Incontinentia pigmenti

INTRODUCTION — Incontinentia pigmenti (IP; Bloch-Sulzberger syndrome, MIM #308300) is an X-linked dominant genodermatosis that is usually lethal in males before birth [1-4]. IP is caused by loss-of-function mutations in the IKBKG (inhibitor of kappa light polypeptide gene enhancer in B cells, kinase gamma) gene, formerly known as NEMO (nuclear factor-kappa-B essential modulator), encoding a regulatory protein named IKK (NEMO) that activates genes involved in cell survival, inflammation, and immunity [5,6].

The disorder is seen almost uniformly in females, although it may occasionally occur in males with somatic mosaicism or XXY karyotype (Klinefelter syndrome) [1]. In females, IP typically presents with a staged, linear, cutaneous eruption and often with anomalies of the teeth, hair, nails, and retina [4]. Approximately one-third of patients have ocular and neurologic abnormalities. Because of the involvement of skin, hair, nails, and teeth, IP can be considered a form of ectodermal dysplasia [2].

This topic will discuss the pathogenesis, clinical presentation, and diagnosis of IP. The ectodermal dysplasias are reviewed separately. (See "Ectodermal dysplasias".)

EPIDEMIOLOGY — IP occurs in approximately 1:40,000 to 1:50,000 births [1,3]. Virtually all cases are seen in females because affected males usually do not survive until birth. Males born with the condition have either somatic mosaicism or an XXY karyotype (Klinefelter syndrome) [7]. (See "Clinical features, diagnosis, and management of Klinefelter syndrome".)

MOLECULAR PATHOGENESIS — In the majority of cases, IP is due to mutations in the IKBKG (inhibitor of kappa light polypeptide gene enhancer in B cells) gene, also known as NEMO (nuclear factor-kappa-B essential modulator), located on chromosome Xq28 [6,8]. These mutations occur "de novo" in approximately 65 percent of the IP cases.

IKBKG encodes the I-kappa-B kinase (IKK)-gamma protein (also called NEMO), a regulatory subunit of the inhibitor of the IKK complex, which activates nuclear factor-kappa-B, leading to the activation of genes involved in cell survival, inflammation, and immunity. (See "Combined immunodeficiencies: Specific defects", section on 'IKBKB deficiency'.)

Approximately 90 percent of the IKBKG mutations in IP are deletions of exons 4 to 10, resulting in complete loss of IKK-gamma function [9-11]. Microdeletions, missense, frameshift, nonsense, and splice-site mutations leading to complete or partial loss of IKK-gamma activity account for the remaining cases [11].

Null mutations are lethal in utero in males, whereas females survive because of X chromosome mosaicism (lyonization). Milder (hypomorphic) IKBKG mutations that impair, but do not abolish, nuclear factor-kappa-B signaling have been found in males with a rare form of X-linked anhidrotic ectodermal dysplasia associated with immunodeficiency (MIM #300291) [12]. (See "Ectodermal dysplasias", section on 'Ectodermal dysplasia and immunodeficiency'.)

Cells lacking IKK-gamma are targets for tumor necrosis factor-induced apoptosis [13,14]. Multiple reports describe reactivation of IP skin lesions from stressors such as vaccines, fevers, and laser treatment [15,16]. It is thought that mutated cells may be vulnerable to unregulated apoptosis in these circumstances. Moreover, IKK-gamma deficiency affects several signaling pathways associated with bone and vascular function and anatomy, as well as immune function [1,11].

It has been suggested that both ocular and neurologic abnormalities in IP may result from a developmental cerebral small-vessel disease induced by the inactivation of IKBKG and, possibly, by the disruption of the transforming growth factor (TGF)-beta-activated kinase (TAK1) upstream of IKBKG [17-19].

CLINICAL FEATURES

Overview — The heterogeneity in the clinical presentation of IP and the apparent lack of genotype-phenotype correlation may be due to the random inactivation of one of the two female X chromosomes (lyonization), which occurs early during embryogenesis and varies depending on tissues. The X-inactivation is extremely skewed in cells expressing the mutated X chromosome, thus favoring the elimination of the mutated IKBKG allele in nearly 90 percent of cases [9].

Due to the X-linked dominant nature of IP, virtually all patients are female. Although the condition is usually lethal for males prenatally, a few cases have been reported in males [7,20-22]. Survival in males is due to somatic mosaicism or chromosomal aneuploidy (47,XXY; Klinefelter syndrome). (See "Clinical features, diagnosis, and management of Klinefelter syndrome".)

