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Schimke immuno-osseous dysplasia is a rare multisystemic disorder caused by biallelic loss of function of the SMARCAL1 gene that plays a pivotal role in replication fork stabilization and thus DNA repair. Individuals affected from this disease suffer from disproportionate growth failure, steroid resistant nephrotic syndrome leading to renal failure and primary immunodeficiency mediated by T cell lymphopenia. With infectious complications being the leading cause of death in this disease, researching the nature of the immunodeficiency is crucial, particularly as the state is exacerbated by loss of antibodies due to nephrotic syndrome or immunosuppressive treatment. Building on previous findings that identified the loss of IL-7 receptor expression as a possible cause of the immunodeficiency and increased sensitivity to radiation-induced damage, we have employed spectral cytometry and multiplex RNA-sequencing to assess the phenotype and function of T cells ex-vivo and to study changes induced by in-vitro UV irradiation and reaction of cells to the presence of IL-7. Our findings highlight the mature phenotype of T cells with proinflammatory Th1 skew and signs of exhaustion and lack of response to IL-7. UV light irradiation caused a severe increase in the apoptosis of T cells, however the expression of the genes related to immune response and regulation remained surprisingly similar to healthy cells. Due to the disease's rarity, more studies will be necessary for complete understanding of this unique immunodeficiency., (© 2024. The Author(s).)

The expression of genes related to the Toll-like receptors (TLRs) signaling pathway were determined. Group A, B and C fed with basal diet and group D, E and F induced TD by feeding a basal diet containing 100 mg·kg -1 thiram. rGSTA3 protein was injected at 20 μg·kg -1 in group B, E and at 50 μg·kg -1 in C, F. Results suggested that lameness and death of chondrocytes were significant on day 14. TLRs signaling pathway related genes were screened based on the transcriptome enrichment, and validated on qPCR. IL-7, TLR2, 3, 4, 5, 7, 15, MyD88, MHC-II, MDA5 and TRAF6 were significantly (p < 0.05) expressed in group E and F as compared to group D on day 14 and 23. IL-7, MHCII, TRAF6, TLR3, TLR5, TLR7, and TLR15 determined insignificant in group D compared to group A on day 23. TD occur in an early phase and alleviated in the later period. rGSTA3 protein can prevent apoptosis and repair degraded chondrocytes., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Schimke immuno-osseous dysplasia (SIOD) is a rare multisystemic disorder with a variable clinical expressivity caused by biallelic variants in SMARCAL1 . A phenotype-genotype correlation has been attempted and variable expressivity of biallelic SMARCAL1 variants may be associated with environmental and genetic disturbances of gene expression. We describe two siblings born from consanguineous parents with a diagnosis of SIOD revealed by whole exome sequencing (WES). Results: A homozygous missense variant in the SMARCAL1 gene (c.1682G>A; p.Arg561His) was identified in both patients. Despite carrying the same variant, the two patients showed substantial renal and immunological phenotypic differences. We describe features not previously associated with SIOD-both patients had congenital anomalies of the kidneys and of the urinary tract and one of them succumbed to a classical type congenital mesoblastic nephroma. We performed an extensive characterization of the immunophenotype showing combined immunodeficiency characterized by a profound lymphopenia, lack of thymic output, defective IL-7Rα expression, and disturbed B plasma cells differentiation and immunoglobulin production in addition to an altered NK-cell phenotype and function. Conclusions: Overall, our results contribute to extending the phenotypic spectrum of features associated with SMARCAL1 mutations and to better characterizing the underlying immunologic disorder with critical implications for therapeutic and management strategies.

Cartilage-hair hypoplasia (CHH) is an autosomal recessive syndromic immunodeficiency with skeletal dysplasia, short stature, hypotrichosis, variable degree of immune dysfunction and increased incidence of anaemia, Hirschsprung disease and malignancy. CHH is caused by variants in the RMRP gene, encoding the untranslated RNA molecule of the mitochondrial RNA-processing endoribonuclease, which participates in for example cell cycle regulation and telomere maintenance. Recent studies have expanded our understanding of the complex pathogenesis of CHH. Immune dysfunction has a major impact on clinical course and prognosis. Clinical features of immune dysfunction are highly variable, progressive and include infections, lung disease, immune dysregulation and malignancy. Mortality is increased compared with the general population, due to infections, malignancy and pulmonary disease. Several risk factors for early mortality have been reported in the Finnish CHH cohort and can be used to guide management. Newborn screening for severe combined immunodeficiency can possibly be of prognostic value in CHH. Regular follow-up by a multidisciplinary team should be implemented to address immune dysfunction in all patients with CHH, also in asymptomatic cases. Haematopoietic stem cell transplantation can cure immune dysfunction, but its benefits in mildly symptomatic patients with CHH remain debatable. Further research is needed to understand the mechanisms behind the variability of clinical features, to search for potential molecular treatment targets, to examine and validate risk factors for early mortality outside the Finnish CHH cohort and to develop management guidelines. This review focuses on the pathogenesis, clinical course and management of CHH., (© 2020 The Authors. Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology.)

