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Background and ObjectivePRRT2 variants have been reported in a few cases of patients with hemiplegic migraine. To clarify the role of PRRT2 in familial hemiplegic migraine, we studied this gene in a large cohort of affected probands.MethodsPRRT2 was analyzed in 860 probands with hemiplegic migraine, and PRRT2 variations were identified in 30 probands. Genotyping of relatives identified a total of 49 persons with variations whose clinical manifestations were detailed.ResultsPRRT2 variations were found in 12 of 163 probands who previously tested negative for CACNA1A, ATP1A2, and SCN1A variations and in 18 of 697 consecutive probands screened simultaneously on the 4 genes. In this second group, pathogenic variants were found in 105 individuals, mostly in ATP1A2 (42%), followed by CACNA1A (26%), PRRT2 (17%), and SCN1A (15%). The PRRT2 variations included 7 distinct variants, 5 of which have already been described in persons with paroxysmal kinesigenic dyskinesia and 2 new variants. Eight probands had a deletion of the whole PRRT2 gene. Among the 49 patients with variations in PRRT2, 26 had pure hemiplegic migraine and 16 had hemiplegic migraine associated with another manifestation: epilepsy (8), learning disabilities (5), hypersomnia (4), or abnormal movement (3). Three patients had epilepsy without migraine: 2 had paroxysmal kinesigenic dyskinesia without migraine, and 1 was asymptomatic.DiscussionPRRT2 should be regarded as the fourth autosomal dominant gene for hemiplegic migraine and screened in any affected patient, together with the 3 other main genes. Further studies are needed to understand how the same loss-of-function PRRT2 variations can lead to a wide range of neurologic phenotypes, including paroxysmal movement disorder, epilepsy, learning disabilities, sleep disorder, and hemiplegic migraine.

Resume Les equipes Ressources de soins palliatifs pediatriques (ERRSPP) suivent de pres l’actualite adulte. L’evolution de la loi Claeys-Leonetti, reconnaissant l’alimentation et l’hydratation artificielles comme des traitements a part entiere pouvant etre arretes en fin de vie a ainsi declenche de nombreuses reflexions au sein de ces structures. Mais qu’en est-il au sein des equipes de soins de pediatrie ? Quelle place occupe cette reflexion autour de l’alimentation et l’hydratation en fin de vie alors que le nourrissage, fonction parentale primaire, occupe une place centrale dans le developpement d’un enfant ? A l’aide d’une etude qualitative princeps, et d’une demarche d’analyse originale, nous tenterons de defricher ce terrain inexplore des representations soignantes et de la place de cette thematique dans l’accompagnement des patients de pediatrie en fin de vie.

Neutropenia and neutrophil dysfunction found in deficiencies in G6PC3 and in the glucose-6-phosphate transporter (G6PT/SLC37A4) are due to accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P), an inhibitor of hexokinase made from 1,5-anhydroglucitol (1,5-AG), an abundant polyol present in blood. Lowering blood 1,5-AG with an SGLT2 inhibitor greatly improved neutrophil counts and function in G6PC3-deficient mice and in patients with G6PT-deficiency. We evaluate this treatment in two G6PC3-deficient children. While neutropenia was severe in one child (PT1), which was dependent on granulocyte cololony-stimulating factor (GCSF), it was significantly milder in the other one (PT2), which had low blood 1,5-AG levels and only required GCSF during severe infections. Treatment with the SGLT2-inhibitor empagliflozin decreased 1,5-AG in blood and 1,5-AG6P in neutrophils and improved (PT1) or normalized (PT2) neutrophil counts, allowing to stop GCSF. On empagliflozin, both children remained infection-free (>1 year - PT2; >2 years - PT1) and no side effects were reported. Remarkably, sequencing of SGLT5, the gene encoding the putative renal transporter for 1,5-AG, disclosed a rare heterozygous missense mutation in PT2, replacing the extremely conserved Arg401 by a histidine. The higher urinary clearance of 1,5-AG explains the more benign neutropenia and the outstanding response to empagliflozin treatment found in this child. Our data shows that SGLT2 inhibitors are an excellent alternative to treat the neutropenia present in G6PC3-deficiency.

