Importance of extracutaneous organ involvement in determining the clinical severity and prognosis of incontinentia pigmenti caused by mutations in the IKBKG gene.

Incontinentia pigmenti (IP) is a rare X-linked skin disease caused by mutations in the IKBKG gene, which is required for activation of the nuclear factor-kappa B signalling pathway. Multiple systems can be affected with highly variable phenotypic expressivity. We aimed to clarify the clinical characteristics observed in molecularly confirmed Korean IP patients. The medical records of 25 females confirmed as IP by molecular genetic analysis were retrospectively reviewed. The phenotypic score of extracutaneous manifestations was calculated to assess the disease severity. The IKBKG gene partial deletion or intragenic mutations were investigated using long-range PCR, multiplex ligation-dependent probe amplification and direct sequencing methods. Among the 25 individuals, 18 (72%) were sporadic cases. All patients showed typical skin manifestations at birth or during the neonatal period. Extracutaneous findings were noted in 17 (68%) patients; ocular manifestations (28%), neurological abnormalities (28%), hair abnormalities (20%), dental anomalies (12%), nail dystrophy (8%). The common exon 4-10 IKBKG deletion was observed in 20 (80%) patients. In addition, five intragenic sequence variants were identified, including three novel variants. The phenotype scores were highly variable, ranging from abnormal skin pigmentation only to one or more extracutaneous features, although no significant difference was observed for each clinical characteristic between the group with sequence variants and that with common large deletion. Our cohort with IP showed heterogeneity of extracutaneous manifestations and high incidence of sporadic cases. Long-term monitoring with multidisciplinary management is essential for evaluating the clinical status, providing adequate genetic counselling and understanding the genotype-phenotype correlation in IP.

Optical Coherence Tomography Angiography and Ultra-Widefield Optical Coherence Tomography in a Child With Incontinentia Pigmenti.

Incontinentia pigmenti (IP) is a rare X-linked dominant disorder that can cause retinal nonperfusion, neovascularization, and retinal detachment. Evaluation of the peripheral retinal vasculature and appropriate treatment can reduce the risk of blindness. The authors report the use of a handheld prototype optical coherence tomography angiography (OCTA) and ultra-widefield OCT (UWF-OCT) during exam under anesthesia of a 2-year-old with a history of severe early onset IP. UWF-OCT and OCTA may be used as noninvasive imaging modalities for IP and similar retinal vascular disorders in supine young children. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:273-275.].

Incontinentia Pigmenti: A Summary Review of This Rare Ectodermal Dysplasia With Neurologic Manifestations, Including Treatment Protocols.

Incontinentia pigmenti is a rare neuroectodermal dysplasia caused by a defect in the IKBKG gene (formerly known as NEMO). There are 27.6 new cases per year worldwide; 65% to 75% are sporadic mutations, and 25% to 35% are familial. It is usually lethal in males, but females survive because of X-inactivation mosaicism. The disorder is typically identified by unique skin findings, a series of four stages that emerge throughout the first year of life. The central nervous system manifestations in the eye and in the brain cause the most disability. Defects of hair, nails, and teeth occur, and there can be other systemic involvement. Surveillance protocols for medical management have been established by the Incontinentia Pigmenti International Foundation. This article will summarize the existing knowledge of this condition and detail the protocols to help manage the care of the infant or child who presents with incontinentia pigmenti.

Severe neuroimaging anomalies are usually associated with random X inactivation in leucocytes circulating DNA in X-linked dominant Incontinentia Pigmenti.

Incontinentia Pigmenti (IP) is a skin disorder with neurological impairment in 30% of cases. The most common disease causing mutation is a deletion of exons 4-10 of the IKBKG gene, located on chromosome Xq28, with skewed X-chromosome inactivation in females, but few cases of random X-inactivation have been reported. We have correlated brain anomalies with X-chromosome inactivation status determined on leucocytes circulating DNA. We reviewed MRI of 18 girls with genetically proven IP. We found three patterns of MRI, normal MRI (n=5), mild white matter abnormalities with cortical and corpus callosum atrophy (n=6), and severe cortical abnormalities suggesting a vascular disease (n=7). Most patients with severe abnormalities had random X-inactivation (6/7,86%), while 80% (4/5) of patients with normal MRI and 100% (6/6) of patients with mild white matter abnormalities had skewed inactivation. These results suggest that skewed chromosome X-inactivation may protect brain from damage, while in case of random inactivation, expression of the mutated IKBKG gene may lead to severe brain lesions.

