Approach to neurocutaneous syndromes: Clinical sciences

Neurocutaneous syndromes are a heterogeneous group of genetic disorders that affect both the skin and the nervous system. Although several neurocutaneous syndromes present with manifestations during infancy and childhood, some are not usually diagnosed until adolescence or early adulthood. The most common neurocutaneous syndromes with childhood onset can be differentiated on the basis of skin lesion morphology.

Now, if a pediatric patient presents with a chief concern suggesting a neurocutaneous syndrome, you should first obtain a focused history and physical examination.

History commonly reveals delayed motor skills; cognitive deficits; and neurologic symptoms, such as weakness. Additionally, the family history might be positive for a neurocutaneous syndrome. The physical examination typically reveals focal neurologic findings and cutaneous lesions.

With these findings, consider the possibility of a neurocutaneous syndrome, and then assess the morphology of your patient’s skin lesions.

Lets take a look at our first skin lesion. If you identify multiple brown macules, known as café-au-lait spots, cafe-au-lait macules or CALMs; consider neurofibromatosis type 1, also known as NF1 or Von Recklinghausen disease. This autosomal dominant condition is caused by mutations of the NF1 gene on chromosome 17.

These patients often have a family history of NF1 in a first-degree relative. Many present with symptoms of neurocognitive dysfunction, such as developmental delay, attention-deficit hyperactivity disorder, or a learning disability.

Meanwhile, the exam typically reveals multiple café-au-lait macules; skin fold freckling, especially in the axillae or inguinal regions; and neurofibromas, which are benign peripheral nerve sheath tumors.

During early childhood, you’ll typically see plexiform neurofibromas, which are irregular, diffuse, and poorly defined, and involve multiple nerve fascicles.

In late childhood or adolescence, patients may develop dermal fibromas, which are small growths just under or above the skin.

These findings are suggestive of NF1, but to confirm the diagnosis, you’ll also need to look for non-cutaneous manifestations. To do so, perform an ophthalmologic examination, order skeletal X-rays, and consider an MRI of the brain. Then, assess NF1 diagnostic criteria .

Criteria for NF1 includes: six or more café-au-lait macules larger than 5 millimeters before puberty, or larger than 15 millimeters after puberty;

skinfold freckling in the axillary or inguinal region; 2 or more dermal neurofibromas or one plexiform neurofibroma; and characteristic skeletal dysplasia, such as sphenoid wing dysplasia.

Other criteria include optic gliomas; Lisch nodules, which are pigmented, dome-shaped iris hamartomas;

an affected first-degree relative; or Noonan syndrome, which is a genetic disorder associated with characteristic facial features, short stature, heart defects, and developmental delay.

If your patient meets at least two of these criteria, diagnose NF1.

Here’s a clinical pearl! Isolated CALMs often occur without underlying pathology, but multiple CALMs can be associated with other conditions such as McCune-Albright syndrome. However, in McCune-Albright syndrome, café-au-lait macules have borders with an irregular “coast of Maine” appearance and are often isolated to one side of the body. On the flip side, in neurofibromatosis, café-au-lait macules have smooth borders resembling the “coast of California”.

Let’s follow that up with a high-yield fact! Neurofibromatosis type 2 and schwannomatosis are less common forms of neurofibromatosis that usually present during late adolescence or adulthood.

Neurofibromatosis type 2 is inherited in an autosomal dominant fashion and is characterized by cutaneous plaques, nodules, meningiomas, cataracts, and bilateral vestibular or “acoustic” schwannomas, which can cause sensorineural hearing loss.

On the other hand, schwannomatosis is a distinct form of neurofibromatosis characterized by multiple schwannomas that affect the peripheral nervous system and spare the vestibular system.

Now let’s switch gears and discuss patients with hypopigmented macules. This finding should make you consider tuberous sclerosis complex, or TSC, an autosomal dominant condition caused by mutations in the tumor suppressor TSC genes on chromosome 9 or 16. Manifestations of TSC are heterogenous and include skin and brain lesions, as well as abnormal growths involving the eyes, kidneys, and heart.

The family history commonly reveals a first-degree relative with TSC, and affected children often have intellectual disabilities or autism spectrum disorder. Many infants with TSC present during infancy with intractable seizures, especially infantile spasms.

As for the skin exam, you’ll typically see characteristic lancinate hypomelanotic macules, also called ash-leaf spots, which are best visualized under a Woods lamp.

Additionally, you may notice Shagreen patches,

which are raised lesions with an orange-peel texture, that are often found in the lumbosacral region.

Some children develop facial angiofibromas on the nose and cheeks that mimic acne, or raised yellow-brown or flesh-colored collagen plaques on the forehead.

If your patient is an adolescent, you may notice periungual fibromas, or small skin nodules under or around the fingernails or toenails.