The clinical features of IP are variable, and there is no clear genotype-phenotype correlation. However, in nearly all patients, the characteristic cutaneous lesions are the first manifestation of IP (table 1).

Cutaneous findings — In the classic presentation, the cutaneous lesions of IP present in a female infant at birth or in the first few months of life and evolve through four characteristic, overlapping stages (table 1):

●Stage 1 (vesicular) – Patterned, tense vesicles and/or pustules, usually overlying an erythematous base, are in most cases noted at birth, or shortly after, on the trunk and extremities (picture 1A-B). These lesions seem to develop along the Blaschko lines (figure 1), which represent the embryologic pathways of migration of cutaneous and appendageal cells, and persist for months [23]. At this stage, the affected infant will often show eosinophilia on routine complete blood counts. This finding might be due to overexpression of eotaxin, a chemotactic factor for eosinophils, which may occur in the setting of IKBKG mutations [1]. These may persist into adulthood [24].

●Stage 2 (verrucous) – Following the initial skin eruption, lesions become more papular or crusted ("wart-like") and maintain their localization along the Blaschko lines (picture 2A-B) [3,25]. This stage usually lasts for a few months, but it can persist for years. It may not occur in all patients.

●Stage 3 (hyperpigmented) – By 6 to 12 months of age, infants show brown or gray-brown, linear and/or swirling macules (picture 3A-C). Stage 3 typically lasts through early adolescence and can persist into adulthood in most patients [24]. In some cases, they will resolve completely or will be followed by a so-called "fourth stage."

●Stage 4 (atrophic/hypopigmented) – This stage is marked by hypopigmented and slightly atrophic, linear macules/patches and is often associated with alopecia. In most patients, stage 4 does not occur.

The clinical presentation in male patients is the same as in female patients. In series of 40 boys with IP, the typical stage 1 vesicular eruption was the most frequent presentation at birth [26]. Stages 2 and 3 were observed in approximately two-thirds of the patients. Extracutaneous manifestations, including neurologic, ophthalmic, and dental anomalies, were present in approximately one-third of patients.

The onset, duration, and degree of overlapping of these stages vary among patients; stage 1 lesions can recur during a febrile illness, laser treatment, vaccination administration, or without a specific trigger [15,27].

The mother of a child with IP may be asymptomatic or show manifestations of the disease [24]. These include hypopigmented, atrophic streaks along the Blaschko lines; nail dystrophy; and ocular, neurologic, or dental abnormalities. The diagnosis may not be made until the birth of an affected child.

Extracutaneous findings

Dental and oral anomalies — Delayed dentition, pegged or conical teeth, as well as anodontia or hypodontia resembling hypohidrotic ectodermal dysplasia are seen in most patients with IP (picture 4). Other oral anomalies that can occur in patients with IP include cleft or high-arched palate and decreased salivary secretion [10,28,29]. In a systematic review of 513 published cases of IP (54 males), the overall prevalence of dental and oral anomalies was 54 percent, with 95 percent being dental anomalies [29].

Anomalies of the skin appendages — Scalp and body hair abnormalities are seen in approximately 25 percent of patients [10]. These include cicatricial alopecia; sparse hair; woolly, wiry, or uncombable hair; and anomalies of the eyebrows and eyelashes (picture 5).

Nail dystrophy may develop in approximately 10 percent of patients, usually during adolescence or early adulthood (picture 6) [30]. It usually involves most or all of the fingernails and toenails. In some patients, osteolytic lesions of the underlying bone have been noted. Painful, subungual, dyskeratotic tumors are rarely associated with IP and are usually seen in adult patients [31-33]. These tumors are frequently misdiagnosed as squamous cell carcinomas or keratoacanthomas.

Breast and nipple anomalies, such as breast hypoplasia and aplasia, nipple hypoplasia, and supernumerary nipples, have also been reported with increased frequency in adult patients with IP [34].

Ocular anomalies — Ocular anomalies have been reported in patients with IP with varying frequency, ranging from approximately 20 to 80 percent of patients [10,35]. They include proliferative retinopathy, microaneurysms, peripheral avascularity, areas of nonperfusion, and macular occlusive disease [36-38]. In a review of 831 patients with IP, 37 percent had ocular anomalies, 50 percent of which involved the retina [10]. Microphthalmia has been reported in approximately 6 percent [24].  