Genetic Disorders with Dyshidrosis: Ectodermal Dysplasia, Incontinentia Pigmenti, Fabry Disease, and Congenital Insensitivity to Pain with Anhidrosis.

Sweating is regulated by various neurohormonal mechanisms. A disorder in any part of the sweating regulatory pathways, such as the thermal center, neurotransmitters in the central to peripheral nerve, innervation of periglandular neurotransmission, and sweat secretion in the sweat gland itself, induces dyshidrosis. Therefore, hereditary disorders with dyshidrosis result from a variety of causes. These diseases have characteristic symptoms derived from each pathogenesis besides dyshidrosis. The information in this chapter is useful for the differential diagnosis of representative genetic disorders with dyshidrosis.

Clinical presentation and spectrum of neuroimaging findings in newborn infants with incontinentia pigmenti.

AIM: To report on the neurological presentation and neuroimaging findings in newborn infants with incontinentia pigmenti. METHOD: The clinical and neurological course including neuroimaging and follow-up data of eight newborn infants with the neurological phenotype of incontinentia pigmenti were retrospectively reviewed. RESULTS: While the clinical picture was polymorphic, the neurological manifestations were defined as encephalopathic and comprised lethargy and seizures in all but one of the infants. Magnetic resonance imaging (MRI) abnormalities were predominantly in the white matter. Diffusion-weighted imaging (DWI) was obtained during the acute phase in seven of the eight infants, showing restricted diffusion in the deep and subcortical white matter but also in the corpus callosum, basal ganglia, thalami, cerebellum, and cerebral peduncles. Susceptibility-weighted imaging (SWI), performed in five infants, showed a variable amount of signal loss, mainly in the white matter, within areas of restricted diffusion. Extensive MRI abnormalities in newborn infants were followed by abnormal neurodevelopment, with significant motor, cognitive, and/or visual problems. INTERPRETATION: To assess the extent of central nervous system involvement, MRI is recommended in the clinical evaluation of infants with incontinentia pigmenti. They have a characteristic pattern of brain lesions seen on MRI, best recognized using DWI and SWI in the acute neonatal phase, which allow the identification of and distinction between ischaemic and haemorrhagic lesions.

Incontinentia pigmenti (Bloch-Sulzberger syndrome).

Incontinentia pigmenti (IP; Bloch-Sulzberger syndrome; OMIM #308300) is an X-linked dominant neurocutaneous disorder with presumed male lethality. It is usually diagnosed in female newborns based on skin features (erythematous, vesicular, or bullous eruption in linear streaks). The skin lesions evolve into a verrucous stage, followed by atrophy and scarring, leaving linear areas of hypopigmentation and hyperpigmented macules in bizarre patterns following Blaschko's lines. Systemic and neurologic complications include focal seizures and hemorrhagic cerebral infarction in infants, and retinal vasculopathy leading to blindness. Hypodontia, conical or pegged teeth, and linear areas of alopecia persist into adulthood. IP is caused by mutation of the IKBKG/NEMO gene on Xq28. Deletion of exons 4 to 10 (NEMOΔ4-10) accounts for about 80% of cases (familial and sporadic). NEMO mutation leads to loss of function of NF-κB, a critical protein that modulates cellular proliferation, apoptosis, and response to proinflammatory factors, leading to the characteristic features of IP. In female carriers, selective loss of cells expressing the mutant X-chromosome results in completely skewed X-inactivation in the majority of cases. Study of mouse models in which various components of the NF-κB pathway (including NEMO) have been knocked out has contributed significantly to our understanding of disease pathogenesis.

