1. NEUROCUTANEOUS DISORDERS AND SYNDROMES
Bořivoj Petrák
Klinika dětské neurologie, 2.LF UK a FN Motol
2019

2. NEUROCUTANEOUS DISORDERS AND SYNDROMES 1)
The earlier term (historical name) „phacomatosis“
Neurocutaneous diseases/syndromes (current name) are congenital and hereditary conditions with lesions both of the skin and the nervous system and the other body organs (bone, eye, kidney, heart, lungs, vessels) - derived from neuroectoderm – neural tube and crest.
They are complex multisystem disorders with very variable clinical features.
They include a large group of neurological disorders that feature cutaneous and eye lesions, central and peripheral nervous system tumors, brain malformations, mental retardation, psychiatric syndrome and seizures.
These units are slowly progressing.

3. NEUROCUTANEOUS DISORDERS AND SYNDROMES 2) Common signs
1) Inheritance
The majority displaying Mendelian inheritance = single gene conditions, and the common neurocutaneous syndrome are autosomal dominant (AD) inherited, with full penetrance (to some age), large expressivity and variability (= wide spectrum of disease phenotypes varying from mild to severe forms), and with much higher cases of new mutations (= sporadic cases).
Other neurocutaneous syndromes (rare units) are autosomal recessively (AR) and X-linked (XD, XR) inherited, some occur as a result of mosaicism for mutations in dominantly inherited lethal genes.

4. NEUROCUTANEOUS DISORDERS AND SYNDROMES 3) Common signs
Example of the inheritance:
Autosomal dominant (AD) inherited: neurofibromatosis von Recklinghausen type 1, tuberous sclerosis, with large number sporadic cases.
Autosomal recessively (AR) inherited: ataxia – telangiectasia
X-linked dominant disorder (XD): incontinentia pigmenti
X-linked recessive disorder (XR): kinky hair syndrome (Menkes syndrome)
mosaicism for mutations in dominantly inherited lethal genes: Proteus sy, Epidermal nevus sy

5. NEUROCUTANEOUS DISORDERS AND SYNDROMES 4) Common signs
2) They are congenital conditions derived from germinal neuroectoderm with lesions of the both the skin and the nervous system (neural tube), and bone, eye, kidney, heart, lungs, vessels (neural crest).
These units are germ cell migration disorders. .

6. NEUROCUTANEOUS DISORDERS AND SYNDROMES 5) Common signs
After recruitment from the ectoderm, the neuroectoderm undergoes three stages of development: transformation into the neural plate, transformation into the neural groove (with associated neural folds), and transformation into the neural tube. After formation of the tube, the brain forms into three sections; the hindbrain, the midbrain, and the forebrain.
The types of neuroectoderm include:
Neural crest: - pigment cells in the skin, - ganglia of the autonomic nervous systém, - dorsal root ganglia, - facial cartilage, - aorticopulmonary septum of the developing heart and lungs, - ciliary body of the eye, adrenal medulla, - parafollicular cells in the thyroid
Neural tube: brain (rhombencephalon, mesencephalon and prosencephalon)
spinal cord and motor neurons
retina
posterior pituitary

7. NEUROCUTANEOUS DISORDERS AND SYNDROMES 6) Common signs
3) Many are associated with high risk for tumors (oncogenesis).
- However neurocutaneous syndromes are mainly hamartomatosis syndromes
- there are common of the benign tumors there
- only a few of have malignant tumors.
Predisposition = tumor suppressor genes
= hypothesis of the two-hit mechanism (hypothesis by Knudson, 1972) Some benign tumors can be destructive and „malignant“ by position

8. NEUROCUTANEOUS DISORDERS AND SYNDROMES 7) Common diseases and syndromes
Neurofibromatosis von Recklinghausen
type 1 (NF1) q11.2, AD, 1:
type 2 (NF2) q12.2, AD, 1: – it occur at adult
Schwanomatosis 22q, AD, 1:40 000, it occur at adult
Tuberous sclerosis complex (M. Bourneville-Pringle, TSC), AD, 1: (USA)
typ 1 (TSC1) 9q34
typ 2 (TSC2) 16p13.3
Sturge-Weber syndrom,(SWS) sporadic cases, 1:50 000
M. von Hippel-Lindau,(VHL) 3p26-p25, AD, 1:36000– – only adult
Ataxia-telangiectasia (AT) 11q22.3, AR, 1:
The other approximately 40 units are rare or very rare.

