Efficacy of haematopoietic stem cell boost as a rescue for poor graft function after haematopoietic stem cell transplantation: A multicentre retrospective study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC).

Haematopoietic stem cell reinjection may be a curative option for poor graft function after haematopoietic stem cell transplantation; however, literature supporting its use remains limited. We conducted a multicentre retrospective study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy, including 55 patients. We demonstrated response rates of nearly 40% and two-year survival of more than 60% in the context of an otherwise deadly complication and we observed that the timing of injection and the degree of cytopenia are strongly associated with outcomes. This study shows the feasibility of the procedure informing on its epidemiology, outcomes and prognostic factors, setting the stage for future guidelines.

Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT.

Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation.

Paroxysmal strabismus and stridor acquired in childhood: Do not overlook calcemia!

Hypocalcemia is known to induce stridor but was rarely reported to cause strabismus. We report the case of a 4-year-old girl who presented with paroxysmal stridor and strabismus with diplopia, persisting for several weeks. Severe hypocalcemia (1.25 mmol/L) was finally diagnosed and was related to hypoparathyroidism, which was the first manifestation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in this patient. Strabismus and stridor both resolved after normalization of calcemia. This case report is a rare observation of paroxysmal strabismus caused by hypocalcemia and it highlights the importance of calcium monitoring in any situation of atypical neurological symptoms.

Cutaneous granulomas with primary immunodeficiency in children: a report of 17 new patients and a review of the literature.

BACKGROUND: Paediatric cutaneous granuloma with primary immunodeficiency (PID) is a rare condition. The physiopathology is unclear, and treatment is challenging. We report on 17 paediatric cases and review the literature. OBJECTIVES: To make dermatologists and dermatopathologists aware of the diagnostic value of skin granulomas in paediatric PID. METHODS: We collected data on 17 patients with cutaneous granulomas and PID registered with us and also reviewed 33 cases from the literature. RESULTS: Cutaneous granuloma was the presenting feature of the PID in 15 of the 50 collated cases. The lesions presented as red-brownish nodules and infiltrated ulcerative plaques, predominantly on the face and limbs. Scleroderma-like infiltration on a single limb was observed in 10% of the cases. The associated PID was ataxia-telangiectasia (52%), combined immunodeficiency (24%), cartilage-hair hypoplasia (6%) and other subtypes (18%). The granulomas were mostly sarcoidal, tuberculoid, palisaded or undefined subtypes. In some patients, several different histopathologic granulomatous patterns were found in the same biopsy. Some granulomas were associated with the presence of a vaccine strain of rubella virus. CONCLUSION: Cutaneous granulomas associated with a PID have a variable clinical presentation. A PID can be suspected when crusty, brownish lesions are found on the face or limbs. The concomitant presence of several histological subtypes in a single patient is suggestive of a PID.

Clinical Heterogeneity of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome: A French Multicenter Retrospective Study.

OBJECTIVE: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an autoimmune disease caused by mutations in the forkhead box protein 3 gene (FOXP3), which encodes a key regulator of immune tolerance. The aim of this study was to describe the clinical heterogeneity of the disease in a national French cohort. METHODS: Multicenter retrospective study of patients diagnosed with IPEX syndrome caused by mutations in FOXP3. RESULTS: Thirty children from 26 families were included. Age at disease onset (median [first to third quartile]) was 1.5 mo [0-84] and at death 3.5 years [0-10.5] (n = 15) indicating a high heterogeneity. Initial presentation was diarrhoea (68%), type 1 diabetes (T1D; 25%), skin lesions (7%) and nephropathy (3%). During the course of the disease the following main symptoms were observed: diarrhoea (100%), skin lesions (85%), T1DM (50%), severe food allergies (39%), haematological disorders (28%), nephropathies (25%), hepatitis (14%) as well as the presence of a variety of autoantibodies. Immunosuppressive mono- or combination therapy led to improvement in eight children. Three boys displayed a stable disease course without any immunosuppressive medication. Overall 10-year survival rate was 43% (42% in transplanted patients and 52% in patients on immunosuppressive therapy). Five out of 22 identified FOXP3 mutations have not been described yet: c.-23 + 1G > A, c.-23 + 5G > A, c.264delC, c.1015C > T and c.1091A > G. The first two produced atypical, attenuated phenotypes. Missense and frameshift mutations affecting the forkhead domain were associated with poor survival (Gehan-Wilcoxon p = 0.002). CONCLUSION: The broad phenotypic heterogeneity of IPEX raises questions about modifying factors and justifies early FOXP3 sequencing in suspected cases.

Next-Generation Sequencing for Diagnosis and Tailored Therapy: A Case Report of Astrovirus-Associated Progressive Encephalitis.

