Genetics/Dysmorphology

Trisomy Syndromes
Down (Trisomy 21) Edward (Trisomy 18) Patau (Trisomy 13)
CNS 1- Mental Retardation 1- Mental Retardation 1- Holoprosencephaly
1- Brushfield spots 1- Microcephaly 1- Microcephaly
2- Upslanting palpebral fissure. 2- Micrognathia 2- Microophthalmia
Facial defects 3- Inner epicanthic folds 3- Prominent occiput 3- Ocular hypotelorism
4- Microganthis &Tongue protrusion 4- Low set malformed ears 4- Bulbous nose
5- Low set small ear 5- Low set malformed ears
6- Delayed fontanel closure 6- Cleft lip/palate
1- Hypotonia 1- Closed fist with : index finger
2- Simian crease overlapping the 3rd digit & 1- Flexed fingers
Extremities 3- short and broad hands 5th digit overlapping the 4th 2- with Polydactyly
4- Hypoplasia of the middle 2- Rocker bottom feet
phalanx of the 5th finger & Hammer toe
Cardiac 1- Endocardial Cushion Defect (MOST COMMON)  lead to PH 1- VSD  MOST COMMON 1- VSD
(major cause of early mortality) 2- VSD > PDA , ASD , MVP 2- ASD 3- PDA 2- ASD 3- PDA
1- Duodenal atresia 2- Esophageal atresia 3- Pyloric stenosis Omphalocele
GIT 4- Hirschbrung disease 5- Malrotation of bowel
1- Polycystic kidney 1- Polycystic kidney
Renal 2- Ectopic and double ureter
1- Acute Lymphocytic Leukemia (ALL)
2- Early onset Alzheimer's disease Prognosis is Very poor, 95% die <1 year of age 1- Single umbilical artery
3- Atlantoaxial instability: ( 10% - 15% Progress over several weeks)
- due to excessive laxity in the posterior transverse ligament 
Complications causes increased mobility between atlas (C1) and the axis (C2) :
a- Behavioral changes b- Torticollis c- urinary incontinence
d- Vertebrobasilarsymptoms : dizziness, vertigo, diplopia.
Risk factor: Advanced e- On examination, upper motor neuron symptoms such as :
maternal age >35 years leg spasticity, hyperreflexia, a positive Babinski sign, clonus
- X-ray: Diagnosed with lateral radiographs of the cervical spine
in flexion, extension, and in a neutral position
- TTT: surgical fusion of (C1) to the (C2).
Sex Chromosome Abnormalities
Turner syndrome (45XO or mosaicism) Noonan syndrome Klinefelter syndrome (47XXY)
Sporadic / Not related to advanced maternal age Not related to advanced maternal age Risk factor: Advanced maternal age
Phenotypically Female with : - Autosomal dominant. - Presence of an extra X chromosome in males (1:500)
1- Short stature
- Phenotypically similar to Turner syndrome but can affect both sexes. - Most common cause of hypogonadism and infertility in males
2- Craniofacial abnormalities: (protruding ears, neck webbing ,
Description low occipital hairline, high arched palate) - Girls with Noonan syndrome have normal XX chromosomes. 1-Tall and thin body
3- Endocrine: Primary Hypothyroidism - Pulmonary stenosis. 2- Gynecomastia + Female hair distribution
4- Chest: Shield shaped thorax / widely spaced nipples 3- Testicular atrophy: Small testes but puberty occurs at normal age
- Mental retardation often present.
5- Cardiac defects : Coarctation of the aorta + biscuspid aortic valve 4- Azoospermia
6- Reproduction: Ovarian dysgenesis  Infertility 5- Mild mental retardation + Psychosocial adjustment abnormalities
7- Renal Anomalies: Horseshoe Kidney, double renal pelvis (U/S)
Diagnosis:
Treatment: (give estrogen/ growth hormone / anabolic steroid) Testosterone levels: Hypogonadism & Hypogenitalism
Patients at higher risk of osteoporosis due to :
a- lower estrogen levels  ttt: give Estrogen Treatment:
b- & only having one copy of X chr. genes involved in bone metabolism Replace testosterone at 11-12 years of age

Common Deletion Syndromes

Prader-Willi Syndrome Angelman Syndrome Cri du chat Wolf-Hirschhorn Velocardiofacial Williams
Imprinting Disorders (different phenotype, same genotype) Deletion entire 5p chromosome arm Deletion 4p16 to end of arm Deletion 22q11 Deletion 7q11.23
Where the phenotype expression depends on whether the genetic defect is inherited from mother or father
75% due to Paternal deletion 15q11-13 60% due to Maternal deletion 15q11–13 1- Mentally: Mental Retardation 1- Mental retardation 1- Mild mental retardation 1- Mental retardation
Characteristic clinical features: Characteristic clinical features: 2- Microcephaly + there is a 2- Speech disorders 2- Cheerful/ friendly personality
2- Multiple cranial abnormalities
characteristic protruding metopic 3- Cleft palate 3- “Elfin facies”
1- Mentally: Mental retardation 1- Mentally: Mental Retardation 3- Seizures
suture in such patients. 4- Cardiac defects: TOF (short, upturned nose; long
2- Craniofacial features: 2- Absent speech or < 6 words
- Narrow bifrontal diameter 3- Happy mood 3- High-pitched cat-like cry philtrum, wide mouth)
5- Significant overbite
- Diamond-shaped eyes 4- Unprovoked laughter 4- Short stature
4- Other manifestations: 6- T-cell deficiency
- Small down-turned mouth "happy puppet Syndrome" 5- Cardiac defects
a- Hypotonia 7- Hypocalcemia
3- Hypotonia at birth or infancy 5- Ataxia. (supravalvular stenosis)
b- Short stature
4- Hyperphagia 6- Hypotonia 8- Association with DiGeorge
c- Moonlike face
5- Obesity (ataxia & hypotonia create the syndrome
d- Hypertelorism
6- Short stature + small hands & feet characteristic “puppet”-like gait)
e- Bilateral epicanthic folds Early mortality can result from
7- Hypothalamic dysfunctions : f- High arched palate associated :
- GH deficiency and g- Wide and flat nasal bridge 1- cardiac complications or
- Hypogonadotropic hypogonadism
80%  Develop Epilepsy
2- DiGeorge syndrome
TTT:
Short stature + obesity + hypotonia usually Detected by fluorescence in
respond to GH administration situ hybridization (FISH)

