[Autoinflammatory diseases associated with RIPK1 mutations: A review of the literature]. / Revue de la littérature sur les maladies auto-inflammatoires associées aux mutations du gène RIPK1.

Autoinflammatory diseases related to RIPK1 mutations have been recently described. Two distinct clinical phenotypes have been reported and depend on the type and location of the mutation. When the mutation is recessive with loss of function, patients develop a combined phenotype of immune deficiency with recurrent bacterial and fungal infections and signs of early inflammatory bowel disease, non-erosive polyarthritis and growth retardation. On the other hand, when the mutation is dominant, gain of function, the manifestations are only auto-inflammatory with extensive lymphoproliferation, oral lesions such as aphthosis or ulcers, abdominal pain and hepatosplenomegaly. The mutations described for the dominant form affect only the cleavage site of caspase 8 and the clinical phenotype is called CRIA for Cleavage-Resistant RIPK1-Induced Autoinflammatory syndrome. The recessive form is severe and life-threatening requiring hematopoietic stem cell transplantation while the dominant form responds well to interleukin-6 receptor antagonists. Thus, RIPK1 mutations can induce various clinical manifestations with two distinct phenotypes. Although still rare, because of their recent description, these diseases can be suspected by an internist, in front of recurrent digestive features and will be increasingly diagnosed in the future through the integration of this gene in the diagnostic chips dedicated to autoinflammatory diseases and early inflammatory bowel diseases, using next generation sequencing.

Partial clinical response to anakinra in severe palmoplantar pustular psoriasis.

BACKGROUND: Palmoplantar pustular psoriasis is a clinical psoriasis variant characterised by a high impact on quality of life and poor response to biologics approved for plaque type psoriasis.The recombinant interleukin-1 (IL-1) receptor antagonist anakinra has been recently used for the treatment of isolated refractory cases of generalised pustular psoriasis with contrasted results. OBJECTIVES: To report the clinical response in two patients treated with anakinra as salvage therapy in two patients with severe palmoplantar pustular psoriasis refractory to currently available antipsoriatic systemic therapies. METHODS: Anakinra was given subcutaneously at the daily dose of 100 mg, and clinical response was evaluated using the palmoplantar psoriasis area and severity index (PPPASI). RESULTS: Only partial and transient responses were observed in both patients, who had to stop anakinra due to lack of efficacy and to side effects. CONCLUSION: Anakinra appears to provide only partial clinical improvement in refractory palmoplantar pustular psoriasis. Prospective clinical studies on larger populations are warranted to investigate more accurately both efficacy and safety of IL-1-inhibiting strategies in pustular psoriasis.

X-linked and autosomal recessive Hypohidrotic Ectodermal Dysplasia: genotypic-dental phenotypic findings.

Hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of ectodermal structures and its molecular etiology corresponds to mutations of EDA-EDAR genes. The aim of this study was first to investigate the genotype and dental phenotype associated with HED and second, to explore possible correlations between dental features and molecular defects. A total of 27 patients from 24 unrelated families exhibiting clinical signs of HED (22 XLHED males, 5 autosomal recessive forms) were retrospectively included. In the sample, 25 different mutations on EDA and EDAR genes were detected; 10 were not previously described. EDA and EDAR mutations corresponded respectively to 80.0% and 20.0% of the mutations. The dental phenotype analysis revealed a mean number of primary and permanent missing teeth ranging respectively from 14.5 (4-20) to 22.5 (10-28); the majority of the patients exhibited dysmorphic teeth. Overall, no differential expression in the degree of oligodontia according to either the mutated gene, the mutated functional sub-domains, or the mutation type, could be observed. Nevertheless, the furin group exhibited severe phenotypes unobserved in the TNF group. Significant differences in the number of some primary missing teeth (incisor and canine) related to EDA-EDAR genes defects were detected for the first time between XLHED and autosomal recessive HED, suggesting differential local effects of EDA-EDAR genes during odontogenesis. The present genotypic-phenotypic findings may add to the knowledge of the consequences of the molecular dysfunction of EDA-NF-kB in odontogenesis, and could be helpful in genetic counseling to distinguish autosomal forms from other HED syndromes.

Mutations in EDARADD account for a small proportion of hypohidrotic ectodermal dysplasia cases.

