1. 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.

2. Causes Molecular Basis of Ehlers-Danlos Syndrome
Type
Old Nomenclature
Protein Abnormality
Gene Abnormality
Chromosome Locus
Classic
Type I/II
Type V collagen
COL5A1, COL5A2
9q q31
Hyper-mobility
Type III
Unknown
Vascular
Type IV
Type III collagen
COL3A1
2q31
Kypho-scoliosis
Type VI
Lysyl hydroxylase deficiency (some)
PLOD1 1p
Arthro-chalasia
Type VII A/B
Type I collagen
COL1A1 COL1A2
17q q22.1
Dermato-sparaxis
Type VIIC
N-proteinase
ADAMST2
5q23-24

3. Ehlers-Danlos syndrome. Skin hyperextensibility

4. Ehlers-Danlos syndrome
Ehlers-Danlos syndrome. Dorsiflexion of all the fingers is easy and absolutely painless.

5. Ehlers-Danlos syndrome
Ehlers-Danlos syndrome. Joint hypermobility is less intense than with other conditions.

6. Ehlers-Danlos syndrome
Ehlers-Danlos syndrome. Note the abnormal ability to elevate the right toe.

7. 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)

8. 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

9. Neurofibromatosis
Neurofibromatosis (NF) is a multisystem genetic disorder commonly associated with cutaneous, neurologic, and orthopedic manifestations.

10. 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

11. 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.

12. 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

13. Café au lait spots

14. 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.

15. Multiple neurofibromas

16. Plexiform neurofibroma of the eyelid

17. A right thigh plexiform neurofibroma

18. 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

19. Neurofibromatosis. Lisch nodules

20. 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.

21. Radiograph showing radial bowing, ulnar bowing, and obliteration of the intramedullary spaces

22. MRI showing a left optic nerve glioma with thickening of the nerve and proptosis.

23. Neurofibromatosis. MRI scan depicting an unidentified bright object (UBO) within the brain parenchyma.

24. 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

25. Prognosis
neurofibromatosis type 1 may reduce overall life expectancy as much as 15 years

26. Marfan syndrome
Marfan syndrome is an inherited connective-tissue 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.

27. Frequency. Mortality. Rase. Age
Marfan syndrome affects about 1 in 10,000 individuals3  and perhaps as many as 1 in
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.

28. Type of inheritance

30. 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.

32. Adult with Marfan syndrome
Adult with Marfan syndrome. Note tall and thin build, disproportionately long arms and legs, and kyphoscoliosis.

34. Arachnodactyly

35. 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

36. Pectus excavatum of moderate severity

37. Positive thumb (Steinberg) sign

38. Positive wrist (Walker) sign

39. Minor criteria 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)

40. Hypermobility of finger joints

41. 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.

42. 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.

43. Pulmonary findings a minor criterion: Skin and integumentary findings
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

44. Stretch marks (striae atrophicae) in the lower back

45. Workup 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

46. Treatment 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.