Central nervous system anomalies — Central nervous system (CNS) abnormalities occur in approximately 25 to 50 percent of patients with IP [24,39]. Neurologic symptoms, which include lethargy, poor feeding, seizures, neurocognitive impairment, and stroke, have been described [10,13,24,40]. CNS abnormalities are in many cases associated with ocular anomalies [1]. (See 'Ocular anomalies' above.)

CNS anomalies can be demonstrated by neuroimaging studies, including magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) [17,41,42]. In one report of eight infants with IP, abnormal MRI findings included patchy signal changes in the cortical gray matter and subcortical and periventricular white matter on T1- and T2-weighted sequences, which match areas with restricted diffusion on DWI, suggesting local inflammation and ischemia as well as hemorrhagic lesions [41,43].

Other — While reports suggesting immune defects in patients with IP do exist, this association is well known in patients with the ectodermal dysplasia/immunodeficiency phenotype, rather than in the more typical patients with IP [44,45]. (See "Ectodermal dysplasias", section on 'Ectodermal dysplasia and immunodeficiency' and "Combined immunodeficiencies: Specific defects", section on 'IKBKB deficiency'.)

Rarely, cardiovascular abnormalities and pulmonary hypertension have been reported in infants with IP [46-49].

PATHOLOGY — A skin biopsy may be especially helpful in the diagnosis of IP when obtained during stage 1 (vesicular). Characteristic histopathologic findings include eosinophilic spongiosis, intraepidermal vesicles containing eosinophils, and apoptotic keratinocytes in the epidermis. The pathologic changes seen in later stages are less specific, although they may show features that support the clinical diagnosis (table 1). A marked melanin incontinence with numerous melanophages in the dermis is noted in stage 3 (hyperpigmented) lesions.

DIAGNOSIS

Clinical suspicion — IP should be suspected in a female infant presenting with characteristic vesicular or hyperpigmented lesions occurring along the Blaschko lines (picture 1A-B). At later stages, although the skin features may be less obvious clinically, the presence of teeth, hair, eye, or central nervous system (CNS) abnormalities should alert the clinician to the possibility of IP.

Diagnostic criteria — Diagnostic criteria for IP were initially established in 1993 and were revised in 2014 [2,10]:

●Major clinical criteria include the typical stages of the skin eruption distributed along the Blaschko lines, tooth anomalies, and demonstration of [50] (see 'Cutaneous findings' above):

•Typical neonatal rash with erythema and vesicobullae (stage 1)

•Verrucous papules or plaques along the Blaschko lines (stage 2)

•Typical hyperpigmentation along the Blaschko lines fading in adolescence (stage 3)

•Linear, atrophic, hairless lesions on limbs or scarring alopecia of the vertex (stage 4)

•Dental agenesis (hypodontia or oligodontia), shape anomalies (peg-shaped incisors, conical teeth, molar cusp pattern alteration), and delayed eruption

•Identification of the common deletion rearrangement in IKBKG

●Minor criteria include the extracutaneous manifestations of IP (see 'Extracutaneous findings' above):

•Ocular anomalies (peripheral retinal neovascularization)

•CNS anomalies

•Alopecia

•Abnormal hair

•Abnormal nails (punctuate depressions, onychogryphosis or ram's horn nails)

•Palate anomalies

•Nipple and breast anomalies

•Maternal history of multiple male miscarriages

•Typical histopathologic findings in a skin biopsy (table 1) (see 'Pathology' above)

At least two or more major criteria or one major and one or more minor criteria are required for the clinical diagnosis of IP.

Genetic testing — In suspected cases with clinical and histopathologic findings suggesting IP, a targeted mutational analysis of deoxyribonucleic acid (DNA) extracted from peripheral blood should be performed to identify the common deletion of exons 4 to 10 in IKBKG, which is present in approximately 70 to 80 percent of cases [4,6,51,52].

Sequence analysis using Sanger sequencing may be needed in those cases (approximately 10 to 15 percent) in which the common deletion is not identified. Of note, next-generation sequencing cannot reliably be used for the molecular analysis of IP due to the presence of the highly homologous nonfunctional pseudogene IKBKGP1 [53].

The detection of mosaic variants in males is especially difficult, as in males with IP, the mosaicism is limited to a small number of mutant cells, which may escape detection by the targeted analysis used in heterozygous females [52]. In these cases, a biopsy of lesional skin (in children) and sperm samples (in adults) are appropriate tissue for sequence analysis. IKBKG variants can be in the blood only in samples taken from IP male newborns because blood leucocytes carrying the mutation could undergo selective apoptosis over time [22].

