Incontinentia Pigmenti: A Series of Six Cases with Isolated Cutaneous Involvement

Abstract

Incontinentia pigmenti (IP) is a rare multi-system genetic disorder mostly affecting females. It presents primarily with cutaneous lesions but is often associated with dental, ocular, neurological, musculoskeletal, and cardiovascular abnormalities. We report a series of one male and five female infants with IP having isolated cutaneous involvement at the time of presentation. In such cases, timely diagnosis of the condition, followed by systemic evaluation and long-term periodic follow-up, is imperative to detect and treat more serious systemic manifestations at an early stage.

Introduction

Incontinentia pigmenti (IP) is a rare genetic disorder with X-linked dominant inheritance. It is also called Bloch–Sulzberger disease after the dermatologists who first described it in 1926 and 1928.[1] It is caused by single-gene mutations involving the NEMO (Nuclear factor-κβ essential modulator) gene, which encodes a regulator protein for various cytokines and adhesion molecules. Disruption in this gene increases susceptibility of cells to cytokine-induced apoptosis. The disorder may affect multiple ectodermal and mesodermal organs, including the skin, teeth, eyes, musculoskeletal system, and central nervous system.[2] We report a series of six infants presenting with IP, solely affecting the skin.

Case Report

First case was a term newborn female of 13 days, born by cesarean delivery, presented with linear blisters on the limbs since birth. The child was fifth-born to non-consanguineous parents, with a 5-year-old female sibling with a history of similar lesions after birth. The mother gave a history of three previous spontaneous abortions. Neither of the parents were affected.

On examination, the baby had tense vesicles and pustules involving bilateral extremities and hyperpigmented coalescing macules on the trunk [Figure 1a]. The lesions showed a linear pattern, following the lines of Blaschko, especially on the lower limbs and trunk. There was no associated scarring. Nikolsky’s sign and Darier’s sign were negative. Hair, nails, and oral mucosa were normal. The child weighed 3 kgs and showed no apparent skeletal abnormality. Systemic examination findings were within normal limits. Physical evaluation of the elder child revealed a few linear hypopigmented macules on the upper extremities, epicanthic folds, a wide nasal bridge, hypodontia, and peg-shaped teeth [Figure 1b].

Figure 1.

Case 1 (a) Vesicobullous and pustular lesions arranged linearly on extremities (b) Hypodontia and peg-shaped teeth in patient’s elder sibling (c and d) Subsidence of vesicles and evolution into hyperpigmented lesions on both lower limbs

Complete hemogram of the patient was normal, except for eosinophilia. Tzanck smear did not show any multi-nucleated giant cells. Serological tests for herpes simplex virus (HSV), human immunodeficiency virus (HIV), and syphilis were negative. HIV and syphilitic serology of the mother were also non-reactive.

Based on the clinical findings, we arrived at the diagnosis of stage 1 IP. Detailed ophthalmologic evaluation, CT brain, and cardiac imaging did not reveal any extracutaneous findings. We advised supportive measures like skin care, avoidance of trauma, maintenance of nutrition, and appropriate antibiotics to treat secondary infection. After 2 months, a few lesions showed verrucous changes, while most vesicles subsided and gave rise to hyperpigmented macules along the same distribution [Figures 1c and d]. The baby is currently in her second year, and periodic systemic evaluation has not indicated any abnormalities to date.

A total of six cases, including the above-mentioned, are summarized in Table 1. Case 2 was a male infant, while the others were females. All cases presented with various stages of IP without any extra-cutaneous manifestations.

Table 1.

Summary of IP patients

	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6
Age at presentation	13 days	2 months	11 days	5 months	1.5 months	6 months
Age of onset	At birth	3 weeks	At birth	At birth	At birth	1 week
Gender	Female	Male	Female	Female	Female	Female
Parental consanguinity	Absent	Absent	Second degree	Absent	Absent	Absent
Family history	Similar complaints in elder sister at birth	NS#	NS#	NS#	NS#	NS#
Lesions at presentation	Linear vesicles and pustules on extremities; hyperpigmented lesions on trunk	Linear vesicles and a few hyperpigmented lesions distributed unilaterally on medial aspect of left leg from groin to ankle [Figure 2]	Linear vesicles and verrucous plaques on extremities; hyperpigmented patches on trunk [Figure 3a]	Hyperpigmented coalescing macules on trunk and extremities in blaschkoid pattern; few verrucous plaques on left popliteal fossa [Figure 4a]	Hyperpigmented macules on trunk and extremities in blaschkoid distribution [Figure 4b]	Linear hyperpigmented lesions on face, trunk and extremities [Figure 4c]
Initial lesions	Vesicles	Vesicles	Vesicles	Hyperkeratotic plaques	Vesicles	Vesicles
Extra-cutaneous manifestations	Absent	Absent	Absent	Absent	None	Absent
Diagnosis	Stage 1 (vesicular) IP	Stage 1 (vesicular) IP	Overlap of Stage 1 (vesicular) and stage 2 (verrucous) IP	Stage 3 (hyperpigmented) IP	Stage 3 (hyperpigmented) IP	Stage 3 (hyperpigmented) IP
Laboratory parameters	Eosinophilia	WNL§	WNL§	WNL§	WNL§	WNL§
Brain and cardiac imaging	NAD¶	NAD¶	NAD¶	NAD¶	NAD¶	NAD¶
Treatment	Supportive	Supportive	Supportive	Reassurance	Reassurance	Reassurance
Follow-up	At 2 years – all lesions evolved into linear hyperpigmented macules; no extracutaneous manifestations	At 5 months – vesicles subsided; hyperpigmented macules present	At 3 months – vesicles subsided and evolved into verrucous plaques [Figure 3b]	Did not come for follow-up	Did not come for follow-up	At 9 months – no new lesions; no systemic abnormality

^#NS=Not significant, WNL=^§Within normal limits, ^¶NAD=No abnormality detected, IP = Incontinentia Pigmenti

Figure 2.

