Incontinentia Pigmenti Clinical Presentation

  • Author: Kara N Shah, MD, PhD; Chief Editor: Dirk M Elston, MD   more...
 
Updated: May 24, 2012
 

History

In most patients, cutaneous manifestations are present at birth or occur within the first 2 weeks of life. The cutaneous manifestations usually appear in a characteristic, chronologic sequence. Other systemic manifestations, including ocular defects, CNS abnormalities, and dental abnormalities, may not be recognized until infancy or early childhood.

A family history of incontinentia pigmenti in the mother is reported to occur in 28% of patients. In most patients (62%), the syndrome occurs sporadically. Germline mutations inherited from the father have been reported in over 80% of cases of sporadic incontinentia pigmenti. Male patients with incontinentia pigmenti generally appear to have a sporadic form. The development of postzygotic mutation and resulting somatic mosaicism is the likely mechanism in most male patients. In a study of 42 boys with incontinentia pigmenti, only 5 had evidence of NEMO gene mutation. The male phenotype is similar to that of the female phenotype, although unilateral presentation is a more common occurrence in boys (15%).

Diagnostic criteria for incontinentia pigmenti have been proposed. In the absence of a family history, the presence of at least 1 major criterion is necessary. The presence of minor criteria supports the diagnosis of incontinentia pigmenti.

  • Major criteria are (1) typical neonatal vesicular rash with eosinophilia; (2) typical blaschkoid hyperpigmentation on the trunk, fading in adolescence; and (3) linear, atrophic hairless lesions.
  • Minor criteria are (1) dental anomalies, (2) alopecia, (3) wooly hair, and (4) abnormal nails.

With a definitive family history, the presence of any major criterion strongly supports the diagnosis of incontinentia pigmenti.

Other characteristic features include the following:

  • Suggestive history or evidence of typical rash, hyperpigmentation, or atrophic hairless lesions
  • Vertex alopecia
  • Dental anomalies
  • Retinal disease
  • Multiple male miscarriages
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Physical

Significant clinical heterogeneity exists in incontinentia pigmenti with regard to ectodermal, ophthalmologic, and neurologic abnormalities, even within families. The cutaneous findings generally progress through 4 distinct characteristic stages, although some stages may overlap temporally and some may not occur at all in individual patients. Affected males often have limited involvement of 1 or 2 limbs.

Anomalies other than those categorized below that have been reported to occur with increased frequency in patients with incontinentia pigmenti include supernumerary nipples, nipple hypoplasia, and breast hypoplasia.

Ectodermal changes

Skin features occur in the following 4 stages:

  • Stage 1 (vesicular) is characterized by the development of red papules and vesicles on an erythematous base that follow Blaschko lines. Lesions are seen predominantly on the extremities but may also occur on the trunk or on the head and neck. The vesicular stage has been reported to occur in 90-95% of patients. In most patients (>90%), lesions are present at birth or develop within the first 2 weeks of life. They resolve within several months. Rarely, self-limiting episodes of recrudescence of vesicular lesions have been reported to occur in older infants and children with incontinentia pigmenti in association with an intercurrent febrile illness or after routine immunization.[4, 5, 6, 7]
  • Stage 2 (verrucous) is characterized by thickened, warty-appearing linear and whorled plaques on an erythematous base that follow Blaschko lines. In general, lesions develop on the extremities and trunk but may also be seen on the head and neck. Verrucous lesions have been reported to occur in 70-80% of incontinentia pigmenti patients. In most patients, verrucous lesions develop in the first few weeks to months of life and subsequently resolve over weeks to months.
  • Stage 3 (hyperpigmented) is characterized by the development of streaks and whorls of brown or slate-gray pigmentation along Blaschko lines; this occurs in 90-98% of incontinentia pigmenti patients. Hyperpigmented lesions usually involve the trunk but may also involve the extremities, the skin folds, or the head and neck. The location of the hyperpigmented lesions does not appear to correlate with areas of prior skin involvement during the earlier vesicular and verrucous stages. Hyperpigmented lesions generally develop within the first few months of life and resolve slowly by adolescence.
  • Stage 4 (atrophic/hypopigmented) is characterized by hypopigmented, atrophic, and reticulate or linear patches observed on the lower extremities, usually involving the calves. Atrophic lesions usually develop during adolescence and persist into adulthood. Atrophic lesions have been reported to occur in 30-75% of incontinentia pigmenti patients.

Abnormal dermatoglyphic patterns have also been reported.

Note the images below:

A 19-day-old female neonate with incontinentia pigA 19-day-old female neonate with incontinentia pigmenti. Clean tense vesicles in linear groups are seen extending from the inner aspect of the right knee to the posterior aspect of the right leg and right sole. A 40-day-old female infant who first presented witA 40-day-old female infant who first presented with incontinentia pigmenti when she was aged 19 days. The vesicles have disappeared, leaving a brownish pigmentation with verrucous lesions. A 20-day-old female neonate with incontinentia pigA 20-day-old female neonate with incontinentia pigmenti. Bullae, vesicles, and verrucous lesions are seen on the lower extremities and buttocks. A 27-day-old female neonate who first presented wiA 27-day-old female neonate who first presented with incontinentia pigmenti when she was aged 20 days. Note the verrucous eruptions with brownish pigmentation in a streaky linear pattern on the left leg.