A boy with X-linked agammaglobulinemia experienced progressive global motor decline, cerebellar syndrome, and epilepsy. All standard polymerase chain reactions for neurotropic viruses were negative on cerebrospinal fluid and brain biopsy. Next-generation sequencing allowed fast identification of a new astrovirus strain (HAstV-VA1/HMO-C-PA), which led to tailor the patient's treatment, with encouraging clinical monitoring over 1 year.

An update on pediatric invasive aspergillosis.

Invasive aspergillosis (IA) is a major cause of morbidity and mortality in immunocompromised adults and children, the number of which has been continuously increasing in the last decades. The purpose of our review was to provide epidemiological, clinical, and biological data and antifungal treatment options in the pediatric population. Several biological assays (galactomannan enzyme immunoassay, ß-D-glucan, detection of Aspergillus spp. DNA) have proven useful adjuncts for the diagnosis of IA in adult studies. However, data on these assays in children is limited by small sample sizes and sometimes conflicting results concerning their sensitivity/specificity. Pediatric treatment recommendations are mainly extrapolated from results of clinical trials performed in adults. It is thus necessary to develop new antifungal formulations specifically adapted to the pediatric population and to evaluate their pharmacokinetic/pharmacodynamic profile, their safety, and their effectiveness in infants and children.

Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry.

OBJECTIVE: To evaluate genetic, demographic and clinical features in patients with cryopyrin-associated periodic syndrome (CAPS) from the Eurofever Registry, with a focus on genotype-phenotype correlations and predictive disease severity markers. METHODS: A web-based registry retrospectively collected data on patients with CAPS. Experts in the disease independently validated all cases. Patients carrying NLRP3 variants and germline-mutation-negative patients were included. RESULTS: 136 patients were analysed. The median age at disease onset was 9 months, and the median duration of follow-up was 15 years. Skin rash, musculoskeletal involvement and fever were the most prevalent features. Neurological involvement (including severe complications) was noted in 40% and 12% of the patients, respectively, with ophthalmological involvement in 71%, and neurosensory hearing loss in 42%. 133 patients carried a heterozygous, germline mutation, and 3 patients were mutation-negative (despite complete NLRP3 gene screening). Thirty-one different NLRP3 mutations were recorded; 7 accounted for 78% of the patients, whereas 24 rare variants were found in 27 cases. The latter were significantly associated with early disease onset, neurological complications (including severe complications) and severe musculoskeletal involvement. The T348M variant was associated with early disease onset, chronic course and hearing loss. Neurological involvement was less strongly associated with V198M, E311 K and A439 V alleles. Early onset was predictive of severe neurological complications and hearing loss. CONCLUSIONS: Patients carrying rare NLRP3 variants are at risk of severe CAPS; onset before the age of 6 months is associated with more severe neurological involvement and hearing loss. These findings may have an impact on treatment decisions.

[SFGM-TC recommendation on indications for allogeneic stem cell transplantation in children with congenital neutropenia]. / Indications d'allogreffe dans les neutropénies constitutionnelles : recommandation de la SFGM-TC.

In this report, we address the issue of allogeneic stem cell transplantation in children with congenital neutropenia. Constitutional disorders with neutropenia are exceptional. Treatment and prevention of severe infections are a major concern in the management of chronic neutropenia. These disorders, especially Kostmann's disease and Shwachman-Bodian-Diamond syndrome, are associated with an increased risk of leukemia. The role of allogeneic stem cell transplantation in these patients is still unclear. In an effort to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the fourth annual series of workshops which brought together practitioners from all member centers and took place in September 2013 in Lille.

[Hurler syndrome: early diagnosis and treatment]. / Syndrome de Hurler : diagnostic et prise en charge précoces.

Hurler syndrome, the most severe form of mucopolysaccharidosis type I (MPS I), is a rare lysosomal storage disease. The overall incidence of MPS I is 0.99-1.99/100,000 live births. Accumulation of glycosaminoglycans causes the progressive dysfunction of multiple organs. We report the case of a 3-week-old newborn who was hospitalized in the Neonatal Intensive Care Unit for feeding problems. Coarse facial features and gingival hypertrophy, associated with axial hypotonia, upper airway obstruction, and moderate hepatomegaly, led to the early diagnosis of MPS I at 3 weeks of age and was confirmed by an abnormally elevated amount of dermatan and heparan sulphate in the urine and complete deficiency of alpha-L-iduronidase lysosomal enzyme activity. The child was homozygous for the p.W402X mutation, located on chromosome 4p16.3 of the alpha-L-iduronidase (IDUA) gene. The clinical condition gradually deteriorated until the age of 4 months, with thoracic and lumbar dysostoses, glaucoma, cerebral ventricular dilatation and cervical spinal stenosis, dilated cardiomyopathy, and umbilical hernia. Early diagnosis allowed enzyme replacement therapy (iaronidase, Aldurazyme(®), Genzyme) started at the age of 5 months, which provided stabilization of the heart disease, significant regression of rhinologic symptoms, and regression of hepatomegaly. Cord blood hematopoietic stem cell transplantation was performed at 11 months of age, allowing optimal preservation of cognitive development.

