Incontinentia pigmenti: genodermatosis multisistémica / Incontinentia pigmenti: multisistemic genodermatosis

Resumen La incontinentia pigmenti es una genodermatosis ligada al cromosoma X, generalmente letal en los hombres. Está causada por una mutación con pérdida de función en el gen IKBKG (inhibitor of kappa polypeptide gene enhancer in B cells kinase gamma), que impide que la proteína NFкβ (nuclear factor kappa-light-chain-enhancer of activated B cells) migre al núcleo y comience la transcripción de factores que amplifican la respuesta inmunitaria y previenen la apoptosis. Por tanto, las células mutantes se vuelven vulnerables a la apoptosis cuando son expuestas a citocinas y provocan vaso-oclusión e isquemia de tejidos como la piel, el sistema nervioso central y la retina. Las lesiones dermatológicas son características; se distribuyen a lo largo de las líneas de Blaschko, las cuales siguen el patrón de migración de las células de la piel en la embriogénesis, y ocurren en el 100% de los pacientes. Las manifestaciones cutáneas aparecen en una secuencia de cuatro fases que inicia desde el nacimiento: vesicular, verrucosa, hiperpigmentada e hipopigmentada. Estas lesiones son relevantes, puesto que orientan al clínico hacia el diagnóstico. Además, se acompañan de anomalías neurológicas, como crisis convulsivas, y múltiples manifestaciones oftalmológicas, como el desprendimiento de la retina. Los pacientes con incontinentia pigmenti, pero sin compromiso oftalmológico o neurológico clínicamente significativo, tienen un pronóstico bueno y una esperanza de vida normal. Las anomalías que se presentan son permanentes, lo que puede generar preocupación en los pacientes.

Abstract Incontinentia pigmenti is an X-linked genodermatosis generally lethal in males; thus, it presents almost exclusively in females. It is caused by a loss-of-function mutation in the IKBKG (inhibitor of kappa polypeptide gene enhancer in B cells, kinase gamma) gene that prevents the NFкβ (nuclear factor kappa-light-chain-enhancer of activated B cells) protein from migrating to the nucleus to begin the transcription of factors that amplify the immune response and prevent apoptosis. Consequently, mutant cells become vulnerable to apoptosis when exposed to cytokines and, in turn, lead to vaso-occlusion and ischemia of tissues, such as the skin, the central nervous system and the retina. Dermatological lesions are characteristic and occur in 100% of patients; they are distributed along Blaschko lines, which follow the pattern of migration of skin cells in embryogenesis. The cutaneous manifestations follow a sequence of four phases since birth: vesicular, verrucous, hyperpigmented and hypopigmented. These lesions are relevant for the disease because they guide the clinician towards the diagnosis. Additionally, they are accompanied by neurological abnormalities, such as seizures, and multiple ophthalmological manifestations, such as retinal detachment. Incontinentia pigmenti patients with no clinically significant ophthalmic or neurological compromise have a good prognosis and a normal life expectancy. The abnormalities present are permanent, which can be a cause of concern for the patients.

Application value of whole exome sequencing in critically ill neonates with inherited diseases / 中国当代儿科杂志

OBJECTIVE@#To study the application value of whole exome sequencing (WES) in critically ill neonates with inherited diseases.@*METHODS@#A total of 66 critically ill neonates with suspected inherited diseases or unclear clinical diagnosis who were admitted to the neonatal intensive care unit were enrolled as subjects. The clinical data of the neonates were collected, and venous blood samples were collected from the neonates and their parents for WES. The clinical manifestations of the neonates were observed to search for related pathogenic gene mutations.@*RESULTS@#Among the 66 critically ill neonates with suspected inherited diseases or unclear clinical diagnosis (34 boys and 32 girls), 14 (21%) were found to have gene mutations by WES. One neonate had no gene mutation detected by WES but was highly suspected of pigment incontinence based on clinical manifestations, and multiplex ligation-dependent probe amplification detected a heterozygous deletion mutation in exons 4-10 of the IKBKG gene. Among the 15 neonates with gene mutations, 10 (67%) had pathogenic gene mutation, 1 (7%) was suspected of pathogenic gene mutation, and 4 (27%) had gene mutations with unknown significance. Among the 15 neonates, 13 underwent chromosome examination, and only 1 neonate was found to have chromosome abnormality.@*CONCLUSIONS@#Chromosome examination cannot be used as a diagnostic method for inherited diseases, and WES detection technology is an important tool to find inherited diseases in critically ill neonates with suspected inherited diseases or unclear clinical diagnosis; however WES technology has some limitation and it is thus necessary to combine with other sequencing methods to achieve an early diagnosis.

Utility of molecular studies in incontinentia pigmenti patients.

The diagnosis of incontinentia pigmenti (IP) is fairly easy in the presence of classical features, but can be difficult in cases with partial or non-classical features, especially in the parents. The demonstration that the disease is caused by mutations in the NEMO gene, has remarkably improved genetic counselling for this disorder. We present four families of IP in whom molecular studies established an unequivocal diagnosis in the affected daughters, and showed two mothers to be carriers, thus allowing accurate genetic counselling and prenatal diagnosis.

Incontinentia Pigmenti in a Newborn with NEMO Mutation

Incontinentia pigmenti (IP) (OMIM #308300) is a rare X-linked dominant neuroectodermal multisystemic syndrome due to mutations in the gene for NF-kappaB essential modulator (NEMO). A term newborn girl who was born with erythematous vesicular eruptions developed recurrent seizures during the first and second weeks of her life. The serial MRIs demonstrated diffuse, progressive brain infarctions and subsequent encephalomalacia as well as brain atrophy. Skin biopsy found it was consistent with the vesicular stage of IP. Genetic analysis revealed a deletion exon 4-10 in NEMO gene associated with IP. We hereby report a Korean female baby with IP confirmed by mutation analysis of NEMO gene.

The Common NF-kappaB Essential Modulator (NEMO) Gene Rearrangement in Korean Patients with Incontinentia Pigmenti

Incontinentia pigmenti (IP) is a rare X-linked dominant disorder characterized by highly variable abnormalities of the skin, eyes and central nervous system. A mutation of the nuclear factor-kappa B essential modulator (NEMO) located at Xq28 is believed to play a role in pathogenesis and the mutation occurs mostly in female patients due to fatal consequence of the mutation in males in utero. This study was designed to identify the common NEMO rearrangement in four Korean patients with IP. Deletion of exons 4 to 10 in the NEMO, the most common mutation in IP patients, was detected in all of the patients by the use of long-range PCR analysis. This method enabled us to discriminate between NEMO and pseudogene rearrangements. Furthermore, all of the patients showed skewed XCI patterns, indicating pathogenicity of IP was due to cells carrying the mutant X chromosome. This is the first report of genetically confirmed cases of IP in Korea.