Familial incontinentia pigmenti (IP; MIM 308310) is a genodermatosis that segregates as an X-linked dominant disorder and is usually lethal prenatally in males. In affected females it causes highly variable abnormalities of the skin, hair, nails, teeth, eyes and central nervous system. The prominent skin signs occur in four classic cutaneous stages: perinatal inflammatory vesicles, verrucous patches, a distinctive pattern of hyperpigmentation and dermal scarring. Cells expressing the mutated X chromosome are eliminated selectively around the time of birth, so females with IP exhibit extremely skewed X-inactivation. The reasons for cell death in females and in utero lethality in males are unknown. The locus for IP has been linked genetically to the factor VIII gene in Xq28 (ref. 3). The gene for NEMO (NF-kappaB essential modulator)/IKKgamma (IkappaB kinase-gamma) has been mapped to a position 200 kilobases proximal to the factor VIII locus. NEMO is required for the activation of the transcription factor NF-kappaB and is therefore central to many immune, inflammatory and apoptotic pathways. Here we show that most cases of IP are due to mutations of this locus and that a new genomic rearrangement accounts for 80% of new mutations. As a consequence, NF-kappaB activation is defective in IP cells.

Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium.

Rett syndrome (RTT) is a neurodevelopmental disorder characterized by loss of acquired skills after a period of normal development in infant girls. The responsible gene, encoding methyl-CpG binding protein 2 (MeCP2), was recently discovered. Here we explore the spectrum of phenotypes resulting from MECP2 mutations. Both nonsense (R168X and R255X) and missense (R106W and R306C) mutations have been found, with multiple recurrences. R168X mutations were identified in six unrelated sporadic cases, as well as in two affected sisters and their normal mother. The missense mutations were de novo and affect conserved domains of MeCP2. All of the nucleotide substitutions involve C→T transitions at CpG hotspots. A single nucleotide deletion, at codon 137, that creates a L138X stop codon within the methyl-binding domain was found in an individual with features of RTT and incontinentia pigmenti. An 806delG deletion causing a V288X stop in the transcription-repression domain was identified in a woman with motor-coordination problems, mild learning disability, and skewed X inactivation; in her sister and daughter, who were affected with classic RTT; and in her hemizygous son, who died from congenital encephalopathy. Thus, some males with RTT-causing MECP2 mutations may survive to birth, and female heterozygotes with favorably skewed X-inactivation patterns may have little or no involvement. Therefore, MECP2 mutations are not limited to RTT and may be implicated in a much broader phenotypic spectrum.

Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots.

Hypohidrotic ectodermal dysplasia (HED), a congenital disorder of teeth, hair, and eccrine sweat glands, is usually inherited as an X-linked recessive trait, although rarer autosomal dominant and recessive forms exist. We have studied males from four families with HED and immunodeficiency (HED-ID), in which the disorder segregates as an X-linked recessive trait. Affected males manifest dysgammaglobulinemia and, despite therapy, have significant morbidity and mortality from recurrent infections. Recently, mutations in IKK-gamma (NEMO) have been shown to cause familial incontinentia pigmenti (IP). Unlike HED-ID, IP affects females and, with few exceptions, causes male prenatal lethality. IKK-gamma is required for the activation of the transcription factor known as “nuclear factor kappa B” and plays an important role in T and B cell function. We hypothesize that “milder” mutations at this locus may cause HED-ID. In all four families, sequence analysis reveals exon 10 mutations affecting the carboxy-terminal end of the IKK-gamma protein, a domain believed to connect the IKK signalsome complex to upstream activators. The findings define a new X-linked recessive immunodeficiency syndrome, distinct from other types of HED and immunodeficiency syndromes. The data provide further evidence that the development of ectodermal appendages is mediated through a tumor necrosis factor/tumor necrosis factor receptor–like signaling pathway, with the IKK signalsome complex playing a significant role.

A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)

NEMO/IKKγ-Deficient Mice Model Incontinentia Pigmenti

Female Mice Heterozygous for IKKγ/NEMO Deficiencies Develop a Dermatopathy Similar to the Human X-Linked Disorder Incontinentia Pigmenti

