Incontinentia pigmenti (IP) is an infrequent genodermatosis with an X-linked dominant pattern of inheritance and a penetrance of 100%. It affects tissues that develop from the endoderm, causing abnormalities in the skin, hair, teeth, eyes and nervous system.1

It was first described in a patient by Garrod in 1906, and its incidence is estimated at approximately 1 in 40000–50000 births, although the exact prevalence is not known, as it remains an underdiagnosed disease.1,2

The onset usually manifests at the level of the skin in the first 2 weeks post birth, and more than 95% of cases occur in female patients.1 There are four cutaneous stages of IP: stage 1 (vesicular); stage 2 (hyperkeratotic); stage 3 (hyperpigmented); and stage 4 (hypopigmented).3 The timing and duration of each stage vary between individuals, and some stages may overlap or even not occur in some cases.4

The mutation responsible for the disease is in the IKBKG gene (previously known as NEMO), located on locus Xq28. This gene encodes a protein (IKK-gamma or NEMO) that activates transcription factor nuclear-kappa B (NF-kB), which in turn regulates the immune response, the inflammatory cascade and mechanisms of cell apoptosis. In 80–90% of cases, the mutation involves deletion of exons 4–10 of the IKBKG gene, while the rest are due to other genetic changes (missense, nonsense or frameshift mutations, microdeletions, etc.) identified by means of DNA sequencing.2,5

This syndrome is lethal in the male sex except in special situations, such as mosaicism, Klinefelter syndrome (XXY karyotype) or hypomorphic mutations in the IKBKG gene.6

In 1993, Landy and Donnai were the first to propose a series of diagnostic criteria for IP, which were later updated by Minić et al. with the inclusion of molecular genetic testing (Table 1).7,8

Due to the general ignorance of this disease, many mild cases are unnoticed and affected individuals reach adulthood without being diagnosed, which facilitates transmission to the disease to the offspring. In addition, in some cases a diagnosis is made but screening and follow-up of potential associated cutaneous and non-cutaneous abnormalities is not performed. In Spain, other authors have published case series of IP, but usually including fewer patients and with a less thorough evaluation of the disease.4,6,9–11

The primary objective of our study was to provide the most detailed possible review of the clinical manifestations of cases of IP diagnosed during childhood in 2 Spanish hospitals and to compare these data with the findings published in the international literature. Our aim was to increase the level of clinical suspicion of health care providers to achieve earlier diagnosis of the disease and promote the coordination of a multidisciplinary follow-up plan for these patients.

We included patients that received a diagnosis of IP during childhood based on genetic testing and/or the clinical criteria modified by Minić et al.7 in the Department of Dermatology of the Hospital Costa del Sol (Marbella) or the Hospital Regional Universitario Materno Infantil (Malaga) between 2004 and 2018. We conducted a retrospective cross-sectional study with collection of clinical, laboratory, radiological and genetic data for each patient from the time of the initial suspicion of IP to the latest follow-up appointment (December 2018): age at onset of typical skin lesions and their evolution, other potential dermatological abnormalities in skin, hair, teeth or nails, complete blood count, molecular genetic tests, histological findings (skin biopsy), neuroimaging tests and neurologic manifestations.

Clinical suspicion of IP was always based on the presence of skin lesions, which were the initial symptom and developed in the neonatal period in every case. This led to histologic examination and genetic testing in most cases, with the diagnosis of IP made based on the criteria mentioned above.7

The study was designed and coordinated by the Departments of Dermatology and Paediatric Neurology with involvement of outpatient and inpatient levels of care, and patients underwent a multidisciplinary evaluation (neonatology, dermatology, paediatric neurology, radiology, ophthalmology and genetics). We received informed consent from the parents prior to the performance of procedures and the collection of data for the study.

We included a total of 13 patients with an IP diagnosis, all of them female. The clinical follow-up of all patients lasted through December 2018, except for patients 3 and 6, who were lost to follow-up.

