Download Lecture 03. General characterization of monogenic pathology

General characterization of
monogenic pathology. Clinical
symptoms and genetics of the
main forms of monogenic
diseases
Ass. prof.
Furdela V.B.
Causes
Molecular Basis of Ehlers-Danlos Syndrome
Type
Old
Nomenclature
Protein
Abnormality
Gene
Abnormality
Chromosome
Locus
Type I/II
Type V collagen
COL5A1,
COL5A2
9q34.2-34.3
2q31
Type III
Unknown
Unknown
Unknown
Type IV
Type III collagen
COL3A1
2q31
Kyphoscoliosis
Type VI
Lysyl hydroxylase
PLOD1
deficiency (some)
Arthrochalasia
Type VII A/B
Type I collagen
COL1A1
COL1A2
17q31-22.5
7q22.1
N-proteinase
ADAMST2
5q23-24
Classic
Hypermobility
Vascular
DermatoType VIIC
sparaxis
1p36.3-36.2
Ehlers-Danlos syndrome. Skin
hyperextensibility
Ehlers-Danlos syndrome. Dorsiflexion of all
the fingers is easy and absolutely painless.
Ehlers-Danlos syndrome.
Joint hypermobility is less intense than
with other conditions.
Ehlers-Danlos syndrome.
Note the abnormal ability to elevate the
right toe.
Types of Ehlers-Danlos Syndromes
• Classic (Types I and II)
– Autosomal dominant
• Major Diagnostic Criteria
– Skin hyperextensibility,
wide atrophic scars, joint hypermobility
• Minor Diagnostic Criteria
– Smooth, velvety skin; easy bruising; molluscoid
pseudotumors; joint hypermobility; muscle hypotonia;
postoperative complication (eg, hernia); positive family
history; manifestations of connective tissue lesions
(eg, hernia, prolapse)
Treatment
• In the event of injuries, take extreme care with the use of
sutures, adhesive strips and wound glues.
• avoid excessive activities on hypermobile joints.
• In the presence of mitral valve prolapse, subacute
bacterial endocarditis (SBE) prevention.
• High-dose (1-4 g/d) ascorbic acid therapy
• desmopressin in the prevention and treatment of bleeding
Neurofibromatosis
• Neurofibromatosis (NF) is a multisystem genetic
disorder commonly associated with cutaneous,
neurologic, and orthopedic manifestations.
Frequency. Rase. Sex
• Incidence of neurofibromatosis type 1 is 1 case in
3 000 persons
• Half of affected individuals represent first cases in
their families as the result of a new genetic event or
mutation
• All races and ethnic backgrounds are equally
affected
• While males and females are equally affected ,
scoliosis may be especially severe in young girls
Causes. Pathophysiology
• Manifestations of neurofibromatosis type 1 are
caused by a mutation in, or a deletion of, the NF1
gene. The gene product, neurofibromin, serves as a
tumor suppressor. Decreased production of this
protein causes various clinical features.
• The NF1 gene is located within the long arm of
chromosome 17.
Clinical criteria for diagnosis
(presence of at least 2 of 7 criteria )
• At least 6 café au lait spots or hyperpigmented macules
• Axillary or inguinal freckles
• Two or more typical neurofibromas or 1 plexiform
neurofibroma
• Optic nerve glioma
• Two or more iris hamartomas (also known as Lisch nodules),
• Sphenoid dysplasia or typical long-bone abnormalities
• First-degree relative with neurofibromatosis type 1
Café au lait spots
Neurofibromas
• Subcutaneous or cutaneous neurofibromas
appear over time in older children, adolescents, and
adults. Puberty and pregnancy may be associated
with increased numbers and more rapid growth of
preexisting lesions.
• Plexiform neurofibromas are more diffuse
growths. They may be associated with bony erosion
and pain, accompanied by overlying
hyperpigmentation or hypertrichosis.
• Neurofibromas rarely grow rapidly.
Multiple neurofibromas
Plexiform neurofibroma of the
eyelid
A right thigh
plexiform
neurofibroma
Ophthalmologic examination
– Optic nerve tumors in children younger than 5 years
– Optic nerve gliomas in older children or even adults with
spontaneous regression.
– Subtle peripheral field defects, color discrimination
difficulties, optic nerve pallor, proptosis may occur in
association with an optic glioma.
– Lisch nodules can occasionally be seen with an
ophthalmoscope
– Patchy choroidal abnormalities and corkscrew retinal
vascular changes
Neurofibromatosis. Lisch
nodules
Orthopedic examination
• Sphenoid dysplasia in patients with plexiform
neurofibroma of the eyelid or temporal region
• Congenital pseudarthrosis. Bowing of the tibia.
