Incontinentia Pigmenti 

Rare Diseases / By

Incontinentia Pigmenti – Introduction

  • Rare, X-linked condition involving defects in IKBKG gene characterized by skin lesions that progress through 4 stages in the first year of life as well as abnormalities in retina, central nervous system, teeth, hair, and nails(1,2,3)

Synonyms

  •  Bloch-Sulzberger syndrome
  •  Bloch-Siemens incontinentia pigmenti
  •  melanoblastosis cutis linearis
  •  Siemens-Bloch type pigmented dermatosis
  •  nevus pigmentosus systematicus

Epidemiology

Incidence/Prevalence

  •  reported incidence 1 case per 40,000-140,000(2)

Risk Factors

  •  family history(2)

Associated Conditions

  • a subset of pathogenic variants in NF-kappa B mainly located in exon 10 have been identified(1)
    •  pathogenic variants appear to result in defective but not absent KF-kappa B, and are associated with milder incontinentia pigmenti (IP) phenotype in females with lower risk of miscarriage of male fetuses
    • surviving males have NF-kappa B-related disorder such as

Etiology and Pathogenesis

Causes

  •  caused by mutation in inhibitor of nuclear factor kappa B kinase subunit gamma (IKBKG) gene present in B cells(1,2,3)

Pathogenesis

Molecular Genetics
  • in normal physiologic state(1,2)
    • IKBKG gene expressed in B cells and encodes nuclear factor kappa beta essential modulator protein (NEMO) or inhibitor of nuclear factor kappa-B kinase, subunit gamma (IKK-gamma)
      • IKK proteins alpha, beta, and gamma form a complex
        •  IKK-gamma is synthesized beginning in early embryogenesis and is expressed universally
        •  IKK-gamma activates NF-kappa-B which in turn upregulates immune response and protects against apoptosis induced by tumor necrosis factor alpha
      •  IKK-gamma (or NEMO) is essential for activation of NF-kappa B pathway (family of transcription factor) that in turn upregulates immune response and prevents cellular apoptosis
  • IKBKG possesses multiple transcript variants encoding different isoforms(1,2)
    •  variety of novel mutations may lead to incontinentia pigmenti (IP) and associated pathologic variants
    • pathogenic variants
      • recurrent 11.7-kb deletion of exons 4-10 in IKBKG (c.399-?_1260+?del)
        • reported in 60%-80% of cases (Indian J Med Res 2011 Apr;133:442full-text)
        • remove exons 4 through 10 which causes loss of function of nuclear factor (NEMO) and diminished NF-kappa B activity in response to varied external stimuli and cause IP
        •  smaller pathogenic variants mainly in exon 10 of IKBKG, result in a protein with decreased activity and may eventually lead to ectodermal dysplasia and immunodeficiency conditions
    •  minor portion of patients with IP exhibit no observable change in IP locus
    • 2 benign variants found in 10%-12% of parents of patients with IP
      •  11.7-kb deletion of exons 4-10 in IKBKGP1 (pseudogene of IKBKG)
      •  duplication of MER67B (two 870-bp direct repeats within IKBKG gene)
  •  14-basepair deletion of IKBKG exon 8 causing incontinentia pigmenti in newborn girl in case report (J Dermatol 2019 Jan;46(1):e26)
  •  mutation in IKBKG exon 4 in patient with severe cholestatic liver disease in case report (Australas J Dermatol 2018 Nov;59(4):e262)
  • mutations in genes other than NEMO resulting in clinical features of IP reported (Clin Dysmorphol 2014 Apr;23(2):52)
    •  heterozygous deletion of p21-activated serine/threonine kinase (PAK6)
    •  heterozygous duplication of mitochondrial flavin adenine dinucleotide-dependent oxidoreductase (AIFM1)
Clinical Pathogenesis
  • normal skin cells (wild type) and skin cells expressing the NF-kappa B pathogenic variant (mutant cells) present on skin surface along the lines of Blaschko (patterns of dermal development during embryogenesis) at birth(3)
    •  both cells compete with one another prior to and during birth on skin surface along lines of Blaschko (patterns of dermal development during embryogenesis)
    •  unknown factor causes mutant cells to produce interleukin which in turn cause the wild type skin cells with intact NF-kappa beta in vicinity to mount an inflammatory response
    •  primary stage of skin manifestations (Stage 1, inflammatory/vesicular stage) develops when mutant skin cells are killed by wild type cells via apoptosis
    •  secondary stage of skin changes may manifest due to a second wave of cell death by IKBKG-deficient cells (mutant cells) that survive first wave of cell death
    •  vesicular flare-ups can appear throughout life in response to a febrile illness as complete line of NF-kappa beta cells is not destroyed on any occasion in totality
  •  NF-kappa B is present in all cell types and is expressed in neurons, astrocytes, microglia, and oligodendrocytes within central nervous system (CNS) where it prevents apoptosis and protects integrity of brain endothelial cells and blood-brain barrier(3)
  • pathogenesis and pathway of CNS involvement unclear, may consist of a multiple of different pathologies(3)
    •  disturbance in blood-brain barrier may favor proconvulsive factors to cause seizures in IP that are unrelated to ischemic stroke
    •  ischemia caused by vascular changes of small and medium cerebral vessels may lead to infarcts, white matter loss, corpus callosum changes, and brain malformations
    •  small vessel pathology seen suggests that vascular occlusion, infarct, and neovascularization may lead to retinal detachment
    •  inflammation may aid in initiating small and medium cerebral vessel disease that may in turn lead to vascular occlusion, infarct
  • NEMO deficiency may lead to(3)
    •  ischemic insult, strokes, and seizures, white matter loss, periventricular leukomalacia and cysts, ventricular dilatation, polymicrogyria, corpus callosum abnormalities, cerebellar atrophy
    •  activation of eosinophilic chemokines and a subsequent inflammatory response, similar to process in skin lesions, and leads to destruction of NF-kappa B-deficient cells in brain
  •  retinal manifestations arise due to vaso-occlusions in retinal arteries and progress to areas of avascularity and underperfusion, eventually leading to precipitating ischemia(2)