Background: Live viral vaccines are generally contraindicated in patients with combined immunodeficiency including cartilage-hair hypoplasia (CHH); however, they may be tolerated in milder syndromes. We evaluated the safety and efficacy of live viral vaccines in patients with CHH., Methods: We analyzed hospital and immunization records of 104 patients with CHH and measured serum antibodies to measles, mumps, rubella, and varicella zoster virus (VZV) in all patients who agreed to blood sampling ( n = 50). We conducted a clinical trial (ClinicalTrials.gov identifier: NCT02383797) of live VZV vaccine on five subjects with CHH who lacked varicella history, had no clinical symptoms of immunodeficiency, and were seronegative for VZV; humoral and cellular immunologic responses were assessed post-immunization., Results: A large proportion of patients have been immunized with live viral vaccines, including measles-mumps-rubella (MMR) ( n = 40, 38%) and VZV ( n = 10, 10%) vaccines, with no serious adverse events. Of the 50 patients tested for antibodies, previous immunization has been documented with MMR ( n = 22), rubella ( n = 2) and measles ( n = 1) vaccines. Patients with CHH demonstrated seropositivity rates of 96%/75%/91% to measles, mumps and rubella, respectively, measured at a medium of 24 years post-immunization. Clinical trial participants developed humoral and cellular responses to VZV vaccine. One trial participant developed post-immunization rash and knee swelling, both resolved without treatment., Conclusion: No serious adverse events have been recorded after immunization with live viral vaccines in Finnish patients with CHH. Patients generate humoral and cellular immune response to live viral vaccines. Immunization with live vaccines may be considered in selected CHH patients with no or clinically mild immunodeficiency., (Copyright © 2020 Vakkilainen, Kleino, Honkanen, Salo, Kainulainen, Gräsbeck, Kekäläinen, Mäkitie and Klemetti.)

In this study, a novel method of continuous coupling of immobilized enzymatic hydrolysis reactor and membrane separation (CIEH-MS) was used to isolate the immunomodulatory peptides from type II collagen (CII) in chick sternal cartilage. The immobilized neutral protease was successfully prepared with an activity of 400.5 U/g. The CIEH-MS system loaded with immobilized neutral protease had high operational stability with enzyme decay constant of 0.0077 and half-life of 89.61 hr. Using a CIEH-MS system, the immunomodulatory peptides were obtained with lymphocyte proliferation of 66.23%, peptide yield of 23.43%, degree of hydrolysis (DH) of 22.41%, and permeate flux of 6.17 L/m 2 h. The peptide fractions were further purified and the P 3-2-4 fraction (RGQLGPM) with 760.4 Da molecular weights exhibited the highest lymphocyte proliferation activity (85.54%) and binding ability to human leukocyte antigen-DRB1 (HLA-DRB1) molecules (133.2 ng/ml). The results demonstrated that CIEH-MS system is an effective way to obtain immunomodulatory peptides from CII. PRACTICAL APPLICATIONS: Chick sternal cartilage is one of the by-products of meat processing, and it is often discarded as waste or used for low-value purposes. CII is the most abundant collagen in chick sternal cartilage, and recently studies have demonstrated that CII peptides possess the ability to induce immunologic tolerance for the treatment of chronic disease. In order to find potential applications for this by-product, immunomodulatory peptides from CII hydrolysates in chick sternal cartilage were isolated using a novel CIEH-MS system. The result showed that CII peptides exhibited a high immunomodulatory activity, and had a potential application in functional foods and medical fields., (© 2019 Wiley Periodicals, Inc.)

Rationale: Spondyloenchondrodysplasia (SPENCD) is an autosomal recessive skeletal dysplasia by biallelic mutations in ACP5 gene encoding tartrate-resistant acid phosphatase (TRAP). The extra-osseous phenotype of SPENCD is pleiotropic and involves neurological impairment and immune dysfunction. Dentofacial abnormalities and orofacial symptoms in SPENCD patients have been little discussed in the literature., Patients Concerns: Herein we present clinical and radiological data regarding 2 siblings with SPENCD. Both patients exhibited short stature, cervical platyspondyly, growth disturbance with multiple skeletal deformities of the wrist, and systemic lupus erythematosus related autoimmunity. They experienced prolonged pain in the temporomandibular joint (TMJ) area and exhibited delayed dental development. One patient presented with midface hypoplasia, retrognathic mandible, and anterior openbite. Computed tomographic images demonstrated delayed spheno-occipital synchondrosis, obtuse cranial base angle, overdeveloped and anteriorly displaced sphenoidal sinuses, and compressed ethmoidal sinuses., Diagnosis: The genetic analysis revealed heterozygous for a missense mutations at ACP5 in both probands., Interventions: Routine follow-up with conservative treatment were conducted for 12 months., Outcomes: The elder sister's orofacial pain was relieved but the boy showed sustained masticatory and cervical muscle pain and TMJ arthralgia which had changed in accordance with systemic condition. No further teeth eruption or skeletal growth was observed in 2 siblings during the follow-up period., Lessons: These findings extend the phenotypic spectrum of SPENCD and indicate that compromised endochondral ossification and the loss of TRAP activity may affect altered dentofacial development and orofacial symptoms.