BACKGROUND: Hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of the eccrine sweat glands, hair and teeth. The X-linked form of the disease, caused by mutations in the EDA gene, represents the majority of HED cases. Autosomal dominant and recessive forms occasionally occur and result from mutations in at least two other genes: EDAR and EDARADD. EDARADD interacts with the TAB2/TRAF6/TAK1 complex, which is necessary for NF-kappaB activation by EDAR. OBJECTIVES: To determine frequency of EDARADD, TRAF6, TAB2 and TAK1 mutations in HED. MATERIALS AND METHODS: We have screened 28 familial or sporadic HED cases with no mutations in the EDA and EDAR genes for EDARADD, TRAF6, TAB2 and TAK1 mutations. RESULTS: We identified one EDARADD 6-bp homozygous in-frame deletion (c.402-407del, p.Thr135-Val136del) in a patient born to consanguineous parents. Functional studies showed that the p.Thr135-Val136del impaired the EDAR-EDARADD interaction and then severely inhibited NF-kappaB activity. In the remaining 27 patients, we failed to find causative mutations in EDARADD, or in TRAF6, TAB2 or TAK1. CONCLUSIONS: Our study demonstrates that EDARADD mutations are not a frequent cause of HED, while mutations in TRAF6, TAB2 and TAK1 may not be implicated in this disease.

Autosomal dominant anhidrotic ectodermal dysplasias at the EDARADD locus.

Anhidrotic ectodermal dysplasia (EDA) is a disorder of ectodermal differentiation characterized by sparse hair, abnormal or missing teeth, and inability to sweat. X-linked EDA is the most common form, caused by mutations in the EDA gene, which encodes ectodysplasin, a member of the tumor necrosis factor (TNF) family. Autosomal dominant and recessive forms of EDA have been also described and are accounted for by two genes. Mutations in EDAR, encoding a TNF receptor (EDAR) cause both dominant and recessive forms. In addition, mutations in a recently identified gene, EDARADD, encoding EDAR-associated death domain (EDARADD) have been shown to cause autosomal recessive EDA. Here, we report a large Moroccan family with an autosomal dominant EDA. We mapped the disease gene to chromosome 1q42.2-q43, and identified a novel missense mutation in the EDARADD gene (c.335T>G, p.Leu112Arg). Thus, the EDARADD gene accounts for both recessive and dominant EDA. EDAR is activated by its ligand, ectodysplasin, and uses EDARADD to build an intracellular complex and activate nuclear factor kappa B (NF-kB). We compared the functional consequences of the dominant (p.Leu112Arg) and recessive mutation (p.Glu142Lys), which both occurred in the death domain (DD) of EDARADD. We demonstrated that the p.Leu112Arg mutation completely abrogated NF-kB activation, whereas the p.Glu142Lys retained the ability to significantly activate the NF-kB pathway. The p.Leu112Arg mutation is probably a dominant negative form as its cotransfection impaired the wild-type EDARADD's ability to activate NF-kB. Our results confirm that NF-kB activation is impaired in EDA and support the role of EDARADD DD as a downstream effector of EDAR signaling.

NF-kappaB-related genetic diseases.

The recent identification of genetic diseases (incontinentia pigmenti, anhidrotic ectodermal dysplasia with immunodeficiency and cylindromatosis) resulting from mutations affecting components of the nuclear factor-kappaB (NF-kappaB) signaling pathway provides a unique opportunity to understand the function of NF-kappaB in vivo. Besides confirming the importance of NF-kappaB in innate and acquired immunity or bone mass control, analysis of these diseases has uncovered new critical roles played by this transcription factor in the development and homeostasis of the epidermis and the proper function of lymphatic vessels. In addition, the identified mutations will help understanding at the molecular level how NF-kappaB is activated in response to cell stimulation.

Linear and whorled nevoid hypermelanosis with bilateral giant cerebral aneurysms.

A 24-year-old woman presented with bilateral giant intracavernous carotid artery aneurysms manifesting as a cavernous sinus syndrome on the left side, and anisocoria, ophthalmic pain, and oculomotor paresis on the left side. Physical examination showed mild hyperextensibility of the metacarpophalangeal joints, amelogenesis imperfecta, and hyperpigmentation following Blaschko lines. Analysis of the NEMO gene for incontinentia pigmenti syndrome and of collagen III for Ehlers-Danlos type IV was normal. Skewed X-inactivation patterns in blood lymphocytes were detected. To the best of our knowledge, this association of linear hyperpigmentation and cerebral aneurysms has never been previously reported.

