1. S. Gianfaldoni, R. Gianfaldoni, A. Nannipieri Department ofDermatology, Pisa.M. Giampietri, M. Ciantelli, L. Bartalena Neonatology Intensive Care Unit,Pisa.A. Tognetti Department of Pathology, Pisa.T. Lotti Department of Dermatology, Florence.Barcelona 2 -5 November

2. Lets talk about Sofia... 3. Sofia is a newborn female (15 days old).She was referred to us with a diffusevesiculo-bullous rash. The rash waspresent from birth. 4. Grandmother: diabetes. Mother: single woman of 31 years. She had noother children or miscarriages. She had a normalmental and physical development. In childhood,she suffered from varicella, rubeola, parotitis andrubella.No pathology exceptfor epilepsy(benzodiazepines).No drugs.No skin, nail or hair alteration. Also, she showedno familiarity for any skin disease.Sierologies negative for VDRL, HIV, HBV, HCV. Father: ? 5. Bornat term by spontaneous vaginal deliveryafter 2,5 hours of ruptured membranes. The entire pregnancy took place regularly anddid not have any complication. SGA - Small for Gestational Age (2.48 Kg). From birth she had seizures.The EEG showed a severely abnormalpattern with frequent multi-focal spikes.The head ultrasound showed a pattern ofimmature SNC. 6. At first the neurologist thought that seizurescouldderive from benzodiazepinesabstinence. Instead, seizures didnt stop likethey didnt depend by the mothers therapy. 7. Height: 48 cm. Weight: 2.6 kg (less than normal). Normal blood pressure(70/40mmHg), pulse rate (120) andbreathing (40). The musculoskeletal system was normalexcept for an hypoplastic mandible. No ocular alterations. No abdominal alterations. 8. Clear,tense blister and bullae oninflammatory bases. No pustules. No signof infection. Right arm, back of right hand, right and leftlegs, left foot, right side of trunk. No scalp or face lesions. Blaschkos lines. No symtoms. Negative Nikolsky test. 9. No mucosal alteration. Hairs: less than normal, wiry and coarse(woolly hair). Nails: dystrophy,onychorrhexis,onycholysis. 10. Bloodtest showed peripheral eosinophilia(>20%). Normal c-reactive proteinandprocalcitonin. Nosigns ofinfection (fever,lymphadenopathy, etc...). 11. Rare before 6 monthsold. Clinical feature. Noother signs ofinflammation(feverand symptoms ofsystemic toxicity). Tzanck smear. 12. No familiarityforHerpes Simplex. Clinical feature. Noother signs ofinflammation (feverand symptoms ofsystemic toxicity). Tzanck smear. 13. Noother signs ofinflammation(feverand symptoms ofsystemic toxicity). Bacterial culture of thelesions. 14. Predominant in adult men. Itchy blisters and papuleson the extensor surfaces(knees, elbows) and onthe sacral region. Theydont follow the lines ofBlaschko. H.E.:abscess in thepapillar dermis. IF: deposition of granularIgA at dermal papillae. 15. Uncommon in childhood. Itchy clear, tense bullaeon inflammatory bases. Extremities. Symmetric. H.E.: subepidermal split. IF: linear deposits of IgGand / or C3 along theepidermal basementmembrane. 16. Usually seen in the fifthdecade of life. Clear, tense bullae, quiteitchy. The bases arentinflammatory. Mucosal lesions. Diffuse or localizd (e.g.Axilla, groin, genitalis). Nikolsky sign is positive. H.E.: intraepidermal split. IF: deposits of IgG and /or C3 along the plasmamembrane ofkeratinocytes. 17. Blistering lesion thatappear afterlighttrauma. H.E.: subepidermaldetachment. IF: IgG and C3 alongthe dermal-epidermaljunction. 18. Skin:vesicularandbolloususrash, localized on the extremeties and onthe trunk (Blanschkos lines). Hair: woolly hairs. Nails:dystrophy, onychorrhexis, onycholysis. SNC: seizures. Skeletal: hypoplastic mandible. Peripheral eosinophilia. We decide to do a skin biopsy to confirm our suspect.The histological examination of the skin lesion confirmed the diagnosis. 19. I.P. 10X:in the epidermis mild acanthosis, foci of eosinophilic spongiosisand occasional dyskeratotic keratinocytes. The dermis shows aninfiltrate of lymphocytes, many eosinophils and nuclear dust derivedfrom eosinophilic karyorrhexis. 20. I.P. 10X: the dermis shows an infiltrate of lymphocytes, many eosinophilsand nuclear dust derived from eosinophilic karyorrhexis. 