Neurofibromatosis & Tuberous Sclerosis Complex

• Neurofibromatosis (NF) and tuberous sclerosis complex (TSC) are neurocutaneous disorders, or phakomatoses.
• Characterized by cutaneous lesions plus peripheral and/or central nervous system neoplasms.
• Like most hereditary cancer syndromes, both are autosomal dominant.
• Despite high penetrance, new cases of NF1 and TSC frequently represent de novo mutations.
• Pleiotropic nature has led to complex classification/diagnostic schemes.
• Dermatologists are frequently involved in clinical diagnosis due to early cutaneous (especially pigmentary) findings.
• In 1982, Riccardi proposed a classification scheme for NF with seven subtypes.
• Molecular elucidation has refined categorization into: NF1, NF2, mosaic/segmental NF1 (formerly NF5), and "NF1-like" syndromes.
• NF1 has the most well-characterized and diagnostic skin findings and is the chapter's main focus.

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• Synonym: von Recklinghausen disease

• Autosomal dominant disorder with incidence ~1 in 2000–3000 births.
• Characteristic clinical features: café-au-lait macules (CALMs), neurofibromas, freckling in axillae and groin, Lisch nodules, and bony defects.
• Nevus anemicus is another common early finding.
• Increased risk of juvenile xanthogranulomas, juvenile myelomonocytic leukemia, and extracutaneous tumors including optic pathway gliomas, malignant peripheral nerve sheath tumors, pheochromocytomas, and other CNS tumors.
• Up to 50% of NF1 patients have a new spontaneous mutation rather than an inherited one.
• Protein product of NF1 (neurofibromin) negatively regulates RAS signaling.
• Other well-characterized forms: mosaic/segmental NF1 and NF2 (vestibular schwannomas).

• NF1-affected individuals described throughout history.
• 1882: von Recklinghausen provided first in-depth report of clinical/pathologic nature of neurofibromas.
• ~50 years later: Viennese ophthalmologist Lisch described iris nodules.
• Mid-20th century: Crowe, Schull, and Neel compiled a landmark monograph comprehensively describing NF manifestations.

• NF1 occurs worldwide.
• Incidence ~1 in 2000 to 3000 births.

• Autosomal dominant inheritance.
• 30%–50% of patients have no affected relatives (likely new spontaneous mutations).
• Possibility of germline mosaicism in a parent, especially with two affected siblings and no prior family history.
• Penetrance approaches 100% in carefully examined adults; expressivity is variable.
• Same underlying mutation can produce a wide range of clinical findings — specific mutation is not the sole determinant of phenotype.
• 1987: international consortium found linkage to pericentromeric region of chromosome 17.
• Balanced translocations involving 17q11.2 in two NF1 patients further refined locus position → led to cloning of the NF1 gene.
• NF1 gene encodes neurofibromin: 327 kDa protein, 2818 amino acids, ≥59 exons.
• >80% of NF1 patients have a mutation predicting truncation of neurofibromin.
• ~5% have a large deletion ("microdeletion") encompassing the entire NF1 gene plus variable flanking genes.
• Usually no clear genotype-phenotype correlation, with exceptions:

1. Single amino acid deletion p.Met922del and missense mutations affecting p.Met1149 or p.Arg1809: associated with absence of neurofibromas; latter two also with a Noonan syndrome-like phenotype.
2. p.Arg1276 or p.Lys1423: associated with cardiovascular abnormalities, Noonan syndrome-like phenotype, and (for p.Arg1276) symptomatic spinal neurofibromas.
3. Missense mutations in NF1 codons 844–848: higher likelihood of major plexiform neurofibromas, symptomatic spinal neurofibromas, optic gliomas, skeletal abnormalities, and malignancies.
4. Recurrent 1.4-megabase pair deletion ("type 1 microdeletion"): more severe phenotype — earlier onset and larger number of neurofibromas, increased risk of MPNST, intellectual disability, facial dysmorphism, overgrowth, connective tissue dysplasia (hyperextensible skin, joint laxity), and cardiac defects.

• Neurofibromin has sequence similarity (central 300–400 amino acid domain) to GTPase-activating proteins (GAPs) → negatively regulates the RAS–MAPK pathway that promotes cell survival/proliferation.
• RAS activity (like all G proteins) requires GTP; neurofibromin/GAPs accelerate hydrolysis of GTP→GDP, terminating RAS signal (tumor suppressor function).
• Neurofibromin also associates with microtubules (consequences unclear).
• As in other AD genodermatoses caused by defective tumor suppressor genes (e.g. basal cell nevus syndrome), a somatic "second-hit" mutation causing loss of heterozygosity (LOH) occurs in skin lesions.
• Biallelic NF1 inactivation found in Schwann cells of neurofibromas and melanocytes of CALMs.
• Mouse model: Nf1 nullizygosity (Nf1−/−) in Schwann cells is necessary but not sufficient for neurofibroma formation.
• Plexiform neurofibromas arose from Nf1−/− Schwann cells only when microenvironment included Nf1+/− mast cells (not wild-type).
• Mast cells appear early in neurofibroma development, are hypermotile in response to KIT ligand (stem cell factor) oversecreted by Nf1−/− Schwann cells.
• Recruited mast cells produce growth factors promoting neurofibroma tumorigenesis.
• Genetic or pharmacologic attenuation of KIT signaling in Nf1+/− mast cells diminishes neurofibroma initiation/progression (relevant to imatinib therapy).

• Myriad and variable frequency; almost every organ system can be involved → wide range of morbidity/mortality.
• Cutaneous manifestations are central to diagnosis.

Oculocutaneous manifestations

• Café-au-lait macules (CALMs): tan to dark brown, uniformly pigmented macules/patches, randomly distributed (except scalp, palms, soles).
• Sharply demarcated, regular borders, often oval shape.
• Diameter: few mm to >4 cm.
• May not be apparent at birth; often more noticeable during first year of life; may fade in later adulthood.
• When within areas of dermal melanocytosis, may be surrounded by a rim of normally pigmented skin (see Ch. 112).
• Larger CALMs, especially with hypertrichosis, should be palpated to exclude underlying plexiform neurofibroma.
• Crowe et al.: 10% of normal population has 1–5 CALMs.
• Burwell et al.: 26% of 732 White schoolchildren had ≥1 CALM >1 cm; ≥6 CALMs found in only 3 children (0.4%) — siblings with a parent with NF1.
• Clinical diagnosis requires a minimum of six CALMs for specificity.
• To avoid confusion with lentigines: CALMs must be >5 mm in prepubertal and >15 mm in postpubertal individuals to satisfy the diagnostic criterion.
• "Freckling" (Crowe sign) in axillae/groin: first noted by Crowe.
• Numerous 1–3 mm brown macules (more akin to lentigines than ephelides), populate intertriginous zones, neck, occasionally most of skin surface.
• Axillary involvement most common (~80% of NF1 patients).
• Usually arises by 4–6 years of age, after CALMs but before neurofibromas.
• Useful clinical sign in evaluating a young child with multiple CALMs.
• Neurofibromas: in fullest expression, thousands may occur (hence "neurofibromatosis").
• Cutaneous neurofibromas (CNFs): most common; proliferations of spindle cells in the dermis.
• Skin-colored to pink, tan, or brown papulonodules, soft/slightly rubbery, few mm to several cm.
• Dome-shaped or pedunculated when fully formed; early lesions barely elevated.
• Invaginate easily with gentle pressure — pathognomonic "buttonhole" sign.
• Usually asymptomatic; occasionally pruritic or irritated.
• Appear as early as 4–5 years of age but more typically develop around puberty; occasional acceleration during pregnancy.
• Subcutaneous neurofibromas (SNFs): deeper in dermis/subcutis, firmer, less well-circumscribed.
• Nearly one-fifth of NF1 patients have ≥1 SNF; one-quarter of these develop tumor-related local complications.
• Less common cutaneous presentations:

1. Blue–red macules due to thick-walled blood vessels plus neurofibromatous tissue in papillary dermis.
2. Pseudo-atrophic macules due to replacement of reticular dermis collagen with neurofibromatous tissue.

• Plexiform neurofibromas (PNFs): track along nerves → tender, firm nodules/masses with "bag of worms" consistency, or diffusely infiltrate skin/fascia/muscle/internal structures.
• ~25% of NF1 patients have clinically apparent PNFs.
• Larger lesions cause soft tissue/bony hypertrophy; massive distortion of head/neck or extremities possible.
• Impingement on nerves → neurologic deficits; (peri)orbital PNFs → visual loss and facial deformity.
• PNFs are probably all congenital in origin.
• Superficial/diffuse lesions usually apparent by age 4–5 years; deep/internal nodular lesions may remain undetected into adulthood unless full-body MRI performed.
• Older children without soft tissue overgrowth from a PNF are unlikely to develop this finding later.
• Hyperpigmentation and hypertrichosis can overlie PNFs, sometimes mimicking congenital melanocytic nevus.
• Malignant peripheral nerve sheath tumors (MPNSTs, "neurofibrosarcomas"): transformation of PNFs occurs in 8%–15% of NF1 patients; peak incidence in young adults.
• Warning signs: rapid growth, increased firmness, persistent pain within an established PNF, or new neurologic deficit.
• MPNSTs can be very aggressive and are often fatal.
• Juvenile xanthogranulomas (JXGs): up to 15%–35% of children with NF1 develop ≥1 during first 2–3 years of life — potential early sign of NF1 when coexisting with multiple CALMs.
• Juvenile myelomonocytic leukemia (JMML): young children with NF1 have 200- to 500-fold greater risk than general pediatric population (incidence 1/2000–1/5000).
• "Triple association" of NF1, JMML, and JXG described; magnitude of additional JMML risk with NF1+JXG vs NF1 alone remains undetermined.
• Neurofibromin regulates myeloid cell proliferation; exact etiopathogenesis of "triple association" unclear.
• Vascular anomalies: nevus anemicus and glomus tumors.
• Nevus anemicus: identified in 55% (92/166) of children and 36% (19/53) of adults with NF1 vs only 2% (6/302) of matched controls (two prospective studies).
• Favors trunk (especially mid chest); more evident after rubbing skin.
• Prevalent and apparent by early childhood — proposed but not yet adopted as diagnostic criterion.
• Glomus tumors: biallelic NF1 inactivation documented within these tumors.
• Often multiple; fingers > toes; paroxysmal pain, cold sensitivity (see Ch. 114).
• Focal swelling, ill-defined reddish discoloration (often of nail bed), nail dystrophy may be observed.
• Lisch nodules (pigmented iris hamartomas): begin ~3 years of age; found in ~90% of NF1 patients by 20 years of age.
• 1–2 mm, dome-shaped, yellow–brown papules; best seen on slit-lamp exam.
• Rarely cause symptoms/complications.
• Choroidal nodules (asymptomatic): present in 80%–100% of adults and 60%–70% of children with NF1 — added to revised diagnostic criteria.
• Near-infrared reflectance imaging required for detection may be technically challenging in younger children.
• Mosaic (segmental) NF1 (formerly NF5): CALMs, freckling, and/or neurofibromas in mosaic distribution patterns (blocks with midline demarcation, often with relative hyperpigmentation of background).
• Results from postzygotic NF1 mutation.
• Up to 30% of patients also have extracutaneous manifestations of NF1.
• If mutation involves gonads (germline mosaicism) as well as skin, chance of full-blown NF1 in offspring.

