Early Diagnosis of Neurocutaneous Syndromes

Neurocutaneous Syndromes: Comprehensive Guide to Early Detection

Neurocutaneous syndromes, also known as phakomatoses, are a group of rare genetic disorders that affect the nervous system, skin, and other body parts, including the brain. These conditions primarily impact individuals aged 18-22 and occur in approximately 1 in 3,000 births.

However, this is a rare disorder; as per statistics, only 1 in 3,000 births suffer from this. Although given its rarity, the disease is quite aggressive and affects the physiological functioning of the body. 

Although the disorder primarily involves the nervous system and the skin it also affects certain parts connected by the nerve fibres like the brain, spinal cord, organs, and even bones. Below we will discuss the disease, its diagnosis, causes, types, and ways to manage it. 

Types of Neurocutaneous Disorder in Child

Depending on the mutation in the genes, there are several types of neurocutaneous diseases. Below, we will list the three common types of neurocutaneous syndrome: 

1.Neurofibromatosis (Types 1 and 2) 
2.Tuberous Sclerosis (TSC 1 and TSC 2) 
3.Sturge Weber Disease 

However, apart from these, there is a list of diseases which can be remembered using the neurocutaneous syndromes mnemonics, “NEUROCUTANIOLS PHAKOMATosis”. 

●N- Neurofibromatosis types 1 and 2, Nevus comedonicus syndrome, 
●E- Epidermal Nevus Syndrome, Ehlers Danlos (Type - IV), 
●U- Wyburn Mason Syndrome 
●R- Ruvalcaba 
●O- Osler-Weber-Rendu Syndrome
●C- Cerebrotendinous xanthomatosis, Cerebello Trigeminal Dermal Dysplasia
●T- Tuberous Sclerosis 
●A- Ataxia Telangiectasia Syndrome (Louis Bar Syndrome), Neurocutaneous Melanosis, Nevoid Basal Cell Carcinoma Syndrome, Nevoid Melanosis.
●I- Incontinentia Pigmenti, Ito (Hypomelanosis of Ito)
●L- Lhermitte Duclos Disease
●S- Sturge Weber Syndrome
●P- PHACES Syndrome, Phacomatosis Pigmento Keratorica, Pallister-Hall Syndrome, Proteus Syndrome, Pigmentoso, Parry-Romberg Syndrome
●H- Haberland Syndrome, Hafner (Garcia Hafner Syndrome) 
●A- Abdallat Davis Farrage Syndrome
●K- Cowden Syndrome, Child Syndrome
●M- Menkes Disease 
●A- Angora Hair Nevus 
●T- Tuber Cinereum Hamartoma
●S- Schimmelpenning Syndrome

All of these types show different symptoms depending on the genes that are specifically affected. 

Here we will specifically deal with the three primary types of neurocutaneous syndromes which are Neurofibromatosis, Tuberous Sclerosis, and Sturge Weber Disease. 

What are the Neurocutaneous Syndromes Symptoms?

There is a list of neurocutaneous syndromes that are generally caused due to mutations in certain portions of the gene. Here, we will discuss three primary types and their symptoms: 

●Neurofibromatosis 1 and 2 Symptoms 
The primary symptom of Neurofibromatosis 1 is light brown patches or pigmentation of the skin. Such spots are also known as cafe-au-lait spots which are fibromas that grow in the nerves and other organs. This is one of the common neurocutaneous syndrome examples that occurs in children and requires medical attention. 
On the other hand, in the case of an NF2 defect or Neurofibromatosis 2 disease, some bilateral vestibular schwannomas or tumours grow on a vestibular nerve branch. Both types 1 and 2 are classic cases of neurocutaneous syndromes found in children and teenagers. 

●Tuberous Sclerosis Symptoms
Some common symptoms of Tuberous Sclerosis are changes in the skin. Such changes include patches of lighter skin, and small areas of thickened, smooth and bumpy skin. Another common symptom includes seizures due to the growth of mass in the brain, which ultimately causes infantile spasm, which involves stiffening of arms and legs. 
Additionally, in many cases, there may be some growths in the lungs, which might cause coughing or breathing problems. These symptoms are usually seen in patients during birth.  

●Sturge Weber Syndrome Symptoms 
There are primarily three main symptoms of Sturge-Weber Syndrome, they are:
1.Port Wine Stain Birthmark: A collection of blood vessels on your skin that appear as purple-to-pink patches. This is usually found on a child's forehead or eyelid. 
2.Glaucoma: This is an increased pressure in your child's eye due to fluid buildup. Later in life, it might lead to loss of vision. 
3.Leptomeningeal Angioma: These are abnormal blood vessels that develop in your child's brain or spinal cord. The result of such abnormal blood flow is generally seizures and one-sided muscle weakness (hemiparesis). 