Hypereosinophilia (HE) is rare but often secondary to a nonhematologic disease such as allergic disorders and parasitic infections. HE can also be associated with hematologic malignancies and be the result of a clonal proliferation or reactive to another hematologic condition. Association of HE with acute lymphoblastic leukemia (ALL) is rare in children. We reported a case of a teenager presented with HE secondary to B-ALL who experienced severe cardiac complications with severe absolute eosinophil count. We compared his clinical evolution with other published cases and we reported 2 mutations linked to B-ALL never described before in this context.

Febrile neutropenia is the most frequent complication in children treated with chemotherapy. Nevertheless, neutropenic children are a very heterogeneous group and invasive bacterial infections concern a minority of patients. Reducing antibiotics would bring many benefits. Yet, we can only explore this strategy if the safety of children is preserved. The main aims of this review were to study the safety and effectiveness of reducing antibiotic use in children with febrile neutropenia in terms of duration, route of administration (oral versus intravenous) and narrowing of antimicrobial spectrum. Cochrane Library, Pubmed and Embase were searched for relevant articles until February 2020. We have included all articles describing controlled trials written in French or in English. The risk of bias was assessed with ROB-2 (Cochrane Handbook for Systematic Reviews of Interventions Version 6.0. 2019, Chap. 8) or ROBINS-1 (Cochrane Handbook for Systematic Reviews of Interventions Version 6.0. 2019, Chap. 25). On 2351 articles, the systematic research retained 13 studies. Nine were used for a meta-analysis comparing oral versus intravenous treatment. We found no pediatric studies concerning de-escalation of empiric broad-spectrum antibiotics. No publication biases were found and almost all of the selected studies were at low risk or with some concern for bias. In comparing oral versus intravenous treatment and early cessation versus continuing antibiotics when no infection is proven, we found no difference in terms of safety (mortality and admission in intensive care unit) and efficacy (need of readmission/antibiotic modification/recurrence of fever). It seems safe and effective to provide oral treatment in low-risk febrile neutropenia and to stop antibiotics when no bacterial infection is proven. Spectrum reduction remains an important topic in pediatric research. Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2022.2055245

STUDY DESIGN: Case report. PURPOSE: The authors used spine shortening as an alternative strategy to intercalary graft fixation to restore permanent spine stability for a 17-month-old infant who received total en bloc spondylectomy (TES) of T11 to treat an embryonic rhabdomyosarcoma. TES involves complete removal of vertebra, compensated by spine reconstruction using intercalary allografts and permanent posterior instrumentation, which is not possible for skeletally immature patients with high growth potential and non-ossified vertebrae. METHODS: Surgery was performed over two consecutive days. During the first day, the tumor was released from its dorsal attachments through the posterior approach. During the second day, the tumor was dissected and excised through the anterior approach, leaving a gap between T10 and T12. The two vertebrae were then drawn toward each other until the gap was bridged. The dural sac slipped into the canal under T10 and T12 with no observable kinking. RESULTS: Fifteen weeks after surgery, thoraco-abdominal CT confirmed fusion of the T10 and T12 vertebral bodies. Three years later, the patient lives a normal life with no major neurological deficits or recurrence of sarcoma. CONCLUSIONS: This case report is the first to demonstrate the feasibility of TES with spine shortening of an entire thoracic segment without spine kinking or damage in an infant. This unprecedented surgical technique allowed complete removal of an embryonic rhabdomyosarcoma, while granting rapid stability and growth potential. LEVEL OF EVIDENCE: IV.

