Hereditary diseases. Congenital malformations. Dr. György Fekete

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

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

Monogenic diseases: 1% of newborn babies Chromosomal aberrations: 0.5% Multifactorial disorders: 1-3%

Monogenic diseases: 1% of newborn babies Chromosomal aberrations: 0.5% Multifactorial disorders: 1-3%

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

Mendelian inheritance Autosomal 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

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

Autosomal recessive (AR) inheritance Consanguinity 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

Sex – linked inheritance The 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

Mitochondrial diseases Semmelweis Egyetem, II. Sz. Gyermekgyógyászati Klinika

Importance Prevalence in newborns: 46-50 %o 25-40 per cent of infant mortality One factor in prematurity and intrauterine dystrophy Severe conditions Burden: child, family, society

Classification Severity: major and minor malformations Major: 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)

Minor malformations Informative morphogenetic variants Non - functional, harmless, esthetical deviations - Epicanthus

Supernumerary nipple

Minor malformations Bifid uvula 4 digits crease

Hypertelorism

Low – set ears

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

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

Craniofacial dysostosis type I Crouzon syndrome

Crouzon syndrome AD, gene: 10q26

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, 8p11.2-11.1(FGFR-1)

Apert syndrome

Pfeiffer syndrome

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

Mandibulofacial dysostosis: Treacher - Collins syndrome

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

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

Recognizable malformations in newborn age Down- syndrome ( trisomy chromosome 21 ) 21q22

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

Prader – Willi syndrome

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

DiGeorge syndrome

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

Spina bifida

Congenital heart disease, pyloric stenosis

Club- foot, congenital dyslocation of the hip

Inguinal hernia , megacolon congenitum (Hirschsprung disease)

Retentio testis, hypospadiasis

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

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

Osteogenesis imperfecta

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)

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

Plexiform neurofibromas potential for transformation into malignant peripheral nerve sheath tumors (malignant schwannomas)

Axillary and/ or inguinal freckling

Optic pathway glioma, spinal neurofibromas 2 or more melanocytic iris hamartomas (Lisch nodules )

Optic glioma precocious puberty , visual loss

Lisch nodules

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

Vascular manifestations Renal artery stenosis Hypertension

First –degree family relative has a proven diagnosis of neurofibromatosis National Institutes of Health Consensus Conference 1987

NF1- symptoms of 59 male and 43 female pediatric patients Males % Females% Café-au-lait sp. 100 100 Neurofibroma 54,2 34,9 Plexiform neurofibroma 33,9 27,9 Freckling 59,3 65,1 Optic glioma 30,5 25,6 Iris nodules 39,0 32,6 Orthop. spine sympt. 61,0 32,6 Other bone lesions 28,8 7,0 Krumbholz A. et al. Monatsch Kinderheilk 2008, 156:893- 898.

Some infants and children present only with „café –au – lait” spots without 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)

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

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

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

Cornelia de Lange syndrome

Cornelia de Lange (Brachmann) syndrome, symptoms Microcephalia,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

Williams - Beuren syndrome- deletion of elastin gene

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

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

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

Hypertension Supravalvular aortic stenosis Peripheral pulmonary stenosis

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

Endocrinological problems Hypothyreoidism Early puberty Early menarche Diabetes mellitus

Radioulnar synostosis

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

Williams- Beuren syndrome Incidence 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

J. C. P. Williams, cardiologist, Auckland, New - Zealand, 1930 - J.C.P. Williams, cardiologist, Auckland, New - Zealand, 1930 - ? Publication in: 1961 Alois J. Beuren, cardiologist, Göttingen, 1919-1984

Genetic counselling Discussion of present and later symptoms Prognosis Pedigree analysis Special care and support of skills Patient organisations

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

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

Inborn errors of metabolism Cystic fibrosis (CF, mucoviscidosis), 1:2500, CF transmembrane conductance regulator (CFTR) gene mutations, 7q31.2 (more than 2000 mutations) Congenital adrenal hyperplasia (CAH, adrenogenital syndrome), 1:5000-8000, CYP21 gene mutations , 6p21.3 Semmelweis Egyetem, II. Sz. Gyermekgyógyászati Klinika

Galactosemia, 1:35000-60000, GALT gene mutations, 9p13 Phenylketonuria (PKU, classic type, phenylalanine hydroxylase (PAH) deficiency),1:10000, PAH gene mutations, 12q22 Galactosemia, 1:35000-60000, 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

Semmelweis Egyetem, II. Sz. Gyermekgyógyászati Klinika

Cystic fibrosis Semmelweis Egyetem, II. Sz. Gyermekgyógyászati Klinika

Cystic fibrosis Semmelweis Egyetem, II. Sz. Gyermekgyógyászati Klinika

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

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

Semmelweis Egyetem, II. Sz. Gyermekgyógyászati Klinika

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

Pompe disease

Pompe disease

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

Reductional malformations of limbs Amely

Fetal alcohol syndrome Intrauterine 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

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.)