Cartilage-hair hypoplasia (CHH) is a skeletal dysplasia with combined immunodeficiency, variable clinical course and increased risk of malignancy. Management of CHH is complicated by a paucity of ...long-term follow-up data, as well as knowledge on prognostic factors. We assessed clinical course and risk factors for mortality in a prospective cohort study of 80 patients with CHH recruited in 1985-1991 and followed up until 2016. For all patients we collected additional health information from health records and from the national Medical Databases and Cause-of-death Registry. The primary outcome was immunodeficiency-related death, including death from infections, lung disease and malignancy. Standardized mortality ratios (SMRs) were calculated using national mortality rates as reference. Half of the patients (57%,
= 46) manifested no symptoms of immunodeficiency during follow-up while 19% (
= 15) and 24% (
= 19) demonstrated symptoms of humoral or combined immunodeficiency, including six cases of adult-onset immunodeficiency. In a significant proportion of patients (17/79, 22%), clinical features of immunodeficiency progressed over time. Of the 15 patients with non-skin cancer, eight had no preceding clinical symptoms of immunodeficiency. Altogether 20 patients had deceased (SMR = 7.0, 95%CI = 4.3-11); most commonly from malignancy (
= 7, SMR = 10, 95%CI = 4.1-21) and lung disease (
= 4, SMR = 46, 95%CI = 9.5-130). Mortality associated with birth length below -4 standard deviation (compared to normal, SMR/SMR ratio = 5.4, 95%CI = 1.5-20), symptoms of combined immunodeficiency (compared to asymptomatic, SMR/SMR ratio = 3.9, 95%CI = 1.3-11), Hirschsprung disease (odds ratio (OR) 7.2, 95%CI = 1.04-55), pneumonia in the first year of life or recurrently in adulthood (OR = 7.6/19, 95%CI = 1.3-43/2.6-140) and autoimmunity in adulthood (OR = 39, 95%CI = 3.5-430). In conclusion, patients with CHH may develop adult-onset immunodeficiency or malignancy without preceding clinical symptoms of immune defect, warranting careful follow-up. Variable disease course and risk factors for mortality should be acknowledged.
Clinical features of the 7 subjects with SAD included rhinosinusitis (n = 6), otitis media (n = 5), warts (n = 3), malignancies (n = 3; lymphoma, basal cell carcinoma, uterus carcinoma), severe ...varicella requiring hospitalization (n = 2), and recurrent herpes simplex virus infection (n = 1). Because mortality due to infections and malignancies is increased in CHH,4 patients surviving into adulthood represent individuals with milder disease. Worldwide, of the 30 subjects with CHH and hematopoietic stem cell transplantation (HSCT) whose genotype has been reported, only 6 patients were homozygous for g.70A>G mutation.6-9 Only 1 Finnish child with CHH, homozygote for g.70A>G mutation, has required HSCT for severe hypoplastic anemia, not for immunodeficiency. ...selection of patients who would benefit from HSCT based on routinely available laboratory parameters is highly cumbersome in a cohort carrying predominantly RMRP g.70A>G mutations. Laboratory parameter Children <18 y (n = 15)∗ Adults 18-45 y (n = 23)∗ Adults >45 y (n = 18)∗ Patients with symptoms of CID∗ Patients without symptoms of CID∗ P value Neutrophils 2.45‡ 3.91 4.36‡ .005 Naive thymic T cells† 0.009 0.036 .022 CD3+ cells 0.66 0.93 .048 CD4+ cells 0.514 0.487‡ 0.699‡ .038 CD8+ cells 0.22 0.33 .018 CD19+ cells 0.150‡ 0.085‡ 0.120 .014 IgA 1.42‡ 1.80 2.75‡ .006 IgG 9.2‡ 10.5 11.7‡ .027 IgG2 1.25‡ 1.98 2.19‡ .034 Antibodies to tetanus toxoid (IU/mL) 0.35‡ 3.50‡ 1.50 .002 1 M.A. de la Fuente, M. Recher, N.L. Rider, K.A. Strauss, D.H. Morton, M. Adair, Reduced thymic output, cell cycle abnormalities,...
Netherton syndrome (NS) is a rare life-threatening syndrome caused by SPINK5 mutations leading to a skin barrier defect and a severe atopic diathesis. NS patients are prone to bacterial infections, ...but the understanding of the underlying immune deficiency is incomplete.