Hair changes include scarring alopecia and are seen in 28-38% of patients. An absence or hypoplasia of the eyebrows and eyelashes has also been reported. Finally, hair is sparse in early childhood; later, it has a lusterless, wiry, and coarse appearance.

Nail features[8] include nail dystrophy, which ranges from mild pitting or ridging of the nail plate to hyperkeratosis and onycholysis. This is observed in 7-40% of incontinentia pigmenti patients, and usually multiple fingernails and toenails are affected. Nail dystrophy may improve with age. Subungual and periungual keratotic tumors associated with pain, bony deformities, and lytic lesions involving the underlying phalanges also may be seen, usually in older children and adults.[9, 10, 11] The fingers are most commonly affected.

Dental and oral abnormalities[12, 13, 14] are seen in 50-80% of patients and can involve both deciduous and permanent teeth. Dental anomalies are permanent and thus serve as a very useful diagnostic finding in older patients. Delayed eruption of dentition, partial anodontia, hypodontia, and conical or pegged teeth are the most common dental findings. Poor enamel quality leading to an increased incidence of dental caries and early dental loss has been reported historically, but this association has been questioned. The most common oral anomalies are cleft palate and high-arched palate.

Ophthalmologic findings [15, 16, 17, 18]

Ophthalmologic findings occur in 20-35% of patients, and asymmetric involvement is common. Retinal vascular changes, optic atrophy, and developmental defects may be seen.[19] Loss of visual acuity and blindness are significant complications. Blindness has been reported to develop in 7% of incontinentia pigmenti patients.

Ophthalmologic manifestations may become evident within the first few weeks to months of life and may progress rapidly to permanent visual deficits.

Retinal vaso-occlusive events with resultant ischemia are believed to be the primary mechanism underlying ocular pathology. Retinal manifestations include retinal detachment, proliferative retinopathy, fibrovascular retrolental membranes, foveal hypoplasia, vitreous hemorrhages, and atrophy of the ciliary body.

Nonretinal manifestations include strabismus, optic nerve atrophy, conjunctival pigmentation, microphthalmia, vortex ("whorl-like") keratitis, cataracts, iris hypoplasia, nystagmus, and uveitis.

Neurologic abnormalities

Neurologic complications occur in 30% of incontinentia pigmenti patients and often manifest within the neonatal period. They are a major cause or morbidity and mortality in affected patients.[19]

Seizures are the most common neurologic complication; they are reported in 20% of patients and usually develop within the first few weeks of life. Neonatal seizures may present days to months before the development of the characteristic cutaneous features.[20, 21]

Neurologic complications may result in part from microvascular vaso-occlusive ischemic events involving the CNS, and recurrent acute stroke may occur.[22, 23] Extensive cerebral infarction involving small and medium-sized cerebral arteries may result in destructive encephalopathy.[1, 24, 25] Involvement of the cerebral hemispheres, cerebellum, and corpus callosum may occur.[26] Progressive periventricular hemorrhagic infarcts have been reported. Other reported brain MRI abnormalities include periventricular and subcortical white matter disease, hypoplasia of the corpus callosum, cerebral atrophy, and cerebellar hypoplasia.[19] In addition to ischemic vascular insult, inflammation and apoptosis are believed to contribute to the development of neurologic sequelae.

Interestingly, resolution of cortical and subcortical white-matter destructive lesions have been reported in several infants with incontinentia pigmenti.[27, 28]

Other neurodevelopmental manifestations include developmental delay, mental retardation, ataxia, spastic paralysis, microcephaly, porencephaly, and periventricular cerebral edema.

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Causes

Incontinentia pigmenti is caused by mutations in the NEMO/IKK -gamma gene, which is located on chromosome Xq28. NEMO/IKK -gamma is the regulatory subunit of the inhibitor kappa kinase (IKK) complex and is required for the activation of the transcription factor NF-kappaB (NF-kB). NF-kB is central to many immune, inflammatory, and apoptotic pathways.

Activation of NF-kB prevents apoptosis in response to the tumor necrosis factor family of cytokines. NF-kB activity is normally regulated via the inhibitor kB protein. Tumor necrosis factor receptor activation results in phosphorylation and inactivation of inhibitor kB by IKK, thus resulting in activation of NF-kB. Loss of IKK activity results in deficient NF-kB activity and increased susceptibility to apoptosis.

Cells that retain IKK activity may produce additional cytokines that trigger apoptosis in neighboring IKK-deficient cells, thus creating an amplification loop that eventually results in the death of all of the IKK-deficient cells. This mechanism is believed to produce the cutaneous manifestations of the vesicular stage of incontinentia pigmenti. The proliferation of surviving IKK-positive cells may result in the production of the verrucous lesions seen in stage 2 of incontinentia pigmenti. The pathophysiology of the hyperpigmented cutaneous findings seen in stage 3 and the atrophic/hypopigmented manifestations of stage 4 remains unknown. Inflammation and subsequent postinflammatory changes may play a role.

