Neurocutaneous syndromes

Neurocutaneous syndromes (phakomatoses) are a diverse class of congenital disorders that affect organs of ectodermal origin, especially the skin, the central nervous system, and the eyes. The disorders most typically included in this class are neurofibromatosis type 1 (NF type 1, von Recklinghausen syndrome), neurofibromatosis type 2 (NF type 2), tuberous sclerosis, von Hippel-Lindau syndrome, Sturge-Weber syndrome, and ataxia telangiectasia. With the exception of Sturge-Weber syndrome, which is caused by a noninherited developmental anomaly of neural crest derivatives, and ataxia telangiectasia, which follows an autosomal recessive inheritance pattern, neurocutaneous syndromes disorders follow an autosomal dominant inheritance pattern, although spontaneous mutations are also possible. Characteristic features include neurofibromas, café au lait spots, axillary freckling, pheochromocytoma, optic glioma, and Lisch nodules (NF 1); bilateral vestibular schwannomas, meningiomas, ependymomas, and bilateral cataracts (NF 2); adenoma sebaceum, ash-leaf spots, shagreen patch, giant cell astrocytoma, cardiac rhabdomyoma, and renal angiomyolipoma (tuberous sclerosis); hemangioblastoma, angiomatosis, bilateral renal cell carcinoma, pheochromocytoma (von Hippel-Lindau syndrome); Port-wine stain and leptomeningeal angioma (Sturge-Weber syndrome); spider angioma, lymphoma, leukemia, gastric carcinoma, and ocular telangiectasia (ataxia telangiectasia). Diagnosis is based on clinical findings and is confirmed by genetic testing. Since there is no curative treatment, the management of neurocutaneous syndromes is symptom-oriented.

Epidemiology

• Incidence
  • Neurofibromatosis type 1: 1:2,500–3,000 ^[1]
  • Neurofibromatosis type 2: ∼ 1:33,000 ^[2]

Etiology

• Neurofibromatosis type 1 and type 2: autosomal dominant inheritance or spontaneous mutation

Pathophysiology

• Mutation of tumor suppressor gene → loss of function → uninhibited cell growth → neurofibroma development
  • NF type 1: NF1 gene mutation (100% penetrance)
    • Encodes neurofibromin protein
    • Located on chromosome 17
    • Inhibition of cell growth and proliferation via inhibition of the Ras signal transduction pathway (Ras activity is inhibited by the stimulation of GTPase)
  • NF type 2: NF2 gene mutation
    • Encodes merlin protein
    • Located on chromosome 22

Clinical features of neurofibromatosis

Neurofibromatosis type 1 (von Recklinghausen syndrome) ^[3]

• Multiple neurofibromas: benign peripheral nerve sheath tumors that originate from neural crest cells and affect the myelinated nerves.
  • Soft, painless nodules: typically manifest under or on the skin
  • Age of onset: adolescence
  • Malignant transformation possible
• Features due to melanocyte dysfunction:
  • Café au lait spots
    • Brown (hyperpigmented), flat macule or patch
    • Age of onset: before 2 years
  • Lisch nodules
    • Pigmented iris hamartomas
    • Age of onset: between 5–10 years
  • Axillary and inguinal freckling: age of onset is between 3–5 years
• Seizures and/or focal neurologic signs due to brain lesions (especially meningiomas)
• Intellectual disability
• Bone involvement
  • Scoliosis
  • Sphenoid wing dysplasia
  • Short stature
  • Cortical thinning
  • Fractures
  • Pseudoarthrosis
• Additional findings
  • Associated with certain tumors
    • Pheochromocytoma ^[4]
    • Nephroblastoma ^[5]
    • Optic pathway glioma (most commonly involving optic nerve) causing unilateral vision loss, proptosis, or precocious puberty
  • Macrocephaly
  • Hypertension
  • Pulmonary stenosis

Think CAFE SPOTS to remember features of NF type 1: Café au lait spots, Axillary freckling, neuroFibromas, nodules in the Eye, Skeletal abnormalities (e.g., Scoliosis), high blood Pressure, Optic Tumor, Stature (usually Short).

Neurofibromatosis type 2 ^[6]

• Age of symptom onset: between 18–24 years ^[2]
• Bilateral vestibular schwannomas (acoustic neuromas)
  • Located in the internal acoustic meatus, affecting the vestibulocochlear nerve
  • Can cause tinnitus, hearing loss, or vertigo
• Early-onset cataracts, usually bilateral
• Multiple cerebral and spinal tumors (especially meningiomas and ependymomas) ^[7]
• Other features: seizures, skin nodules, and/or cafe au lait spots (not specific for NF type 2)

In NF Type 2, the mutation is in chromosome Twenty-2 and the clinical findings (schwannoma and cataracts) manifest on 2 sides.

