Incontinentia pigmenti (IP), also known as Bloch-Sulzberger syndrome, was first described in the literature in 1906 by Garrod.1 It is a rare X-linked dominantly inherited syndrome manifesting at birth or early childhood. The principal feature is characteristic skin lesions first presenting as vesiculobullous lesions that progress to whorl-like pigmentary lesions over four distinct stages.2 IP also includes ocular abnormalities, primarily occurring in the retina, such as vascular occlusion, neovascularization, hemorrhages, foveal abnormalities, and exudative and tractional detachments. Pathologic changes in the central nervous system, teeth, and hair are also common. Diagnosis is clinical, based on systemic and ocular examination as well as genetic testing and skin biopsy. There is no treatment for the disease as a whole; however, manifestations may be managed medically or surgically.
The incidence of IP is typically estimated at one case per 40,000 (0.0025%), however some estimates quote one case per 140,000.3 Through the date of this submission, 2,133 affected individuals have been reported in the medical literature through 2014, but it is unknown if each case reported is a unique individual.3–6 Because IP is an X-linked dominant disease, affected male fetuses typically do not survive, and therefore the great majority (90% to 97%) of living affected individuals are female.5,7 As of 2014, our review of the literature yielded 131 published cases of IP in males (or 6.14% in our review of the literature).3,5 The gender distribution may vary based on geographic location, with certain East Asian regions reporting a higher percentage of male IP patients (13.6%).8 IP has high genetic penetrance and variable phenotypic expressivity. Most cases are sporadic;9 IP is familial in only 10% to 25% of cases, and family history is the only known risk factor.10 It has also been suggested that certain autoimmune conditions, most notably systemic lupus erythematous and Sjögren’s syndrome, may be associated with IP.8 Differences in expressivity may be explained by lyonization in females, resulting in functional mosaicism.7 Living males are likely to be affected with Klinefelter syndrome, in which an extra X chromosome is present, or have somatic mosaicism.7,11,12 There is no evidence that environmental factors play a role in the pathogenesis of IP. IP appears to be more common in whites than individuals of other races.
IP is due to mutation in the IKBKG gene (approved name: inhibitor of the kappa light polypeptide gene enhancer in B-cells, kinase gamma), which is located on the X chromosome at position q28.9,13,14 This 23-kb gene consists of 10 exons with three non-coding exons and encodes for the NEMO (nuclear factor κß essential modulator) protein or IKK-γ (inhibitor of nuclear factor kappa-ß kinase, subunit gamma).7 IKK-γ (NEMO) forms trimers with IK alpha and beta, thus forming the IK kinase enzyme complex. NEMO is the regulatory complex of the enzyme. The IK kinase enzyme cleaves Iκß (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor), which is an inhibitory protein complex bound to nuclear factor–κß (NF-κß; nuclear factor kappa-light-chain-enhancer of activated B cells).13–15
NF-κß is a complex family of transcription factor proteins that upregulates the immune response and also prevents cellular apoptosis. In its inactive state, NF-κß is sequestered in the cell cytoplasm, bound by the Iκß inhibitory complex. However, when activated by various cytokines, IK kinase (including NEMO) cleaves the Iκß inhibitory complex from NF-κß, allowing NF-κß to move into the nucleus and initiate transcription of immune factors that prevent cellular apoptosis.14 Through this cascade, IKK-γ (or NEMO) is a critical protein that is necessary for activation of the NF-κß pathway. IK kinase is activated by various intrinsic factors, including tumor necrosis factor-κ.9,13,14,16
The most common genetic mutation in IP is an approximately 11.7-kb deletion (c.399-?_1260+?del) in the IKBKG gene that removes exons 4 through 10, causing loss of function of NEMO and reduced NF-κß activity. This mutation occurs in 80% of those with IP.10,12,13,15 Mutations in the IKBKG gene that completely eliminate NF-κß activity result in IP.17 While most cases (80%) of IP are caused by frameshift or nonsense mutations that lead to a complete loss of function, some may only involve a partial loss of NEMO activity.18 Mutations that allow for residual activity can lead to ectodermal dysplasia and immunodeficiency conditions.19 There are multiple unique mutations, many just recently reported, that may lead to IP.18 This has led to a variety of pathologic variants.18 A minority of patients with IP have been found to have no observable changes in the IP locus.6 Lacking NF-κß, IP cells are highly sensitive to pro-apoptotic signals and die easily.17,20 IKK-γ knockout mouse models have demonstrated phenotypes resembling IP.21–23
