‫‪2017/2018‬‬

‫‪Pediatrics genetic‬‬
‫‪disorders‬‬
‫‪By Dr ali bel kheir‬‬

‫أعرض عن الجاهل السفيه‪-‬فكل ماقال فهو فيه‬

‫ماضر بحر الفرات يوما‪-‬ان خاض بعض الكالب فيه‬
‫)االمام الشافعي(‬
Index:
subjects paper Important in
Introduction 2 Paper exam
Autosomal dominant 3 Paper exam(VIP)
Autosomal recessive
X-linked dominant 4 Paper exam(VIP)
X-linked recessive
Down syndrome (trisomy 21) 6 Paper exam (VIP)clinic
Edwards syndrome 10 Paper exam
Patau syndrome (trisomy 13) 11 Paper exam
Turner syndrome 12 Paper exam
Klinefelter Syndrome 13 Paper exam
Noonan syndrome 14 Paper exam
Williams's syndrome 14 Paper exam
Prader Willi syndrome 15 Paper exam
DiGeorge syndrome 15 Paper exam
Marfan Syndrome 17 Paper exam
Alagille Syndrome 17 Paper exam

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 Introduction
Composition:
 Chromosome has 2 Chromatid which connect to eash other at centromere

Number of chromosomes:
 44 autosomes+2 sex XX in female- XY in male
 Mutation=its change in bases sequence in gene
……………………………………………………………………………………………………………………….
Family tree-Pedigree symbols
 essential part of genetic evaluation

Mendelian inheritance
1. Autosomal dominant
2. Autosomal recessive
3. X-linked recessive
4. X-linked dominant

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 Autosomal dominant Autosomal recessive
 commonest mode of Mendelian  Affected(homozygous)
inheritance  Both parents are carrier (horizontal
 %50 chance of inheriting the abnormal transmission)
gene from affected parent (with  Two carrier parents have 25% risk of
exception) having an affected child
 Affected (homozygos or heterozygous)  Consanguious marrage%
 Both sexes are equally affected.  Males and females are equally
 Both sexes can transmit to offspring. affected.
 No generation is skipped (unless not  Males and females can each
completely transmit a copy of mutated gene.
expressed).  Recurrence risk for parents with a
 Every affected child has a parent with previous affected child is 25 %.
the disorder, except new or  The risk of parents who are carrying
spontaneous mutation a mutated gene to have an affected
child is one-fourth or 25%.
Examples: Examples:
1. Achondroplasia 1. Congenital adrenal hyperplasia
2. Ehlers–Danlos syndrome 2. Cystic fbrosis
3. Familial hypercholesterolaemia 3. Friedreich ataxia
4. Huntington disease 4. Galactosaemia
5. Marfan syndrome 5. Glycogen storage diseases
6. Myotonic dystrophy 6. Mucopolysaccharide(except type2)
7. Neurofbromatosis 7. Oculocutaneous albinism
8. Noonan syndrome 8. Phenylketonuria
9. Otosclerosis 9. Sickle cell disease
10.Polyposis coli 10.Tay–Sachs disease
11.Tuberous sclerosis. 11.Thalassaemia
12.Werdnig–Hoffmann disease

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 X-linked dominant
 Affected (homo or heterozygous)
 Affected father transmitted disease to
all daughter but never to this sons
 Affected Mather transmit the trait to
half of her offspring
X-linked recessive
 Affect males
 Female carrier (can be affected)
 No father sons transmission
 Female carriers have a 25 % risk
for having an affected son, a
25% risk for a carrier daughter,
and 50% chance of having a child
that does not inherit the
mutated X-linked gene.
 Queen Victoria,a carrier for
Haemophilia A,and her family.It
shows affected males in several
generations

Examples: Examples:
1. Vitamin D resistant rickets: X-linked 1. Colour blindness (red–green)
hypophosphatemia 2. Duchenne and Becker muscular
2. Rett syndrome dystrophies
3. Most cases of Alport syndrome 3. Fragile X syndrome
4. Incontinentia pigmenti 4. G6PD
5. Goltz syndrome 5. Haemophilia A and B
6. Hunter syndrome
(mucopolysaccharidosis II)

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Examples of family tree:
Autosomal recessive X-linked dominant

Autosomal dominant

X-linked recessive

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 Chromosomal abnormalities
Down syndrome (trisomy 21)
 Its commonest autosomal numerical disorder due trisomy 21
 1:650.
 It affect male and female-and all races

Types and causes:

1. Non disjunction:
•Common 94%
•Its due failure of chromosomes to
Disjunction normally during meiosis
Before fertilization
•Source of extra chromosome is maternal in 97%
•Recurrent rate increased with maternal age at:
 35 yrs1:385
 40 yrs1:110
 44 yrs1:37
 Karyotype47(+21)XX or XY

2. Translocation:
 4%
•Chromosome 21 translocate into another acrocentric
Chromosomes 14 (main), 15,21,22
=Robertsonian translocation
•parental chromosomal analysis is
Recommended:
 One of the parents may well carry the
Translocation in Balanced form
(In 25% of cases)
 The risk of recurrence is 10–15% if the
Mother is the translocation carrier and
About 2.5% if the father is the carrier.

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  Phenotybe of baby46 (t21q/14q)xx or xy
For parentsbalanced translocation carreir 45 (t21q/14q)
If translocation between
21 and 14 ,15,22 or between 21 and 21

 abortion  abortion
 Balanced rranslocation carrier  Down syndrome(100%)
 Down syndrome
 Normal

3. mosiac:
 1%
•It caused due non disjunction after fertilization
•Some of the cells are normal and some have trisomy 21.
•The phenotype is sometimes milder in Down syndrome mosaicism
 Karyotype47(+21)XX-XY + 45(-21) +46 XX-XY

Clinical pictures:
1. Delay mental milestonesMR
2. Delay motor milestonescentral hypotonia(+) acrobat sign

3. Skull: 4. Eyes:
1. Mild microcephaly 1. Hypertelorism
2. Brachycephaly 2. Epicanthal fold
3. Flat occipit 3. Upward slanting eyes
4. Wide delay closer ant fontanelle 4. Bruchfield iris
5. Wide delay closer 3th fontanelle
6. Fine silky hair

7. Mouth:
5. Ears: low set ears
1. Small mouth
6. nose: small nose with depressed nasal
2. Protruding fissured
bridge
Tongue
3. Delay teething

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Note:
 Hypertelorism= abnormally large distance between pupils (‫)مكان عين تالتة‬
 Hypertelorismdistance Between two medial epicanthus X100
distance Between two lateral epicanthus
 normal=38(+-)6
 if below 32= Hypotelorism
 if above 44= Hypertelorism

8. Heart:
 it’s found in about 50% of pts
 AVSD (ECD) then VSD are the most common
9. abdomin:
 distended with umbilical hernia
10. genitalia:
 hypogonadism-undescended tests
11. hands:
 short and board
 Simian crease=found normally in 1% of population
 Clinodactyly
12. feet:
 Short and board
 sandal sign
 leading=ape crease
13.in general:
 Pale
 Small stature
………………………………… ………………………………………………………………………
Complications:
1. Immunodeficiency recurrent infections  chest, skin, otitis media
2. Neurological:
 Moderate to severe MR
 epilepsy
 Autism
 Increased risk Alzheimer.
 Atlanta axial instability (dislocation) with risk of spinal cord injury.
3 . Cardiac: 50% of ptsCHD  recurrent HF, recurrent chest infection
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4. Respiratory:
 Recurrent chest infections
 Obstructive sleep apnea due to large tonsils, adenoids, tongue
5. Genitourinary: Renal anomalies and hypogonadism.
6. Hematological: AML (20 times more common).
7. Endocrinal:
 Acquired hypothyroidism
 Diabetes mellitus
 Addison disease
8. Gastrointestinal anomalies:
 Doudenal atresia and GERD
 Hirschsprung's disease.
 Coeliac disease
 Imperforate anus
 Annular pancreas
9. Visual impairment: cataracts (3%), squints, myopia
10. Others: Obesity, hearing loss , psychiatric disorders
11. FertilityMales with Down syndrome usually do not father children, while
females have lower rates of fertility (present in 30–50% of women)

Investigations:
1.using FISH technique (Fluorescence in situ hybridization)
2- karyotyping:
A. For the baby to Confirm Down syndrome
B. For the parents if the baby translocation type
3- For suspected anomalies:
A. ECHO
B. Hormonal assay
4- Prenatal diagnosis
1. Fetal U\S at 15-20 weeks Nuchal pad thickness =6mm
2. Maternal α feto protein (Low).
3. Unconjugated estriol (Low)
4. β Human chorionic gonadotropin (Elevated).
5. Pregnancy associated plasma protein A

