Neurofibromatosis and Tuberous Sclerosis Complex


Introduction

Neurofibromatosis (NF) and tuberous sclerosis (TS) are neurocutaneous disorders, or phakomatoses. They are characterized by cutaneous lesions as well as peripheral and/or central nervous system neoplasms. Like most hereditary cancer syndromes, NF and TS are autosomal dominant in inheritance. Despite a high penetrance for both diseases, new cases of NF type 1 (NF1) and TS frequently represent de novo mutations. The pleiotropic nature of these two neurocutaneous syndromes has led to complex schemes for their classification and diagnosis. Dermatologists are frequently asked to participate in the clinical diagnosis of patients with NF1 and TS due to the early appearance of cutaneous, especially pigmentary, findings. Advances in the molecular characterization of these disorders have revealed related, but distinct, pathogenic mechanisms.

In 1982, Riccardi proposed a classification scheme for patients with NF ( Table 61.1 ). Elucidation of the molecular bases of NF1, NF2, segmental/mosaic NF1 (formerly known as NF5), and “NF1-like” syndromes has further refined the categorization of patients. Among these conditions, NF1 has the most well-characterized and diagnostic skin findings and is the main focus in this chapter.

Table 61.1
Riccardi's classification of neurofibromatosis.
RICCARDI'S CLASSIFICATION OF NEUROFIBROMATOSIS
Category Description
NF1 von Recklinghausen disease
NF2 Acoustic schwannoma
NF3 * Mixed (central and peripheral neurofibromas)
NF4 * Variant
NF5 * , Segmental café-au-lait macules, neurofibromas, or both, affecting one or more dermatomes
NF6 * , Café-au-lait macules only
NF7 * Late onset
NF-NOS Not otherwise specified

* Primarily of historical/conceptual interest.

Now referred to as mosaic (segmental) NF1.

Includes Legius (NF1-like) syndrome.

Neurofibromatosis Type 1

Synonym

▪ von Recklinghausen disease

Key features

  • NF1 is an autosomal dominant disorder with an incidence of approximately 1 in 3000 births

  • Characteristic clinical findings include café-au-lait macules, neurofibromas, freckling in the axillae and groin, Lisch nodules, and bony defects

  • Patients with NF1 have an increased risk of developing juvenile myelomonocytic leukemia and a variety of extracutaneous tumors, including optic gliomas, malignant peripheral nerve sheath tumors, pheochromocytomas, and CNS tumors

  • Up to 50% of patients with NF1 have a new spontaneous mutation rather than an inherited mutation

  • The protein product of NF1 (neurofibromin) is involved in the negative regulation of Ras signaling

  • Other well-characterized forms of NF include segmental/mosaic NF1 and NF2 (vestibular schwannomas)

History

Individuals with NF1 have been described throughout history . In 1882, von Recklinghausen provided the first in-depth report of the clinical and pathologic nature of the neurofibromas. Fifty years later, the Viennese ophthalmologist Lisch described the iris nodules that were more recently recognized as an important criterion in the clinical diagnosis of NF. In the mid twentieth century, Crowe, Schull, and Neel compiled a landmark monograph with a comprehensive description of the manifestations of this disease .

Epidemiology

NF1 occurs worldwide. Its incidence is approximately 1 in 3000 births .

Pathogenesis

NF1 is inherited in an autosomal dominant manner. Most large series have found that 30–50% of patients have no affected relatives and thus likely harbor new spontaneous mutations . There is also the possibility of germline mosaicism in a parent, especially when two siblings develop NF1 in the absence of a prior family history. The penetrance of NF1 approaches 100% in carefully examined adults , but expressivity is variable. A wide range of clinical findings and complications can develop among individuals with the same underlying mutation. The specific NF1 mutation is therefore not the only factor that determines phenotype.

In 1987, an international consortium found evidence of linkage to the pericentromeric region of chromosome 17 in families with NF1 . Subsequent descriptions of two NF1 patients with balanced translocations involving the long arm of chromosome 17 (17q11.2) further refined the position of the NF1 locus . The localization data derived from these studies led to the cloning of the NF1 gene .

