Wat is Incontinentia Pigmenti - Oorzaken, Symptomen en Behandeling van Deze Huidziekte

Patient Management

A typical work-up might include a detailed clinical genetics/dysmorphology-based examination, detailed genetic and histologic studies, and depending on symptoms, CNS imaging (eg, brain MRI), selected X-rays, complete ophthalmologic/funduscopic examination, audiology, echocardiogram, ultrasound examinations of the viscera (liver, spleen, kidneys, pelvis), general laboratory screens (CBC, chemistries, urinalysis), and other subspecialty consultations as indicated by the other evaluations.

Treatment must be individualized, tailored to the specific problems identified, eg, management of seizures or congenital heart disease. Occasionally, a recognizable phenotype such as Pallister-Killian syndrome or mosaic Turner syndrome may be suggested from the physical examination itself.

Genetics re-evaluation every 6-12 months is useful during the first few years of life. This can be helpful in assessing growth patterns and screening for hemihyperplasia, as well as malformations and developmental delay that may not be apparent earlier in infancy. Standard of care guidelines for medical management of selected chromosomal disorders such as Turner syndrome have been published and can also be applied to mosaic cases. Other follow-up will be dictated by the nature of HMI-associated physical and neurologic abnormalities. Clinical genetics re-evaluation and counseling should be offered again during adolescence and prior to an anticipated pregnancy if a prospective parent is affected with HMI and genetic mosaicism.

Unusual Clinical Scenarios to Consider in Patient Management

Management and prognosis in HMI depends on the precise genetic diagnosis and the extent of the mosaicism. Both are sometimes difficult to fully assess, but the nature of the defect may directly impact management and prognosis, as well as genetic counseling. Therefore, every effort should be made to identify the genetic basis of each case of HMI unless the distribution of pigmentary mosaicism is very limited and growth and development seem entirely normal. In addition, other clinical screening, including potentially costly imaging studies, may also be appropriate.

Background

A karyotype analysis survey was performed on 115 patients and revealed chromosomal anomalies in 60 (52%). [8] Many patients have a chromosomal mosaic pattern, often leading to the generation of 2 cell lineages, which produce patterns of hypopigmented and hyperpigmented skin. X-chromosome alterations are not unusual in hypomelanosis of Ito syndrome, and recent evidence points to X-chromosome inactivation, activation, and mosaicism as the main causes of these different patterns of cell behavior in the skin.

The nevus of Ito, like Nevus of Ota, is a hyperpigmentary dermal melanocytosis developing as a consequence of disturbances or failures during migration of melanocytes from the neural crest towards the epidermis. [9]

Perhaps this can also be found in other tissues, such as the fundus (tessellated or radial pigmentation of the fundi), iris (hypopigmentation), and the brain (areas with abnormal cell morphology and neuroblast migration side by side with normal patterns). Karyotyping the blood cells may not be diagnostic, a skin biopsy for fibroblasts may be necessary to detect the hypomelanosis of Ito–related chromosomal anomalies.

A familial form of hypomelanosis of Ito syndrome is noted, however, less than 3% of the patients have a family history of hypomelanosis of Ito–type skin lesions. Although hypomelanosis of Ito syndrome is most commonly a de novo occurrence, familial cases appear to be transmitted as an autosomal dominant trait. In one family, a 16% trisomy 2 mosaicism was identified. [10]

Pathophysiology

NF-kB is a transcription factor involved in expressing multiple genes, including cytokines, chemokines, growth factors, adhesion molecules, and regulators of apoptosis.[16][17] NF-kB activation prevents apoptosis induced by the tumor necrosis factor (TNF) family of cytokines. NF-kB is mainly inactive in most cells, and various stimuli trigger activation of NF-kB. These stimuli include interleukin-1 (IL-1), TNF alpha, antigen receptors (T-cell receptor and B-cell receptor), genotoxic stress (ultraviolet radiation, gamma radiation, reactive oxygen intermediates), lipopolysaccharide (bacterial endotoxin), and double-stranded RNA (viral infection).[18]

The 'canonical' NF-kB is a heterodimer consisting of p50 and p65 (RelA).[19] NF-kB is kept inactivated in the cytosol when it is complexed with inhibitory protein IκBα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha). Various stimuli activate the IκB kinase (IKK) after attaching to and activating the receptors. IKK phosphorylates IkB, which leads to the degradation of IkB and thereby activation of NF-kB. Activated NF-kB enters the nucleus to bind with response elements (RE) of DNA (deoxyribonucleic acid) and brings out the various changes in cellular functions.[20] The mutation of IKK results in complete disruption of the signaling pathway and virtually no NF-kB activity after stimulation of NEMO/IKK-deficient cells.

Peripheral eosinophilia is noted in patients with IP. The increased production of eosinophils in the bone marrow and increased migration of eosinophils into the circulation causes this eosinophilia. An activated eosinophil secretes granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine that induces eosinophil differentiation and maturation in the bone marrow. Activated IKK cells have been found to induce elevated expression of GM-CSF in peripheral eosinophils via the NF-kB pathway.[21]

GM-CSF works as an autocrine factor to promote eosinophil survival, further elevating peripheral counts. IL-5, a cytokine released by Th2 (T-helper type 2) cells, stimulates the production of eosinophils in the bone marrow and their release into the peripheral blood. NF-kB pathway activation indirectly stimulates the transcription of IL-5. Currently, the mechanisms of NF-kB pathway activation and T helper cell participation in IP are not precisely known. Eotaxin is thought to contribute to tissue eosinophilia in recent studies of the pathophysiology of IP. Several eotaxin promoters possess NF-kB binding sites, including one encoding an eotaxin chemokine previously isolated from blister fluid and crusted scales of patients with IP.[22]