21. Becausethe spontaneous improvementand resolution of skin lesions, we didntprescribe topical or systemic steroids. We prescribed only an antibiotic therapy toavoid secondary infections of the lesions. 22. Two weekslater.... 23. Thevesiculo-bullous rashwasdisappeared. Linear warty lesions. Back of right hand and of left foot (fingersand toes), right and left legs. No lesions on the trunk. Woolly hairs. Nails distrophy. Onychorrhexis,onycholysis. 24. X-linked genodermatosis. It is a systemic diseasethat involves tissue of ectodermic and mesodermic origin, including cutaneous tissue, teeth, eyes andthe central nervous system, amongst other organs. 25. Thedisease has been reported by Bloch in1926, and Sulzberger in 1928. The name incontinentia pigmenti isrelated to the histological characteristics ofthe lesions during the third, pigmentarystage, of the disease. It is melaninincontinence by melanocytes in the basalepidermal layer and its presence in thesuperficial dermis. 26. Prevalence is unknow. More than 700 cases havebeen reported in the world literature up-to-date. IP occurs in approximately 1 in 50.000 newborns1or in 1 in 10.000 of female newborns. The disease is predominant in women (male-femaleratio 1:37). Less than 3% of cases are male and derives byother genetical disorder, not completely understood. Most cases have been described in white persons.Also other races (e.g. Korean, brasilian, cinese) areaffected. About 50% of the IP cases have a positive familyhistory. 27. IPis a hereditary, X-linked dominantdisorder. It has high penetrance but expressivityhighly variable. IP is a single gene disorder, caused bymutations in the NEMO/IKK/IKBKG gene. 28. NEMO is a 23kb gene, composed of 10 exons. It islocated on Xq28. NEMO is the essential modulator of NF-kB. NF-Kb is a transcriptor factor involved in immune andinflammatory responces and in protecting cells fromtumor necrosis factor induced apoptosis. Normally, NF-kB is described in the cellular cytoplasm. It is inactivatedby the linking of a protein IkB. Flogistic stimulant (like TNF, IL1, LPS, etc) activate theIkk complex. The Ikk kinase complex is made of twokinases (Ikk and Ikk) and a regulatory subunit, NEMO. The Ikk complex phosphorize the IkB protein, which isdegraded. NF-kB comes in the nucleus and starts theinflammatory responces. 29. IkkIkk Ikk IkNF-kBBNucleus 30. TNIL-F 1IkkIkk Ikk IkNF-kBBNF-kB Nucleus 31. Other phenotypes associated with NEMOmutation:EDA-ID (anhidrotic ectodermal dysplasia andimmunodeficiency)OL-EDA-ID (osteopetrosis and lymphedema inEAD-ID) 32. Deletion of exons 4 through 10 (70-80% of IPpatients). Other alteration in NEMO: small duplications,substitutions and deletions. In male carrying a NEMO mutation this is linked toembryonic lethality. Femalesurvives for the X chromosomeinactivation (lyonization), which occur duringearly embryogenesis. Many infant boys with the disease had evidence ofKlinefelters syndrome (47,XXY karyotype).Affected surviving male have also been found withhypomorphic alleles or somatic mosaicism for thecommon IKBKG deletion. 33. Also inflammatory reactions and epidermal eosinophilrecruitment in the initial stage of IP seems to beimportant in the disorder. Theexact mechanism of epidermal eosinophilaccumulation has not been yet determined. Eotaxin is an eosinophil-selective chemokine, which isproducted by specificleucocytes(includingeosinophils, macrophages, Tcells) and some structuralcells (including endothelial cells, fibroblasts andepithelial cells). Eotaxin is strongly expressed in the epidermis of IPlesional skin. Probably eotaxin is producted during theinflammatory responces due to the activation of NF-kB. 34. The clinical presentation of IP varyconsiderably even among family members.They range from subtle cutaneous anddental involvement to a complexsyndrome, sometimes deadly. 35. Skinmanifestations are themost common. Characteristic skinlesionsevolve through four stages. The skin abnormalities occuralong lines of embryonic andfetal skin development, know asBlaschkos lines. Blaschkoslines correspond with cellmigration or growth pathwaysthat are established duringembryogenesis. 