The NF1 gene encodes neurofibromin, a 327 kDa protein composed of 2818 amino acids, and consists of at least 59 exons ( Fig. 61.1 ) . Over 80% of NF1 patients have a mutation that predicts truncation of the neurofibromin protein, and ~5% of patients have a large deletion (“microdeletion”) that encompasses the entire NF1 gene plus variable flanking genes . Although there is usually no clear genotype–phenotype correlation, exceptions include: (1) the single amino acid deletion p.Met922del and a missense mutation affecting p.Arg1809, each associated with an absence of neurofibromas and the latter with a Noonan syndrome-like phenotype ; and (2) a recurrent 1.4-mega-base pair deletion (“type 1 microdeletion”) resulting in a more severe phenotype . The latter includes an earlier onset and larger number of neurofibromas, an increased risk of malignant peripheral nerve sheath tumors, cognitive deficiencies, facial dysmorphism, overgrowth, and connective tissue dysplasia (e.g. hyperextensible skin, joint laxity) .

Fig. 61.1, The neurofibromatosis 1 gene and neurofibromin.

Sequence similarities between a central 300–400 amino acid domain within neurofibromin and G TPase- a ctivating p roteins (GAPs) led to recognition of neurofibromin's role in the negative regulation of the Ras– m itogen- a ctivated p rotein k inase (MAPK) pathway that promotes cell survival and proliferation (see Fig. 61.1 and Fig. 55.4 ) . Like all G proteins, Ras activity requires GTP. Neurofibromin and other GAPs accelerate the hydrolysis of GTP to GDP, thereby terminating the Ras signal and functioning as tumor suppressor proteins. Neurofibromin also associates with microtubules , although the consequences remain unclear.

As observed in other autosomal dominant genodermatoses (e.g. basal cell nevus syndrome) caused by a defective tumor suppressor gene, a somatic “second hit” mutation inactivating the remaining allele of the gene (i.e. causing loss of heterozygosity [LOH]) can be found within skin lesions of NF1. Biallelic NF1 inactivation has been identified in Schwann cells from neurofibromas as well as melanocytes from café-au-lait macules in patients with NF1 . In a mouse model, Nf1 nullizygosity ( Nf1 −/− ) in Schwann cells was shown to be necessary, but not sufficient, for neurofibroma formation ; however, plexiform neurofibromas did arise from Nf1 −/− Schwann cells when the microenvironment included Nf1 +/− (rather than wild-type) mast cells . The latter cells appear early in neurofibroma development and are hypermotile in response to the c-Kit ligand (stem cell factor), which is oversecreted by Nf1 −/− Schwann cells. Once recruited, mast cells produce growth factors that likely promote neurofibroma tumorigenesis ( Fig. 61.2 ). Of note, genetic or pharmacologic attenuation of kit signaling in Nf1 +/− mast cells has been found to diminish neurofibroma initiation and progression (see Treatment section below).

Fig. 61.2, Role of the tumor microenvironment in neurofibroma formation.

Clinical Features

The clinical features of NF1 ( Table 61.2 ) are myriad and vary in frequency . Through decades of careful study, almost every organ system has been found to be involved in NF1. However, the cutaneous manifestations of NF1 represent particularly important clinical features and have a central role in its diagnosis .

Table 61.2
Major clinical features of neurofibromatosis type 1.
JXGs, juvenile xanthogranulomas.
MAJOR CLINICAL FEATURES OF NEUROFIBROMATOSIS TYPE 1
Cutaneous
  • Neurofibromas (60–90%)

  • Café-au-lait macules (>90%)

  • Axillary and/or inguinal freckling (~80%)

  • Plexiform neurofibroma (25%)

  • Nevus anemicus (30–50%)

  • Juvenile xanthogranuloma (15–35% in first 3 years of life)

Ocular
  • Lisch nodules (~90% by 20 years of age)

  • Choroidal nodules (>80% of adults)

  • Neovascular glaucoma, retinal vasoproliferative tumors

Skeletal
Cranial
  • Macrocephaly (20–50%)

  • Hypertelorism (25%)

  • Sphenoid wing dysplasia (<5%)

