Inheritance patterns Inheritance Patterns nThe inheritance patterns trace the transmission of genetically encoded traits, conditions or diseases to offspring. nThere are several modes of inheritance: nSingle Gene or Mendelian nMultifactorial nMitochondrial n Single Gene Inheritance nGenetic conditions caused by a mutation in a single gene follow predictable patterns of inheritance within families. nSingle gene inheritance is also referred to as Mendelian inheritance as that follow transmission patterns he observed in his research on peas. Monogenic disorders n nPrecise and well-established risks can be given regarding its occurrence in other family members nDNA analysis is possible in some cases n n n Monogenic diseases nTypicaly in childhood- not exclusively! nLess then10% manifest after puberty, n 1% after reproductive age nIncidence of monogenic disorders- 0,36% n Mendelian inheritance-types nThere are four types of Mendelian inheritance patterns: nAutosomal dominant nAutosomal recessive nX-linked recessive nX-linked dominant Autosomal Dominant nthe gene responsible for the phenotype is located on one of autosomes nThe sexes are involved equally nConditions are manifest in heterozygotes nAffected individual's have one normal copy of the gene and one mutant copy of the gene neach offspring has a 50% chance on inheriting the mutant allele. Pedigree AD inheritance • the risk 50% healthy ill AD - diseases n nNeurofibromatosis types I and II nAchondroplasia nMyotonic dystrophy nHuntington disease n n n Neurofibromatosis nmember of the neurocutaneous syndromes (phakomatoses) nNF type I- from nerve tissue grows benign tumors (neurofibromas) nNF1 gene-neurofibromin(17q11.2) nCafé au lait spots,Neurofibromas, plexiform Neurofibromas naxillary and inguinary freckling, Iris Hamartomas(Lisch nnodules),MR 10-30%, skeletal symptoms nNF type II- central type-bilat.acoustic Neurinomas (Tumors of the vestibulocochlear Nerve )-hearing loss, Meningiomas, n Ependymomas,Gliomas,Astrocytomas, juvenile cortical Cataract Retinal hamartoma ,no Lisch nodules nNF2 gene- merlin (22q12.2) nNeoplasias nVariation in expression n50% new mutations. n n Myotonic dystrophy I ntrinucleotide repeat expansion (CTG)n in the dystrophia myotonica-protein kinase gene (DMPK) 19q13.32 nMyotonia (delayed muscle relaxation after contraction), cataract,atrial arrythmias, hypogonadism, testicular atrophy ncongenital form(over 2000 repeats)-hypotonia, poor feeding,severe mental retardation, prenatal polyhydramnios, reduced fetal movement n nMyotonic dystrophy type 2 (DM2), also called proximal myotonic myopathy (PROMM)-rarer than DM1 and generally manifests with milder signs and symptoms. nSpecific defect -repeat of the CCTG tetranucleotide in the ZNF9 gene (3q21.3). n Achondroplasia nAutosomal dominant with complete npenetrance n80% cases new mutations n100% of the mutations are G380R in FGFR3 nPaternal age effect n n Short-limb dwarfism identifiable at birth nMean male adult height, 131 cm nmean female height, 124 cm nFrontal bossing ,megalencephaly nmidface hypoplasia,low nasal bridge achondroplasia prvé medicinske zobrazenie Huntington disease na progressive disorder of motor, cognitive, and psychiatric disturbances. The mean age of onset is 35 to 50 years and the median survival time is 15 to 18 years after onset. nThe diagnosis of HD rests on positive family history, characteristic clinical findings-Hyperreflexia ,Chorea ,Dementia Bradykinesia ,Rigidity, psychiatric:depression,psychotic symptoms, outbursts of aggression; nexpansion of 36 or more CAG trinucleotide repeats in HTT (the huntingtin gene 4p16.3). nTreatment of manifestations: neuroleptics ,anti-parkinsonian agents , psychotropic drugs or some antiepileptic drugs . Supportive care with attention to nursing needs, dietary intake, special equipment, and eligibility for state benefits. n HD- genetic counseling nPredictive testing in asymptomatic adults at 50% risk is possible but requires careful thought nincluding pretest and post-test genetic counseling n Asymptomatic at-risk individuals younger than age 18 years should not have predictive testing. nprenatal testing by molecular genetic testing is possible for pregnancies at 50% risk. Prenatal testing for pregnancies at 25% risk cannot be performed because genetic status of the at-risk parent