Case in Point: A Young Girl With Cafe au Lait Spots

A 9-year-old girl presents with multiple hyperpigmented lesions, some of which have been present since birth (Figure 1). The lesions have increased in size and number. There is no history of seizures. Her 40-year-old mother has multiple skin nodules (Figure 2).

More than 20 brownish macules are noted on the child's chest, back, abdomen, arms, and thighs. The macules are ovoid with sharp, well-defined borders. Twelve are larger than 1 cm in diameter.

The patient has mild thoracic scoliosis. Height, 134 cm (50th percentile); weight, 25.2 kg (25th percentile). Heart rate, 76 beats per minute; blood pressure, 90/55 mm Hg. The remainder of the examination results are normal.

TYPE 1 NEUROFIBROMATOSIS: AN OVERVIEW

Type 1 neurofibromatosis (NF1), previously known as von Recklinghausen disease, is characterized by multiple café au lait spots, intertriginous freckling, iris hamartomas (Lisch nodules), and neurofibromas. NF1is the most common single-gene disorder that affects the nervous system.¹ It is the most prevalent neurocutaneous syndrome and accounts for about 90% of all cases of neurofibromatosis.²

NF1 occurs in 1 of every 3000 to 4000 live births. There is no gender or racial predilection.³

Figure A

Figure B

PATHOGENESIS

NF1 is inherited in an autosomal dominant fashion; the gene has been mapped to chromosome 17q11.2.⁴ About 50% of cases are sporadic and attributable to a new mutation.¹ By the age of 8 years, the penetrance is close to 100%.⁵ Thus, at-risk children who do not have manifestations of NF1 by the age of 10 years are probably unaffected.There is variable expressionamong families.⁶

The gene encompasses more than 350 kb of genomic DNA andis intrinsically hypermutable.^7,8 The gene directs the synthesis of neurofibromin, which has a role in tumor suppression. Neurofibromin is expressed mainly in Schwann cells, astrocytes, oligodendrocytes, leukocytes, and theadrenal medulla.⁸ Inactivation of the gene, either through allelic loss or mutation, results in reduced neurofibromin production, which leads to uncontrolled cell growth or tumor formation.⁴ Neurofibromin is also involved in the differentiation of the neuronal neurotransmitter phenotype and in synapse formation.⁹

Figure C

CLINICAL MANIFESTATIONS

Café au lait spots. These ovoid, uniformly brown macules are found in almost all children with NF1. They are frequently present at birth and increase in size, number, and pigmentation with age.¹⁰ There is a predilection for the trunk and extremities. The scalp, face, palms, and soles are usually spared.^6,11 The number and location of café au lait spots have no relationship to the number and location of future neurofibromas.¹² However, a large hyperpigmentated lesion with an irregular border that ispresent at birth might herald an underlying plexiform neurofibroma.¹²

Neurofibromas. These benign peripheral nerve sheath tumors are composed of an extracellular matrix and a heterogeneous mixture of Schwann cells and fibroblasts.¹³ Cutaneous neurofibromas--the most common neurofibroma--often appear during puberty or pregnancy and increase in size and number with age.^10,14 These painless, soft, flesh-colored, andnodular or pedunculated lesionsoften invaginate into the skin and cause a "buttonholing" sensation when gentle digital pressure is applied to the surface.¹¹ In contrast, subcutaneous neurofibromas, which are usually much harder and more painful, are deeply seated in the dermis and, therefore, less circumscribed.^6,11 Plexiform neurofibromas are often present at birth and result from diffuse thickening of nerve trunks.¹⁰ They may be locally invasive and associated with bone erosion and pain; overgrowth of an extremity and malignant transformation are possible.^1,15

Intertriginous freckling. Freckles develop in the axillae, inguinal areas, or submammary regions by late childhood in about 80% of children with NF1.¹ Intertriginous freckling is not related to sun exposure and is pathognomonic of NF1 (Crowe sign).¹⁶