International audience; BackgroundHeterogeneous data have been reported on high-dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) in Wilms tumors (WTs). We aimed to define its safety and efficacy in the French cohort, and to compare this management to current international recommendations.MethodsData prospectively collected from children, adolescents, and young adults with WT treated with HDCT/ASCR between 2000 and 2016 in French centers were retrospectively analyzed. Toxicity was reported according to CTCAE v4.03.ResultsFifty-four patients received HDCT/ASCR (first line, n = 13; recurrence, n = 41). Their median age at the time of ASCR was 5.3 years (range 2.2–21.6). Main nonhematological acute grades 3–4 toxicities were digestive and renal. No significant difference of toxicity rate was observed among HDCT regimens and schedules. Two patients died shortly after ASCR (renal and multiorgan failure), and one heavily pretreated patient died of late respiratory failure. The selection criteria applied to define those patients eligible for HDCT/ASCR retrospectively matched to those currently used in the International Society of Pediatric Oncology (SIOP) UMBRELLA protocol for 38 patients, with encouraging survival rates compared to published data. The objective response rate to HDCT was 21%, with a disease control rate after HDCT of 85%. After a median follow-up of 7 years, the 5-year event-free survival (EFS) and overall survival (OS) were 54% (95% CI: 32%–76%) and 62% (95% CI: 31%–82%) for frontline patients, and 57% (95% CI: 39%–71%) and 69% (95% CI: 52%–81%) at recurrence.ConclusionHDCT was feasible and showed encouraging results in well-defined settings. Data from the current prospective protocol will help to better evaluate HDCT impact on survival.

The vast majority of adult cancer cells achieve cellular immortality by activating a telomere maintenance mechanism (TMM). While this is mostly achieved by the de-silencing of hTERT telomerase gene expression, an alternative homologous recombination-based and telomerase-independent mechanism, known as ALT (Alternative Lengthening of Telomeres), is frequently activated in a subset of tumors, including paediatric cancers. Being absent from normal cells, the ALT mechanism offers interesting perspectives for new targeted cancer therapies. To date, however, the development of better translationally applicable tools for ALT detection in tumor sections is still needed. Here, using a newly derived ALT-positive cancer cell mouse xenograft model, we extensively examined how the previously known ALT markers could be used as reliable tools for ALT diagnosis in tumor sections. We found that, together with the detection of ultra-bright telomeric signals (UBS), an ALT hallmark, native telomeric FISH, that detects single-stranded C-rich telomeric DNA, provides a very sensitive and robust tool for ALT diagnosis in tissues. We applied these assays to paediatric tumor samples and readily identified three ALT-positive tumors for which the TMM was confirmed by the gold-standard C-circle amplification assay. Although the latter offers a robust assay for ALT detection in the context of research laboratories, it is more difficult to set up in histopathological laboratories and could therefore be conveniently replaced by the combination of UBS detection and native telomeric FISH. Supplementary Information The online version contains supplementary material available at 10.1186/s43556-021-00055-y.

IntroductionJuvenile idiopathic arthritis (JIA) represents a very heterogeneous disease. As such, it has been a challenge to describe the disease activity of JIA cohorts. Our objective was to describe the first Belgian cohort of children with JIA by assessing their disease characteristics, outcomes, and potential markers of prognosis.MethodsThe CAP48 cohort is a multicentric observational study of children with recent or well-established diagnosis of JIA (naïve or not to treatment at baseline), evaluated every 3 to 6 months during a follow-up of 10 years.ResultsThere were 125 children included, composing of 25 naïve and 100 established patients. Their median age at onset was 6.2 and 4.2 years in the naïve and established cohort respectively, with a predominance of female. All subtypes of JIA were represented in both cohorts. The mean DAS28-CRP and JADAS10-CRP at baseline in naïve patients was 2.52 and 6.0 respectively. Uveitis occurred in 19% of patients and was strongly associated with presence of antinuclear antibodies (odds ratio of 6). Among naïve patients, 55% were in remission at 12 months according to ACR criteria and JADAS10 scores, in contrast with 100% achieving DAS28 remission. ConclusionThis first cohort study in Belgium allowed to compare its data to other existing cohorts and to evaluate quality of care in Belgian French-speaking hospitals. Additionally, it highlighted a superiority of JADAS10 over DAS28 to monitor and evaluate remission in JIA. This study also underlined a need for more accurate markers of prognosis to improve treatment and long-term outcomes.

