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Psychocutaneous disorders and the quality of life in neurofibromatosis type 1 (von Recklinghausen).

INTRODUCTION

Genodermatosis have always been a real public health problem due to a variety of mucocutaneous manifestations, as well as due to their major impact on the quality of life.

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen' s disease, is an autosomal dominant transmitted genodermatosis, caused by NF1 gene mutations, which is located on chromosome 17q11.2 and has an incidence of 1: 3,000-5,000 births (1). The NF1 gene encodes a protein with GTPase activity called neurofibromina, which also acts as a tumour suppressor protein. A number of cases occurs as sporadic Recklingkausen's disease, being caused by novo mutations (2).

The first description of neurofibromatosis was performed by Friedrich von Recklinghausen in 1882, and in 1982 Riccardi classified it into 8 subtypes (3), the most common of which are NF 1 and NF type 2. The first type is characterized by multiple cafe au lait patches and neurofibromas, along the peripheral nerves, whereas in the second form, vestibular schwannomas usually bilateral, and similarly, meningioma or other tumours of the central nervous system occur (4).

The improvement of patients' quality of life primarily aims a multidisciplinary approach disease, in which the psychodermatology covers all aspects of how the mind and body interact in terms of onset, the form and progression of cutaneous disease (5).

THE POLYMORPHISM OF CLINICAL MANIFESTATIONS

Cutaneous symptoms within Recklinghausen neurofibromatosis are various and complex, ranging from simple giant plexiform neurofibromas to pigmentation spots with affectation of the central nervous system or other internal organs.

Cutaneous lesions:

--cafe au lait macules appear in early childhood, like oval, well defined hyper-pigmentated spots, with 0.5-10 cm variable diameter, found all over the skin, most commonly on the chest and abdomen; their size and number increase with age; in 20% of cases appear small brown macules, being so called pseudofreckels or lentigines (Crowe's sign--axillary and/or groin "frec kling") (6, 7);

--neurofibromas usually starts at puberty as superficial skin colour tumours, which are round or oval in shape, some pedunculated or sessile, having variable sizes, painless and disseminated on trunk; also may be present deep subcutaneous or under fascia tumours, on the path of peripheral nerves, with hard consistency, on the average with 2 cm diameter, located on the front forearms, laterocervical region, lumbar regions and thighs (7);

--plexiform neurofibromas are deep subcutaneous tumours, with soft consistency and variable size, within can be palpate some tough cords (plexiform neuromas); sometimes very large sizes are met in dermatolysis Alibert (on trunk), and neuromatos elephantiasis Virchow with inferior limbs disposal (7);

--intense itching may be present in people who have multiple neurofibromas on cutaneous surface, suggesting the role of mast cells degranulation (1).

Neuropsychiatric manifestations are the consequence of the existence of neurofibromas in the central or peripheral nervous system. Involvement of peripheral nerves leads to severe pain, paresthesia, motor or trophic disorders, while affection of central nervous system is represented by optic gliomas optic manifested by decreased visual acuity, increased intracranian pressure, and precocious puberty (8). It was found that children diagnosed with neurofibromatosis type 1 cognitive can also have cognitive disorders expressed by attention deficit, learning disabilities, and impaired social and emotional relationships. The most common problems are caused by the difficulty of learning to read, spell and doing arithmetic (9). Hyperactivity disorders with attention deficit and comportamental abnormalities (10) were also reported. In general, intelligence is not affected. However, 3% of cases of neurofibromatosis type 1 occurs with mental retardation having an IQ between 85 and 10011.

Other clinical changes

Ocular lesions suggestive of this disease are Lisch nodules; they occur in 90% of cases in the form of superficial pigmented lesions around the iris, without symptoms, they are difficult to be seen with the naked eye, being visible at fante lamp examination (4).

Skeletal deformities found in Recklinghausen's disease are: scoliosis, osteopenia, sphenoid dysplasia, tibial congenital dysplasia and pseudoarthrosis. Heerva showed, in a study, that the risk of bone fractures is five times higher in adults with neurofibromatosis and three times higher in children than in healthy persons (10).