History and Physical

Clinical Presentation

  • presentation and course of incontinentia pigmenti (IP) varies, but typical features include(1,2,3)
    • skin lesions (occur in almost 100% of patients) that progress through stages and continue into adulthood
      •  bullous stage – characterized by erythema followed by blister-like bullous eruptions that typically present at age 6-8 weeks but may be present at birth
      •  verrucous stage – characterized by wart-like verrucous papules and keratotic patches that typically present in first few weeks or months of life and disappear by age 6 months
      •  hyperpigmented stage – characterized by swirling or whirling macular patches of hyperpigmentation that typically present anywhere between infancy and adolescence, but mostly fades by early adulthood
      •  hypopigmented/atretic stage – characterized by patchy areas of hypopigmentation, mainly arranged in streaks or whorls and mostly present during adolescence and persists into adulthood (may be permanent)
    •  abnormalities in teeth, hair, and nails
    •  central nervous system abnormalities such as seizures, ataxia, motor problems, learning difficulties, and microcephaly
  • other features may include
    •  eosinophilia (up to 65%) in blood count reported in up to 88% of patients with IP(1)
    • skeletal malformations which may affect 20% of patients, including
      •  scoliosis
      •  hemivertebra
      •  spina bifida
      •  syndactyly
      •  ear defects
      •  increased number of ribs
      •  chondrodystrophy
      •  clubfoot
      •  short stature
      •  dwarfism
    • Reference – An Bras Dermatol 2014 Jan-Feb;89(1):26full-text
  • skin lesions at birth or during neonatal period reported in 100% of female children with incontinentia pigmenti
    •  based on cohort study
    • 25 female children with incontinentia pigmenti were assessed
    • median age at initial visit was 1 month
    • median follow-up of 2.7 years
    • skin lesions in 100%
      • clinical stages at initial visit were vesicular in 40%, verrucous in 16%, hyperpigmented in 28%, and hypopigmented in 4%
      • distribution of lesions included lower extremities (92%), upper extremities (64%), and trunk (64%)
    • Reference – Exp Dermatol 2021 May;30(5):676
  • status epilepticus and hyperpigmented whorls reported in 6-month-old girl with IP following viral respiratory infection in case report (J Epilepsy Res 2017 Dec;7(2):118full-text)

History

Family History (FH)

  • ask about family history of(1)
    •  incontinentia pigmenti
    •  multiple male miscarriages

