Incontinentia Pigmenti

X-linked dominant multisystem genodermatosis caused by loss-of-function variants in the IKBKG (NEMO) gene, usually lethal in male conceptuses and characterised by sequential skin lesions along the lines of Blaschko, dental, hair and nail anomalies, retinal vasculopathy and central nervous system injury.

Literature and regulatory information update: 17 October 2026; integration of the French national protocol (HAS PNDS): 6 November 2026.

0. Initial Reference Table

Table 0.1 identifies the main entity and the allelic IKBKG disorders that enter the differential diagnosis; table 0.2 summarises the first-visit data for incontinentia pigmenti (IP). Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) and its form with osteopetrosis and lymphoedema (OL-EDA-ID) appear here only as differential diagnosis and allelic disorder.

Table 0.1 — Identification of the entities

Sources for table 0.1: GeneReviews, OMIM, Orphanet, GeneGuidance, VariantValidator and the GeneReviews on hypohidrotic ectodermal dysplasia [1–11].

Table 0.2 — Incontinentia pigmenti: first-visit data

1. Introduction

1.1. Founding descriptions

Incontinentia pigmenti is a genodermatosis in which the skin, teeth, hair, nails, retina and central nervous system (CNS) are variably affected, in a pattern that reflects the functional mosaicism of heterozygous women. OMIM accepts that Garrod described the first case in 1906, in a girl with typical pigmentary changes, intellectual disability and tetraplegia [2]. Bardach described the condition in 1925 in monozygotic twin girls, under the designation of systematised naevi, and Bloch coined the term "incontinentia pigmenti" for the skin lesions in 1926 [22]. Sulzberger published independent observations shortly afterwards; the 2025 retinopathy consensus review dates that work to 1928 and OMIM to 1927, and the eponym Bloch-Sulzberger syndrome became established from these two descriptions [2, 15]. The name describes a histological finding: melanin pigment appears to "escape" from the basal layer of the epidermis into the dermis, where it is taken up by melanophages, and this dermal deposit produces the swirling pattern reminiscent of a marble cake [2, 15].

1.2. From the inheritance pattern to mapping

In Carney's worldwide compilation of 1976 there were 653 published cases, 593 female, 16 male and 44 with sex not stated [2]. Pfeiffer proposed in 1960 autosomal dominant inheritance limited to females, and Lenz suggested in 1961 X-linked dominant inheritance with male lethality; the observation of IP in a boy with a 47,XXY karyotype and the excess of miscarriages of male fetuses in the families supported this second hypothesis [2]. The apparent heterogeneity of the 1980s resulted from sporadic patients with X;autosome translocations with a breakpoint at Xp11, which led to the postulation of an "IP1" locus, whereas linkage studies in families with several affected members excluded Xp11 and located the gene at Xq28, close to the DXS52 marker and the factor VIII gene [1, 2].

1.3. Milestones of the molecular discovery

In 2000, the International Incontinentia Pigmenti Consortium (Smahi and colleagues) showed that variants in the NEMO gene (IKBKG), located about 200 kb proximal to the factor VIII gene, cause IP, that a recurrent genomic rearrangement accounts for 80% of new mutations and that patients' cells fail to activate nuclear factor kappa B (NF-κB) [23]. NEMO had been cloned in 1998 by complementation of a cell line lacking an NF-κB response and identified as the regulatory subunit (IKK-γ) of the IκB kinase (IKK) complex [1, 22]. In 2001, Aradhya and colleagues confirmed that the recurrent exon 4–10 deletion accounts for the great majority of variants and showed that it arises predominantly in paternal meiosis [2, 24]. In the same year, Zonana and Döffinger described boys with hypohidrotic ectodermal dysplasia and immunodeficiency due to hypomorphic variants of the same gene, establishing EDA-ID as an allelic disorder of IP [25, 26]. The clinical criteria of Landy and Donnai (1993) were revised by Minić and colleagues in 2014, by the French HAS PNDS in 2019 and by the European ERN-Skin consensus in 2020, a revised version of the same work [14, 16, 27, 28]. In 2025, the International Conference on Incontinentia Pigmenti (ICIP), organised by the NFED and Oregon Health & Science University, produced the first international consensus on screening, staging and treatment of the retinopathy, published in 2026 [15, 29].

1.4. Nomenclature and reclassifications

The designation "IP type I" (IP1, locus at Xp11) has been abandoned. Sybert considered the IP1/IP2 nomenclature misleading in 1994, because none of the 40 X;autosome translocation cases then published met the criteria for IP, and Happle concluded in 1998 that these patients, without a previous inflammatory phase, had hypomelanosis of Ito, that is, pigmentary mosaicism [2, 30]. OMIM now lists hypomelanosis of Ito under number 300337, formerly designated IP1, and IP under 308300, with "IP type II" as an old title [2]. GeneReviews considers the designation IP type I incorrect, and the term "incontinentia pigmenti achromians", used as a synonym for hypomelanosis of Ito, has also fallen into disuse because it suggests a non-existent relationship [1, 2]. Some reference books still use the expression "IP type 2", which should be read as a synonym for IP [31]. The gene was called NEMO until the symbol IKBKG was adopted; the neighbouring partial pseudogene, formerly NEMOP, is IKBKGP1. The GeneReviews text mistakenly attributes the former name "IKBKGP1" to IKBKG, an error contradicted by the legend of figure 6 of the same document [1].

1.5. Definition of the entities of the article

Incontinentia pigmenti (OMIM 308300) is the disease of women heterozygous for an IKBKG loss-of-function variant and of the rare men who survive because of a 47,XXY karyotype or somatic mosaicism [1, 32]. Hypomorphic variants, which reduce without abolishing NF-κB signalling, cause in men EDA-ID (OMIM 300291, which since the merger of entries includes the former OL-EDA-ID, 300301), immunodeficiency 33 without ectodermal dysplasia (OMIM 300636) and, through a different splicing mechanism, NEMO-NDAS (OMIM 301081) [3, 4, 33]. The mothers of these boys may have mild IP, and some women with non-skewed X inactivation express immunological or autoinflammatory phenotypes [3, 34]. This article covers IP; the allelic entities are described insofar as they enter the differential diagnosis and the counselling of families.

2. Molecular Genetics and Pathophysiology

2.1. The IKBKG gene and the architecture of the Xq28 locus

IKBKG spans about 23 kb at Xq28 and, in the MANE Select transcript NM_001099857.5, has nine coding exons (exons 2 to 10) preceded by four alternative non-coding first exons (1A to 1D) [10, 12]. Transcription depends on two promoters: promoter A, unidirectional, drives exons 1A and 1D and lies in intron 2 of the G6PD gene, which is on the opposite strand; promoter B is bidirectional and shared with G6PD [12]. The transcript NM_003639, used by GeneReviews (version 3, now 4), has 10 exons and the same c. and p. numbering for the variants checked in VariantValidator, so variants published on either transcript are comparable without conversion [1, 10]. About 22 kb from the gene, in inverted orientation, lies the unprocessed partial pseudogene IKBKGP1, which reproduces exons 3 to 10 with more than 99% identity, is not transcribed and lacks the first two exons [1, 12, 16]. Gene and pseudogene are included in a 35.7 kb segmental duplication formed by two low-copy repeats (LCR1 and LCR2) in opposite orientation [12]. Within IKBKG itself there are two 870 bp MER67B direct repeats, one in intron 3 and another downstream of exon 10; unequal recombination between them removes exons 4 to 10 and produces the recurrent deletion of about 11.7 kb [1, 3]. This organisation, with direct and inverted repeats and an almost identical pseudogene, explains the high rate of de novo rearrangements and is also the main source of technical error in diagnosis (section 5.4) [35, 36].

2.2. The NEMO protein and the NF-κB pathway

The 2.8 kb cDNA encodes an acidic protein of 419 amino acids, rich in glutamate and glutamine (about 13% each), with a leucine zipper between residues 315 and 342 [1]. From the amino to the carboxyl terminus, the protein has helices HLX1 and HLX2, coiled-coil domains CC1 and CC2, the ubiquitin-binding NUB domain, the leucine zipper (LZ) and a terminal zinc finger (ZF) [12]. NEMO is the regulatory subunit of the IKK complex, which includes the catalytic kinases IKK-α (whose deficiency causes an immunodeficiency of the alternative NF-κB pathway) and IKK-β; it has no enzymatic activity of its own, but it is indispensable for signals from tumour necrosis factor (TNF) receptors, interleukin 1 (IL-1) receptors and Toll-like receptors to activate the complex, phosphorylate IκBα and release NF-κB to the nucleus [1, 9]. The gene is expressed ubiquitously from early embryogenesis [24]. One of the targets of NF-κB is the anti-apoptotic programme that protects cells from TNF-α-induced death; without functional NEMO, cells become highly sensitive to pro-apoptotic stimuli [1, 23]. The Brazilian textbook of genetic syndromes states that the gene "encodes the nuclear transcription factor NF-kB" and places it at "Xp28"; IKBKG encodes the NEMO modulator, not NF-κB, and the locus is Xq28 [1, 37]. Clinical severity tracks residual signalling: abolished signalling gives IP with male lethality, reduced signalling gives EDA-ID in men and mild IP in women [9]. Because it is haploinsufficient, the gene has a ClinGen haploinsufficiency score of 3 (sufficient evidence) and a triplosensitivity score of 0 [9].

2.3. Cellular mechanism: apoptosis and selection against the mutant X

In heterozygous women, random X inactivation creates two cell clones in each tissue: one expressing the normal X and another expressing the X with the variant [16, 38]. In keratinocytes of the mutant clone, the failure to activate NF-κB in response to TNF leads to cell death and local inflammation, manifested by the eosinophil-rich vesicles of stage 1 and by keratinocyte apoptosis visible at all stages [15, 16]. The progressive elimination of cells with the active mutant X leads to extremely skewed X inactivation: 98% of women with IP had a completely skewed pattern in peripheral blood leucocytes [2, 22]. In fibroblasts from normal and hyperpigmented skin, Wieacker and colleagues found only clones with the non-mutant X active, and Migeon and colleagues documented in 1989 selective elimination in fibroblast cultures and, to a variable degree, in haematopoietic tissue [2]. Selection can be observed over time: in a female infant with IP and transient immunodeficiency, the inactivation pattern in leucocytes was random at 24 and 30 months and skewed at 38 and 48 months, when the immunodeficiency disappeared [2]. Late recurrences of inflammatory lesions, described by Bodak and colleagues in five children, arose on previously hyperpigmented streaks, almost always after an infection, and were attributed to the persistence of mutant keratinocytes that undergo apoptosis under the stimulus of cytokines such as TNF-α [2]. GeneReviews also mentions the hypothesis that failure of the NEMO carboxy-terminal domain to recruit A20 prevents termination of the NF-κB response, which would contribute to the exuberant inflammation and eosinophilia [1].

2.4. Tissue mechanisms

In the skin, the sequence of stages corresponds to the death of the mutant clone and its replacement by the normal clone, with dermal melanin incontinence and, in stage 4, loss of hair follicles and sweat glands [2, 16]. In the retina and the CNS, the injury is mainly vascular. It is postulated that TNF-mediated inflammation leads to occlusion of capillary beds, best seen in the retina, where peripheral non-perfusion precedes anastomoses, neovascularisation and tractional detachment [15, 16]. Evidence of microvascular anomalies supports the view that CNS dysfunction is secondary to ischaemic or haemorrhagic events [1]. Vascular endothelial growth factor (VEGF) levels in the aqueous humour increase with retinopathy severity, which provides the rationale for antiangiogenic agents [39]. The arginine methyltransferases PRMT1 and PRMT5, activated by the NF-κB pathway, are required for normal epidermal development [15]. In the thymus, TNF-mediated death of thymic epithelial cells reduces the organ: the thymic volume of six patients under 12 years of age was about 10 times lower than that of 21 matched controls, the thymus of a hemizygous male fetus at 19 weeks weighed one fifth of normal, and in female Nemo+/− mice the thymic reduction was rescued by inactivation of the TNFR1 receptor [40]. According to the authors, thymic dysfunction explains the production of neutralising autoantibodies against type I interferons (IFN) in about 40% of women from 6 years of age (section 3.9) [40]. In hemizygous male conceptuses, the exact mechanism of lethality is unknown; Nemo-null mice die between embryonic days 12.5 and 13 with hepatic degeneration due to apoptosis [1, 2, 41]. A case of severe haemorrhage and death of a hemizygous newborn at 24 hours, in a family with a duplication in exon 10, also suggested a disturbance of haemostasis [3].