 Karyotyping for maternal amniotic fluid cells or chorionic villous sample for
early diagnosis in suspected cases
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Management:
1- Genetic counseling of the parents and education of them about the case and
Possible progression.
2- General health support  good nutrition, vaccination, vitamin supply, ...
3- Management of complications and early screening of hypothyroidism and
Cataract
4- Rehabilitation as any case of mental retardation.
Prognosis:
 At least 50% of affected individuals live longer than 50 years
 The most frequent causes of death are respiratory infections
(bronchopneumonia) and congenital heart disease
 Most common cause of sudden death is Atlanto axial dislocation
……………………………………………….………………………………………………………………………
Edwards syndrome
 Trisomy 18 Karyotyping47+18 XX or XY
 1:6000 live birththe second-most common autosomal trisomy, after
Down syndrome
 80% of those affected are female
 The incidence increases as the mother's age increases
 almost always results from nondisjunction during meiosis
clinical pictures and complication:
1.Low birthweight
2.Head
 Microcephaly-Prominent occiput
 Dysmorphic face
o micrognathia
o cleft lip/cleft palate
o hypertelorism
o upturned nose, narrow eyelid folds (palpebral fissures)
o ptosis
 low-set, malformed ears
3. Extremities
 hypertonia
 closed fits with overlapping fingers
 rocker bottom heel
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4. chest-abdomen
 Short sternum
 CHD (VSD-PDA-ASD)
 omphalocele
5. General
 MR
 Renal anomaly
 feeding difficulties, breathing difficulties
investigation:
1. The diagnosis is confirmed by chromosome analysis.
2. U\S (second trimester)confirmed antenatal by amniocentesis and
chromosome analysis
Prognosis:
 50% will live up to 2 mts and 5-10% will live up to 1yr
 Major causes of death include apnea and heart abnormalities
…………………………………………………………………………………………………………………………..
Patau syndrome (trisomy 13)
 Trisomy 13 Karyotyping 47+13 XX or XY
 1:10 000 live birth
 may results from nondisjunction (there other causes as down)
 The incidence increases as the mother's age increases
Clinical pictures and complication:
1. Microcephaly-MR
2. Dysmorphic face
3. Scalp defect=cutis aplasia
4. Brain malformation
5. Cleft lip and palate
6. microphthalmia , other eye defects
7. Polydactyly
8. Cardiac (VSD-ASD-PDA) and renal malformations.
 Prognosis5% live more than 6 mts

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Turner syndrome
 Classic form (45 X0)
 Deletion of short arm of one X-chromosome.
 Incidence 1 in 2000 live-born female infants (as most cases are aborted)
Clinical picture:
At birth: -
1. Transient lymphoedema in dorsa of hands and feet.
2. Low birth weight
3. Short stature – a cardinal feature
4. Loose skin at neck nape
Later on: -
 Ugly short stature female
 Normal mentality
 Low post hair line
 Recurrent otitis media
 Webbing of the neck
 Delayed puberty- Hashimoto’s thyroiditis
 Hypothyroidism
 CHD COA, Non stenotic bicuspid aortic V
 Wide spaced nipples
 Cubitus valgus (wide carrying angle)
 Spoon-shaped nails
 Renal anomalies
 Ovarian dysgenesis (streak gonads) resulting in infertilityalthough
Pregnancy may be possible with in vitro fertilization using donated ova
 Pigmented moles
N.B: Mosaic turner may have only short stature, amenorrhea without
dysmorphism
Diagnosis:
1. Buccal smear Barr body (-ve)
2. Karyotyping: Diagnostic (45 X0)
Treatment:
 Growth hormone therapy
 Estrogen replacement for development of secondary sexual characteristics
at the time of puberty (but infertility persists)
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Klinefelter Syndrome:
 Extra X-chromosome in a male  (47, XXY) due to non-disjunction.
 the most common chromosomal disorder associated with male
hypogonadism and infertility.
Clinical picture:
 Mental retardation
 Gyneacomastia
 diminished facial hair
 Feminine distribution of fat.
 Atrophic testis, Gynaecomastia, azospermia ,sterility.
 Infertility  most common presentation
 Pubertal development may appear normal
 Tall stature
 High risk of breast cancer- extra testicular germ cell tumors
Diagnosis:
1. Buccal smear Barr body (+ve)
2. Karyotyping: diagnostic (47, XXY)
Treatment: some males benefit from testosterone therapy
……………………………………………… ………………………………………………………………
Fragile X syndrome
 X-linked recessive disorder
 Affect 1 in 2500-4000 males (can affect females)
 the most common cause of inherited MR
Intellectual disability, and autism and is the 2th most common cause of
Genetically associated mental deficiencies, after trisomy 21
 It's most common genetic cause (not numerical) of MR in male
 Caused due mutation in the FMR1 gene
 Diagnosis done by DNA analysis expansion of the CGG trinucleotide repeat
Affecting FMR gene on x chromosome
Clinical features:
 Moderate–severe learning difficulty
 Macrocephaly
 Macro-orchidism – postpubertal
 Characteristic facies 
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 Long face, large everted ears, prominent mandible
Broad forehead, most evident in affected adults
 Mitral valve prolapse, joint laxity, scoliosis, autism, hyperactivity.
Noonan syndrome (male turner)
 autosomal dominant
 congenital disorder that affects both males and females equally
 male version of Turner's syndrome
 karyotype is normal
 The principal features include:
1. Congenital heart defect  PS, ASD, HCM
2. Short stature
3. Learning problemsmild mental retardation (25%)
4. pectus excavatum
5. Impaired blood clotting
6. Characteristic facial features including:
 Triangle face
 webbed neck - wide-spaced nipples
 flat nose bridge
 hypertelorism-down slanting eyes
 low-set ears
7. Delayed puberty
8. micropenis and cryptorchidism in males
……………………………………………………………………………………………………..……………………
Williams's syndrome
 caused by deletion of genetic material on chromosome 7
which contain codes for the protein elastin synthesis
 The principal features include:
1. full-term infants with prenatal growth delay
2. Microcephaly
3. Elfin facies:
 Lacy pattern of the irises can be observed in children with blue eyes.
 Short upturned nose
 Flat nasal bridge
 Long philtrum
 Wide mouth(ear to ear smile)