Diagnostics

• MRI of the brain and spine with contrast: to detect e.g., neurofibromas, meningiomas
• Ophthalmological exam: to detect optic glioma in NF type 1
• Auditory testing: to detect acoustic neuromas in NF type 2
• Genetic testing: mutations in NF1 gene or NF2 gene

Differential diagnosis

• Cafe au lait spots
  • McCune-Albright syndrome
  • Fanconi anemia
  • Tuberous sclerosis
  • Ataxia telangiectasia
  • Noonan syndrome
  • Bloom syndrome ^[8]
    • Etiology: mutations in the BLM gene → deficient helicase enzyme
    • Clinical features
      • Short stature
      • Skin rash (butterfly shaped on nose and cheeks, photosensitive), teleangiectasia of hands and arms, cafe-au-lait spots
      • Increased risk of cancer (e.g., leukemia)
• Schwannoma
  • Schwannomatosis
  • Sporadic vestibular schwannoma

Treatment

• Excision or resection of tumors (e.g., meningiomas)
• Surgery for kyphoscoliosis in NF type 1
• Drugs targeting the mTOR pathway (e.g., sirolimus) to reduce tumor growth

Prognosis

• Increased mortality due to malignant transformation of tumors
• Average life expectancy
  • NF type 1: ∼ 60 years ^[9]
  • NF type 2: ∼ 40 years ^[10][11]

Epidemiology

• Incidence is ∼ 1:6,000 ^[12]

Etiology

• Autosomal dominant inheritance or spontaneous mutation

Pathophysiology

• Mutation of tumor suppressor genes (variable expression) → loss of function → unchecked cell growth → tumor development
• Tumor suppressor genes
  • TSC1 gene on chromosome 9 encodes hamartin protein
  • TSC2 gene on chromosome 16 encodes tuberin protein

Clinical features ^[13][14]

• Intellectual disability (caused by brain lesions)
• Infantile spasms
  • Occur in children < 3 years of age
  • Involves head bobbing, flexor spasms, extensor spasms, and/or movements that mimic the startle response
  • May manifest with psychomotor regression or behavioral changes
• Other types of seizures (e.g., focal seizures)
• Skin manifestations
  • Adenoma sebaceum (facial angiofibroma): benign tumor composed of blood vessels and fibrous connective tissue
    • Age of onset: between 3–4 years of age; development of lesions increases during adolescence
    • Features
      • Mostly located around the nose and cheeks
      • Distribution resembles a butterfly shape
      • Can have an acne-like appearance
  • Ash-leaf spots: hypopigmented (white) macules on the trunk and extremities
    • Age of onset: present since birth
    • Three or more spots are diagnostic
    • Visualized using black light emitted by a Wood lamp
  • Shagreen patch: flesh-colored papule in the lumbosacral region with an orange-peel appearance
  • Skin hamartomas
  • Ungual fibromas: flesh-colored papules that grow under (subungual) or around the nails (periungual)
• Small benign tumors
  • Brain tumors
    • Hamartomas: can be cortical (glioneuronal hamartoma or tuber), subcortical, and/or subependymal
    • Giant cell astrocytoma
      • Benign, slow-growing tumor of mixed glial cells that is associated with tuberous sclerosis.
      • Typically arises in periventricular areas and, if symptomatic, presents subacutely with evidence of obstructive hydrocephalus (e.g., headache, papilledema)
  • Cardiac rhabdomyoma
    • Present in > 50% of affected individuals
    • May cause symptoms of mitral regurgitation and/or congestive heart failure
  • Renal disease: may manifest with a feeling of abdominal fullness and/or macrohematuria
    • Renal cysts
    • Angiomyolipoma
    • Renal carcinoma ^[15]

HAMAARTOMASS: Hamartomas, Ash leaf spots, Mind (intellectual disability), Adenoma sebaceum, renal Angiomyolipoma, Rhabdomyoma, Tumor suppressor genes (TSC1 gene and TSC2 gene), autosomal dOminant, Mitral regurgitation, Astrocytomas, Seizures, and Shagreen patches.