DEAR EDITOR, The feasibility of testing multiple genes at once using Next Generation Sequencing, particularly Whole Exome Sequencing (WES), has expanded the phenotypic spectrum associated with many disease genes. Distinguishing atypical presentation from combined gene effects and incidental from causal findings can however be challenging, particularly when composite phenotypes are themselves extremely rare. [...]

Introduction In the management of juvenile idiopathic arthritis (JIA), there is a lack of diagnostic and prognostic biomarkers. This study assesses the use of serum calprotectin (sCal) as a marker to monitor disease activity, and as a classification and prognosis tool of response to treatment or risk of flares in patients with JIA. Methods Eighty-one patients with JIA from the CAP48 multicentric cohort were included in this study, as well as 11 non-paediatric healthy controls. An ELISA method was used to quantify sCal with a commercial kit. Results Patients with an active disease compared with healthy controls and with patients with inactive disease showed an eightfold and a twofold increased level of sCal, respectively. sCal was found to be correlated with the C-reactive protein (CRP) and even more strongly with the erythrocyte sedimentation rate. Evolution of DAS28 scores correlated well with evolution of sCal, as opposed to evolution of CRP. With regard to CRP, sCal could differentiate forms with active oligoarthritis from polyarthritis and systemic forms. However, sCal brought an added value compared with the CRP as a prognosis marker. Indeed, patients with active disease and reaching minimal disease activity (according to Juvenile Arthritis Disease Activity Score) at 6 months following the test had higher sCal levels, while patients with inactive disease had higher sCal levels if a flare was observed up to 3–9 months following the test. Conclusions This study confirms the potential uses of sCal as a biomarker in the diagnosis and follow-up of JIA.

Diagnosis of EBV-driven T/NK-cell lymphoproliferative disorders and chronic active EBV diseases is often difficult. Fournier et al. report a flow-FISH cytometry assay allowing rapid identification of EBV-infected cells in blood and accurate diagnoses. It represents a powerful tool to study pathophysiological mechanisms of EBV-LPD., Epstein-Barr virus (EBV) preferentially infects epithelial cells and B lymphocytes and sometimes T and NK lymphocytes. Persistence of EBV-infected cells results in severe lymphoproliferative disorders (LPDs). Diagnosis of EBV-driven T or NK cell LPD and chronic active EBV diseases (CAEBV) is difficult, often requiring biopsies. Herein, we report a flow-FISH cytometry assay that detects cells expressing EBV-encoded small RNAs (EBERs), allowing rapid identification of EBV-infected cells among PBMCs. EBV-infected B, T, and/or NK cells were detectable in various LPD conditions. Diagnosis of CAEBV in 22 patients of Caucasian and African origins was established. All exhibited circulating EBV-infected T and/or NK cells, highlighting that CAEBV is not restricted to native American and Asian populations. Proportions of EBV-infected cells correlated with blood EBV loads. We showed that EBV-infected T cells had an effector memory activated phenotype, whereas EBV-infected B cells expressed plasma cell differentiation markers. Thus, this method achieves accurate and unambiguous diagnoses of different forms of EBV-driven LPD and represents a powerful tool to study their pathophysiological mechanisms.