36. STAGE 1 BULLOUS STAGE STAGE 2 VERRUCOUS STAGE STAGE3 - HYPERPIGMENTATIONSTAGE STAGE 4 - ATRETIC STAGE 37. Is present in 90% of the patients at birth or within the first two weeksof life. It can occur in utero and dont progress after birth. Clear, tense bullae on inflammatory bases. Sometimes the eruptionsmay appear infectious. The bullae are accompanied or followed bysmooth red nodules or plaques. The lesions tend to follow the lines of Blaschko. The lesions aretipically described on the extremities (linear pattner) and on the trunk(linear or circumferential pattern). The face is usually spared,although scalp lesions are quite common. The stage 1 rash generally disappears by age 18 months.Recurrence of stage 1 lesions can be observed. Histopathologically, stage 1 is characterized by eosinophilicspongiosis, intraepidermal vesicles. The dermis shows non-specificinflammatory changes with a a cellular infiltrate, including numerouseosinophils. 38. Usually, stage 2 follows between the second and sixth weeks of life.It persists for a few months and in 80% of cases fades by the age ofsix months. It is characterized by a hypertrophic, wart-like rash, similar to the firststage pattern. Histopathologically, the lichenoid papules are characterized bydyskeratotic keratinocytes, hyperkeratosis, acanthosis andpapillomatosis. Also macrophages laden with melanin are present inthe upper dermis. We can also describe inflammation of epidermisand dermis (epidermal spongiosis, cellular infiltrate includingnumerous eosinophils). 39. Most characteristic stage for IP. Usually it begins between age six months and oneyear, and persist into adulthood. Spontaneousimprovement and resolution of skin lesions is generalthe rule. Brownish linear and whorled streaks that follow theBlaschkos lines (blue-grey or slate to brown). The bizarre splashed or Chinese figure distribution arediagnostic. Sometimes we also describe linear ormacular teleangiectasias. Histopathologically, stage 3 is characterized by melaninincontinence by melanocytes in the basal epidermallayer and its presence in the superficial dermis. 40. About 14% of patients exhibits a fourthstage. Hypopigmentation in the areas of theprevious hyperpigmentation, with atrophy. Histopathologically, stage 4 is characterized by epidermal atrophy and decreased, normal or small melanocytes. Sometimes, skin appendages are absent. 41. Theonset and duration of each stage varyamong individuals, and not all individualsexperience all four stages. Stage 1 and 3are more common than stage 2 and 4. Different skin manifestations: palmo-plantarhyperhidrosis, port wine stain, cleft lip andpalate, abnormalities of mammary tissue(aplasia of the breast, supernumerarynipples ). 42. HAIRNAILS 40% of patients . Scarring alopecia (28-38%). First three digits of the Thin hair . hands. Woolly hair (lusterless, wiry Multiple digits on multipleand coarse).limbs. Mostcommonnailalterations:onychodystrophy,onychogryphosis,pitting,yellow discoloration. Subungeal and periunguealkeratotic tumors may appearat the later stage. 43. 80% of all IP patients. Both the deciduous and permanent dentition maybe affected. The most common dental alterations are: delayeddentition (18%), partial anodontia (43%),hypodontia (40%) and abnormally shaped teeth(e.g. cone or peg-shaped teeth or accessorycusps) (30%). Dental abnormalities if not treated adequately, willlead to problems in masticatory and occlusalfunction, and probably psychosocial problems dueto a compromised esthetic appearance. 44. 40% of the cases. Asymmetric involvement is the mostcommon. The defects include strabismus,cataract,conjuntival pigmentosa uveitis, optic nerveatrophy, retinal vascular abnormalities, bluesclera, exudative chorioretinitis, retinalglioma. In most of patients with ocular defects,prognosis is not good: many of them becomeblind. 45. 25% of IP cases. Seizures are the most common symptoms(prognostic indicator). Other neurologic symptoms include:spasticor paralyticquadriplegia,hemiparesis, cerebralatrophy, microcephaly andencephalopathy. The majority of individual with IP areintellectually normal. The incidence ofmental retardation is about 25-35%. 