The most suggestive cardiovascular disorders are hypertension, various vasculopathy (stenosis, occlusions, aneurysms, pseudoaneurysms, fistulas) and congenital heart defects (pulmonary artery stenosis, aortic stenosis, aortic artery coarctation) (12).

QUALITY OF LIFE IN NEUROFIBROMATOSIS TYPE 1

The quality of life of dermatological patients represents a challenge because, on one hand, skin diseases are major causes of morbidity due to symptoms and clinical signs, and on the other hand, they are affecting psychosocial relations, leading to anxiety, depression, embarrassment, isolation, absenteeism at work or school (13).

Neurofibromatosis type 1 has a major impact on the quality of life both through its complications, and the aesthetic appearance of the patient affected by this disease. The severity of neurofibromatosis type 1 can be appreciated by the Riccardi scale, and according to it, the grade 1 refers to minimal lesions, consisting of isolated cafe au lait and Lisch nodules, without compromising patients' quality of life; grade 2 requires a sufficient number of skin lesions so that the disease becomes apparent and a cause for concern, but with no significant impact on the quality of life; in grade 3 there is a significant impairment of quality of life, but it can be well-managed, and in grade 4, a severe affectation is indicated, being difficult to be managed due to neurological complications and malignant transformations (14).

Dermatological index of the quality of life (DLQI) questionnaire is specifically designed for dermatological diseases and is used both for measuring the quality of life and for comparison with other cutaneous diseases (13).

Children with learning disabilities will fail to touch their academic potentials regardless of the cultural or socioeconomic environment they live in. Behavioural problems include sleep or socialization disorders, and low self-esteem (15). It is recommended that these children should be subjected to neuropsyhological screening testing at early ages and, subsequently, to detailed interdisciplinary tests, in order to optimize their quality of life (10).

DISCUSSIONS

Neurofibromatosis type 1, either with familial or sporadic nature, is characterized by a wide spectrum of clinical manifestations, from simple hyperpigmentated asymptomatic macules, to giant neurofibromas and/or plexiform neurofibromas, that influence the central nervous system and other internal organs. The diagnose of Recklinghausen's disease is based on relevant criteria developed by the National Institutes of Health in Bethesda, and according to them, a patient is diagnosed with this disease if it shows at least two of the following symptoms (16):

--6 or more cafe au lait spots, with diameter [greater than or equal to] 0.5 cm during puberty and [greater than or equal to] 1.5 cm at adulthood;

--2 or more neurofibromas or a plexiform neurofibroma;

* axillary or inguinal lentiginosis (Crowe sign);

* optical gliomas;

* 2 or more Lisch nodules;

* skeletal abnormalities (sphenoid, tibia bones);

* a grade I relative with NF1.

NF 1 mutation carriers have a moderate risk of developing cancers, and the most common are rhabdomyosarcomas, duodenal carcinoid tumours, pheochromocytoma, rhabdomyosarcoma, and myelomonocytic leukemia in children (Table 1).

From the moment of diagnosis, the patient with Recklinghausen disease should be carefully monitorised, although clinical manifestations are minimal and do not affect psychosocial comfort. There is no specific treatment for this disease and the management of these patients lies in their surveillance and their I degree relatives (11) (table no. 2) and therapeutic intervention in case of complications.

There are also required complex programs that include psychological counselling, psycho-education, stress management through the development of centres where patients can benefit from these health and psychological services (17).

Developing methods for genetic diagnosis have allowed the study of genotype--phenotype, observing that people with microdeletions of the gene NF 1 have a more severe phenotype, with a higher risk of developing neurofibromas at a younger age and also malignant tumours of peripheral nerves (10).

CONCLUSIONS

Von Recklinghausen's disease, through this varied spectrum of clinical manifestations, the cutaneous lesions in particular, is creating a significant impact on the quality of life. Even if sometimes the symptoms/signs are minimal, expressed by hyperpigmentated spots and neuro fibromas, they adversely affect the patient's social relationships and, ultimately, they leads to isolation, anxiety and depression.

