriate virilization, and to improve psychosocial status. Regular testosterone injections can promote strength and facial hair growth; build a more muscular body type; increase sexual desire; enlarge the testes; improve mood, self-image, and behavior; and protect against precocious osteoporosis. Speech and behavioral therapy A multidisciplinary team approach can assist in improving speech impairments, academic difficulties, and other psychosocial and behavioral problems. In children, early speech and language therapy is particularly helpful in developing skills in the understanding and production of more complex language. Males with Klinefelter syndrome should receive a comprehensive psychoeducational evaluation to assess their areas of strengths and weaknesses. The information obtained from these evaluations may be helpful in planning appropriate resources and classroom placement. Physical and occupational therapy Physical therapy should be recommended in boys with hypotonia or delayed gross motor skills that may affect muscle tone, balance, and coordination. Occupational therapy is advised in boys with motor dyspraxia. Treatment for infertility Men with Klinefelter syndrome were considered infertile until 1996. Over the last decade, developments in microsurgical techniques and advances in artificial reproductive technologies (ART) allowed more than 50% of patients with Klinefelter syndrome to have their own children through the combination of microsurgical testicular sperm extraction (TESE) and the use of freshly retrieved sperm for in-vitro fertilization (IVF). The fact that sperm can be found in the testes of men with Klinefelter syndrome has challenged the previous assumption that men with Klinefelter syndrome are always sterile. Viable spermatozoa can now be extracted from the testes via surgical biopsy, and a spermatozoon can be directly injected into an ovum. More than 60 children have been born worldwide after successful
  9. 9. intracytoplasmicsperm injection (ICSI) in couples in which the male partner has Klinefelter syndrome. A minority of men with Klinefelter syndrome have viable sperm in their ejaculate and are able to provide sperm for cryopreservation for future pregnancies. Microdissection testicular sperm extraction is an effective sperm retrieval technique in men with Klinefeltersyndrome.Men with hypogonadism who respond to medical therapy may have a better chance of sperm retrieval. Genetic counseling The recurrence risk is not increased above that in the general population. Physicians should provide parents with information from unbiased follow-up studies of children with Klinefelter syndrome. The best time to reveal the condition to an affected male is probably mid-to-late adolescence, when he is old enough to understand his condition. Reproductive genetic counseling Sperm from patients with the nonmosaic 47,XXY karyotype has been used successfully in assisted reproduction. Origin of the meiotic products of patients with the nonmosaic 47,XXY karyotype remains unclear. First, mosaicism cannot be excluded in the nonmosaic 47,XXY karyotype. Indeed, the presence of a normal XY germ cell line in the testis could explain the production of normal haploid sperm in these apparently nonmosaic patients. Nevertheless, lymphocyte karyotyping neither predicts the chromosomal constitution of the testis cells nor the presence or absence of spermatogenesis. ICSI per se is also associated with an increased risk of producing a chromosome anomaly in offspring. IVF is also associated with an increased risk for de-novo chromosomal aberrations, especially those involving the sex chromosomes. Reproductive genetic counseling of patients with the 47,XXY karyotype remains difficult. Some authors have recommended preimplantation or prenatal diagnosis after ICSI using sperm cells from patients with the 47,XXY karyotype. Arguments from authors who propose a preimplantation genetic diagnosis (PGD) include the increased risk of producing sex chromosomal-abnormal offspring (the unbalanced offsprings are 47,XXX
  10. 10. or 47,XXY karyotypes). DOWN SYNDROME  The most common chromosomal disorder (1:800 to 1:1000 newborns).  The chromosome number 21 is present in triplicate.  The origin of the extra chromosome maybe maternal or paternal.  The risk in the newborns: Age of mother Risk in newborns 15-29 1:1550 30-34 1:800 35-39 1:270 40-44 1:100 >45 1:50 BASIC DEFECTS:a) Non-dysjunction – 95% Meiotic division does not occur for no. 21 chromosome. One of the gamete carries an extrachromosomes. b) Translocation – 4% Translocation of the third no. 21 chromosome to another chromosome. c) Mosaicism – 1%
  11. 11. Results from a mitotic division error that occurred during earlu embryonic development. CLINICAL FEATURES :A) Dysmorphic features 1) Dysmorphic facial features Flat facial profile Short, upslanting palpebral fissures Brushfield spots on iris Flat nasal bridge with epicanthal folds Small mouth with protruding tongue Small retroplaced chin Short ears with abnormal ear lobes that are usually downfolded Cataract and squint are common High arched palate with small teeth ‘scrotal’ (furrowed) tongue 2) Other dysmorphic features Small head (microcephaly), brachycephaly (flat occiput) Skin- excess posterior neck skin Short stature Short sternum Small genitalia Short, broad hands and fingers marked by incurved fifth finger (clinodactyly) with hypoplastic middle phalanx Single palmar crease (Simian crease)
  12. 12. Wide gap between first and second toes (sandle gap) B) Functional and structural abnormalities 1) Hypotonia – most noticeable in the newborns. 2) Mental retardation and developmental delay. 3) cardiac defects – a) endocardial cushion defects b) septal defects c) A-V communis d) ventricularseptal defects e) patentductusarteriosus 4) abdomen – a) duodenal atresia and Hirschsprung disease b) small penis c) cryptorchidism 5) 6) 7) 8) dysplastic pelvis. hypothyroidism and leukaemia. a pattern of dementia much like Alzheimer’s disease. Social aspects – behave as good babies, happy children and tend towards mimicry, are friendly and have a good sense of rhythm and enjoy music.