Safety of hematopoietic stem cell transplantation from hepatitis B core antibodies-positive donors with low/undetectable viremia in HBV-naïve children.

Scarce data exist on allogeneic hematopoietic stem cell transplantation (HSCT) outcomes in hepatitis B virus (HBV)-naïve recipients from HBV-experienced donors. Long-term follow-up is herein reported for 17 allogeneic HSCT performed in 13 HBV-naïve children from HBc-antibodies-positive donors between 2006 and 2012. Four donors were HBs-antigen-positive, with detectable but low viremia in 2 cases (<2 log10IU/ml). HBV-DNA was undetectable in all transplanted cell products. Recipients' HBV prophylaxis consisted of pre-transplant vaccination, polyvalent immune globulins, specific anti-HBV immune globulins, and/or oral lamivudine in 3, 12, 8, and 8 children, respectively. No case of HBV transmission occurred based on negative close monitoring of recipients' HBV serology and plasma HBV-DNA during a median follow-up of 22 months. In case of undetectable viremia in the donor, prophylaxis with vaccination and/or immune globulins in the recipient seems to be sufficient and lamivudine prophylaxis might be unnecessary to prevent viral transmission. In case of undetectable viremia in the donor, a systematic screening of HBV DNA in the stem cell product might be unnecessary to confirm the low risk of viral transmission. Prior exposure to HBV in the donor should not be considered a contraindication to HSCT.

Morphometry and epidermal fas expression of unexposed aged versus young skin.

BACKGROUND: Identifying the molecular mechanisms of intrinsic aging is critical in developing modalities for reversal of cutaneous aging. OBJECTIVE: The objective was to evaluate the expression of epidermal Fas, epidermal thickness, collagen, and elastic fibers degeneration in unexposed skin of aged individuals compared with young ones. MATERIALS AND METHODS: Skin biopsies were taken from normal skin of the back of 22 old subjects (age range: 48-75 years) and 15 young subjects (age range: 18-28 years). Skin sections were stained with hematoxylin and eosin, Masson trichrome, orcein. Epidermal thickness was measured with image analyzer and scoring was done for collagen and elastic fiber degeneration. Fas immunostaining was done. Quantitative and qualitative data were compared statistically between the old and young subjects. RESULTS: A statistically significant decreased epidermal thickness was found in old compared with young skin (P<0.05). A statistically significant number of patients showed decreased epidermal thickness, density, and fragmentation of both collagen and elastic fibers in old compared with young skin (P<0.001). Epidermal Fas expression was detected in 19 of 22 old subjects (86.4%) compared with 2 of 15 young subjects (13.3%) (P<0.001). There was no statistically significant correlation between age of old subjects and each of epidermal thickness, collagen, and elastic fiber degeneration. CONCLUSION: The decreased epidermal thickness and morphological alteration of collagen and elastic fibers are not correlated with aging and Fas-mediated apoptosis could be involved in thinning of the epidermis in unexposed aged skin.

[Post-thymus transplant vitiligo in a child with Foxn1 deficiency]. / Vitiligo post-greffe thymique chez un enfant porteur d'un déficit en Foxn1.

BACKGROUND: Foxn1 transcription factor deficit leads to immune deficiency, with hair and nail abnormalities. We report the case of a patient also presenting localized leucoderma. CASE REPORT: A 3-year-old boy underwent thymus transplantation at the age of 9 months for Foxn1 deficiency. He had developed urticaria and autoimmune hypothyroidism after thymus grafting. On examination, he had universal non-scarring alopecia, nail changes (atrophy, partial onycholysis and longitudinal grooves) and leucoderma on both big toes. DISCUSSION: This is the first description of leucoderma occurring in a patient with Foxn1 deficiency, as well as the first report of this pigment abnormality following thymus transplantation. The pathogenic hypotheses discussed were post-graft vitiligo and leucoderma induced by Foxn1 deficiency.

Is recurrent epistaxis from Kiesselbach's area (REKAS) in any relationship to the hemorrhoidal disease?