Incontinentia Pigmenti: A Comprehensive Review and Update.

Incontinentia pigmenti (IP) is a rare syndrome with skin lesions, ocular abnormalities in the retina and elsewhere, central nervous system abnormalities, and teeth defects. The authors present an updated review of the literature, highlighting diagnosis, epidemiology, pathophysiology, clinical features, and management of IP. IP is an X-linked dominant syndrome with an incidence of 0.0025%; most patients are female. IP is caused by a mutation in the IKBKG gene, causing a loss of function of NF-κß, leaving cells susceptible to apoptosis from intrinsic factors. The cardinal feature of IP is four stages of skin distinctive lesions. Of those with IP, 36.5% have detectable eye pathology and 60% to 90% of those have retinal issues. Peripheral avascularity and macular occlusive disease commonly occur. The authors performed a comprehensive review of Medline from 1947 to 2014. All papers mentioning IP in ophthalmologic journals were reviewed as well as applicable publications from other medical specialties.

Incontinentia pigmenti: report on data from 2000 to 2013.

We report here on the building-up of a database of information related to 386 cases of Incontinentia Pigmenti collected in a thirteen-year activity (2000-2013) at our centre of expertise. The database has been constructed on the basis of a continuous collection of patients (27.6/year), the majority diagnosed as sporadic cases (75.6%). This activity has generated a rich source of information for future research studies by integrating molecular/clinical data with scientific knowledge. We describe the content, architecture and future utility of this collection of data on IP to offer comprehensive anonymous information to the international scientific community.

Systematic review of central nervous system anomalies in incontinentia pigmenti.

The objective of this study was to present a systematic review of the central nervous system (CNS) types of anomalies and to consider the possibility to include CNS anomalies in Incontinentia pigmenti (IP) criteria. The analyzed literature data from 1,393 IP cases were from the period 1993-2012. CNS anomalies were diagnosed for 30.44% of the investigated IP patients. The total number of CNS types of anomalies per patient was 1.62. In the present study there was no significantly higher number of anomalies per patient in females than males. The most frequent CNS types of anomalies were seizures, motor impairment, mental retardation, and microcephaly. The most frequently registered CNS lesions found using brain imaging methods were brain infarcts or necrosis, brain atrophies, and corpus callosum lesions. IKBKG exon 4-10 deletion was present in 86.00% of genetically confirmed IP patients. The frequency of CNS anomalies, similar to the frequency of retinal anomalies in IP patients, concurrent with their severity, supports their recognition in the list of IP minor criteria.

NEMO syndrome (incontinentia pigmenti) and systemic lupus erythematosus: a new disease association.

Congenital diseases are increasingly being recognised in adults because of clinical mimicry, variable clinical picture or rarity of the disease; pregnancy is a valuable diagnostic occasion. The present case is the first report of an association report between NEMO syndrome (an acronym of the mutated, non-functioning gene, NF-kB essential modulator), a rare X-linked disease, characterised by developmental anomalies, immunodepression and skin lesions, and systemic lupus erythematosus (SLE). A 35-year-old patient affected by SLE sought clinical advice in the 8th week of gestation. The diagnosis of SLE dated back to the age of 24, when multisystemic manifestations (pleuropericarditis, weight loss, alopecia, skin involvement, joint pain, kidney involvement) were observed. She had been treated with steroids since 1999; immunosuppressive drugs had been added for short periods. Developmental anomalies were present, including oligodontia, retinal problems, anomalies of the corpus callosum and pes planovalgus. Family history included multiple miscarriages, dental malformations and oligodontia and skin blistering in the first months of life. On these bases, incontinentia pigmenti (IP; or NEMO syndrome) was diagnosed and confirmed by genetic testing. The NEMO gene is implicated in immune deficiencies as well as in autoimmune diseases. This report may suggest a role for NF-kB essential modulator in the pathogenesis of SLE, in the context of the complex immunologic deficiencies increasingly associated with autoimmune diseases.

Early infantile manifestations of incontinentia pigmenti mimicking acute encephalopathy.