Major Clinical Features of NF1

• Cutaneous
• Neurofibromas (60%–90%)
• Café-au-lait macules (>90%)
• Axillary and/or inguinal freckling (~80%)
• Plexiform neurofibroma (25%; up to 50% with detection via whole-body MRI)
• Nevus anemicus (30%–50%)
• Juvenile xanthogranuloma (15%–35% in first 3 years of life)
• Ocular
• Lisch nodules (~90% by 20 years of age)
• Choroidal abnormalities (>80% of adults, 60%–70% of children)
• Neovascular glaucoma, retinal vasoproliferative tumors
• Skeletal — Cranial
• Macrocephaly (20%–50%)
• Hypertelorism (25%)
• Sphenoid wing dysplasia (<5%)
• Skeletal — Spinal
• Scoliosis (5%–10%)
• Spina bifida
• Skeletal — Limbs
• Dysplasia of long bone cortex (5%), pseudarthrosis (2%)
• Skeletal — Other
• Generalized osteopenia (~50%), osteoporosis (~20%)
• Short stature (~30% <3rd percentile)
• Pectus deformity (30%–50%)
• Tumors
• Optic pathway glioma (15%–20% of children) (± precocious puberty)
• Malignant peripheral nerve sheath tumors (3%–15%)
• Pheochromocytoma (~1%)
• Juvenile myelomonocytic leukemia
• CNS tumors other than optic pathway gliomas (~5%)
• Rhabdomyosarcoma, especially of the genitourinary tract
• Duodenal carcinoid
• Somatostatinoma
• Parathyroid adenoma
• Gastrointestinal stromal tumors (GIST)
• Breast cancer (~5- and ~10-fold increased risk in women <50 and <40 years of age, respectively)
• Neurologic
• T2 hyperintensities on brain MRI (50%–75%)
• Learning difficulties (30%–50%)
• Seizures (~5%)
• Intellectual impairment (severe in <5%)
• Aqueductal stenosis and hydrocephalus (~2%)
• Cardiovascular
• Hypertension (~30%): essential > renal artery stenosis or pheochromocytoma
• Pulmonic stenosis (~1%)
• Renal artery stenosis (~2%)
• Cerebrovascular anomalies (2%–5%), including vascular stenoses and aneurysms

Diagnostic Criteria — Revised Diagnostic Criteria for NF1 and Mosaic NF1

• Diagnostic criteria for NF1: requires two or more of the following in an individual without a parent diagnosed with NF1, and one or more in an individual with a parent diagnosed with NF1:
• Six or more café-au-lait macules >5 mm in prepubertal individuals and >15 mm in postpubertal individuals*
• "Freckling" in the axillary or inguinal region*
• Two or more neurofibromas of any type or one plexiform neurofibroma
• Optic pathway glioma
• Two or more Lisch nodules (iris hamartomas) or two or more choroidal abnormalities†
• A distinctive osseous lesion such as sphenoid dysplasia, anterolateral bowing of the tibia, or pseudoarthrosis of a long bone
• A heterozygous pathogenic NF1 variant with a variant allele fraction of 50% in apparently normal tissue (e.g. white blood cells)
• Diagnostic criteria for mosaic NF1: requires any of the following in an individual without a parent diagnosed with NF1:
• A heterozygous pathogenic NF1 variant with a variant allele fraction significantly <50% in apparently normal tissue AND one of the other NF1 criteria above
• An identical heterozygous pathogenic NF1 variant in two anatomically independent affected tissues, in the absence of a pathogenic NF1 variant in unaffected tissue
• A clearly segmental distribution of CALMs or cutaneous neurofibromas AND either another NF1 criterion‡ or offspring diagnosed with NF1
• One of the clinical NF1 criteria above other than CALMs AND offspring diagnosed with NF1
• *If only CALMs and freckling are present, at least one should be bilateral; diagnosis is most likely NF1 but may rarely be another condition such as Legius syndrome.
• †Defined as bright, patchy nodules imaged by optical coherence tomography/near-infrared reflectance imaging.
• ‡If only CALMs and freckling present, diagnosis is most likely mosaic NF1 but may rarely be mosaic Legius syndrome or constitutional mismatch repair deficiency syndrome.

Disorders Associated with Multiple Café-au-Lait Macules (CALMs)

• Neurofibromatosis and related disorders
• NF1: AD; six or more CALMs in >90% of patients; mutations in NF1 gene.
• NF2: AD; six or more CALMs in minority of patients; mutations in NF2 gene.
• Mosaic (segmental) NF1 (formerly NF5): neurofibromas alone or CALMs ± freckling in block-like/mosaic pattern; postzygotic NF1 mutation, may involve gonads.
• Legius syndrome: AD; six or more CALMs in >80%, intertriginous freckling in ~50%; lack neurofibromas, Lisch nodules, optic pathway gliomas, typical osseous lesions of NF1; macrocephaly and learning disabilities common; lipomas, hypopigmented macules, vascular anomalies in minority; loss-of-function mutations in SPRED1 gene (inhibits MAPK signaling).
• Watson syndrome: AD; short stature; pulmonic stenosis; ID; may have Lisch nodules, axillary/inguinal freckling, neurofibromas; allelic with NF1; 60/100 CALM prevalence.
• Jaffe–Campanacci syndrome: AD; disseminated non-ossifying fibromas of long and jaw bones; hypogonadism or cryptorchidism; ID; giant cell granulomas (jaws); usually due to NF1 mutation.
• Noonan syndrome: AD; short stature; pterygium colli; characteristic facies; cardiac defects (esp. pulmonic valve stenosis); skeletal and testicular abnormalities; keratosis pilaris atrophicans; lymphedema; melanocytic nevi; activating mutations in PTPN11 > SOS1, RAF1, RIT1 > KRAS, NRAS, MAP2K1, LZTR1, SHOC2 (with loose anagen hair); NF1–Noonan overlap phenotype may have NF1 mutations.
• Noonan syndrome with multiple lentigines (LEOPARD syndrome): AD; darker "café noir" macules; Lentigines, ECG abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth, Deafness; mutations in PTPN11; 38/100 CALM prevalence.
• Cardio-facio-cutaneous syndrome: AD; short stature; characteristic facies; low-set ears; cardiac defects; ID; sparse curly hair; dry skin to generalized ichthyosiform eruption; activating mutations in MAPK pathway genes — BRAF > MEK1, MEK2 > KRAS.
• Constitutional mismatch repair deficiency syndrome (formerly Turcot syndrome type 1): AR; multiple CALMs ± axillary freckling, neurofibromas and/or CNS gliomas (features of NF1) plus hypopigmented macules, pilomatricomas, hematologic malignancies, colorectal carcinoma; NF1-like skin findings often mosaic; biallelic mutations in DNA mismatch repair gene (PMS2 > MSH6 > MLH1, MSH2) with microsatellite instability; HNPCC (Lynch) syndrome in heterozygotes.
• McCune–Albright syndrome: sporadic, presumably lethal unless mosaic; polyostotic fibrous dysplasia; endocrine hyperfunction (esp. gonads, e.g. precocious puberty); CALMs apparent in infancy, often several shades darker with irregular borders, classically end at midline, may follow lines of Blaschko in broad bands; activating mutations in GNAS1 (encodes Gsα); 35/100 CALM prevalence.
• Other disorders
• Tuberous sclerosis complex (TSC): AD; ID; seizures; hypopigmented macules; angiofibromas; fibrous plaques; mutations in TSC1 and TSC2.
• Piebaldism: AD; CALMs in involved as well as uninvolved skin; mutations in KIT proto-oncogene.
• Familial progressive hyper- and hypopigmentation: AD; CALMs of variable sizes admixed/overlapping with lentigines and hypopigmented macules/patches; activating mutations in KITLG gene.
• Westerhof syndrome: AD; congenital hypo- and hyperpigmented macules; ID; growth retardation.
• Carney complex (NAME and LAMB syndromes): AD; darker "café-noir" macules, lentigines, blue nevi; cutaneous and atrial myxomas; endocrine neoplasia of adrenal glands, pituitary gland, and/or testes; mutations in PRKAR1A.
• Partial unilateral lentiginosis: unilateral agminated lentigines; unilateral CALMs may be present; debatable neurologic/psychiatric associations; possible relationship to mosaic NF1.
• Bannayan–Riley–Ruvalcaba syndrome (overlapping with Cowden as PTEN hamartoma tumor syndrome): AD; penile lentigines; vascular malformations; lipomas; intestinal hamartomas; macrocephaly; mutations in PTEN gene; ≤10% have CALMs.
• Cowden syndrome: AD; multiple tricholemmomas; cobblestoning of oral mucosa; palmoplantar keratoses; sclerotic fibromas, hamartomas, carcinoma of breast/thyroid/genitourinary/colon; mutations in PTEN gene; ≤10% have CALMs.
• Ataxia–telangiectasia: AR; telangiectasias of conjunctivae, head/neck, acral sites; premature canities; cerebellar ataxia; abnormal DNA repair; lymphomas and leukemias; immunodeficiency; sinopulmonary infections; mutations in ATM gene; 20/100 CALM prevalence.
• Bloom syndrome: AR; telangiectatic erythema of face; photosensitivity; growth retardation; increased sister chromatid exchanges; malignancies; hypogonadism; mutations in BLM gene (RecQ protein-like-3 DNA helicase).
• Fanconi anemia: AR; generalized hyperpigmentation, esp. flexural ± guttate hypopigmented macules; pancytopenia; skeletal malformations (e.g. aplasia radii); chromosomal fragility and malignancies (e.g. AML); see Table 67.10.
• Mosaic chromosomal anomalies: particularly ring chromosomes (7, 11, 12, 15, 17); rearrangements of 7 and 14; ring 7 also associated with vascular lesions (hemangiomas, capillary malformations) and congenital melanocytic nevi.
• Extensive epidermal and sebaceous nevi: mosaic; "syndrome" includes seizures, ID, musculoskeletal and ocular abnormalities; hypophosphatemic vitamin D-resistant rickets; see Table 62.6 for genes.
• Multiple endocrine neoplasia 1 (MEN1): AD; tumors of pituitary, parathyroid, pancreatic islet cells; multiple facial angiofibromas, collagenomas, gingival papules, confetti-like hypomelanotic macules, lipomas; MEN1 gene.
• Multiple endocrine neoplasia 2B (MEN2B): AD; mucosal neuromas; marfanoid habitus; medullary thyroid carcinoma; intestinal ganglioneuromatosis; pheochromocytoma; mutations in RET proto-oncogene.
• Silver–Russell syndrome: growth retardation; triangular face; clinodactyly 5th finger; hemihypertrophy; epigenetic changes on chromosome 15p13 or maternal uniparental disomy of chromosome 7; 45/100 CALM prevalence.
• Tricho-hepato-enteric syndrome: AR; CALM and lentigines on hips and legs; diffuse pigmentary dilution (skin and hair), woolly hair; dysmorphic facies with hypertelorism; intractable diarrhea, liver disease; immune deficiency; mutations in TTC37 or SKIV2L.
• Tay syndrome (single family): ?AR; growth retardation; ID; triangular face; cirrhosis; trident hands; premature canities; vitiligo.
• Gastrocutaneous syndrome (single family): AD; multiple lentigines; peptic ulcer/hiatal hernia; hypertelorism; myopia.
• Mukamel syndrome: AR; premature graying (infancy); lentigines; depigmented macules; ID; spastic paraparesis, microcephaly, scoliosis.
• Johnson–McMillin syndrome: probable AD; alopecia; anosmia; deafness; hypogonadism; microtia.
• Single case reports of multiple CALMs also associated with X-linked hypohidrotic ectodermal dysplasia, woolly hair, and osteoma cutis.
• Multiple CALMs may also be seen in patients with segmental pigmentation disorder (see Ch. 67).