Eight of the patients underwent evaluation in the Department of Dermatology in the first 30 days post birth, and the remaining 5 before age 1 year. All patients experienced the onset of cutaneous manifestations during the neonatal period. All had onset with vesicular lesions along the Blaschko's lines, overlapping in 2 cases with lesions in the hyperpigmented stage (case 3) and verrucous stage (case 9).

The evolution of skin lesions was varied, with stages alternating and overlapping in time, and in some cases without manifestation of some stage (Fig. 1).

Figure 1.

Stages of skin involvement. (A) Vesicular (case 4). (B) Verrucous (case 5). (C) Hyperpigmented (case 4). (D) Hypopigmented (case 1).

(0.07MB).

Patients that exhibited more severe inflammatory activity received topical treatment of the cutaneous lesions consisting of corticosteroids in 4 patients (cases 1, 2, 9 and 10) and steroids combined with fusidic acid in 1 patient (case 5), all of who exhibited a good response (Table 2).

Noncutaneous dermatologic abnormalities resulting from IP (in hair and nails) only occurred in 3 of the patients (Table 2).

Neuroimaging tests, including cranial ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) scans, were performed in all patients and revealed involvement of the brain in 6 patients, associated with clinical manifestations in only 3. In 2 of the patients, the initial cranial ultrasound did not detect any abnormalities (cases 4 and 10), but a subsequent cranial MRI scan did.

Three patients exhibited CNS involvement in the form of convulsive seizures. These same patients experienced psychomotor retardation, while the rest of the patients did not (Table 3).

The ophthalmological follow-up detected abnormalities in 5 cases, all involving the retina, and associated with preterm birth in 1 case (Table 3).

Dental abnormalities occurred in 7 of the 11 patients that remained in follow-up (in cases 3 and 6, patients were lost to follow-up before tooth eruption), and included abnormalities in the number or morphology of the teeth and delays in tooth eruption (Table 3 and Fig. 2).

Figure 2.

Conical teeth (case 11).

(0.05MB).

Laboratory tests detected significant abnormalities in blood (eosinophilia), with no other relevant findings in 4 of the patients (cases 1, 2, 3 and 6) (Table 3).

Eleven patients underwent molecular genetic testing of peripheral blood samples, which detected deletions in exons 4–10 of the IKBKG gene in 8 cases (targeted PCR amplification to identify deletions in exons 4–10), no changes in this gene in 1 patient (case 7) and the pathogenic variant p.Gln268Ter (c.802C>T) of the IKBKG gene in the heterozygous state in 2 patients (cases 12 and 13).

The first molecular test performed in case 13 (analysis of deletions in exons 4–10 by means of long-range PCR) did not find any changes. For this reason, the IKBKG gene was sequenced (Sanger sequencing of coding regions and spicing sites of the IKBKG gene for subsequent comparison with the reference sequence NM_003639.3), which led to detection of the pathogenic variant p.Gln268Ter (c.802C>T), which produces a premature stop codon and therefore a truncated protein that may not be functional and causing the disease.

Cases 12 and 13 corresponded to patients born after in vitro fertilization of a donor egg in the same fertility clinic. This fact arose suspicion that both eggs could have come from the same donor, for which reason genetic testing in case 12 was aimed from the beginning to ruling out the pathogenic variant p.Gln268Ter (c.802C>T).

In case 7, due to a clinical presentation compatible with mosaicism (lesions restricted to a single portion of the body) and a negative result of molecular testing of blood samples (IKBKG sequencing after amplification PCR of coding exons and splicing sites and comparison with reference sequence NM_003639.3, and deletion and insertion analysis by means of Multiplex Ligation-dependent Probe Amplification [MLPA] assay), genetic testing of a skin biopsy sample was attempted, but could not be performed due to technical difficulties.

The mean age at the time of molecular genetic testing was 8 months. A skin biopsy sample was collected in 8 patients, always in the first 30 days from birth, with features compatible with IP (eosinophilic spongiosis) in all cases (Table 2).

