Cafe Au Lait patches

• tan/light brown macules/patches with well defined borders
• pathogic if > 3cm or > 6 on body
• 19% of normal children have 1 cafe au lait spot
• Smooth borders, 'coast of california': neurofibromatosis
• Irregular borders, 'coast of maine': McCune albright

Neurofibromatosis- 1 aka von Recklinghausen's disease

(Chrom 17 - 17 letters in neurofibromatosis; and also in 'von recklinghausens' dz of bone)

1. Most common of the neurocutaneous syndromes (1/3000)
2. AD inheritance (50%) with full penetrance
3. Sporadic occurrence (50%)
4. Males = females
5. Gene localized to chromosome 17
6. Diagnosis made if meets 2 of the 7 criteria

NF COLOR

• autosomal dominant; Chrom 17, defect in neurofibromin, a tumor suppressor gene. 50% new mutations. 95% of patients with clinical features of NF-1 have this mutation.
• **Some patients who have café au lait spots, axillary freckling, macrocephaly and suspected to have NF-1 have no identifiable mutations in the neurofibromin gene, but have mutations for SPRED-1. (1)
• N- neurofibromas:  small skin colored nodules are multiple solitary. Need 2 or more neurofibromas or one plexiform neurofibroma; may be present at birth or may not appear until adolescence; normally, cutaneous neurofibromas do not develop until preadolescence
  • Plexiform neurofibroma occurs in only 5 percent of patients with NF1. Characteristics:
  • A nerve that has become thick and misshapen due to the abnormal growth of cells and tissues that cover the nerve
  • diffuse, elongated fibromas coursing along the nerves.
  • frequently involve the trigeminal or upper cervical nerves.
  • often appear within the first 2 years of life
  • two types of plexiform neurofibromas, nodular and diffuse
  • Diffuse plexiform neurofibroma, also known as elephantiasis neurofibromatosa has an overgrowth of epidermal and subcutaneous tissue associated with a wrinkled and pendulous appearance.
• F- freckling: groin or axillary (Crowe's sign)
• C- cafe-au-lait spots: need 6 more more, criteria varie by puberty: Prepubertal= >5 mm/ Postpubertal= >15mm (10% of normal population have </=4); 90% of NF have cafe au lait patches. The edges are smooth, aka "coast of california" vs coast of maine in McCune albright.
• O- osseus deformities, i.e pseudoarthrosis of tibia or clavicle, sphenoid winging/dysplasia (can have pulsating exophthalmos, cortical thinning- found in 51% of pts. Cortical thinning + pseudoarthrosis of the tibia = anterior bowing.
• L- Lisch nodules: iris hamartomas- found in 90% of pts >6 yrs old
• O- optic glioma
• R- relatives: family history of first-degree relative: helps in remembering that this is inherited in an Autosomal Dominant fashion; +family hx in 50% of cases

Dx= 2 criteria met
Associated concerns to consider:

• Neurologic complications, macrocephaly, epilepsy (10%) , cerebral artery dysplasia,
• Psychologic disturbances; learning/behaviour problems
• Precocious puberty: can be due to lesions of the optic chiasm and hypothalamus
• Hypertension due to renal artery dysplasia w/ stenosis, pheochromocytoma (if hypertensive, do renal arteriogram)
• Glaucoma
• 5% risk of malignancy:
  • CNS tumors, such as optic gliomas, meningiomas, astrocytomas, among others
  • neurofibrosarcoma (Nerve sheath tumor)
  • pheochromocytoma (adults, watch for HTN)
  • leukemia
  • wilms

Tuberous Sclerosis (Autosomal dominant, chrom 9)

• Prominent features: seizures (95%), MR (60%), intracranial calcification (50%); autism, tumors of various organs, cutaneous lesions
• Autosomal dominent with variable penetrance; chrom 9 and 16
  • Chrom 9: TSC-1 gene codes for hamartin
  • Chrom 16: TSC-2 gene codes for tuberin
• No cafe-au-lait spots
• The diagnosis is based on meeting criteria falling into major and/or minor criteria:

DIAGNOSIS:

• Definite= either 2 major, or 1 major and 2 minors
• Probable= 1 major and 1 minor
• Possible= 1 major
• Possible=  2 or more minors

Major:

1. Facial angiofibromas (adeoma sebaceum) appear in childhood.
2. Nail: Nontraumatic ungual or periungual fibroma
3. Ash leaf spots (>3): white, hypopigmented macules (thumb or leaf shaped), may be >100, anywhere, often on trunk/buttocks. Hard to see in light skinned infants. Look closely. Can use a woods/UV lamp. These are usually the first lesions to appear.
4. Shagreen patch (connective tissue nevus), especially in lumbosacral region

'Masses: nodules and -oma's' (7)

• 3 in the brain:
  1. Cortical tuber
  2. Subependymal nodule (benign tumors growing into the ventricles)
  3. Subependymal giant cell astrocytoma
• Multiple retinal nodular hamartomas (retinal phakomas)
• Cardiac rhabdomyoma- single or multiple, benign
• Lymphangiomyomatosis
• Renal angiomyolipoma

Minor:

• Multiple randomly distributed pits in dental enamel
• Hamartomatous rectal polyps
• Bone cysts
• Cerebral white matter migration lines
• Gingival fibromas
• Nonrenal hamartoma
• Multiple renal cysts, can mimic ADPKD
• "confetti"-skin lesions

There are great pictures in Zitelli of each of these diagnostic characteristics (too big a file to add to the e-mail).  There are other neurocutaneous syndromes that you need to consider  when presented with a patient with neurologic symptoms, intracranial lesions, cutaneous abnormalities, mental retardation or developmental delay.

CHLA Chief Resident Pearl Jan 2005
CHLA Board Review 2005

Sturge-Weber Syndrome, Port Wine Stain, Kasabach-Merritt, Klippel-Trenaunay-Weber, type-1 (NF-1), tuberous sclerosis)

1. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Brems H; Chmara M; Sahbatou M; Denayer E; Taniguchi K; Kato R; Somers R; Messiaen L; De Schepper S; Fryns JP; Cools J; Marynen P; Thomas G; Yoshimura A; Legius E.  Nat Genet. 2007 Sep;39(9):1120-6. Epub 2007 Aug 19. Abstract: We report germline loss-of-function mutations in SPRED1 in a newly identified autosomal dominant human disorder. SPRED1 is a member of the SPROUTY/SPRED family of proteins that act as negative regulators of RAS->RAF interaction and mitogen-activated protein kinase (MAPK) signaling. The clinical features of the reported disorder resemble those of neurofibromatosis type 1 and consist of multiple cafe-au-lait spots, axillary freckling and macrocephaly. Melanocytes from a cafe-au-lait spot showed, in addition to the germline SPRED1 mutation, an acquired somatic mutation in the wild-type SPRED1 allele, indicating that complete SPRED1 inactivation is needed to generate a cafe-au-lait spot in this syndrome. This disorder is yet another member of the recently characterized group of phenotypically overlapping syndromes caused by mutations in the genes encoding key components of the RAS-MAPK pathway. To our knowledge, this is the first report of mutations in the SPRY (SPROUTY)/SPRED family of genes in human disease.