Physical

General Physical

  • check for
    •  findings of primary pulmonary hypertension(1)
    • signs of heat intolerance (3)
      •  tactile fever
      •  lethargy
      •  red ears and skin
      •  irritability

Skin

  • Incontinentia pigmenti – Blisters and pustules on lower leg in neonate with incontinentia pigmenti.Copyright© 2014, EBSCO Information Services.
  • Incontinentia pigmenti – Blisters and pustules on arm in neonate with incontinentia pigmenti.Copyright© 2014, EBSCO Information Services.
  • examine for lesions(1,2)
    • stage 1 (inflammatory/vesicular/blistering/bullous stage)
      •  characterized by marked erythema with linear vesicles, bullae, and pustules
      •  lesions often present at birth or may develop during first 2 weeks of life and disappear by age 18 months
      •  occurs in 90% of patients
    • stage 2 (verrucous stage)
      •  characterized by wart-like verrucous papules and keratotic patches
      •  appears in first few weeks or months of life and disappear by age 6 months
      •  in some instances lesions remain through adulthood or show up later during disease progression in form of linear verrucous striae leaning towards palms and soles
      •  occurs in 70% of patients
    • stage 3 (hyperpigmented stage)
      •  characterized by swirling or whirling macular patches of hyperpigmentation
      •  may occur anywhere between infancy and adolescence, but mostly fades by early adulthood
      •  occurs in 98% of patients
    • stage 4 (hypopigmented/atretic stage)
      •  characterized by patchy areas of hypopigmentation that are mainly arranged in streaks or whorls
      •  cutaneous atrophy and absence of hair mainly on the lower extremities
      •  mainly develops during adolescence and persists into adulthood (may be permanent)
      •  occurs in 28% of patients
    •  Reference – An Bras Dermatol 2014 Jan-Feb;89(1):26
  • hair may be affected in 28%-38% of patients and most common manifestations include(3)
    •  alopecia
    •  coarse wooly hair at vertex
    •  sparse, brittle hair
    •  hypoplasia or absence of eyebrows and eyelashes
  • hair abnormalities reported in 20% of 25 female children with incontinentia pigmenti in retrospective cohort study (Exp Dermatol 2021 May;30(5):676)

HEENT

  •  examine for papules, vesicles, and pustules with a linear pattern along lines of Blaschko on head(3)
  • assess for ocular anomalies(2,3)
    •  majority of patients have normal vision
    •  eye involvement reported to occur in 35%-77% of studied populations and prevalence of unilateral or bilateral blindness reported to be between 7% and 23% (An Bras Dermatol 2014 Jan-Feb;89(1):26)
    •  arise from vaso-occlusion of periphery and macula which lead to ramifications of neovascularization, preretinal gliosis, and retinal detachment
    • rare eye abnormalities include
      • microphthalmos
      • cataracts
      • optic nerve atrophy
    • cortical blindness may occur leading to total blindness or only light perception
    • other anomalies include(1,3)
      • retinal gliosis
      • retinal detachment
      • strabismus
      • cataracts
      • optic atrophy
      • retinal pigmentary abnormalities
    • assess abnormalities of optic nerve head, macula, and far peripheral retina by performing dilated fundus examination(3)
    • ocular anomalies reported in 62% of 122 eyes of 61 children (median age 3.7 months, 95% female) with incontinentia pigmenti in retrospective cohort study (Acta Ophthalmol 2019 May;97(3):265full-text)
    • abnormal retinal findings including avascularity, neovascularization, hemorrhage, and tractional retinal membrane reported in 28% of 25 female children with incontinentia pigmenti in retrospective cohort study (Exp Dermatol 2021 May;30(5):676)
  • look for dental and oral anomalies, which are reported in more than half of patients based in a cohort study of 1,286 patients with incontinentia pigmenti
    • anomalies included
      • dental (95.05%)
      • oral (4.95%)
    • 465 types of dental and/or oral anomalies in 279 patients (54.38%) and included
      • cleft palate and high arched (gothic) palate (palate anomalies) in 30.43%
      • dental shape anomalies in 36.42%
      • hypodontia in 31.22%
      • delayed dentition in 17.87%
      • dental caries in 0.31%
    •  Reference – Clin Oral Investig 2013 Jan;17(1):1
  • dental anomalies including hypodontia and/or conical teeth reported in 12% of 25 female children with incontinentia pigmenti in retrospective cohort study (Exp Dermatol 2021 May;30(5):676)