Optic glioma and other tumors. Optic gliomas occur primarily in children younger than 5 years and are detected by neuroimaging in 15% to 20% of persons with NF1.¹⁷ These tumors are pilocytic astrocytomas; they tend to grow slowly and be asymptomatic. In about 20% of affected children, vision disturbance, proptosis, or precocious puberty develops; the most common presenting symptom is asymmetric noncorrectable vision loss.¹⁰ With a unilateral lesion, the ipsilateral pupil dilates, rather than constricts, in response to light.^10,11 Precocious puberty is found in 3% of children with NF1 who have an optic glioma that involves the optic chiasm.⁶ In contrast, optic glioma is present in most children with NF1 in whom precocious puberty develops.^6,18

Other intracranial tumors include ependymomas, meningiomas, and neurilemomas.¹⁰ Dumbbell-shaped neurofibromas can develop in the spinal cord and cause compression syndromes. Patients with NF1 are at increased risk for malignancies, such as myeloid leukemia, pheochromocytoma, rhabdomyosarcoma, carcinoid tumor, Wilms tu-mor, neuroblastoma, and malignant peripheral nerve sheath tumor.^7,10,11 Juvenile xanthogranuloma occurs with increased frequency in patients with NF1.^10,11

Lisch nodules. Melanocytic hamartomas of the iris--yellow-brown, dome-shaped elevations on the iris surface--are best identified with a slitlamp examination. Although Lisch nodules do not cause vision dysfunction, they are present in 95% of affected children older than 10 years.^7,10

Osseous lesions. Some examples are sphenoid wing dysplasia, scoliosis, cortical thinning of the long bones, and pseudarthrosis.^8,12 Other skeletal abnormalities include macrocephaly, megadactyly, and pectus excavatum.¹ Short stature is common.

Learning disabilities. About 40% of children with NF1 have a learning disability.⁷ Neurocognitive deficits, abnormal visuospatial performance, receptive and expressive language problems, attention deficit hyperactivity disorder, incoordination, and clumsiness are common in children with NF1.^19-21 Mental retardation is only slightly more common than it is in the general population.^1,3,11In 60% to 70% of children with NF1, MRI demonstrates unidentifiable bright objects, frequently in the basal ganglia, brain stem, and cerebellum.⁸ The lesions do not exert any mass effect, are not visible on aCT scan, and often resolve over time. The relationship of these lesions to cognitive dysfunction is unclear.⁸

Epilepsy. The prevalence of seizures in personswith NF1 is about 5% to 7%.^7,22 Complex partial seizures are the most common form.²²

Cardiovascular abnormalities. Congenital heart disease, especiallyvalvular pulmonary artery stenosis, occurs with increased frequency in NF1 patients.¹ About 6% of persons with NF1 have hypertension, which may be secondary to renal artery stenosis, coarctation of the aorta, or pheochromocytoma.⁴

DIAGNOSIS

NF1 is diagnosed clinically based on NIH criteria (Table).²³ Two or more of the diagnostic criteria must be present. Apart from identification of the NF1 gene, no laboratory test confirms the diagnosis. DNA analysis of the gene is neither widely available nor clinically helpful in most situations. Gene testing may be helpful in prenatal diagnosis.

Multiple café au lait spots--the most important hallmark of NF1--may be the only clinical manifestation in young children. Café au lait spots are also associated with type 2 neurofibromatosis, segmental neurofibromatosis, McCune-Albright syndrome, tuberous sclerosis, multiple mucosal neuroma syndrome, Bloom syndrome, Fanconi anemia, ataxia telangiectasia, Noonan syndrome, Proteus syndrome, Klippel-Trenaunay-Weber syndrome, Watson syndrome, and multiple lentigines syndrome.^6,12,24,25 The distinctive features of each condition allow a fairly straightforward differentiation from NF1.

MANAGEMENT

Although there is currently no cure for NF1, laser surgery can reduce the appearance of cutaneous neurofibromas. All first-degree relatives of an affected patient should be examined for cutaneous manifestations and should undergo a slitlamp examination to determine whether the case is sporadic or familial.^1,17 Notify patients with a family history of the 50% recurrence rate.¹² For sporadic cases, the risk of another affected child is low and is based on the rare occurrence of germinal mosaicism.¹²

Children at risk for NFI should undergo the following:

•Ophthalmologic examination for optic glioma, performed semiannually during the first 5 years of life and yearly thereafter.

•Annual physical examination that includes assessment of the spine for scoliosis, measurement of blood pressure, neurodevelopmental evaluation, and Tanner staging for precocious puberty.

References:

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