Neurologic manifestations

• Optic pathway gliomas: occur in 15%–20% of children with NF1, usually before 10 years of age, leading to symptoms in 30%–50% of affected individuals.
• Behavior variable: spontaneous regression to progressive visual compromise and proptosis from tumor expansion.
• Precocious puberty occurs in ~3% of children with NF1, typically associated with an optic pathway glioma.
• Non-optic CNS tumors occur in ~5%; pheochromocytomas in ~1% of NF1 patients.
• T2 hyperintensities ("unidentified bright objects") on T2-weighted brain MRI: 50%–75% of children with NF1.
• Most commonly in basal ganglia, brainstem, cerebellum.
• Evolve over time; may contribute to cognitive impairment via thalamocortical dysfunction.
• Severe intellectual impairment uncommon; learning difficulties in 30%–50% of affected children; increased likelihood of ADD, headaches, sleep disturbances.
• Seizures develop in ~5% of NF1 patients; no specific cortical lesions linked to abnormal EEG activity.

Skeletal manifestations

• Macrocephaly, hypertelorism, and scoliosis are common cranioskeletal abnormalities.
• Osteopenia: frequent finding — potential factors include vitamin D deficiency and increased bone turnover.
• Pseudarthrosis of long bones (most often tibia): highly distinctive but less common; begins as bowing, progresses to erosion of bone cortex, pathologic fractures, false joint formation.
• Sphenoid wing dysplasia: congenital, typically unilateral bony defect in posterior orbital wall, may present as pulsating exophthalmos.

Cardiovascular manifestations

• Hypertension common: essential hypertension most frequent; renovascular stenosis (especially in children) and unsuspected pheochromocytomas may be causes.
• Other manifestations listed in Table 61.1.

Timing of onset of clinical manifestations

• Prevalence of features evolves over first two decades of life.
• PNFs and skeletal defects: probably congenital.
• CALMs and nevus anemicus: evident at birth or apparent during first few years of life.
• Intertriginous freckling, Lisch nodules, optic pathway gliomas: usually by school-age years.
• Multiple CNFs: typically start closer to puberty.
• Diagnosis via classic clinical criteria (excluding genetic testing) established in 97% of affected individuals by age 8 years and 100% by age 20 years.

• CALMs, CNFs, and MPNSTs histologically similar to sporadic counterparts.
• CALMs: increased epidermal melanin; nonspecific findings may include giant melanosomes and higher melanocyte number vs surrounding skin.
• CNFs: well-circumscribed but unencapsulated dermal collection of small nerve fibers and loosely arranged spindle cells (scanty pale cytoplasm, elongated wavy nuclei) — mixture of fibroblasts, Schwann cells, perineural cells in collagenous stroma with variable mucin and scattered mast cells; bland nuclei; mitotic activity should raise suspicion of malignancy.
• PNFs: specific to NF1; large hypertrophied nerves surrounded by spindle-shaped fibroblasts/Schwann cells in myxoid matrix, plexiform growth pattern; may extend diffusely into papillary/reticular dermis; stroma may be more collagenous than myxoid; organoid differentiation may form Meissner corpuscle-like structures.
• MPNSTs: tight intersecting bundles of spindle cells; alternating cellular and myxoid areas; S100 positive but more pleomorphic with wavy hyperchromatic nuclei; increased mitotic activity; perivascular whorling; areas of bony/cartilaginous differentiation, hyalinized nodules may be present.

• In complete expression, classic clinical criteria are met and diagnosis is straightforward.
• In infants, diagnosis can be difficult because age-dependent features have not yet developed.
• Revised diagnostic criteria incorporate genetic testing, update clinical features (addition of choroidal abnormalities), and emphasize distinction from mosaic NF1 and overlapping conditions (e.g. Legius syndrome).
• Approach to children with multiple CALMs:
• Series of 110 children (median age 3 years; range 1 month–17 years) presenting with CALMs but no other NF1 features:
• 34/44 (77%) with ≥6 "typical" CALMs (distinct regular borders, uniform pigmentation) eventually met NF1 criteria (almost all before age 6 years).
• 2/15 (15%) with ≥6 "atypical" CALMs (smudgy irregular borders, non-homogeneous pigmentation).
• 0/51 with <6 CALMs.
• Comprehensive, highly sensitive NF1 molecular analysis available: targeted massively parallel/NGS, MLPA (copy number variation), and RNA-based testing.
• These techniques identify the pathogenic variant in ≥95%–98% of non-founder patients meeting classic clinical criteria.
• Can detect low-level mosaicism (down to 3%–5% variant allele frequency with NGS), deep intronic splice variants, and deletions missed by conventional genomic DNA sequencing.
• Molecular testing enables more accurate diagnosis in young children/atypical presentations, and prenatal/preimplantation diagnosis.
• Mosaic NF1: unilateral lentigines in axilla/groin may also be seen in partial unilateral lentiginosis (PUL) or a large speckled lentiginous nevus (nevus spilus).
• Segmental conditions sharply demarcated at midline, though bilateral involvement occasionally occurs.
• Presence of CALMs plus lentigines increases likelihood of NF1.
• If no detectable mutation in peripheral blood, diagnosis confirmed by analyzing NF1 in melanocytes/Schwann cells cultured from a lesional skin biopsy (CALM or neurofibroma).
• Legius syndrome: patients with familial tendency to develop multiple "typical" NF1-like CALMs (often with intertriginous freckling), without neurofibromas or Lisch nodules and no NF1 mutation.
• ~70% of such individuals have a heterozygous germline mutation inactivating SPRED1 (inhibits RAS–RAF interaction, negatively regulating MAPK signaling like neurofibromin).
• AD condition; accounts for ~2% of all patients meeting classic clinical NF1 criteria.
• Constitutional mismatch repair deficiency (CMMRD): biallelic germline mutations in a mismatch repair gene; frequently presents with multiple CALMs, sometimes with other NF1 features (intertriginous freckling, neurofibromas, gliomas).
• Often segmental/regional distribution of skin findings; postzygotic NF1 mutations documented in affected tissues.
• Additional suggestive findings: siblings but not parents with NF1 features, personal/family history of malignancies (especially Lynch syndrome-related cancers, see Ch. 63), consanguinity.
• NGS panels now available to assess NF1, SPRED1, and other "RASopathy" genes.
• NF2 historically discussed with NF1, but clinical manifestations/molecular genetics are distinct:
• Less common; lower frequency of cutaneous findings than NF1; Lisch nodules not a feature of NF2.
• Diagnosis typically rests on vestibular schwannoma.
• 1990 diagnostic criteria for NF2 included neurofibromas as an index tumor; 1997 update excluded neurofibromas from NF2 diagnostic criteria.
• Mautner et al.: 60% of NF2 patients had skin tumors, usually schwannomas (flat or spherical, nodular subcutaneous tumors of peripheral nerves on limbs/trunk).
• One-third of affected individuals in this series had CALMs; only 2/88 patients had six or more CALMs.
• In young children with NF2, schwannomas may present as hypertrichotic, slightly hyperpigmented plaques.
• McCune–Albright syndrome: CALMs present at birth or apparent during infancy; polyostotic fibrous dysplasia; endocrine hyperfunction (most commonly precocious puberty).
• Activating mutation in gene encoding Gsα → increased intracellular cAMP.
• Compared to NF1 CALMs: generally larger, linear (broad bands along lines of Blaschko) or segmental distribution, usually do not cross midline, irregular border resembling "coast of Maine."
• Most common sites: head, neck, trunk, buttocks.
• PNFs need to be distinguished from congenital melanocytic nevi (especially when hyperpigmented with hypertrichosis); avoid misdiagnosing large congenital melanocytic nevi with "satellite" lesions and prominent neurotization as NF1.