9. NEUROCUTANEOUS DISORDERS AND SYNDROMES 8) Recommended resources
Neurocutaneous Disorders. Ed. Roach ES and Miller VS. Cambridge Univ. Press, 2004, UK.
Child Neurology. Ed. Menkes JH, Sarnat HB, Maria BM, seventh edition, Chapter 12th, Neurocutaneous syndromes., 2009, Lippincott Williams and Wilkins.

10. NEUROFIBROMATOSIS VON RECKLINGHAUSEN TYP 1
(NF1) 10

11. NEUROFIBROMATOSIS VON RECKLINGHAUSEN TYP 1 (NF1) 1)
The most common neurocutaneous syndrome
NF1 is a distinct disorder and is not related to neurofibromatosis type 2 (NF2)
Multisystem disorder
Affecting 1 in individuals worldwide without regard for ethnic or racial background
NF1 is AD inherited, with full penetrance (to adult age), large expressivity and variability (= wide spectrum of disease phenotypes varying from mild to severe forms),
30-50% new mutation = sporadic cases

12. NEUROFIBROMATOSIS VON RECKLINGHAUSEN TYP 1 (NF1) 2)
The NF1 gene was identifed at 1987
Is located on the long arm of chromosome 17q11.2 near the centromere
60 exons, 335 kilobases of genomic DNA (kbDNA)
The NF1 gene product is termed neurofibromin, 13 kb mRNA, 2818 AMK
Tumor-suppressor gene, LOH
Exist DNA analysis

13. NEUROFIBROMATOSIS VON RECKLINGHAUSEN TYP 1 (NF1) 3)
Neurofibromin:
Neurofibromin is a GTPase-activating protein (GAP), which functions to inhibit ras activity (activation of ras promotes cell division and proliferation).
Neurofibromin, as a negative regulator of ras, may function as a tumor suppressor by inhibiting the ras-mediated cell proliferation signal.
Loss of neurofibromin = increasing ras activity and cell proliferation, and it that fashion promote tumor formation.

14. NEUROFIBROMATOSIS VON RECKLINGHAUSEN TYP 1 (NF1) 4)
NF1 and tumors:
Hamartomas
Benign tumors: peripheral nervous system:
- neurofibromas (NF) = are composed of Schwann cells and fibroblasts + may contain perineural cells, mast cells
NF may be classified into: a) cutaneous NF, b) subcutaneous NF, c) deep nodular NF, d) plexiform neurofibroma (plex.NF)

15. NEUROFIBROMATOSIS VON RECKLINGHAUSEN TYP 1 (NF1) 5)
Central nervous system – optic pathway gliomas (grade I pilocytis astrocytoma) are in the 15-20% of NF1 individuals, and low grade glioma in the other localisation (pons, basal ganglia) of the brain and/or less in the spinal cord.
Optic pathway glioma (OPG) may be found at any location along the optic pathway – most commonly at optic chiasm and at optic nerve (including bilateral affection).
The age of presentation is usually under 6 (10) years.
- from ½ to 2/3 OPG are asymptomatic = with any health problem.
Symptomatic OPG with proptosis, optic dysfunction, decrese visual acuity, color vision changes, visual loss, strabismus, optic nerve atrophy, papilledema.

16. NEUROFIBROMATOSIS VON RECKLINGHAUSEN TYP 1 (NF1) 6)
Only a small fraction of NF1-associated symptomatic OPG require treatment.
Remember!! The OPG with the exclusion of NF1 (NF1-unassociated) are serious oncologic disease and require treatment always.
Treatment of NF1-associated symptomatic OPG has recently included chemoterapy – with carboplatinum and vincristine.
Radiation was standard treatment to 2000, it was leave for great risk of cognitive, endocrine and vascullar changes (moya-moya sy).
Surgical treatment of the intraorbital/prechiasmatic OPG was leave for great risk of the visual loss, ptosis.

