Neurofibromatosis and Tuberous Sclerosis Complex

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).

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.

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.

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 .

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.

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 .

“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 .

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.

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 .