1 Hereditary diseases. Congenital malformations.Dr. György Fekete

2 Congenital malformationsConception – organogenesis - birth Genetic causes Environmental factors (teratogens) Visible/ recognazible at birth Later manifestation

3 Genetic conditions: causes of acute and chronic diseasesOnset of disease: fetus,infant, child, adult Genetic abnormalities may produce: congenital malformations, metabolic disturbances,specific organ dysfunction, abnormalities of sexual differentiation

4 Monogenic diseases: 1% of newborn babiesChromosomal aberrations: 0.5% Multifactorial disorders: 1-3%

5 Monogenic diseases: 1% of newborn babiesChromosomal aberrations: 0.5% Multifactorial disorders: 1-3%

6 Inherited conditions If a single allele has a detectable effect: dominant If two functionally identical alleles cause the effect: recessive XY males are hemizygous for genes on the X chromosome

7 Mendelian inheritanceAutosomal dominant inheritance If one parent displays a dominant condition and is heterozygous for the gene, each child has a 50% chance of receiving the single allele and of manifesting the condition Not all individuals with the affected gene my be symptomatic Penetrance: percentage of patients with the gene mutation who manifest symptoms

8 Expressivity: spectrum of severity in patiens having clinical manifestationExamples:achondroplasia, Crouzon syndrome, neurofibromatosis type I, II, Marfan syndrome,hereditary angioneurotic edema (HANE)

9 Autosomal recessive (AR) inheritanceConsanguinity increases the risk The risk of two carriers of gene mutation having a child with AR diseases is 1 in 4 : 25% Examples:phenylketonuria, cystic fibrosis, congenital adrenal hyperplasia, sickle cell disease, Gaucher disease, Pompe disease

10 Sex – linked inheritanceThe gene locus is on the X chromosome When the mother is a carrier of the gene mutation, 50% of male offspring will have the disease, and 50% of female offspring will be carriers All daughters of the ill father will be obligate carriers Examples: Duchenne muscular dystrophy (DMD),hemophilia A and B, adrenoleukodystrophy, Fabry disease

11 Mitochondrial diseasesSemmelweis Egyetem, II. Sz. Gyermekgyógyászati Klinika

12 Importance Prevalence in newborns: 46-50 %o25-40 per cent of infant mortality One factor in prematurity and intrauterine dystrophy Severe conditions Burden: child, family, society

13 Classification Severity: major and minor malformationsMajor: hindering significant organ functions Isolated (GI atresias, Fallot – tetralogy) Multiple: two or more organs, organ systems Genetic: chromosome aberration, monolocus, other mechanism (uniparental disomy, genomic imprinting, triplet expansion, mitochondrial) Teratogens (TORCH, chemicals, drugs, irradiation) Genetic + environmental (multifactorial, complex diseases)

14 Minor malformations Informative morphogenetic variantsNon - functional, harmless, esthetical deviations - Epicanthus

15 Supernumerary nipple

16 Minor malformations Bifid uvula 4 digits crease

17 Hypertelorism

18 Low – set ears

19 Craniofacial dysmorphy („peculiar face”)Elements of face are forming from the 4. embryonal week. Face of fetus: 8. gestational week

20 Ossification anomalies of sutures (craniostenosis)Craniosynostosis (+ corpus callosum agenesia, hydrocephalus )

21 Crouzon syndrome AD, gene: 10q26

22 Crouzon syndrome Apert syndrome (Acrocephalosyndactyly type I) Gene: 10q26,fibroblast growth factor receptor-2 (FGFR-2) Advanced paternal age ( > 45 yrs) Pfeiffer syndrome (Acrocephalosyndactyly type V) Gene: 10q26, 8p (FGFR-1)

23 Splits Split lip / palate (cheilo- gnatho- palatoschisis)

24 Mandibulofacial dysostosis: Treacher - Collins syndrome

25 Steps of examination Parents, sibs, grandparents: resemblance? (photos!) Anatomical/ morphological deviation? Isolated or multiple? Psychomotor retardation? Other minor malformations? Hidden malformations (internal organs) ? Teratogenic exposition? Special methods / investigations Councelling: prognosis, therapy