Chest

  • look for(1,3)
    •  supernumerary nipples
    •  nipple asymmetry
    •  breast aplasia
  •  assess for mammary tissue anomalies including aplasia of breast, supernumerary nipples, or nipple asymmetry, reported in 11% of patients(3)

Extremities

  • alterations in some or all nails of hand and feet reported in 40% of patients and include(3)
    •  yellowish pigmentation
    •  nail dystrophy
    •  longitudinal or transverse slits
    •  painful periungual and subungual keratotic tumors
  • nail dystrophy reported in 8% of 25 female children with incontinentia pigmenti in retrospective cohort study (Exp Dermatol 2021 May;30(5):676)

Neuro

  • perform neurological examination, specifically evaluating for(1,3)
    •  learning difficulties
    •  intellectual disability
    •  motor problems
    • ataxia
  • seizures, motor impairment, and intellectual disability reported in about 5%-10% of patients based on a systematic review of observational studies of 1,393 patients with incontinentia pigmenti (IP)
    • central nervous system (CNS) anomalies present in 393 patients (30.4%) and average number of CNS types of anomalies per patient was 1.62
      •  seizures in 11.84%
      •  intellectual disability in 7.25%
      •  motor impairment in 5.74%
    •  Reference – Orphanet J Rare Dis 2013 Feb 13;8:25full-text
  • CNS abnormalities(3)
    •  presentation varies but when CNS involvement occurs it is likely severe and most disabling
    •  mainly begin within first week of life but may appear in utero
    •  do not constitute major or minor criteria of IP
    • neurologic manifestations reported in 30% of patients with IP and include
      •  microcephaly
      •  learning difficulties
      •  seizures
      •  motor problems
      •  ataxia
    • infants may exhibit acute epileptic encephalopathy
      •  most common seizure types include focal clonic seizures and epileptic spasms
      •  10% of affected patients experience seizures after age 1 year

Diagnosis

Making the Diagnosis

  • diagnosis is established clinically by presence of > 1 major criteria which consists of skin lesions that occur in stages from birth to adulthood(1)
    • bullous stage – characterized by erythema followed by vesicobullous eruptions that typically present at age 6-8 weeks but may be present at birth
    •  verrucous stage – characterized by warty papules and keratotic patches that typically present in first few weeks or months of life and disappear by age 6 months
    •  hyperpigmented stage – characterized by swirling or whirling macular patches of hyperpigmentation that typically present anywhere between infancy and adolescence, but mostly fades by early adulthood
    •  hypopigmented/atretic stage – characterized by patchy areas of hypopigmentation that are mainly arranged in streaks or whorls that typically present during adolescence and persists into adulthood (may be permanent)
  • minor criteria support the diagnosis and include(1,2)
    •  hypodontia or anodontia, microdontia, abnormally shaped teeth
    •  alopecia or woolly hair
    •  mild ridging or pitting of nails; onychogryposis
    •  peripheral neovascularization
    •  family history consistent with X-linked inheritance or a history of multiple miscarriages of male fetuses
    •  seizures, intellectual disability
    •  typical skin histologic findings (eosinophilic infiltration and/or extracellular melanin granules)
    •  supernumerary nipples and breast aplasia
    •  cleft palate and high arched palate (Clin Oral Investig 2013 Jan;17(1):1)
  •  if clinical features are inconclusive, genetic testing can be used to confirm diagnosis(1)