can reveal. Linkage analysis can be used for preimplantation genetic diagnosis nFamilies may benefit from referral to a local HD support group for educational materials and psychological support. n n Autosomal Recesive nRecessive conditions are clinically manifest only when an individual has two copies of the mutant allele. nFemales and males are affected equally nWhen two carriers mate, each child has a 25% chance of being homozygous wild-type (unaffected); a 25% chance of being homozygous mutant (affected); or a 50% chance of being heterozygous (unaffected carrier). n Pedegree - AR inheritance •The risk for next child 25% carrier carrier healthy ill carrier healthy Consanguinity nConsanguineous marriage is the union of individuals having a common ancestor. It is categorized as 1st, 2nd and 3rd degree nConsanguineous marriages increase the risk of manifestation autosomal recesive diseases in offsprings ngenetic consanguinity is expressed n with the coefficient of relationship- is defined as the fraction of homozygous due to the consanguinity under discussion AR - diseases nCystic fibrosis n(frequency of heterozygotes CR- 1/26) n nPhenylketounria (1/40) n nCongenital adrenal hyperplasia (1/40) n nSpinal muscular atrophy (1/60-80) n Cystic fibrosis nLocalized on chromosome 7q nCFTR gene nFrequency of Cystic Fibrosis in the Czech Republic: about 1/3000 nFrequency of heterozygots in the Czech Republic about 1/25-1/29 nAbout 1900 mutations in CFTR gene were identified n CF-ethnical differences n frequence of CF frequence of heterozygotes n nCaucasians 1/3000 1/25 n nHispanics 1/9000 1/46 n nAmer. Africans 1/15000 1/60 n nAsians 1/32000 1/90 Cystic fibrosis nChronic bronchopulmonary infection Bronchiectasis ,Asthma ,Pseudomonas colonization nPancreatic insufficiency in 80%, Biliary cirrhosis, Meconium ileus in neonates (10-15%) Distal intestinal obstruction syndrome Rectal prolapse nMale infertility (98%) due to congenital bilateral absence of the vas deferens (CBAVD) ,Female decreased fertility due to thickened cervical secretions and chronic lung disease nLaboratory Abnormalities - High sweat sodium and chloride Hyponatremic dehydratation, rarely Hypercalciuria Abnormal nasal potential differences High newborn serum levels of immunoreactive trypsinogen n Respiratory tract liver pankreas intestine reproductiv failure sweat gland The reason for CFTR gene analysis nSuspition on Cystic fibrosis in a patient nCystic fibrosis in the family nPartners of heterozygots for Cystic fibrosis nRepeated fetal loss nSterility nRelationship of the partners nOthers n CFTR gene - distrubitions of mutations Most frequent CFTR mutations in Czech population Mutation Frequency in CR (%) F508del 70,7 CFTRdele2,3(21kb) 6,4 G551D 3,7 N1303K 2,8 G542X 2,1 1898+1 GtoA 2,0 2143delT 1,1 R347P 0,74 W1282X 0,6 Congenital adrenal hyperplasia- CAH n nGroup of congenital enzymatic defects of adrenal steroidogenesis n nmost frequent- 21-hydroxylase deficiency(CYP21 deficiency, 6p21) n n CAH-symptoms nDue to inadequate mineralocorticoids: n vomiting due to salt-wasting leading to dehydratation and death nDue to excess androgens: n virilization ,ambiguous genitalia, in some females, such that it can be initially difficult to determine sex, early pubic hair and rapid growth in childhood, n precociosus puberty or failure of puberty,infertility due to anovulation,enlarged clitoris and shallow vagina n Phenylketonuria-PKU nPhenylalanine hydroxylase (PAH) deficiency results in intolerance to the dietary intake of the essential amino acid phenylalanine and produces a spectrum of disorders including phenylketonuria (PKU), non-PKU hyperphenylalaninemia (non-PKU HPA), and variant PKU. nPAH gene 12q24 nSymptomes:intellectual disability and other serious health problems -seizures, delayed development, behavioral problems, psychiatric disorders are also common, lighter skin and hair,eczemas nTreatment elimination diet nDiagnosis/testing. PAH deficiency can be diagnosed by newborn screening n Spinal muscular atrophy-SMA nSpinal muscular atrophy (SMA) is characterized by progressive muscle weakness resulting from degeneration and loss of the anterior horn cells ( lower motor neurons) in the spinal cord and the brain stem nuclei. Onset ranges from before birth to adolescence or young adulthood. Poor weight gain, sleep