46. Havebeen observed, including hemivertebra, hemiatrophy, syndactily, congenital dislocation of the hip, club foot, dwarfism, scoliosis, supernumerary ribs. 47. Uncommon. Atrialseptal defects, acyanotic tetralogy of Fallot, ventricular endomyocardial fibrosis, tricuspid insufficiency, unilateral acheiria and primary pulmonary hypertension. 48. Commonin IP. They include functional abnormalities ofneutrophils and lymphocytes and defectsin polymorphonuclear chemotaxis. Alsoeosinophilia up to 50% in the peripheralblood is usual in first inflammatory stage ofIP. 49. No strict diagnostic criteria for IP exist. The diagnosis is mainly clinical. Family history consistent with X-linkedinheritance or a history of multiplemiscarriages also supports the diagnosis. 50. MAJOR CRITERIA (skin lesions thatMINOR CRITERIAoccur in stages from infancy toadulthood)Erythema followed by blister, in a Teeth: hypodontia, anodontia,linear distribution stage 1microdontia, abnormally shaped teethHyperpigmented streaks and whorls Hair: alopecia, woolly hairthat respect Blaschkos lines stage 3Pale, hairless, atrophic linear streaks Nails: onychodystrophy,or patches stage 4onychogryphosis, pitting,yellowdiscoloration.Ocular alterations(retinalneovascularization)The clinical diagnosis of IP can be made if at least one of themajor criteria is present. The presence of minor criteria supportsthe diagnosis; the complete absence of minor criteria shouldraise doubt regarding the diagnosis. 51. Peripheral eosinophilia. Histological examination of a skin biopsy. Immunofluorescent antibody/antigen mapping(negative). Molecular genetic testing (NEMO mutation). X-chromosome inactivation studies (femalewith IP have skewed X-chromosomeinactivation in which the X-chromosome withthe mutant IKBKG allele is preferentiallyinactivated). Prenatal diagnosis: analysis of DNA extracted from fetal cells obtained by amniocentesis (15 to 18 weeks gestation) or chorionic villus sampling (10 to 12 weeks gestation). 52. STAGE OF IP DIFFERENTIAL DIAGNOSISSTAGE 1 Infectious: bullous impetigo, herpessimplex, varicella.Immune-mediated: dermatitisherpetiformis, epidermolysis bullosaacquisita, bullous systemic lupuserythematosus, linear IgA bullousdermatosis, bullous pemphigoid,pemphigus vulgaris.STAGE 2 Verrucae vulgaris, linear epidermalnevi, molluscum contagiosum.STAGE 3 Skin hyperpigmentation,hypomelanosis of Ito.STAGE 4 Vitiligo, piebaldism and other skinhypopigmentation, scars. 53. 1. Physical examination with particular emphasis on the skin, hair, nails, neurologic system.2. Ophthalmological examination.3. Dental examination (?).4. EEG and MRI if neurological abnormalities are present.5. Magnetic resonance angiography if neurological deficits are consistent with a stroke like pattern.6. Developmental screening, with further evaluation if significant delay are identified. 54. Theprognosis is generally good anddepends onextracutaneousmanifestations. For persons without significant neonatal orinfantile complications, life expectancy isconsidered to be normal. Women with IP have a higher than usualrisk of pregnancy loss, presumably relatedto low viability of male fetuses. 55. Because IP is a systemic disorder, a multidisciplinary approach to management is crucial.A complete neurologic examination iswarrented for all IP infants. Regular visits to a pediatric ophthalmologist isessential during the first year of life. Laserphotocoagulation and vascular endothelialgrowth factor inhibitor seem to be goodtreatments for retinal vascular abnormalities. Concerning teeth, referral for radiologicevaluation and dental intervention by the ageof two years is appropriate. 56. Management in the newborn period is aimedat reducing the risk of infection of blistersusing standard medical management. Spontaneous improvement and resolution ofskin lesions is general the rule. Topical and systemic steroids have beenprescribed to limit the stage 1 and 2 rashes. Theuse oflasertreatmentofhyperpigmentation should be discouragedbecause it has been reported to trigger anextensive vesciculobullous eruption.