Background: Mutations in RMRP , encoding a non-coding RNA molecule, underlie cartilage-hair hypoplasia (CHH), a syndromic immunodeficiency with multiple pathogenetic mechanisms and variable phenotype. Allergy and asthma have been reported in the CHH population and some patients suffer from autoimmune (AI) diseases. Objective: We explored AI and allergic manifestations in a large cohort of Finnish patients with CHH and correlated clinical features with laboratory parameters and autoantibodies. Methods: We collected clinical and laboratory data from patient interviews and hospital records. Serum samples were tested for a range of autoantibodies including celiac, anti-cytokine, and anti-21-hydroxylase antibodies. Nasal cytology samples were analyzed with microscopy. Results: The study cohort included 104 patients with genetically confirmed CHH; their median age was 39.2 years (range 0.6-73.6). Clinical autoimmunity was common (11/104, 10.6%) and included conditions previously undescribed in subjects with CHH (narcolepsy, psoriasis, idiopathic thrombocytopenic purpura, and multifocal motor axonal neuropathy). Patients with autoimmunity more often had recurrent pneumonia, sepsis, high immunoglobulin (Ig) E and/or undetectable IgA levels. The mortality rates were higher in subjects with AI diseases ( χ ( 2 ) 2 = 14.056, p = 0.0002). Several patients demonstrated serum autoantibody positivity without compatible symptoms. We confirmed the high prevalence of asthma (23%) and allergic rhinoconjunctivitis (39%). Gastrointestinal complaints, mostly persistent diarrhea, were also frequently reported (32/104, 31%). Despite the history of allergic rhinitis, no eosinophils were observed in nasal cytology in five tested patients. Conclusions: AI diseases are common in Finnish patients with CHH and are associated with higher mortality, recurrent pneumonia, sepsis, high IgE and/or undetectable IgA levels. Serum positivity for some autoantibodies was not associated with clinical autoimmunity. The high prevalence of persistent diarrhea, asthma, and symptoms of inflammation of nasal mucosa may indicate common pathways of immune dysregulation.

Objective: To analyze the clinical characteristics of spondyloenchondrodysplasia with immune dysregulation (SPENCDI). Methods: The clinical manifestations, laboratory examinations, treatment and genetic analysis of a patient diagnosed with SPENCDI who was admitted to the Department of Pediatrics in Peking Union Medical College Hospital in October 2016 were analyzed. Then literature review was done after searching articles in PubMed and several Chinese databases with the key words "spondyloenchondrodysplasia with immune dysregulation" up to the date of November 2017. Results: A 12-year-old girl was admitted to local hospital for complaint of "recurrent fever over one month" in October 2016. She was diagnosed with type Ⅱ autoimmune hepatitis for abnormal liver function, elevated immunoglobulin G, positive anti-liver-kidney microsomal antibody and medium to severe interface hepatitis verified by liver biopsy. Systemic lupus erythematosus was also suspected based on positive antinuclear antibody and anti-dsDNA antibody, decreased complements, reduced white blood cells and hemoglobin. Methylprednisolone and azathioprine were started based on the diagnosis. However, she experienced mycoplasma pneumoniae and suspected fungal infections during the treatment. Detailed history revealed the history of developmental retardation since birth, and cerebral palsy diagnosed when she was 2 years old. She also underwent surgery at the age of eight for eversion of her right foot. Based on the abnormal findings of immune system, skeleton and nervous system, certain primary immunodeficiency disease was speculated. Gene sequencing was performed, which revealed compound heterozygous mutations in ACP5 gene (NM&#95;001111035.2) (c.798dupC, p. S267Lfs*20, paternal; c.716G>A, p. G239D, maternal). With X-ray of the vertebrae showed multiple platyspondyly, the diagnosis was corrected as SPENCDI and type Ⅱ autoimmune hepatitis. Then she was treated with prednisone (60 mg/d) and mycophenolate mofetil (1.5 g/d). All symptoms resolved on 3-month follow-up, with normalized activity indexes of autoimmune hepatitis and systemic lupus erythematosus. A total of 25 articles (1 Chinese, 24 English) were reviewed, with 74 SPENCDI patients reported. The most common manifestations were skeletal abnormalities (74/74, 100%), autoimmune diseases (47/74, 63.5%), dwarfism (45/74, 60.8%), and nervous system symptoms (25/74, 33.8%). A few patients with simple spondyloenchondrodysplasia were treated with growth hormone, and those who with autoimmune diseases were treated with immunosuppressants, all of whom were improved to certain extent. Conclusions: Vertebral and metaphyseal dysplasia, nervous system symptoms, and strong predisposition to autoimmune diseases are the hallmarks of SPENCDI. SPENCDI should be considered in dwarf with or without autoimmune diseases or nervous system symptoms.

In humans, the pathogenesis of diabetes is characterised by two major pancreatic β cell defects: a reduction in β cell mass and the failure of β cells to produce enough insulin. Over the past two decades, multiple studies involving cell cultures, animal models and human subjects have established the importance of the protein kinase RNA-like endoplasmic reticulum kinase (PERK) in the adaptive functional capacity of pancreatic β cells during embryonic development and into adulthood. In this review, we will highlight major findings identifying PERK as a crucial player in β cell physiology and in diabetes., (© 2017 Société Française des Microscopies and Société de Biologie Cellulaire de France. Published by John Wiley & Sons Ltd.)