difficulties, pneumonia, scoliosis, and joint contractures are common complications. nSMN1 gene(5q12.2-q13.3)- About 95%-98% of individuals with SMA are homozygous for a deletion nClinical subtypes: n severe infantile acute SMA (Werdnig-Hoffman disease) n infantile chronic SMA n juvenile SMA,(Kugelberg-Welander disease) n adult-onset SMA. n n X-linked Recesive n ntraits are fully evident in males because they only have one copy of the X chromosome. nFemales are not affected as severaly as males or are not affected nAn affected male cannot transmit the trait to his sons, because the trait is on X-chromosome, and the father must necessarily transmit his Y-chromosome to a son nAll of the daughters of an affected male must be carriers, because the only X-chromosome that the father can give to a daughter contains the mutation n n X-linked Recesive nRisk for daughters of a carrier mother- 50% for carrier n nRisk for sons of carrier mother n- 50% for disease Pedigree X- recesive inheritance X XY XX X XY XR - diseases nHemophilia A and B n nDuchenne and Becker muscular dystrophy n n Hemophilia nHemophilia A (clotting factor VIII deficiency,F8,Xq28)- 80% cases nHemophilia B(factor IX deficiency, F9, Xq27)-20% cases nCharacteristic symptoms vary with severity. In general symptoms are internal or external bleeding episodes nComplication:deep muscle bleeding,haemarthrosis,intracranial hemorrhage,adverse reaction to clotting factor treatment,transfusion transmitted infection Dystrophinopathies nThe dystrophinopathies include a spectrum of muscle disease caused by mutations in DMD gene, which encodes the protein dystrophin-Xp21.2 nDuchenne muscular dystrophy (DMD) usually presents in early childhood by delays in sitting and standing independently. Proximal weakness causes a waddling gait and difficulty climbing. DMD is rapidly progressive, with affected children being wheelchair dependent by age 12 years. Cardiomyopathy occurs in individuals with DMD after age 18 years. Few survive beyond the third decade, with respiratory complications and cardiomyopathy being common causes of death. nBecker muscular dystrophy (BMD) is characterized by later-onset skeletal muscle weakness; individuals move independently into their 20s. Despite the milder skeletal muscle involvement, heart failure from DCM is a common cause of morbidity and the most common cause of death in BMD. Mean age of death is in the mid-50s. n Duchenn/Becker muscular dystrophy sejmout0017 sejmout0018 X linked-dominant nThe pattern may at first glance be mistaken for AD inheritance, but if offspring of affected males are considered,all sons are unafected,all daughters are affected nSometimes the disorder is seen only in the heterozygous females, the affected(hemizygous) males being undetected or appearing as an excess of spontaneous abortion n nIncontinentia pigmenti nVitamin D resistant rickets nRett syndrome Fragile X syndrome nmost common form of inherited mental retardation - developmental delay, variable levels of mental retardation, and behavioral and emotional difficulties. n - characteristic physical traits-macrocephaly,coarse facies ,large forehead,long face,prominent jaw ,large ears. Macroorchidism-postpubertal n nGenerally, males are affected with moderate mental retardation and females with mild mental retardation. n nFMR1 gene- FRAXA (Xq27.3) na trinucleotide (CGG)n repeat expansion of greater than 200 repeats. n Genetic risks in cancer Cancer- genetic connection n80% sporadic cancers n n10% common cancers n n5-10% - familial tumour syndromes following mendelian n n Hereditary tumour syndromes n2 or more cases of occurrence in the family nParticularly young age at onset nCombination of certain types of cancer(breast and ovarian cancer, uterine and colorectal ca) nAny evidence of one of the rare tumour syndromes nBilateral occurrence in paired organs nMultiple cancers in a single individual nStrong family history of a single form of cancer nMendelian inheritance, usually AD Common cancers n2 or more cases of occurrence in the family nIncidence in later life(older age) nunclear inheritance (random occurrence, environmental factors, genetic factors - genes with low penetrance, polygenic inheritance) Familial tumour syndromes with folloving AD inheritance- examples nBreast cancer ( BRCA 1,2 ) nLynch syndrome ( HNPCC) ( MMR genes, MLH1, MSH2, PMS1, PMS2, MLH6) nFAP ( APC gene) nLi Fraumeni syndrome - P53 gene nVon Hippel Lindau syndrome (VHL gene) nMEN 1 a 2 (Ret oncogene) nRetinoblastoma- ( Rb gene) nNeurofibromatosis 1,2 - gene NF1,2 nWilms´ tumour (WT1gene) nCowden disease (PTEN) n Primary prevention nReduce pollutants- no smoking, alcohol… n ndiet with reduced fat, meat, spicy dishes, sausages nenough fiber, at least 4 to 5 portions of fruit and vegetables a day nstress prevention nprevention of sunburn nadequate physical activity Secondary prevention nSpecific procedures for monitoring or preventive treatments given at different syndromes with regard to the amount of risk and patient age n Hereditary Breast and Ovarian Cancer Syndrome nBRCA1, BRCA2 nHigh risks of breast and ovarian ca nOther:carcinoma of the uterus, prostate, stomach,colorectal, pancreas nSecondary prevention: selfmonitoring, UZ, mammography,NMR,tumor markers, occult blood test, colonoscopy, gastroscopy, mastectomy and ovariectomy n HNPCC-Lynch syndrome nMMR genes, MLH1, MSH2, PMS1, PMS2, MLH6) nHigh risk of colorectal ca nOther: ca of uterine, stomach, liver, kidneys, brain tu nSecondary prevention: colonoscopy, gastroduodenoscopy, gynecology(vaginal US), abdominal US, tu markers, urological ex., MMG, FAP nAPC gene nMultiple adenomatous polyps nAge: 7-35 nHigh risk of colorectal ca, other: meduloblastoma, thyreoid ca,hepatoblastoma, ca of pancreas, stomach nSecondary prevention: colonoscopy, gastroscopy, protecticve bowel resection Von Hippel-Lindau syndrome nGene VHL nRetinal hemangioblastomas, hemangioblastomas of CNS, multiple renal, pancreatic or hepatal cysts, pheochromocytoma, nSecondary prevention: ophtalmology,neurology,endocrinology, CT,NMR,US Li-Fraumeni syndrome ngeneTP53 nbreast cancer, soft tissue sarcoma, osteosarcoma, brain tumors, adrenal tumors, leukemia,melanoma, gastric, pancreatic, colorectal ca, etc. nDifficult prevention n Neurofibromatosis nGene NF1,NF2 nSecondary prevention: neurology, dermatology, ophtalmology, orthopedy, ORL, CT,NMR,US… n Presymptomatic testing nSpecific nProtocol procedures nUp to 18 years (exception-FAP, MEN, VHL, Rb,WT, NF-where can offer prevention in children) ncompletely voluntary nGenetic consultation before testing-meaning informed consent, follow-up information nGenetic consultation after notification of the result of test-resulting risks, prevention (surveillance, surgery, chemoprevention) nTransmission contact to specialist –doctors providing preventive monitoring, including a psychologist Problemes n nEthical: we can not eliminate tumor formation difficult prevention in some syndromes nPsychological: high risks lifetime n high risks for children n division of family members on healthy x ill nSocial: risk of discrimination such as commercial insurers, employers Preconception counseling nBirth control nMonitoring of spontaneous chromosomal aberrations ncryopreservation of gametes nmonitoring risk pregnancies nPrenatal diagnosis, nIVF-PGD n Syndromes of chromosomal instability nSpecific mendelian disorders showing a generalized tendency to malignancy especially in early life nFollow autosomal recesive inheritance-most nInborn errors of DNA repair nImmune deficiencies Syndromes predisposing to malignancy-examples nXeroderma pigmentosum AR nFanconi pancytopenia AR nAtaxia teleangiectasia AR nBloom syndrome AR nCockayne syndrome AR nNijmegen syndrome AR nWerner syndrome AR nWiskot-Aldrich syndrome XR Mitochondrial inheritance nMitochondrias are organelles found in the cytoplasm of cells and they have multiple copies of a circular chromosome- mitochondrial DNA n Because only egg cells contribute mitochondria to the developing embryo, only mothers can pass on mitochondrial conditions to their children- maternal inheritance nThe primary function of mitochondria is conversion of molecule into usable energy. Thus many diseases transmitted by mitochondrial inheritance affect organs with high-energy use such as the CNS,heart, skeletal muscle, liver, and kidneys. n Mitochondrial diseases nMitochondrial Myopathy,Encephalopathy ,Lactic acidosis and Stroke-like Episodes MELAS nLeber hereditary optic Neuropathy- LHON nMyoclonic Epilepsy associeted with ragged-red Fibers- MERRF nNeuropathy, Ataxia and Retinitis pigmentosa n NARP Pedigree- usual situation