Факоматозы: обзор нейрокожных синдромов.

Phakomatoses, also known as neurocutaneous syndromes, are a group of multisystemic diseases that most prominently affect structures primarily derived from the ectoderm such as the central nervous system, skin and eyes. The majority of phakomatoses are single gene disorders that may be inherited in an autosomal dominant, autosomal recessive or X linked pattern. Presentations may vary dramatically between patients with the same particular syndrome due to mosaicism, variable expressivity, and penetrance. Many phakomatoses are caused by mutations which alter functioning of the RAS–mitogen activated protein kinase (MAPK) pathway that regulates cellular growth, differentiation, proliferation and death. This results in a tendency for individuals with these mutations to develop various types of benign or malignant tumors depending on the particular mutation. The presence of these tumors may result in functional and/or cosmetic problems depending on their type and location.

The term phakomatosis originated in 1923, when the Dutch ophthalmologist van der Hoeve used the term phakoma to refer to a "mother spot" or birthmark, the Greek term for 'birthmark'. Over time, the number of neurocutaneous syndromes have increased and there are several dozen that have been characterized.

There are a large number of neurocutaneous syndromes that exceed the scope of this article. Therefore, characteristics of a few of the more common types are summarized.

Neurofibromatosis type 1 is the most common phakomatosis and it affects approximately 1 in 2500 3000 live births. It is a genetic disorder due to a germline mutation in the NF1 gene. This gene encodes a protein called neurofibromin that is involved in controlling cellular growth. Malfunction of the gene results in multisystem manifestations involving the skin, central nervous system, peripheral nervous system, eyes and musculoskeletal system. The condition is inherited in an autosomal dominant manner. However, approximately one half of patients with this condition have no family history and the mutation occurs spontaneously. In most instances, neurofibromatosis type 1 can be diagnosed clinically according to consensus criteria and genetic testing is only used in atypical presentations or for family planning decisions. Café au lait spots are one of the most characteristic features of neurofibromatosis type 1. They are hyperpigmented lesions of the skin that increase in number and size during the first years of life. They are present in almost all patients but do not have malignant potential. Freckling in the axillary and inguinal regions are another common presenting feature seen in as many as 90% of patients during childhood. They may result in significant morbidity as they may cause organ compression, vascular occlusions, bone destruction, pain and cosmetic issues. Plexiform neurofibromas are seen in 30 50% of patients. Neurocognitive impairment, attention deficit hyperactivity disorder,  autism spectrum disorder and behavioral disorders are also commonly seen in patients with neurofibromatosis type 1. Epilepsy is seen in 4 7% of patients. Musculoskeletal system manifestations can develop in patients with neurofibromatosis type 1. Common findings include sphenoid wing dysplasia, osteopenia, osteoporosis, anterior chest wall deformities as well as scoliosis. Patients are at a much greater risk for fractures than the general population. Relative to the general population the risk for certain types of cancer is increased significantly. For instance, the risk for brain tumors and breast cancer is increased by 5 times.]] Neurofibromatosis type 2 is an autosomal dominant condition that affects approximately 1 in 35,000 40,000 people. It is caused by mutations in the NF2 gene on chromosome 22 which has a high penetrance though most patients do not present with symptoms until adulthood. Approximately half of patients have de novo mutations and as many as 59.7% are mosaic. Patients who present in childhood tend to have a more severe phenotype. Bilateral vestibular schwannomas are the most characteristic finding and in the vast majority of cases are benign. However, they are responsible for significant morbidity and are responsible for the most common presenting symptom of hearing loss in adults. They can also less commonly present with dizziness or balance impairment. It is estimated that schwannomas occur in over 90% of patients. Meningiomas are the second most common tumor in NF2. Approximately half of patients have an intracranial meningioma and extramedullary spinal meningiomas occur in one fifth of patients. Spinal cord ependymomas occur in 20 50% of patients but they are asymptomatic in the majority of cases. This leads to impaired regulation of cellular proliferation, survival, homeostasis, migration and other critical functions. The most typically affected organs include the brain, skin, kidney, heart and lung. The incidence of TSC is approximately 1 in 6,000 live births. Similar to other neurocutaneous disorders there is variable penetrance and expressivity. It usually presents during the first few years of life and is medically refractory in two thirds of patients. Approximately, one third of patients have infantile spasms. SEGAs occur in 10 15% of patients and are a major potential cause of morbidity and potentially mortality. They tend to present during the first 20 years of life. TSC Associated Neuropsychiatric Disorder (TAND) refers to the behavioral, intellectual and psychiatric manifestations of TSC including autism spectrum disorder, attention deficit hyperactivity disorder, intellectual disability, depression and anxiety. Approximately 90% of patients will have at least 1 symptom of TAND. Lymphangioleiomyomatosis (LAM) occurs in the lung and may result in pneumothorax, cystic lung destruction and pleural effusions. Symptoms which occur as a result may include fatigue, chest pain and shortness of breath. It occurs in approximately 30 40% of women with TSC, up to 80% by the age of 40, and it is much less common in men. Renal angiomyolipomas and cysts are the most common manifestations of TSC involving the kidney. Renal disease is among the most common causes of early death in TSC. One study found that renal lesions were present in 80% of patients by a mean age of 10.5 years. Renal cell carcinoma occurs in 2 5% of patients with TSC at a mean age of 28–30 years. Cardiac rhabdomyomas are benign hamartomas and are the most common cardiac manifestations of TSC. It is found in approximately two third of newborns with TSC. Most of the time they do not cause symptoms and spontaneously regress. In a minority of cases, they may result in heart failure, arrhythmias, and murmurs.

