Spotty

Nervous System & Special Senses


Diagnosis and reasoning

Pigmented lesions are extremely common in the pediatric age group, and can range from being completely benign, to being a herald of serious dermatological or systemic disease.


In this specific child's case, a closer look at the 'brown spots' show them to be café au lait patches. These lesions can be an early sign of certain neurocutaneous disorders; conversely, they are also found in completely normal individuals.


The number and size of the patches are helpful in establishing their significance; in this respect, note that she has six or more café au lait spots larger than five millimeters in diameter. This is suggestive of neurofibromatosis type 1 (NF1), and warrants a search for the other features of the disease.


Further examination reveals freckling in the axillary and inguinal regions, while slit lamp examination reveals Lisch nodules (hamartomas of the iris); considered along with the café au lait spots, these account for three of the seven diagnostic criteria for NF1; the pr

esence of just two is sufficient to establish the diagnosis.

Note that McCune-Albright syndrome and tuberous sclerosis are also known to present similarly; however, the first of these is typically associated with precocious puberty, while the skin lesions respect the midline, and are larger with irregular borders. Tuberous sclerosis is characterized by cafe au lait spots with hemangiomas and a history of convulsions.


His evaluation should not stop there; it is important to determine if other stigmata are present; in particular, a skeletal survey is of value in detecting associated osseous lesions, such as thinning of the long bone cortex.


Note that while magnetic resonance imaging (MRI) is of use in detecting optic gliomas and other central tumors, this is not routinely indicated. Skin biopsies are of little value in the absence of neurofibromas.


As NF1 is transmitted in an autosomal dominant fashion, screening both of her parents is essential; that said, the lack of a family history suggests that this is probably a de novo mutation.


Laser treatment of the cafe au lait patches is not generally recommended, as this can cause permanent hyperpigmentation, hypopigmentation, or scarring. Neither is neurosurgical referral indicated in the absence of neurological signs and symptoms.

Note also that there is no rationale for chemotherapy in this patient.

Discussion

Neurofibromatosis type 1 (NF1) is a multisystem neurocutaneous disorder; it is inherited in an autosomal dominant manner, and is the most common such condition, with an estimated incidence of 1 in 2,500 to 1 in 3,000 individuals worldwide.


The disease is associated with mutation of the NF1 gene; this is located on the long arm of chromosome 17, and is responsible for production of neurofibromin, a tumor suppressor that downregulates the Ras oncogene family (which enhance cell growth and proliferation).


Mutation of the NF1 gene causes a marked decrease of neurofibromin, resulting in a significantly higher incidence of both benign and malignant neoplasms, particularly of the nervous system.

Benign nerve sheath tumors termed 'neurofibromas' are the hallmark of NF1. These can be cutaneous or plexiform, with the latter consisting of multiple neurofibromas along a specific nerve course; they can also transform into malignant peripheral nerve sheath tumors (MPNSTs).


Other frequently encountered tumors include optic gliomas, which involve the optic nerve; they are frequently bilateral and often involve the chiasm. Lisch nodules are benign hamartomas of the iris which consist of proliferations of melanocytes and fibroblasts.

These patients also have a higher incidence of other malignancies of neural crest origin, as well as certain leukemias and lymphomas.


It has also been postulated that mutation of the NF1 gene exerts a direct effect on growth and musculoskeletal metabolism; these patients may experience hypotonia, bony dysplasias, bony erosions, and cortical thinning.


As NF1 is inherited in an autosomal dominant fashion, a single gene deletion is sufficient to cause the disease. However, about half of cases are due to de novo mutations; the mutation rate for NF1 (~1:10,000) is among the highest known for any gene in humans.


The clinical manifestations of NF1 vary significantly between patients, with the spectrum ranging from being almost unaffected, to severe, full-blown manifestations. Most patients are diagnosed after the age of 10 years, unless there is a family history, in which case the condition is often detected in infancy.


The earliest manifestation is café au lait patches, which are often present at birth; however, these are not pathognomonic, being found in 10% of the normal population, and also being associated with other conditions such as McCune-Albright syndrome, NF type 2 or DNA repair syndromes.


Neurofibromas may develop during childhood, but are usually encountered after puberty. SuperficIal lesions can cause significant cosmetic disfigurement, while those in proximity to the central nervous system can give rise to hydrocephalus or paraplegia, secondary to compression.


Optic gliomas are usually asymptomatic but may sometimes affect the visual fields and acuity. Lisch nodules may be seen as brownish or hypopigmented spots in the iris, but are often only apparent following slit-lamp examination.


Skeletal surveys are of use in excluding associated long bone diseases such as scoliosis or thinning of the bone cortex. Magnetic resonance imaging (MRI) of the brain will help detect central tumors, but is not routinely recommended, as these are usually asymptomatic.

Molecular genetic testing for NF1 is rarely required, except in young patients with isolated clinical findings and no family history of the condition.


Note that the National Institutes of Health (NIH) has developed a seven point clinical criteria for the diagnosis of NF1; at least two of these should be present to establish the diagnosis:

(1) six or more cafe au lait spots >5 mm in diameter in prepubertal patients or >15 mm in diameter in postpubertal patients;

(2) two or more neurofibromas or one plexiform neurofibroma;

(3) freckling in the axillary and/or inguinal regions;

(4) optic glioma;

(5) two or more Lisch nodules (iris hamartomas);

(6) a distinctive osseous lesion, such as sphenoid wing dysplasia or cortical thinning of the long bones;

(7) a first-degree relative with NF1.


Unfortunately, there is no definitive treatment for NF1; neurofibromas which cause cosmetic disfigurement can be removed surgically, although results are often unsatisfactory.


Minor bone diseases can be managed with vitamin D supplementation, although severe deformities such as dystrophic scoliosis may require surgical management. Patients with cognitive problems, learning disabilities and incoordination may need special educational programs.


Many of these individuals have low self-esteem, with subsequent psychological issues; these should be managed appropriately. Genetic counseling is essential, given the autosomal dominant transmission of the disease.


MPNST transformation is a devastating complication. While the treatment of choice is surgical excision, this is often tricky because of severe tissue infiltration, and rapid metastasis to distant sites such as the lungs.


Note also that these patients should be followed up annually, in order to identify and treat complications, and assess their growth, visual acuity, and size of the neurofibromas.

Most patients with NF1 live normal lives, although their life expectancy is about eight years less than that of the average population; the main causes of morbidity and mortality are malignancies, and compressive injury by the neurofibromas.

Take home messages

1. Neurofibromatosis-1 (NF1) is a multisystem neurocutaneous disorder inherited in an autosomal dominant fashion. Almost half of cases are due to de novo mutations.

2. Café au lait spots and neurofibromas are two of the most recognizable signs of the disease, but individually, are not pathognomonic.

3. The seven-point National Institutes of Health (NIH) criteria allow for the accurate diagnosis of NF1.

4. No specific treatment for NF1 exists; regular follow-up is mandatory for the early detection of complications.

References

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