26 Special methods Laboratory data Imaging techniques (CT, MRI)Cytogenetics DNA analysis Biochemical studies

27 Recognizable malformations in newborn ageDown- syndrome ( trisomy chromosome 21 ) 21q22

28 Patau -, Edwards- syndromePatau- syndrome (trisomy chromosome 13) Edwards- syndrome (trisomy chromosome 18)

29 Prader – Willi syndrome

30 Turner syndrome (45,X): lymphedema on the back of the hand / feet, pterygium colli

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32 DiGeorge syndrome

33 Isolated malformations / newbornsAnencephaly Spina bifida Hip dyslocation Atresias of esophagus and bowels Pyelectasy (obstructive uropathy) Diaphragma hernia Omphalokele Hirschsprung disease (megacolon congenitum) Congenital heart disease

34 Spina bifida

35 Congenital heart disease, pyloric stenosis

36 Club- foot, congenital dyslocation of the hip

37 Inguinal hernia , megacolon congenitum (Hirschsprung disease)

38 Retentio testis, hypospadiasis

39 Clinical signs and data of a possible chromosome aberrationMalformations, dysmorphisms of the skull and face (craniofacial dysmorphy) Mental retardation Multiorgan involvement Maternal age: 35 yrs or more

40 Achondroplasia 1:5000, gene mutacions of fibroblast growth factor receptor-3 gene, 4p16.3

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42 Osteogenesis imperfecta

43 Neurofibromatosis type 1 (NF1)Prevalence: 1/ 2500 – 1/3000 Diagnostic criteria: 2 or more of the following points are present 6 or more café- au -lait spots, diameter > 5 mm. (prepuberty), and > 15 mm. (postpuberty)

44 2 or more neurofibromas (fibromatous tumors of the skin), or at least one plexiform neurofibroma

45 Plexiform neurofibromaspotential for transformation into malignant peripheral nerve sheath tumors (malignant schwannomas)

46 Axillary and/ or inguinal freckling

47 Optic pathway glioma, spinal neurofibromas2 or more melanocytic iris hamartomas (Lisch nodules )

48 Optic glioma precocious puberty , visual loss

49 Lisch nodules

50 Specific bone lesions Dysplasia of long bones , pseudoarthrosis of tibia, thinning of long bone cortex

51 Vascular manifestationsRenal artery stenosis Hypertension

52 First –degree family relative has a proven diagnosis of neurofibromatosisNational Institutes of Health Consensus Conference 1987

53 NF1- symptoms of 59 male and 43 female pediatric patientsMales % Females% Café-au-lait sp Neurofibroma , ,9 Plexiform neurofibroma , ,9 Freckling , ,1 Optic glioma 30, ,6 Iris nodules , ,6 Orthop. spine sympt. 61, ,6 Other bone lesions , ,0 Krumbholz A. et al. Monatsch Kinderheilk 2008, 156:

54 Some infants and children present only with „café –au – lait” spotswithout any other neurofibromatosis symptom and sign (innocent spots): regular pediatric observation is needed macrocephaly (occipitofrontal circumference: >97. percentile) short stature (< 3. percentile), early dentition (< 5 mo.) : suspected NF1 new mutation complications: learning disabilities, mental retardation, tumors (CNS, neurofibrosarcoma)

55 NF1-gene , chromosome 17 (17q11.2)Genetic code of neurofibromin synthesis. Regulation of signal –transduction -protein RAS GTPase activation 61 exons NF1 gene mutations occur also in juvenile myelomonocytic leukemia, Watson syndrome, and breast cancer 50% of cases are due to de novo mutations Sporadic occurrence is associated with advanced paternal age

56 Differential diagnosisHealthy children: 19 / 1000 newborn babies (Michalk D, Schönau E,1999) Ovarial cysts Juvenile xanthogranuloma

57 Legius syndrome SPRED1 mutations (15q13.2)NO Lisch nodules,  neurofibromas, optic gliomas, bone lesions Subcutaneous lipomas in adults 7 coding exons

58 Cornelia de Lange (Brachmann) syndrome, symptomsMicrocephalia,brachycephalia Deep anterior and posterior hair border Synophrys (thick, meeting eyebrows) Ptosis, nystagmus, myopia Micrognathia long philtrum Thin lips, „carp” mouth Cheilo –gnatho - palatoschisis Malformations of limbs Hypoplastic penis, cryptorchism Mental retardation

59 Williams - Beuren syndrome- deletion of elastin gene

60 K.M. female child Birth date: 02. 28. 2009. Presentation: 08. 23. 2010.Symptoms : Somatic and psychomotoric developmental delay Hypotonic muscles Craniofacial dysmorphy

61 History First child, healthy parentsMother was 24, father 27 when she was born Birth weight: 2640 g., length: 45 cm, 39. gestational week, normal delivery , Apgar: 10/10