Incontinentia Pigmenti 2 (IP2) is an X-linked dominantdisorder with male lethality. Affected females display acharacteristic skin eruption that evolves through fourclassic stages, frequently accompanied by dental andretinal abnormalities. Non-random (skewed)X-inactivation in peripheral blood leukocytes and infibroblasts has been observed in females with IP2;however, sample sizes have been small and methods ofanalysis varied. We have examined X-inactivation in alarge group of multigenerational IP2 families, in smallerfamilies, and in isolated cases. Ninety-eight percent ofaffected females in multigenerational IP2 pedigreesshow completely skewed patterns of X-inactivation,while only ∼10% of a normal control population isskewed. Results both in small families and in newmutation cases with subsequent segregation consistentwith Xq28 linkage are similar. Isolated cases show alower percentage (85%) of skewed affected individuals;this difference may be due to inaccurate clinicalascertainment. The parent of origin of new mutationscould be determined in 15 families; paternal newmutations were twice as common as maternal. Fibro-blast subclones from a biopsy at the boundary of a skinlesion in a newborn IP2 patient were isolated, andclones with either one or the other X active wereidentified, demonstrating that cells with the activedisease-bearing X chromosome are still present instage I skin lesions.INTRODUCTIONFamilial Incontinentia Pigmenti (IP2) is a neurocutaneousgenodermatosis which segregates as an X-linked dominant traitwith prenatal male lethality (for review, see ref. 1). In affectedfemales, its most prominent phenotypic features involve the skinand its derivatives, the eye and the central nervous system. Thisdisorder is diagnosed in affected females at or soon after birth bythe presence of a progressive erythematous and vesicular rash. Thisrash becomes sequentially verrucous, pigmented, then atrophic, andmay leave adolescents and adults with areas of linear and reticularhypopigmentation. Other manifestations include cicatricial al opecia,hypodontia or anodontia, eosinophilia (in the early stages),peripheral vascular abnormalities and cicatrization of the retina,and other secondary ocular findings. The penetrance of the diseaseapproaches 100%, but its expressivity is highly variable, evenwithin families.Linkage of IP2 to Xq28 markers was demonstrated in 1989 ( 2);subsequently, IP2 was localized more precisely to the regionsurrounding and most likely telomeric to DXS52 (3). Morerecently, the region of interest has been narrowed to Xq28 distalto Factor VIII; the highest LOD scores are found with DXS1108(θ = 0.00) (4).Non-random X inactivation in patients with IP2 has beenreported by several groups. Migeon et al. (5), using G6PDvariants and an RFLP at the HPRT locus which detects adifferentially methylated HpaII site, observed that thechromosome bearing the normal allele at the IP locus is the activeX in the majority of skin fibroblasts in affected females in threefamilies. Variable skewing in peripheral blood leukocytes wasalso observed in these families, which was unexpected since thistissue had not previously been thought to be involved in thisdisease. Analysis of G6PD isozymes showed a more randomdistribution in red blood cells, suggesting that red cell progenitorsare less likely to be affected negatively by the IP mutation thanare white cell progenitors. Other investigators (6) used somaticcell hybrid analysis to compare skin biopsies taken from normaland hyperpigmented (stage III) areas of the skin; the same Xchromosome was found to be active in every clone, regardless ofwhether it was derived from normal or hyperpigmented skin.These authors concluded that invasion of affected skin by normalcells most likely takes place at the transition from theinflammatory (I) to the verrucous (II) stage, and that their resultssupport the model that normal cells have a proliferativeadvantage. A third study ( 7), again with RFLP analysis, producedcontradictory results. Extreme skewing was found in a minorityof cases, and in most of these cases it was not possible todetermine parental origin of the inactive X chromosome; in theone fully informative family with extreme skewing, the X

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Selection Against Mutant Alleles in Blood Leukocytes is a Consistent Feature in Incontinentia Pigmenti Type 2

Male patients with Bloch-Sulzberger incontinentia pigmenti (IP type II) are rare and more severely affected than their female counterparts, with a significant occurrence of sex chromosome aneuploidy. This document introduces a new male IP type II patient and reviews 48 males reported with IP. Twenty-eight of the 49 patients meet current criteria for diagnosis of IP type II. The phenotype is variable and the incidence of documented developmental delay is 25%. Five patients had Klinefelter syndrome (47,XXY). Most patients were reported prior to 1961 when chromosome analysis was not available. Biopsy and laboratory reports considered to be “consistent with” the diagnosis of IP were seen in patients meeting criteria as well as those who would not currently be given the diagnosis. The histologic findings considered diagnostic are varied. This variability may be accounted for by differences in stage of disease, biopsy site, histologic technique, and reporting style. Conversely, this may indicate that the diagnostic weight given to the biopsy should be reconsidered. Eosinophilia was not a consistent finding. Overall, differences in reporting, ascertainment, and length of follow-up lead to difficulty in interpreting or predicting the natural history of males with IP type II. Based on the existing literature, they appear to have a higher rate of mental retardation than the general population, but there does not appear to be a correlation between severity of physical and mental involvement. The presence of sex chromosome aneuploidy documented in the more recent cases emphasizes the need for chromosome analysis in any male patient suspected of IP type II. Am. J. Med. Genet. 77:201–218, 1998. © 1998 Wiley-Liss, Inc.

Male cases of incontinentia pigmenti: Case report and review

Incontinentia pigmenti (IP) is a genodermatosis that segregates as an X linked dominant trait with male lethality. The disease has been linked to Xq28 in a number of studies. A few affected males have been documented, most of whom have a 47,XXY karyotype. We report a family with two paternally related half sisters, each affected with IP. The father is healthy, clinically normal, and has a 46,XY normal male karyotype. Linkage analysis of 12 polymorphic markers (two X linked and 10 autosomal) confirms paternity. X inactivation studies with the human androgen receptor (HUMARA) indicate that the paternal X chromosome is inactivated preferentially in each girl, implying that this chromosome carries the IP mutation, and that the father is a gonadal mosaic for the IP mutation.

https://jmg.bmj.com/content/jmedgenet/32/11/887.full.pdf

Angela E. Scheuerle

Papers

Selection Against Mutant Alleles in Blood Leukocytes is a Consistent Feature in Incontinentia Pigmenti Type 2

Male cases of incontinentia pigmenti: Case report and review

Gonadal mosaicism for incontinentia pigmenti in a healthy male.

Macroglossia: more than meets the eye.