In male patients, karyotyping should be considered as well, due to the possibility of IP in the setting of chromosome aneuploidy 47,XXY (Klinefelter syndrome) [54,55].

Definitive diagnosis — The definitive diagnosis of IP is established by demonstrating a pathogenic deletion of exons 4 to 10 or a pathogenic mutation in IKBKG. If genetic testing is not available, at least two or more major criteria or one major and one or more minor criteria are required to establish the diagnosis. (See 'Genetic testing' above and 'Diagnostic criteria' above.)

DIFFERENTIAL DIAGNOSIS — The skin conditions that should be included in the differential diagnosis of IP depend on the stage of the IP eruption (see 'Cutaneous findings' above):

●Herpes simplex virus infection – Neonates with any vesicular eruption must be suspected to have herpes simplex virus (HSV) infection. If the lesions are oriented along the Blaschko lines, HSV becomes less likely. Scrapings of vesicular contents for Tzanck smear, direct fluorescent antibody staining, or culture should be obtained for the diagnosis of possible HSV. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis".)

●Neonatal varicella – In newborns born to mothers exposed to the varicella zoster virus within two weeks of delivery, the eruption starts as macules and rapidly progresses to papules and then to characteristic vesiculopustular lesions that heal in 7 to 10 days. The diagnosis can be confirmed by detection of the virus using polymerase chain reaction (PCR) from vesicular swabs or scrapings, scabs from crusted lesions, or tissue from biopsy samples. (See "Varicella-zoster infection in the newborn".)

●Staphylococcal infection – Staphylococcal skin infection should be considered in any infant presenting with pustular lesions. A Gram stain and culture of pustule content should be performed to rule out Staphylococcus aureus infection. (See "Impetigo".)

●Epidermal nevus – The second or "warty" stage of IP can be confused with epidermal nevus. A skin biopsy may be useful in this instance to assist with diagnosis. (See "Epidermal nevus and epidermal nevus syndrome".)

●X-linked reticulate pigmentary disorder – X-linked reticulate pigmentary disorder is a rare condition inherited in a recessive X-linked fashion that can be seen in male and female individuals. Females will present with patchy hyperpigmentation. Male cases have the same pigmentation as in stage 3 IP in addition to systemic manifestations, including recurrent respiratory infections, failure to thrive, corneal dyskeratosis, gastrointestinal disorders, and hypohidrosis [56]. (See "Congenital and inherited hyperpigmentation disorders", section on 'X-linked reticulate pigmentary disorder'.)

●Pigmentary mosaicism – Pigmentary mosaicism (hypomelanosis of Ito) is characterized by patchy or linear hyper- and hypomelanosis occurring along the Blaschko lines. In up to 30 percent of cases, pigmentary mosaicism is associated with eye, brain, or musculoskeletal abnormalities [23]. Genetic testing for mutations of IKBKG (inhibitor of kappa light polypeptide gene enhancer in B cells, kinase gamma) can differentiate pigmentary mosaicism from IP. (See "Pigmentary mosaicism (hypomelanosis of Ito)".)

●Naegeli-Franceschetti-Jadassohn syndrome or Naegeli syndrome – This dominantly inherited condition presents with reticulated hyperpigmentation and palmoplantar keratoderma in addition to hypohidrosis. This disorder has been associated with mutations in keratin 14 [57]. (See "Congenital and inherited hyperpigmentation disorders", section on 'Naegeli-Franceschetti-Jadassohn syndrome'.)

MANAGEMENT — The management of IP may involve multidisciplinary care depending upon the presence and severity of cutaneous and extracutaneous manifestations in the individual patient [50]:

●Cutaneous lesions – The vesiculobullous lesions of the early stage of IP usually require only gentle wound care with mild detergents and emollients. Topical corticosteroids and topical tacrolimus have been used successfully for severely inflamed areas [58,59]. Patients with signs of secondary skin infection require treatment with local or systemic antimicrobial therapy. Stage 2 lesions, if significant and impacting movement of digits or extremities, may require emollients or topical retinoids. No treatment is generally needed for stage 3 or 4 skin lesions.

●Ophthalmologic involvement – Ophthalmologic consultation and surveillance should be performed for all suspected and confirmed cases of IP [60]. Devastating eye complications may present suddenly without proper monitoring [4]. Eye examinations are recommended monthly until age four months, then every three months from age four months to one year, every six months from age one to three years, and annually after age three years.