Spinal
  • Scoliosis (5–10%)

  • Spina bifida

Limbs
  • Dysplasia of long bone cortex (5%), pseudarthrosis (2%)

Other
  • Generalized osteopenia (~50%), osteoporosis (~20%)

  • Short stature (~30% <3 rd percentile)

  • Pectus deformity (30–50%)

Tumors
  • Optic glioma (10–15%) (with or without precocious puberty)

  • Malignant peripheral nerve sheath tumors (3–15%)

  • Pheochromocytoma (~1%)

  • Juvenile myelomonocytic leukemia

  • CNS tumors other than optic gliomas (~5%)

  • Rhabdomyosarcoma, especially of the genitourinary tract

  • Duodenal carcinoid

  • Somatostatinoma

  • Parathyroid adenoma

  • Gastrointestinal stromal tumors (GIST)

  • Breast cancer (~5-fold increased risk in women <50 years of age)

Neurologic
  • Unidentified bright objects (UBO) on 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

Oculocutaneous manifestations

Café-au-lait macules (CALMs) are tan to dark brown (depending on the degree of constitutive pigmentation), uniformly pigmented macules and patches that are randomly distributed on the body, with the exception of the scalp, palms, and soles. The CALMs of NF1 are sharply demarcated with regular borders and often have an oval shape ( Fig. 61.3 ); the diameter can vary from a few millimeters to >4 cm. CALMs may not be apparent at birth and frequently become more noticeable during the first year of life; fading of these lesions during later adulthood has also been described . When located within areas of dermal melanocytosis, CALMs may be surrounded by a rim of normally pigmented skin (see Ch. 112 ). Larger CALMs, especially those with associated hypertrichosis, should be palpated to exclude the possibility of an underlying plexiform neurofibroma (see below).

Fig. 61.3, Café-au-lait macules and “freckling”.

Crowe et al. reported that 10% of the normal population has one to five CALMs, and Burwell et al. found that 26% of 732 white schoolchildren had at least one CALM >1 cm in diameter. In the latter study, ≥6 CALMs were found in only three children (0.4%) and they were siblings with a parent who had NF1. For the clinical diagnosis of NF1, a minimum of six CALMs is required to meet the specificity of this criterion ( Tables 61.3 and 61.4 ). To avoid confusion with lentigines, CALMs must be >5 mm in prepubertal individuals and >15 mm in postpubertal individuals in order to satisfy this diagnostic criterion for NF1.

Table 61.3
NIH diagnostic criteria for neurofibromatosis type 1.
Updated diagnostic criteria including recently recognized manifestations (e.g. nevus anemicus, choroidal nodules) and NF1 gene testing are under development. When a multistep, comprehensive analysis of the NF1 gene is performed (see text), an underlying mutation can be detected in ≥95% of non-founder patients who fulfill these diagnostic criteria.
NIH DIAGNOSTIC CRITERIA FOR NEUROFIBROMATOSIS TYPE 1
Two or more of the following must be present:

  • Six or more café-au-lait macules >5 mm in prepubertal individuals and >15 mm in postpubertal individuals

  • Two or more neurofibromas of any type or one plexiform neurofibroma

  • “Freckling” in the axillary or inguinal regions

  • Optic gliomas

  • Two or more Lisch nodules (iris hamartomas)

  • Osseous lesion, such as sphenoid wing dysplasia or thinning of long bone cortex, with or without pseudarthrosis

  • First-degree relative (parent, sibling or offspring) with NF1 by the above criteria

