S. Gianfaldoni, R. Gianfaldoni, A. Nannipieri – Department ofDermatology, Pisa.M. Giampietri, M. Ciantelli, L. Bartalena –...
Let’s talk about Sofia...
Sofia is a newborn female (15 days old).She was referred to us with a diffusevesiculo-bullous rash. The rash waspresent fr...
 Grandmother: diabetes. Mother: single woman of 31 years. She had no  other children or miscarriages. She had a normal  ...
 Born  at term by spontaneous vaginal delivery  after 2,5 hours of ruptured membranes. The entire pregnancy took place r...
At first the neurologist thought that seizurescould      derive   from     benzodiazepine’sabstinence. Instead, seizures d...
 Height: 48 cm. Weight: 2.6 kg (less than normal). Normal             blood           pressure  (70/40mmHg), pulse rate...
 Clear,    tense blister and bullae on  inflammatory bases. No pustules. No sign  of infection. Right arm, back of right...
 No mucosal alteration. Hairs: less than normal, wiry and coarse  (“woolly hair”). Nails:       dystrophy,    onychorrh...
 Blood  test showed peripheral eosinophilia  (>20%). Normal       c-reactive     protein    and  procalcitonin. No     ...
 Rare   before 6 months  old. Clinical feature. No    other signs of  inflammation      (fever  and symptoms of  system...
 No     familiarity    for  Herpes Simplex. Clinical feature. No    other signs of  inflammation       (fever  and symp...
 No    other signs of  inflammation      (fever  and symptoms of  systemic toxicity). Bacterial culture of the  lesions.
 Predominant in adult men. Itchy blisters and papules  on the extensor surfaces  (knees, elbows) and on  the sacral regi...
 Uncommon     in childhood. Itchy clear, tense bullae  on inflammatory bases. Extremities. Symmetric. H.E.: subepider...
 Usually seen in the fifth  decade of life. Clear, tense bullae, quite  itchy. The bases aren’t  inflammatory. Mucosal ...
 Blistering   lesion that  appear       after  light  trauma. H.E.:     subepidermal  detachment. IF: IgG and C3 along ...
 Skin:      vesicular      and    bollousus  rash, localized on the extremeties and on  the trunk (Blanschko’s lines). H...
I.P. 10X:in the epidermis mild acanthosis, foci of eosinophilic spongiosisand occasional dyskeratotic keratinocytes. The d...
I.P. 10X: the dermis shows an infiltrate of lymphocytes, many eosinophilsand nuclear dust derived from eosinophilic karyor...
 Because    the spontaneous improvement  and resolution of skin lesions, we didn’t  prescribe topical or systemic steroid...
Two weekslater....
 The      vesiculo-bullous       rash    was  disappeared. Linear warty lesions. Back of right hand and of left foot (f...
X-linked genodermatosis. It is a systemic diseasethat involves tissue of ectodermic and mesodermic origin, including cutan...
 The  disease has been reported by Bloch in  1926, and Sulzberger in 1928. The name “incontinentia pigmenti” is  related...
 Prevalence is unknow. More than 700 cases have  been reported in the world literature up-to-date. IP occurs in approxim...
 IP  is a hereditary, X-linked dominant  disorder. It has high penetrance but expressivity  highly variable. IP is a si...
   NEMO is a 23kb gene, composed of 10 exons. It is    located on Xq28.   NEMO is the essential modulator of NF-kB.   N...
Ikkγ        Ikkα         Ikkβ         IkNF-kB    B        Nucleus
TNIL-      F 1                    Ikkγ              Ikkα         Ikkβ               IkNF-kB          B      NF-kB         ...
Other phenotypes associated with NEMOmutation:EDA-ID (“anhidrotic ectodermal dysplasia andimmunodeficiency”)OL-EDA-ID (“os...
 Deletion of exons 4 through 10 (70-80% of IP  patients). Other alteration in NEMO: small duplications,  substitutions a...
 Also inflammatory reactions and epidermal eosinophil  recruitment in the initial stage of IP seems to be  important in t...
The clinical presentation of IP varyconsiderably even among family members.They range from subtle cutaneous anddental invo...
 Skin    manifestations are the  most common. Characteristic     skin  lesions  evolve through four stages. The skin ab...