The mothers of 9 patients underwent genetic testing, with detection of the same mutation found in the index case in 7. The other 2 mothers had a clinical diagnosis of IP and reported that the results of genetic testing (performed in a different laboratory outside Spain) were compatible with the disease, but did not produce the corresponding reports.

Our study includes a series of cases of IP for which we collected all the available data on the clinical course of the patients, including photographic, genetic and laboratory evidence. It evinced the considerable variation in the documented clinical manifestations associated with IP in different organs and systems.

Mutations in the IKBKG gene consisting of deletions in exons 4–10 were found in most of the cases under study, in agreement with the previous literature (80–90%).1,2 In our case series, sequencing of the IKBKG gene led to the identification of a novel mutation not described to date (pathogenic variant p.Gln268Ter [c.802C>T]). This underscores the importance of sequencing this gene in every case in which targeted analysis of deletions in exons 4–10 turns out to be negative.

Within our case series, we ought to highlight the presence of 1 case of somatic mosaicism (case 7). In these cases, if genetic testing of blood samples with sequencing of the entire IKBKG gene (including deletion and insertion analysis using MLPA) gives negative results, performance of genetic testing in samples of skin affected by the disease is recommended.12

Since this disease is lethal in males, it should be suspected in mothers with recurrent miscarriage of male foetuses, a history that was present in the mothers of some of the patients in our series.6,8,13

Due to the X-linked dominant pattern of inheritance of IP, genetic testing of the mother is recommended if the mother has not been evaluated in the past. However, it is important to take into account that 65% of IP cases result from de novo mutations.2 The percentage in our series was lower, as de novo mutations only occurred in 2 of the patients under study (18%, cases 4 and 9).

In agreement with previous studies, blistering (vesicular stage) was the first cutaneous manifestation to develop in all cases at onset in the neonatal period, in some cases overlapping with other stages.2,12

Outbreaks of skin lesions may develop without an apparent cause, but in some instances may be associated to intercurrent infection, as occurred in one of our patients.

Only 2 patients in the case series had hair anomalies (15.3%, cases 4 and 5) in the form of cicatricial alopecia and thinning hair on the scalp, a proportion that was lower compared to previous studies (>50%)1–3,14 (Fig. 3).

Figure 3.

Cutaneous involvement in scalp with alopecic plaque (case 5).

(0.07MB).

Nail lesions may affect between 7% and 40% of patients with IP and develop between ages 3 and 45 years (mean, 26 years).1,3,7 In our study they only occurred in 1 patient (7%, case 5); however, these are abnormalities that develop with age, so monitoring for their future development must continue. In some cases, at later ages, patients may develop painful keratotic subungual or periungual tumours that cause pain or deformities caused by osteolysis of the underlying phalanxes, and, in very rare cases, subungual squamous cell carcinoma.1,3,7,12

Central nervous system (CNS) manifestations occur in 30–50% of patients with IP, with development of heterogeneous lesions in the brain (infarction or involvement of white or grey matter at different levels). Although their pathogenesis has not been fully elucidated, it appears to be related to vasculopathy in the brain resulting from the inflammatory activity associated with the disease.1,2,9,15 Our findings were consistent with the previous literature, as some form of CNS abnormality was detected in 50% of patients evaluated by means of diffusion-weighted MRI of the head.

Cranial ultrasonography can be used for initial assessment in the neonatal period, although MRI can contribute more information, especially using the diffusion-weighted imaging mode.2,15

In some cases, the initial cranial ultrasound may be normal, but subsequent cranial MRI scans may reveal the presence of lesions, as was the case of 2 patients in our study (cases 4 and 10). This may suggest that the lesions developed sometime between performance of the ultrasound scan and performance of the MRI scan, false negatives of ultrasound examination due to technique limitations or incorrect interpretation, or to the higher sensitivity of MRI compared to ultrasonography. On the other hand, we ought to highlight that ultrasound detected signs of vascular calcification in case 1, whereas the subsequent cranial MRI scan was normal. These findings suggest that transfontanellar ultrasound may not suffice for neurologic assessment of patients with IP, and that a cranial MRI scan should be performed as early as possible. Some studies recommend performance of magnetic resonance angiography for a more accurate assessment of the degree of vasculopathy.15,16

Neurologic changes manifest in the form of seizures, intellectual disability, motor impairment (paresis/spastic paralysis) or microcephaly.1,2,9,10,15 In the neonatal period, the clinical presentation of CNS involvement usually consists of seizures or altered level of consciousness.15

In our series, only 3 patients experienced seizures (cases 3, 5 and 10), and they were the same patients that developed other neurologic abnormalities (hemiparesis in 2 and psychomotor development in 1).