62 Craniofacial dysmorphySunken nasal bridge Epicanthal fold Long philtrum Prominent lower lip Hypodontia Mikrodontia Blue/ green iris

63 Hypertension Supravalvular aortic stenosisPeripheral pulmonary stenosis

64 Other symptoms Kyphoscoliosis, arthropathyInguinal and umbilical hernia Loose skin Chronic constipation, diverticulosis Deep voice Sensoneural hearing loss Congenital malformations of kidneys Laboratory: Hypercalcemia Nephrocalcinosis

65 Endocrinological problemsHypothyreoidism Early puberty Early menarche Diabetes mellitus

66 Radioulnar synostosis

67 Friendly, extroverted personality, („cocktail party personality”)Mild cognitive disturbances Good vocabulary Good skill to music, singing

68 Williams- Beuren syndromeIncidence 1 : 8000 , sporadic, unbalaned meiotic cross - over 7q11.23mMckrodeletion Deletion of elastin gene and neighbouring genes GTF2IRD1 (General transcription factor II-I repeat domain containing protein 1) GTF2I (General transcription factor II-I) Genetic diagnostic methods: - FISH - DNA analysis

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70 J. C. P. Williams, cardiologist, Auckland, New - Zealand, 1930 -J.C.P. Williams, cardiologist, Auckland, New - Zealand, ? Publication in: 1961 Alois J. Beuren, cardiologist, Göttingen,

71 Genetic counselling Discussion of present and later symptoms PrognosisPedigree analysis Special care and support of skills Patient organisations

72 Marfan syndrome 1:16000-25000, fibrillin-1 gene mutations, 15q21.1Semmelweis Egyetem, II. Sz. Gyermekgyógyászati Klinika

73 Syndrome Defects of multiple tissuesPatients’ phenotypes are similar to each other Characteristic presentation symptoms Clinical diagnosis is feasible in most cases

74 Inborn errors of metabolismCystic fibrosis (CF, mucoviscidosis), 1:2500, CF transmembrane conductance regulator (CFTR) gene mutations, 7q31.2 (more than 2000 mutations) Congenital adrenal hyperplasia (CAH, adrenogenital syndrome), 1: , CYP21 gene mutations , 6p21.3 Semmelweis Egyetem, II. Sz. Gyermekgyógyászati Klinika

75 Galactosemia, 1:35000-60000, GALT gene mutations, 9p13 Phenylketonuria (PKU, classic type, phenylalanine hydroxylase (PAH) deficiency),1:10000, PAH gene mutations, 12q22 Galactosemia, 1: , GALT gene mutations, 9p13 Biotinidase deficiency, 1:24000, BTD gene mutations, 3p25 Glycogen storage diseases (von Gierke) Mucopolysaccharidoses (Hurler/Scheie) Semmelweis Egyetem, II. Sz. Gyermekgyógyászati Klinika

76 Semmelweis Egyetem, II. Sz. Gyermekgyógyászati Klinika

77 Cystic fibrosis Semmelweis Egyetem, II. Sz. Gyermekgyógyászati Klinika

78 Cystic fibrosis Semmelweis Egyetem, II. Sz. Gyermekgyógyászati Klinika

79 Robert Guthrie (1916- 1995) Semmelweis Egyetem,II. Sz. Gyermekgyógyászati Klinika

80 Tandem mass spectrometrySeparation of molecules according to their charge/ mass relation following conversion of metabolites into ions Semmelweis Egyetem, II. Sz. Gyermekgyógyászati Klinika

81 Semmelweis Egyetem, II. Sz. Gyermekgyógyászati Klinika

82 Hurler disease (MPS I) Semmelweis Egyetem,II. Sz. Gyermekgyógyászati Klinika

83 Pompe disease

84 Pompe disease

85 Clinical signs and data of monolocus hereditary diseasesMultiorgan involvement (syndrome) Recurrent familial occurrence Consanguinity Characteristic phenotype

86 Reductional malformations of limbsAmely

87 Fetal alcohol syndromeIntrauterine and postnatal dystrophy, microcephaly Short, thin eye openings, epicanthus Deep nasal bridge Small nose Hirsutism on the frontal region Low-set ears, ear lobe deformities Flat os zygomaticum High palate, cheilo- gnatho- palatoschisis Thin upper lip, smooth philtrum Micrognathia

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89 Drug abuse Amphetamins (Ecstasy, metamfetamin/ice/, speed)Small doses: no malformation High doses, continuous use: cong. heart disease, cheilo- gnatho - palatoschisis Other teratogenic agents (alcohol, smoking, etc.)