Background: Mutations in the long noncoding RNA RNase component of the mitochondrial RNA processing endoribonuclease (RMRP) give rise to the autosomal recessive condition cartilage-hair hypoplasia (CHH). The CHH disease phenotype has some overlap with dyskeratosis congenita, a well-known "telomere disorder." RMRP binds the telomerase reverse transcriptase (catalytic subunit) in some cell lines, raising the possibility that RMRP might play a role in telomere biology., Objective: We sought to determine whether a telomere phenotype is present in immune cells from patients with CHH and explore mechanisms underlying these observations., Methods: We assessed proliferative capacity and telomere length using flow-fluorescence in situ hybridization (in situ hybridization and flow cytometry) of primary lymphocytes from patients with CHH, carrier relatives, and control subjects. The role of telomerase holoenzyme components in gene expression and activity were assessed by using quantitative PCR and the telomere repeat amplification protocol from PBMCs and enriched lymphocyte cultures., Results: Lymphocyte cultures from patients with CHH display growth defects in vitro, which is consistent with an immune deficiency cellular phenotype. Here we show that telomere length and telomerase activity are impaired in primary lymphocyte subsets from patients with CHH. Notably, telomerase activity is affected in a gene dose-dependent manner when comparing heterozygote RMRP carriers with patients with CHH. Telomerase deficiency in patients with CHH is not mediated by abnormal telomerase gene transcript levels relative to those of endogenous genes., Conclusion: These findings suggest that telomere deficiency is implicated in the CHH disease phenotype through an as yet unidentified mechanism., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Syndromic primary immunodeficiencies are rare genetic disorders that affect both the immune system and other organ systems. More often, the immune defect is not the major clinical problem and is sometimes only recognized after a diagnosis has been made based on extra-immunological abnormalities. Here, we report two sibling pairs with syndromic primary immunodeficiencies that exceptionally presented with a phenotype resembling early-onset common variable immunodeficiency, while extra-immunological characteristics were not apparent at that time. Additional features not typically associated with common variable immunodeficiency were diagnosed only later, including skeletal and organ anomalies and mild facial dysmorphism. Whole exome sequencing revealed KMT2A-associated Wiedemann-Steiner syndrome in one sibling pair and their mother. In the other sibling pair, targeted testing of the known disease gene for Roifman syndrome (RNU4ATAC) provided a definite diagnosis. With this study, we underline the importance of an early-stage and thorough genetic assessment in paediatric patients with a common variable immunodeficiency phenotype, to establish a conclusive diagnosis and guide patient management. In addition, this study extends the mutational and immunophenotypical spectrum of Wiedemann-Steiner and Roifman syndromes and highlights potential directions for future pathophysiological research.

Defective regulation of type I interferon response is associated with severe inflammatory phenotypes and autoimmunity. Type I interferonopathies are a clinically heterogenic group of Mendelian diseases with a constitutive activation of this pathway that might present as atypical, severe, early onset rheumatic diseases. Skin vasculopathy with chilblains and livedo reticularis, interstitial lung disease, and panniculitis are common. Recent studies have implicated abnormal responses to nucleic acid stimuli or defective regulation of downstream effector molecules in disease pathogenesis. As observed for IL1-β and autoinflammatory diseases, knowledge of the defects responsible for type I interferonopathies will likely promote the development of targeted therapy.

Purpose: Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in ACP5. We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases., Methods: We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations., Results: We observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy., Conclusions: Our data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia.

The triggering receptor expressed on myeloid cells (TREM) 2 is a member of the immunoglobulin superfamily of receptors and mediates signaling in immune cells via engagement of its co-receptor DNAX-activating protein of 12 kDa (DAP12). Homozygous mutations in TREM2 or DAP12 cause Nasu-Hakola disease, which is characterized by bone abnormalities and dementia. Recently, a variant of TREM2 has also been associated with an increased risk for Alzheimer disease. The selective expression of TREM2 on immune cells and its association with different forms of dementia indicate a contribution of this receptor in common pathways of neurodegeneration., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Type I interferonopathies are a group of Mendelian disorders characterized by a common physiopathology: the up-regulation of type I interferons. To date, interferonopathies include Aicardi-Goutières syndrome, familial chilblain lupus, spondyenchondromatosis, PRoteasome-associated auto-inflammatory syndrome (PRAAS) and Singleton-Merten syndrome. These diseases present phenotypic overlap including cutaneous features like chilblain lupus, that can be inaugural or present within the first months of life. This novel set of inborn errors of immunity is evolving rapidly, with recognition of new diseases and genes. Recent and improved understanding of the physiopathology of overexpression of type I interferons has allowed the development of targeted therapies, currently being evaluated, like Janus-kinases or reverse transcriptase inhibitors., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Microglia have been implicated in various neurological and psychiatric disorders in rodent and human postmortem studies. However, the dynamic actions of microglia in the living human brain have not been clarified due to a lack of studies dealing with in situ microglia. Herein, we present a novel technique for developing induced microglia-like (iMG) cells from human peripheral blood cells. An optimized cocktail of cytokines, GM-CSF and IL-34, converted human monocytes into iMG cells within 14 days. The iMG cells have microglial characterizations; expressing markers, forming a ramified morphology, and phagocytic activity with various cytokine releases. To confirm clinical utilities, we developed iMG cells from a patient of Nasu-Hakola disease (NHD), which is suggested to be directly caused by microglial dysfunction, and observed that these cells from NHD express delayed but stronger inflammatory responses compared with those from the healthy control. Altogether, the iMG-technique promises to elucidate unresolved aspects of human microglia in various brain disorders.