 STAGE 1 – BULLOUS STAGE STAGE 2 – VERRUCOUS STAGE STAGE    3 - HYPERPIGMENTATION  STAGE STAGE 4 - ATRETIC STAGE
   Is present in 90% of the patients at birth or within the first two weeks    of life. It can occur in utero and don’t p...
   Usually, stage 2 follows between the second and sixth weeks of life.    It persists for a few months and in 80% of cas...
 Most characteristic stage for IP. Usually it begins between age six months and one  year, and persist into adulthood. S...
 About   14% of patients exhibits a fourth  stage. Hypopigmentation in the areas of the  previous hyperpigmentation, wit...
 The  onset and duration of each stage vary  among individuals, and not all individuals  experience all four stages. Stag...
HAIR                                  NAILS                                       40% of patients .   Scarring alopecia ...
 80% of all IP patients. Both the deciduous and permanent dentition may  be affected. The most common dental alteration...
 40% of the cases. Asymmetric involvement is the most  common. The defects include strabismus,      cataract,  conjunti...
 25%   of IP cases. Seizures are the most common symptoms  (prognostic indicator). Other     neurologic symptoms includ...
 Have  been observed, including hemivertebra, hemiatrophy, syndactily, congenital dislocation of the hip, club foot, dwar...
 Uncommon. Atrialseptal defects, acyanotic tetralogy of Fallot, ventricular endomyocardial fibrosis, tricuspid insuffici...
 Common    in IP. They include functional abnormalities of  neutrophils and lymphocytes and defects  in polymorphonuclea...
 No strict diagnostic criteria for IP exist. The diagnosis is mainly clinical. Family history consistent with X-linked ...
MAJOR CRITERIA (skin lesions that                  MINOR CRITERIA    occur in stages from infancy to              adulthoo...
 Peripheral eosinophilia. Histological examination of a skin biopsy. Immunofluorescent antibody/antigen mapping  (negat...
STAGE OF IP   DIFFERENTIAL DIAGNOSISSTAGE 1       Infectious: bullous impetigo, herpes              simplex, varicella.   ...
1.   Physical examination with particular emphasis on     the skin, hair, nails, neurologic system.2.   Ophthalmological e...
 The    prognosis is generally good and  depends             on        extracutaneous  manifestations. For persons witho...
Because IP is a systemic disorder, a multidisciplinary approach to                       management is crucial.A     comp...
 Management     in the newborn period is aimed  at reducing the risk of infection of blisters  using standard medical man...
INCONTINENTIA PIGMENTI: A CASE REPORT- serena gianfaldoni
INCONTINENTIA PIGMENTI: A CASE REPORT- serena gianfaldoni
INCONTINENTIA PIGMENTI: A CASE REPORT- serena gianfaldoni
INCONTINENTIA PIGMENTI: A CASE REPORT- serena gianfaldoni
INCONTINENTIA PIGMENTI: A CASE REPORT- serena gianfaldoni
INCONTINENTIA PIGMENTI: A CASE REPORT- serena gianfaldoni
INCONTINENTIA PIGMENTI: A CASE REPORT- serena gianfaldoni
INCONTINENTIA PIGMENTI: A CASE REPORT- serena gianfaldoni
INCONTINENTIA PIGMENTI: A CASE REPORT- serena gianfaldoni
INCONTINENTIA PIGMENTI: A CASE REPORT- serena gianfaldoni
INCONTINENTIA PIGMENTI: A CASE REPORT- serena gianfaldoni
INCONTINENTIA PIGMENTI: A CASE REPORT- serena gianfaldoni
INCONTINENTIA PIGMENTI: A CASE REPORT- serena gianfaldoni
INCONTINENTIA PIGMENTI: A CASE REPORT- serena gianfaldoni
INCONTINENTIA PIGMENTI: A CASE REPORT- serena gianfaldoni
INCONTINENTIA PIGMENTI: A CASE REPORT- serena gianfaldoni
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INCONTINENTIA PIGMENTI: A CASE REPORT- serena gianfaldoni

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INCONTINENTIA PIGMENTI: A CASE REPORT
Incontinentia Pigmenti is a rare X-linked genodermatosis, caused by mutations in the NEMO/IKKγ/IKBKG gene.
It is a systemic disease that involves tissue of ectodermic and mesodermic origin, including cutaneous tissue, teeth, eyes and the central nervous system, amongst other organs.