Table 61.4
Disorders associated with multiple café-au-lait macules (CALMs).
Multiple CALMs may also be seen in patients with segmental pigmentation disorder (see Ch. 67 ). AD, autosomal dominant; AR, autosomal recessive; ID, intellectual disability; KITLG ; KIT ligand; MAPK, mitogen-activated protein kinase.
DISORDERS ASSOCIATED WITH MULTIPLE CAFÉ-AU-LAIT MACULES
Disorder Notes
Neurofibromatosis and related disorders
Neurofibromatosis 1 (NF1) AD; six or more CALMs in >90% of patients; mutations in NF1 gene; see text
Neurofibromatosis 2 AD; six or more CALMs in minority of patients; mutations in NF2 gene; see Table 61.6
Mosaic (segmental) NF1 (formerly neurofibromatosis 5) Neurofibromas alone or CALMs ± “freckling” in a block-like or other mosaic pattern; due to a postzygotic NF1 mutation, which may involve the gonads in some patients
Legius (NF1-like) syndrome AD; six or more CALMs in >80% and intertriginous “freckling” in ~50% of patients; lack neurofibromas, Lisch nodules, optic gliomas, and typical osseous lesions of NF1; macrocephaly and learning disabilities are common; lipomas, hypopigmented macules, and vascular anomalies in minority; loss-of-function mutations in SPRED1 gene, the protein product of which inhibits MAPK signaling
Watson syndrome AD; short stature; pulmonic stenosis; ID; may also have Lisch nodules, axillary/inguinal freckling, and neurofibromas; allelic with NF1; 60/100 *
Jaffe–Campanacci syndrome Disseminated non-ossifying fibromas of long and jaw bones; hypogonadism or cryptorchidism; D; 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 (allelic with LEOPARD syndrome) > SOS1, RAF1, RIT1 > KRAS, NRAS, MAP2K1, CBL, SHOC2 (with loose anagen hair), and rarely other genes; patients with an NF1–Noonan overlap phenotype have mutations in NF1 gene
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 (childhood tumor syndrome with NF1 phenotype; formerly Turcot syndrome type 1) AR; multiple CALMs, axillary freckling, neurofibromas and/or CNS gliomas (features similar to NF1) as well as hypopigmented macules, hematologic malignancies, and colorectal carcinoma; patients have mutations in both copies of a DNA mismatch repair gene, e.g. MLH1, MSH2, MSH6, PMS2 ; hereditary non-polyposis colorectal cancer (HNPCC) syndrome can occur in heterozygotes
McCune–Albright syndrome Not inherited; presumably lethal unless in mosaic state; polyostotic fibrous dysplasia; hyperfunction of endocrine glands, esp. gonads (e.g. precocious puberty); CALMs usually appear during infancy and can overlie bony changes; CALMs classically end at midline, but so can larger CALMs of NF; CALMs may follow lines of Blaschko; activating mutations in the GNAS1 gene that encodes G s α; 35/100 *
Disorders with additional cutaneous findings
Tuberous sclerosis complex (TSC) AD; ID; seizures; hypopigmented macules; angiofibromas; fibrous plaques; mutations in TSC1 and TSC2 genes; see text
Westerhof syndrome AD; congenital hypo- and hyperpigmented macules; ID; growth retardation
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 and overlapping with lentigines and hypopigmented macules and patches; activating mutations in KITLG gene
Mukamel syndrome AR; premature graying (infancy); lentigines; depigmented macules; ID; spastic paraparesis, microcephaly, scoliosis
Noonan syndrome with multiple lentigines (LEOPARD syndrome) AD; darker “café noir” macules; L entigines, E CG abnormalities, O cular hypertelorism, P ulmonic stenosis, A bnormal genitalia, R etardation of growth, D eafness syndrome; mutations in PTPN11 ; 38/100 *
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 Agminated lentigines; debatable if associated neurologic or psychiatric problems; unilateral axillary freckling and Lisch nodules have been described (such patients likely have mosaic NF1)
Bannayan–Riley–Ruvalcaba syndrome AD; penile lentigines; vascular malformations; lipomas; intestinal hamartomas; macrocephaly; mutations in PTEN gene; ≤10% of patients have CALMs
Cowden syndrome AD; multiple tricholemmomas; cobblestoning of oral mucosa; palmoplantar keratoses; sclerotic fibromas, hamartomas and carcinoma of breast, thyroid, colon; mutations in PTEN gene; ≤10% of patients have CALMs
Gastrocutaneous syndrome AD; multiple lentigines; peptic ulcer/hiatal hernia; hypertelorism; myopia
Ataxia–telangiectasia AR; telangiectasias of conjunctivae, head/neck, and acral sites; premature canities; cerebellar ataxia; abnormal DNA repair; lymphomas and leukemias; immunodeficiency; sinopulmonary infections; mutations in ATM gene; 20/100 *
Bloom syndrome AR; telangiectatic erythema of face; photosensitivity; growth retardation; increased sister chromatid exchanges; malignancies; hypogonadism; mutations in BLM gene that encodes the 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. acute myelogenous leukemia
Chromosomal anomalies/mosaicism In particular, ring chromosomes (7, 11, 12, 15, 17); rearrangements of 7 and 14; ring 7 also associated with vascular lesions (hemangiomas and 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 62.7 for genes
Multiple endocrine neoplasia 1 AD; tumors of the pituitary, parathyroid, and pancreatic islet cells; multiple facial angiofibromas, collagenomas, gingival papules, confetti-like hypomelanotic macules, lipomas; MEN1 gene
Multiple endocrine neoplasia 2B AD; mucosal neuromas; marfanoid habitus; medullary thyroid carcinoma; intestinal ganglioneuromatosis; pheochromocytoma; mutations in RET proto-oncogene
Johnson–McMillin syndrome Probable AD; alopecia; anosmia; deafness; hypogonadism; microtia
Tricho-hepato-enteric syndrome AR; CALM and lentigines on hips and legs; diffuse pigmentary dilution (skin & hair), woolly hair; dysmorphic facies with hypertelorism; intractable diarrhea, liver disease; immune deficiency; mutations in TTC37 or SKIV2L
Tay syndrome ?AR; growth retardation; ID; triangular face; cirrhosis; trident hands; premature canities; vitiligo
Other disorders §
Russell-Silver syndrome Growth retardation; triangular face; clinodactyly 5th finger; hemihypertrophy; epigenetic changes on chromosome 15p13 or maternal uniparental disomy of chromosome 7; 45/100 *