Purpose: To study the changes in the immunological status in 2 children with cartilage hair hypoplasia (CHH)., Methods: A 4-6 year immunological follow-up from infancy., Results: In infancy the children presented a combined T cell and B cell immunodeficiency which partly resolved in time. Mitogen-induced T cell proliferation values fluctuated but lymphopenia has remained constant. Both patients had no recent thymic emigrants (TREC). Both children have suffered from a prolonged viral infection. Hypogammaglobulinemia normalized during the first years of life but both children have a specific antibody deficiency (SAD)., Conclusions: The changes in the immunological status in CHH patients emphasize the importance of a regular follow-up. SAD should be searched for in CHH. The absence of TRECs supports combined immunodeficiency and possible need of hematopoietic stem cell transplantation.

The concept of grouping Mendelian disorders associated with an upregulation of type I interferon is not currently recognized in the medical literature. Here, we argue that such a concept has scientific validity and clinical utility. Specifically, we discuss a group of conditions, including Aicardi-Goutières syndrome, spondyloenchondrodysplasia, and cases of systemic lupus erythematosus with complement deficiency, in which an upregulation of type I interferons is apparently central to their pathogenesis. We believe that these diseases can usefully be considered to represent a novel set of inborn errors of immunity, and that the recognition of such diseases as type I interferonopathies will have significance in the development and use of targeted therapies., (© 2011 New York Academy of Sciences.)

Background: Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive disorder characterized by short-limbed skeletal dysplasia. Some patients also have defects in cell-mediated immunity and antibody production. Granulomatous inflammation has been described in patients with various forms of primary immunodeficiencies but has not been reported in patients with CHH., Objective: We sought to describe granulomatous inflammation as a novel feature in patients with CHH, assess associated immunodeficiency, and evaluate treatment options., Methods: In a retrospective observational study we collected clinical data on 21 patients with CHH to identify and further characterize patients with granulomatous inflammation., Results: Four unrelated patients with CHH (with variable degrees of combined immunodeficiency) had epithelioid cell granulomatous inflammation in the skin and visceral organs. Anti-TNF-α mAb therapy in 3 of these patients led to significant regression of granulomas. However, 1 treated patient had fatal progressive multifocal leukoencephalopathy caused by the JC polyomavirus. In 2 patients immune reconstitution after allogeneic hematopoietic stem cell transplantation led to the complete disappearance of granulomas., Conclusion: To the best of our knowledge, this is the first report of granulomatous inflammation in patients with CHH. Although TNF-α antagonists can effectively suppress granulomas, the risk of severe infectious complications limits their use in immunodeficient patients., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

DAP12, an immunoreceptor tyrosine-based activation motif-bearing adapter protein, is involved in innate immunity mediated by natural killer cells and myeloid cells. We show that DAP12-deficient mouse B cells and B cells from a patient with Nasu-Hakola disease, a recessive genetic disorder resulting from loss of DAP12, showed enhanced proliferation after stimulation with anti-IgM or CpG. Myeloid-associated immunoglobulin-like receptor (MAIR) II (Cd300d) is a DAP12-associated immune receptor. Like DAP12-deficient B cells, MAIR-II-deficient B cells were hyperresponsive. Expression of a chimeric receptor composed of the MAIR-II extracellular domain directly coupled to DAP12 into the DAP12-deficient or MAIR-II-deficient B cells suppressed B cell receptor (BCR)-mediated proliferation. The chimeric MAIR-II-DAP12 receptor recruited the SH2 domain-containing protein tyrosine phosphatase 1 (SHP-1) after BCR stimulation. DAP12-deficient mice showed elevated serum antibodies against self-antigens and enhanced humoral immune responses against T cell-dependent and T cell-independent antigens. Thus, DAP12-coupled MAIR-II negatively regulates B cell-mediated adaptive immune responses.

Background: Cartilage-hair hypoplasia (CHH) is characterized by metaphyseal dysplasia, bone marrow failure, increased risk of malignancies, and a variable degree of immunodeficiency. CHH is caused by mutations in the RNA component of the mitochondrial RNA processing (RMRP) endoribonuclease gene, which is involved in ribosomal assembly, telomere function, and cell cycle control., Objectives: We aimed to define thymic output and characterize immune function in a cohort of patients with molecularly defined CHH with and without associated clinical immunodeficiency., Methods: We studied the distribution of B and T lymphocytes (including recent thymic emigrants), in vitro lymphocyte proliferation, cell cycle, and apoptosis in 18 patients with CHH compared with controls., Results: Patients with CHH have a markedly reduced number of recent thymic emigrants, and their peripheral T cells show defects in cell cycle control and display increased apoptosis, resulting in poor proliferation on activation., Conclusion: These data confirm that RMRP mutations result in significant defects of cell-mediated immunity and provide a link between the cellular phenotype and the immunodeficiency in CHH., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Cartilage hair hypoplasia (CHH) is an autosomal recessive disorder caused by mutations in the ribonuclease mitochondrial RNA-processing (RMRP) gene. Although its most constant feature is metaphyseal dysplasia with short stature, CHH is associated with extraskeletal defects such as thin hair, anemia, immunodeficiency, and increased incidence of lymphomas. The spectrum of immunologic phenotypes in CHH translates into clinical severity. Whereas T-cell deficiency may remain subclinical or may result in severe combined immunodeficiency or Omenn syndrome, humoral immunodeficiency has only rarely been noted in these patients. Here we report the diagnosis of CHH in a woman who presented with severe short stature and a full-blown antibody deficiency, clinically resembling common variable immunodeficiency. Sequencing of the RMRP gene revealed compound heterozygosity for two novel mutations (g.68&#95;69delinsTT and g.76C>T). Despite the late onset of immunodeficiency in the patient, its clinical course was severe, and the patient died 3 years after the first diagnosis., (Copyright 2010 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