17. NEUROFIBROMATOSIS VON RECKLINGHAUSEN TYP 1 (NF1) 7)
Malignancies in NF1
Peripheral nervous system:
Malignant peripheral nerve sheat tumor (MPNST) – derived from Schwann cells (de novo) or from plexiform NF after malignant transformation.
Risk of MPNST is with a rate of 2-10%
Other malignancies:
Pheochromocytoma
Hemoblastoses
Wilm´s tumor
Rhabdomyosarcoma
GIST (gastrointestinal stromal tumor)
Neuroblastoma

18. NEUROFIBROMATOSIS VON RECKLINGHAUSEN TYP 1 (NF1) 8)
Diagnostic criteria NF1
At least two clinical features from the list of the diagnostic criteria must be present in order to establish diagnosis of NF1.
Diagnostic criteria:
Six or more café- au- lait macules, greater than 5 mm in diameter in a prepubertal patient and 1.5 cm in a postpubertal patients.
Axillary or inquinaly freckling
Two or more NF and/or one or more plexiform NF.
OPG
Two or more Lisch nodules
Characteristic bony lesion
First-degree relative with NF1

19. NEUROFIBROMATOSIS VON RECKLINGHAUSEN TYP 1 (NF1) 9)
Other clinical manifestation NF1
Hypersignal areas on T2-weighted images =
= Focal areas of signal intensity (FASI)
Skoliosis and skeletal abnormality and changes
Hydrocephalus – glioma x aqueductal stenosis
Other: macrocephaly, short statue, learning disabilities, ADD and ADHD, endocrinopathy.
Rare findings: fibromuscular dysplasy, stroke (incl. moya-moya syndrome), hypertension (renovasculary), epilepsy (7%).

20. NEUROFIBROMATOSIS VON RECKLINGHAUSEN TYP 1 (NF1) 10)
Other clinical manifestation NF1
Hypersignal areas on T2-weighted images = Focal areas of signal intensity (FASI)
Synonyms = Commonly they are referred as unidentified bright object (UBO) or hamartoma
They have been identified in the cerebellum, brain stem, thalamus, and basal ganglia, especially in 86% children and adolescents.
Histological analysis – vacuolar or spongiotic alteration of the myeline in the white matter
It is not a tumor – theoretical risk of the low-grade glioma
- it distinguished by the absence of mass-effect and/or enhancement by contrast matter

21. NEUROFIBROMATOSIS VON RECKLINGHAUSEN TYP 1 (NF1) 11)
Other clinical manifestation NF1
Skoliosis and skeletal abnormality and changes – from 10 years of age, 2% in orthopedic surgery
FASI
Hydrocephalus – glioma x aqueductal stenosis
Other: macrocephaly, short statue, learning disabilities, ADD and ADHD, endocrinopathy.
Rare findings: fibromuscular dysplasy, stroke (incl. moya-moya syndrome), hypertension (renovasculary), epilepsy (7%).

22. NEUROFIBROMATOSIS VON RECKLINGHAUSEN TYP 1 (NF1) 12)
Other clinical manifestation NF1
Hydrocephalus – glioma x aqueductal stenosis (in cohort of the children with NF1 in Paediatric Neurology Dpt. Motol)
The development of obstructive hydrocephalus 25/275 = 9%
The development due to aqueductal stenosis 7/275 (2.5%), resp. 7/25(28%)
FASI
Skoliosis and skeletal abnormality and changes
Other: macrocephaly, short statue, learning disabilities, ADD and ADHD, endocrinopathy.
Rare findings: fibromuscular dysplasy, stroke (incl. moya-moya syndrome), hypertension (renovasculary), epilepsy (7%).

23. NEUROFIBROMATOSIS VON RECKLINGHAUSEN TYP 1 (NF1) 13)
Other clinical manifestation NF1
Other: macrocephaly, short statue, learning disabilities, ADD and ADHD, endocrinopathy.
FASI
Skoliosis and skeletal abnormality and changes
Hydrocephalus – glioma x aqueductal stenosis
Rare findings: fibromuscular dysplasy, stroke (incl. moya-moya syndrome), hypertension (renovasculary), epilepsy (7%).