2.5. Variant spectrum

The recurrent exon 4–10 deletion produces a truncated protein with the 133 amino-terminal amino acids and at least 26 novel amino acids, unable to respond to upstream signals [3]. Its frequency depends on the series and the denominator. Aradhya and colleagues identified 277 variants in 357 unrelated patients, and the recurrent deletion accounted for 90% of the variants identified [3]. GeneReviews gives about 65% of women with IP by targeted deletion testing [1]. In the international immunological cohort of 131 women, the deletion was present in 82% of patients and 80% of families [40]. In the Danish cohort, it accounted for 72.2% of the 54 genetic diagnoses, and point variants for 18.5% [13]. In the series from three European departments, it was found in 14 of 24 patients tested [42]. The retinopathy consensus review states 70–80%, and the 2019 French PNDS states 80% of cases [14, 15]. The remaining variants are small deletions or insertions (about 54%) and substitutions (about 46%), mostly with a premature stop codon; missense variants are about 15% [12]. There is a cluster of variants in the GC-rich exon 10, mainly deletions and duplications in a tract of seven cytosines [1, 43]. Conte and colleagues described 21 novel point variants (14 with total loss of function and 7 with partial loss, including 2 splicing and 5 missense) and non-recurrent deletions due to aberrant recombination that may involve the pseudogene and G6PD [35, 36]. The locus variant database is in LOVD (IKBKG.lovd.nl) and in IKBKGbase [1, 36].

Table 2.1 — Normalised IKBKG variants (transcript NM_001099857.5; GRCh38)

Sources for table 2.1: ClinVar, VariantValidator, OMIM, GeneReviews and original articles [1, 3, 10, 12, 44–48]. The recurrent deletion has imprecise boundaries that cannot be tested in VariantValidator; the c. notation is that of GeneReviews. The variants of the Rosain cohort, published on transcript NM_001099857 in abbreviated notation, are written on NM_001099857.5 with the three-letter code without change in numbering: c.628_651delinsCG p.(Glu210ArgfsTer64), c.646del p.(Glu216SerfsTer65), p.(Tyr241Ter), c.756_765del p.(Arg254GlufsTer24), c.850del p.(Leu284Ter), c.1110dup p.(Ala371ArgfsTer24), c.1204dup p.(Tyr402LeufsTer5), p.(Lys326del), p.(Ala314Pro) and p.(His413Tyr) (protein consequences confirmed in VariantValidator; variants published only at protein level keep the article's designation); all variants tested in a TNF-dependent reporter assay had loss of function [40]. The historical OMIM variants ("M407V" or the 10 bp insertion after nucleotide 127) keep the published designation; the variant designated "P62X" is NM_001099857.5:c.184C>T, which on this transcript encodes p.(Arg62Ter), so the letter "P" of the historical designation does not correspond to residue 62 of the reference protein [3, 10].

2.6. Origin of de novo variants and predisposing alleles

De novo variants arise more often on the paternally derived X. In the founding study, 10 of the 12 recurrent deletions of established origin had occurred in male gametogenesis [2]. Aradhya and colleagues estimated paternal origin in 70% of families, and Parrish and colleagues, in 15 families, found paternal mutations twice as frequent as maternal ones [2, 49]. The mechanism is intrachromosomal misalignment in meiosis, facilitated by the MER67B repeats and the adjacent pseudogene, which also allows gene conversion events [2, 49]. Between 10 and 12% of the parents of patients with IP carry one of two benign variants that are rare in the control population: the 11.7 kb exon 4–10 deletion in IKBKGP1 or an MER67B duplication that replicates the exon 4–10 region downstream of the normal gene; these alleles appear to be "at risk" of generating the pathogenic deletion de novo in the offspring [1, 50]. Rearrangements between other repeated elements of the locus produce recurrent benign variants with an estimated population frequency of 1–2% [1]. Some pathogenic variants originate in the pseudogene and are transferred to the gene by non-allelic homologous recombination [48].

2.7. Penetrance, expressivity, genotype-phenotype correlations and modifiers

Penetrance is high and most patients express the phenotype in the first months, but expressivity is highly variable, and an adult woman may have no obvious findings [1]. The European consensus does not recognise a clear genotype-phenotype correlation [16]. Mariath and colleagues described four families with 15 cases, all with the recurrent deletion, in which mild and severe forms coexisted with different types of dental, ocular, neurological and nail involvement, and proposed the existence of modifier genes [2]. The degree of skewing of X inactivation modulates the phenotype: loss-of-function variants are associated with more marked skewing, and skewing correlates negatively with severity and CNS involvement; hypomorphic variants affect more tissues [12]. Exon 10 variants associated with milder IP in women are associated with a lower risk of miscarriage, because male fetuses who inherit them may survive with EDA-ID [1]. In males, variants affecting the carboxy-terminal zinc finger generally give a more severe picture, with immunodeficiency and ectodermal dysplasia, whereas those in the leucine zipper or the amino-terminal coiled coils give less severe pictures without ectodermal dysplasia [3]. A variant in another gene may add to the phenotype: a girl with IP due to post-zygotic mosaicism for the NEMOΔ4-10 deletion also had a MED13L variant (NM_015335.5:c.1708_1709del p.(Ser570PhefsTer27); published on NM_015335.4) responsible for syndromic intellectual disability, which calls for consideration of a multilocus diagnosis when the neurological picture exceeds what is expected [51].

2.8. Men with incontinentia pigmenti

Despite the designation of a male-lethal disease, there are well-documented men. GeneReviews considers that all men with IP described had a 47,XXY karyotype, estimated in about 7% of men with IP, or somatic mosaicism [1, 32, 52]. In the series of 18 men of Fusco and colleagues, the recurrent deletion was found in 3 (16%), always in somatic mosaic form [1, 53]. One man had low-level 46,XY/47,XXY mosaicism, detected only by interphase fluorescence in situ hybridisation (FISH), with no demonstrable IKBKG variant [54]. Two men with low-level mosaicism for a loss-of-function variant had the highest proportion of abnormal cells in fibroblasts and sperm, and one of them transmitted IP to his daughter [46]. In the Danish cohort, the four men had partial skin lesions suggestive of mosaicism, and fewer than three had genetic confirmation in peripheral blood [13]. Segmental IP, limited to one limb, is compatible with mosaicism [1]. Smith's textbook adds a third survival mechanism, the less deleterious variant, mainly of exon 10 [22]; GeneReviews classifies these patients within the EDA-ID spectrum, with constant immunodeficiency, and records a single man with EDA-ID and IP skin lesions, carrying c.1167dup [1, 47]. The two readings describe the same phenomenon with different nosological boundaries; clinically, a boy with IP lesions should be studied for karyotype, mosaicism and immunodeficiency. Men with IP have more neurological anomalies than women [1].

2.9. Allelic disorders

Table 2.2 — Mendelian phenotypes of IKBKG

The same variant may produce IP in a woman and EDA-ID in her son, as happens with c.1167dup and p.(Ter420Trp) [3, 44]. A woman carrying a variant at position +1 of the 5' untranslated region, which alters splicing, did not have IP but had adult-onset immunodeficiency with non-tuberculous mycobacterial infection, pulmonary aspergillosis and B lymphopenia [56]. A girl with IP and the variant NM_001099857.5:c.613C>T p.(Gln205Ter) in exon 5 developed NEMO-NDAS because X inactivation was not skewed, whereas her mother, a carrier of the same variant with skewing, did not have the syndrome [34]. The EDA-ID, OL-EDA-ID and IMD33 spectrum is treated by HSCT.

3. Clinical Spectrum and Manifestations by System

3.1. Data sources and what each cohort measures

Published frequencies vary because cohorts differ in recruitment, period, examination method and definition of involvement. Series from reference centres and patient associations concentrate severe or familial cases; registry-based studies underestimate manifestations that are not recorded in the medical records; and the frequency of retinal involvement doubles when fluorescein angiography is used instead of ophthalmoscopy [13, 17]. The French PNDS, based on the 2013 Orphanet summary, estimates that about half of patients have extracutaneous manifestations, highly variable in intensity and timing relative to the skin lesions [14]. Table 3.1 summarises the main cohorts.

Table 3.1 — Reference cohorts and series

3.2. Skin: the four stages

Skin lesions follow the lines of Blaschko, linear on the limbs and circumferential on the trunk; unlike dermatomes, these lines do not correspond to innervation but to the migration pathways of embryonic cells, and they make functional mosaicism visible [1, 38]. The sequence of stages is the rule, but not all patients go through all four, more than one type of lesion may coexist and the location may change from one stage to the next [1, 2]. Lesions are present at birth or appear in the first two weeks in about 90% of patients [15]. In the Danish cohort, 93.3% had documented Blaschko-linear lesions [13].

Table 3.2 — Skin stages: timing, frequency and histology

Sources for table 3.2: GeneReviews, European consensus, reference books and the retinopathy consensus review [1, 16, 22, 31, 37, 59].

Stage 1 may mimic an infection: the bullae are erythematous, sometimes pustular, and the fluid is rich in eosinophils, with marked peripheral eosinophilia [1, 31]. The vesicles resolve within weeks and may be replaced by new flares; a case of vesiculobullous eruption at 5 years of age, in a girl who already had stage 4 lesions, shows that the timing is not rigid [1]. Late linear inflammatory flares, months or years after the neonatal period, arise on the pigmented streaks and are frequently triggered by viral infection or fever [2, 16]. The French PNDS also cites reactivation of inflammatory lesions after the 12-month vaccines, and stresses that these late flares should raise the diagnosis even when IP has never been recognised, with recourse to histology if necessary [14]. Lichenoid verrucous lesions occur in about one third of cases, mainly on the dorsum of the hands and feet [22]. Stage 3 is the most characteristic but may be limited, and the whole skin must be examined, including groins and axillae [1]. The marble-cake pigmentation may or may not coincide with the sites of the bullous and verrucous lesions [22]. The onset of stage 3 differs between sources: GeneReviews gives 6 months to 1 year and states that hyperpigmentation is not present at birth, the Oxford textbook gives 3 to 6 months and the European consensus "the first months" [1, 16, 59]. Stage 4 appears to be independent of the previous stages: there may be no true hypopigmentation but rather loss of hair and glands, and in the European series of Hübner it was observed as early as 1 year of age [1, 16, 42]. In adult women, residual hyperpigmentation in the folds or the alopecic hypopigmented streaks on the legs may be the only sign; a woman aged 30 years or more may have no skin changes [1, 16]. Heat intolerance is frequent in adult women and there may be hypohidrosis [16].

3.3. Hair and nails

Alopecia affects the scalp, trunk and limbs. Patchy alopecia of the vertex may correspond to scars from stages 1 and 2, but also occurs without previous lesions; hair is fine and sparse in early childhood and later dull, coarse and thick ("woolly"), often on the vertex, without shaft anomalies; eyelashes and eyebrows may be sparse [1, 16]. Scarring alopecia of the vertex has been described in 28–38% [37]. In the Danish cohort, 26.7% had hair involvement (hypotrichosis or focal alopecia in 21.3%, woolly hair in 5.3%), compared with 78% in the European series of Hübner [13, 42]. Nail dystrophy ranges from mild ridging or pitting to severe dystrophy and onychogryphosis; it is associated with stage 2, may be transient, mimics onychomycosis and is described in 40% (Oxford textbook), 7–40% (Brazilian textbook) and 16% (Denmark) [1, 13, 37, 49]. A single chronic longitudinal streak was observed in 28% of a series of 53 patients [57]. Subungual keratotic tumours appear later, between 3 and 45 years of age and usually after puberty, are painful and may erode the phalanx; the European consensus recommends biopsy to exclude benign or malignant nail tumours [16, 22].

3.4. Teeth and orofacial region

Dental anomalies are the most constant extracutaneous manifestations and persist throughout life. They comprise hypodontia or oligodontia, microdontia, conical teeth or teeth with accessory cusps, molars with fewer cusps and delayed eruption or impaction; enamel and dental strength are normal [1, 16]. In the European consensus, multiple agenesis affects about 60% in the primary dentition and about 90% in the permanent dentition, crown anomalies about 70%, and there are dentomaxillary dysmorphias (class II in 40%, class III in 30%, transverse underdevelopment) [16]. In the permanent dentition, the maxillary lateral incisors and second premolars are most often missing, followed by the mandibular premolars [16]. The incisors present often have shape anomalies, such as a notch, a missing proximal angle or a "grain of rice" appearance [14]. Frequencies in other series are more than 50% (Smith), 80% (Oxford), 70% (Brazilian textbook), 81% (Hübner) and 58.7% in Denmark, where 52% had hypodontia or oligodontia and 20% conical teeth [13, 22, 37, 42, 49]. High-arched palate, cleft lip and palate (1.5%) and microcephaly are occasional findings [16, 22].