McKusick type metaphyseal chondrodysplasia, or cartilage hair hypoplasia (CHH), is a rare autosomal recessive osteochondrodysplasia secondary to a mutation in the RMRP gene. In addition to the metaphyseal chondrodysplasia and the short-limb dwarfism, patients may present with a multisystemic disease, associating immune deficiency with recurrent infantile or childhood infections, hematological abnormalities, and gastrointestinal dysfunction. The probability of malignancy is increased in these patients, as are disimmune manifestations. We report on a 12-year-old girl with a new mutation of the RMRP gene and a severe multisystemic CHH (hematological and pulmonary lesions, severe immune deficiency, arthritis, pancreatic insufficiency, malabsorption, chronic diarrhea) receiving parenteral nutrition who presented with acute symptomatic hypocalcemia and hypercalciuria associated with the presence of autoantibodies directed against the calcium-sensor receptor. At the same time, there was an important escalation of diarrhea. Corticosteroids led to a progressive improvement of biological signs (hypocalcemia, hypoparathyroidism). By contrast, gastrointestinal symptoms and malabsorption did not improve. To our knowledge, this is the first report of autoimmune hypoparathyroidism in CHH.

Cartilage-hair hypoplasia (CHH) is one of the well-known immuno-osseous dysplasias (IOD), which are a combination of skeletal dysplasia and immunodeficiency. It is characterized by disproportionate short stature, fine sparse hair, ligamentous laxity, hematological abnormalities with anemia, a predisposition to malignant tumors, and recurrent infections usually due to cellular and/or humoral immunodeficiency. However, there is a significant overlap of clinical findings among the other IODS such as Schimke's IOD. Here, we present a case of CHH with mild skeletal changes and immunological findings associated with recurrent otitis media, neutropenia, and lymphopenia. With this report, we once more emphasize the difficulty in assessing young individuals with CHH presenting with mild ectodermal findings and subtle radiographic changes.

Cartilage-hair hypoplasia is a short limbed skeletal dysplasia associated with impairments in host-defense. To better understand the clinical heterogeneity of this disorder, we studied 25 Amish patients with homozygous mutations in RMRP (RMRP 70 A>G). Despite mutation homogeneity, eight (32%) patients had severe or recurrent infections, two (8%) of these children underwent bone-marrow transplantation for combined immunodeficiency, and the remainder were healthy. Features distinguishing patients who underwent bone marrow transplantation from others were shorter birth length, and lower serum IgG, undetectable serum IgA, and elevated circulating NK cells before 2 years of age. Irrespective of clinical phenotype, most patients had lymphopenia and reduced lymphocyte proliferation to mitogens in vitro. Our cohort analysis suggests that many patients with cartilage-hair hypoplasia are at risk for infection susceptibility particularly during the first 2 years of life. Gauging this risk is difficult, and thus careful monitoring of all patients with cartilage-hair hypoplasia is warranted.

Background: Cartilage hair hypoplasia is an autosomal recessive type of metaphyseal chondrodysplasia, caused by mutations in the ribonuclease mitochondrial RNA processing (RMRP) gene. Typical features of cartilage hair hypoplasia include short stature, a predisposition to malignancy, and a variable degree of impairment of cellular immunity., Objective: We sought to describe the heterogeneity of clinical and immunologic phenotype in 12 consecutive patients with RMRP mutations who were referred to 2 different institutions for immunologic evaluation., Methods: We have retrospectively analyzed the clinical and laboratory features in 12 patients with molecular defects in the RMRP gene. T-cell repertoire was investigated by quantitating Vbeta families' expression and analyzing their diversity. T-cell receptor excision circle analysis was used to study thymic output., Results: All 12 patients had significant immune abnormalities, leading to severe immune deficiency in 9. CD8 lymphocytopenia was identified as a novel phenotype associated with RMRP mutations. Significant, even intrafamilial, phenotypic heterogeneity was observed. In 3 cases, severe immunodeficiency was the only phenotypic manifestation associated with RMRP mutations, a novel finding. Mutations leading to significant immune defects were most often located in the promoter, and the first case of a compound heterozygote for 2 such mutations is reported., Conclusion: This report broadens the spectrum of phenotypes associated with RMRP mutations and suggests that mutations in this gene should be considered when evaluating patients with combined immune deficiency, regardless of the presence of other manifestations.

Although the diagnosis of spondyloenchondrodysplasia (SPENCD) can only be made in the presence of characteristic metaphyseal and vertebral lesions, a recent report has highlighted the pleiotropic manifestations of this disorder which include significant neurological involvement and variable immune dysfunction. Here we present two patients, one of whom was born to consanguineous parents, further illustrating the remarkable clinical spectrum of this disease. Although both patients demonstrated intracranial calcification, they were discordant for the presence of mental retardation, spasticity and white matter abnormalities. And whilst one patient had features consistent with diagnoses of Sjögren syndrome, polymyositis, hypothyroidism and severe scleroderma, the other patient had clinical manifestations and an autoantibody profile of systemic lupus erythematosus. These cases further illustrate the association of SPENCD with immune dysregulation and highlight the differential diagnosis with Aicardi-Goutières syndrome and other disorders associated with the presence of intracranial calcification. Undoubtedly, identification of the underlying molecular and pathological basis of SPENCD will provide important insights into immune and skeletal regulation., (Copyright 2008 Wiley-Liss, Inc.)