24. NEUROFIBROMATOSIS VON RECKLINGHAUSEN TYP 1 (NF1) 14)
Other clinical manifestation NF1
Rare findings: fibromuscular dysplasy, stroke (incl. moya-moya syndrome), hypertension (renovasculary), epilepsy (7%).
Hypersignal areas on T2-weighted images = Foci of altered signal intensity (FASI)
= Focal areas of signal intensity (FASI)
Skoliosis and skeletal abnormality and changes
Hydrocephalus – glioma x aqueductal stenosis
Other: macrocephaly, short statue, learning disabilities, ADD and ADHD, endocrinopathy.

25. NEUROFIBROMATOSIS VON RECKLINGHAUSEN TYPE 2
(NF2)

26. NEUROFIBROMATOSIS VON RECKLINGHAUSEN TYPE 2 (NF2) 1)
NF2 is a distinct disorder and is not related to NF1
NF2 predisposes affected individuals to the development of billateral vestibular schwannomas
Multi-(benign)tumor disease (everyone= two or more)
Affecting 1 in individuals worldwide
NF2 is AD inherited, with onset in adolescent and young adult age.
50% new mutation = sporadic cases
The NF2 gene was identifed at Is located on the long arm of chromosome 22q12.2, contains 17 exons. The NF2 gene product is termed schwannomin (=merlin)
Tumor-suppressor gene, LOH

27. NEUROFIBROMATOSIS VON RECKLINGHAUSEN TYP 2 (NF2) 2)
Exist possibility of DNA analysis
The majority of individuals with NF2 present with
hearing loss – accompanied/preceded by tinnitus, and dizziness or imbalance as the first symptom
A significant number of patients present initially with cranial meningioma, spinal tumor or cutaneous tumor (20-30%).
Between 60 and 80% of patients with NF2 have evidence of cataract – presenile posterior subcapsular lenticular opacities

28. NEUROFIBROMATOSIS VON RECKLINGHAUSEN TYP 2 (NF2) 3)
Diagnostic criteria for NF2
Bilateral vestibular schwannomas or family history of NF2 +
Unilateral vestibular schwannoma or
Any two of : meningioma, glioma, neurofibroma, schwannoma, and presenile posterior subcapsular lenticular opacities
Additional criteria - Cerebral calcification

29. NEUROFIBROMATOSIS VON RECKLINGHAUSEN TYP 2 (NF2) 4)
Management issues
The onset symptoms = only 10% of cases are symptomatic before 10 years of age
Screening for vestibular schwannomas should begin around years of age – audiological testing, brainstem auditory evoked potential (BAEP)
MRI scans are the imaging technique of choice = detect smaller tumors (+ contrast) than CT and avoid the risk of radiation
Therapy – surgical management – otolaryngology, neurosurgery + new techniques: brainstem implants
- clinical genetic = prenatal diagnosis, preimplantation diagnosis

30. TUBEROUS SCLEROSIS COMPLEX (TSC)
M.BOURNEVILLE - PRINGLE

31. TUBEROUS SKLEROSIS COMPLEX 1)
The second most common disease of the neurocutaneous syndrome group
Multisystem disorder (brain, skin, heart, kidneys, liver, lung, bone).
Population-based studies suggest a prevalence of 1 in individuals worldwide without regard for ethnic or racial background
TSC is AD inherited, with large expressivity and variability (= wide spectrum of disease phenotypes varying from subtle findings to severe forms), and 60%- 80% result from sporadic cases.
Germline mosaicism accounts for 1% or 2%
Two genes are responsible for TSC
TSC type 1 - chromozome 9q34.3, hamartin
TSC type 2 - chromozome 16p13.3, tuberin
hamartin-tuberin complex – two genes cause similar phenotypes because they interact in the same process = mTOR kinase pathway (mammalian Target of Rapamycin) – phosphorylation and growth/proliferation of the cells

32. TUBEROUS SKLEROSIS COMPLEX 2)
Diagnostic criteria TSC – the last upgrade at 2012
Part A) Genetic diagnostic criteria
Part B) Clinical diagnostic criteria
Two groups of the diagnostic features exist:
– major features (11)
- minor features (6)
Definite TSC diagnosis:
Genetic: The identification of either a TSC1 or TSC2 pathogenic mutation in DNA from normal tissue is sufficient to make a define diagnosis of TSC.
Clinical:
Either two major features or one major feature + two minor features.
Probable TSC diagnosis: One major feature + one minor feature
Suspect TSC diagnosis: One major feature or two or more minor features.
(Northrup H et al., 2013)