The name “incontinentia pigmenti” is related to the histological characteristics of the lesions during the third, pigmentary stage, of the disease. It is melanin incontinence by melanocytes in the basal epidermal layer and its presence in the superficial dermis.
Incontinentia pigmenti is really an uncommon disease.
IP occurs in approximately 1 in 10.000 of female newborns.
The disease is predominant in women: less than 3% of cases are male and derives by other genetical disorder, not completely understood.
Most cases have been described in white persons. Also other races (e.g. Korean, brasilian, cinese) are affected.
About 50% of the IP cases have a positive family history.
The clinical presentation of IP vary considerably even among family members. They range from subtle cutaneous and dental involvement to a complex syndrome, sometimes deadly.
Although IP affects many organ systems, the skin manifestations are the most common. Characteristic skin lesions evolve through four stages: 1)bullous stage; 2)verrucous stage; 3) pigmentary stage; 4) atretic stage. Tipically, the skin abnormalities occur along the Blaschko’s lines.
The hair is usually normal but sometimes we describe hair alteration. Alopecia may occur on the scalp and also on the trunk and extremities. Hair may be also thin or lusteriess, wiry and coarse (“woolly hair”). About 40% of patients have nail abnormalities. The most common nail alterations are onychodystrophy, onychogryphosis, pitting, yellow discoloration. Subungeal and periungueal keratotic tumors may appear at the later stage.
Extracutaneous manifestation can also been documented in patients with IP (dental abnormalities, ocular defects, neurological disorders, abnormalities of the musculoskeletal or cardiovascular system).
The diagnosis is mainly clinical. Family history consistent with X-linked inheritance or a history of multiple miscarriages also supports the diagnosis. Peripheral eosinophilia is a suggestive sign in early diagnosis. The histological examination of a skin biopsy could confirm the diagnosis. Also the molecular genetic testing (NEMO mutation) and the X-chromosome inactivation studies are important to confirm the diagnosis.
The prognosis is generally good and depends on extracutaneous manifestations.
Women with IP have a higher than usual risk of pregnancy loss, presumably related to low viability of male fetuses.
Because IP is a systemic disorder, a multidisciplinary approach to management is crucial.
Spontaneous improvement and resolution of skin lesions is general the rule. - Disclaimer-

This PPT is loaded as student material "as is", from the VRF Vitiligo Master Class Barcelona

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INCONTINENTIA PIGMENTI: A CASE REPORT- serena gianfaldoni

  1. 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. 2. Let’s talk about Sofia...
  3. 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. 4.  Grandmother: diabetes. Mother: single woman of 31 years. She had no other children or miscarriages. She had a normal mental and physical development. In childhood, she suffered from varicella, rubeola, parotitis and rubella. No pathology except for epilepsy (benzodiazepines). No drugs. No skin, nail or hair alteration. Also, she showed no familiarity for any skin disease. Sierologies negative for VDRL, HIV, HBV, HCV. Father: ?
  5. 5.  Born at term by spontaneous vaginal delivery after 2,5 hours of ruptured membranes. The entire pregnancy took place regularly and did not have any complication. SGA - Small for Gestational Age (2.48 Kg). From birth she had seizures. The EEG showed a severely abnormal pattern with frequent multi-focal spikes. The head ultrasound showed a pattern of immature SNC.
  6. 6. At first the neurologist thought that seizurescould derive from benzodiazepine’sabstinence. Instead, seizures didn’t stop likethey didn’t depend by the mother’s therapy.
  7. 7.  Height: 48 cm. Weight: 2.6 kg (less than normal). Normal blood pressure (70/40mmHg), pulse rate (120) and breathing (40). The musculoskeletal system was normal except for an hypoplastic mandible. No ocular alterations. No abdominal alterations.
  8. 8.  Clear, tense blister and bullae on inflammatory bases. No pustules. No sign of infection. Right arm, back of right hand, right and left legs, left foot, right side of trunk. No scalp or face lesions. Blaschko’s lines. No symtoms. Negative Nikolsky test.
  9. 9.  No mucosal alteration. Hairs: less than normal, wiry and coarse (“woolly hair”). Nails: dystrophy, onychorrhexis, onycholysis.
  10. 10.  Blood test showed peripheral eosinophilia (>20%). Normal c-reactive protein and procalcitonin. No signs of infection (fever, lymphadenopathy, etc...).