In the absence of a specific treatment, the management of the patient with von Recklinghausen' s disease primarily consists of careful monitoring, with yearly clinical examination, counselling for both the patient and his/her first degree relatives, genetic evaluations and counselling in order to determine the risk of transmission to descendants. Thus, interdisciplinary collaboration of specialists in dermatology, psychiatry, neurology, ophthalmology, internal medicine, and genetics can achieve an improvement in the quality of life, whose mainstay is regaining self confidence, understanding the mechanisms of disease transmission and the patients' interaction with all aspects of social life.

ACKNOWLEDGEMENTS AND DISCLOSURES

The authors state that they are no declared conflicts of interest regarding this paper.

REFERENCES

(1.) Wienecke, R. Malformations and Genodermatoses in Burgdorf, W. H. C., Plewig, G., Wolff, H. H., Landthaler M., Editors. Braun-Falco's Dermatology, Third Edition, Springer, 2009, pp. 745-753.

(2.) Covic, M., Stefanescu, D., Sandovici, I. Genetica Medicaid, Ed. Polirom, Iasi, 2004: 377-378.

(3.) Patrascu, V. Boli Dermatologice si Infectii sexual-transmisibile, editia a Il-a, Ed. Sitech, Craiova, 2012: 372-375.

(3.) Irvine, A. D., Mellerio, J. E, Genetics and Genodermatoses in Burns, T., Stephen Breathnach, S., Cox, N., Griffiths, C., Editors. Rook's Textbook of Dermatology, Vol. 1, Eighth Edition, Blackwell Publishing, 2010, pp. 15.15-15.20.

(4.) Millard, L. G., Millard, J. Psychocutaneous Disorders in Burns, T., Stephen Breathnach, S., Cox, N., Griffiths, C., Editors. Rook's Textbook of Dermatology, Vol. 1, Eighth Edition, Blackwell Publishing, 2010, pp. 64.1-64.3.

(5.) Allanore, L., Wolkenstein, P. Neurofibromatoses in Saurat, J. H., Lachapelle, J. M., Lipsker, D., Thomas, L., Editors. Dermatologie et infections sexuellement transmisibles, 5 edition, 10: 485-488.

(6.) Bucur, G., Opris, D. A. Boli dermatovenerice: enciclopedie, editia a II-a, Ed. Medicala Nationals, Bucuresti, 2001: 519-520.

(7.) Kocova, M., Kochova, E., Sukarova-Angelovska, E. Optic glioma and precocious puberty in a girl with neurofibromatosis type 1 carrying an R681X mutation of NF1: case report and review of the literature, BMC Endocr Disord. 2015; 15: 82.

(8.) Hyman, S. L., Shores, A., North, K. N. The nature and frequency of cognitive deficits in children with neurofibromatosis type 1, Neurology, 2005; 65(7):1037-44.

(9.) Hirbe, A. C, Gutmann, D. H. Neurofibromatosis type 1: a multidisciplinary approach to care. The Lancet Neurology, 2014; 13: 834-843.

(10.) Tonsgard, J. H. Manifestations and Management of Neurofibromatosis Type 1. Seminars in Paediatric Neurology, Elsevier, 2006; 13:2-7.

(11.) Friedman, J. M., Arbiser, J., Epstein, J. A., et al. Cardiovascular disease in neurofibromatosis 1: Report of the NF1 Cardiovascular Task Force. Genetics in Medicine 2002; 4: 105-111.

(12.) Tejada, C. S., Mendoza-Sassi, R. A., Almeida Junior, H. L., et al. Impact on the quality of life of dermatological patients in southern Brazil. An Bras Dermatol., 2011; 86(6): 1113-21.

(13.) Wolkenstein, P., Zeller, J., Revuz, J., et al. Quality-of-Life Impairment in Neurofibromatosis Type 1A Cross-sectional Study of 128 Cases. Arch Dermatol. 2001; 137(11): 1421-1425.

(14.) Ferner, R. E., Huson, S. M., Thomas, N., et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. 2007; 44: 81-88.

(15.) Bezniakow, N., Gos, M., Obersztyn, E. The rasopathies as example of Ras/Mapk pathway disturbances--Clinical presentation and molecular pathogenesis of selected syndromes. Developmental Period Medicine. 2014; 3: 285-296.