Diagnostics ^[16]

• ECG: cardiac rhabdomyoma can cause ventricular hypertrophy and arrhythmias
• EEG: seizure activity
• Imaging
  • Echocardiography: rhabdomyoma (common in the apex of the left ventricle)
  • Abdominal MRI: renal cyst, angiomyolipoma, and/or carcinoma
  • Contrast cerebral CT/MRI
    • Tumors (e.g., giant cell astrocytomas)
    • Enlarged ventricles (tumors in the periventricular area commonly cause obstructive hydrocephalus)
• Genetic testing: mutation of TSC1 or TSC2 gene

Differential diagnosis

• Conditions associated with ash-leaf spots
  • Nevus anemicus
  • Hypomelanosis of Ito
  • Vitiligo
  • Piebaldism
• Conditions associated with angiofibroma
  • Birt-Hogg-Dube syndrome
  • MEN-1 syndrome
• Conditions associated with shagreen patch
  • Birt-Hogg-Dube syndrome
  • MEN-1 syndrome
• Other hamartoma syndromes
  • Cowden syndrome
  • Juvenile polyposis syndrome
  • Peutz-Jeghers syndrome
  • Gorlin syndrome

Treatment ^[16]

• Seizure control
  • Infantile spasms: vigabatrin or ACTH
  • Anticonvulsants
• mTOR inhibitors: to treat renal angiomyolipoma and inoperable giant cell astrocytoma
• Removal of angiofibroma (laser treatment or electrosurgery)
• Surgery in the case of:
  • Obstructive hydrocephalus (with ↑ ICP)
  • Drug-resistant seizures

Prognosis ^[17]

• Renal disease and epilepsy are the most common causes of death.
• Life expectancy depends on severity of disease but can be normal if symptoms are mild and complications are treated accordingly.

Epidemiology

• Incidence: ∼ 1:36,000 ^[18]

Etiology

• Autosomal dominant inheritance or spontaneous mutation

Pathophysiology

• VHL gene: tumor suppressor gene on the short arm of chromosome 3
  • Encodes VHL protein (pVHL)
  • Deletion of VHL gene → impaired ubiquitination and elimination of hypoxia-inducible factor 1a; → loss of function → tumor and cyst development

Clinical features ^[19][20]

Characterized by the development of numerous benign and malignant tumors

• Vascular tumors (hemangioblastoma or angiomatosis)
  • Common in retina, cerebellum, brainstem, and/or spine
  • Can cause vision loss or focal neurological deficits
  • Hemangioblastomas are highly vascularized lesions whose cells have hyperchromatic nuclei.
• Bilateral renal cell carcinoma: can cause flank pain, hematuria, and/or renal dysfunction
• Pheochromocytoma: can cause episodic hypertension with paroxysmal headaches, palpitations, and/or diaphoresis
• Renal, pancreatic, and/or adrenal cysts
• Endolymphatic sac tumor
  • Bilateral disease is a pathognomonic feature
  • Can cause hearing loss, tinnitus, and/or vertigo
• Cystadenoma: located in the broad ligament or epididymis

Von HIPPEL-Lindau syndrome: Hemangioblastoma, Increased risk of renal cell carcinoma, Pheochromocytoma, Pancreatic lesions (cysts, cystadenomas, and neuroendocrine tumors), Eye Lesions (retinal angiomas or hemangioblastomas).

Diagnostics ^[20][21]

• Laboratory studies
  • BUN and/or creatine to rule out renal impairment
  • Plasma catecholamines and urinary catecholamine metabolites to screen for pheochromocytoma
• Fundoscopic eye exam: retinal hemangioblastoma
• Imaging
  • Abdominal ultrasound, CT, or MRI: to detect renal cell carcinoma and renal/pancreatic cysts
  • CT/MRI of the brain and spine: to detect hemangioblastoma
  • CT/MRI of internal auditory canal: endolymphatic sac tumors
• Audiogram: endolymphatic sac tumors
• Genetic testing: mutations in VHL gene

Differential diagnosis

• Familial pheochromocytoma syndromes
  • MEN 2 syndrome
  • Neurofibromatosis type 1
  • Hereditary paraganglioma-pheochromocytoma syndrome
• Renal and pancreatic cysts: autosomal dominant polycystic kidney disease

Treatment ^[22]

Mainly consists of regular surveillance and, if necessary, surgical treatment of tumors

• Retinal or CNS hemangioblastoma: resection
• Renal cell carcinoma: nephrectomy or radiofrequency ablation
  • Alternative to surgery: antiangiogenic medications (e.g., receptor tyrosine kinase inhibitors such as sunitinib)
• Pheochromocytoma: resection

Prognosis ^[23]

• CNS hemangioblastoma is the main cause of death.
• Average life expectancy: 60 years for women and 67 years for men

Epidemiology

• Incidence: ∼ 1:50,000 ^[24]