  11. 11.  Rare before 6 months old. Clinical feature. No other signs of inflammation (fever and symptoms of systemic toxicity). Tzanck smear.
  12. 12.  No familiarity for Herpes Simplex. Clinical feature. No other signs of inflammation (fever and symptoms of systemic toxicity). Tzanck smear.
  13. 13.  No other signs of inflammation (fever and symptoms of systemic toxicity). Bacterial culture of the lesions.
  14. 14.  Predominant in adult men. Itchy blisters and papules on the extensor surfaces (knees, elbows) and on the sacral region. They don’t follow the lines of Blaschko. H.E.: abscess in the papillar dermis. IF: deposition of granular IgA at dermal papillae.
  15. 15.  Uncommon in childhood. Itchy clear, tense bullae on inflammatory bases. Extremities. Symmetric. H.E.: subepidermal split. IF: linear deposits of IgG and / or C3 along the epidermal basement membrane.
  16. 16.  Usually seen in the fifth decade of life. Clear, tense bullae, quite itchy. The bases aren’t inflammatory. 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 plasma membrane of keratinocytes.
  17. 17.  Blistering lesion that appear after light trauma. H.E.: subepidermal detachment. IF: IgG and C3 along the dermal-epidermal junction.
  18. 18.  Skin: vesicular and bollousus rash, localized on the extremeties and on the trunk (Blanschko’s 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. 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. 20. I.P. 10X: the dermis shows an infiltrate of lymphocytes, many eosinophilsand nuclear dust derived from eosinophilic karyorrhexis.
  21. 21.  Because the spontaneous improvement and resolution of skin lesions, we didn’t prescribe topical or systemic steroids. We prescribed only an antibiotic therapy to avoid secondary infections of the lesions.
  22. 22. Two weekslater....
  23. 23.  The vesiculo-bullous rash was disappeared. Linear warty lesions. Back of right hand and of left foot (fingers and toes), right and left legs. No lesions on the trunk. Woolly hairs. Nail’s distrophy. Onychorrhexis, onycholysis.
  24. 24. X-linked genodermatosis. It is a systemic diseasethat involves tissue of ectodermic and mesodermic origin, including cutaneous tissue, teeth, eyes and the central nervous system, amongst other organs.
  25. 25.  The disease has been reported by Bloch in 1926, and Sulzberger in 1928. The name “incontinentia pigmenti” is related to the histological characteristics of the lesions during the third, pigmentary stage, of the disease. It is melanin incontinence by melanocytes in the basal epidermal layer and its presence in the superficial dermis.
  26. 26.  Prevalence is unknow. More than 700 cases have been reported in the world literature up-to-date. IP occurs in approximately 1 in 50.000 newborns1 or in 1 in 10.000 of female newborns. The disease is predominant in women (male-female ratio 1:37). Less than 3% of cases are male and derives by other genetical disorder, not completely understood. Most cases have been described in white persons. Also other races (e.g. Korean, brasilian, cinese) are affected. About 50% of the IP cases have a positive family history.
  27. 27.  IP is a hereditary, X-linked dominant disorder. It has high penetrance but expressivity highly variable. IP is a single gene disorder, caused by mutations in the NEMO/IKKγ/IKBKG gene.
  28. 28.  NEMO is a 23kb gene, composed of 10 exons. It is located on Xq28. NEMO is the essential modulator of NF-kB. NF-Kb is a transcriptor factor involved in immune and inflammatory responces and in protecting cells from tumor necrosis factor induced apoptosis. Normally, NF- kB is described in the cellular cytoplasm. It is inactivated by the linking of a protein IkB. Flogistic stimulant (like TNF, IL1, LPS, etc) activate the Ikk complex. The Ikk kinase complex is made of two kinases (Ikkα and Ikkβ) and a regulatory subunit, NEMO. The Ikk complex phosphorize the IkB protein, which is degraded. NF-kB comes in the nucleus and starts the inflammatory responces.