Key Features of NF2

• Autosomal dominant transmission; affects approximately 1 in 40,000 individuals.
• Approximately half of cases due to de novo mutations rather than inherited germline mutations (similar to NF1).
• Bilateral vestibular schwannomas, meningiomas, and spinal tumors.
• Two-thirds of patients develop cutaneous schwannomas; approximately 50% develop CALMs, but fewer in number compared to NF1.*
• No Lisch nodules or mental retardation/learning disabilities.
• NF2 gene located on chromosome 22q12, encodes cytoskeleton-associated protein of ~600 amino acids named merlin/neurofibromin 2, structurally related to the ERM (ezrin-radixin-moesin) protein family of membrane-cytoskeleton linkers.
• *In two large series (n=161), only two individuals had more than five CALMs of the required size to meet NF1 criteria, and over half of those with any CALMs had only one (41 of 72).

• Requires a multidisciplinary approach; multispecialty NF clinic can optimize care.
• Dermatologists often assist in establishing diagnosis in affected children.
• Evaluation of newly diagnosed individuals: thorough history (personal, family) and physical exam with attention to signs/symptoms of disease manifestations.
• Initial care should include in-depth educational discussion (natural history, possible medical complications and neurodevelopmental sequelae, psychosocial considerations) and genetic counseling.
• Goals of longitudinal care: early recognition/treatment of complications, maximization of academic/vocational achievement, minimization of psychosocial impact.

Evaluation and Management of NF1 Patients

• At the time of diagnosis and annually:
• Offer genetic testing at time of diagnosis, especially if atypical clinical features or helpful for reproductive planning.
• Dermatologic examination, especially if a PNF involves the skin.
• Surgical consultation if painful, disfiguring, or bothersome neurofibromas.
• Consider baseline MRI if deeper extension of PNF.
• Urgent PET-CT if rapid growth, increased firmness, or persistent pain within an established PNF or development of a new neurologic deficit.
• Neurologic evaluation.
• Consider baseline brain/orbital MRI in pediatric patients* (role in asymptomatic patients controversial).
• Brain/orbital and/or spinal MRI if neurologic signs/symptoms develop.
• Cardiac assessment (at initial diagnosis) and measurement of blood pressure.
• Renal MRA (or spiral CT/CT angiography if impaired renal function) and plasma free metanephrines if hypertension develops.
• Evaluation for scoliosis (via forward bend test), other skeletal abnormalities (e.g. tibial bowing), and vitamin D deficiency† (osteoporosis occurs at an earlier age in NF1 — consider DEXA based on age/risk factors).
• Referral to orthopedics and vitamin D supplementation as indicated.
• At the time of diagnosis ± annually, depending on age:
• Ophthalmologic examination with visual testing and assessment for pubertal development/accelerated linear growth (prior to puberty; consider twice yearly ophthalmologic exam until age 6 years).
• Brain/orbital MRI if signs/symptoms of optic pathway glioma.
• Neurodevelopmental/behavioral evaluation (annually only in children/adolescents).
• Measurement of head circumference (annually only in young children).
• Screening for breast cancer with clinical examination + mammography ± MRI (beginning at age 30 years).
• Potentially affected family members:
• Consider genetic testing for the mutation identified in the proband.
• Dermatologic examination for cutaneous manifestations of NF1.
• Ophthalmologic examination for Lisch nodules.
• During yearly visits, also ask about: fingertip pain from glomus tumors, other chronic pain/itch, signs/symptoms of pheochromocytoma (palpitations, sweating), and depression.
• CALMs do not need or respond well to treatment (may be desired for cosmetic purposes); laser therapy → CALMs tend to persist or recur (see Ch. 137).
• During adolescence/adulthood, removal of CNFs may be indicated for functional/cosmetic reasons.
• Simple surgical excision = treatment of choice for selected bothersome lesions.
• Laser ablation or electrocautery can remove numerous small CNFs, but recurrences common and hypertrophic scarring may develop.
• PNF surgery in early childhood: multidisciplinary teams often required to excise deep/extensive neurofibromatous tissue; lesions tend to recur following surgery.
• Lifelong surveillance for MPNST development essential, particularly for patients at increased risk due to:
• Known presence of PNFs.
• Polyneuropathy secondary to multiple nerve root tumors.
• History of radiation therapy (reports of MPNSTs arising in radiation field).
• Germline NF1 microdeletion.
• Increase in growth rate, firmness, pain, or neurologic symptoms of a PNF merits further evaluation.
• 18F-FDG PET-CT or functional MRI with DWI/ADC mapping can aid early detection of malignant transformation within PNFs and guide biopsy of suspicious areas.
• Histologic evaluation recommended for symptomatic lesions with SUVmax ≥3.5 on PET-CT with delayed imaging (4 hours after 18F-FDG injection).
• Selumetinib (MEK inhibitor): FDA approved 2020 for symptomatic, inoperable PNFs in pediatric patients (≥2 years of age) with NF1; clinical trials showed durable tumor shrinkage (median 28%).
• Selumetinib and other MEK inhibitors (e.g. trametinib) have shown clinical benefit for gliomas as well as PNFs in NF1 patients.
• Targeted therapies under investigation for PNFs and other tumors in NF1: inhibitors of KIT receptor on mast cells and other tyrosine kinases (e.g. imatinib mesylate, cabozantinib), mTOR (e.g. sirolimus), VEGFRs, and other components of the MAPK pathway as well as PI3K/AKT, JAK/STAT3, and Hippo/YAP pathways.
• Resources: Neurofibromatosis Network (www.nfnetwork.org), Neurofibromatosis Clinics Association (www.nfpittsburgh.org), Children's Tumor Foundation (www.ctf.org), Nerve Tumours UK (www.nervetumours.org.uk).

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• Synonyms: Tuberous sclerosis; Bourneville disease; Bourneville–Pringle disease; Epiloia (epilepsy, low intelligence, angiofibroma).

• Autosomal dominant disorder with incidence ~1 in 10,000 births.
• Key cutaneous features: hypopigmented macules, facial angiofibromas, collagenomas, and ungual fibromas.
• Characteristic oral findings: gingival fibromas and dental enamel pits.
• Hamartomas found in the eye and several internal organs, including brain, kidneys, heart, lungs.
• Seizures, mental deficits, and neuropsychiatric disturbances are common.
• Up to 75% of cases are due to new spontaneous mutations.
• Mutations identified in two genes: TSC1 and TSC2; protein products are hamartin and tuberin, respectively.

• AD disorder characterized by seizures, intellectual deficits, and skin findings including hypomelanotic macules and facial angiofibromas.
• As with NF1, cutaneous lesions often the initial clinical features; dermatologists routinely assist in diagnosis.

• Mid-1800s: Virchow recognized scleromas in the brain; von Recklinghausen described a similar patient with scleromas and myomata in the heart.
• 1880–1900: Bourneville provided first systematic descriptions of the disease, including neural and cutaneous findings.
• Vogt posited the classic triad of epilepsy, low intelligence, and angiofibromas (Vogt triad) in 1908.
• Sherlock coined the term "epiloia" a few years later.
• 1920: van der Hoeve described the significance of retinal hamartomas, terming them "phakomas" (hence "phakomatosis").
• At that time, examination of the ocular fundi was the only external access to the CNS before death.

• Incidence ~1 in 10,000 births.
• Overall prevalence estimated between 1 in 10,000 and 1 in 30,000.

• Hamartomatous condition with disordered cellular proliferation, migration, and differentiation.
• Autosomal dominant inheritance, but majority of affected individuals have new spontaneous mutations.
• 1980s: TSC kindreds mapped disease locus to chromosome 9q34 in a subset of affected families; second disease locus found on chromosome 16p13.
• 1994: Povey et al. studied 32 TSC families — about half linked to chromosome 9q34 (TSC1), other half to chromosome 16p13 (TSC2).
• 1993: TSC2 gene identified on chromosome 16; deleted or mutated in families linked to this region.
• TSC2: 41 exons, encodes 1807 amino acid, 200 kDa protein — tuberin.
• Tuberin contains a GAP domain.
• Tuberin stimulates GTPase activities of RAB5 (endocytosis) and RHEB (RAS-related protein that activates the mTOR pathway).
• By "turning off" RHEB, tuberin inhibits cell growth/proliferation resulting from mTOR signaling.
• mTOR is a central regulator of cellular responses to nutrition, energy levels, and growth factors.
• TSC1 gene: identified 1997; 23 exons, encodes 130 kDa protein — hamartin.
• Hamartin shares no sequence homology with tuberin or other known tumor suppressor genes.
• Hamartin interacts with tuberin and other cytoskeletal components; functions with tuberin to negatively regulate mTOR signaling.
• In TSC patients, mTOR inhibition by sirolimus (rapamycin) and related agents can have therapeutic benefit.
• In large series, TSC2 mutations identified more frequently than TSC1, overall ratio ~3:1.
• In familial cases, more equal proportion of TSC2/TSC1 mutations.
• TSC2 mutations tend to have a more severe phenotype than TSC1.
• Familial TSC due to TSC2 mutations tends to have a milder phenotype than de novo cases (likely reflects decreased reproduction likelihood in more severely affected individuals).
• Some patients with mild sporadic TSC are mosaics for a TSC1/TSC2 mutation; with gonadal involvement, may pass on generalized disease to offspring.
• Mouse models:
• Heterozygous Tsc1+/− mice: develop renal and extrarenal tumors (e.g. hepatic hemangiomas) with loss of wild-type Tsc1 allele.
• Heterozygous Tsc2+/− mice: high incidence of multiple bilateral renal cystadenomas, liver hemangiomas, lung adenomas; progression to renal carcinoma, fatal bleeding from liver hemangiomas, angiosarcomas occasionally observed.
• These mice also show abnormalities in learning/memory associated with hyperactive hippocampal mTOR signaling.
• Treatment of adult mice with sirolimus improved cognitive function.