* Estimates of prevalence of CALMs .

To date, observed in a single family.

Overlapping conditions collectively referred to as PTEN hamartoma tumor syndrome.

§ Single case reports of multiple CALMs in association with X-linked hypohidrotic ectodermal dysplasia, woolly hair, and osteoma cutis.

In its fullest expression, NF1 can manifest with thousands of neurofibromas in an affected individual, hence the appellation neurofibromatosis ( Fig. 61.4 ). Several variants of neurofibromas are observed in NF1. Most commonly, proliferations of spindle cells occur within the dermis, leading to cutaneous neurofibromas (CNFs). CNFs are skin-colored to pink, tan, or brown papulonodules that are soft or slightly rubbery in texture and can range from a few millimeters to several centimeters in diameter. While fully formed CNFs are often dome-shaped or pedunculated, early lesions may be barely elevated. They invaginate easily with gentle pressure, exhibiting the pathognomonic “buttonhole” sign. Although usually asymptomatic, lesions may become pruritic or, occasionally, irritated. CNFs appear as early as 4–5 years of age but more typically develop around puberty, with occasional acceleration of growth during pregnancy.

Fig. 61.4, Multiple cutaneous neurofibromas.

Subcutaneous neurofibromas (SNFs) occur deeper in the dermis and subcutis, tending to be firmer and less well-circumscribed than CNFs. Nearly one-fifth of NF1 patients have at least one SNF , and one-quarter of these individuals develop tumor-related local complications. Less common cutaneous presentations of neurofibromas in patients with NF1 include: (1) blue–red macules due to thick-walled blood vessels as well as neurofibromatous tissue within the papillary dermis ( Fig. 61.5 ); and (2) pseudo-atrophic macules due to replacement of collagen in the reticular dermis with neurofibromatous tissue .

Fig. 61.5, Spectrum of cutaneous neurofibromas.

Plexiform neurofibromas (PNFs; Fig. 61.6 ) may track along nerves to create tender, firm nodules or masses in the subcutaneous tissue with a “bag of worms” consistency upon palpation, or they can infiltrate diffusely to involve various layers of the skin, fascia, muscle, or even internal structures. Approximately 25% of NF1 patients have clinically apparent PNFs. Larger lesions may cause soft tissue and bony hypertrophy, and massive distortion of the head and neck or extremities occasionally develops. Impingement upon nerves can lead to neurologic deficits.