In those with mutated IKBKG genes who lack protective NF-κß activity, endothelial cells and other cells throughout the body may over-express chemotactic factors, such as eotaxin, specific for eosinophils, possibly explaining why serum eosinophilia is common in IP patients, and that the epidermal skin lesions also show extensive involvement of eosinophils.20,24 Eosinophils, combined with other factors, lead to extensive inflammation, affecting skin and endothelial cells.24
It is thought this inflammation may be a common pathway in IP, leading to vaso-occlusion and ischemia, causing retinal, dermatological, and neurologic manifestations.21,25 The retinal manifestations are the result of vaso-occlusions in the retinal arteries leading to areas of avascularity and underperfusion,25 in turn, precipitating ischemia. As in many ischemic retinal conditions, neovascularization can occur with damaging sequelae. Likewise, in the central nervous system, the cerebral and cerebellar atrophy as well as other neurologic sequelae are likely due to vaso-occlusive ischemia causing nerve cell death.9,26
Parents will typically describe characteristic skin lesions (Figure 1), often described as a rash starting within a few months of birth; this is the most common presenting complaint. Skin lesions occur in nearly 100% of IP patients and are considered to be nearly pathognomonic if they fit the specific pattern, stage progression, and time line.2,27 The skin lesions themselves are fairly benign and typically only cause cosmetic issues. In those suspected to have IP, a thorough skin examination must be done, although skin lesions are typically not difficult to find. Most persons with IP begin to express the phenotypic skin lesions at or near birth. The lesions go through four stages progressively, usually persisting into adulthood. These stages are:9,26,27
Stage 1: Vesicular stage – marked erythema with linear vesicles, bullae, and pustules; multiple crops may appear and are often present at or near birth; occurs in 90% of patients.
Stage 2: Verrucous stage – wart-like verrucous papules and keratotic patches; occurs in the first few weeks or months of life; occurs in 70% of patients.
Stage 3: Hyperpigmented stage – swirling or whirling macular patches of hyperpigmentation; occurs anywhere between infancy and adolescence but usually fades by early adulthood; occurs in 98% of patients.
Stage 4: Hypopigmented stage – patchy areas of hypopigmentation, usually arranged in streaks or whorls; often with cutaneous atrophy; usually present by early adulthood; occurs in 28% of patients.
Dermatologic lesions of incontinentia pigmenti. (A) Stage 1, vesicular stage, with marked erythema with linear vesicles, bullae, and pustules. (B) Stage 2, verrucous stage, with wart-like verrucous papules and keratotic patches. (C) Stage 3, hyperpigmented stage, with swirling or whirling macular patches of hyperpigmentation. (D) Stage 4, hypopigmented stage, with patchy areas of hypopigmentation, usually arranged in streaks or whorls. (Source: www.dermaamin.com; used with written permission from Dr. Jehad Ali.)
These skin lesions have a specific pattern of distribution along the Lines of Blaschko, which are patterns of dermal development during embryogenesis. These lesions commonly occur on the side of the trunk but usually spare the face. However, if these lesions are not present, IP cannot be ruled out. Also, skin lesions may be subtle and not obvious to parents and care providers, or the skin findings may be mistaken for other skin pathologies. Interestingly, while skin findings are typically diffuse, and approximately 15% of males with IP have focal or unilateral skin findings.28
The differential diagnosis based on dermatologic findings of IP is extensive. It includes congenital herpetic infection, impetigo/epidermolysis bullosa, warts or molluscum contagiosum, hypomelanosis of Ito, scarring, and vitiligo. Naegeli syndrome is a rare condition affecting the skin and ectoderm that can appear similar to the skin lesions of IP; it does not have significant eye findings.29
Although IP has multiple dermatologic manifestations and is often considered a primarily dermatologic condition, the eye and brain are most impacted in terms of functional loss. Eye manifestations are very common in IP patients. A thorough ophthalmologic examination must be performed early on patients suspected of having IP. A recent comprehensive review of IP reported the prevalence of ophthalmic findings to be 36.5%, although other sources have found it to be 25% to 77%.3–5,30,31 Each IP patient has an average of 2.16 ocular anomalies, and 56% of ophthalmologic findings are considered vision-threatening.5 Ocular manifestations may be generally divided into retinal and nonretinal findings. The natural history of retinal manifestations of IP leads to a common end point of retinal detachment and retrolental mass; however, the process can halt at any stage and spontaneously regress, leaving various sequelae.