3.5. Eyes

Ocular involvement is the main cause of preventable disability. Its frequency depends on the method: about 30% in historical series, 20–77% in GeneReviews, more than one third in the French PNDS, 35–70% in the European consensus, 34% in the Rosain cohort and 22.6% in the Danish cohort, where 14.7% had documented retinal vasculopathy, 12% visual loss and 6.7% strabismus [1, 13, 14, 16, 31, 40]. In the multicentre series of Danford, with a median age of 9 months, indirect ophthalmoscopy detected retinal pathology in 18 of 35 patients (51%) and fluorescein angiography in 26 of 35 (74%; P=0.048) [17]. The primary lesion is non-perfusion of the peripheral retina, mainly temporal, followed by arteriovenous anastomoses, tortuosity and vascular loops, haemorrhages, neovascularisation at the junction between perfused and non-perfused retina, dragged vessels and tractional detachment [15, 16]. Avascularity may extend to the mid-periphery and the posterior pole, unlike retinopathy of prematurity and familial exudative vitreoretinopathy, which has consequences for laser treatment [39]. In the macula there is thinning of the inner and outer retina, reduced density of the vascular plexuses on optical coherence tomography angiography (OCT-A), enlargement or absence of the foveal avascular zone and foveal hypoplasia [15, 39]. Basilius and colleagues related anomalies of the inner foveal layers and of the avascular zone to poor vision in children under 5 years of age [2]. Other manifestations are multifocal lesions of the retinal pigment epithelium (RPE), asymptomatic cornea verticillata, retinal artery occlusion, ischaemic optic neuropathy, optic atrophy, microphthalmia, cataract and secondary strabismus or nystagmus [15, 16, 60]. The French PNDS describes macular vasculopathy as suspected on clinical examination from an altered foveal reflex and on OCT from retinal thinning, but requires fluorescein angiography for diagnosis; it considers cornea verticillata and multifocal hypo- or hyperpigmented RPE lesions highly suggestive of IP in an infant, and notes that the eye rarely reveals the disease [14]. In Goldberg's retrospective series compiled in that protocol, multifocal RPE lesions affected 39% of eyes, retinal non-perfusion 31% and detachment 8% (12 patients); in another series, of 9 eyes of 13 patients, the course of capillary occlusions was stable in 2 eyes, progressive in 2 and progressive with reopening and vascular remodelling in 3, and there was 1 central retinal artery occlusion and 2 tractional detachments [14].

Retinal detachment has a bimodal distribution. Tractional detachment, due to fibrovascular contraction, occurs in early childhood; rhegmatogenous detachment, due to atrophic holes at the junction between perfused and non-perfused retina, occurs later [15]. In the Chen cohort (50 eyes of 25 patients, median follow-up of 9.3 years), 22% of eyes (11/50) had detachment, tractional mainly up to 2.5 years of age and all rhegmatogenous after 14 years; of the 7 eyes with tractional detachment only one had successful surgical repair, and half of the rhegmatogenous detachments were successfully repaired [15, 39]. O'Doherty and colleagues observed visually significant findings in 5 of 11 patients and loss of 6 of 22 eyes from detachment, usually early; OMIM transcribes this proportion as 47%, whereas 5/11 corresponds to 45% [2]. The maximum risk of detachment is in childhood and it almost never appears after 6 years of age in the classical reading, but the Chen data and the late sequelae described in the 2025 consensus (tractional retinoschisis, late tractional detachment in eyes previously treated with laser) justify lifelong surveillance [1, 15, 22]. About 10% of patients progress to severe retinal scarring with significant visual loss [22]. Median retinal severity was higher in patients with CNS disease (2 versus 1; P=0.034), which suggests a common vasculopathy [17].

3.6. Central nervous system

CNS involvement occurs in about 30% of patients and is the main cause of severe morbidity [1, 15]. The true incidence is uncertain, because mildly affected patients without neurocognitive problems may not reach care, and it is more frequent in sporadic than in familial cases [1]. In the Danish cohort, 30.7% had CNS involvement, 13.3% seizures, 9.3% spastic paresis or motor deficit, 8% ischaemic stroke and 8% cognitive impairment [13]. In the European series of Hübner, neurological involvement reached 53% [42]. The French PNDS places at between 15% and 30%, depending on the series, the patients with secondary cognitive impairment associated with motor deficit (hemiparesis, paraparesis or tetraparesis) [14]. Among patients with CNS involvement, the European consensus reports seizures in 42%, motor deficit (hemiparesis, paraparesis or tetraparesis) in 26% and intellectual disability or learning difficulties in up to 20% [16]. Overall data vary: seizures in 14% and persistent in 6% in the Oxford textbook, in 20% in Smith's textbook and in about 7% of all diagnosed patients in the review by Meuwissen and Mancini, where about 25% of patients with neurocognitive problems had had at least one seizure [1, 22, 49, 61].

CNS injury is concentrated in the neonatal period. In 88% of patients, CNS problems manifest by the end of the first year, and recurrent seizures or strokes later in childhood occur in about 10% [16]. Of the 35 patients with seizures and known age at onset, 32 had onset in the first year, and 14 of 25 with described recurrence had a single seizure; focal clonic seizures are the most frequent [1, 61]. Partial seizures may appear from 24 hours of life, before any visible skin lesion [16]. Neurovascular changes are most common in the first year, and only three cases have been described after 4 years of age [1]. Magnetic resonance imaging (MRI) shows two patterns: mild changes of the periventricular white matter with T2 hyperintensity, sometimes with cortical and corpus callosum atrophy; and severe cortical lesions of vascular type, with multiple areas of restricted diffusion outside arterial territories, contrast enhancement, microhaemorrhages and ischaemic sequelae such as focal cortical atrophy and ulegyria [16]. Outside the neonatal period, sequelar clastic white matter lesions are described and, in severe cases, cerebral calcifications, interpreted as the consequence of a microvascular mechanism attested by cytotoxic oedema of the white matter and by the focal cortical lesions on neonatal MRI [14]. Periventricular leucomalacia was present in 27 of 43 patients with neurocognitive impairment, mainly in those with seizures [1]. In the newborn girl described by Tomotaki, MRI on day 15 showed simultaneously acute lesions, with multiple foci of restricted diffusion in the right frontal lobe, the temporal lobes, the thalamus and the basal ganglia, and chronic lesions with cortical laminar necrosis and subcortical encephalomalacia in the frontal, left parietal and occipital lobes, consistent with the clinical deteriorations on days 4 and 13; CNS lesions may therefore recur within a few days [62]. There are lethal forms due to extensive antenatal injury or status epilepticus [16]. Primary anomalies of brain development are rare and have been described in isolated cases: agenesis of the corpus callosum with occipital encephalocele, polymicrogyria and grey matter heterotopias [1]. Acute disseminated encephalomyelitis and infantile encephalopathy have also been described [22]. Neonatal seizures, present in about 20%, correlate with the degree of cerebrovascular injury and are a sign of poor neurodevelopmental prognosis; patients without neonatal CNS changes usually have normal development, and no new neurological symptoms have been observed in adolescence or adulthood [16, 22, 37].

3.7. Cognition and learning

The cognitive spectrum ranges from normal function to severe intellectual disability, which is uncommon [1]. Pizzamiglio and colleagues assessed 10 women with the recurrent deletion recruited through the Italian association: the 7 without intellectual disability had deficits in calculation, arithmetic reasoning and reading, but not in writing, and the remaining 3 had mild to severe intellectual disability [63]. In a second series of 14 girls aged 1 to 12 years, 9 had normal development and 5 mild to severe intellectual disability; 2 of the 4 of school age with normal intelligence had specific difficulties in calculation and mathematical reasoning [22, 64]. The European consensus includes learning disorders without intellectual disability (dyslexia, dyscalculia), even without motor deficit [16]. The Oxford textbook reports learning difficulties in 10% of affected women, severe in 3% [49]. In men, a 47,XXY karyotype may add its own component to the cognitive phenotype [1].

Psychiatric risk is not defined. The literature review of the French PNDS, written with the participation of a reference centre for rare diseases with psychiatric expression (GénoPSY), found a single published case of bipolar disorder, in a patient who also had subungual tumours, and concludes that it is not possible to distinguish between absence of increased risk and lack of studies [14]. The authors note that the Xq28 region has been associated with psychiatric disorders in psychiatric genetics studies, an association that is regional and has not been demonstrated for IKBKG, and draw attention to psychiatric symptoms, possible at any age, that are reactive to motor and visual disability and to changes of the face and limbs that affect body image [14]. Cognitive disorders may exist without motor deficit, which justifies targeted assessments even in patients without visible neurological sequelae [14, 63].

3.8. Breast and lactation

Breast anomalies range from unilateral breast aplasia, known but uncommon, to hypoplasia, asymmetry and inverted, hypoplastic or supernumerary nipples, and are more common than in the general population [1, 2, 16]. Their frequency is probably underestimated, because the series focus on prepubertal children [1]. The European consensus draws attention to lower milk production and to breastfeeding difficulties [16].

3.9. Immunity, thymus and infections

IP is not traditionally considered an immunodeficiency, but there are three lines of evidence of immune compromise. In the Rosain cohort, 36% of the 131 women (47/131) had neutralising autoantibodies against IFN-α2 and/or IFN-ω, none against IFN-β, with a prevalence of about 40% from 6 years of age; the autoantibodies appeared between 5 and 15 years of age and did not correlate with genotype, familial or sporadic form, X skewing, CNS or eye involvement [40]. Of the 11 patients with autoantibodies exposed to SARS-CoV-2 before vaccination, 4 had critical or severe disease requiring oxygen and 3 moderate pneumonia; one had H1N1 pneumonia and another yellow fever vaccine-associated neurological disease, after vaccination at 54 years of age [40]. All 10 patients infected after COVID-19 vaccination had mild or asymptomatic disease, and none of the 20 positive patients vaccinated with the measles, mumps and rubella (MMR) vaccine had reactions [40]. A female infant without autoantibodies had critical COVID-19 at 2 weeks, after receiving corticosteroids for IP in the first days of life [40]. In the Danish cohort, 12% had recurrent infections and 20% atopic comorbidity, without a comparison group [13]. A female infant with IP and a frameshift variant in exon 7 had recurrent infections with raised IgM and low IgG, treated with intravenous immunoglobulin, and the immunodeficiency disappeared when X inactivation became skewed [2]. Roberts and colleagues proposed that the male neonatal phenotype includes lethal haematopoietic and immunological disorders [2].

3.10. Other manifestations

Leucocytosis with up to 65% eosinophils is common in stages 1 and 2, is not consistently associated with other manifestations and resolves spontaneously [1]. Pulmonary arterial hypertension has been described in a few cases: a 2023 review counted six cases in the literature, four of whom died before 1 year of age, and described a 2-month-old female infant successfully treated with pulmonary antihypertensive and anti-inflammatory therapy [65, 66]. Cardiovascular manifestations are rare [16]. Skeletal anomalies (hemivertebrae, kyphoscoliosis, supernumerary rib, syndactyly, hemiatrophy, short limbs) are reported in about 20% in Smith's textbook and in 14% in the Brazilian textbook, and limb defects in 4% in Denmark [13, 22, 37]. Short stature appears in the OMIM clinical synopsis [60]. In 2026, the first documented association, with genetic confirmation, between IP and complete pituitary aplasia with ectopic neurohypophysis was described in Portugal, in a girl with short stature, growth hormone deficiency, central adrenal insufficiency and central diabetes insipidus (section 10) [45]. Dacryostenosis and eczema are occasional [22].

3.11. Manifestations by age and untreated natural history

In the fetal period, affected male conceptuses are usually lost in the first trimester or early second trimester, and hydrops may be seen on ultrasound at 8–13 weeks [49]. In the newborn and infant, stage 1, eosinophilia, seizures and ischaemic CNS lesions and active retinal vasculopathy predominate [1, 16]. In the second half of the first year and in early childhood, verrucous lesions regress, hyperpigmentation appears and delays in tooth eruption become evident [1]. At school age, learning disorders and agenesis of the permanent dentition become apparent [16]. In adolescence and adulthood, the pigmentation fades, the nails may develop dystrophy or subungual tumours and the risk of rhegmatogenous detachment increases [15, 22]. Untreated natural history data come mainly from series prior to systematic photocoagulation and from untreated eyes: in the Wald series (1993), a patient with untreated active neovascularisation progressed to detachment and visual loss [39]. Life expectancy is normal in people without significant neonatal or childhood complications [1].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age and context

In the prenatal period, suspicion arises from repeated miscarriages of male fetuses or recurrent non-immune fetal hydrops in male fetuses. Cao and colleagues described three Chinese families with recurrent hydrops, increased nuchal translucency, cervical cystic hygroma and generalised oedema in the male fetuses, negative microarray and next-generation sequencing (NGS) and mothers with subtle ectodermal signs (hypopigmented streaks, patchy alopecia, dental anomalies); the exon 4–10 deletion was detected only by gene-targeted long-range PCR and multiplex ligation-dependent probe amplification (MLPA) [67]. In a Portuguese family, a termination of pregnancy for medical reasons at 16 weeks for fetal hydrops, in a 46,XY fetus, preceded the birth of the affected sister (section 10) [45].