Vascular diseases are a major threat to human health nowadays. Hypertension, cardiovascular disease and varicose vain disease including hemorrhoids, are now increasingly recognized as inflammatory diseases. The role of inflammation cytokines in the pathogenesis of these diseases is very important. The lamina propria in the nasal mucosa is rich in blood vessels and humoral mediators. Recurrent epistaxis from Kiesselbach's area syndrome (REKAS) was first mentioned as early as 1985. It has been found that 90% of patients suffering from recurrent epistaxis from Kiesselbach area syndrome simultaneously suffered from hemorrhoids. Clinical observations suggest a possible mutual pathophysiologic relationship between Kiesselbach's and anorectal venous plexus. This relationship is also suggested in the reverse direction: significantly more than two thirds of primarily hemorrhoidal patients (83.01%) showed simultaneous vascular dilatations within their Kiesselbach plexuses, but none of these patients had ever have recurrent nose bleeds. There is one more thing they did not have (contrary to REKAS group)--anterior septal deformity. Furthermore, REKAS and hemorrhoidal disease, despite being different clinical entities, frequently appear in the primarily REKAS patients or their closest relatives (more than 90% out of all!). At the same time, all of REKAS patients did have a certain degree of the anterior septal deformity, which primarily hemorrhoidal patients did not have at all. Therefore we presume that Kiesselbach's vascular plexus in the Little's area of the nasal septum belongs to the same group as anorectal venous plexus does (others of this group are brain, esophagus, and lower leg venous system). We also presume that the anterior septal deformity is a crucial factor for the onset of the inflammation of the nasal vestibule skin (vestibulitis nasi), while vestibulitis nasi precipitates the onset of typical recurrent nose bleeds from the Kiesselbach's plexus.

Could we prevent unilateral cleft lip/palate in the future?

Surveillance studies have shown that cleft lip and palate is one of the commonest craniofacial anomalies, occurring in approximately 1 in 500 live births. Previous studies on craniofacial form in unilateral cleft lip/palate subjects have been carried out, but most attention has been focused on the deformity of the bony septum whereas the deformities of the nasal spine and cartilaginous component of the septum had received little attention. Our recent study was based on monitoring a very specific type of nasal septal deformity, type 6, and its relation to the unilateral cleft lip/palate disease. This type is very anteriorly located and refers to the cartilaginous part of the nasal septum and the inter-maxillary bone itself. Rhinoscopic view shows a typical, almost horizontal, unilateral groove at the nasal septum located very anteriorly. At the opposite septal side, but corresponding location, there is so called basal crest. The results of our study showed that the incidence of type 6 septal deformity was very high not only in unilateral cleft lip/palate children (80.6%) but also in their parents (58% in at least one of them). In contrast, in our previous study this type of septal deformity was seen in only 3.7% of non-unilateral cleft lip/palate children before puberty, rising to 7.4% in students and 9.4% in adults. In other words, perhaps we can expect the onset of unilateral cleft lip/palate in the offspring of parents who both have a type 6 septal deformity. Perhaps there is a gene responsible for the onset of both type 6 septal deformity and the cleft. If these clinical entities belong to the same gene, the cleft per se could perhaps disappear from the Earth in a near future owing to the gene therapy which will be able to eliminate it before the baby is born or even conceived.

Cutaneous manifestations of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome.

BACKGROUND: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder characterized by neonatal autoimmune enteropathy, diabetes and thyroiditis, food allergies and skin rash. IPEX syndrome is caused by mutations in FOXP3, a master control gene of regulatory T cells (Tregs), resulting in absent or dysfunctional Tregs. Data in the literature are scarce and the cutaneous manifestations are rarely depicted. OBJECTIVES: To evaluate the frequency and characteristics of cutaneous manifestations found in IPEX. METHODS: Retrospective single-centre study of a case series of IPEX. Patients' data were retrieved from medical files and numerous parameters concerning general and cutaneous characteristics of the disease were recorded. RESULTS: Ten children with IPEX were studied. Cutaneous involvement was present in seven of 10 children; age at onset was 0-4 months, median 1.5. All patients presented with atopic dermatitis (AD). Three presented more psoriasiform lesions. Eczema was severe; most affected areas were lower limbs, trunk and face. Pruritus was present in four of seven, and painful fissurary cheilitis in four of seven. Hyper-IgE was found in seven of 10 and hypereosinophilia in five of 10. Skin biopsies showed eczematiform or psoriasiform features. Affected patients were improved by dermocorticoids; no clear improvement was obtained with immunosuppressive regimens. Other features were urticaria secondary to food allergies and staphylococcal sepsis, mostly Staphylococcus aureus and catheter related. CONCLUSIONS: AD seems to be a frequent finding in IPEX syndrome, which is characterized by Treg anomalies. This hints to a possible role of Tregs in AD, which is then discussed in this study.