Laser treatment of retinal neovascularization may be indicated to prevent retinal detachment [61]. There are a few reports of the use of intravitreal bevacizumab and ranibizumab (inhibitors of the vascular endothelial growth factors) as an adjunctive treatment to laser photocoagulation in children with IP [62-64], though necrotizing enterocolitis has also been reported as an associated complication [65].

●Neurologic involvement – For significant central nervous system involvement, ongoing neurologic follow-up will be needed. High-dose corticosteroids have been used for the treatment of severe seizure not responding to anticonvulsants [66,67].

●Dental anomalies – Dental consultation and management are indicated in all patients with IP at the time of teeth eruption or by age six months. Orthodontic care may be needed in mild cases. Severe cases with anodontia or hypodontia require coordinated care by dentists and oral surgeons from an early age. Use of flexible dentures is useful as early as two to three years to preserve jaw development [68].

GENETIC COUNSELING — Individuals affected with IP and families should be offered genetic consultation for consideration of mutation testing. Following molecular confirmation of the diagnosis in an affected child, parental testing should be offered whether or not the mother shows clinical signs suggestive of IP. Given the high frequency of de novo mutations in IP, estimated at approximately 65 percent, the mother may or may not have a pathogenic variant of IKBKG.

Affected women have a 50 percent probability of transmitting the mutated X allele at conception. Since IP is lethal for the male embryo, the expected ratio among liveborn children is approximately 33 percent unaffected females, 33 percent affected females, and 33 percent unaffected males [4]. Rare cases of father-to-daughter transmission of IP have been documented, due to germline mosaicism in fathers [69].

Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in the family has been identified. Preimplantation genetic testing can also be performed [28]. (See "Preimplantation genetic testing".)

SUPPORT GROUPS — Support groups, such as the Incontinentia Pigmenti International Foundation, and organizations in other countries (eg, Italy [IPASSI]) provide immeasurable assistance to patients and their families/caregivers and should be fully engaged. Additional information can be found on the National Foundation for Ectodermal Dysplasias website.

PROGNOSIS — Individuals with IP who do not have clinically significant ophthalmologic or neurologic involvement have an excellent prognosis and a normal life expectancy. The skin, hair, or dental abnormalities are permanent and may be a cause of concern for some patients. For patients with brain or ocular involvement, the clinical course and prognosis is variable, based upon the type and extent of anomalies.

Women with IP are at increased risk for pregnancy loss, due to low viability of affected male fetuses.

SUMMARY AND RECOMMENDATIONS

●Definition and pathogenesis – Incontinentia pigmenti (IP) is an X-linked dominant genodermatosis that is usually lethal in males in utero. In females, it classically presents with a staged cutaneous eruption; variable developmental abnormalities involving the teeth, hair, and nail; and ocular and neurologic abnormalities. IP is caused by mutations in the IKBKG gene, also known as NEMO, encoding a regulatory protein involved in the activation of genes involved in cell survival, inflammation, and immunity. (See 'Introduction' above and 'Molecular pathogenesis' above.)

●Clinical presentation – Due to the X-linked dominant nature of IP, virtually all patients are female. In the classic presentation, the cutaneous lesions of IP are first noted during the neonatal period and evolve through four stages of variable duration: vesicular (picture 1A-B), verrucous (picture 2A-B), hyperpigmented (picture 3A-C), and atrophic/hypopigmented. Lesions are typically distributed along the lines of Blaschko on the trunk and extremities. Common extracutaneous findings include dental, hair, and nail anomalies. Ocular and neurologic abnormalities occur in approximately one-third of the cases. (See 'Clinical features' above.)

●Diagnosis – The clinical diagnosis of IP is based upon the presence in a female patient of the typical stages of the skin eruption distributed along the Blaschko lines. Minor diagnostic criteria include dental, hair, ocular, and neurologic abnormalities and typical histopathologic findings in a skin biopsy (table 1). The diagnosis is confirmed by molecular genetic testing demonstrating a loss-of-function mutation in the IKBKG gene. (See 'Diagnosis' above.)

●Management – The management of IP depends upon the significance of the cutaneous and extracutaneous involvement. The vesicular lesions of the early stage usually require only gentle wound care with mild detergents and emollients. Topical corticosteroids may be helpful for severely inflamed areas. Early pediatric ophthalmology evaluation and follow-up is recommended to prevent ocular complications. Dental and neurologic consultation are also indicated for all patients with IP. (See 'Management' above.)