OBJECTIVE: We retrospectively reviewed six patients with incontinentia pigmenti (IP) who had encephalopathic manifestations during early infancy. METHODS: We enrolled six patients who met the following criteria from the mailing list of the Annual Zao Conference: (1) diagnosis of IP; (2) encephalopathic manifestations with reduced consciousness and clusters of seizures by 6 months of age; and (3) no evidence of central nervous system infection or metabolic derangement. RESULTS: The onset of the encephalopathic events was within the first 2 months of life in all but one patient. All had clusters of focal clonic seizures. The duration of seizures was typically 5 min. The seizures ceased within 5 days in all patients. Various degrees of reduced consciousness were observed in association with the frequent seizures. Diffusion-weighted imaging during the acute phase showed reduced water diffusion in the subcortical white matter, corpus callosum, basal ganglia, thalami, and internal capsule in two patients. Scattered subcortical white matter lesions were observed on fluid-attenuated inversion-recovery images in two patients. CONCLUSIONS: The encephalopathic manifestations in patients with incontinentia pigmenti were characterized by seizure clusters and reduced consciousness, albeit of relatively short duration. Magnetic resonance imaging abnormalities were predominant in the subcortical areas in most patients.

Incontinentia pigmenti: presentación neonatal: a propósito de un caso clínico / Incontinentia pigmenti: neonatal presentation: a purpose of clinical case

La incontinentia pigmenti (IP) también conocida como síndrome de Bloch-Sulzberger, es una genodermatosis infrecuente ligada al cromosoma X que afecta tejidos derivados del neuroectodermo: piel, faneras, ojos, sistema nervioso central y dientes. En la etapa neonatal se plantean diagnósticos diferenciales como el impétigo ampollar, herpes neonatal, citomegalovirus, mastocitosis, epidermólisis ampollar hereditaria. El diagnóstico temprano permite detectar las posibles patologías asociadas, que son determinantes para el pronóstico del paciente.

Incontinentia pigmenti, also known as Bloch-Sulzberger syndrome, is a rare congenital X-linked genodermatosis with variable involvement of tissues derived from neuroectoderm and mesoderm skin, hair, nails, eyes and central nervous system. Differential diagnoses are manifested in the neonatal period, such as bullous impetigo, neonatal herpes, cytomegalovirus, mastocytosis and hereditary epidermolysis bullosa. Early diagnosis allows detection of associated diseases which determine the patients prognosis.

Incontinentia pigmenti: treatment of IP with topical tacrolimus.

Incontinentia pigmenti (IP), or Bloch-Sulzberger syndrome, is a rare X-linked dominant genodermatosis primarily affecting females. Although IP affects many organ systems, the hallmark feature of this disease is its characteristic cutaneous eruption along the lines of Blaschko that evolves through four distinct stages: inflammatory/vesiculobullous, verrucous, hyperpigmented and hypopigmented/ atrophic. We describe a case of IP in its vesicular stage that completely resolved with topical Protopic (tacrolimus) 0.1% ointment. The treatment successfully halted the progression of disease through its subsequent disfiguring stages.

Incontinentia pigmenti with encephalocele in a neonate: a rare association.

Incontinentia pigmenti is a rare, X-linked dominant multisystem genodermatosis affecting ectodermal and mesodermal tissues. After the skin, the central nervous system is the second-most affected system. We report a neonate with incontinentia pigmenti and encephalocele, as a feature of the central nervous system involvement, to stress this uncommon association.

Common genodermatoses: what the pediatrician needs to know.

Recognizing the patterns of the skin findings and establishing the correct diagnosis can also help avoid subjecting patients to unnecessary tests, such as lumbar punctures to rule out herpes simplex virus in neonates with a Blaschkoid distribution of vesicles in incontinentia pigmenti. The cutaneous features of genetic disorders provide important clues to the underlying diagnoses for conditions such as tuberous sclerosis, neurofibromatosis, incontinentia pigmenti, and help direct the diagnostic evaluation and health supervision in those individuals.