• Diagnosis often involves a dermatologist as some of the earliest findings are cutaneous.

Oculocutaneous manifestations

• Time course for cutaneous findings shown in Fig. 61.13.
• Hypomelanotic macules: hypopigmented (not depigmented, as in vitiligo).
• Wood's lamp can help detect subtle lesions, especially in lightly pigmented children.
• Usually present at birth or within first few months of life; appearance sometimes delayed until early childhood in fair-skinned individuals.
• Multiple configurations; small (<2 cm) polygonal or "thumbprint"-shaped macules most common.
• Lance-ovate hypopigmented macule ("ash leaf spot"): rounded at one end, tapered at other; named after Eastern Mountain ash tree; 1–12 cm in size; less frequent than polygonal macules but characteristic of TSC.
• Over 90% of TSC patients have more than one hypomelanotic macule; some have >100 lesions.
• "Guttate" hypopigmented macules ("white freckles"/"confetti" macules): 1–2 mm, especially on extremities.
• Occur in <5% of affected infants but are probably the most specific pigmentary manifestation of TSC.
• ~1%–4% of healthy infants/children have a circumscribed hypopigmented macule/patch (nevus depigmentosus).
• Debard and Richardet: examined skin of 9737 infants aged 1–18 months — 0.7% had one or two white spots >1 cm; no unaffected infant had more than three spots.
• → Presence of three or more hypomelanotic macules (≥5 mm) chosen as a major diagnostic criterion.
• Clusters of scalp hair, eyebrows, or eyelashes may be lighter or white (poliosis) when underlying skin is affected.
• Café-au-lait macules (CALMs): reported in up to 30% of TSC patients, usually evident within first few months of life.
• Most TSC patients have fewer than the six CALMs required to diagnose NF1.
• Angiofibromas (formerly "adenoma sebaceum"): not typically present at birth.
• Begin to appear in centrofacial area as early as first 2 years of life; by adolescence, present in ~80% of TSC patients.
• High frequency of somatic second-hit CC>TT "UV signature" mutations identified in TSC-related facial angiofibromas, suggesting a role for UV light in pathogenesis.
• May begin as erythematous macules on cheeks/forehead, mature into pink to red or red-brown papules/papulonodules, may coalesce into plaques.
• Papules often dome-shaped with smooth, shiny surface.
• Except mosaic TSC, facial angiofibromas have bilateral and symmetric distribution.
• Because one or two angiofibromas (fibrous papules) are relatively common in the general population, presence of at least 3 angiofibromas required as diagnostic criterion.
• Fibrous cephalic plaque: larger variant of angiofibroma on face/scalp in ~20% of TSC patients.
• Favor forehead; usually firm, yellow-brown to pink-tan.
• May slowly enlarge over time; when on scalp typically lack hair.
• Shagreen ("leather") patch: a type of collagenoma; characteristic truncal lesion.
• Most common in lumbosacral area; typically begins ~2 years of age (occasionally earlier).
• Eventually observed in approximately half of TSC patients.
• Skin-colored to hyperpigmented plaques up to 10 cm in diameter, often uneven surface; multiple lesions may be present.
• Distinctive feature: prominent but slightly depressed follicular openings — "pigskin-like" appearance.
• "Folliculocystic and collagen hamartoma" (FCCH): comedones and keratin-containing cysts plus collagen deposition.
• When present, fibrous cephalic plaques, shagreen patches, and FCCH — plus segmental forms of hypomelanosis, congenital lymphedema, and lipomatosis — are thought to reflect superimposed (type 2) mosaicism due to a second-hit mutation arising during early prenatal development (see Ch. 62).
• Ungual fibromas (Koenen tumors): begin later in childhood, can continue to form throughout adulthood.
• Periungual fibromas: arise from proximal or lateral nail fold, occur most commonly around toenails.
• Subungual fibromas: originate under nail plate; longitudinal red streaks with proximal narrowing ("red comets") favor fingernails.
• Can lead to distortion of nail plate (e.g. longitudinal groove) without a visible tumor.
• Molluscum pendulum: soft, pedunculated, skin-colored papules/nodules resembling large acrochordons; favor flexural areas (neck, axillae, groin).
• Intraoral fibromas: described in 20%–70% of individuals with TSC; higher prevalence in adults than children.
• Gingiva most common location; also buccal/labial mucosa and occasionally tongue.
• Dental enamel pits: seen in nearly all TSC patients, compared with <10% (to, upon close examination, 70%) of unaffected individuals.
• One study found >10 pits in 70% of TSC patients but only 4% of controls.
• Retinal lesions: present in about half of TSC patients; retinal hamartomas in ~40%.
• Most common morphologic type: flat, translucent lesion (70%), followed by multinodular "mulberry" lesion (55%), then transitional-type lesion (9%).
• Punched-out areas of retinal depigmentation also found in about 40% of affected individuals.
• Most ocular lesions in TSC patients do not lead to visual loss.

Neurologic manifestations

• Infantile spasms: occur in ~70% of infants with TSC.
• Last several minutes; massive flexion or extension of limbs, trunk, head for <1–3 seconds, occurring in series separated by intervals of a few seconds.
• Typically begin at about 3 months of age (as opposed to other TSC-associated seizures, which usually develop after 1 year of age).
• EEG changes characterizing infantile spasms: hypsarrhythmia.
• Intellectual disabilities of varying degrees occur with high frequency in children and adults with TSC.
• Spectrum of TSC-associated neuropsychiatric disorders (TAND) also includes autism, attention deficit disorder, aggressive behaviors, and psychiatric conditions.
• Subependymal nodules: multiple nodules along ventricular surface seen on MRI (more sensitive) or CT in >80% of TSC patients by 2 years of age.
• Progressively calcify; found in almost all patients by puberty.
• Subependymal giant cell astrocytomas (SEGAs): affect 5%–15% of TSC patients; usually develop during childhood.
• Unlike subependymal nodules, SEGAs tend to enlarge over time → may lead to hydrocephalus and neurologic symptoms; exhibit contrast enhancement on MRI/CT.
• Cortical dysplasia types: cerebral white matter radial migration lines and the highly characteristic tubers (glioneuronal hamartomas), detectable by MRI in ~90% of patients.

Cardiovascular manifestations

• Cardiac rhabdomyomas: detectable prenatally and after birth by echocardiography or MRI; found in >80% of infants with TSC.
• Tend to involute during the first 3 years of life; often disappear altogether by adulthood.
• Arrhythmias, especially Wolff–Parkinson–White syndrome, appear more common in affected individuals.

Renal manifestations

• Multiple bilateral angiomyolipomas: frequently noted on routine renal ultrasounds.
• Most asymptomatic, especially in childhood and when <4 cm diameter.
• Tend to enlarge and increase in number with age; may lead to life-threatening hemorrhage.
• Children with TSC who develop severe renal cysts often have a contiguous gene syndrome in which both TSC2 and the polycystic kidney disease (PKD) genes are lost in a single large chromosomal deletion.
• Occasionally renal cell carcinomas develop in TSC patients.

Other manifestations

• Pulmonary lymphangioleiomyomatosis: often asymptomatic; occurs in at least 30%–40% of women with TSC.
• High-resolution CT: appears as cysts.
• Men rarely develop this manifestation; estrogen suspected to stimulate growth of pulmonary smooth muscle cells.
• Can occur sporadically due to biallelic somatic TSC2 mutations; renal angiomyolipomas also develop in a subset of these patients.
• Multifocal micronodular pneumonocyte hyperplasia, hamartomatous gastrointestinal polyps, congenital segmental lymphedema, other vascular anomalies, segmental lipomatosis, and hemihypertrophy have also been reported in TSC.

Major Clinical Features of TSC

• Cutaneous
• Facial angiofibromas (~80%) and fibrous plaque of the forehead (~20%)
• Hypomelanotic macules (90%–100%) — polygonal; lance-ovate (ash leaf); confetti
• Shagreen patch (40%–50%)
• Ungual fibromas (30%–60%)
• Molluscum pendulum
• Café-au-lait macules
• Ocular
• Retinal hamartomas (~40%)
• Achromatic retinal patches (~40%)
• Retinal astrocytoma
• Skeletal
• Cystic areas of bone rarefaction, especially phalanges
• Dental
• Pitted enamel (>90%)
• Intraoral fibromas (up to 70%)
• Pulmonary
• Lymphangioleiomyomatosis (≥30%–40% of women)
• Renal
• Multiple bilateral angiomyolipomas (75%–90%)
• Cysts (30%)
• Carcinoma
• Endocrine
• Precocious puberty
• Hypothyroidism
• Neurologic
• Cortical dysplasia (cortical tubers and cerebral white matter radial migration lines) (>90%)
• Subependymal nodules* (>80%)
• Subependymal giant cell astrocytoma† (5%–15%)
• Seizures (70%–95%), including infantile spasms (~60%)
• Intellectual impairment (>50%)
• Cardiovascular
• Myocardial rhabdomyoma‡ (80% of infants)
• Wolff–Parkinson–White syndrome
• *Nearly all patients by puberty.
• †Also known as subependymal giant cell tumor.
• ‡Increasingly difficult to distinguish from normal myocardium after the first few years of life.