  13. 13. C) Common complications 1) Death due to congenital heart disease and lower respiratory tract infection. 2) Chronic rhinitis. 3) Conjunctivitis. 4) Periodontal disease.  Risk of recurrence  Non-dysjunction – subsequenct chances are 1% in addition to the risk of high maternal age.  Mosaicism – if one child is Down, the subsequent chances is 1%.  Translocation – subsequent chances are 5% to 100%
  14. 14. MANAGEMENT A) Principle of genetic counselling  To be given after confirmation of diagnosis.  Both the parents should be present.  Given by a team of physician, geneticist and psychiatrist.  A number of sittings are required. B) Counselling  Explain the parents about the disease, that the child is going to be mentally retarded, require special schooling.  Explain about congenital heart diseases, other abnormalities, social performances is good-smiles, laughs (lovable moron), interested in music and mimicry.  Counselling about the recurrence risk. C) Antenatal diagnosis 1) Initial screening with  maternal serum markers PAPP-A and betaHCG ( 1st trimester) Serum alpha fetoprotein (AFP), HCG, unconjugated estriolandinhibin A (2nd trimester)  Fetal ultrasonography 1st trimester – nuchal translucency and nasal bone 2nd trimester - Increased nuchal fold thickness, short femur and humerus length and duodenal atresia. 2) Prenatal karyotyping Chorionic villous sampling – can be carried out between 10 to 12 weeks of pregnancy (transcervical or transabdominal). Amniocentesis – on 16 to 18 weeks Cordocentesis – after 18 weeks The risk of fetal loss after CVS is 3-4%, after cordocentesis is 3% and after amniocentesis is 0.5-1 %.
  15. 15.  Recommended follow up for patients of Down Syndrome 0-1 month infancy Clinical examination Chromosomal study Stimulation programme Growth assessment Thyroid screening hearing vision Cervical spine x-ray ECG and echocardiography Psychosocial development & behavioural assessment + (or 1st visit) + (or 1st visit) + + + 1-5 year + + 5- 13 year + + + 3 yearly + + + + 3 yearly + 3 yearly + First visit or clinical suspicion / abnormal ECG + + + +
  16. 16. EDWARD’S SYNDROME(TRISOMY 18) First described in 1960 by Edwards et al. Incidence : 1 in 3000 live births. It is the second most common autosomal trisomy among live births. Genetics : Presence of three chromosome 18 instead of the normal two. This is due to an error in cell division,known as meiotic dysjunction. CLINICAL FEATURES                   Failure to thrive Severe developmental delay Hypertonia-extreme rigidity Head-Microcephaly, dolichocephaly,prominent occiput, strawberry-shaped head Face-Small eyes, upturned nose, small mouth, small jaw( micrognathia) ,low set and malformed ear Hands -Clenched hands with index finger overlapping middle finger, little finger overlapping ring finger, due to flexion deformity of fingers -Underdeveloped nails -Simple dermal arches on nearly all digits -Very short fourth digits with a single crease Thorax Shield-like chest, short sternum Abdomen- Inguinal or umbilical hernia, part of the intestinal tract is outside the stomach (omphalocele) Small pelvis Rocker bottom feet , prominent calcaneum, short dorsiflexed of first toe Skin mottling Heart  Congenital Heart Defects  Ventricular SeptalDefect(90%)  Patent DuctusArteriosus(70%)  Atrial SeptalDefect(20%)  Valvular regurgitation may occur at multiple sites  Coarctation of aorta Eesophageal atresia Kidney anomalies Undescended testis Vertebral abnomalies Arthrogryposis (Stiff joint) Psychomotor retardation
  17. 17. INVESTIGATION:  To confirm diagnosis  Karyotyping  To diagnose complication  Complete blood count  Urine examination  Chest X-ray  X-ray of bones, cranium,vertebralcolumn,pelvis  ECHO and ECG for congenital heart defects  Ultrasonography of abdomen
  18. 18. TREATMENT  Resuscitation is often required at birth. Baby is kept in intensive care unit. -Poor sucking ability so nasogastric tube is needed  Surgery maybe needed to correct defects or abnormalities, eg. Heart defects, omphalocele, hernia  Access to programs and services as required eg.physical therapy, speech therapy, educational support, social, vocational, and medical services.  Genetic counseling and joining a support group is recommended. COMPLICATIONS:        Spontaneous abortion Stillbirth Apnoea Congestive heart failure Early infant death Failure to thrive Mental retardation PROGNOSIS: Prognosis is very bad due to life-threatening medical complications. Mortality rate is high just before and after the baby born.The median survival is about 3 months.