Differential Diagnosis

  • differential diagnoses of skin manifestations include
    • for stage 1 rule out(1,3)
      • bacterial skin infectious such as staphylococcal bullous impetigo, crusted pustular streptococcal lesions, or pustular eruptions such as with Listeriosis
      • other congenital or neonatal infections such as
        • syphilis
        • toxoplasmosis
        • varicella
        • herpes simplex
          • bacterial cultures, viral cultures, and/or polymerase chain reaction testing of lesions considered diagnostic for these infectious diseases
      • epidermolysis bullosa
        • blistering of skin manifesting after light trauma are characterisitic and diagnosis established by
          • skin biopsy analysis
          • transmission electron microscopy or immunofluorescent antibody/antigen mapping
          • molecular genetic testing
      • other neonatal bullous eruptions such as bullous mastocytosis, epidermolytic ichthyosis, or congenital pemphigus
    • for stage 2 rule out
      • warts
      • molluscum contagiosum
      • epidermal nevus
      • linear lichen planus
      • linear psoriasis
      • lichen striatus
      • nevus sebaceous
      • contact dermatitis
    • for stage 3 rule out
      • epidermal nevus
      • phytophotodermatitis
      • pigmentary mosaicism
      •  hypomelanosis of Ito
      • postinflammatory pigment alteration
    • for stage 4 rule out
      •  scarring
      •  vitiligo (with localized alopecia)
      •  piebaldism
      • postinflammatory pigment alteration
      • lichen striatus (hypopigmented phase)
    •  Reference – (1,3), Pediatr Ann 2015 Aug;44(8):e194
  • differential diagnoses of ocular findings include(1,2)
    • retinopathy of prematurity (ROP)
    •  familial exudative vitreoretinopathy
    •  Eales retinopathy
    •  sickle cell retinopathy
    •  Norrie disease spectrum
    •  shaken baby syndrome
    •  retinal neovascularization seen in retinopathy of prematurity and familial exudative vitreoretinopathy
  • differential diagnoses of dental manifestations include

Testing Overview

Imaging Studies

  • perform magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) with and without contrast at diagnosis(1,3)
    •  initial imaging should be performed as soon as possible, preferably during neonatal period
    •  diffusion-weighted and susceptibility-weighted imaging should be used
    •  repeat if presence of seizures, retinal neovascularization, or other neurologic anomalies
    •  in patients with neurologic deficit that is consistent with stroke-like pattern, MRA may help identify cerebrovascular lesions
    • observations on brain imaging may include
      • periventricular leukomalacia
      • hemorrhagic stroke in children
      •  agenesis of corpus callosum with occipital encephalocele (rare)
      •  polymicrogyria (rare)
      •  gray matter heterotopias (rare)
      • central nervous system lesions based on systematic review of 1,393 case reports of incontinentia pigmenti
  • fluorescein angiogram to evaluate the vasculature of the eye should be strongly considered(2,3)
    •  assess for retinal vascular abnormalities, neovascularization, hemorrhage, and exudative leakage
    •  may need to be performed under anesthesia
    •  perform preferably as soon as possible or before infant is discharged from hospital

Biopsy and Pathology

  • consider skin biopsy in patients with suspected incontinentia pigmenti in whom an IKBKG pathogenic variant is not identified on molecular genetic testing(1,2)
    • in affected females, characteristic clinical features, eosinophilic infiltration, and deposits of free or intramacrographic melanin granules may suggest or confirm diagnosis
    • in affected males, histologic examination of skin biopsy may help identify incontinentia pigmenti, especially in instances of mosaicism
    • seldom used now due to availability and sensitivity of genetic testing
    • same skin biopsy may be used for routine pathologic examination following molecular genetic testing
    • biopsy may also be considered to distinguish single stage 2 lesions from warts

Genetic Testing

  •  perform genetic testing in patients in whom incontinentia pigmenti suspected, but clinical features are inconclusive(1)
  • diagnosis is confirmed if any of the following are identified(1)
    •  heterozygous IKBKG pathogenic variant in female patient
    •  hemizygous IKBKG pathogenic variant in male patient
    •  mosaicism for an IKBKG pathogenic variant in male patient
  • consider single-gene testing in patients with a lack of pathogenic variant(1,2)
    •  most pathogenic variants can be identified via this method
    •  testing may involve targeted analysis of common 11.7-kb IKBKG deletion with simultaneous or sequential analysis of IKBKG sequence followed by gene-targeted deletion/duplication analysis
    •  presence of highly homologous pseudogene IKBKGP1 may make analysis difficult
    •  consider genetic testing on tissue sample (such as skin form an affected site, sperm) if initial blood testing is negative in males with suspect mosaicism
  • consider multigene panel that includes IKBKG and other genes if necessary depending on conditions that need to be ruled out(1)
    •  panel may include sequence analysis, deletion/duplication analysis, and/or other nonsequencing-based tests
    •  in presence of IKBKGP1, use sequencing methods other than next generation sequencing