Survival of male patients with incontinentia pigmenti carrying a lethal mutation can be explained by somatic mosaicism or Klinefelter syndrome.

Incontinentia pigmenti (IP), or "Bloch-Sulzberger syndrome," is an X-linked dominant disorder characterized by abnormalities of skin, teeth, hair, and eyes; skewed X-inactivation; and recurrent miscarriages of male fetuses. IP results from mutations in the gene for NF-kappaB essential modulator (NEMO), with deletion of exons 4-10 of NEMO accounting for >80% of new mutations. Male fetuses inheriting this mutation and other "null" mutations of NEMO usually die in utero. Less deleterious mutations can result in survival of males subjects, but with ectodermal dysplasia and immunodeficiency. Male patients with skin, dental, and ocular abnormalities typical of those seen in female patients with IP (without immunodeficiency) are rare. We investigated four male patients with clinical hallmarks of IP. All four were found to carry the deletion normally associated with male lethality in utero. Survival in one patient is explained by a 47,XXY karyotype and skewed X inactivation. Three other patients possess a normal 46,XY karyotype. We demonstrate that these patients have both wild-type and deleted copies of the NEMO gene and are therefore mosaic for the common mutation. Therefore, the repeat-mediated rearrangement leading to the common deletion does not require meiotic division. Hypomorphic alleles, a 47,XXY karyotype, and somatic mosaicism therefore represent three mechanisms for survival of males carrying a NEMO mutation.

A recurrent deletion in the ubiquitously expressed NEMO (IKK-gamma) gene accounts for the vast majority of incontinentia pigmenti mutations.

Incontinentia pigmenti (IP) is an X-linked dominant disorder characterized by abnormal skin pigmentation, retinal detachment, anodontia, alopecia, nail dystrophy and central nervous system defects. This disorder segregates as a male lethal disorder and causes skewed X-inactivation in female patients. IP is caused by mutations in a gene called NEMO, which encodes a regulatory component of the IkappaB kinase complex required to activate the NF-kappaB pathway. Here we report the identification of 277 mutations in 357 unrelated IP patients. An identical genomic deletion within NEMO accounted for 90% of the identified mutations. The remaining mutations were small duplications, substitutions and deletions. Nearly all NEMO mutations caused frameshift and premature protein truncation, which are predicted to eliminate NEMO function and cause cell lethality. Examination of families transmitting the recurrent deletion revealed that the rearrangement occurred in the paternal germline in most cases, indicating that it arises predominantly by intrachromosomal misalignment during meiosis. Expression analysis of human and mouse NEMO/Nemo showed that the gene becomes active early during embryogenesis and is expressed ubiquitously. These data confirm the involvement of NEMO in IP and will help elucidate the mechanism underlying the manifestation of this disorder and the in vivo function of NEMO. Based on these and other recent findings, we propose a model to explain the pathogenesis of this complex disorder.

X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling.

The molecular basis of X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) has remained elusive. Here we report hypomorphic mutations in the gene IKBKG in 12 males with EDA-ID from 8 kindreds, and 2 patients with a related and hitherto unrecognized syndrome of EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID). Mutations in the coding region of IKBKG are associated with EDA-ID, and stop codon mutations, with OL-EDA-ID. IKBKG encodes NEMO, the regulatory subunit of the IKK (IkappaB kinase) complex, which is essential for NF-kappaB signaling. Germline loss-of-function mutations in IKBKG are lethal in male fetuses. We show that IKBKG mutations causing OL-EDA-ID and EDA-ID impair but do not abolish NF-kappaB signaling. We also show that the ectodysplasin receptor, DL, triggers NF-kappaB through the NEMO protein, indicating that EDA results from impaired NF-kappaB signaling. Finally, we show that abnormal immunity in OL-EDA-ID patients results from impaired cell responses to lipopolysaccharide, interleukin (IL)-1beta, IL-18, TNFalpha and CD154. We thus report for the first time that impaired but not abolished NF-kappaB signaling in humans results in two related syndromes that associate specific developmental and immunological defects.