Other Syndromes
Fragile X syndrome - The syndrome results from: a ful lmutation in the FMR 1 gene caused by an increased number of CGG trinucleotide repeats accompanied by aberrant methylation of the FMR 1 gene.
Most common cause of Mental - Affected males of Fragile X syndrome have 3 LARGE : 1- Macrocephaly (Large Head)+ long face,prominent forehead 2- Large protruding ears 3- Large testes
Retardation in boys Behavioral: 1- Attention Deficit Hyperactivity Syndrome 2- Autism
- Infant with Multiorgan Enlargement: D.D: Congenital hypothyroidism
Beckwith-Wiedemann 1- Macrosomia 2- Macroglossia 3- Pancreatic B-cell hyperplasia: Hypoglycemia & Hyperinsulinemia Presents with :
syndrome 4- Visceromegaly 5- Omphalocele 5- Microcephaly 1- Hypotonia
- Usually sporadic BUT - Additional features include: 1- Prominent eyes 2- Prominent occiput 3- Ear creases 2- Macroglossia
- Some involving familial inheritance - Complications: 3- Umbilical hernia  Instead of omphalocele.
1- Hypoglycemia may be severe and intractable  TTT: subtotal pancreatectomy may be needed. 4- Head circumference of patients with congenital hypothyroidism may be increased
Associated with duplication of whereas patients with Beckwith syndrome have microcephaly.
chromosome 11 p (Encoding for IGF-2)
2- Patients have an increased risk of neoplasms such as: Wilms' tumor, Hepatoblastoma, Gonadoblastoma
- Obtain U/S & serum AFP every 6 months through 6 years of age to look for Wilm's Tumor/Hepatoblastoma 5- NO Hypoglycemia and hyperinsulinemia.
- Sporadic: defect in the G-prote in cAMP-kinase function in the affected tissue  thereby resulting in autonomous activity of that tissue.
McCune-Albright - It is a rare condition characterized by 3P: 1- Precocious puberty 2- Pigmentation: cafe au lait spots 3- Polyostotic fibrous dysplasia (multiple bone defects).
syndrome - It is responsible for 5% of the cases of female precocious puberty,
- may be associated with other endocrine disorders, as : 1- Hyperthyroidism, 2- Prolactin- or GH-secreting pituitary adenomas 3- Adrenal hypercortisolism.

Miscellaneous Autosomal Dominant Disorders

Osteogenesis imperfecta Marfan syndrome Ehlers-Danlos syndrome Myotonic muscular dystrophy (MMD)Steinert disease
- Caused by defect in type 1 collagen - Connective tissue disorders, caused by mutation of fibrillin-1 gene. It's a disorder of collagen structure. - Second most common muscular dystrophy in the United States.
- Patients have a weak bone matrix that leads to : - Clinical Features : - The pathologic distinct in that all types of muscles (i.e., smooth,
- Clinical Features :
1- Frequent fractures 1- Tall stature for age 2- Long face with crowded teeth striated, cardiac) are involved.
2- Bowing of the bones. 3- Long arm 4- Long thin fingers= Arachnodactyly ("spider fingers") - Clinical Features :
1- Hypermobile joints
- Types (4 types): 5- Sand legs. 6- Prominent sternum A)Patient initially appears normal at birth,  then slowly develops
2- Hyperelastic skin
All types can have : (1) Hypo : Hypotonia 3- Easy bruising Proximal muscle weakness and progressive muscle wasting :
1- Joint HYPERlaxity 2- HYPOtonia (2) Hyper: Hypermobilityof the joints & 4- Poor wound healing 1- Distal muscles of hands: atrophy of thenar & hypothenar
3- Early hearing loss 4- Wormian bones. Hyperelastic skin with diminished recoil 2- Posterior forearm muscle
(3) Cardiac: Aortic root dilatation (MR)  diastolic murmur Severe complications such as: 3- Anterior compartment of the lower legs
- Type II is the most severe form of OI and is usually lethal Ascending Aortic Dissection 1- Organ rupture B) Emaciated extremities, positiveGowers sign, winged scapula,
within the first year of life. Mitral Valve Prolapse 2- Severe hemorrhage may occur. and myotonia (delayed muscle relaxation)
- Types I, III, and IV can all be further categorized by the
(4) Ophthalmology: Iridodonesis from: Ectopia lentis / Lens dislocation C) Characteristic facial appearance :
presence or absence of dentinogenesis imperfect :
Myopia / blue sclera - Temporal wasting - Thin cheeks - Upper lip: inverted V shape
-- It's a disorder of tooth development (primary &
permanent teeth affected) Neurological: Dural ectasia D) Endocrine manifestations include :
-- The teeth are : discolored (bluish gray / yellow-brown), Progressive ectasia of the dura & neural foramina, and erosion of the - Diabetes mellitus - Testicular atrophy - Frontal baldness
translucent & weak. vertebral bone resulting consequently in enlargement of spinal canal. - Hypothyroidism.