What is Incontinentia Pigmenti?

History
Cause and symptoms
Genetics
Epidemiology
Case series
Diagnosis and treatment
References

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Incontinentia pigmenti (IP) is a rare multisystemic condition with characteristic skin lesions. Also known as Bloch-Sulzberger syndrome, it affects different sites of the body, including the skin, eyes, hair, teeth, nails, and central nervous system.

The existence of neurological and/or visual impairment influences the severity of the disease. IP is an X-linked dominant disorder that primarily develops at birth or during early childhood.

Incontinentia pigmenti can develop due to mutations in the IKBKG or the NEMO gene. It mostly affects women; however, there have been accounts of males being affected as well.

History

Garrod was the first to describe IP in the literature in 1906. He described a girl who had normal pigmentary alterations, along with mental impairment and tetraplegia.

In 1964, Kuster and Olbing documented a mentally disabled woman with imperfect dentition and a history of congenital skin rashes. She was the mother of one son and eleven daughters. Six of the girls had incontinentia pigmenti and imperfect dentition.

In 1987, Spallone investigated 7 affected members of a family that had a total of 14 affected members across three generations. In the family, there were numerous miscarriages, several of which were identified as male. The most common ocular ailments, according to Spallone, were vascular abnormalities of the retina and diseases of the retinal pigment epithelium.

Finally, in 1993, Landy and Donnai published a comprehensive assessment of the disorder. They pointed out that dermatologic traits often appear in four phases, albeit not all stages may occur at the same time, and some stages may overlap.

Cause and symptoms

IP is caused by a mutation in the NEMO (Nuclear Factor B, Essential Modulator) and IKBKG (Inhibitor of Kappa polypeptide gene enhancer in B-cells, Kinase Gamma) genes on the X-chromosome.

Skin lesions, ocular abnormalities, abnormalities of the central nervous system, and dental deformities are characteristic clinical manifestations of incontinentia pigmenti. The main feature is that the skin lesions begin as vesiculobullous lesions and proceed through four phases to whorl-like pigmentary lesions.

An erythematous blistering rash appears at birth or within the first six weeks of life in stage I, followed by hyperkeratotic verrucous papules and plaques in stage II. Hyperpigmented whorls characterize Stage III, which is most noticeable from the first weeks of life through puberty.

Hypopigmented lines and the absence of skin appendages such as hair follicles and sweat glands characterize Stage IV, which typically appears on the lower limbs in early adulthood. Stage III and IV cutaneous signs might be mild, and they can go unnoticed.

IP also comprises vascular occlusion, foveal anomalies, neovascularization, hemorrhages, and exudative and tractional detachments, which occur primarily in the retina. Neurological signs are observed in 30% of IP patients, and they are one of the leading causes of morbidity and mortality.

Seizures, acute disseminated encephalomyelitis, infantile encephalopathy, and ischemic stroke were among the clinical manifestations identified. Changes in the teeth and hair are other common pathologic changes.

Genetics

Recurrent deletion of exons 4–10 of the IKBKG/NEMO gene is found in the majority of cases. There have also been reports of non-recurrent genomic rearrangements in the IP locus and point mutations in the IKBKG/NEMO coding area.

The regulatory subunit of the Inhibitor of the kappaB (IkB) Kinase (IKK) complex, NEMO/IKK, is necessary for the canonical NF-kB pathway activation, which is implicated in many key physiological and pathological processes. The majority of IP female patients have a skewed X-inactivation.

Since the absence of the NEMO/IKK protein makes IP cells more susceptible to apoptosis, the X-chromosome-related IKBKG/NEMO mutation creates an imbalanced X-inactivation in female IP patients, as it does in other X-linked disorders. The extensive apoptosis in males is accountable for their early embryonic death. Male patients with IP have been recorded on occasion.

Epidemiology

The birth prevalence of IP is estimated to be 1 in 143,000. IP has a birth rate of 1.2 per 100,000 in Europe, according to Orphanet. This X-linked dominant syndrome mostly affects women, but there have been cases of males being affected as well. It has been shown that it is frequently fatal in males.

Geographically, the gender distribution may differ, with certain East Asian locations reporting a larger number of male IP patients. White people appear to be more affected than people of other races.