Case 2: Linear vesicles and hyperpigmented streaks on left leg

Figure 3.

Case 3 (a) Multiple vesicles and pigmented hyperkeratotic plaques along Blaschko’s lines (b) Predominance of verrucous plaques with subsidence of vesicles after 2 months

Figure 4.

(a) Case 4: Coalescing hyperpigmented macules in blaschkoid distribution with a hyperkeratotic plaque on the left popliteal fossa (b) Case 5: Hyperpigmented lesions in S-shaped distribution on the lateral trunk (c) Case 6: Linear hyperpigmented lesions on lower extremities

Discussion

IP is a rare condition reported in approximately 1 in 40,000 neonates, almost exclusively affecting females (F:M = 37:1).[3] Mutations in the NEMO gene in males are usually associated with intrauterine death. Therefore, in our first case, the previous spontaneous abortions reported by the mother may have been affected male fetuses. Interestingly, one of the IP patients we encountered was a male presenting with mild cutaneous features. Survival of affected males, although extremely rare, has been reported in the literature and attributed to various causes, including chromosomal abnormalities such as Klinefelter’s syndrome (47, XXY) and somatic mosaicism.[1] Gupta et al. described two males aged 5 years and 20 days, presenting with a mild variant of the disease.[4] Similarly, the limited extent of disease in our patient may be indicative of a somatic mosaicism.

Although IP is a multi-system disease, it’s primary presentation usually occurs with cutaneous features. Skin lesions typically appear along developmental paths of cell migration called Blasckho’s lines and progress through four stages: vesicular, verrucous, hyperpigmentary, and hypopigmentary or atrophic.[3] The onset and duration of each stage vary among individuals, with considerable overlap between stages, or the absence of certain stages in the sequence.[1,3] The vesicular stage may begin in-utero, at birth, or within the first 2 weeks and last for up to 18 months. The hyperpigmented stage is the most frequently encountered stage, seen in 98% of patients, appearing as linear or whorled brownish streaks in bizarre, splashed, or Chinese figure patterns. The fourth stage of hypopigmentation usually develops in adolescence or adulthood.[3] Our patients presented with lesions of the first three stages, with most of them showing verrucous plaques concurrently with vesicular or hyperpigmented lesions. Other cutaneous features such as port wine stain, palmoplantar hyperhidrosis, and hair and nail abnormalities have been described in IP patients previously, although none were noted in our patients.

Extracutaneous manifestations have been widely reported in IP, affecting about 70–80% of patients.[5] Dental abnormalities like delayed dentition, hypodontia, and abnormally shaped or peg-shaped teeth are the most commonly reported associations.[2,4,5] Ocular defects like strabismus, cataract, nystagmus, uveitis, retinal dysfunction, optic nerve atrophy, and blindness have been described in almost 40% of patients.[3] 30–50% of infants may present with neurological symptoms, including seizures, spastic paralysis, developmental delays, and mental retardation.[3,5] Musculoskeletal and cardiac anomalies have also been described.[3] Although none of our patients showed any systemic involvement on detailed evaluation, it should be noted that all the cases presented in infancy, when dental, ocular, or neurological defects may not be apparent. Thus, periodic follow-up with dermatology, pediatrics, dentistry, ophthalmology, and neurology is crucial in all cases.

It is essential to differentiate early vesicular lesions from congenital syphilis, neonatal herpes, and varicella through appropriate investigations. Eosinophilia is a feature of the early inflammatory stage.[3] Reassurance, along with supportive measures in the form of skin care, maintenance of hygiene, and nutrition are the mainstay of treatment. Additionally, antibiotics may be added in the presence of a secondary infection. Genetic counseling and educating parents regarding the disease prognosis and necessity of regular follow-up until adolescence is an important aspect of management.[3]

Conclusion

IP is a multi-system disorder commonly presenting with cutaneous symptoms, for which the patient initially reports to dermatologists. Our report emphasizes that this multi-system disease may sometimes manifest with skin lesions alone. However, teeth, eye, neurological, musculoskeletal, and cardiac involvement, when present, may have serious implications and should be investigated in all patients. Therefore, apart from managing the cutaneous manifestations, dermatologists play a pivotal role in the timely diagnosis of the condition, so as to advise multi-disciplinary evaluation and early treatment initiation for associated extracutaneous abnormalities.

Declaration of patient consent

The parents/caregivers of all patients described in this manuscript have given written informed consent to the publication of their case details and photographs.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.