Cartilage-hair hypoplasia is a rare, autosomal recessive primary immunodeficiency disorder characterized by predominantly T-cell deficiency and metaphyseal chondrodysplasia. The authors summarize current knowledge on molecular genetics, diagnostic characteristics and therapeutic options of this inherited immunodeficiency.

The association of cartilage hair hypoplasia (CHH) with severe combined immunodeficiency (SCID) has been known for more than three decades. Bone marrow transplantation (BMT) remains the only effective treatment that might cure SCID. Surprisingly little has been reported on the experience with BMT in CHH. We report here survival and long-term reconstitution of immunity after BMT in three patients with CHH. Regardless of whether a related human leukocyte antigen-matched or unrelated matched donors were used as the source of BMT, all patients are alive and well 5-20 years after BMT. Engraftment appears robust with most cells of donors origin. Repeated evaluation of the immune system showed normal cellular and humoral immunity. Our results should encourage the use of BMT in patients with CHH who have profound immunodeficiency.

Background: Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive multisystemic disorder caused by mutations of the SMARCAL 1 gene (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1)., Clinical Features: Main clinical features are: disproportional growth deficiency due to spondyloepiphyseal dysplasia, nephrotic syndrome with focal and segmental glomerulosclerosis, and defective cellular immunity. Patients with severe SIOD have life-limiting complications like cerebral ischemia due to vaso-occlusive processes. Only a few patients reached adulthood., Case Reports: The clinical course of four adult SIOD patients is presented., Conclusion: Even patients with severe SIOD can reach adulthood. Therefore, doctors working in the field of internal medicine and family doctors should be familiar with the clinical picture of SIOD.

Cartilage-hair hypoplasia (CHH), or McKusick type metaphyseal chondrodysplasia, was first recognized as a distinct entity in the Old Order Amish in the USA, but was later identified in other groups, and found to be unusually frequent among Finns. CHH is highly pleiotropic with manifestations that include short stature, defective cellular immunity and predisposition to several cancers. CHH is caused by mutations in the RNA component of RNase MRP (RMRP, ribonuclease mitochondrial RNA processing) and is transmitted as an autosomal recessive trait. In the present work, a Spanish CHH patient was extensively characterized at the immunological and molecular DNA level. Several parameters of cellular and humoral immunity were analyzed in this patient: lymphocyte subpopulation, proliferative responsiveness in mitogen stimulation and quantification of serum immunoglobulins. Sequencing of the RMRP gene allowed identification of two mutations in the patient: a +4 C>T substitution previously described on one allele, and a duplication of 15 nucleotides at position -11 on the other allele. This mutation has not previously been described.

We report two patients with Schimke immuno-osseous dysplasia (SIOD). SIOD is characterised by growth retardation, renal failure, spondylo-epiphyseal dysplasia, specific phenotype and defective cellular immunity. These two children demonstrated a bone dysplasia with characteristic radiographic appearances. We postulate that SIOD should be considered in all cases of growth failure with an unclassifiable bone dysplasia. Repeated urine tests for proteinuria could be helpful in reaching the correct diagnosis.

Unlabelled: Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive spondylo-epiphyseal dysplasia. The characteristic features of SIOD include 1) short stature with hyperpigmented macules and an unusual facies, 2) proteinuria with progressive renal failure, 3) lymphopenia with recurrent infections, and 4) cerebral ischaemia. Although 25 patients have been reported with this disorder, the clinical course and phenotype of SIOD are not well characterized. This report summarizes the clinical findings, course and treatment of reported patients and includes 14 additional patients with SIOD. We emphasize the high incidence of cerebral ischaemia and ocular abnormalities, define the high incidence of thyroid dysfunction and blood cytopenia, and confirm the absence of effective and durable medical therapies., Conclusion: Schimke immuno-osseous dysplasia is a multi-system autosomal recessive disorder with variable expression that affects the skeletal, renal, immune, vascular, and haematopoietic systems. Medical therapy is limited especially for more severely affected individuals.

The mesomelic chondrodysplasias are a heterogeneous group of dwarfing disorders characterized by shortness of the middle segments of limbs. We report on a 25-week fetus with disproportionate shortness of limbs with an apparently distinct form of mesomelic dysplasia. Radiographic findings at necropsy included ulnar deviation of hands, talipes equinovarus, distal tapering of the humeri, and hypoplastic fibulae, radii, and ulnae. Chondro-osseous morphology showed mild shortness of the physeal columns, overgrowth of perichondral bone, peripheral ingrowth of mesenchymal cells into the physis, and numerous areas of fibrillar degeneration with rings of collagen surrounding the chondrocytes. Ultrastructural findings included a degenerated territorial matrix, pericellular halos of collagen, and dilated loops of rough endoplasmic reticulum in chondrocytes. The radiographic appearance of the long bones is distinct from that of previously described mesomelic dysplasias. The chondro-osseous morphologic findings and the distal tapering of the humerus are somewhat reminiscent of atelosteogenesis type II, but the pattern of matrix degeneration and the presence of inclusion bodies in the chondrocytes distinguish it from disorders of sulfate transport.