Sturge Weber syndrome occurs in approximately 1 in 20,000 50,000 live births and is caused by a somatic activating mutation in GNAQ. Normally, GNAQ is involved in cell growth signal transmission. The greatest risk is associated with port wine stains that appear to involve the entire V1 distribution followed by partial V1 involvement. Port wine stains are most often unilateral but can be bilateral. Typically, brain and eye involvement occur on the same side as the port wine stain. Over time, port wine stains can develop soft tissue or bone hypertrophy, proliferative nodules, and progressive ectasia which can lead to significant disfigurement. The two most common ocular manifestations include glaucoma and choroidal hemagioma. Glaucoma is estimated to occur in 30 70% with a bimodal peak occurring at the time of birth in 60% and between childhood and adolescence in 40%. The most frequent form of glaucoma is open angle however closed angle glaucoma may also occur. The choroidal hemangioma occurs in 40 50% of patients. They are usually asymptomatic but they may become thickened over time and may be associated with an increased risk for glaucoma. Seizures typically develop within the first two years of life and occur in 75 100% of patients. Status epilepticus occurs in approximately 50% of patients. Approximately 25% of patients develop drug resistant epilepsy. In these cases, surgery may be pursued with the two main approaches being lesionectomy and hemispherectomy. Cortically mediated visual field defects and hemiparesis occur in approximately one third and one half of patients, respectively.]] Von Hippel Lindau (VHL) disease is an autosomal dominant condition caused by mutations of the VHL gene. Approximately one in five cases are de novo rather than familial and it has nearly complete penetrance. VHL occurs in an estimated 1 in 36,000 45,000 live births. CNS hemangioblastomas are the cardinal feature of VHL and occur in as many as 80% of cases. The most common locations include the cerebellum, spinal cord and brainstem. Tumor growth rates can be highly variable. Treatment options include resection and radiation. One longitudinal study that followed patients for a mean period of 7.3 years found that in individuals with unilateral disease 100% had bilateral involvement by the age of 56 years. Blindness or severe visual impairment occurs in less than 10% of patients. Laser photocoagulation and cryotherapy are the most common surgical treatments. Nephron sparing surgery allows for preservation of kidney function and 10 year survival rates up to 81%. Additional manifestations of VHL may include pheochromocytomas in as many as 16% of patients with VHL. They are most often unilateral but can be bilateral or multifocal. Approximately 5% are malignant. Less than 10% with neuroendocrine tumors will develop metastases.

The majority of neurocutaneous syndromes are single gene disorders however they are caused by different genes and have different inheritance patterns. For instance, neurofibromatosis 1 and 2, Tuberous sclerosis complex, Von Hippel Lindau syndrome and Legius syndrome are inherited in an autosomal dominant manner. Incontinentia pigmenti is X linked dominant and Sturge Weber syndrome is sporadic. Some neurocutaneous disorders are found exclusively as mosaics such as Sturge Weber syndrome and Proteus syndrome. Others such as neurofibromatosis type 1 and 2 as well as tuberous sclerosis complex can potentially be mosaics but may not be. Mosaicism may be suspected in cases with either a mild or incomplete presentation of a neurocutaneous disorder. A definitive diagnosis is most likely to be obtained if testing of affected tissues is possible. Patients and families of those affected by neurocutaneous disorders often benefit from genetic counseling. It may provide an opportunity to provide a better understanding of the potential risk to future offspring as well as to improve coping with the various implications of the condition. If desired, a prenatal diagnosis can be obtained by either amniocentesis or chorionic villus sampling. Another potential option is preimplantation genetic diagnosis where an embryo that does not have the mutation can be selectively implanted into the mother.

Many neurocutaneous syndromes have established diagnostic criteria which may facilitate a diagnosis without necessarily requiring genetic testing. For instance, neurofibromatosis types 1 and 2, tuberous sclerosis complex and incontinentia pigmenti have formal diagnostic criteria. Whereas other syndromes such as Noonan syndrome with multiple lentigines, for instance, do not. In cases where conditions that do not have diagnostic criteria are suspected, genetic testing is more likely to be necessary. Diagnostic criteria are not perfect as sensitivity and specificity is not 100%. Similarly, genetic testing can produce false negatives. For example, genetic testing is positive in only 75 90% of cases of tuberous sclerosis complex. Thus, clinicians must apply clinical judgement when evaluating an individual suspected to have a neurocutaneous syndrome.

The treatment of each neurocutaneous syndrome is unique. For some neurocutaneous syndromes such as neurofibromatosis 1 and tuberous sclerosis complex there are guidelines with recommendations for surveillance and management. For less common syndromes such guidelines are not yet available. Surveillance is a necessity for many neurocutaneous syndromes because new manifestations may develop over time which may only be detected with specific and focused testing. Thus, patients may be advised to obtain particular evaluations (e. g., MRI, ophthalmologic or dermatological examinations) within recommended intervals over time with the aim of detecting new manifestations of the syndrome early on. Most of the currently available treatments for neurocutaneous syndromes do not address the underlying genetic cause. For example, epilepsy surgery in tuberous sclerosis complex or vestibular schwannoma surgery in neurofibromatosis type 2. However, there are some treatments that do address the underlying cause such as the use of mTOR inhibitors in tuberous sclerosis complex. There are currently significant efforts underway to develop additional treatments that address the underlying causes of neurocutaneous syndromes. Neurocutaneous syndromes are complex, lifelong conditions that have the potential to affect many different organ systems over time. Thus, patients may benefit from a multidisciplinary approach for care. Integrated, multidisciplinary clinics have developed in an effort to optimize the long term care for patients with neurocutaneous syndromes. Specialties represented at these clinics may include genetics, neurology, ophthalmology, hematology oncology, neurosurgery, psychiatry, dermatology and more.