  19. 19. PATAU SYNDROME (TRISOMY 13) INTRODUCTION -it is a chromosomal condition associated with severe intellectual disability and physical abnormalities in many part of body -result from having 3 copies of chromosomes 13 in each cell in body instead of 2 INCIDENCE -1 per 5000 births -although women at any age can have a child with trisomy 13 , the chance of having a child with this condition increases as a woman gets older PROGNOSIS -majority of cases die in the first 6months of life. -survivors have severe mental defects and seizures and they fail to thrive
  20. 20. CHARACTERISTICS -severe developmental and physical retardation -microcephaly with sloping forehead -holoprosencephaly type of defect with varying degrees of incomplete development of forebrain, olfactory and optic nerves -micropthalmia, coloboma of iris, retinal dysplasia, cataract -malformations of ears -cleft lip with or without cleft palate -capillary hemangiomata are characteristic -abnormalities of fingers and toes like polydactyly,flexion deformities and long and hyperconvex nails -congenital heart disease in 80% of patients like ventricular septal defects, patent ductusarteriosus and arterial septal defect There is an overlap between clinical features of trisomy 13 and 18.The highest discriminating values are ECTODERMAL SCALP DEFECTS and HARELIP and CLEFT PALATE in trisomy 13 , and ELONGATED SKULL and SIMPLE ARCHES on all digits for trisomy 18
  21. 21. CRI DU CHAT SYNDROME INTRODUCTION In 1963, Lejeune et al described a syndrome consisting of multiple congenital anomalies, mental retardation, microcephaly, abnormal face, and a mewing cry in infants with a deletion of a B group chromosome (Bp-), later identified as 5p-. DEFINITION Cri du chat syndrome - also known as 5p- syndrome and cat cry syndrome - is a rare genetic condition that is caused by the deletion (a missing piece) of genetic material on the small arm (the p arm) of chromosome 5. The cause of this rare chromosomal deletion is unknown. PATHOPHYSIOLOGY A partial deletion of the short arm of chromosome 5 is responsible for the characteristic phenotype. The characteristic cry is perceptually and acoustically similar to the mewing of kittens. This unusual cry is due to structural abnormalities of the larynx (eg, laryngeal hypoplasia) and CNS dysfunction. The laryngeal appearance may be normal or may exhibit marked anatomical abnormalities such as floppy epiglottis, small larynx, and asymmetric vocal cords. However, the cause of the characteristic cry cannot be entirely ascribed to the larynx. A developmental field may connect the brain and the affected clivus region of the cranial base with the laryngeal region from which the characteristic cry derives. This area of the brain is probably deformed in patients with cri-du-chat syndrome. The characteristic cry usually disappears over time. Cri-du-chat syndrome is caused by a partial or total deletionof genetic material on the short arm of chromosome 5. The size of the deletion could affect from region 5p15.3 to the complete loss of the short arm. Most of the cases are due to 1. de novo deletion (80%), 2. parental translocation (10%) 3. cytogenetic rare aberrations (10%) A deletion of 5p15.3 results in the manifestation of a catlike cry and speech delaywhereas a deletion of 5p15.2 results in the presentation of the other major clinical features of the syndrome.