Management

Management Overview

  • refer to multidisciplinary team to establish extent of disease and needs in individual diagnosed with incontinentia pigmenti (IP) including(1)
    •  clinical geneticist and/or genetic counsellor
    •  pediatric dermatologist
    •  ophthalmologist
    •  pediatric neurologist
    •  pediatric cardiologist
    •  pedodontist
    •  speech pathologist and/or pediatric nutritionist
  • for management of eye manifestations, consider(1,2)
    • medications(2)
      •  antivascular endothelial growth factor as primary treatment or adjunctive treatment to laser photocoagulation in patients with refractory or bilateral cases of neovascularization
      •  dexamethasone in addition to standard antiseizure medication therapy such as adrenocorticotropic hormone and prednisolone in patients with seizures
    • surgery(1,2)
      •  laser photocoagulation or cryotherapy in patients with peripheral avascular retina or retinal neovascularization
      •  pars plana vitrectomy in patients with retinal detachment
  • for skin manifestations
  • for management of neural manifestations(1,2)
    •  consider brain magnetic resonance imaging (MRI) for functional neurologic abnormalities and/or retinal neovascularization to probe occlusive consequences of IP in the brain
    •  refer to pediatric neurologist or developmental pediatrician to evaluate neurologic function
    •  consider addition of dexamethasone to standard antiseizure medication therapy for treating seizures
  • other therapies may include(1,3)
    •  oatmeal baths to relieve discomfort of skin eruptions
    •  cool liquids, ice packs, and shade to address episodes of heat intolerance
    •  air-conditioned classroom or school bus for school children may be necessary
    •  developmental programs and special education for children with developmental delay
    •  delivery management in pregnant women with retinal problems to minimize or eliminate labor and subsequently avoid retinal detachment
  • advise patient or caretaker to avoid trauma to head, skin, and rupturing of blisters(1)
  • perform routine follow-up to monitor for dental, eye, and central nervous system manifestations(1,2)

Activity

  • advise patient that for prevention of secondary complications, it is best to avoid(1)
    •  opening or rupturing of blisters, or any trauma to the skin
    •  head trauma, which may result in retinal detachment
  •  maintain blistered areas by cleaning and bandaging as they progress to healing(1)

Medications

  • consider intravitreal antivascular endothelial growth factor (VEGF) as primary treatment or adjunctive treatment to laser photocoagulation for neovascularization, particularly in refractory or bilateral cases(2)
    • intravitreal bevacizumab (0.03 mL single injection) used to treat 2 female siblings with incontinentia pigmenti (IP) reported to result in vascularization to mid-periphery including a vascularized fovea (which was avascular before injection), but recurrence of some peripheral neovascularization in 1 case and no recurrence in second case at 7 months of follow-up in case series (J Pediatr Ophthalmol Strabismus 2013 Oct 29;50 Online:e52)
    • intravitreal ranibizumab reported to result in regression of retinal neovascularization, vascular tortuosity, and nonperfused region of retina by 12 months in twin 5-week-old girls with IP with retinal vascular occlusion, arteriovenous anastomoses, avascularization, vascular tortuosity, and hemorrhage in case series (J AAPOS 2018 Aug;22(4):325)
    •  intravitreal ranibizumab as adjunctive therapy used to treat 4-year-old girl with IP with proliferative retinopathy and who did not respond to panretinal laser photocoagulation reported to result in regression of proliferative retinopathy without systemic side effects in case report (Retin Cases Brief Rep 2017 Fall;11(4):352)
    •  intravitreal bevacizumab (1.25 mg/0.05 mL injection) as adjunctive therapy used to treat 11-month-old boy with clinically and genetically established IP and who failed laser photocoagulation therapy and developed retinal detachment with extensive neovascularization reported to result in regression of neovascularization in case report (Semin Ophthalmol 2009 Mar-Apr;24(2):70)
  • consider dexamethasone in addition to standard antiseizure medication therapy for treating seizures3
    • dexamethasone (initial dose 0.25 mg/kg/day) in 2-day-old female with IP and exhibiting severe neonatal encephalopathy led to cessation of clinical seizure activity in case report (J Child Neurol 2015 Jan;30(1):100)
    • difluocortolone valerate 0.1% and chlorquinaldol 1% reported to result in complete resolution of lesions by 5 days in 18-day-old female neonate with IP in case report (Clin Exp Dermatol 2009 Dec;34(8):e611)
  • consider topical tacrolimus or corticosteroids for speeding up resolution of inflammatory stage
    •  topical tacrolimus (Protopic 0.1% ointment, twice-daily formulation) used to treat 4-week-old female with IP and linear distribution of vesicles and bullae and grouped vesicles with yellow crusting reported to result in clearance of inflammatory plaques by 6-8 weeks and halted progression of disease in case report (J Drugs Dermatol 2009 Oct;8(10):944)
    •  topical corticosteroid (difluocortolone valerate 0.1% cream, twice-daily) and an antiseptic (chlorquinaldol 1% cream, twice-daily) used to treat 18-day-old female neonate with vesiculobullous stage of IP reported to result in complete resolution of lesions by 5 days in case report (Clin Exp Dermatol 2009 Dec;34(8):e611)