• Hypopigmented macules: reduction in amount of epidermal melanin but normal number of melanocytes; melanocytes have poorly developed dendrites.
• Electron microscopy: small, immature melanosomes with reduced number, degree of melanization, and transfer to keratinocytes.
• Angiofibromas: irregular proliferation of fibrous tissue and blood vessels; expansion of hamartomatous process can compress adnexae; characteristic concentric perifollicular fibrosis.
• Fibrous cephalic plaques: similar histopathologic findings.
• Shagreen patch and ungual fibromas: represent collagenomas.
• Dermis replaced by thick bundles of collagen; elastin fibers typically absent; fibroblasts may be large and morphologically atypical.
• Various fibrous lesions in TSC thought to belong to the same histopathologic spectrum, with perifollicular fibrosis a characteristic feature; cystic component occasionally evident (as in FCCH).

• Diagnostic criteria for TSC revised in 1998 and updated in 2012.
• Four of the major features are cutaneous — thorough dermatologic exam frequently helps establish diagnosis.
• Seizures occur in majority of affected infants; TSC possibility often considered in asymptomatic infants with multiple hypomelanotic macules (approach outlined in Fig. 61.21).
• Echocardiography can help establish diagnosis in infants; easier to perform in this age group than brain MRI to detect CNS lesions.
• Conventional genetic testing (sequencing plus deletion/duplication analysis) identifies a pathogenic TSC1/TSC2 variant in ~85% of individuals meeting clinical criteria.
• Targeted NGS (including deletion/duplication analysis) increases yield to ~95%, enabling detection of intronic splice site and mosaic pathogenic variants (which tend to result in relatively mild disease).
• Analysis of DNA from a lesional skin biopsy (e.g. angiofibroma) may be necessary for mosaic TSC with more limited involvement.
• Multiple endocrine neoplasia type 1 (MEN1): can present with multiple facial angiofibromas, collagenomas, gingival papules, and confetti-like hypomelanotic macules (see Ch. 63).
• Birt–Hogg–Dubé syndrome: multiple facial angiofibromas and collagenomas observed in adults (see Ch. 111).
• Multiple collagenomas can occur in: Cowden syndrome (storiform variant/sclerotic fibromas; see Ch. 63), Buschke–Ollendorf syndrome (dermatofibrosis lenticularis disseminata; see Ch. 116), and familial cutaneous collagenoma.
• Clinical differential for facial angiofibromas: acne vulgaris and trichoepitheliomas.
• Individual acneiform lesions should resolve over weeks.
• Trichoepitheliomas usually less red; biopsy often required.
• Additional causes of multiple facial papules listed in Table 36.2 and Figure 111.5.
• Nevus depigmentosus: common cause of congenital hypopigmented macule/patch; some infants have more than one.
• Larger nevus depigmentosus with segmental distribution (segmental pigmentation disorder) or following lines of Blaschko may be composed of multiple hypopigmented macules/patches within affected areas.
• Features distinguishing TSC hypopigmented lesions from postinflammatory hypopigmentation (e.g. atopic/seborrheic dermatitis) and the amelanosis of piebaldism or vitiligo are presented in Fig. 61.21.
• Idiopathic guttate hypomelanosis (IGH): may resemble the confetti-like leukoderma of TSC; however IGH is acquired, favoring shins and extensor forearms of older adults.
• Congenital smooth muscle hamartoma: can present during infancy as a firm, skin-colored to hyperpigmented plaque resembling a shagreen patch.
• Accentuates with rubbing (pseudo-Darier sign).
• Contains follicular papules due to hyperplastic arrector pili muscles.
• Has associated hypertrichosis rather than prominent but depressed follicular orifices.
• Histologically: intradermal bundles of smooth muscle rather than collagen.

2012 Revised Diagnostic Criteria for TSC

• Major Features
• Hypomelanotic macules (≥3, diameter ≥5 mm) — cutaneous
• Facial angiofibromas (≥3) or fibrous cephalic plaque — cutaneous
• Ungual fibromas (≥2) — cutaneous
• Shagreen patch — cutaneous
• Multiple retinal hamartomas — extracutaneous
• Cortical dysplasias (including tubers and cerebral white matter radial migration lines) — extracutaneous
• Subependymal nodules — extracutaneous
• Subependymal giant cell astrocytoma — extracutaneous
• Cardiac rhabdomyoma — extracutaneous
• Lymphangioleiomyomatosis — extracutaneous
• Angiomyolipomas (≥2; renal >> other organs, e.g. liver) — extracutaneous
• Minor Features
• "Confetti" skin lesions — cutaneous
• Dental enamel pits (≥3) — cutaneous
• Intraoral fibromas (≥2) — cutaneous
• Retinal achromic patch — extracutaneous
• Multiple renal cysts — extracutaneous
• Non-renal hamartomas — extracutaneous
• Definite clinical diagnosis: either two major features* or one major feature plus ≥2 minor features.
• Possible clinical diagnosis: either one major feature or ≥2 minor features.
• Definite genetic diagnosis: identification of a pathogenic variant in either TSC1 or TSC2 in DNA from the blood or normal tissue.
• *With the exception of lymphangioleiomyomatosis + angiomyolipomas (this combination alone does NOT meet criteria for two major features without another finding).

• Nearly every organ can be affected; clinical findings vary tremendously even within families.
• Certain signs/complications appear at birth; others develop much later in life.
• 2012 International TSC Consensus Conference Recommendations and 2019 United Kingdom Guidelines summarize evaluation/management (referenced in text; content not reproduced in extracted source).
• Investigations should focus on detecting potentially significant and treatable disease manifestations/complications; genetic counseling important for affected individuals and families.
• In clinical trials, systemic therapy with mTOR inhibitors sirolimus and everolimus has led to:
• Regression of SEGAs.
• Control of recalcitrant seizures.
• Reduction in size of renal angiomyolipomas.
• Improvement of lung function in women with lymphangioleiomyomatosis.
• Given UV-induced mutations implicated in facial angiofibromas, sun protective measures may be of utility.
• Use of electrosurgery, dermabrasion, and ablative fractional or pulsed dye lasers has led to variable results for angiofibromas.
• Topical sirolimus (rapamycin): employed to treat angiofibromas, fibrous plaques, and hypomelanotic macules, with limited systemic absorption.
• More irritation produced by commercially available 0.1% solution (Rapamune® 1 mg/ml) than compounded 0.1%–1% ointment, cream, and gel formulations.
• Reduced erythema and flattening of angiofibromas typically seen within 3 months of initiating daily topical therapy, especially if treatment initiated at ≤10 years of age.
• Randomized placebo-controlled studies:
• Sirolimus 0.2% gel twice daily for 3 months: angiofibromas improved in 60% (18/30) of patients vs 0% (0/31) with placebo.
• Sirolimus 1% daily for 6 months: improved in 82% (45/55) of patients vs 25% (13/51) with placebo (p<0.001).
• Relapses typically occur upon discontinuation.
• Maintenance with thrice weekly applications has limited efficacy.
• Combination of topical sirolimus 0.1% and calcitriol 0.0003% may result in a more durable response than sirolimus alone.
• Resources: TSC Alliance (www.tscalliance.org), National Institute of Neurological Disorders and Stroke (www.ninds.nih.gov/health-information/disorders/tuberous-sclerosis-complex), Tuberous Sclerosis Association (www.tuberous-sclerosis.org).

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• Chapter covers 3 exemplar inherited skin tumour syndromes: neurofibromatosis type 1 (NF1), tuberous sclerosis complex, familial adenomatous polyposis (FAP), plus an overview of other inherited tumour syndromes with cutaneous manifestations.
• These 3 have diverse clinical and genetic features, requiring disease-specific knowledge for diagnosis, targeted interventions, and cancer surveillance plans.
• All 3 share: multiple benign skin tumours (often pathognomonic) and a significant risk of cutaneous and non-cutaneous neoplasia.

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• Comprise several distinct genetic disorders causing tumours around nerves plus other pathological features.
• 3 main forms: NF1, NF2, schwannomatosis.
• NF1 (most common): multiple café-au-lait macules + neurofibromas along peripheral nerves.
• NF2: bilateral vestibular schwannomas (acoustic neuromas) + meningiomas; cutaneous schwannomas may present as dermal plaques/nodules.
• Schwannomatosis: tumours on cranial, spinal, peripheral nerves → chronic pain, altered sensation, muscle weakness; linked to germline SMARCB1 and LZTR1 pathogenic variants; NO cutaneous manifestations.

• MIM 162200.
• Inherited neuroectodermal abnormality: ≥6 café-au-lait spots, axillary freckles, cutaneous neurofibromas, plexiform neurofibromas, Lisch nodules (pigmented iris hamartomas).

• Autosomal dominant, almost 100% penetrance by age 5.
• Sporadic cases up to 50% — explained by parental gonadal mosaicism and high de novo mutation rate.
• Prevalence ~1/2500–3300 births. Mosaic forms with incomplete features frequent.
• NF1 gene on chromosome 17, encodes neurofibromin; spans 335 kb, ≥59 exons, 4 major alternatively spliced transcripts. Neurofibromin expressed in keratinocytes and melanocytes in normal adult skin.
• Neurofibromin = Ras GTPase activating protein (RasGAP), negatively regulates Ras-MAPK pathway (important in neuroectodermal cells — neurons, melanocytes).
• NF1 is a 'RASopathy' — one of several conditions where pathogenic variants deregulate Ras signalling as a key step to phenotype development.
• Most NF1 germline variants alter reading frame or insert premature stop codons → loss of function; no mutational hotspot — private variants per individual/family. Contiguous gene deletions (including neurofibromin + adjacent genes) → more severe phenotype, often with developmental delay.
• Tumour suppressor gene: heterozygous germline variant + homozygous variants demonstrated in cutaneous neurofibromas — classic Knudson 'two-hit' hypothesis. Requirement for a somatic second hit partly explains delayed neurofibroma onset and variable expression; second hits occurring in utero are thought to explain plexiform neurofibroma formation.