  29. 29. Ikkγ Ikkα Ikkβ IkNF-kB B Nucleus
  30. 30. TNIL- F 1 Ikkγ Ikkα Ikkβ IkNF-kB B NF-kB Nucleus
  31. 31. Other phenotypes associated with NEMOmutation:EDA-ID (“anhidrotic ectodermal dysplasia andimmunodeficiency”)OL-EDA-ID (“osteopetrosis and lymphedema inEAD-ID”)
  32. 32.  Deletion of exons 4 through 10 (70-80% of IP patients). Other alteration in NEMO: small duplications, substitutions and deletions. In male carrying a NEMO mutation this is linked to embryonic lethality. Female survives for the X chromosome inactivation (“lyonization”), which occur during early embryogenesis. Many infant boys with the disease had evidence of Klinefelter’s syndrome (47,XXY karyotype). Affected surviving male have also been found with hypomorphic alleles or somatic mosaicism for the common IKBKG deletion.
  33. 33.  Also inflammatory reactions and epidermal eosinophil recruitment in the initial stage of IP seems to be important in the disorder. The exact mechanism of epidermal eosinophil accumulation has not been yet determined. Eotaxin is an eosinophil-selective chemokine, which is producted by specific leucocytes (including eosinophils, macrophages, Tcells) and some structural cells (including endothelial cells, fibroblasts and epithelial cells). Eotaxin is strongly expressed in the epidermis of IP lesional skin. Probably eotaxin is producted during the inflammatory responces due to the activation of NF-kB.
  34. 34. The clinical presentation of IP varyconsiderably even among family members.They range from subtle cutaneous anddental involvement to a complexsyndrome, sometimes deadly.
  35. 35.  Skin manifestations are the most common. Characteristic skin lesions evolve through four stages. The skin abnormalities occur along lines of embryonic and fetal skin development, know as Blaschko’s lines. Blaschko’s lines correspond with cell migration or growth pathways that are established during embryogenesis.
  36. 36.  STAGE 1 – BULLOUS STAGE STAGE 2 – VERRUCOUS STAGE STAGE 3 - HYPERPIGMENTATION STAGE STAGE 4 - ATRETIC STAGE
  37. 37.  Is present in 90% of the patients at birth or within the first two weeks of life. It can occur in utero and don’t progress after birth. Clear, tense bullae on inflammatory bases. Sometimes the eruptions may appear infectious. The bullae are accompanied or followed by smooth red nodules or plaques. The lesions tend to follow the lines of Blaschko. The lesions are tipically 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 eosinophilic spongiosis, intraepidermal vesicles. The dermis shows non-specific inflammatory changes with a a cellular infiltrate, including numerous eosinophils.
  38. 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 of six months. It is characterized by a hypertrophic, wart-like rash, similar to the first stage pattern. Histopathologically, the lichenoid papules are characterized by dyskeratotic keratinocytes, hyperkeratosis, acanthosis and papillomatosis. Also macrophages laden with melanin are present in the upper dermis. We can also describe inflammation of epidermis and dermis (epidermal spongiosis, cellular infiltrate including numerous eosinophils).
  39. 39.  Most characteristic stage for IP. Usually it begins between age six months and one year, and persist into adulthood. Spontaneous improvement and resolution of skin lesions is general the rule. Brownish linear and whorled streaks that follow the Blaschko’s lines (blue-grey or slate to brown). The bizarre splashed or Chinese figure distribution are diagnostic. Sometimes we also describe linear or macular teleangiectasias. Histopathologically, stage 3 is characterized by melanin incontinence by melanocytes in the basal epidermal layer and its presence in the superficial dermis.
  40. 40.  About 14% of patients exhibits a fourth stage. Hypopigmentation in the areas of the previous hyperpigmentation, with atrophy. Histopathologically, stage 4 is characterized by epidermal atrophy and decreased, normal or small melanocytes. Sometimes, skin appendages are absent.
  41. 41.  The onset and duration of each stage vary among individuals, and not all individuals experience all four stages. Stage 1 and 3 are more common than stage 2 and 4. Different skin manifestations: palmo-plantar hyperhidrosis, port wine stain, cleft lip and palate, abnormalities of mammary tissue (aplasia of the breast, supernumerary nipples ).
  42. 42. HAIR NAILS  40% of patients . Scarring alopecia (28-38%).  First three digits of the Thin hair . hands. Woolly hair (lusterless, wiry  Multiple digits on multiple and coarse). limbs.  Most common nail alterations: onychodystrophy, onychogryphosis, pitting, yellow discoloration.  Subungeal and periungueal keratotic tumors may appear at the later stage.