Surgery and Procedures

  • consider laser photocoagulation or cryotherapy in patients with peripheral avascular retina and retinal neovascularization(1,2)
    • may reduce risk of complications such as
      •  retinal detachment
      •  vitreous hemorrhage
      •  preretinal fibrosis
      •  exudation
    •  10% of patients are reported to have complications despite laser photocoagulation or cryotherapy
    •  laser photocoagulation with red diode laser in 4-year-old female with avascular peripheral retina and subtotal tractional; exudative retinal detachment reported to result in regression of retinal neovascularization and cessation of vascular leakage at 5 months of follow-up in case report (Retina 2010 Apr;30(4):708)
    •  early indirect laser photocoagulation in 18-day-old female infant with incontinentia pigmenti with preproliferative retinopathy resulted in regression of retinopathy without any signs of tractional retinal detachment at 1-year follow-up in case report (Acta Ophthalmol 2010 Mar;88(2):267)
  • consider pars plana vitrectomy in patients with retinal detachment(2)
    •  vitrectomy should be performed by a vitreoretinal surgeon (2)
    •  vitrectomy performed in 4 children (6 eyes) with incontinentia pigmenti reported to halt progression of retinopathy in case series (Arch Ophthalmol 1993 May;111(5):614)

Consultation and Referral

  • refer patients to(1)
    •  ophthalmologist familiar with incontinentia pigmenti (IP) and/or diseases of retina in patients with retinal neovascularization
    •  dermatologist or pediatric dermatologist for patients with considerable skin involvement
    •  pedodontist when aged 6 months or when teeth erupt (whichever event takes place first)
    •  speech pathologist and/or pediatric nutritionist in cases where deferred or insufficient eruption of primary teeth interferes with chewing and/or speech development
    •  pediatric neurologist in patients with seizures, spasticity, or focal deficits
    •  clinical geneticist and/or genetic counselor
    •  pediatric cardiologist for management of neonates with pulmonary hypertension
    • genetic counselor for
      •  young adults who are affected, possess an IKBKG pathogenic variant, or are at risk
      •  at-risk relatives to facilitate early diagnosis and treatment

Other Management

  •  consider oatmeal baths to relieve discomfort of skin eruptions(3)
  • when episodes of heat intolerance or overheating occur consider(3)
    •  cool liquids and/or cool bath
    •  ice packs for groin and axilla
    •  shade
  •  air-conditioned classroom or school bus for school children may be necessary(3)
  •  for developmental delay, children should be provided with apt developmental stimulation and special education(1)
  • pregnancy management(1)
    •  overall health and management do not differ from normal
    •  risk of pregnancy loss may be higher in women with incontinentia pigmenti (IP), but pregnancy should be managed in a standard manner
    •  for women with retinal problems, consider delivery management to minimize or eliminate labor in order to avoid retinal detachment

Follow-up

  •  reconsider genetic testing at puberty for reproductive purposes(3)
  • evaluations should be performed to determine extent of disease and needs in individuals diagnosed with incontinentia pigmenti (IP)(1)
    •  physical examination, especially of skin, hair, nails, and neurologic system, to determine presence and extent of manifestations
    •  developmental evaluation in instances where significant delays are identified
  • recommendations for surveillance(1,2)
    •  monitor for excessive inflammation and signs of systemic involvement
    •  routine assessment by pedodontist or dentist for dental anomalies
    • monitoring for eye manifestations should include
      •  dilated eye examinations immediately following birth
      •  monthly for the first 4 months
      •  every 3 months for 1 year
      •  twice per year up to aged 3 years
      •  annually after age 3 years
    •  frequency of examinations should be increased in children who have known eye manifestations
    •  retinal signs not likely to manifest after aged 1 year
    •  consider lifelong retinal follow-up in absence of unexceptional neonatal period, as retinal signs such as new onset retinal detachments have been reported on rare occasions in patients > 40 years old