Background Liver metastases are rare in children with Wilms tumor (WT), and their impact on the outcome is unclear. Patients and methods The French cohort of patients with WT presenting liver metastases at diagnosis and enrolled in the International Society of Pediatric Oncology (SIOP) 2001 study was reviewed. Results From 2002 to 2012, 906 French patients were enrolled in the SIOP2001 trial. Among them, 131 (14%) presented with stage IV WT and 18 (1.9%) had liver metastases at diagnosis. Isolated liver metastases were displayed in four of them. After preoperative chemotherapy, persistent liver disease was reported in 14/18 patients, and 13 of them underwent metastasectomy after nephrectomy. In resected liver lesions, the same histology of the primary tumor was reported for three patients, blastemal cells without anaplasia were identified in one patient with DA-WT, and post-chemotherapy necrosis/fibrosis was identified for the other 10 patients. For the four patients who had liver and lung surgery, both sites had nonviable cells with post-chemotherapy necrosis/fibrosis. Six patients had hepatic radiotherapy. Sixteen patients achieved primary complete remission and were alive at the last follow-up (median follow-up: 6.4 years). The only two deceased patients presented diffuse anaplasia histology. The five-year EFS and OS were 83% (60%-94%) and 88% (66%-97%), respectively. Conclusion Liver involvement does not appear to be an adverse prognostic factor in metastatic WT. The role of hepatic surgery and radiotherapy remains unclear, and should be carefully considered in case of persistent liver metastases, according to histology and radiological response to other metastatic sites.

Ras-associated autoimmune leukoproliferative disorder (RALD) is a clinical entity initially identified in patients evaluated for an autoimmune lymphoproliferative syndrome (ALPS)-like phenotype. It remains a matter of debate whether RALD is a chronic and benign lymphoproliferative disorder or a pre-malignant condition. We report the case of a 7-year-old girl diagnosed with RALD due to somatic KRAS mutation who progressed to a juvenile myelomonocytic leukemia phenotype and finally evolved into acute myeloid leukemia. The case report prompted a literature review by a search for all RALD cases published in PubMed and Embase. We identified 27 patients with RALD. The male-to-female ratio was 1:1 and median age at disease onset was 2 years (range 3 months-36 years). Sixteen patients (59%) harbored somatic mutations in KRAS and 11 patients (41%) somatic mutations in NRAS. The most common features were splenomegaly (26/27 patients), autoimmune cytopenia (15/16 patients), monocytosis (18/24 patients), pericarditis (6 patients), and skin involvement (4 patients). Two patients went on to develop a hematopoietic malignancy. In summary, the current case documents an additional warning about the long-term risk of malignancy in RALD.

A 7-year-old boy with a history of low-risk acute lymphoblastic leukemia developed multiple intussusceptions shortly after the end of maintenance therapy. Explorative laparotomy showed >10 polyps in the small intestine. Histologic examination revealed intestinal smooth muscle sarcomas associated with Epstein-Barr virus. The patient recovered well after partial cuneiform resection of the largest polyps and treatment with sirolimus. This case report indicates that these tumors may arise even after moderate transient immunosuppression and that association with acute lymphoblastic leukemia is possible although rarely described. We discuss the potential benefit of the mTor/Akt signal inhibitors as treatment for these tumors.