In the newborn and young infant, the typical manifestation is erythema followed by vesicles or bullae, linear on the limbs and circumferential on the trunk, usually sparing the face, with blood eosinophilia and negative cultures; the linear arrangement is the key to ruling out an infection [1, 16]. Suspicion should also arise in the presence of unexplained neonatal seizures, encephalopathy, ischaemic stroke or vascular retinopathy, because seizures may appear from 24 hours of life, before the skin lesions, and there are newborns with neurological and ocular manifestations without the typical lesions [16, 39]. In the second half of the first year, linear verrucous lesions or whorled hyperpigmentation without an observed bullous phase lead to retrospective suspicion [1]. In the child, hypodontia, conical incisors and delayed eruption, associated with vertex alopecia or pigmented streaks, complete the picture [16]. In adult women, the diagnosis is often made after that of a daughter: conical or missing teeth, alopecic hypopigmented streaks on the legs, vertex alopecia, nail changes and miscarriages of male fetuses should be actively sought, because adult women may be unaware of mild childhood findings and may have had cosmetic treatment of teeth, hair and nails [1, 16]. In males, segmental or partial Blaschko-linear lesions suggest somatic mosaicism or a 47,XXY karyotype; a boy with ectodermal dysplasia, severe infections and a mother with mild IP suggests EDA-ID [1, 13].

Age at diagnosis has improved: in the Danish cohort, the median was 3 years overall (interquartile range, IQR, 0–29), but 3 weeks (IQR 1–11) in children born during the study period [13]. The median age at diagnosis in patients with retinal findings was 19 days in one review and about 3.1 months in other series [15]. The positive predictive value of ICD-10 code Q82.3 in the Danish national registry was only 73% (95% CI 63–81%): among those excluded were coding errors (congenital naevus, cerebral vascular malformations), pigmentary mosaicism and other ectodermal dysplasias [13].

4.2. Warning and emergency signs

Table 4.1 — Warning signs and immediate management

4.3. Newborn screening

There is no newborn screening for IP, and unlike retinopathy of prematurity there are no universal retinal screening programmes; ophthalmological and neurological assessment only begins after suspicion, which contributes to diagnostic delay [39]. GeneGuidance recommends organising ophthalmological surveillance before neonatal discharge, and the ICIP consensus sets the first retinal examination within 1 month of diagnosis [9, 15].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

The criteria of Landy and Donnai (1993) were based on the four skin stages and required at least one major criterion in the absence of a family history [1, 27]. Minić and colleagues updated them in 2014 on the basis of a meta-analysis of the literature with more than 2000 patients: the major criteria remain the skin stages, and the minor criteria now include dental, ocular, CNS, hair, nail, palate, breast and nipple anomalies, multiple miscarriages of male fetuses and skin histopathology [2, 28]. The 2020 European consensus raised the teeth and the recurrent exon 4–10 deletion to major criteria [16].

Table 5.1 — Diagnostic criteria systems

Sources for table 5.1: [1, 13–16, 28, 37].

The differences have practical consequences. A girl with hypodontia and conical incisors, with no observed skin lesions, meets the European criteria but not those of Minić without another finding; a patient with the recurrent deletion meets them by definition in the European system, which does not include other pathogenic variants among the major criteria [13, 16]. The 2019 French PNDS and the European consensus published in 2020 by the same group of experts use the same combination rule, but not the same list. The PNDS classifies hypereosinophilia and suggestive skin histology as major criteria, does not include the verrucous stage, the teeth or the recurrent deletion among the major criteria and places the teeth among the minor ones; the text of the same protocol states, however, that dental anomalies became a major criterion after a revision, which makes it internally inconsistent [14]. The 2020 consensus resolves the inconsistency: it moves eosinophilia to minor, because it is common in the first months of life, and histology also to minor, and adds stage 2, the teeth, scarring alopecia of the vertex and the exon 4–10 deletion to the major criteria [16]. With the PNDS list, isolated eosinophilia in a newborn would suffice for a major criterion, which does not happen with the 2020 list; the 2020 version, later and revised, is the reference when the two diverge [14, 16]. The ICIP consensus considers that the diagnosis is mainly clinical and that confirmatory genetic testing is not mandatory [15]. The Brazilian textbook stresses that the diagnosis is clinical and that, at the date of the edition, molecular testing was not accessible to most patients in its setting [37].

5.2. Histology and non-molecular investigations

Skin biopsy is indicated when no variant is identified and the findings are borderline, and it is most useful in men, especially if mosaicism is considered, because the same sample can be used for molecular testing [1]. The combination of eosinophilic spongiosis, hyperkeratosis, melanin incontinence and keratinocyte apoptosis is highly suggestive; in adults, stage 4 may be the only sign, and absence of adnexa with apoptotic keratinocytes is sought [16]. Extracellular melanin granules and the eosinophilic infiltrate suggest the diagnosis in women [1]. In the series compiled by the French PNDS, histology was useful in 26 biopsies of stage 4 lesions from adult women with moderate forms (Fraitag, 2009), and characteristic histopathological changes were present in all the biopsied patients of a Japanese series of 10 cases (Okita, 2013) [14]. In the Danish cohort, only 8% had recorded histopathological findings [13]. The full blood count shows leucocytosis with eosinophilia in stages 1 and 2 [1]. X-inactivation studies, by digestion with a methylation-sensitive enzyme and amplification of the polymorphic androgen receptor (AR) or RP2 locus, document skewing and serve as a supporting criterion; they also help identify carrier relatives when the proband's variant has not been found [1, 12]. Retinal assessment includes dilated indirect ophthalmoscopy, wide-field fluorescein angiography and, when possible, optical coherence tomography (OCT) and OCT-A; examination under general anaesthesia with a wide-field camera (RetCam) is often necessary in infants [15, 39]. Brain MRI with diffusion, MR angiography when the deficit suggests stroke, EEG, orthopantomography and, in men, karyotype or FISH for 47,XXY complete the assessment [1, 9, 16].

5.3. Molecular testing: order and yield

Single-gene testing is the most effective strategy. The first step is testing for the recurrent exon 4–10 deletion by IKBKG-specific long-range PCR, alone or simultaneously with sequencing of the gene; gene-targeted deletion and duplication analysis follows [1, 16]. The European consensus places the overall detection rate at about 80% [16]. The reference method for point variants is gene-specific long-range PCR followed by Sanger sequencing [12].

Table 5.2 — Proportion of pathogenic variants identified by method in patients with IP

These percentages are proportions of variants detected by each method in patients with a clinical diagnosis, not clinical sensitivities of the test [1]. In the Danish cohort, 84% of tested patients had molecular confirmation, a proportion that rose to 93% in those born during the study period [13].

5.4. Limits of the tests

The IKBKGP1 pseudogene, with more than 99% identity in exons 3–10, is the main source of error. In short-read sequencing (exome or panels), reads map ambiguously to the gene and the pseudogene, depth and mapping quality fall and the calling software may not even call the variants, which requires manual inspection in the genome browser and does not allow one to know whether the variant is in the gene or in the pseudogene [12]. GeneReviews recommends that, in panels, IKBKG be analysed by methods other than NGS and that deletion/duplication designs take the pseudogene into account [1]. The exon 4–10 deletions escaped short-read NGS in the three families with recurrent male hydrops of Cao and colleagues [67]. A normal MLPA does not exclude a point variant, and Sanger sequencing with non-specific primers amplifies gene and pseudogene, with a distorted allelic ratio [12]. RNA analysis may fail for two cumulative reasons: nonsense-mediated decay and skewed X inactivation, which at a ratio of 85:15 reduces the fraction of the mutant allele to about 7.5%, below the detection threshold of Sanger sequencing (about 20%) [12]. In men, somatic mosaicism may prevent detection in blood, and other tissues should be analysed, such as skin from an affected area or sperm [1, 46]. The existence of recurrent benign variants in the pseudogene (exon 4–10 deletion in IKBKGP1) and of MER67B duplications requires assays that distinguish the deletion in the gene from the deletion in the pseudogene [1, 50]. A negative result does not exclude IP, because about 5% of patients with a clinical diagnosis have no variant identified at the locus [1].

Recent technologies overcome some of these limits. Nanopore sequencing (Oxford Nanopore Technologies, ONT) with adaptive sampling locates the variant in the gene or the pseudogene and, through haplotype-specific methylation of the promoters, shows which allele is preferentially inactivated: in the German family of Ahting, the methylated fraction of the promoter on the maternal haplotype with the variant was 71.7% against 7.9% on the paternal haplotype [12]. Optical genome mapping (OGM) identified Xq28 deletions of variable size in paediatric patients with inconclusive studies [69]. Bioinformatics pipelines that mask IKBKGP1 and long-read sequencing are also used, especially for variants that originate in the pseudogene and are transferred to the gene [12, 48].

5.5. Report content, variants of uncertain significance and segregation

The report should state the gene, the transcript with version (NM_001099857.5), the variant in Human Genome Variation Society (HGVS) nomenclature with the genomic notation (GRCh38), the zygosity or mosaic status with the allelic fraction, the method and how the pseudogene was excluded, and the classification according to the ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) criteria [10, 12]. A variant of uncertain significance (VUS) neither confirms nor excludes the diagnosis [1]. Familial segregation, study of the mother, demonstration of skewed X inactivation and, when necessary, functional assays of TNF-dependent NF-κB activation help reclassify: the variant c.363_367del was classified as likely pathogenic by the PVS1 and PM2 criteria after demonstration of maternal segregation and skewed X inactivation (mother 95:5, proband 85:15) [12]. In patients without a molecular diagnosis, storing DNA for future techniques is recommended [1].

5.6. Practical algorithm

Table 5.3 — Diagnostic algorithm

5.7. Prenatal and preimplantation diagnosis

Prenatal diagnosis by chorionic villus sampling or amniocentesis is possible when the familial variant is known, but it does not predict severity, given the phenotypic variability [1, 16]. The fetal karyotype guides counselling: in a 46,XX fetus with the variant, IP of unpredictable severity is expected; in a 46,XY fetus, the high risk of loss after the first trimester is discussed; in a 47,XXY fetus, the more severe male phenotype and Klinefelter syndrome are discussed [1]. Devriendt and colleagues described a 46,XY fetus with the at-risk haplotype identified at 10 weeks, a normal ultrasound and fetal death documented at 20 weeks, with severe growth restriction as the only finding [2]. Preimplantation genetic testing for monogenic disorders (PGT-M) is technically difficult because of the pseudogene, the terminal location of the region and the need for indirect linkage analysis for large deletions (section 8.5) [70].

6. Differential Diagnosis

6.1. Principles

The differential diagnosis changes with the stage at which the patient is seen, and the discriminating question is always the same: do the lesions follow the lines of Blaschko, have they gone through an inflammatory phase and do they regress spontaneously? [1, 16]. GeneReviews recommends considering another diagnosis in the presence of skeletal involvement not secondary to a neurological deficit, gross neurological deficit, severe alopecia, atypical hyperpigmentation or gross hypopigmentation; segmental limb asymmetry is not usual, although a terminal transverse acromelia of the upper limb has been described [1]. A child with IP may have a skin infection at the same time, and signs of infection should be investigated in their own right [1]. Blaschko-type pigmentation indicates mosaicism, chromosomal or functional due to an X-linked disorder, and also occurs in women with DDX3X or PHF6 variants [59].

Table 6.1 — Differential diagnosis

6.2. Differential diagnosis by stage

In stage 1, the differential is with neonatal infections (herpes simplex, varicella, bullous impetigo) and, in severe cases, with epidermolysis bullosa and the bullous dermatoses of early childhood; infections are accompanied by fever and toxicity and scraping and cultures are diagnostic, whereas epidermolysis bullosa forms blisters after minor trauma [1, 16]. The linear arrangement and eosinophilia point towards IP [16]. The Brazilian textbook adds epidermolytic hyperkeratosis and congenital syphilis [37]. The French PNDS adds dermatitis herpetiformis and bullous impetigo to the bullous dermatoses to be excluded, notes that these rarely follow a linear topography and points out that Blaschko-linear epidermolytic epidermal hamartomas are the main source of confusion; the other X-linked dermatoses with linear lesions in girls (focal dermal hypoplasia, Conradi-Hünermann-Happle chondrodysplasia punctata) differ in appearance from IP vesicles [14]. In stage 2, warts and molluscum contagiosum cause confusion only when IP is mild: numerous lesions in the linear pattern make IP more likely, but an isolated lesion may require biopsy; the European consensus includes chondrodysplasia and epidermal naevus [1, 16]. In stage 3, the differential is with pigmentary mosaicism; spontaneous regression is the strongest argument in favour of IP [16]. In stage 4, scars, vitiligo, localised alopecia, piebaldism and hypomelanosis of Ito are the differentials, and biopsy (absence of adnexa with apoptosis) helps to decide [1, 14, 16].