Etiology

• Congenital noninherited developmental anomaly of neural crest derivatives

Pathophysiology

• Somatic mosaic mutation of GNAQ gene
• Gain-of-function mutation in one copy of gene → malformation of capillaries

Clinical features ^[25]

Vascular malformations involving the following:

• Skin: port-wine stain (nevus flammeus)
  • Nonneoplastic birthmark
  • Commonly seen in the CN V1 and CN V2 dermatomes of the face
  • Typically unilateral
• CNS
  • Leptomeningeal angioma: benign vascular tumor involving the arachnoid and pia mater (leptomeninges)
    • Ipsilateral to port-wine stain
    • Commonly involves the parietal or occipital lobes
    • Atrophy and calcifications in the cerebral cortex underlying the tumor
  • Seizures/epilepsy
  • Intellectual disability
  • Recurrent stroke-like episodes: manifests with hemianopia or hemiparesis
• Eye: episcleral angioma, causing ↑ IOP and early-onset glaucoma ^[26]

SSTURGGE-Weber: Sporadic, port-wine Stain, Tram-Track calcifications, Unilateral, Recurrent strokes or seizures, Glaucoma, GNAQ gene, Epilepsy.

Diagnostics

• Eye exam: IOP measurement to rule out glaucoma
• EEG: to detect seizure activity
• Imaging
  • CT or skull radiograph: gyriform, curvilinear, parallel opacities with a tram-track appearance
  • MRI of the brain with contrast: enhancement of leptomeningeal angiomas
  • Angiography: to detect abnormal vessel structure
• Genetic testing: mutation in GNAQ gene
• CSF analysis: elevated protein in case of secondary microhemorrhage

Differential diagnosis

• Port-wine stain: Klippel Trenaunay syndrome

Treatment

• Seizure control: anticonvulsants or surgery
• Glaucoma management: See “Treatment” in glaucoma.
• Pulsed laser therapy for removal of port-wine stain
• Low-dose aspirin to prevent stroke-like episodes ^[27]

Prognosis ^[28][29]

• Severity of the disease depends on:
  • Extent of skin and brain involvement
  • Age of onset of seizures
• Life expectancy is normal.

Epidemiology

• Incidence is 1:100,000 ^[30]

Etiology

• Autosomal recessive inheritance

Pathophysiology

• ATM gene mutation → defective dsDNA break repair → accumulation of mutations → tumor development and immunodeficiency (combined B and T cell immunodeficiency)

Clinical features ^[31]

• Neurological features
  • Cerebellar involvement
    • Age of onset: 6–18 months
    • Atrophy of the cerebellar vermis and hemispheres
    • Symptoms
      • Truncal swaying
      • Gait ataxia
      • Dyssynergia
      • Muscle hypotonia
      • Sudden falls
  • Movement abnormalities
    • Chorea
    • Athetosis
    • Dystonia
    • Myoclonic jerks
  • Eye involvement
    • Oculomotor apraxia
    • Nystagmus
    • Strabismus
• Spider angiomas: telangiectasia that mainly involves the conjunctiva and face
• Immunodeficiency (B and T cell deficiency)
  • Manifests with recurrent sinopulmonary infections
  • Commonly associated with IgA deficiency (e.g., mucosal infection, transfusion-related anaphylaxis)
  • ↑ AFP
• Increased risk of malignancy
  • Lymphoma
  • Leukemia
  • Gastric carcinoma

The 4 A's of ataxia telangiectasia: ATM gene, Ataxia, spider Angiomas, and IgA deficiency.

Avoid x-ray exposure because of high sensitivity to radiation and increased risk of malignancy.

Diagnostics

• Serology
  • ↑ AFP ^[32][33]
  • ↓ IgA, IgG, and IgE
  • Lymphopenia
• Genetic testing: mutation of ATM gene
• Contrast MRI: may show cerebellar atrophy

Differential diagnosis ^[31]

• Cerebral palsy
• Friedreich ataxia
• Ataxia-telangiectasia-like-disorder type 2
• Ataxia with oculomotor apraxia type 1
• Ataxia with oculomotor apraxia type 2
• RIDDLE syndrome
• Niemann-Pick disease
• Gaucher disease

Treatment

• Antibiotic therapy: for acute infection and/or prophylaxis
• IV immunoglobulin therapy, depending on the severity of Ig deficiency

Prognosis

• Variable rate of progression
• Affected individuals typically require a wheelchair by adolescence.
• Malignancy is the most common cause of death. ^[34]
• Average life expectancy: 25 years of age ^[35]