  22. 22. SYMPTOMS The symptoms of cri du chat syndrome vary among individuals. The variability of the clinical symptoms and developmental delays may be related to the size of the deletion of the 5p arm. The clinical symptoms of cri du chat syndrome usually include a high-pitched cat-like cry, mental retardation, delayed development, distinctive facial features, small head size (microcephaly), widely-spaced eyes (hypertelorism), low birth weight and weak muscle tone (hypotonia) in infancy. The cat-like cry typically becomes less apparent with time. Most individuals who have cri du chat syndrome have difficulty with language. Half of children learn sufficient verbal skills to communicate. Some individuals learn to use short sentences, while others express themselves with a few basic words, gestures, or sign language. Other characteristics may include feeding difficulties, delays in walking, hyperactivity, scoliosis, and significant retardation. A small number of children are born with serious organ defects and other life-threatening medical conditions, although most individuals with cri du chat syndrome have a normal life expectancy. Both children and adults with this syndrome are usually friendly and happy, and enjoy social interaction.
  23. 23. DIAGNOSIS The diagnosis of cri du chat syndrome is generally made in the hospital at birth. A health care provider may note the clinical symptoms associated with the condition. The cat-like cry is the most prominent clinical feature in newborn children and is usually diagnostic for the cri du chat syndrome. Additionally, analysis of the individual's chromosomes may be performed. The missing portion (deletion) of the short arm of chromosome 5 may be seen on a chromosome analysis. If not, a more detailed type of genetic test called FISH analysis may be needed to reveal the deletion. TREATMENT No specific treatment is available for this syndrome. Children born with this genetic condition will most likely require ongoing support from a team made up of the parents, therapists, and medical and educational professionals to help the child achieve his or her maximum potential. With early and consistent educational intervention, as well as physical and language therapy, children with cri du chat syndrome are capable of reaching their fullest potential and can lead full and meaningful lives.
  24. 24. CYSTIC FIBROSIS Cystic fibrosis occur result of mutation at chromosome 7 (7q13). It is an autosomosal recessive genetic disorder which affects mostly on lungs ,pancrease, liver and intestine. The defects occur at Delta F508 which denotes a single deletion at 508 position of protein. This causes mutation in a gene for a protein cystic fibrosis transmembrane conductance regulator (CFTR). It is required for regulation of sweats, digestive fluid, and mucus. Mostly the disease appear when two CFTR gene are missing due to disorder recessive nature. PATHOLOGY - - CFTR required movements of chorides and sodium ions across the epthelial membrane. Hence it lead to thick inspissatedsecreation in the epithelial lining of lungs , sweats glands, pancreases and intestinal mucosa. Causes trigger inflammatory reaction leading to fibrosis Lead to formation thick mucus plugs result in collapse, stasis, obstruction and infection in affected organ
  25. 25. CLINICAL FEATURES 1.Gastrointestinal: - Meconium ileus in neonates - Malapsorbtion - Chronic diarrhoea constipation - Ileoceacal intussusception - Fibrosingcolonopathy 2.Heapatobiliary -fatty liver -jaundice -potral hypertension -hepatic failure -gallstones 3.Pancreatic -chronic pancreatitis -Exocrine and endocrine dysfunction 4.Nutritional -vitamin defficiency mainly fat soluble vitamins -micronutrient deficiency
  26. 26. DIAGNOSIS -Diarrhoea during early infancy associated with the respiratory problem(pneumonia) -Trypsin and duodenal juice and stools reduced -x-ray show pulmonory involvement -level of chlorides in sweat above 60 mEq/L TREATMENT Supportive treatment includes medicines and home treatment. 1. Nutrition: caloric dense food with enough carbohydrates and protein content. Rich in polyunsaturated fatty acid and fat soluble vitamins 2. Medical treatment: enzyme supplement: lipase Infants:2000-4000 units lipase /120ml formula 1-4 years:1000-2000 units lipase/kg/meal >4 years: 200-2000 units lipase/kg/meal - use antacids sodium bicarbonate and antihistamine along with enyzme -taurine and lecithin given to provide substrates for increased hepatic synthesis of bile acid - misoprostol given in resistant case to inhibit gastric acid secreation and stimulate bicorbanatesecreation in upper gut. - long term antibiotic to prevent pulmonary complication -aerosol therapy with mucolytics agent such as Dnase and acetylcystein -ursodeoxycholic acid improves bile flow -Breathing exercise with chest physiotherapy -salt(1-2gm/day) to compensates excessive loss of chlorides