Neurofibromatosis and Tuberous Sclerosis

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Neurofibromatosis and Tuberous Sclerosis

• Neurofibromatosis (NF) and tuberous sclerosis (TS) are neurocutaneous disorders (phacomatoses) characterized by skin lesions as well as neoplasms of the central and peripheral nervous systems.

• Cutaneous manifestations (especially pigmentary findings) are often the first clinical signs of NF type 1 (NF1) and TS.

• Both disorders have autosomal dominant inheritance, although ~30–50% of patients have unaffected parents and harbor new, spontaneous mutations.

• Education of patients/parents about the condition, attention to psychosocial concerns, and genetic counseling represent important components of care.

Neurofibromatosis Type 1 (von Recklinghausen Disease)

• Incidence of approximately 1 in 3000 births.

• The NF1 tumor suppressor gene encodes the neurofibromin protein, which negatively regulates the RAS-mitogen-activated protein kinase (MAPK) pathway that promotes cell survival and proliferation.

• Patients with NF1 have a constitutive (germline) NF1 mutation plus a somatic ‘second hit’ mutation inactivating the other copy of the gene in affected tissues (e.g. Schwann cells in neurofibromas, melanocytes in café-au-lait macules [CALMs]).

• The major clinical features of NF1 are outlined in Table 50.1 and depicted in Figs. 50.1–50.5; Fig. 50.6 shows the time course of their development.

Fig. 50.1 Café-au-lait macules and ‘freckling’. Oval-shaped, light-to medium-brown patches with regular borders and uniform pigmentation (A, B). Numerous 1- to 3-mm lentigines are most commonly found in the axilla (Crowe’s sign) (B) but can also develop in other sites such as the perioral region (C). A, C, Courtesy, Julie V. Schaffer, MD.

Fig. 50.2 Multiple cutaneous neurofibromas. Soft, skin-colored to pinkish tan, dome-shaped or polypoid, well-demarcated papules and nodules of various sizes (A, B) in patients with NF1. Neurofibromas may be superimposed on café-au-lait macules and lentigines (B). Courtesy, Julie V. Schaffer, MD.

Fig. 50.3 Spectrum of cutaneous neurofibromas. Lesions range from subtle blue-red macules (A) to exophytic nodules with associated hypertrichosis (B). Courtesy, Julie V. Schaffer, MD.

Fig. 50.4 Plexiform neurofibromas. A A hyperpigmented plaque that may be misdiagnosed as a congenital melanocytic nevus or (if not palpated) a café-au-lait macule. Note the widespread ‘freckling’ on the trunk. B A poorly circumscribed, sagging pink mass. Courtesy, Julie V. Schaffer, MD.

Fig. 50.5 Lisch nodules. Multiple yellow-brown papules of the iris.

Fig. 50.6 Development of clinical features in neurofibromatosis type 1. The time course of major diagnostic lesions that develop in NF1. During the first few years of life, a child may have only café-au-lait macules. Adapted from DeBella K, Szudek J, Friedman JM. Use of the National Institutes of Health criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics 2000;105:608–614.

• The NIH diagnostic criteria for NF1 (Table 50.2) are met in 97% of patients by age 8 years.

Table 50.2

Classic diagnostic criteria for neurofibromatosis type 1 (NF1).

Reproduced with permission from NIH Conference: Neurofibromatosis Statement. Arch. Neurol. 1988;45:575–578.

• An approach to infants or young children with ≥6 CALMs is presented in Fig. 50.7.

Fig. 50.7 Approach to a young child with six or more café-au-lait macules (CALMs). More than half of these patients will eventually be diagnosed with NF1 or, less often, another CALM-associated syndrome (see Table 50.3). The latter should be considered if other signs of NF1 do not develop.

• Comprehensive NF1 gene analysis with ≥95% sensitivity is available; this can help to establish the diagnosis in atypical presentations or young children not yet meeting criteria.

• DDx: other disorders that can manifest with multiple CALMs are summarized in Table 50.3.

Table 50.3

Other disorders associated with multiple café-au-lait macules (CALMs).

Of note, approximately 30% of the general population has at least one CALM.

^† DDx may include a large speckled lentiginous nevus (nevus spilus) or partial unilateral lentiginosis (see Chapter 92).

^* Multiple CALMs in small minority of affected individuals.

AD, autosomal dominant; AR, autosomal recessive; JMML, juvenile myelomonocytic leukemia; KP, keratosis pilaris; LEOPARD, lentigines/electrocardiogram abnormalities/ocular hypertelorism/pulmonary stenosis/abnormalities of genitalia/retardation of growth/deafness syndrome; MAPK, mitogen-activated protein kinase; NF1, neurofibromatosis type 1.