(16.) Daphne Wang, B. S., Smith, K. B., Esparza, S., et al. Emotional functioning of patients with neurofibromatosis tumour suppressor syndrome. Genetics in Medicine, 2012; 14: 977-982.

Laura GHEUCA SOLOVASTRU--M. D., Ph. D., Senior Dermatologist at "St Spiridon" Emergency Hospital Iasi; Professor at "Grigore T. Popa" University of Medicine and Pharmacy, Dermatology Discipline, Iasi, Romania

Adriana-Ionela PATRASCU--M. D. Dermatologist, CMI Lauderma, Iasi, Romania

Alina STINCANU--M. D. Dermatologist at "St Spiridon" Emergency Hospital Iasi, Romania

Elena ANDRESE--M. D. Dermatologist, Teaching Assistant at "Grigore T. Popa" University of Medicine and Pharmacy Iasi, Dermatology Discipline, Iasi, Romania

Ioana-Alina GRAJDEANU--Resident Dermatologist at "St. Spiridon" Emergency Hospital Iasi, Romania

Laura STATESCU--M. D., Ph. D. Senior Dermatologist at "St Spiridon" Emergency Hospital Iasi, Teaching Assistant at "Grigore T. Popa" University of Medicine and Pharmacy Iasi, Dermatology Discipline, Iasi, Romania

Dan VATA--M. D., Ph. D. Senior Dermatologist at "St Spiridon" Emergency Hospital Iasi, no. 2 str. Vasile Conta, lecturer at "Grigore T. Popa" University of Medicine and Pharmacy Iasi, Dermatology Discipline, Iasi, Romania

Tatiana TARANU--M. D., Ph. D., Senior Dermatologist at CFR Hospital Iasi; Associate Professor at "Grigore T. Popa" University of Medicine and Pharmacy Iasi, Faculty of Dental Medicine, Iasi, Romania

Correspondence:

Dan VATA

M. D., Ph. D. Senior Dermatologist at "St. Spiridon" Emergency Hospital Iasi No. 2 Str. Vasile Conta, Lecturer at "Grigore T. Popa" University of Medicine and Pharmacy Iasi, Dermatology Discipline

E-mail: dan.vata@umfiasi.ro Tel.: +40.741.084.264 corresponding author, Iasi, Romania

Submission: September, 12th, 2016

Acceptance: October, 20th, 2016
Table no. 1. The risk of malignant transformation (10)

Neoplasm                            Risk

Optical gliomas                     15-20%
Other cerebral tumours              5 times higher
Peripheral nerve tumours            8-13%
Gastrointestinal stromal tumours    4-25%
Mammary neoplasm                    5 times higher
Leukemia                            7 times higher
Carcinoid duodenal tumours          1%
Pheochromocytoma                    0.1-5.7%
Rhabdomyosarcoma                    1.4-6%

Table no. 2. The management of patients with NF 1 (11)

Age group               Monitoring criteria

0-8 years     * Careful clinical examination:
                --inspection of long bones;
                --limb asymmetry;
                --scoliosis;
                --cognitive functions: thinking,
                  language, learning.
8-15 years    * Careful clinical examination:
                --limb asymmetry;
                --scoliosis;
                --neurofibromas.
              * School performance:
                --Attention deficit;
                --Learning deficit.
              * Self-esteem;
              * Social behaviour.
16-21 years   * Careful clinical examination
                [right arrow] neurofibromas;
              * Evaluation of physical pain
                by imaging studies;
              * School performance;
              * Self-esteem;
              * Social behaviour;
              * The risk of disease transmission.
> 21 years    * Careful clinical examination
                [right arrow] neurofibromas;
              * Monitoring blood pressure;
              * Physical pain evaluation by
                imaging studies;
              * Risk assessment of cancer;
              * Social behaviour;
              * Career/Job.
              * Clinical evaluation of both parents;
Parents       * If one parent has the disease,
                all children should be examined;
              * Understanding the risk of
                transmission to descendants (50%).
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Author:Solovastru, Laura Gheuca; Patrascu, Adriana-Ionela; Stincanu, Alina; Andrese, Elena; Grajdeanu, Ioan
Publication:Bulletin of Integrative Psychiatry
Article Type:Report
Date:Dec 1, 2016
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