We only found an association between imaging tests and neurologic manifestations in 2 cases (3 and 10); the rest of the girls with abnormal findings in imaging tests were clinically asymptomatic. However, these patients are still young, so it is important that we continue to monitor their neurodevelopment to further clarify this finding.

Eye anomalies occur in approximately 20–35% of patients with IP (wide range depending on the study: 16–77%),1,7 and are frequently associated with neurologic changes, with blindness in 7% of patients. It is believed that the mechanisms underlying the damage to the retina involve tissue ischaemia resulting from vaso-occlusive events.1,2,17

Our study identified some form of eye anomaly associated with IP in 4 cases (30%), and neurologic abnormalities in only 1 patient (case 10). Most of the patients with retinal involvement required laser treatment, and 1 required surgery for a unilateral detached retina and eventually enucleation of the eye. It is particularly important to be careful in the diagnosis of retinopathy of prematurity, as occurred in case 5, as it may be confused with anomalous development of retinal vessels.14 Our patients did not exhibit nonretinal eye anomalies associated with IP (strabismus, optic nerve atrophy, ptosis, iris hypoplasia, conjunctival pigmented lesions, microphthalmia, vortex keratitis, cataracts, nystagmus and uveitis).1,14

Dental abnormalities occur in 50–80% of affected individuals, most frequently peg teeth, followed by hypodontia, tooth agenesis, delayed tooth emergence and loss of teeth.1,11 Our findings were consistent with this (abnormalities found in 63% of patients that underwent a dental evaluation). There are other abnormalities of the oral cavity associated with IP, most frequently cleft palate and high-arched palate, although dental malocclusion and facial asymmetry can also occur (Fig. 2).1,2,11

Breast anomalies have been described in 11–30% of patients with IP, most frequently supernumerary nipples, but also possibly hypoplasia or aplasia.3,7,12 In our series, breast anomalies only happened in 1 patient that had a supernumerary nipple (case 2).

Another finding associated with IP is leucocytosis with eosinophilia, especially during stages 1 and 2.7,12,17 Our retrospective review of cases revealed eosinophilia in 4, in every case in the neonatal period and in most cases during stages 1 or 2. This test was performed when patients required it for conditions other than IP (risk of infection in neonatal period, infectious disease, etc.).

Different studies have described patients with IP with autoimmune disorders, immunodeficiencies and malignancies, which is related to the modulator role of NF-kB.3,18,19

The patients in our series did not exhibit any such comorbidities; however, it is necessary to continue the follow-up to watch for their potential development.

Our study was limited by the loss to follow-up of several patients who moved to other cities or did not return to the clinic for follow-up; another limitation is the young age of the patients, which did not allow us to obtain information on abnormalities that develop through the years.

We found that diagnosis of IP occurred earlier in the cases detected in the past 5 years, probably due to an increased knowledge of the disease. It is important to establish a comprehensive follow-up plan covering the lifespan of the patient, including preconception and prenatal genetic counselling.16 The purpose of such a plan is to detect the signs and disorders associated with IP to prescribe targeted treatment as soon as possible and prevent complication, especially those involving the CNS and eyes, which are determinants of the prognosis of IP.2,10,20

In conclusion, we present the most detailed study published to date on the subject of IP in Spain, with findings similar to those of larger case series published in the international literature, which highlights the importance of providers being aware of this disease and of carrying out a multidisciplinary evaluation and follow-up.

The authors have no conflicts of interest to declare.