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 Prominent lower lip
 widely spaced teeth
 micrognathia, and periorbital fullness
5. The voice may be hoarse.
6. Nails hypoplastic
7. the skin soft and lax
8. Developmental delay
9. Cardiovascular problemsAS
10. Transient hypercalcaemia

…………………………………………………………………………………………………………………………
Prader Willi syndrome
 caused by deletion of genetic material on chromosome 15
 The principal features include:
1. Characteristic facies including :
 Prominent nasal bridge
 Excess fat, especially in the central portion of the body
 High, narrow forehead
 Thin upper lip
 Downturned mouth
 Almond-shaped eyes
2. Hypotonia
3. Neonatal feeding difficulties
4. Failure to thrive in infancy
5. Obesity in later childhood
6. Hypogonadism
7. Developmental delay
8. Learning difficulties.
……………………………………………………………………………………………….
DiGeorge syndrome
 caused by the deletion of a small piece of chromosome 22
 autosomal dominant
 Cardiac abnormality (especially tetralogy of Fallot)-Abnormal facies
Thymic aplasia-Cleft palate-Hypocalcemia/Hypoparathyroidism

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 Alagille Syndrome
• Microdeletion of the 20p12 gene corresponding to JAG1
 autosomal dominant
Clinical presentation
• Triangular face and pointed chin
• Cholestasis due to bile duct paucity
• Jaundice, and pruritus
• Xanthomas
• Supravalvar pulmonary stenosis (67% of patients with
peripheral pulmonary stenosis)
• Ocular defect (posterior embryotoxon)
• Butterfly vertebrae

Marfan Syndrome
 Autosomal dominant defect of connective tissue.
 Defect in FBN1 gene on chromosome 15; which codes for fibrillin.
 Boys and girls are equally affected.
 Most common cause of death due to aortic dissection and rupture of aorta.

Some of Major criteria Minor Criteria

• Skeletal system  Skeletal
– Pectus carinatum (pigeon breast) – High arched palate
– Pectus excavatum (funnel chest) – Moderate pectus excavatum
– Wrist sign (overlapping of the thumb – Joint hypermobility
and 5th finger when encircling the wrist • Cardiovascular
– Scoliosis >20 % – Mitral valve prolapse
– Reduced extension of the elbow • Pulmonary
(<170%) – Dilatation of the main pulmonary
artery
• Ocular system – Spontaneous pneumothorax
– Ectopia lentis - displacement • Skin
Cardiovascular – Striae atrophicae
– Dilatation of the ascending aorta – Recurrent incisional hernias
– Dissection of the ascending aorta
• Dura
– Lumbosacral dural ectasia (dilatation)
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 ‫)‪Diagnosis based on clinical diagnostic criteria (Ghent Criteria‬‬

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