Introduction De plus en plus de preuves indiquent que l’analyse du tissu synovial peut fournir des informations sur la physiopathologie, mais aussi des informations individuelles cliniquement pertinentes dans les arthrites inflammatoires a l’âge adulte. On sait peu de choses sur la pathologie synoviale dans l’arthrite juvenile idiopathique (AJI), notamment en ce qui concerne la variabilite des caracteristiques histopathologiques entre les patients. Evaluer l’heterogeneite des principales caracteristiques synoviales (hyperplasie des synoviocytes et infiltration des cellules immunitaires) chez les patients atteints d’AJI et les comparer a une cohorte de jeunes adultes ( Patients et methodes Les biopsies synoviales ont ete prelevees a l’aide d’une mini arthroscopie du genou ou d’une biopsie guidee par echographie lors d’une injection intra-articulaire dans l’articulation. Les tissus ont ete inclus dans de la paraffine puis les sections ont ete colorees a l’hematoxyline et a l’eosine. L’hyperplasie des synoviocytes (SH) et l’infiltration des cellules immunitaires (ICI) ont ete evaluees par un pathologiste experimente sur une echelle semi-quantitative de 0 a 3. Resultats 34 patients atteints d’AJI (âge (median±SD) : 15,5 ± 6,47 ans, AJI oligo-articulaire n = 28/34, AJI polyarticulaire n = 6/34, positivite ANA-RF-ACPA = 56 %-10 %-3 %) et 22 patients atteints de PR (âge (median ± SD) : 24,3 ± 2,6 ans, positivite ANA-RF-ACPA = 10 %–36 %–32 %) ont ete inclus. Les scores individuels de SH et ICI etaient correles a la fois dans l’AJI (r de Spearman = 0,503, valeur p = 0,0024) et la PR (r de Spearman = 0,636, valeur p = 0,0015). Il n’y avait pas de difference significative dans les scores SH et ICI entre les 2 groupes avec un score SH (Q25-Q50-Q75) dans l’AJI = 0,5-1,125-2 et dans la PR = 0,75-2-2) ; score ICI (Q25-Q50-Q75) dans l’AJI = 1-2-2 et dans la PR = 0,75–2–2,25). La variabilite intra-groupe des deux caracteristiques evaluees etait comparable entre les 2 groupes (coefficient de variation SH : 72,2 % pour l’AJI et 68,2 % pour la PR ; coefficient de variation ICI : 52,2 % pour l’AJI et 71,2 % pour la PR). Chez les patients atteints d’AJI, il n’y avait pas de difference significative dans les scores SH/ICI entre les groupes en fonction de la positivite des ANA, de l’atteinte oligo ou polyarticulaire ou du traitement en cours. Toutes les procedures ont ete bien tolerees. Conclusion En etudiant les principales caracteristiques histologiques de la synovite, nous n’avons trouve aucune difference entre les patients atteints d’AJI et les jeunes patients atteints de PR. En outre, nous rapportons un degre similaire d’heterogeneite inter-patients dans les caracteristiques pathologiques synoviales des patients atteints d’AJI et de PR. Ces variations ne s’expliquent pas par des caracteristiques cliniques communes. Pour savoir si elles sont liees a des signatures moleculaires differentes, comme cela a ete suggere dans la PR adulte, des investigations supplementaires sont prevues en utilisant le sequencage de l’ARN total de la synoviale

Fibrolamellar carcinoma (FLC) is a rare variant of hepatocellular carcinoma, occurring in children and young adults without underlying liver disease. The diagnosis is based on morphological characteristics of the tumor, supplemented by immunohistochemistry and/or genetic testing. Recently, the presence of a characteristic DNAJB1-PRKACA fusion gene has been associated with FLC. Herein, we report a case of FLC presenting as peritoneal carcinomatosis in a 14-year-old female. Interestingly, no liver tumor was seen on imaging, and an alternative possibility is that the tumor arose outside the liver as a hepatoid carcinoma with fibrolamellar features.