6.3. Hypomelanosis of Ito and pigmentary mosaicism

Hypomelanosis of Ito presents with hypopigmented streaks and whorls, best seen with Wood's lamp, without an inflammatory prodromal phase; the lesions are often not detected in the newborn and become apparent in the first months in 80% [71]. About 70% of children have associated anomalies, intellectual disability affects 30–50%, there are seizures and, in 7%, hemihypertrophy with a risk of Wilms tumour; the aetiology is heterogeneous, with chromosomal or genetic mosaicism, and the recurrence risk is low [31, 71]. Skin karyotyping is indicated when there is developmental delay or malformations [71]. Historically, the confusion between hypomelanosis of Ito and IP produced the terms "IP1" and "incontinentia pigmenti achromians"; no patient with hypomelanosis of Ito has the conical teeth or the vascular retinopathy of IP [2, 30].

6.4. X-linked syndromes with linear lesions

Goltz syndrome, due to PORCN variants, and microphthalmia with linear skin defects syndrome (MLS), due to HCCS variants, share with IP X-linked dominant inheritance with male lethality and Blaschko-linear lesions, but have dermal atrophy with fat herniation (Goltz) or microphthalmia with linear defects of the face and neck, sclerocornea and agenesis of the corpus callosum (MLS) [31]. CHILD syndrome, also an X-linked dominant genodermatosis, was studied by optical genome mapping together with IP in patients with inconclusive studies [69]. X-linked dyskeratosis congenita has the DKC1 gene in the same Xq28 region, but a study of 23 women with IP found no DKC1 variants, and the two diseases are not allelic [2].

6.5. Paediatric vascular retinopathies

The peripheral retinal neovascularisation of IP may be confused with retinopathy of prematurity and with familial exudative vitreoretinopathy, X-linked recessive within the Norrie spectrum (NDP) or autosomal dominant; these diseases have no skin findings, and the detachment of IP may look similar to that of X-linked vitreoretinopathy [1, 72]. Unlike retinopathy of prematurity and familial exudative vitreoretinopathy, the avascularity of IP may extend towards the posterior pole [39].

6.6. Allelic disorders of IKBKG

EDA-ID and OL-EDA-ID enter the differential diagnosis of a boy with ectodermal dysplasia and severe infections; in OL-EDA-ID there is also mild osteopetrosis, a bone-within-bone appearance, metaphyseal striations and lymphoedema, and infections are accompanied by a weak inflammatory response, with delayed or absent fever, leucocytosis, C-reactive protein and immunoglobulins [55]. NEMO-NDAS, described in 2020, is one of the four Mendelian phenotypes of IKBKG: the germline variants lead to overexpression of the NEMO-Δex5 isoform, which stabilises IKKi and increases NF-κB activation and IFN production in T cells, monocytes and macrophages [33, 48]. A 2026 review gathered eight children (six boys) with onset between 2 and 48 weeks, panniculitis, hepatosplenomegaly, fever, lymphopenia and, in several, CNS haemorrhage and uveitis; anti-TNF agents (adalimumab, infliximab, etanercept) gave partial responses and tofacitinib had no effect [48]. The authors describe the picture as dominated by IFN-γ from γδ T cells, whereas Eigemann and colleagues described a type I interferonopathy in a woman with IP and NEMO-NDAS; the two readings have not been reconciled [34, 48]. In a woman with IP, NEMO-NDAS should be considered in the presence of recurrent fever, oral ulcers, hepatitis, neutropenia or panniculitis, especially if X inactivation is not skewed [34].

7. Treatments and Risk Management Strategies

7.1. Principles and initial assessment

There is no treatment targeting the cause and no authorised medicine for IP, and there are no randomised trials of any intervention [9, 15]. Management is symptomatic, multidisciplinary and guided by the risk to each organ in the first months; the French PNDS calls for a coordinator of the care pathway, usually the dermatologist, because exclusively cutaneous forms are the most frequent and skin lesions are the earliest and most diagnostic, supported by a network of experts [14]: the main objective is to detect and treat the retinopathy before detachment and to recognise and treat acute CNS injury in the neonatal period [15, 16]. The European consensus is based on level 4 evidence (series and retrospective studies), grade C, and the ICIP consensus states that there is no level 1, 2 or 3 evidence on the safety and efficacy of retinal interventions [15, 16].

Table 7.1 — Assessment after diagnosis

7.2. Skin

Blisters should not be opened, should be kept clean and dry during healing and protected from trauma, and the newborn should be monitored for excessive inflammation and systemic signs [1, 22]. Discomfort may be relieved with topical medication and oatmeal baths [1]. The European consensus allows a local antiseptic in the newborn to prevent infection, and the Brazilian textbook mentions topical antibiotics in the vesicular phase and urea-containing emollients in the verrucous phase, without stating drugs, concentrations or dosages [16, 37]. The French PNDS does not recommend topical or systemic antibiotics for IP lesions, which are initially sterile, and allows only local antisepsis in the newborn to prevent superinfection; this position differs from that of the Brazilian textbook [14, 37]. Secondary infections are treated like any cellulitis [1]. In severe inflammatory or verrucous lesions, topical corticosteroids, topical tacrolimus (to be avoided in the newborn) and oral and intravenous corticosteroids have been used with some success in a few reports; because the lesions regress spontaneously, the need for treatment and the benefit-risk balance must be justified [16]. The case reports compiled in the French PNDS provide the only published dosages: in a newborn, diflucortolone valerate 0.1% combined with the antiseptic chlorquinaldol 1%, twice daily, cleared the vesicles in 5 days (Kaya, 2009); in a child, topical tacrolimus 0.1% led to regression of the vesicles (Jessup, 2009); and systemic corticosteroids were described in a 1994 report (Calza) [14]. The protocol restricts the use of topical corticosteroids to intense and disabling inflammatory phases and insists on not exposing the child to unnecessary iatrogenic harm [14]. In the Portuguese case, the stage 1 lesions resolved with a topical corticosteroid alone [45]. The persistent lesions of stage 4 are not sequelae of the inflammatory lesions and do not respond to these treatments [16]. Laser treatment of hyperpigmented lesions triggered recurrent inflammatory flares and should be avoided; in a 1997 report, limited treatment with a ruby laser was followed by an extensive vesiculobullous eruption; photoprotection is recommended [14, 16].

Late subungual verrucous tumours require biopsy and, when painful, surgical excision with curettage of the bone, sometimes repeated [16]. In one case, oral etretinate for 6 months led to complete regression (dose not stated in the consensus or in the PNDS), and in another, topical retinoic acid 0.05%, applied twice daily for 6 months, relieved the pain within 1 month and the tumour regressed within 6 months; these are isolated reports [14, 16]. The PNDS also allows CO2 laser for periungual tumours [14].

7.3. Retinopathy

7.3.1. Staging

The 2025 ICIP consensus proposed a staging system based on ophthalmoscopy and wide-field fluorescein angiography, which in practice replaces the earlier classifications of Holmström (2000), Huang (2017) and Danford (2022) [15]. The review by Tseng and colleagues (2026) organises treatment according to the five-grade classification of Peng (2019), in which isolated RPE changes form a grade of their own [39].

Table 7.2 — ICIP staging of the retinopathy and recommended management

Source for table 7.2: [15]. There are no known cases of progression after a normal baseline angiogram [15].

7.3.2. Laser photocoagulation and cryotherapy

Laser photocoagulation of non-perfused retina is the mainstay of treatment of proliferative retinopathy, and has been used since the 1970s [39]. The European consensus recommends, in the presence of peripheral vasculopathy, urgent referral to a specialised centre for examination under general anaesthesia with retinal photography and angiography, followed by argon laser photocoagulation of the zones of non-perfusion, with a further session if new lesions appear [16]. The French PNDS, from which that consensus derives, specifies that the initial examination follows the screening protocol for retinopathy of prematurity, with full dilation and indirect ophthalmoscopy by an ophthalmologist trained in examining the newborn retina, that retinal assessment is urgent from the clinical diagnosis and that the laser is applied externally [14]. The reports on which that recommendation rests, compiled in the protocol, are isolated cases with diode or argon photocoagulation: regression of neovascularisation in 2 weeks maintained at 4 and 6 months (Nguyen, 2001; DeVetten, 2007), complete regression at 5 months after 764 burns (Ranchod, 2010), absence of tractional detachment 1 year after early laser (Batioglu, 2010) and a 4-month-old infant treated with 1200 burns (Escudero, 2009); in the Irish series of O'Doherty, laser stopped progression in 2 of 11 patients, but one had a detachment months later, and in 3 Australian cases there was 1 good outcome with cryotherapy, 1 laser failure and 1 failure without treatment (Balaratnasingam, 2009) [14]. Michel and colleagues (19 patients, 7 with retinopathy) and Nakao and colleagues (3 patients, 6 eyes) described that early laser in infants with extensive avascularity reduced progression to neovascular complications, with results maintained for up to 6 years; Nakao applied treatment thresholds derived from retinopathy of prematurity [39]. Other authors observed recurrence of vascular anomalies requiring additional laser: in the series of Bryan (14 patients), 6 eyes progressed and required further sessions, without detachment or vitreous haemorrhage [39]. Laser is therefore not a one-off treatment, and follow-up must be prolonged [39]. The review recommends that laser be guided by fluorescein angiography, because avascularity may extend into the mid-periphery and because the operator may inadvertently reach the macula: in one of Nakao's patients, expansion of laser scars near the macula caused macular degeneration [39]. Complications described include detachment due to contraction of regressing neovessels, rare arterial and venous occlusions after laser and a chorioretinal anastomosis after five laser cycles [15, 39]. Retinal reperfusion after photocoagulation was described in 2026 [73]. Cryotherapy was used at the end of the twentieth century; Chen and colleagues described a 2-month-old female infant treated with cryotherapy and laser who developed detachment due to fibrovascular contraction at 7 years of age, and in their cohort prophylactic ablation did not prevent tractional detachment in 3 of 4 infants, compared with 1 of 6 eyes treated in older children and adults [39].

7.3.3. Intravitreal antiangiogenic agents

Intravitreal anti-VEGF agents are used as adjuncts or alternatives to laser in aggressive neovascularisation or when media opacity prevents laser; their use in IP is off-label and the evidence is limited to uncontrolled reports [15, 39]. Shah (bevacizumab, 2 eyes) and Wang (ranibizumab 0.025 mL, 5 patients, 8 eyes) described regression of neovascularisation, almost always followed by laser for long-term control; conbercept (0.025 mL) has been used in Chinese series [39]. Reported complications include disease recurrence, retinal ischaemia with cotton-wool spots after conbercept and necrotising enterocolitis in a newborn after intravitreal bevacizumab at a dose of 625 µg, extrapolated from retinopathy of prematurity; the Tseng review therefore recommends ranibizumab rather than bevacizumab, because of its lower systemic absorption [39]. Laser has a permanent effect, whereas anti-VEGF is cleared from the eye within a short time and serves as a temporary measure, without resolving the chronic production of VEGF by the avascular retina; the therapeutic model proposed by Liang combines laser to avascular zones and anti-VEGF for active neovascularisation [39]. In the neonatal case of Mohammad, retinal exudates were treated with laser photocoagulation and intravitreal ranibizumab on day 18 of life (dose not stated in the article) [74].

7.3.4. Vitreoretinal surgery

In operable retinal detachment, pars plana vitrectomy, scleral buckling, gas or silicone oil tamponade and laser are combined according to extent, age and macular involvement; surgical treatment generally follows the principles used in retinopathy of prematurity and familial exudative vitreoretinopathy [39]. Results are worse in tractional detachment of the infant than in rhegmatogenous detachment of older children and adults [15, 39]. The Tseng review proposes considering vitrectomy earlier (Peng stage 3) in the presence of persistent vitreous haemorrhage in a child, because of the risk of amblyopia, and accepts that in an eye with unilateral total detachment observation may be preferable to repeated surgery with a high risk of a blind and painful eye [39]. There are no published series on the treatment of the end stage (neovascular glaucoma, phthisis bulbi) [39].