• Part A (individual without an NF1-diagnosed parent): ≥2 of the following:
• ≥6 café-au-lait macules (>5 mm prepubertal, >15 mm postpubertal)
• Axillary or inguinal freckling
• ≥2 neurofibromas of any type OR 1 plexiform neurofibroma
• Optic pathway glioma
• ≥2 iris Lisch nodules (slit-lamp) or ≥2 choroidal abnormalities (bright patchy nodules on OCT/NIR imaging)
• A distinctive osseous lesion (sphenoid dysplasia, anterolateral tibial bowing, or long-bone pseudarthrosis)
• A heterozygous pathogenic NF1 variant with variant allele fraction of 50% in normal tissue (e.g. white blood cells)
• Note: if only pigmentary findings present, diagnosis is most likely NF1 but exceptionally could be Legius syndrome; at least one pigmentary finding should be bilateral. Sphenoid wing dysplasia not a separate criterion with an ipsilateral orbital plexiform neurofibroma.
• Part B: a child of an NF1-diagnosed parent merits diagnosis if ≥1 of the Part A criteria are present.

• NIH 1988 Consensus criteria, revised 2019, widely used — require ≥2 criteria.
• Café-au-lait macules (CALMs): sharply defined light brown patches, 0.5–50 cm (majority ≤10 cm); first feature to appear in all children — reported by age 4 in all, within first year of life in 82%; increase in size/number through the first decade.
• Cutaneous neurofibromas: soft, sessile, dome-shaped, sometimes pedunculated tumours from peripheral nerves/supporting structures (neurilemmal cells); most numerous on trunk/limbs, hundreds may be present, few mm–several cm. Blue-red macules and pseudoatrophic macules also occur (neurofibroma variants). Pruritus may be a symptom — thought histamine-mediated (mast cells, antihistamine response), though ketotifen (mast cell blocker) has NOT resolved cutaneous neurofibromas long-term, utility unclear.
• Plexiform neurofibromas: diffuse, elongated, along a nerve's course, frequently trigeminal/upper cervical nerves; usually present within the first 2 years of life; may arise in peripheral nerves and spinal cord; distinctive 'bag of worms' feeling on palpation; may involve sensory/motor nerves, viscera, blood vessels.
• Freckling: frequent in axillae, virtually pathognomonic (Crowe sign); present in ~70%; appears slightly later than CALMs (youngest reported case age 3); may also occur in groin/other intertriginous areas.
• Lisch nodules: dome-shaped iris lesions on slit-lamp exam; occur in >90% of patients, increasing with age; do NOT occur in mosaic NF1 or NF2.
• Oral lesions: in up to 37% — papillomatous neurofibromas of palate, buccal mucosa, tongue, lips.
• Skeletal abnormalities: kyphoscoliosis in 2%; sphenoid wing dysplasia characteristic; pseudarthrosis of tibia/radius in 1% (may be asymptomatic); short stature and macrocephaly uncommon; a generalised bone metabolic defect from neurofibromin loss of function explains increased osteopenia/osteoporosis risk — early identification permits timely treatment.
• Additional extracutaneous features: cutaneous severity does NOT reliably predict extent of disease elsewhere. Learning difficulties in 25–30% of children; physical development may be impaired; speech impediments, hypertelorism, headaches common. Endocrine disturbances: precocious puberty, acromegaly, Addison disease, hyperparathyroidism, gynaecomastia, phaeochromocytoma. Renovascular hypertension may occur in children. Lower urinary tract involvement → urinary symptoms. Constipation from colonic musculature dysfunction. Gastrointestinal stromal tumours may cause haemorrhage/obstruction. High prevalence of cardiovascular abnormalities; can be complicated by pulmonary hypertension.
• Neurological disease from NF1 tumours: most common solitary intracranial tumour = optic nerve glioma; astrocytomas and schwannomas also occur; possibly sex-dependent, more symptomatic in females. Intracranial tumours may cause epilepsy (seizures can also occur without demonstrable focal lesion).
• Malignant tumours in NF1:
• Sarcomatous change within a neurofibroma: 1.5–15%, more often in deeper than cutaneous lesions; rare before age 40 but can occur in early childhood; slow growth, late metastasis, but frequent local recurrence.
• Malignant peripheral nerve sheath tumours (MPNSTs): highly aggressive sarcomas. Enlargement or pain of cutaneous neurofibromas should raise suspicion of malignant change (though rapid enlargement can also be from intralesional haemorrhage).
• Other associated malignancies: Wilms tumour, rhabdomyosarcoma.
• Juvenile xanthogranulomas (JXGs) in children with NF1 have been linked to juvenile myelomonocytic leukaemia (JMML) — JXGs seen in 5–10% of NF1 children under 2; a recent case-control study suggests the JMML risk in NF1+JXG patients may have been previously overestimated.
• Multiple CALMs + acute lymphoblastic leukaemia/lymphoma should raise suspicion of constitutional mismatch repair deficiency (CMMRD) as an alternate diagnosis.

• Highly variable; majority have a benign course. Diagnosis frequently made after childhood.
• CALMs present at birth or (more commonly) develop in early childhood, increasing throughout life. Cutaneous neurofibromas appear in childhood, increase rapidly at puberty (possible hormonal influence) — though lesions may be present at birth and progressively enlarge.
• Difficult to prognosticate from cutaneous extent alone. Extensive urinary/GI/CNS involvement carries poor prognosis.
• Pregnancy appears to induce rapid progression/new neurofibroma development in some cases, but a recent small controlled study of 26 pregnant NF1 patients suggests this is not generally the case.
• Long-term cohort follow-up shows reduced life expectancy related to malignancy and complications such as hypertension from renal artery stenosis or phaeochromocytoma.

• Diagnosis established on clinical criteria. Cutaneous neurofibromas are clinically/histologically distinctive.
• CALMs (usually the earliest sign) can be isolated findings in 10–20% of normal individuals — 1–2 CALMs alone have little diagnostic significance without other criteria.
• other conditions featuring café-au-lait macules: Legius syndrome (SPRED1); Constitutional mismatch repair deficiency/CMMRD (MLH1, MSH2, MSH6, PMS2); Cowden syndrome (PTEN); Noonan syndrome with multiple lentigines (PTPN11); McCune–Albright syndrome (GNAS); Naevoid basal cell carcinoma syndrome (PTCH1).
• Molecular genetic testing now inexpensive and more widely used when diagnosis uncertain, but majority of cases diagnosed on clinical features alone. Enables prenatal/presymptomatic and preimplantation genetic diagnosis.

• Detailed clinical assessment of proband and family members (may identify other affected individuals).
• Annual clinical review recommended: blood pressure, head circumference, scoliosis assessment, painful lumps (possible MPNST), eye examination.
• Manchester checklist (UK) widely used — covers skeleton, eyes, neurological, development, skin, education/behaviour (children); general, psychological burden, neurological, blood pressure, eyes, women (breast cancer screening), pregnancy, other new symptoms (adults).
• MRI in children with macrocephaly or focal neurological signs/symptoms. UK practice: MRI screening only if neurological/ophthalmological anomalies; USA practice: routine cranial MRI screening for all infants.
• Multidisciplinary clinic management ideal, established in several centres.
• Symptomatic/growing cutaneous neurofibromas: usually surgical; ablative laser for smaller lesions (risk of hypertrophic/atrophic scars — preliminary test treatment recommended). Surgery also indicated for suspected malignant change (increased size/pain).
• 2020: selumetinib (Ras-MAPK/MEK pathway inhibitor) FDA-licensed for paediatric patients ≥2 years with symptomatic, inoperable plexiform neurofibromas. New therapies under investigation in clinical trials.
• Genetic counselling: balance informing about complications vs causing unnecessary alarm; 50% of an affected patient's children likely to be affected, disease may be severe; unaffected first-degree relatives unlikely to carry the gene — cascade genetic testing can reassure.
• Women with NF1: increased breast cancer risk age 40–50, classified 'moderate' (3–8%) per NICE guidelines — annual mammography from age 40 recommended.

• Presents as café-au-lait spots, cutaneous neurofibromas, sometimes visceral neurofibromas, limited typically to one side or a body region.
• Represents somatic mosaicism involving NF1 — only some cells carry a heterozygous pathogenic variant.
• Systematic review: transmission of germline NF1 to the next generation reported in 2.5–6.4% of mosaic NF patients.

Revised diagnostic criteria for mosaic NF1

• Met if any of:
• A heterozygous NF1 variant with allele fraction significantly <50% in normal tissue AND one other NF1 diagnostic criterion (excluding an affected parent).
• An identical heterozygous NF1 variant in 2 anatomically independent affected tissues (absent in unaffected tissue) — note: neurofibroma + overlying hyperpigmented skin = one tissue only; different tissues from the same primary lesion = one tissue only.
• A clearly segmental distribution of CALMs or cutaneous neurofibromas AND another NF1 diagnostic criterion (excluding an affected parent).
• OR a child fulfilling NF1 diagnostic criteria + the parent showing only one NF1 criterion from: axillary/inguinal freckling, optic pathway glioma, ≥2 Lisch nodules or ≥2 choroidal abnormalities, distinctive osseous lesion, ≥2 neurofibromas or 1 plexiform neurofibroma.
• Note: if only CALMs and freckling present, most likely mosaic NF1 but rarely could be mosaic Legius syndrome or CMMRD.