Background:Increasing evidence indicates that synovial tissue analysis can deliver pathophysiological insights but also individual clinically-relevant information in adult-onset inflammatory arthritides. Little is known about synovial pathology in juvenile idiopathic arthritis, especially regarding inter-patient variability of histopathological features.Objectives:To assess the heterogeneity of main synovial features (synoviocyte hyperplasia and immune cells infiltration) in juvenile idiopathic arthritis (JIA) patients and a cohort of young adults (Methods:Synovial biopsies were sampled using needle arthroscopy or ultra-sound (US) guided biopsy during intra-articular joint injection. Tissue was embedded in paraffin then sections were stained with hematoxylin and eosin. Synoviocyte hyperplasia (SH) and immune cells infiltration (ICI) was assessed by an experienced pathologist on a 0 – 3 scale where 0 represents the absence of the feature and 3 the highest level.Results:34 JIA patients (age (median ±SD): 15.5±6.47 years, oligo-articular JIA n=28/34, polyarticular JIA n=6/34, ANA-RF-ACPA positivity=56%-10%-3%) and 22 RA (age (median ±SD): 24.3±2.6 years, ANA-RF-ACPA positivity=10%-36%-32%) patients were included. Synovial tissue was obtained from knee (n=49/56), wrist (n=4/56) or metacarpophalangeal/intercarpophalangeal joints (n=3/56), using US guided biopsy in 27% of patients and needle arthroscopy in 73%.Individual scores of SH and ICI were correlated in both JIA (Spearman’s r=0.503, p value=0.0024) and RA (Spearman’s r=0.636, p value=0.0015). There was no significant difference in SH and ICI scores between the 2 groups (SH score (Q25-Q50-Q75) in JIA= 0.5-1.125-2 and in RA = 0.75-2-2; ICI score (Q25-Q50-Q75) in JIA= 1-2-2 and in RA = 0.75-2-2.25). Intra-group variability of the two assessed features was comparable between the 2 groups (SH coefficient of variation: 72.2% for JIA and 68.2% for RA; ICI coefficient of variation: 52.2% for JIA and 71.2% for RA). Within JIA patients, there was no significant difference in SH/ICI scores between groups based on ANA positivity, oligo or polyarticular involvement nor ongoing treatment.Conclusion:Studying main histological features of synovitis, we found no difference between JIA and young RA patients. Furthermore, we report a similar degree of inter-patient heterogeneity in synovial pathological features of JIA and RA patients. These variations were not explained by common clinical characteristics. Whether they relate to different molecular signatures as suggested in adult RA will be further investigated using bulk tissue RNA sequencing.Acknowledgements:This work was funded in part by Cap48 (RTBF). Clément Triaille is funded by the Fonds National de la Recherche Scientifique (FNRS, Communauté française de Belgique) and Fondation Saint-Luc (Cliniques Universitaires Saint-Luc).Disclosure of Interests:Clément Triaille: None declared, Cécile Boulanger: None declared, Tatiana Sokolova: None declared, Laurent Meric de Bellefon: None declared, Adrien Nzeusseu Toukap: None declared, Christine Galant: None declared, Nisha Limaye: None declared, Bernard Lauwerys Employee of: currently employed at UCB Biopharma, Patrick Durez: None declared.

The cardinal features of Ectrodactyly, Ectodermal dysplasia, Cleft lip/palate (EEC), and Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndromes are ectodermal dysplasia (ED), orofacial clefting, and limb anomalies. EEC and AEC are caused by heterozygous mutations in the transcription factor p63 encoded by TP63. Here, we report a patient with an EEC/AEC syndrome-like phenotype, including ankyloblepharon, ED, cleft palate, ectrodactyly, syndactyly, additional hypogammaglobulinemia, and growth delay. Neither pathogenic mutations in TP63 nor CNVs at the TP63 locus were identified. Exome sequencing revealed de novo heterozygous variants in CHUK (conserved helix-loop-helix ubiquitous kinase), PTGER4, and IFIT2. While the variant in PTGER4 might contribute to the immunodeficiency and growth delay, the variant in CHUK appeared to be most relevant for the EEC/AEC-like phenotype. CHUK is a direct target gene of p63 and encodes a component of the IKK complex that plays a key role in NF-κB pathway activation. The identified CHUK variant (g.101980394T>C; c.425A>G; p.His142Arg) is located in the kinase domain which is responsible for the phosphorylation activity of the protein. The variant may affect CHUK function and thus contribute to the disease phenotype in three ways: (1) the variant exhibits a dominant negative effect and results in an inactive IKK complex that affects the canonical NF-κB pathway; (2) it affects the feedback loop of the canonical and non-canonical NF-κB pathways that are CHUK kinase activity-dependent; and (3) it disrupts NF-κB independent epidermal development that is often p63-dependent. Therefore, we propose that the heterozygous CHUK variant is highly likely to be causative to the EEC/AEC-like and additional hypogammaglobulinemia phenotypes in the patient presented here.