Retinal findings are common and include avascularity, neovascularization, hemorrhages, persistent fetal vasculature, foveal atrophy, macular vascular aneurysms, arteriovenous anastomoses, and exudative and tractional detachments.4,25,30–32 In those eyes with vision-threatening findings, 72% have retinal anomalies,5 and retinal detachment has been reported in 10% of cases.4 It is thought that these retinal manifestations are due to the vaso-occlusive nature of the pathologic process.4,25,30–32 The inflammatory derangement associated with NF-κß abnormalities may play a role in abnormal fibrovascular proliferations and retinal dysplasia.25 Retinal findings most often occur in the first year of life.33 The retina alone is often involved and thus may avoid early detection in an infant or young child on casual observation without specific retinal investigation.
Retinal manifestations can be divided into peripheral and macular findings. An avascular peripheral retina is a significant feature of IP and is often considered the classic retinal finding (Figure 2).4,31,34 Large areas of the peripheral retina may become avascular, similar to the findings in retinopathy of prematurity. As with most ischemic retinal processes, neovascularization can often be found at the edges of the avascular retina and can lead to the blinding complications of IP such as hemorrhages and retinal detachment. Arborized and anastomotic vessels can be seen in the equatorial retina.4,35 Fibroglial components may sometimes be seen on the superficial retina, likely representing active tractional elements or possibly regressed neovascularization.35 Typically, neovascularization of the retina is more pronounced in the periphery, similarly to retinopathy of prematurity, although it can occur anywhere in the retina.36 The extent of avascular retina may very significantly, but is almost always present to some extent, sometimes only demonstrated angiographically.4,32 Aneurysmal-like vascular dilations also may be present.37,38 Peripheral diffuse mottled pigmentation may sometimes be present due to ischemic damage to the retinal pigment epithelium.4,31
Retinal imaging of the eye in an infant with incontinentia pigmenti. (A) Fundus photograph. (B) Fundus photograph after scatter laser treatment. (C) Earlier images from fluorescein angiography showing peripheral neovascularization. (D) Later images from fluorescein angiography showing peripheral neovascularization. (Images reprinted from DeVetten G, Ells A. Fluorescein angiographic findings in a male infant with incontinentia pigmenti. J AAPOS. 2007;11(5):511–512. Used with permission from Elsevier.)
While much of the published literature focuses on peripheral manifestations of IP, macular pathology occurs as well and has significant impact on visual acuity, although often less obvious on examination. A blunted foveal pit and absence of normal parafoveal vascular pattern are characteristic of IP and are caused by vessel occlusion and subsequent remodeling during macular development.32,36 This foveal abnormality has improperly been described in the literature as “foveal hypoplasia.”35 Intraretinal microvascular anomalies may also be seen in the macula, similar to those found in diabetic retinopathy, consistent with ischemic retinopathy.39 Due to the vasoocclusive nature of IP, central retinal artery occlusion may occur causing a foveal cherry-red spot, as choroidal perfusion is not typically affected; however, observing this occlusive event in its acute stage is rare.32,36
Fluorescein angiography is a critical study in the ophthalmic investigations for IP and should be performed in every suspected IP case if feasible.4,40 Retinal vascular abnormalities may sometimes only be detectable angiographically and are important for early identification and management.32 Often, enlargement of the foveal avascular zone is seen on the angiogram, which can be accompanied by large areas of avascularity anywhere in the retina.4,30,32,35 Areas of capillary non-perfusion in the macula may change over time due to ongoing ischemic events.32,36 Neovascularization, hemorrhage, and exudative leakage can be seen but would usually be associated with findings on ophthalmoscopy. The leakage on fluorescein angiography is variable but typically less extensive in IP than with retinopathy of prematurity.32 Overall, it is important to note that macular pathology may be undetectable by ophthalmoscopy, appearing only on angiographic images.35,39 Fluorescein angiography is typically conducted in a neonatal unit or operating theater when required for an infant.41 Because retinal findings typically occur before age 2, most patients require examinations under anesthesia. However, angiographic information may be obtainable in an office setting with the use of non-contact ultra-widefield retinal imaging.41
Progressive occlusive sequelae seen in such conditions as retinopathy of prematurity, diabetic retinopathy, and sickle cell retinopathy follow a similar natural history to IP. Although no formal guidelines have been published for screening or follow-up, retinal involvement and progression must be determined early. The following schedule of monitoring has been discussed in the literature: dilated eye examinations soon after birth, monthly for the first 4 months, every 3 months for 1 year, and twice per year up to 3 years of age.31,42 The frequency of examinations should be increased in children who have known eye manifestations. If there are no retinal signs by 1 year of age, they are unlikely to develop later.33,42 Rarely, IP patients older than 40 years have been reported to have new-onset retinal detachments, illustrating the importance of lifelong retinal follow-up despite an unremarkable neonatal period.43
Additional nonretinal ocular manifestations of strabismus and nystagmus (17% to 18%), optic atrophy (5% to 17%), cataracts, uveitis, conjunctival pigmentation, corneal epithelial and stromal keratitis, and iris hypoplasia have been reported.4,5,26 Optic atrophy may present bilaterally.44 Corneal vortex epithelial keratopathy has been reported in IP,45,46 as well as various patterns of superficial and subepithelial linear opacities that appear to be benign.31 These nonretinal ocular manifestations often may develop somewhat later than retinal issues, but typically are seen before age 2.31 Phthisis bulbi can be the end result of ocular IP, as one may expect. Cortical blindness may be present, causing total blindness or only light perception.