Molecular genetic testing nDetection of mutations nSearch asymptomatic carriers nPaternity and relationship testing nPrenatal diagnosis, PGD nPredictive testing of diseases with onset n in adulthood nOnkogenetic -diagnosis, predictive testing Diseases with a single causative mutation nHuntington disease nMyotonic dystrophy nFragile X syndrome n ØDNA analysis can confirm or exclude disease n DNA diagnosis difficult n nLarge genes nPrivate-unique mutations ndisease with multiple genes responsible n n n Multifaktorial –polygenic inheritance Charakterization ndisease with multifactorial inheritance include not mendelian types of inheritance ndiseases exhibit familial aggregation, because the relatives of affected individuals more likely than unrelated people to carry diseases predisposing predisposition Charakterization nin the pathogenesis of the disease play a basic role non-genetic factors ndisease is more common among close relatives and in distant relatives is becoming less frequent nrisk of recurrence can be determined empirically Empirical risk nThe risk of recurrence of the disease observed in similar families and relatives of the same degree of kindship n Examples nCongenital heart defects (VCC) 4-8/1000 nCleft lip and palate (CL/P) 1/1000 nNeural tube defects (NTD, anencephaly, spina bifida,..) 0,2-1/1000 nPylorostenosis nCongenital hip dislocation nDiabetes mellitus – most types nIschemic heart desease nEsential epilepsy Common congenital defects Congenital heart defects nIncidence-0,5 - 1% in liveborn infants population n etiology not known mostly nabout 3% - chromosomal syndromes (+21,+13,+18, 45,X, 18q-, 4p-, del 22q11- DiGeorge sy) nsome mendelian syndromes associated with congenital heart disease (Holt-Oram, Williams, Noonan, Ivemark... Congenital heart disease - genetic risks Congenital heart disease genetic risks Cleft lip and palate nPopulation incidence CLP 1/500-1/1000 nMultifactorial mostly nWith chromosomal trisomies (+13,+18) nSyndromes associated with CL/CP/CLP n(van der Woude sy, EEC sy, Pierre Robin sequence…) nPrenatal diagnosis by ultrasonography not sure Cleft lip and palate- genetic risks Neural tube defects nMultifactorial inheritance (risk for I. degree relatives about 2 - 4%) nMaternal serum AFP screening nPrenatal diagnosis by ultrasonography nRaised AFP levels in amniotic fluid nPrimary prevention in pregnancies by folic acid nRisk populations - probably related to nutritional status Teratogens Teratogens nteratogen is a substance whose by effect on embryo or fetus may cause abnormal development action may be direct or through the maternal organism Human Teratogens nPhysical (radiation, heat (fever), mechanical impact) nChemical (chemicals, drugs) n nBiological (infectious agents...) nMetabolic imbalance (disease mother) n The effect of teratogens depends on : ndose n nlength of the action ncontact time ngenetic equipment of the fetus and the mother Critical period n14.-18. day after conception – the rule „all or nothing “ n n18.-90. day – organogenesis nThe most sensitive period for the emergence of developmental defects nbetween 5. to 7. week of pregnancy is the most sensitive period for individual organs n Critical periods n3th to 6th week - CNS, heart 4th to 7th week - limbs and eyes 6th to 8th week - teeth late 6th - to 12th week – palate 7th-12th week - external genitalia 4th to 12th week - ears n X-rays nmutagenic effect teratogenic effects n growth retardation, major congenital malformations ,fetal death border dose - 0.6 Gy teratogenic dose - 2.0 Gy conventional X-ray examination. dose of 0.01 Gy ncalculation of radiation doses-Institute of Nuclear safety n Drugs nDistribution of medicines in practice into categories n A n B n C n D n X nFood and Drug Administration, 1980 A nin controlled studies have shown no evidence of risk to the fetus in the first trimester of fetal development or influence in the next period of pregnancy product appears to be safe B nAnimal reproduction studies have shown adverse effects, but in controlled studies in women have not been confirmed C nAnimal studies confirm the teratogenic embryotoxic or other adverse effects on the fetus, nnon-controlled studies in women nlack of studies in animals and humans product should be administered with caution and only in cases where the benefit for the woman of