1. Hereditary diseases. Congenital malformations.
Dr. György Fekete

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

4. 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

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

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

7. 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

8. 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

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

10. 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

11. 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

12. Mitochondrial diseases
Semmelweis Egyetem,
II. Sz. Gyermekgyógyászati Klinika

13. 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

14. 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)

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

16. Supernumerary nipple

17. Minor malformations
Bifid uvula
4 digits crease

18. Hypertelorism

19. Low – set ears

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

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

22. Craniofacial dysostosis type I Crouzon syndrome

23. Crouzon syndrome
AD, gene: 10q26

24. 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)

25. Apert syndrome

26. Pfeiffer syndrome

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

28. Mandibulofacial dysostosis: Treacher - Collins syndrome

29. 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

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

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

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

33. Prader – Willi syndrome

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

36. DiGeorge syndrome

37. 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

38. Spina bifida

39. Congenital heart disease, pyloric stenosis

40. Club- foot, congenital dyslocation of the hip

41. Inguinal hernia , megacolon congenitum (Hirschsprung disease)

42. Retentio testis, hypospadiasis

43. 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

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

46. Osteogenesis imperfecta

47. 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)

48. 2 or more neurofibromas (fibromatous tumors of the skin), or at least one plexiform neurofibroma

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

50. Axillary and/ or inguinal freckling

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

52. Optic glioma precocious puberty , visual loss

53. Lisch nodules

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

55. Vascular manifestations
Renal artery stenosis
Hypertension

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

57. NF1- symptoms of 59 male and 43 female pediatric patients
Males % 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:

58. 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)

59. 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

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

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

62. Cornelia de Lange syndrome

63. 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

64. Williams - Beuren syndrome- deletion of elastin gene

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

67. 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

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

69. Hypertension Supravalvular aortic stenosis
Peripheral pulmonary stenosis

70. 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

71. Endocrinological problems
Hypothyreoidism
Early puberty
Early menarche
Diabetes mellitus

72. Radioulnar synostosis

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

74. 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

76. 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,

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

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

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

81. 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: , CYP21 gene mutations , 6p21.3
Semmelweis Egyetem,
II. Sz. Gyermekgyógyászati Klinika

82. 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

83. Semmelweis Egyetem,
II. Sz. Gyermekgyógyászati Klinika

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

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

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

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

88. Semmelweis Egyetem,
II. Sz. Gyermekgyógyászati Klinika

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

90. Pompe disease

91. Pompe disease

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

93. Reductional malformations of limbs
Amely

94. 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

96. 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.)