The differential diagnosis for the ophthalmologist of the ocular findings of IP includes retinopathy of prematurity, familial exudative vitreoretinopathy, Eales retinopathy, sickle cell retinopathy, the Norrie disease spectrum, and even shaken baby syndrome.4,47 However, skin findings are not associated with these conditions.
The neurological manifestations of IP lead to considerable morbidity and are the foremost cause of death in IP.9 Neurologic findings are present in 30% of IP cases.48 These abnormalities are typically limited to the brain and include convulsive disorders, spastic paralysis, motor retardation, and mental retardation. Seizures (69%), followed by cognitive (32%) and motor delays (40%), are the most common.48 Learning disabilities, most pronounced in the areas of arithmetic and reading, have also been observed in patients with IP.49 Of note, significant central nervous system manifestations in the neonate may denote a poor overall long-term prognosis. Importantly, over 90% of central nervous system symptoms will appear before age 2.50 Brain imaging will often show cerebral ischemia (46%), as might be expected in the setting of vascular occlusion; atrophy (32%), dilated ventricles, hydrocephalus, corpus callosum lesions, and brain cysts also may be occur.48 Cortical blindness may sometimes be present due to vascular occlusions in the occipital cortex.32,51 Neurologic consultation and magnetic resonance brain imaging (MRI) should be obtained in every patient with IP.
Dental problems occur in nearly 54% to 80% of affected individuals.9,52 Even a limited dental examination will often yield missing, small, or abnormally shaped teeth. The most common dental abnormalities are absence of teeth (32% to 43%) or shape anomalies (36%).9,52 General examination may also reveal alopecia in 38% of patients and nail abnormalities in 7% to 40% of patients.2,9,27 Breast abnormalities may also be present.9,27
Of note, though a different disease entirely and not clinically similar in presentation to IP, X-linked hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID) is also due to reduced function mutation of NF-κß on the IKBKG gene and has skin findings as well.9
In 1993, Landy and Donnai proposed a set of clinical diagnostic criteria for IP.2 The criteria focus on whether the suspected patient has a first-degree relative with IP. If an affected relative exists, then only one of the following is needed for diagnosis of IP: (1) history or evidence of typical skin lesions; (2) pale, hairless, atrophic linear skin streaks; (3) dental anomalies; (4) alopecia, wiry coarse hair; (5) retinal disease; or (6) multiple miscarriages of male fetuses.
If a first-degree relative with IP cannot be established and genetic data is unavailable, one major criteria and two or more minor criteria are needed for diagnosis. Overall, if none of the major criteria are present, then diagnosis other than IP should be considered.2
Major criteria — skin lesions, occurring in stages from infancy to adulthood:
- Erythematous lesions followed by vesicles anywhere on the body, sparing the face, usually in a linear distribution
- Hyperpigmented streaks and whorls respecting lines of Blaschko, occurring mainly on the trunk and sparing the face, fading in adolescence
- Pale, hairless, atrophic linear streaks or patches
- Hypodontia or anodontia, microdontia, abnormally shaped teeth
- Alopecia, wiry coarse hair
- Mild nail ridging or pitting, hypertrophied, curved nails
- Retinal abnormalities
In 2014, based on extensive recent published data, Minic et al suggested the following changes to the diagnostic criteria.27 The major criterion was the presence of one of the stages of the characteristic IP skin lesions. They also updated the minor criteria to include central nervous system abnormalities, extra-retinal ocular anomalies, multiple miscarriages of male fetuses, typical skin histologic findings, dental abnormalities, hair and nail abnormalities, nipple and breast abnormalities, palate anomalies, and IP pathohistological findings. The presence of characteristic mutations in the IKBKG gene and a family history of IP were also factored into the diagnosis.