Note the following:

  • The peripheral eosinophilia seen in the early stages of incontinentia pigmenti may result from the production of eotaxin, an eosinophil-selective cytokine, during the inflammatory cascade that results from a loss of NEMO/IKK -gamma activity. Activation of eosinophils with subsequent release of cellular proteases may trigger the development of the vesicular stage of incontinentia pigmenti.[29]
  • The pathophysiology underlying the CNS manifestations in incontinentia pigmenti are unknown, but inflammation resulting from loss of NEMO/IKK -gamma activity may contribute to the development of vascular occlusive events.
  • Females with hypomorphic mutations in NEMO/IKK -gamma may have few clinical manifestations of incontinentia pigmenti.
  • A single mutation in NEMO/IKK -gamma involving the deletion of exons 4 through 10 accounts for most (80%) incontinentia pigmenti mutations.
  • The NEMO gene is part of a segmental duplication or low copy repeat (LCR), which contains both NEMO and its pseudogene IKBKGP. A local high frequency of microhomologies, macrohomologies, tandem repeats, and repeat/repetitive sequences contribute to a high rate of nonallelic homologous recombination involving NEMO, resulting in the development of de novo deletion mutations.[30]
  • Hypomorphic mutations in the zinc-finger domain of NEMO/IKK -gamma result in X-linked recessive ectodermal dysplasia and immunodeficiency. A family history of incontinentia pigmenti may be elicited. Such mutations result in decreased but not absent IKK activity and thus allow for low-level NF-kB activation.
  • Hypomorphic mutations in the stop codon of NEMO/IKK -gamma result in the X-linked dominant ectodermal dysplasia osteopetrosis lymphedema syndrome.
  • Confirmation of NEMO/IKK -gamma mutations in males is difficult due to the high rate of post-zygotic mosaicism.
  • NEMO/IKK -gamma knockout mice manifest a cutaneous phenotype similar to female incontinentia pigmenti patients and develop neurologic sequelae, although they do not develop dental or ocular abnormalities. They also develop diffuse apoptosis of splenic and thymic lymphocytes, which does not occur in human incontinentia pigmenti patients.[31, 32]
  • Genetic testing for NEMO/IKK -gamma mutations is available through the Baylor College of Medicine Medical Genetics Laboratories.
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Contributor Information and Disclosures
Author

Kara N Shah, MD, PhD  Associate Professor, Departments of Pediatrics and Dermatology, University of Cincinnati College of Medicine; Medical Director, Pediatric Dermatology, Cincinnati Children's Hospital

Kara N Shah, MD, PhD is a member of the following medical societies: American Academy of Dermatology, American Academy of Pediatrics, and Society for Pediatric Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

Bernice R Krafchik, MBChB, FRCPC  Professor Emeritus, Department of Pediatrics, Section of Dermatology, University of Toronto

Bernice R Krafchik, MBChB, FRCPC is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, Canadian Medical Association, College of Physicians and Surgeons of Ontario, Royal College of Physicians and Surgeons of Canada, and Society for Pediatric Dermatology

Disclosure: Nothing to disclose.

David F Butler, MD  Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH  Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Glen H Crawford, MD  Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital

Glen H Crawford, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Phi Beta Kappa, and Society of USAF Flight Surgeons

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD  Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

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A 19-day-old female neonate with incontinentia pigmenti. Clean tense vesicles in linear groups are seen extending from the inner aspect of the right knee to the posterior aspect of the right leg and right sole.
A 40-day-old female infant who first presented with incontinentia pigmenti when she was aged 19 days. The vesicles have disappeared, leaving a brownish pigmentation with verrucous lesions.
A 20-day-old female neonate with incontinentia pigmenti. Bullae, vesicles, and verrucous lesions are seen on the lower extremities and buttocks.
A 27-day-old female neonate who first presented with incontinentia pigmenti when she was aged 20 days. Note the verrucous eruptions with brownish pigmentation in a streaky linear pattern on the left leg.
Histologic features of a vesicle in a 20-day-old female neonate who presented with incontinentia pigmenti. The epidermis shows acanthosis, spongiosis, and vesicles, which contain an inflammatory infiltrate that includes eosinophils. The epidermis between the vesicles also shows dyskeratotic cells, either singly or in small clusters (hematoxylin and eosin, original magnification X100).
A 7-month-old female infant with incontinentia pigmenti. Brownish pigmentation in a linear whorled or reticular pattern is present on the trunk.
A 1-year-old girl who first presented with incontinentia pigmenti when she was aged 7 months. Note that the pigmentation on the left thigh and leg is similar to that on the trunk.
A 6-year-old girl who first presented with incontinentia pigmenti when she was aged 7 months. Note that the brownish pigmentation on the trunk has largely disappeared, and a small area of pigmentation is left.
Histologic features of the pigmented skin from a 6-year-old girl with incontinentia pigmenti. An inflammatory infiltrate that includes eosinophils is present in the epidermis. Many melanophages are seen in the upper part of the dermis (hematoxylin and eosin, original magnification X100).
 
 
 
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