Case series

Hubner et al., 2022 conducted a multicenter case series investigation with 30 individuals with incontinentia pigmenti at three European dermatology departments. Twenty patients were assessed clinically and genetically, while the remaining 10 were assessed simply genetically.

With a median age of three years, the study included 28 females and two men. All 20 patients with clinical information had cutaneous symptoms. Ninety percent of the patients were found to be in Stage I.

Stage IV was found to affect patients as young as one year old. Dental, hair, and neurological anomalies were all more common than previously thought. In 14 of the 24 patients, genetic testing found the common exon 4–10 loss, as well as seven other harmful variations, including three previously unknown mutations.

In three more cases, no genetic changes were discovered. The phenotype in this investigation ranged from little cutaneous involvement to severe multisystemic diseases. 

Diagnosis and treatment

IP is diagnosed clinically by the presence of four distinct lesions that appear in four stages, each of which overlaps. A variety of extracutaneous defects have been offered as minor criteria for the diagnosis of IP, in addition to cutaneous criteria.

IP has a wide spectrum of phenotypic manifestations, ranging from minor findings like hair whorls and mild nail dystrophy to severe manifestations like optic nerve atrophy, seizures, and global developmental delay.

If clinical symptoms are ambiguous, identification of a heterozygous IKBKG pathogenic mutation in a female proband or a hemizygous IKBKG pathogenic variant in a male proband validates the diagnosis.

There is no cure for IP because it has a genetic basis, and therapy is restricted to symptom management. Affected children who do not have serious difficulties during infancy have a normal life expectancy. Dermatological, genetic, ophthalmological, neurological, and dental consultations should be sought due to the complex nature of the condition.

Developmental therapy may be required. To avoid infection or severe scarring, skin lesions should be treated symptomatically. There are presently no genetic therapies available for IP.

IP is still a clinical diagnosis that should be confirmed by standard histology and genetic testing, especially in situations where the diagnosis is ambiguous or mildly impacted. Extracutaneous involvement should be assessed at the time of diagnosis and at regular intervals, as some symptoms may develop over time.

References

• Hübner S, Schwieger-Briel A, Technau-Hafsi K, et al. (2022). Phenotypic and genetic spectrum of incontinentia pigmenti – a large case series. Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology: JDDG, 20(1), 35–43. doi:10.1111/ddg.14638
• Wang R, Lara-Corrales I, Kannu, P, et al. (2019). Unraveling incontinentia pigmenti: A comparison of phenotype and genotype variants. Journal of the American Academy of Dermatology, 81(5), 1142–1149. doi:10.1016/j.jaad.2019.01.093
• Swinney CC, Han DP, & Karth PA (2015). Incontinentia Pigmenti: A Comprehensive Review and Update. Ophthalmic Surgery, Lasers & Imaging Retina, 46(6), 650–657. doi:10.3928/23258160-20150610-09
• Fusco F, Paciolla M, Conte MI, et al. (2014). Incontinentia pigmenti: report on data from 2000 to 2013. Orphanet Journal of Rare Diseases, 9, 93. doi:10.1186/1750-1172-9-93
• Poziomczyk CS, Recuero JK, Bringhenti L, et al. (2014). Incontinentia pigmenti. Anais Brasileiros de Dermatologia, 89, 26-36. doi:10.1590/abd1806-4841.20142584
• Minić, S., Trpinac, D., & Obradović, M. (2014). Incontinentia pigmenti diagnostic criteria update. Clinical Genetics, 85(6), 536–542. doi:10.1111/cge.12223
• Meuwissen ME, & Mancini GM (2012). Neurological findings in incontinentia pigmenti; a review. European Journal of Medical Genetics, 55(5), 323–331. doi:10.1016/j.ejmg.2012.04.007
• Scheuerle AE, & Ursini MV (1999). Incontinentia Pigmenti. In M. P. Adam (Eds.) et. al., GeneReviews®. University of Washington, Seattle. https://europepmc.org/article/NBK/nbk1472#free-full-text
• INCONTINENTIA PIGMENTI; IP. [Online] OMIM. Available at: https://omim.org/entry/308300

Further Reading