its administration exceeds the potential risk to the fetus D nrisk to the human fetus is known nmedicine may be administered in a situation where its use for a woman needed (lifesaving) nno other safer drug is available n X nstudies in animals and in humans clearly demonstrate a teratogenic effect ndrugs absolutely contraindicated in pregnancy n Drugs with teratogenic effect nThalidomid nHydantoin nValproic acid nAnti coagulans - Warfarin nTrimetadion nAminopterin nMethotrexat nCyklophosphamid n n n Drugs with teratogenic effect nRetinoids nLithium nThyreostatic drugs nAndrogens nPenicilamin nEnelapril, Captopril nAntituberkulotics-Streptomycin Thalidomide ncongenital heart defects nlimb reduction anomalies nOther congenital defects (gastrointestinal, urogenital tract orofacial – ears anomalies, CNS defects..) Hydantoin nare used to treat a wide range of seizures types. n nAtypicaly face, growth retardation, mild mental retardation, behavioral problems, hypoplastic nails and fingers n Aminopterin a Methotrexat nfolic acid antagonist facial dysmorfism, cleft lip and/or palate, small mandible, ears anomalies, hydrocephaly, growth and mental retardation, miscarriages n Warfarin ncoumarin antikoagulans nfacial dysmorfism – nasal cartilage hypoplasia, CNS - defects n Retinoids nCleft lip and palate, mikrognatia, eyes anomalies, ears dysplasia nDefects of CNS nThymus hypoplasia nLimb defects Infection nToxoplasmosis nRubella nCytomegalovirus nHerpesvirus nOthers (parvovirus, antropozoonosis, chlamydia..) n n abbreviation TORCH Consequences of Infections ndirect infection of the fetus and its consequences ninfection of the placenta-failure of the exchange of oxygen and nutrients nprolonged high fever mother may affect fetal development, even without direct infection nsevere, life-threatening infection of the mother at the same time threatens the life of the fetus ninfection of the membranes can cause premature labor or miscarriage otherwise healthy fetus nSome developmental disorders can cause by infection treatment n Toxoplasmosis nchorioretinitis nhydrocephaly or microcephaly nintracranial calcification, mental retardation nicterus, hepatosplenomegalia, carditis nprematurity n npositiv IgM in the mother – treatment with Rovamycin nPrenatal dg.: serology, DNA-PCR Rubella nhearing and vision impairment (cataract, glaucoma, mikroftalmia, blidness) nmental retardation nCong. heart defects nicterus, hepatosplenomegalia n nprevention- vaccination Cytomegalovirus nIntrauterin growth retardation nmikrocephaly, cacification in the brain, mental retardation, nhepatosplenomegaly n nRepeated maternal infection is possible nPrenatal dg.: serology,DNA-PCR Varicella zoster nSkin lesions and defects nBrain domage, mental retardation nEye defects n nPrenatal dg. - serology, DNA-PCR Metabolic dysbalance nFetal alcohol syndrome (FAS) nMaternal Phenylketonuria nMaternal Diabetes mellitus nMaternal Hypothyreosis Fetal alcohol syndrom nHypotrophy, growth retardation, mental retardation nfacial dysmorphism nCongenital heart defects nLimb defects n nAbuse of 60g pure alcohol / day (longterm) nCombine with malnutrition, folic acid deficiency, inadequate health care... Maternal Phenylketonuria nLow birth weith nhypertonia nmikrocefaly, mental retardation nCong. heart defects nhyperaktivity n n Diabetes mellitus nrisk of congenital malformations to the fetus 2-3x higher CNS - anencephaly, microcephaly cardiovascular and genitourinary anomalies skelet - caudal regression syndrome face - cleft palate, eye involvement Prevention - preconception compensation n Hypothyreosis ncoarse facial features, macroglossia, inverted nose brachycephalia dry skin, sleepiness, constipation delayed bone maturation Untreated - short stature, oligophrenia, hearing loss, disruption hips (duck walk) Hyperthyreosis - rather risk SA n Genetic consulting nPrimary prevention (pre-conception advice, based on the history of an optimal procedure) nSecondary prevention (adjust therapy during pregnancy, to ensure specific prenatal. diagnosis) Extreme solutions – genetic indication of interruption of pregnancy n n Medical termination of pregnancy nuntil the end of 24th. week of pregnancy in Czech Republic- of law n(governed by the Act and the Decree of the Ministry of Health in CR) nIt indicates only a clinical geneticist! n n