Unlabelled: Cartilage-hair hypoplasia (CHH), an autosomal recessive chondrodysplasia, results in severe growth failure, sparse hair and impaired cellular immunity. Lymphocyte subpopulations and proliferative responsiveness in mitogen stimulation were analysed in 35 patients of whom 31% had an increased incidence of infections the year prior to the evaluation. Of the patients, 57% had a decreased CD4+ cell count which led to a decreased total count of T-lymphocytes in 52% and a subnormal CD4 +/CD8 + cell ratio in 32%. The B-lymphocyte count was usually normal. The natural killer cell count was above reference values in 40% of the patients. The lymphocyte stimulation indices as studied with phytohaemagglutinin , Concanavalin A and pokeweed mitogen were subnormal in 69%, 69% and 83% of the patients, respectively. The numbers of lymphocytes, T-lymphocytes and CD4+ cells, and the pokeweed mitogen stimulation index. but not the other measured parameters, correlated significantly with the proness to infections during the preceding year. However, the correlation was reverse with higher counts in the patients who had had recurring infections. The observed significant correlations may reflect immunological stimuli caused by recurring infections., Conclusion: The presently used parameters of cellular immunity poorly predict the clinical outcome of an individual cartilage-hair hypoplasia patient. All patients, irrespective of their in vitro immunological competence, have to be carefully followed because of possibility of serious infections and malignancies.

Unlabelled: Schimke immuno-osseous dysplasia is a multisystem disorder consisting of spondylo-epiphysial dysplasia, progressive renal insufficiency due to focal segmental glomerulosclerosis, and immunodeficiency. Cerebrovascular complications have only been described in five patients. Here we report a patient with prominent neurological symptoms most likely caused by transient ischaemic attacks., Conclusion: Neurological symptoms consisted of repeated brief spells of hemiparaesthesia, motoric aphasia and diplopia. MRI studies of the CNS revealed progressive white matter lesions. Morphological changes as well as neurological deficits are compatible with cerebral ischaemia.

Cartilage hair hypoplasia is a rare autosomal recessive form of short-limbed dwarfism associated with a cellular immunodeficiency. In eight patients, the authors studied the presence of T cell subsets and in vitro T cell function in order to address the basis for the immunological disorder. Both the proliferative response to phytohaemagglutinin (PHA) and the PHA-induced IL2 production were 60% lower compared with controls (P = 0.007 and 0.005, respectively). The impaired proliferative response could not be restored by addition of IL-2. This result is in accordance with a decrease in the percentage of activated T cells expressing the p55 subunit of the IL-2 receptor complex (CD25). The results define more precisely that T cells from cartilage hair hypoplasia patients are defective in the transition from the G0 to the G1 phase of the cell cycle. Furthermore, the data demonstrate that several CHH patients show a reduced proportion of CD45RA+ 'naive' T cells. However, the in vitro impairment of T cell function cannot solely be explained by imbalance between 'naive' and 'memory' T cells. Although CHH patients with a history of recurrent respiratory tract infections showed the most aberrant in vitro immune parameters, a clear relationship between clinical data and in vitro parameters could not be established for the whole patient group.

We report a 3-year-old girl with the association of spondyloepiphyseal dysplasia, nephrotic syndrome, and signs of defective cellular immunity. The findings are similar to those reported by Spranger et al., which have become known as Schimke immunoosseous dysplasia.

Unlabelled: We diagnosed cartilage-hair hypoplasia (CHH) in a female child with prenatal-onset short stature, metaphyseal chondrodysplasia, and severe combined immunodeficiency leading to recurrent, severe respiratory tract infections. The patient required several hospital admissions during her 1st year of life and failed to thrive in spite of antimicrobial therapy and hypercaloric nutrition. Bone marrow transplantation (BMT) from an HLA-identical sister was performed at age 16 months after conditioning with busulphan and cyclophosphamide, using 9 x 10(8) nucleated bone marrow cells/kg body weight. Graft-versus-host disease prophylaxis consisted of cyclosporine and methotrexate. The post-transplantation period was uneventful. She developed full and sustained chimerism as demonstrated by DNA analysis of granulocytes and mononucleated cells on days 44, 69 and 455 post BMT. Cellular immunity was completely reconstituted at 4 months, humoral immunity at 15 months post BMT. The patient is alive and well 24 months post BMT without medication, but the radiological osseous changes persist, and longitudinal growth remains markedly below the 10th percentile for CHH standards; her height at age 3 years 4 months is 66 cm., Conclusion: In this patient with unusually severe CHH, bone-marrow transplantation has fully corrected the immune deficiency but has had no influence on the course of the chondrodysplasia.

We report on a 1 year old boy with cartilage-hair hypoplasia (CHH). He suffered from recurrent upper respiratory infections and short-limbed dwarfism. As with most patients with CHH, he had impaired cellular immunity as determined by lymphocyte reactivity. In addition, he had a selective IgG2 deficiency. This combination of immunodeficiencies has not previously been reported for patients with CHH. His recurrent upper respiratory infections were likely to be associated with cellular immunodeficiency and IgG2 deficiency.

We describe a case of semi-lethal chondrodysplasia with skeletal manifestations, detectable at birth, typical of the round femoral inferior epiphysis dysplasia (RFIED) or 'Glasgow' variant. Immunological abnormalities and Hirschsprung disease, so far described only in cartilage hair hypoplasia (CHH), were documented during the first months of life in our patient. These findings confirm the hypothesis that RFIED is a form of CHH with early infantile onset.