• NF1 is part of a family of related conditions from deregulated Ras-MAPK signalling — termed RASopathies.
• Autosomal dominant disorders from pathogenic variants in genes regulating the Ras-MAPK pathway.
• Disorders include: capillary malformation–arteriovenous malformation syndrome, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, NF1, Noonan syndrome (NS), NS with multiple lentigines (formerly LEOPARD syndrome).
• Because they share a pathway, they share phenotypic features including skin tumours and pigmentary/hair abnormalities.
• Additional RASopathy-associated genes: RIT1, SOS2, RASA2, RRAS — detected in NS-phenotype patients.
• Regrouping driven by recognition that Ras-MAPK pathway-targeted therapies could serve as a general treatment approach.

• Neurofibromatosis type 1 — NF1 (neurofibromin, RasGAP) — CALMs; intertriginous freckling; neurofibromas and plexiform neurofibromas; iris Lisch nodules; osseous dysplasia; optic pathway glioma; normal/mild neurocognitive impairment; predisposition to other cancers.
• Noonan syndrome — PTPN11, SOS1, RAF1, KRAS, NRAS, SHOC2, CBL (phosphatase, RasGEF, kinase, GTPase, GTPase, scaffolding, E3 ubiquitin ligase) — craniofacial dysmorphism (broad forehead, hypertelorism, down-slanting palpebral fissures, ptosis, high-arched palate, low-set posteriorly rotated ears); congenital heart defects; short stature; undescended testicles; ophthalmological abnormalities; bleeding disorders; normal/mild neurocognitive impairment; cancer predisposition.
• Noonan syndrome with multiple lentigines — PTPN11, RAF1/CRAF — same as NS, plus possible development of multiple skin lentigines with age; unclear cancer predisposition.
• Capillary malformation–arteriovenous malformation — RASA1 (p120-RasGAP) — multifocal capillary malformations ± arteriovenous malformations/fistulae; unclear cancer predisposition.
• Costello syndrome — HRAS (GTPase) — craniofacial features similar to NS but potentially coarser; congenital heart defects; failure to thrive; short stature; ophthalmological abnormalities; multiple skin manifestations incl. papilloma; normal/mild neurocognitive impairment; hypotonia; cancer predisposition.
• Cardio-facio-cutaneous syndrome — BRAF, MAP2K1, MAP2K2, KRAS (kinases, GTPase) — craniofacial features similar to NS; congenital heart defects; failure to thrive; short stature; ophthalmological abnormalities; multiple skin manifestations incl. progressive naevus formation; normal/mild neurocognitive impairment; hypotonia; unclear cancer predisposition.
• Legius syndrome — SPRED1 — CALMs; intertriginous freckling; macrocephaly; normal/mild neurocognitive impairment; no apparent cancer predisposition.

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• MIM 191100 (TSC1), 613254 (TSC2).
• Genetic disorder of hamartoma formation in many organs — skin, brain, eye, kidney, heart. 'Complex' emphasises multisystem involvement and highly variable expression.
• Characteristic skin lesions: angiofibromas, connective tissue naevi, periungual fibromas, 'ash-leaf' white macules — typically with epilepsy and intellectual impairment.

• Incidence 1/10 000 (Oxford region); 1/27 000 (west of Scotland); birth incidence possibly 1/5800 — makes TSC, with NF1, one of the more common single-gene disorders.

• Autosomal dominant, great variability of expression even within a family.
• ~Half of TSC families linked to TSC1, the other half to TSC2; minority carry no coding variant in either.
• TSC1 encodes hamartin; TSC2 encodes tuberin. Both are tumour suppressor genes — loss of heterozygosity demonstrated for both loci in various hamartomas.
• No obvious phenotypic differences between TSC1- and TSC2-linked families.
• TSC2 locus deletion analysis identified one specific correlation: severe polycystic kidney disease, from a contiguous gene deletion involving both TSC2 and the polycystic kidney disease gene PKD1.

• Characteristic features: skin lesions, intellectual impairment, epilepsy — wide variation in age of onset/severity.
• Onset before age 5 with cutaneous changes or epilepsy is typical, though diagnosis may be delayed until adolescence/adulthood.
• Diagnostic criteria agreed by the Tuberous Sclerosis Alliance — definitive diagnosis requires 2 major features.

Skin lesions (60–70% of cases; 4 pathognomonic types)

1. Angiofibromas: rarely present at birth/infancy, usually appear ages 3–10 (sometimes later); often more extensive at puberty then unchanged; firm, discrete, red-brown, telangiectatic papules, 1–10 mm, from naso-labial furrows to cheeks/chin, occasionally ears.
2. Periungual fibromas (Koenen tumours): appear at/after puberty; smooth, firm, flesh-coloured protuberances from nail folds, usually 5–10 mm (can be much larger); may be the only clinically evident abnormality.
3. Connective tissue naevi (shagreen patches): irregularly thickened, slightly elevated, soft, skin-coloured plaques, usually lumbo-sacral.
4. White ovoid/ash-leaf-shaped macules: 1–3 cm, most easily seen under Wood light; frequently trunk/limbs; valuable sign — may be present at birth/early infancy, years before other signs, suggesting TSC diagnosis in infants with convulsions. Caveat: hypopigmented macules seen in 2–3/1000 apparently normal newborns — presence alone is not diagnostic.

• Other cutaneous manifestations: firm fibromatous plaques (forehead — Fig 78.7, scalp); soft pedunculated fibromas (neck, axillae); eyelash poliosis; fibromatous tumours on gums/palate; small dental enamel pits (used as early diagnostic sign in children).
• Mosaic TSC: reported where only one syndrome component is clinically evident (postmortem often shows other organ involvement); unilateral multiple facial angiofibromas reported in 2 mosaic TSC patients.

Neurological features

• Learning difficulties in 60–70%, may be progressive, but deterioration after normal childhood development is uncommon.
• Some present with behavioural disorders and normal intelligence; self-injury behaviour common (up to 10%). Psychotic symptoms (including schizophrenia) sometimes develop, possibly not higher than general population.
• Epilepsy in 84% — usually begins infancy/early childhood, often preceding skin lesions by years; less often delayed to puberty/adulthood; attacks may be focal, often progressively more frequent/severe (long remissions possible); treatment can be challenging, occasionally requiring surgery. Intracranial malignant change occurs in a few patients.

Ocular signs

• Occur in 50%, may be hard to detect. Retinal phacomas: white streaks along vessels or small rounded tumours near the disc. Pigmentary/other retinal abnormalities can occur. Symptoms rare but scotomas or amaurosis possible. Hypopigmented iris spots may be analogous to skin ash-leaf macules.

Cardiac rhabdomyomas

• Detected by echocardiography in >50% of infants; may cause early death, though recent evidence suggests most regress in early infancy and again in adolescence. Prenatal detection now possible by fetal echocardiography — often the initial diagnostic clue.

Renal involvement

• Angiomyolipoma (benign renal parenchymal tumour), less commonly renal cysts.

Pulmonary involvement

• Uncommon. Lymphangioleiomyomatosis (LAM): almost exclusively females, clinically manifests in the 2nd decade with increasing dyspnoea and recurrent spontaneous pneumothorax. Males may develop multifocal micronodular pulmonary hyperplasia (MPPH).

Gastrointestinal and endocrine

• GI: usually hamartomatous colonic polyps.
• Endocrine: pituitary-adrenal dysfunction, thyroid disorders, premature puberty.

• Mortality significantly increased — one study: 5-fold higher than age/gender-matched population; another review: mortality 4.8–8.3% over 8–17.4 years follow-up.
• Death usually from sudden unexplained death in epilepsy (SUDEP), kidney-related complications, or infection.

• Major features: hypomelanotic macules (≥3, ≥5 mm); angiofibromas (≥3) or fibrous cephalic plaque; ungual fibromas (≥2); shagreen patch; multiple retinal hamartomas; cortical dysplasias (tubers and cerebral white matter radial migration lines); subependymal nodules; subependymal giant cell astrocytoma (SEGA); cardiac rhabdomyoma; lymphangioleiomyomatosis (LAM); angiomyolipomas (≥2).
• Minor features: 'confetti' skin lesions; dental enamel pits (>3); intraoral fibromas (≥2); retinal achromic patch; multiple renal cysts; non-renal hamartomas.
• Definite diagnosis: 2 major features, or 1 major + ≥2 minor features.
• Possible diagnosis: 1 major feature, or ≥2 minor features.
• Note: LAM + angiomyolipomas alone (without other features) does NOT meet criteria for definite diagnosis.

• Telangiectasia and lack of comedones/pustules distinguish angiofibromas from acne vulgaris; biopsy useful if uncertainty vs other genetic conditions with facial papules (e.g. CYLD cutaneous syndrome, Birt–Hogg–Dubé syndrome).
• White ash-leaf macules seen under Wood light. MRI brain, CT kidneys, ophthalmological examination should be requested.
• Genetic testing of TSC1/TSC2 positive in 85% of cases, routinely performed. ~60–70% of TSC cases are de novo. Parental genetic testing available once a child's variant is identified (influences counselling). 50% inheritance risk for children of an affected parent. Family screening/genetic counselling via clinical genetics referral.

• Managed by dedicated TSC multidisciplinary teams (renal, neurology, genetics, dermatology).
• Cosmetic improvement of angiofibromas: topical mTOR inhibitors in patients not on systemic mTOR inhibitors (e.g. everolimus); more papular/nodular lesions treated surgically or with ablative lasers.
• UK guideline summarises organ-specific surveillance/management.
• Systemic everolimus now licensed and useful for many visceral tumours and neurological complications, including epilepsy.

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• These syndromes show how a range of genes are important for normal function of multiple tissues, and how the skin can indicate an underlying genetic disease.
• Personal/family history, full skin exam, and (in some cases) biopsy are important steps toward diagnosis and choosing relevant genetic tests.
• Important for confirming diagnosis, genetic counselling, family planning, therapeutic selection — often performed within a multidisciplinary team.

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