Fig. 50.8 Segmental neurofibromatosis. A cluster of soft, pink to pink-brown papules limited to the thigh. There were no associated café-au-lait macules. Courtesy, Jean L. Bolognia, MD.

• Management of NF1 requires a multidisciplinary approach (Table 50.4).

Table 50.4

Evaluation and management of neurofibromatosis 1 (NF1) patients.

Tuberous Sclerosis

• Incidence of approximately 1 in 10 000 births.

• Hamartomatous disorder caused by mutations in either the TSC1 or TSC2 gene; both encode proteins (hamartin and tuberin, respectively) that negatively regulate the mammalian target of rapamycin (mTOR) pathway that promotes cell growth.

• TSC2 mutations are associated with more severe disease and are threefold more common than TSC1 mutations in TS patients overall.

• Fig. 50.9 shows the time course for the development of cutaneous findings in TS.

Fig. 50.9 Development of cutaneous features in tuberous sclerosis. Hypomelanotic macules are usually the only cutaneous finding at birth.

• Hypomelanotic macules may be very subtle or inapparent in individuals with lightly pigmented skin, and a Wood’s light can help to identify them.

• The hypomelanotic macules in TS patients vary in number (few to >100) and size (<1 to >10 cm); their shapes are polygonal more often than resembling an ‘ash leaf’ – rounded at one end, tapered at the other (Fig. 50.10A).

– DDx: nevus depigmentosus is a common (1–5% of healthy children) cause of one or two hypopigmented macule(s) or patch(es); Fig. 50.11 presents an approach to infants/young children with ≥3 hypomelanotic macules.

Fig. 50.10 Hypopigmentation in tuberous sclerosis. A Ash leaf macule. B ‘Confetti’ macules of guttate leukoderma. B, Courtesy, Jean L. Bolognia, MD.

Fig. 50.11 Approach to an infant with three or more hypomelanotic macules or patches. A child with fewer than three macules and no family history of tuberous sclerosis (TS) has an extremely low likelihood of having this disease.

• Numerous small, confetti-like hypopigmented macules (especially on the extremities) represent a relatively specific finding for TS (Fig. 50.10B).

• Angiofibromas (formerly known as ‘adenoma sebaceum’) are smooth, dome-shaped, pink to red-brown papules (Fig. 50.12); they favor the central face and sometimes coalesce to form plaques.

– DDx: multiple facial angiofibromas can occur in multiple endocrine neoplasia type 1 (MEN1) and Birt–Hogg–Dubé syndrome (see Chapter 91).

Fig. 50.12 Facial angiofibromas. Multiple shiny, dome-shaped papules on the cheeks and nose of an adolescent. Courtesy, Julie V. Schaffer, MD.

• Variants of angiofibromas include cephalic fibrous plaques (e.g. on forehead), ungual fibromas (Koenen tumors; toes > fingers) (Fig. 50.13), and molluscum pendulum (resembling large skin tags) in flexural sites.

Fig. 50.13 Periungual fibromas of tuberous sclerosis. Multiple fibromas of the toes arising in a periungual location.

• Shagreen patches are connective tissue nevi with a predilection for the lower back; they present as skin-colored, hyperpigmented or (less often) hypopigmented plaques with an uneven, pigskin-like surface (Fig. 50.14).

Fig. 50.14 Connective tissue nevi (shagreen patches) in tuberous sclerosis. These plaques can be hyperpigmented (A) or hypopigmented (B) relative to the patient’s background skin. The surface is said to resemble leather or pigskin. B, Courtesy, Julie V. Schaffer, MD.

• Infantile spasms affect ~70% of TS patients, typically beginning at 3–6 months of age; mental deficiency and neuropsychiatric conditions (e.g. autism, attention deficit disorder) are common.

• Additional extracutaneous manifestations and diagnostic criteria are listed in Table 50.5.

Table 50.5

Revised diagnostic criteria for tuberous sclerosis complex.

In contrast to NF1, café-au-lait macules are found in a minority of patients and are usually few in number. Green background = cutaneous lesions.

• Recommendations for evaluation and management are presented in Table 50.6.

• Rx: systemic administration of mTOR inhibitors (rapamycin [sirolimus], everolimus) for astrocytomas, renal angiomyolipomas, and pulmonary lymphangioleiomyomas; topical rapamycin, lasers (pulsed dye or ablative), and electrosurgery to treat angiofibromas.

For further information see Ch. 61. From Dermatology, Third Edition.

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