  43. 43.  80% of all IP patients. Both the deciduous and permanent dentition may be affected. The most common dental alterations are: delayed dentition (18%), partial anodontia (43%), hypodontia (40%) and abnormally shaped teeth (e.g. cone or peg-shaped teeth or accessory cusps) (30%). Dental abnormalities if not treated adequately, will lead to problems in masticatory and occlusal function, and probably psychosocial problems due to a compromised esthetic appearance.
  44. 44.  40% of the cases. Asymmetric involvement is the most common. The defects include strabismus, cataract, conjuntival pigmentosa uveitis, optic nerve atrophy, retinal vascular abnormalities, blue sclera, exudative chorioretinitis, retinal glioma. In most of patients with ocular defects, prognosis is not good: many of them become blind.
  45. 45.  25% of IP cases. Seizures are the most common symptoms (prognostic indicator). Other neurologic symptoms include: spastic or paralytic quadriplegia, hemiparesis, cerebral atrophy, microcephaly and encephalopathy. The majority of individual with IP are intellectually normal. The incidence of mental retardation is about 25-35%.
  46. 46.  Have been observed, including hemivertebra, hemiatrophy, syndactily, congenital dislocation of the hip, club foot, dwarfism, scoliosis, supernumerary ribs.
  47. 47.  Uncommon. Atrialseptal defects, acyanotic tetralogy of Fallot, ventricular endomyocardial fibrosis, tricuspid insufficiency, unilateral acheiria and primary pulmonary hypertension.
  48. 48.  Common in IP. They include functional abnormalities of neutrophils and lymphocytes and defects in polymorphonuclear chemotaxis. Also eosinophilia up to 50% in the peripheral blood is usual in first inflammatory stage of IP.
  49. 49.  No strict diagnostic criteria for IP exist. The diagnosis is mainly clinical. Family history consistent with X-linked inheritance or a history of multiple miscarriages also supports the diagnosis.
  50. 50. MAJOR CRITERIA (skin lesions that MINOR CRITERIA occur in stages from infancy to adulthood) Erythema followed by blister, in a Teeth: hypodontia, anodontia, linear distribution – stage 1 microdontia, abnormally shaped teeth Hyperpigmented streaks and whorls Hair: alopecia, woolly hair that respect Blaschko’s lines – stage 3 Pale, hairless, atrophic linear streaks Nails: onychodystrophy, or patches – stage 4 onychogryphosis, pitting, yellow discoloration. Ocular alterations (retinal neovascularization)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. 51.  Peripheral eosinophilia. Histological examination of a skin biopsy. Immunofluorescent antibody/antigen mapping (negative). Molecular genetic testing (NEMO mutation). X-chromosome inactivation studies (female with IP have skewed X-chromosome inactivation in which the X-chromosome with the mutant IKBKG allele is preferentially inactivated). 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. 52. STAGE OF IP DIFFERENTIAL DIAGNOSISSTAGE 1 Infectious: bullous impetigo, herpes simplex, varicella. Immune-mediated: dermatitis herpetiformis, epidermolysis bullosa acquisita, bullous systemic lupus erythematosus, linear IgA bullous dermatosis, bullous pemphigoid, pemphigus vulgaris.STAGE 2 Verrucae vulgaris, linear epidermal nevi, molluscum contagiosum.STAGE 3 Skin hyperpigmentation, hypomelanosis of Ito.STAGE 4 Vitiligo, piebaldism and other skin hypopigmentation, scars.
  53. 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. 54.  The prognosis is generally good and depends on extracutaneous manifestations. For persons without significant neonatal or infantile complications, life expectancy is considered to be normal. Women with IP have a higher than usual risk of pregnancy loss, presumably related to low viability of male fetuses.
  55. 55. Because IP is a systemic disorder, a multidisciplinary approach to management is crucial.A complete neurologic examination is warrented for all IP infants. Regular visits to a pediatric ophthalmologist is essential during the first year of life. Laser photocoagulation and vascular endothelial growth factor inhibitor seem to be good treatments for retinal vascular abnormalities. Concerning teeth, referral for radiologic evaluation and dental intervention by the age of two years is appropriate.
  56. 56.  Management in the newborn period is aimed at reducing the risk of infection of blisters using standard medical management. Spontaneous improvement and resolution of skin lesions is general the rule. Topical and systemic steroids have been prescribed to limit the stage 1 and 2 rashes. The use of laser treatment of hyperpigmentation should be discouraged because it has been reported to trigger an extensive vesciculobullous eruption.

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