Thinning and angulation of long. Bowing of the
forearm is less common.
• Thoracic cage asymmetry with flaring or prominence
of the inferior ribs.
• Scoliosis, with or without kyphosis.
Radiograph
showing radial
bowing, ulnar
bowing, and
obliteration of the
intramedullary
spaces
MRI showing a left optic nerve
glioma with thickening of the
nerve and proptosis.
Neurofibromatosis.
MRI scan depicting
an unidentified
bright object (UBO)
within the brain
parenchyma.
Treatment
• Biannual examinations for children younger than 5 years,
and annual examinations thereafter
• Annual eye examinations
• cutaneous examination to search for new neurofibromas
and progression of preexisting lesions.
• a careful search for skeletal involvement
• Check blood pressure at every visit
• Ask parents about the child's neurodevelopmental
progress
Prognosis
• neurofibromatosis type 1 may reduce overall life
expectancy as much as 15 years
Marfan syndrome
• Marfan syndrome is an inherited connectivetissue disorder (the most common single-gene
malformation syndromes) transmitted as an
autosomal dominant trait.
• Marfan syndrome is named after
Antoine Marfan, the French
pediatrician who first described the
condition in 1896.
Frequency. Mortality. Rase. Age
• Marfan syndrome affects about 1 in 10,000
individuals3 and perhaps as many as 1 in 30005000.
• Cardiovascular disease (aortic dilatation and
dissection) is the major cause of morbidity and
mortality.
• Marfan syndrome is panethnic.
• Marfan syndrome may be diagnosed prenatally, at
birth, or well into adulthood.
Type of inheritance
Skeletal findings
• taller and thinner than their family members.
• limbs are disproportionately long compared with
the trunk
• Arachnodactyly
– For the skeletal system to be involved, at least 2
major criteria or 1 major criterion plus 2 minor
criteria must be present.
Adult with Marfan
syndrome. Note tall
and thin build,
disproportionately
long arms and legs,
and kyphoscoliosis.
Arachnodactyly
–
Major criteria
• Pectus excavatum that requires surgery or pectus
carinatum
• Positive wrist (Walker) and thumb (Steinberg) signs
• Scoliosis greater than 20˚
• Reduced extension of the elbows (<170°)
• Pes planus
• Protrusio acetabuli
Pectus excavatum of moderate
severity
Positive thumb (Steinberg) sign
Positive wrist (Walker) sign
Minor criteria
•
•
•
•
•
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Pectus excavatum of moderate severity
Scoliosis less than 20°
Thoracic lordosis
Joint hypermobility
Highly arched palate
Dental crowding
Typical facies (dolichocephaly, malar hypoplasia,
enophthalmos, retrognathia, down-slanting
palpebral fissures)
Hypermobility of finger joints
Ocular findings
• The major criterion is ectopia lentis
• Minor criteria:
–
–
–
–
–
Flat cornea
Increased axial length of the globe
Cataract in patients younger than 50 years
Hypoplastic iris or hypoplastic ciliary muscle
The most common refraction error is myopia due to
elongated globe and amblyopia.
– Glaucoma (patients younger than 50 years)
– Retinal detachment
• At least 2 minor criteria must be present.
Cardiovascular findings
• Major criteria
– Aortic root dilatation in 70-80%.
– Aortic dissections involving the ascending
aorta
• Minor criteria:
–
–
–
–
Mitral valve prolapse (55-69%).
Dilatation of proximal pulmonary artery
Calcification of mitral annulus (patients < 40 yrs)
Dilatation of abdominal or descending thoracic aorta
(patients < 50 yrs)
• For the cardiovascular system to be involved, a minor criterion
must be present.
Pulmonary findings
a minor criterion:
– Spontaneous pneumothorax
– Apical blebs on chest radiography
• Skin and integumentary findings
• Minor criteria:
– Striae atrophicae in the absence of marked weight
changes on the shoulder, mid back, and thighs.
– Recurrent or incisional hernia
Stretch marks (striae atrophicae) in the lower
back
Workup
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Genetic testing - screening the entire FBN1 gene
Molecular studies of the fibrillin gene
Radiography: Chest, Pelvis
Echocardiography
CT and MRI of the lumbosacral spine
Aortography
ECG
Measure blood pressure
Ophthalmoscopy
Treatment
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Moderate restriction of physical activity
Endocarditis prophylaxis (Intravenous antibiotic)
Echocardiography at annual intervals
Beta-blocking treatment
Anticoagulant medications
Conservative treatment of protrusio acetabuli
Myopia is treatable with refraction.
Patients with flat feet may wear shoes with
adequate arch support.