33. TUBEROUS SKLEROSIS COMPLEX 3)
Part A) Genetic diagnostic criteria
The identification of either a TSC1 or TSC2 pathogenic mutation in DNA from normal tissue is sufficient to make a define diagnosis of TSC. A pathogenic mutation is defined as a mutation that clearly inactivates the function of the TSC1 or TSC2 proteins (eg, out of frame indel or nonsense mutation), prevents protein synthesis (eg, large genomic deletion), or is a missence mutation whose effect on protein function has been established by functional assessment ( Other TSC1 or TSC2 variants whose effect on function is less certain do not meet these criteria and are not sufficient to make a definite diagnosis of TSC. Note that 10% to 25% of TSC patients have no mutation identified by conventional genetic testing, and normal result does not exclude TSC, or have any effect on the use of Clinical Diagnostic Criterïa to diagnose TSC.
(Northrup H et al., 2013)

34. TUBEROUS SKLEROSIS COMPLEX 4)
Part B: Clinical diagnostic criteria
Major features (11)
Hypomelanotic macules (3 or more, at least 5-mm diameter)
Angiofibromas (3 or more) or fibrous cephalic plaque
Ungual fibromas (2 or more)
Shagreen patch (1-4 skin)
Multiple retinal hamartomas
Cortical dysplasias (includes tubers+cerebral white matter radial migration lines)
Subependymal nodule (SEN)
Subependymal giant cell astrocytoma (SEGA) (6-8 brain)
Cardiac rhabdomyoma (CR)
Lymphangioleiomyomatosis (LAM) (A combination of the 2 major clinical features LAM and angiomyolipomas without other features does not meet criteria for a definite diagnosis).
Angiomyolipomas (2 or more) (9-11 organs) (Northrup H et al., 2013)

35. TUBEROUS SKLEROSIS COMPLEX 5)
Minor features (6)
„Confetti“ skin lesion
Dental enamel pits (more than 3)
Intraoral fibromas (2 or more)
Retinal achromic patch
Multiple renal cysts
Non-renal hamartomas
(Northrup H et al, 2013)

36. TUBEROUS SKLEROSIS COMPLEX 6)
Clinical manifestation – skin lesions 1/
Hypomelanotic macules:
are found in over 90% of patients = three or more
one or two of these lesions occur in normal individuals
they can be found in the newborn, the progression later
they occur less often in the scalp hair or eyelids = poliosis
these hamartomas shines brightly in ultraviolet light
Facial angiofibromas:
are found in about 75% of patients
contain both vascular and connective tissue elements
become apparent during the preschool years, progression later
Therapy – surgical management – otolaryngology, neurosurgery + new techniques: brainstem implants
- clinical genetic = prenatal diagnosis, preimplantation diagnosis

37. TUBEROUS SKLEROSIS COMPLEX 7)
Clinical manifestation – skin lesions 2/
3. Shagreen patch:
textured skin lesion are found in about 30% of patients
they are most often found on the back or flank area
histologically they have character of epidermal naevus
become apparent during the preschool/school years
4. Ungual fibromas:
nodular fleshy tumors arising adjacent to, or underneath, the nails. Single lesions sometimes develop after trauma.
contain both vascular and connective tissue elements
are found in about 15-20% of TSC patients - occurred in adolescents or adult

38. TUBEROUS SKLEROSIS COMPLEX 8)
Clinical manifestation – brain lesions 1/
Cortical tuber:
are found in over 100% of TSC patients
they can be found in the newborn, the „progression“ later with myelinization
they occur
these dysplastic areas
Subependymal nodule (SEN)
are found in about 100% of TSC patients
contain calcification
Minimal lifetime growth

39. TUBEROUS SKLEROSIS COMPLEX 9)
Clinical manifestation – brain lesions 2/
3. Subependymal giant cell astrocytoma (SEGA):
are found in over 12-16% of TSC patients
they can be found in the newborn only rarely, the „progression“ later
they can to occur obstruction of the foramina Monroe and development of hydrocephalus

40. TUBEROUS SKLEROSIS COMPLEX 10)
Clinical manifestation – neurologic dysfunction
The predominant neurologic manifestations of TSC are mental retardation, epileptic seizures, and behavioral abnormalities. But individuals with little or no neurologic impairment exist.
Mental retardation (40-60%) – intellectual function ranges from above average to profound mental retardation.
Epileptic seizures
are found in about 90% of patients
of various types, including infantile spasms (West sy)
therapy – vigabatrine (Sabril tbl) and/or combination of the antiepileptic drugs.
epileptic surgery is possible.