Complications and Prognosis

Complications

  • 10% of children with peripheral avascular retina reported to have ophthalmologic complications despite therapy (laser photocoagulation, or cryotherapy, or pars plana vitrectomy) including(2)
    •  vitreous hemorrhage
    •  exudation
    •  preretinal fibrosis
    •  tractional retinal detachment
  •  pulmonary hypertension rare and typically found within first few weeks of life(3)
  • neural manifestations include
  • ophthalmological manifestations progressing to total retinal detachment observed in case series
    • 3 female infants (mean age 51 days) with IP and retinal manifestations were treated and followed for mean 3 months
      •  ophthalmological manifestations prior to treatment included 3,600 of avascular retina, abnormal retinal vascular proliferation, dilated vessels with peripheral anastomosis, hemorrhage into vitreous humor, telangiectatic vessels involving central retina with sparing of optic disc and macula, fibrovascular stalk within anterior chamber and extending in to vitreous humor from retina
      •  treatments included cryotherapy, prophylactic panretinal laser photocoagulation, refractive correction, and patching of right eye for 12 hours daily
    • outcomes at follow-up included
      •  total retinal detachment in left eye leading to prosthesis implantation at aged 2 years
      •  total retinal detachment with macular involvement in right eye leading to blindness
      •  no retinal detachment in infant treated with cryotherapy
    •  Reference – Pediatr Int 2009 Feb;51(1):141
  • IP reported to be associated with intellectual disability including deficiencies in arithmetic reasoning and reading skills
    •  based on case series
    • 10 women (mean age 33 years) with IP with IKBKG/ NEMO gene deletion in Xq28 had cognitive assessment
      •  7 had normal intellectual ability (IQ > 70) and 3 had intellectual deficiencies (IQ 45-70)
      •  cognitive assessment included the Wechsler Adult Intelligence scale and tests examining reading, arithmetic, and writing skills
    •  among 7 patients with normal IQ, most had deficient reading and arithmetic scores, however, all 7 patients had adequate writing skills
    •  Reference – PLoS One 2014;9(1):e87771PDF
  •  oligodontia with only 4 teeth within oral cavity in 2-year-old female with IP had delayed eruption of primary and permanent teeth along with conical and peg-shaped anterior teeth at 5-year follow-up in case report (J Dent (Tehran) 2016 Aug;13(4):295PDF)

Prognosis

  •  life expectancy is normal in affected individuals who do not have considerable neonatal or infantile complications(1)
  •  neurological manifestations of IP may progress to substantial morbidity, and reported to be leading cause of death in IP(2)

Prevention and Screening

Prevention

  •  preimplantation diagnosis is possible in families with known IKBKG pathogenic variant(1)

Screening

  • consider prenatal testing for at-risk pregnancies; fetal karyotype should be determined in order to provide accurate genetic counseling(1)
    •  for fetal karyotype 46,XX, there is a 50% chance the fetus will be affected with incontinentia pigmenti
    •  for fetal karyotype 46,XY, counsel parent that there is an increased likelihood of miscarriage of affected males after the first trimester
    •  for fetal karyotype 47,XXY, counsel parent that the fetus may be affected with severe incontinentia pigmenti and klinefelter syndrome

Guidelines and Resources

Guidelines

Review Articles

  •  to search MEDLINE for (Incontinentia pigmenti) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis

Patient Information

References

General References Used

  1. Scheuerle AE, Ursini MV. Incontinentia pigmenti. GeneReviews 2017 Dec 21full-text.
  2. Greene-Roethke C. Incontinentia Pigmenti: A Summary Review of This Rare Ectodermal Dysplasia With Neurologic Manifestations, Including Treatment Protocols. J Pediatr Health Care. 2017 Nov – Dec;31(6):e45-e52.
  3. Minić S, Trpinac D, Obradović M. Incontinentia pigmenti diagnostic criteria update. Clin Genet. 2014 Jun;85(6):536-42.

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