Fig. 61.6, Plexiform neurofibromas.

Unlike other neurofibromas, PNFs are probably all congenital in origin. Superficial and/or diffuse lesions usually become clinically apparent by the age of 4 or 5 years , while deep/internal nodular lesions may remain undetected even in adulthood unless a full-body MRI is performed . Older children without evidence of soft tissue overgrowth related to a PNF are unlikely to develop this finding later in life. Both hyperpigmentation and hypertrichosis can overlie PNFs , sometimes leading to misdiagnosis as a congenital melanocytic nevus (see Fig. 61.6 ).

The transformation of PNFs into malignant peripheral nerve sheath tumors (MPNSTs, also known as “neurofibrosarcomas”) occurs in 3–15% of patients with NF1 , with a peak incidence in young adults. The onset of rapid growth, increased firmness, or persistent pain within an established PNF or the development of a new neurologic deficit may herald malignant degeneration ( Table 61.5 ; see Management section ). MPNSTs can be very aggressive and are often fatal .

Table 61.5
Evaluation and management of neurofibromatosis 1 (NF1) patients.
CT, computed tomography; MRI, magnetic resonance imaging; PET-CT, positron emission tomography–computed tomography.
EVALUATION AND MANAGEMENT OF NEUROFIBROMATOSIS 1 (NF1) PATIENTS
At time of diagnosis and annually during childhood and adolescence (unless otherwise indicated)
  • Dermatologic examination (especially if a plexiform neurofibroma [PNF] is present)

    • Surgical consultation if painful or disfiguring neurofibromas

    • PET-CT if rapid growth, increased firmness, or persistent pain within an established PNF or the development of a new neurologic deficit *

  • Ophthalmologic examination with visual assessment (prior to age 8 years)

    • Orbital/brain MRI if signs/symptoms of optic glioma

  • Evaluation for scoliosis and tibial bowing

    • Referral to orthopedics if scoliosis develops

  • Neurologic examination, developmental/behavioral evaluation, and (in young children) measurement of head circumference

    • Orbital/brain and/or spinal MRI if neurologic signs/symptoms develop

    • Comprehensive developmental assessment prior to starting school and if problems arise

  • Cardiac assessment and measurement of blood pressure

    • Referral to cardiology if murmur is detected

    • Renal arteriography and 24-hour urine collection for catecholamines and metanephrines if hypertension develops

  • Assessment for pubertal development

    • Orbital/brain MRI and referral to endocrinology if precocious puberty develops

Minimum annual evaluation for adults with uncomplicated disease
  • Dermatologic evaluation if PNF is present

    • PET-CT for indications described above

  • Neurologic examination (especially if a PNF is present)

    • MRI and/or other studies as indicated if neurologic signs/symptoms develop

  • Measurement of blood pressure

    • Evaluation as described above if hypertension develops

  • In women, screening for breast cancer with clinical examination + mammography ± MRI (beginning by age 40 years)

Potentially affected family members
  • Dermatologic examination for cutaneous manifestations of NF1

  • Ophthalmologic examination for Lisch nodules

  • Consider genetic testing if a mutation has been identified in the proband

* Immediate assessment is required for any of these findings.

The role of neuroimaging in asymptomatic patients is controversial.

“Freckling” in the axillae and groin in NF1 patients was first noted by Crowe and is referred to as “Crowe's sign” (see Fig. 61.3 ). Numerous 1–3 mm brown macules (more akin to lentigines than ephelides) typically populate these intertriginous zones, the neck, and, occasionally, the majority of the skin surface (see Figs 61.3 & 61.4 ). Involvement of the axillae is most common, occurring in about 80% of NF1 patients . The lesions usually arise by 4–6 years of age, following the emergence of CALMs but preceding the development of neurofibromas. As a result, intertriginous “freckling” is a useful clinical sign in the evaluation of a young child with multiple CALMs .