41. TUBEROUS SKLEROSIS COMPLEX 11)
Management issues 1/
The onset symptoms = the first clinical feature TSC is cardiac rhabdomyoma (CR). CR(s) are sometimes seen on prenatal ultrasound - it is necessary long time follow-up = early diagnosis TSC, and complications, particularly development of epilepsy.
Periodic evaluation to detect the more serious complications (CR, cardiac arrhythmias, epilepsy), mental retardation,behavioral disorders (autism, hyperkinesis, ADHD sy), tumors (SEGA, renal tumors, LAM).
MRI is the imaging technique of choice = detect cortical and cortico-subcortical lesions (tuber), and SEGA (+ contrast enhancement ). Calcified subependymal nodules are best demonstrated with CT.

42. TUBEROUS SKLEROSIS COMPLEX 12)
Management issues 2/
4. Therapy
- epilepsy – antiepileptic drugs (AED) including vigabatrin (Sabril tbl), combination
– surgical management – LAM, renal cyst and angiolipoma
- neurosurgery - hydrocephalus, epileptosurgery, and brain tumors/SEGA
- clinical genetic = evaluation including molecular examination/DNA analysis, prenatal diagnosis, preimplantation diagnosis

43. STURGE – WEBER syndrome
(SWS)
(encephalofacial angiomatosis)

44. Sturge – Weber syndrome (SWS) 1)
SWS is a rare neurocutaneous disorder.
Population-based studies suggest a prevalence of in individuals worldwide without regard for ethnic or racial background
SWS is inherited, but only sporadic case/ new mutation.
Hypothesis = mosaicism of the lethal gene.
Tumor risk – pheochromocytoma, angioma (organs)

45. Sturge – Weber syndrome (SWS) 2)
SWS is associated with – diagnostic criteria:
unilateral or bilateral port-wine stain(s) of the face = area of the 1th (and 2nd) nervus trigeminus branche(s)
+ but only 8% to 20% of individuals with this port-wine stain develop SWS and neurological dysfunction
2) ipsilateral leptomeningeal angioma = malformation of blood vessels in the pia mater
+ gyral calcification (classic feature = „trolley track“) on CT examination of the head
+ extensive cerebral atrophy
+ MRI examination with gadolinium contrast (!) is necessary
3) glaucoma, occurs in 71% of the patients, episcleral hemangioma, development peaks at two ages,
+ buphthalmos (born with an enlarged globe)

46. Sturge – Weber syndrome (SWS) 3)
SWS is often associated with:
seizures (simple partial seizures and sec.generalization)
+ epilepsy occurs in up to 80% of SWS patients
+ epilepsy occurs in up to 93% with bil.brain involvement
+ other seizure types = infantile spasms, tonic-clonic seizures, myoclonic and gelastic seizures
hemiparesis + arrested growth in the weak extremities
hemianopia
mental retardation and/or developmental delay (less than 10% of SWS patients with bilateral involvement are intelectually normal)
cognitive dysfunction (frequently) and attention deficit hyperactivity disorder (ADHD sy).
headache, migraine and/or stroke-like episodes

47. Sturge – Weber syndrome (SWS) 4)
Therapy:
Epilepsy = anticonvulsants (AED)
- complete seizure control is possible only in some patients = improve the quality of life
patients with unilateral brain lesions who fail to respond to medication (catastrophic epilepsy) may benefit from extensive surgical resection (epilepto-surgery).
Skin lesions – laser therapy (pulsed dye laser treatment)
Glaukoma = oral carbonic anhydrase inhibitors p.o.
= surgical – goniotomy, (older) trabeculectomy
Vascular trombosis (leptomeningeal angiomatosis) – aspirin in daily dosis – prevention of stroke-like episodes

48. Thank you