7.4. Acute central nervous system injury

In the neonatal period, treatment has two aims: to control status epilepticus or repeated seizures with antiepileptic drugs chosen according to the semiology and the age, and to limit injury with anti-inflammatory treatment [16]. The French PNDS names intravenous phenytoin (Dilantin®, the designation used in France) or an oral antiepileptic drug for symptomatic treatment, and justifies the anti-inflammatory approach by interpreting status epilepticus as the expression of an inflammatory vasculitis [14]. The PNDS and the European consensus propose corticosteroids as first line, with intravenous methylprednisolone (Solu-Medrol®) followed by an oral corticosteroid for some weeks, without specifying doses; TNF blockers have been used occasionally and appear promising, but have not been studied [14, 16]. The basis of this recommendation is case reports, and the published doses come from them. Tomotaki and colleagues described a term female newborn (37 weeks, 2165 g) with linear vesicles at birth, a reduced level of consciousness and weak sucking on day 4 and further deterioration on day 13; on arrival at the reference centre, on day 15, she had no sucking and reacted little to stimuli, the amplitude-integrated EEG showed a discontinuous trace and MRI showed multiple acute infarcts with diffusion restriction alongside chronic lesions with encephalomalacia, with normal C-reactive protein, blood count, coagulation, cultures and echocardiogram [62]. The authors interpreted the acute lesions as active inflammation and started prednisolone at 2 mg/kg/day on day 15; they maintained the dose for 1 week and tapered it progressively until withdrawal on day 33 of life, about 2.5 weeks of treatment, with no daily maximum or route described [62]. They chose prednisolone for its anti-inflammatory effect and did not give corticosteroid pulses because there were no signs of intense systemic inflammation, and they acknowledge that the appropriate type and dose of corticosteroid are unknown [62]. On the day after initiation, consciousness, sucking and the skin lesions improved and the EEG trace became continuous; the MRI on day 19 showed no new lesions and the foci of diffusion restriction had decreased, and that of day 43 also showed no new lesions, but atrophy of the chronic lesions had increased [62]. Improvement of the acute phase did not prevent sequelae: at 6 months head control was incomplete and at 7 months West syndrome appeared, treated with adrenocorticotrophic hormone [62]. The evidence table of the PNDS summarises this outcome as cured encephalopathy, which does not correspond to the published follow-up [14, 62]. The authors also cite a 7-month-old infant with acute disseminated encephalomyelitis after Mycoplasma pneumoniae infection who improved with corticosteroids, and argue for repeating MRI with diffusion whenever neurological symptoms recur or worsen, in order to identify treatable acute lesions [62]. In the same table, Wolf and colleagues (2015) obtained a reduction in seizure activity with high-dose dexamethasone, and another report by Wolf (2005), of diffuse cortical necrosis presenting as encephalitis, controlled the seizures of a newborn with phenobarbital 10 mg/kg, lorazepam 0.1 mg/kg and fosphenytoin 20 mg/kg, loading doses without a maintenance dose or maximum stated in the compilation, combined with dexamethasone and then hydrocortisone [14]. As no IP source states the dose of methylprednisolone, the available reference is the US label of Solu-Medrol®, by extrapolation: in children, the initial dose ranges from 0.11 to 1.6 mg/kg/day, in three or four doses, not falling below 0.5 mg/kg per 24 hours; the high-dose regimen is 30 mg/kg intravenously over at least 30 minutes, which may be repeated every 4–6 hours for 48 hours and is generally not continued beyond 48–72 hours, and the administration of more than 0.5 g in less than 10 minutes has been associated with arrhythmias and cardiac arrest; formulations with benzyl alcohol as preservative are contraindicated in preterm infants, and benzyl alcohol toxicity is greater in newborns [75]. The switch to an oral corticosteroid may follow the regimen of Mohammad's case (prednisolone 2 mg/kg/day with weekly tapering over 4 weeks), which matches the initial dose of Tomotaki's case, where tapering was shorter [62, 74]. In Mohammad's case, a newborn with generalised clonic seizures on day 14, multifocal areas of diffusion restriction and eosinophilia of 7.0 × 10⁹/L received levetiracetam and oral prednisolone 2 mg/kg/day with weekly tapering over 4 weeks; she had no recurrence of seizures, serial EEGs were normal and at 8 months neurodevelopment was normal [74]. In that case, single-cell RNA sequencing showed broad immune activation, with interferon response genes, immunoglobulins and S100A8/A9, reversed after the corticosteroid, mainly in neutrophils and monocytes [74]. Li and colleagues reported a newborn with encephalopathy and small-vessel vasculopathy with petechial haemorrhages in whom the corticosteroid was only introduced later, because of hypsarrhythmia, with resolution [76]. The ICIP consensus cites a case of control of status epilepticus with oral prednisone and levetiracetam and reports of the use of infliximab [15]. Gillet and colleagues described a fulminant course, with status epilepticus, diffuse retinal ischaemia and cerebral palsy [77]. Systemic corticosteroids are therefore an off-label option supported by reports and by the European consensus, without a comparative trial; the infant without autoantibodies in Rosain's cohort who had critical COVID-19 at 2 weeks of age had received corticosteroids for IP in the first days, which reinforces the need for infection surveillance during corticosteroid therapy [40]. MRI should be repeated when neurological symptoms appear or worsen, in order to identify acute lesions [62].

Gene therapy, cited in the PNDS and in the European consensus as a proposal to attenuate severe cerebrovascular disease, has not progressed beyond the preclinical phase [14, 16]. It is an in vivo gene addition therapy directed at the cerebral endothelium, and not at the skin: Körbelin and colleagues selected, by in vivo screening of libraries of peptides displayed on the capsid of adeno-associated viruses (AAV), a capsid variant (AAV-BR1) with a highly specific and durable tropism for the endothelial cells of the cerebral microvasculature, and used it to deliver murine Nemo under the CAG promoter [78]. In heterozygous female Nemo−/+ mice, injected intravenously at birth (6 × 10¹⁰ genome particles per animal), the vector reduced «string vessels» (empty basement membranes without endothelial cells) on day 8 to the level of normal animals, decreased endothelial apoptosis, normalised albumin extravasation across the blood-brain barrier and was associated with greater body weight; in adult mice with conditional inactivation of Nemo in the cerebral endothelium, prior injection reduced string vessels and barrier permeability [78]. The groups contained 3 to 18 animals, the cutaneous mortality of the model between days 8 and 12 prevented assessment of the long-term effect in the heterozygous model, and the authors argue that sparing peripheral cells would avoid effects attributed to NEMO outside the CNS, such as the stimulation of atherosclerosis [78]. In the neonatal model, the vector was given on the day of birth, when string vessels were not yet increased, that is, before the vascular injury became established [78]. There are no human studies, no registered interventional trials and no clinical safety data [79].

7.5. Rehabilitation and neurological sequelae

Rehabilitation starts early: physiotherapy for motor deficit, speech and language therapy, occupational therapy, psychomotor therapy and orthoptics according to the deficit, with neuropsychological assessment of memory, executive functions, attention, visuospatial abilities, praxis, oral and written language, logical-mathematical reasoning and social cognition [16]. The difficulties with calculation and reading described in women without intellectual disability justify early neuropsychological assessment even in children with apparently normal development [63, 64]. Developmental stimulation and special educational support are indicated when needed [1].

The French PNDS adds rules of interpretation and organisation. Cognitive assessment is not reduced to the intelligence quotient; the reading of the results must take into account motor and visual comorbidities and the iatrogenic effect of antiepileptic drugs, and the results must always be explained to the patient and the family [14]. Early rehabilitation (physiotherapy, psychomotor therapy and, later, speech and language therapy) is organised by the paediatric neurologist, in early intervention structures or in private practice, and is maintained throughout life whenever necessary, centred on the person (cognitive remediation, re-education) or on the environment (educational and occupational adaptations, specialised guidance) [14]. Psychomotor therapy may begin in the first months in an infant who moves poorly, speech and language therapy from 2–3 years of age, and occupational therapy mainly at school age, when there is difficulty holding a pencil or writing, with support from computer-assisted learning [14]. Psychological support should always be offered, whatever the form of the disease, with attention to adolescence and to the aesthetic impact of dental agenesis, and the support of a classroom assistant is often indispensable in order to keep the child in mainstream education [14]. Coordination may be ensured by the attending physician or by the neurologist, with recourse to specialised hospital or medico-social teams in complex situations [14]. Table 7.3 summarises the scope of each professional.

Table 7.3 — Professionals involved in disability care and their respective scope

Source of table 7.3: [14].

7.6. Teeth

Oral rehabilitation follows the ages of the European consensus (table 11.1): early oral examination at 2–3 years; at 3–4 years, prosthesis or restoration of the primary teeth if agenesis interferes with feeding or speech and crown build-up of abnormal incisors; at 6 years, panoramic radiography and early dentofacial orthopaedics; at 7 years, restoration of conical lateral incisors; at 9–12 years, surveillance of eruption; at 12 years, pre-prosthetic and pre-implant orthodontics; at the end of growth, definitive implant-prosthetic rehabilitation [16]. Cone beam computed tomography (CBCT) is mandatory before implants, possibly with bone or mucogingival grafts, and dental autotransplantation is not recommended [16]. The French PNDS, which defines the same schedule, specifies that the prosthesis at 3–4 years is a removable paediatric prosthesis in cases of multiple agenesis, that rehabilitation in the adult requires a joint assessment by implantology, periodontology, dentofacial orthopaedics and prosthodontics, and refers to the 2010 HAS technical guide on implant-prosthetic treatment of adults with multiple dental agenesis linked to a rare disease [14]. The dental evidence it compiles comes from case reports: regular prevention every 6 months, preservation of the primary molars to replace absent premolars and a provisional prosthesis in the mixed dentition (Chen, 2017); maxillary expansion followed by fixed pre-prosthetic orthodontics in a 16-year-old adolescent (Doruk, 2003); success of fixed prostheses on implants in a series of 112 patients with oligodontia, among them 1 with IP, after a mean follow-up of 28 months (Worsaae, 2007); and dental assessment as early as possible, with greater attention from 3 years of age (Santa-Maria, 2017) [14]. GeneReviews allows dental implants from 7 years of age, as in the ectodermal dysplasias, and recommends speech and language therapy or a paediatric dietitian if the absence of deciduous teeth interferes with chewing or speech [1]. The difference in the age for implants (7 years in GeneReviews, end of growth in the European consensus for definitive rehabilitation) reflects the practice of each source and should be decided by the oral rehabilitation team.

7.7. Pulmonary hypertension, immunity and other complications

Neonatal pulmonary hypertension is treated according to the usual standards, with paediatric cardiology; the 2023 case was controlled with pulmonary antihypertensive and anti-inflammatory therapy, with no doses stated in the abstract [1, 65]. Rosain and colleagues recommend, as an authors' opinion and not as a guideline, testing for anti-type I IFN autoantibodies before live attenuated vaccines such as that against yellow fever, maintaining COVID-19 vaccination and annual influenza vaccination, and, in a patient with autoantibodies exposed to SARS-CoV-2, considering early IFN-β (which the autoantibodies spare), monoclonal antibodies, antivirals or recombinant IFN-λ [40]. In NEMO-NDAS associated with IP, TNF inhibitors gave partial responses (section 6.6) [34, 48]. The pituitary deficiency of the Portuguese case was treated with hormone replacement (section 10) [45].

7.8. Medicines used in incontinentia pigmenti

All the medicines in table 7.4 are used off-label in IP, except the hormone replacement of the Portuguese case, which has its own indication independent of IP. No guideline sets doses for IP: the French PNDS and the European consensus name the medicines without posology, and the doses stated are those of the cited reports (many compiled in the evidence table of the PNDS) and, for methylprednisolone, those of the US label, by extrapolation; they do not constitute a validated posology for IP [14–16, 39, 75].

Table 7.4 — Medicines: described use, reported dose and precautions

7.9. Regulatory status

Table 7.5 — Regulatory situation in the US and the EU

7.10. Available evidence: studies and series

There are no randomised trials or registered interventional trials in IP. On 17 October 2026, ClinicalTrials.gov had only observational studies: the French national cohort RaDiCo-FARD (NCT05954416, INSERM), which includes IP among nine rare skin diseases, with 900 planned participants and estimated primary completion in March 2027; a study completed in 2012 on the role of the pseudogene (NCT00976586, Taiwan, n=50); a study on placental transfer of anti-IFN-α autoantibodies, not specific to IP (NCT06371235); and a study of the prevalence of neurocutaneous syndromes in children (NCT07843823), with planned start in September 2026 [79]. The EU Clinical Trials Register was not searched. Table 7.6 summarises the observational studies on which the recommendations rest.

Table 7.6 — Reference observational studies

None of these studies has a randomised control group, none presents confidence intervals for the treatment effect, and outcomes are not comparable across series because staging criteria, age at presentation, extent of ischaemia and use of angiography differ [15, 39]. Absence of progression in a small series does not demonstrate efficacy, because the retinopathy may regress spontaneously and tertiary centre series select more severe patients [15, 17]. Cases of neurological corticosteroid therapy with a good outcome do not exclude publication bias or spontaneous improvement, and the optimal dose and duration have not been studied [16, 76]. Unfavourable results have also been published: recurrences after laser and anti-VEGF, necrotising enterocolitis after bevacizumab and tractional detachment after prophylactic ablation [39].

7.11. Developments in the last 12 months

Table 7.7 — Developments from October 2025 to October 2026

No new medicines, interventional trials, opinions or regulatory authorisations for IP were identified in this period [18, 79]. The therapeutic research lines described in the ICIP consensus are preclinical: induced pluripotent stem cell models with IKBKG inactivated by CRISPR-Cas9 and the exploration of early immunosuppressants, given the raised TNF-α in patients [15].