The IKBKG gene is the only known gene associated with IP. Approximately 80% of affected individuals have the 11.7-kb deletion removing exons 4 through 10 from the IKBKG gene.15 Targeted mutation analysis is available to look for this mutation. In addition, other small IKBKG mutations have been found in 8.6% of those with IP, most often occurring in exon 10, and sequence analysis can detect these mutations.15 Also, in females with skewed lyonization in which the X chromosome with the mutant IKBKG allele is inactivated, X-chromosome inactivation studies may be useful. In males with suspected IP, karyotyping and fluorescence in situ hybridization to look for evidence of 47,XXY may be done.15 A genetic specialist should be consulted to determine which tests are most applicable to a specific patient. Importantly, although genetic testing is sensitive, lack of confirmation by genetic testing in the presence of a convincing clinical presentation should not rule out the disease.
If a proband is identified, clinical examination of family members and genetic testing of the mother is warranted. If a parent has IP and IKBKG mutation, the risk of conceiving a fetus with IP is 50%. However, most affected males die in utero, meaning that an affected mother has a near 33% probability to giving birth to either an affected female, unaffected female, or unaffected male.9 In parents without IP or an IP-related IKBKG mutation who have had a child with IP, the risk of a subsequent child having IP is less than 1%.9 Prenatal diagnosis of fetuses with a family history of IP is possible via multiplex polymerase chain reaction DNA analysis of tissue obtained by amniocentesis or chorionic villus sampling.
Eosinophilia occurs particularly in stages I and II and may sometimes reach as high as 65% of leukocytes.9,24 Skin biopsy and histology to evaluate eosinophilic infiltration and deposits of free or intramacrophagic melanin granules may be helpful in confirming the diagnosis in an individual with borderline or questionable findings in whom molecular genetic testing has not identified a disease-causing mutation.9,53 Skin biopsy, while once the cornerstone of diagnosis, is now rarely needed given the availability and sensitivity of genetic testing. If suspicion is high and genetic testing from blood samples are non-diagnostic, then genetic studies from a skin sample may provide a higher yield.
Because IP has a genetic basis, there is no cure and treatment is limited to symptom management. Affected individuals without severe complications in infancy typically have a normal life expectancy. Because IP is a multifaceted condition, dermatologic, genetic, ophthalmic, neurologic, and dental consultations should be obtained.54 Generally, magnetic resonance imaging of the brain should be obtained to investigate the occlusive consequences of IP in the brain.9,26 Electroencephalogram should be obtained if seizures are present. Developmental therapy may be needed. Skin lesions should be managed symptomatically to avoid infection or excessive scaring. Genetic therapies are not currently available for IP.
In the eye, peripheral avascular retina is often treated similarly to retinopathy of prematurity with laser photocoagulation55,56 or cryotherapy,57,58,59 although no large controlled trials have validated this treatment.9,25,30,32 The occurrence of retinal detachments should be monitored with regular ophthalmological examinations, and surgical repair of detachments by pars plana vitrectomy may be attempted by a vitreoretinal surgeon if appropriate.34 Ten percent of children still proceed to a severe complication such as vitreous hemorrhage, exudation, preretinal fibrosis, and tractional retinal detachment despite these treatments.4
A few cases detailing the use of intravitreal anti-vascular endothelial growth factor (VEGF) in a patient with IP have been published. The first study reported that injection led to regression of neovascularization, but the ultimate outcome for the patient was poor.60 The more recent study showed complete resolution of neovascularization in two patients, after one injection. There was no recurrence at 7 months in one of the two patients.61 Considering the increasing utility of intravitreal anti-VEGF in other pediatric vascular pathology (ie, retinopathy of prematurity), this may be a promising adjunctive treatment to laser photocoagulation, especially in refractory or bilateral cases; however, at this time it would still be considered experimental.