As many as 15–35% of children with NF1 develop one or more juvenile xanthogranulomas (JXGs) during the first 2–3 years of life, making these lesions a potential early sign of NF1 when they coexist with multiple CALMs . Young children with NF1 also have a 200- to 500-fold greater risk of developing juvenile myelomonocytic leukemia (JML; incidence 1/2000–1/5000) than does the general pediatric population. Although a “triple association” between NF1, JML, and JXG has been described , the magnitude of additional risk of JML in children with NF1 plus JXGs compared to NF1 alone remains to be determined. Neurofibromin is known to regulate the proliferation of myeloid cells, but the exact etiopathogenesis of the “triple association” remains unclear.

Vascular anomalies that have been recognized as manifestations of NF1 include nevus anemicus and glomus tumors . In two prospective studies, a nevus anemicus was identified in a total of 55% (92/166) of children and 36% (19/53) of adults with NF1, compared to only 2% (6/302) of age- and sex-matched controls . These lesions favor the trunk, especially the mid chest, and become more evident after rubbing the skin. Because nevus anemicus is prevalent in NF1 patients and apparent by early childhood, its use as a diagnostic criterion has been proposed .

Biallelic inactivation of NF1 has been documented within glomus tumors in NF1 patients . The tumors are often multiple and develop on the fingers > toes; like their sporadic counterpart, present with paroxysmal pain and sensitivity to cold (see Ch. 114 ). Focal swelling, ill-defined reddish discoloration (often of the nail bed), and nail dystrophy may be observed.

Pigmented iris hamartomas, or Lisch nodules, begin to develop at about 3 years of age and are found in ~90% of NF1 patients by 20 years of age . These 1–2 mm, dome-shaped, yellow–brown papules are best seen on slit-lamp examination ( Fig. 61.7 ). Lisch nodules rarely lead to symptoms or complications. Asymptomatic choroidal nodules are also present in 80–100% of adults and 60–70% of children with NF1, and their use as a diagnostic criterion has been suggested. However, the near-infrared reflectance imaging required for detection of these lesions may be technically challenging in younger children .

Fig. 61.7, Lisch nodules.

In mosaic (segmental) NF1 (formerly known as NF5), cutaneous neurofibromas, CALMs, and/or “freckling” are present in one or more dermatomes (especially for neurofibromas; Fig. 61.8A ) or in other mosaic distribution patterns such as blocks with midline demarcation (especially for CALMs and freckling; Fig. 61.8B ). This form of NF1 results from a postzygotic NF1 mutation, and up to 30% of patients also have extracutaneous manifestations of NF1 . If the mutation involves the gonads (germline mosaicism) as well as the skin, there is a chance of full-blown NF1 in the patient's offspring.

Fig. 61.8, Mosiac neurofibromatosis.

Neurologic manifestations

Optic gliomas occur in up to 15% of children with NF1 . The behavior of these CNS neoplasms is variable, ranging from asymptomatic enlargement to progressive visual compromise and proptosis due to tumor expansion . Precocious puberty occurs in about 3% of children with NF1, most of whom have optic gliomas . Non-optic CNS tumors occur in ~5% and pheochromocytomas in ~1% of NF1 patients .

In MRI studies of the brain, T2-weighted unidentified bright objects (UBOs) can be observed in 50–75% of children with NF1 . These are most commonly seen in the basal ganglia, brainstem, and cerebellum. UBOs have been shown to evolve over time , and they may contribute to cognitive impairment via thalamocortical dysfunction .

Although severe intellectual impairment is uncommon, learning difficulties occur in 30–50% of affected children ; there is also an increased likelihood of attention deficit disorder, headaches, and sleep disturbances. Seizures develop in about 5% of NF1 patients, although no specific cortical lesions have been linked to the abnormal EEG activity .

Skeletal manifestations

Macrocephaly , hypertelorism, scoliosis , and osteopenia are common cranioskeletal abnormalities in individuals with NF1. A highly distinctive but less common finding is pseudarthrosis of the long bones, most often the tibia. This congenital defect begins as bowing and eventually results in erosion of the bone cortex, leading to pathologic fractures and false joint formation (pseudarthrosis) . Sphenoid wing dysplasia is a congenital, typically unilateral bony defect in the posterior wall of the orbit that may present as pulsating exophthalmos .

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