There might be some other developmental defects that your child faces, like: 

1.Developmental Delay 
2.Headaches or Migraine 
3.Hypothyroidism
4.Intellectual Disability, etc. 

Symptoms tend to vary from one person to another based on the severity of the defects. 

What are the Causes of Neurocutaneous Syndrome?

The aetiology of this disorder may vary depending on the type. Here are the common causes: 

●Neurofibromatosis Type 1 and 2 Causes

Neurofibromatosis 1 is known as Recklinghausen's disease and makes up for 96% of the neurofibromatosis cases. The disorder is primarily caused due to germline mutation of the NF1 gene. The protein product of the NF1 gene is neurofibromin, a protein that helps in the cell cycle by inhibiting the RAS/MAPK and P13K-AKT-mTOR signal pathways. 

Therefore, primarily due to genetic mutation and abnormal signalling, the chances of tumours increase. Additionally, in cases of spinal NF1 mutation, the patients show Spinal nerve compression. 

In cases of NF2 mutation, it is called schwannomatosis which is an autosomal dominant neurocutaneous disorder. The NF2 protein codes for the protein Merlin (schwannomin), which is a tumour suppressor for CNS-based tumours. Mostly half of the NF2-based neurocutaneous syndrome occurs due to spontaneous mutation of the localised damage. 

●Tuberous Sclerosis Causes 

Tuberous Sclerosis Complex or TSC is caused by autosomal sporadic mutation in the TSC1 or TSC 2 gene. TSC 1 encodes hamartin and TSC 2 encodes tuberin protein. These proteins jointly help in regulation of cell proliferation, forming the TSC 1:TSC 2 complex. 

Mutation in either of the genes negatively affects the mTOR (mammalian target of the Rapamycin pathway). Ultimately, such unregulated cell proliferation results in cellular overgrowth and localised complications. 

●Sturge Weber Syndrome Causes 

The main cause behind the Sturge Weber Syndrome is a postzygotic somatic mutation GNAQ on chromosomal address 9q21.2.  Such mutations trigger improper activation of the Gαq protein, which contributes to phakomatosis pigmentovascularis. 

Ultimately, due to such pressurised vessels or excessive capillaries around the trigeminal nerve, there is tissue atrophy and tramline calcification. 

Diagnosis of Neurocutaneous Syndromes

Primarily, neurocutaneous syndrome is a congenital disease, therefore it is revealed mainly through genetic tests. The primary defect that an expert looks for is a mutation in the protein-encoding genes. 

From here, you can understand that molecular and genetic tests are aimed at detecting specific mutations in the chromosome. In neurocutaneous syndrome paediatrics, the usual methods of diagnosis are as follows:

Thus, the diagnosis spans genetic and molecular diagnosis along with neurocutaneous syndromes radiology tests, like X-rays, MRI, and CT Scans as per doctor’s recommendations. Now we will see some of the possible causes of such neurocutaneous diseases in children. 

Possible Treatment and Management 

Several treatments apply to the neurocutaneous syndrome based on their severity. In the common cases of NF 1, TSC (1 & 2) and GNAQ gene mutation prevention or management requires the usage of pathway inhibitors. 

Some common inhibitors of the gene mutation are:

●As per emerging therapeutics, Neurofibromatosis 1 (NF 1) can be treated with selumetinib, which is an MEK inhibitor. 
●For NF2, anti-angiogenic agents can be used to manage the spread of the disease. 
●mTOR inhibitors may also be used for managing the effects of TSC1 and 2 gene mutation in children. 

Surgical Procedure: 

For a complex case or tumour formation, the most effective way to resolve the disease is through surgical procedures. If a patient is constantly going through epileptic episodes, confirm your health professional for getting a resective surgery. 

As per data, in TSC mutations resective surgery can provide a cure to 55-60% of the patients. However, it must be mentioned that planning an epileptic surgery can be complicated due to the presence of multiple lesions. Always consult with a professional before seeking out such treatments. 

For NF 1 and 2-based neurocutaneous syndrome generally, microsurgeries serve as one of the ways of treatment, on confirmation of expert professionals. In case of GNAQ gene-based Sturge-Weber Syndrome, surgical procedures are beneficial to reduce refractory seizures in patients. 

Final Words 

Neurocutaneous syndromes are a group of genetic mutations that affect specific organs during their cell cycle. It induces a tumour-like overgrowth or excessive cell mass formation in the body. Although there are numerous neurocutaneous syndromes examples, NF1&2, TSC1&2, along with GNAQ genes are mostly affected. 

To manage its effects or find a solution to the problem, it is important to contact a paediatrician. Overall the usage of precision medicine and targeted therapies might reduce the aggravation of the cell cycle problems.