7.12. Agents to avoid, pregnancy, lactation, perioperative care and transition

Cosmetic laser of hyperpigmented lesions, topical tacrolimus in the newborn and opening of blisters should be avoided [1, 16]. According to Rosain, live attenuated vaccines should be preceded by testing for anti-type I IFN autoantibodies [40]. For anti-VEGF use in newborns, the 2026 review prefers ranibizumab to bevacizumab because of its lower systemic absorption [39]. There is no specific recommendation to avoid contact sports, but parents should be informed that head injury may precipitate detachment, especially before 7 years of age, and that any assessment of head injury should include a full eye examination [1].

Pregnancy generally proceeds without differences from the general population, with an increased risk of miscarriage due to loss of affected male fetuses, often around the 3rd or 4th month; pregnancy loss is managed according to the usual standards, and fertility is not otherwise compromised [1]. In women with retinal disease, GeneReviews suggests delivery management that minimises or eliminates labour, to reduce the risk of detachment [1]. In lactation, breast hypoplasia, nipple anomalies and lower milk production may hinder breastfeeding and justify early support [16]. Perioperatively, retinal examination under general anaesthesia should be coordinated with other procedures whenever possible in infants; the sources consulted do not describe anaesthetic risks specific to IP.

Transition from paediatric to adult care should be an intentional and coordinated process, with genetic counselling at that stage, therapeutic education programmes and maintenance of lifelong ophthalmological surveillance [15, 16]. The French PNDS defines it as a progressive process addressing the medical, psychosocial and educational needs of the adolescent in their social, cultural and economic context, recommends an annual visit at a reference centre until adulthood and directs families to the French portal "Transition Maladies Rares" (https://transitionmaladiesrares.com/), with transition tools and programmes [14]. The PNDS does not address anaesthesia, pregnancy or lactation beyond what concerns the breast, and does not include an emergency card [14].

7.13. Guidelines and divergences

Table 7.8 — Recommendations of guidelines and consensus statements

The two divergences with clinical impact are the systematic use of fluorescein angiography and the timing of laser. The European consensus requires clinical examination of the peripheral retina at diagnosis and reserves angiography under anaesthesia for patients with vasculopathy, whereas the ICIP consensus requires wide-field angiography in all patients, even with a normal examination, on the basis of the Danford series, in which angiography raised detection from 51% to 74% of patients [15–17]. The European consensus treats zones of non-perfusion with laser as soon as they are identified, and the ICIP consensus considers the data insufficient to treat stage 1, leaving the decision to the centre [15, 16]. The diagnostic criteria also diverge (section 5.1), including between the 2019 French PNDS and its 2020 European version [14, 16]. The remaining divergences of the PNDS have less impact but should be known. The PNDS dermatological schedule provides for six-monthly visits between 6 months and 5 years, whereas the 2020 article indicates annual visits in that period, and the article itself combines "three-monthly in the first year" with "monthly in the first 6 months" [14, 16]. The PNDS advises against topical and systemic antibiotics, which the Brazilian textbook mentions for the vesicular phase [14, 37]. The proportion of de novo cases is more than 50% (about two thirds in the genetics section) in the PNDS and more than 75% in the 2020 article [14, 16]. The PNDS care pathway table also brings together earlier ophthalmological schedules, one of which (Holmström, 2000) allowed surveillance to stop at 3 years in the absence of lesions, a position abandoned by the PNDS, the 2020 consensus and the ICIP, which maintain annual examinations throughout life (section 11.2) [14–16]. Dosages, absent from all guidelines, come from case reports and, for methylprednisolone, from the label, by extrapolation (table 7.4) [14, 75].

8. Reproductive Options and Family Counselling

8.1. Mode of inheritance and proportion of de novo cases

IP is transmitted in an X-linked dominant manner and is lethal in most male conceptuses [1]. The proportion of de novo cases depends on the cohort: 65% (59 of 91) of women with the recurrent deletion in the Fusco series (2009), 75.6% sporadic cases at the Italian reference centre, 55% (47 of 85) in the international Rosain cohort, more than 75% according to the European consensus, more than 50% (with 10–25% familial cases) and about two thirds according to the French PNDS, and 46.7% in the Danish cohort, where 53.3% had a positive family history [1, 13, 14, 16, 40, 58]. The Danish proportion of familial cases is double that reported in other series (about 25–30%), which the authors attribute to identification of relatives in the national registry [13]. De novo variants occur mainly on the paternal allele [1, 49].

8.2. Recurrence risks by scenario

Table 8.1 — Risks for offspring and siblings

In a couple in which the proband's mother meets criteria or has another affected first-degree relative, the mother is heterozygous [1]. When the variant is identified in the proband, the mother should be tested, because expressivity is variable and an adult may be unaware of the mild findings she had in childhood [1, 22]. The Oxford textbook recommends careful examination of the parents, especially the mother, because of the possibility of asymptomatic mosaicism [49]. The French PNDS lists what to look for in the mother: history of neonatal eruption, minimal skin lesions (scalp alopecia, hypochromic and atrophic macules in bands), subtle dental signs (conical teeth, talon cusps), ocular signs and miscarriages [14]. The presence in one parent of a benign predisposing allele (deletion in the pseudogene or MER67B duplication), found in 10–12% of the parents of patients, suggests a risk of generating the pathogenic deletion de novo, but the sources consulted do not quantify that risk [1, 50].

8.3. Cascade testing and at-risk relatives

Apparently asymptomatic at-risk relatives, older and younger, should be assessed in order to start ophthalmological surveillance early: by molecular testing when the familial variant is known and, otherwise, by examination of the skin, teeth, hair, nails and retina and by neurological assessment [1]. When the proband's variant has not been identified, X-inactivation studies may help identify carriers by skewing [1]. Other relatives are at risk only when one of the parents has the variant [1].

8.4. Prenatal diagnosis

Prenatal diagnosis by chorionic villus sampling or amniocentesis is possible when the familial variant is known, but it does not predict severity [1, 16]. Determination of the fetal karyotype guides the discussion (section 5.7) [1]. Ultrasound may show hydrops in affected male fetuses between 8 and 13 weeks, and losses generally occur in the first trimester or early second trimester [49]. In a 46,XY fetus with the at-risk haplotype, the ultrasound was normal at 10 weeks; fetal movements ceased about two weeks before the 20-week ultrasound, which showed fetal death with severe growth restriction [2]. Recurrent non-immune fetal hydrops in male fetuses, with negative NGS, should lead to testing for the deletion in both parents and careful examination of the mother [67].

8.5. Preimplantation genetic testing

Preimplantation genetic diagnosis of IP appeared on the list of monogenic conditions licensed by the UK Human Fertilisation and Embryology Authority (HFEA) [85]. The French PNDS confirms that preimplantation diagnosis is possible, by in vitro fertilisation with transfer of embryos without the maternal variant, and cites the method of single-cell co-amplification of Xq28 polymorphic markers for indirect diagnosis, described jointly for four loci of the same region (haemophilia A, X-linked adrenoleukodystrophy, X-linked hydrocephalus and IP) [14]. PGT-M is technically difficult: the pseudogene prevents direct analysis, the terminal location of the region limits informative markers and large deletions require indirect linkage analysis, which needs informative relatives [70]. In a 29-year-old woman with de novo IP (exon 4–10 deletion, mother negative), without informative relatives, two simultaneous trophectoderm biopsies of at least 4 embryos allowed the haplotypes to be built; after 2 antagonist stimulation cycles, intracytoplasmic sperm injection (ICSI) and PGT-M, 10 euploid embryos without the deletion were obtained [70]. A historical approach from 1996, which transferred only male embryos selected by FISH on the assumption that carriers would not survive, found 57% aneuploid embryos and ended in a miscarriage of a fetus with trisomy 9; it does not correspond to current practice [2].

8.6. Content of counselling

The diagnosis of IP in a newborn often leads to the diagnosis of the mother or other female relatives, and the emotional burden and sense of maternal responsibility should be anticipated [1]. The ideal time to assess risk and discuss prenatal or preimplantation diagnosis is before pregnancy, and counselling should be offered to affected, carrier or at-risk young adult women, including during transition to adult care [1, 16]. Counselling should explain phenotypic variability within the same family, the impossibility of predicting severity from the genotype, the risk of male pregnancy loss and the possibility of EDA-ID in the sons of mothers with hypomorphic variants [1, 2, 16]. Testing of at-risk minor girls has direct medical benefit, because it defines the need for retinal surveillance in the first years [1, 15]. Psychological support should be offered to all families, and DNA from probands without a molecular diagnosis should be stored [1, 16].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

Estimates of the frequency of IP differ by more than an order of magnitude because they measure different things: birth prevalence in congenital anomaly registries, point prevalence in the population, cases accumulated in the literature or incidence without a stated source. Table 9.1 brings together the values and their limitations.

Table 9.1 — Frequency estimates

The Danish cohort gives a birth prevalence about double the earlier European estimates, and the authors attribute the difference to active case validation and the inclusion of clinical databases in addition to the hospital registry [1, 13]. None of these estimates is a validated prevalence for the USA as a whole or for Europe as a whole, and there is no estimate of the prevalence of the EDA-ID phenotypes [9].

9.2. Sex distribution

The female:male ratio is about 20:1 according to Orphanet and the French PNDS; in the Danish cohort, 94.7% were women (a ratio of about 1:9 between men and women), and in Carney's compilation there were 593 women and 16 men [1, 2, 13, 14]. The men identified almost always have partial lesions suggestive of mosaicism [13].

9.3. Ancestry, founder populations and country data

The sources consulted do not describe founder variants or differences in frequency between populations; the recurrent deletion arises de novo by recombination at the locus in all populations studied, which explains its universal frequency [1, 35]. The Brazilian textbook asserts a 98% predominance in females "and in the white race", without a primary source, and this ethnic association is not corroborated by the multinational cohorts [37, 40]. The immunological cohort of Rosain included patients from France (65 patients from 51 families), Italy (22), Serbia (13), Belgium (7), Brazil (7 from 6 families), Japan (7), USA (6), Germany (2), Canada (1) and Switzerland (1) [40]. In Italy, the reference centre associated with the IPGB gathered 386 cases between 2000 and 2013 [1, 58]. In France, the national RaDiCo-FARD cohort includes IP [79]. Chinese series contribute part of the data on anti-VEGF and fetal hydrops [39, 67]. In Portugal, the sources consulted include the 2026 case of pituitary aplasia, described by teams from the Local Health Units of Lezíria, Oeste and São José; there are no Portuguese epidemiological data in the sources consulted [45]. In Brazil, in addition to the seven patients of the Rosain cohort, the 2021 textbook of genetic syndromes states that molecular testing was not accessible to most patients in its setting and cites case reports published in Brazilian dermatology and ophthalmology journals [37, 40]. The absence of data in these sources does not demonstrate the absence of published studies.

9.4. Special populations

Men with IP (47,XXY or mosaic) have a more severe neurological phenotype and require testing in tissues other than blood [1]. Undiagnosed adult women, identified through a daughter or repeated miscarriages, may have only subtle dental or skin signs and also need retinal examination, because of the risk of late rhegmatogenous detachment [1, 15]. Pregnant women with retinal disease need delivery planning (section 7.12) [1]. Children with neurological impairment need retinal examination under anaesthesia, because cooperation is limited and retinal severity is greater when there is CNS disease [17, 39].

9.5. Reference networks and patient associations

In Europe, ERN-Skin (European reference network for rare and complex skin diseases, 56 centres and 9 thematic groups) has an ectodermal dysplasia thematic group that includes IP, coordinated by Smail Hadj-Rabia and Holm Schneider [19]. The 2020 European consensus resulted from collaboration between two ERN-Skin healthcare providers, the French FIMARAD network and Italian centres [16]. The patient associations involved in the consensus were Incontinentia Pigmenti France (IPF) and I.P.ASS.I. Onlus (Incontinentia Pigmenti Associazione Italiana) [16, 20]. In the USA, the NFED maintains pages on IP and organised the 2025 international conference with Oregon Health & Science University [21, 29]. GeneReviews also mentions the Incontinentia Pigmenti International Foundation (IPIF), GARD, MedlinePlus and the IPGB, and the Oxford textbook the UK Ectodermal Dysplasia Society; the IPIF and I.P.ASS.I. websites did not respond on 17 October 2026 [1, 31]. The LOVD and IKBKGbase variant databases gather the variants of the locus [1, 36].

In France, IP has had a HAS PNDS since 2019, coordinated by Christine Bodemer at the MAGEC reference centre for rare skin diseases (Necker-Enfants Malades Hospital, Paris), with the FIMARAD network, and written with reference centres for ophthalmology (OPHTARA, Necker), rare oral and dental diseases (O-Rares, Strasbourg), rare malformations of the face and oral cavity (MAFACE, Rothschild Hospital) and rare diseases with psychiatric expression (GénoPSY, Bron), with the neurology and genetics departments of Necker and with the IPF association [14]. The protocol provides for an annual visit at the reference centre until adulthood and refers the less usual manifestations (for example cardiovascular) to that centre, so that the organ specialist decides together with the IP team [14]. Disability support relies on the French medico-social structures, summarised in table 9.2; the PNDS does not mention the long-term condition scheme (ALD) [14].

Table 9.2 — French organisation of care (HAS PNDS, 2019)

Source for table 9.2: [14]. The Incontinentia Pigmenti France association took part in drafting the protocol and is indicated as a contact for families [14, 20].

10. Illustrative Clinical Case

10.1. Incontinentia pigmenti with pituitary aplasia (Portugal, 2026)

Valério and colleagues, from teams of the Local Health Units of Lezíria (Santarém District Hospital), Oeste (Caldas da Rainha) and São José (Dona Estefânia Hospital, Lisbon), described in 2026 a girl with genetically confirmed IP and complete pituitary aplasia, followed for three years [45]. The family history included a termination of pregnancy for medical reasons at 16 weeks for fetal hydrops, with a 46,XY karyotype and an autopsy compatible with a non-specific multiple malformation syndrome, which the authors interpret as compatible with the male lethality of IP [45]. The patient's pregnancy was complicated by gestational diabetes in the first trimester, and the anomaly scan showed hyperechogenic bowel with dilated loops, without other structural anomalies. She was born at 37 weeks, by spontaneous vaginal delivery, weighing 3620 g (−0.79 standard deviation scores, SDS), with a length of 42 cm (−2.8 SDS) and head circumference of 32 cm (−0.9 SDS), classified by the authors as small for gestational age. On neonatal examination she had a narrow palate and subtle facial dysmorphism; on day 6, nasopharyngolaryngoscopy and computed tomography confirmed bilateral choanal hypoplasia, which improved with a short course of intranasal corticosteroid. Newborn metabolic screening and transfontanellar ultrasound were normal [45].

On day 11, erythematous macules appeared on the perineum that spread to the scalp, back and proximal thighs and progressed to vesicles (stage 1), then to infiltrated linear plaques (stage 2), hyperpigmentation along the lines of Blaschko (stage 3) and, finally, scarring lesions and linear alopecia (stage 4) [45]. Figure 1 of the article, photographed on day 15, shows vesicular lesions on the back and shoulder, with an isolated linear lesion progressing along a line of Blaschko; these lesions resolved with a topical corticosteroid alone (figure 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC13412604/figure/FIG1/) [45]. Genetic testing identified the heterozygous pathogenic IKBKG variant c.1178del p.(Pro393LeufsTer58); the article does not state the transcript, and the variant was confirmed in VariantValidator on the MANE transcript NM_001099857.5 (NC_000023.11:g.154564379del) [10, 45]. It lies in exon 10, next to the cytosine tract where the recurrent variants of that exon cluster [1, 3].

Because weight and height were always below the 3rd centile, she was referred to paediatric endocrinology at 4 years of age, weighing 12.5 kg (−2.07 SDS) with a height of 91.7 cm (−2.82 SDS) [45]. IGF-1 was 11.4 ng/mL (reference 53.0–216), corticotrophin (ACTH) 4.3 pg/mL (reference 7.2–63.3) and basal cortisol 2 μg/dL (reference 2.4–15), with normal thyroid function (TSH 1.21 mIU/L; free T4 1.14 ng/dL); bone age was delayed by more than 2 years by the Greulich-Pyle method. Daytime enuresis, initially attributed to the neurodevelopmental profile, was later recognised as central diabetes insipidus [45]. MRI showed pituitary aplasia, with absence of the adenohypophysis and neurohypophysis in the sella and a T1-hyperintense nodular focus on the floor of the hypothalamus, interpreted as an ectopic neurohypophysis (figure 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC13412604/figure/FIG2/) [45]. Growth hormone deficiency was diagnosed without a stimulation test, because the auxological criteria, the structural hypothalamic-pituitary defect and deficiency of at least one other pituitary hormone were met [45].

At 4 years and 7 months she started daily subcutaneous somatropin at 20–25.6 µg/kg/day, adjusted according to IGF-1 and growth velocity, and oral hydrocortisone at 9–11 mg/m²/day; oral desmopressin at 60–120 µg/day was started at 5 years and 6 months [45]. Over three years, IGF-1 normalised (262 ng/mL; reference 87.3–324), ACTH and cortisol rose to 7.4 pg/mL and 7.29 μg/dL, the height z-score went from −2.32 to −1.58 SDS and the body mass index z-score from −0.17 to +1.1 SDS, without adverse effects or worsening of the skin lesions (figure 3, growth chart with the start of each treatment: https://pmc.ncbi.nlm.nih.gov/articles/PMC13412604/figure/FIG3/) [45]. At 7 years and 7 months, psychomotor development, language and cognition were appropriate, ophthalmological assessments were normal, there were no seizures, and she remained under stomatological follow-up for hypoplasia of the molars of the left maxillary arch [45]. The figures were consulted through the legends in the full text of the article; the images were not viewed.

The case has three lessons. The first is that a history of miscarriage of a male fetus with hydrops is a retrospective clue to maternal or familial IP (the sources do not describe the clinical or genetic status of the mother) [45, 49]. The second is that subtle endocrine signs, such as enuresis, may be mistaken for neurodevelopmental problems [45]. The third is that somatropin, whose mediator IGF-1 stimulates keratinocyte proliferation, did not worsen quiescent skin disease over three years, an observation limited to one patient [45]. The authors propose a low threshold for assessing pituitary function in patients with IP and growth failure or signs of hormone deficiency; this proposal is based on a single case and is not part of the guidelines, and generalisation to asymptomatic patients has not been studied [16, 45].

10.2. Neonatal encephalopathy treated with corticosteroids (2025)

Mohammad and colleagues described a newborn girl with vesicles from day 3, with a typical stage 1 biopsy (dyskeratotic keratinocytes, lymphocytic and eosinophilic infiltrate), who on day 14 had generalised clonic seizures with bifrontal seizures on the EEG, controlled with levetiracetam [74]. MRI showed multifocal areas of restricted diffusion in the centrum semiovale, deep white matter, internal capsules, corpus callosum and frontal and occipital cortex, compatible with cytotoxic oedema; there was eosinophilia of 7.0 × 10⁹/L and raised transaminases (ALT 238, AST 792 and GGT 326 U/L), which normalised at 4 weeks and were attributed to idiopathic neonatal hepatitis [74]. She received oral prednisolone 2 mg/kg/day with weekly tapering over 4 weeks, and the retinal exudates were treated with laser photocoagulation and intravitreal ranibizumab on day 18 [74]. Genetic testing showed the recurrent exon 4–10 deletion, de novo. There was no recurrence of seizures, serial EEGs were normal and at 8 months neurological development was normal [74]. The corticosteroid therapy in this case follows the proposal of the European consensus, but the good outcome of one case does not demonstrate the effect of treatment [16].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Life expectancy is normal in people without significant neonatal or childhood complications [1]. Prognosis depends on the extracutaneous manifestations, mainly neurological and ophthalmological, which are decided in the first year: 88% of CNS problems manifest by the end of the first year, seizures in the first week of life indicate a worse neurodevelopmental prognosis, and patients without neonatal CNS changes usually have normal development, without new neurological symptoms in adolescence or adulthood [16, 22, 37]. Recurrent seizures and strokes later in childhood occur in about 10% [16]. Lethal forms result from extensive antenatal injury, status epilepticus or, rarely, pulmonary hypertension (four of six described cases died before 1 year of age) [16, 65]. In a Chinese series of 33 patients, one died of neurological complications [39].

In the eye, retinal detachment affected 22% of eyes in the Chen cohort and visual loss 12% of the Danish cohort; about 10% of patients progress to severe retinal scarring [13, 22, 39]. The visual prognosis of tractional detachment in infants is poor (one surgical success in seven eyes in the Chen cohort), and that of rhegmatogenous detachment in adolescents and adults is better [39]. Macular vascular remodelling and retinal thinning persist regardless of treatment, and late tractional detachments have been described in eyes treated with laser, which keeps the risk lifelong [15]. Dental anomalies are permanent and determine the need for rehabilitation until the end of growth [16]. Hyperpigmentation fades in the second or third decade, and stage 4 lesions and scarring alopecia persist [16, 22]. About 40% of women from 6 years of age have anti-type I IFN autoantibodies, with an increased risk of severe viral disease [40].

The separation between natural history and treated disease is imperfect: historical series, such as that of O'Doherty (6 of 22 eyes lost to detachment), predate systematic angiographic screening, and recent series with early laser describe stabilisation in most treated eyes, without a control group [2, 39].

11.2. Surveillance

The ophthalmological schedules of the sources diverge. The 2025 ICIP consensus is the most recent and the only one that requires wide-field angiography in all patients; the European consensus defines fixed dates for clinical examination in the first 2 years; GeneReviews keeps the earlier monthly, three-monthly and six-monthly schedule; the Brazilian textbook proposes monthly examination in the first two years and Smith's textbook monthly examinations in the first 2–3 months [1, 15, 16, 22, 37]. The 2019 French PNDS uses the same ophthalmological and neurological schedules as the European consensus and adds the six-monthly dermatological schedule until 5 years and an annual visit at a reference centre [14]. Its care pathway table brings together the earlier ophthalmological schedules, which show how practice has evolved: examination under general anaesthesia as soon as possible and, with a normal retina, six-monthly examination, or, with an abnormal retina at birth, angiography and fortnightly examinations for 3 months, monthly for 6 months and three-monthly for 1 year, with lifelong surveillance if there is a lesion (O'Doherty, 2011); annual examination throughout childhood (Wong, 2004); monthly examinations until 3–4 months, three-monthly until 1 year, six-monthly until 3 years and annually thereafter, with stopping allowed at 3 years in the absence of lesions (Holmström, 2000); and, in the French online treatise Thérapeutique Dermatologique (Morice-Picard, 2013), monthly dermatological and neurological examinations in the 1st year and six-monthly until 5 years, with monthly ophthalmological examination until 4 months, three-monthly until 1 year, six-monthly until 3 years and annually thereafter (Morice-Picard, 2013) [14]. Table 11.1 presents the recommendations with their source; where they diverge, the table records both.

Table 11.1 — Surveillance

12. Summary and Final Considerations

Incontinentia pigmenti is an X-linked dominant disease caused by loss-of-function variants in IKBKG, which encodes NEMO, the regulatory subunit of the IKK complex indispensable for NF-κB activation. In heterozygous women, cells expressing the mutant X die by TNF-dependent apoptosis and are progressively replaced, which produces extremely skewed X inactivation and a disease that evolves in phases; in hemizygous male conceptuses, the absence of NEMO is lethal, and the rare affected men have a 47,XXY karyotype or somatic mosaicism. The recurrent exon 4–10 deletion, generated de novo by recombination between MER67B repeats, mainly in paternal meiosis, is present in 65–82% of patients depending on the cohort, and the IKBKGP1 pseudogene makes a testing strategy that circumvents it mandatory, with long-range PCR as first line.

The diagnosis is clinical and rests on the four Blaschko-linear skin stages, the dental, hair and nail anomalies and the family history, with criteria that differ between the Minić system and the 2020 European consensus. The most recent validated birth prevalence is 2.37 per 100,000 live births in Denmark, about double the earlier European estimates. Prognosis is decided in the first year by vascular injury of the retina and the CNS: the retinopathy, present in up to three quarters of infants when fluorescein angiography is used, requires retinal examination in the first month after diagnosis, wide-field angiography in the following three months and lifelong surveillance, and neonatal ischaemic CNS injury, marked by seizures in the first weeks, is treated with antiseizure medicines and, according to the European consensus, with corticosteroids, without a comparative trial.

There is no targeted treatment or authorised medicine, and all pharmacological therapy is off-label; neither the French PNDS nor the European consensus sets doses, and the available dosages come from case reports. Gene therapy targeted at the cerebral endothelium remains limited to mouse models. Angiography-guided laser photocoagulation of non-perfused retina is the mainstay of treatment of proliferative retinopathy, with anti-VEGF as an adjunct; oral rehabilitation follows a schedule until the end of growth. The discovery of anti-type I IFN autoantibodies in about 40% of women and the description of hypopituitarism, pulmonary hypertension and NEMO-NDAS broaden the spectrum beyond the skin, teeth, eyes and brain. Counselling should explain the expected distribution of one third affected girls, one third unaffected girls and one third unaffected boys among the children of an affected woman, the risk of male pregnancy loss, the residual risk below 1% in simplex cases and the impossibility of predicting severity, and should be offered before pregnancy, with prenatal diagnosis or PGT-M when the variant is known.

13. References

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