We analyzed blood lymphocyte phenotypes and function in relation to clinical infections in 11 Finnish NS patients, aged 3 to 17 years, and healthy age-matched controls. The proportion of B cells (CD19
) and naïve B cells (CD27
, IgD
) were high while memory B cells (CD27
) and switched memory B cells (CD27
IgM
IgD
), crucial for the secondary response to pathogens, was below or in the lowest quartile of the reference values in 8/11 (73%) and 9/11 (82%) patients, respectively. The proportion of activated non-differentiated B cells (CD21
, CD38l
) was below or in the lowest quartile of the reference values in 10/11 (91%) patients. Despite normal T cell counts, the proportion of naïve CD4
T cells was reduced significantly and the proportion of CD8
T central memory significantly elevated. An increased proportion of CD57
CD8
T cells indicated increased differentiation potential of the T cells. The proportion of cytotoxic NK cells was elevated in NS patients in phenotypic analysis based on CD56DIM, CD16
and CD27
NK cells but in functional analysis, decreased expression of CD107a/b indicated impaired cytotoxicity. The T and NK cell phenotype seen in NS patients also significantly differed from that of age-matched atopic dermatitis (AD) patients, indicating a distinctive profile in NS. The frequency of skin infections correlated with the proportion of CD62L
T cells, naïve CD4
and CD27
CD8
T cells and with activated B cells. Clinically beneficial intravenous immunoglobulin therapy (IVIG) increased naïve T cells and terminal differentiated effector memory CD8
cells and decreased the proportion of activated B cells and plasmablasts in three patients studied.
This study shows novel quantitative and functional aberrations in several lymphocyte subpopulations, which correlate with the frequency of infections in patients with Netherton syndrome. IVIG therapy normalized some dysbalancies and was clinically beneficial.
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.
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 (
= 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.
A large proportion of patients have been immunized with live viral vaccines, including measles-mumps-rubella (MMR) (
= 40, 38%) and VZV (
= 10, 10%) vaccines, with no serious adverse events. Of the 50 patients tested for antibodies, previous immunization has been documented with MMR (
= 22), rubella (
= 2) and measles (
= 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.
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.
Desmoplakin (DSP) and Desmoglein 1 (DSG1) variants result in skin barrier defects leading to erythroderma, palmoplantar keratoderma and variable AQ4 other features. Some DSG1 variant carriers present ...with SAM syndrome (Severe dermatitis, multiple Allergies, Metabolic wasting) and a SAM-like phenotype has been reported in 4 subjects with different heterozygous DSP variants. We report here a patient with a novel DSP spectrin region (SR) 6 variant c.1756C>T, p.(His586Tyr), novel features of brain lesions and severe recurrent mucocutaneous herpes simplex virus infections, with a favourable response to ustekinumab. Through a review of reported cases of heterozygous variants in DSP SR6 (n = 15) and homozygous or compound heterozygous variants in DSG1 (n = 12) and SAM-like phenotype, we highlight phenotypic variability. Woolly hair, nail abnormalities and cardiomyopathy characterize patients with DSP variants, while elevated immunoglobulin E and food allergies are frequent in patients with DSG1 variants. Clinicians should be aware of the diverse manifestations of desmosomopathies.
Mutations in
, 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.
We explored AI and allergic manifestations in a large cohort of Finnish patients with CHH and correlated clinical features with laboratory parameters and autoantibodies.
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.
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 (
= 14.056,
= 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.
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.
Cartilage–hair hypoplasia (CHH) is a syndromic inborn error of immunity caused by variants in the RMRP gene. Disease manifestations vary, and their ability to predict outcome is uncertain. The ...optimal management of infants with CHH who do not fulfill classical severe combined immunodeficiency (SCID) criteria is unknown.
We described longitudinal changes in lymphocyte counts during childhood and explored correlations of early childhood clinical and laboratory features with clinical outcomes on long-term follow-up of CHH patients.
Immunologic laboratory parameters, birth length, the presence of Hirschsprung disease, and severe anemia correlated to the primary end points of respiratory and severe infections. We implemented traditional statistical methods and machine learning techniques.
Thirty-two children with CHH were followed up for 2.7 to 22.1 years (median, 8.2 years, in total 331.3 patient-years). None of the patients had classical SCID. Median lymphocyte subclass counts, apart from CD16+/56+ cells, were subnormal throughout childhood, but did not show age-related decline seen in healthy children. Low immunoglobulin levels were uncommon and often transient. Respiratory and/or severe infections developed in 14 children, 8 of whom had low naive T-cell counts, absent T-cell receptor excision circles, and/or partial “leaky” SCID–level lymphopenia. Shorter birth length correlated with lower lymphocyte counts and the occurrence of infections. Of the laboratory parameters, decreased naive T-cell counts and abnormal lymphocyte proliferation responses contributed most to the development of severe infections. In addition, all participants with absent T-cell receptor excision circles developed severe infections. Opportunistic infections occurred only in children with leaky SCID–level lymphopenia.
Shorter birth length and a combination of laboratory abnormalities can predict the development of severe infections in children with CHH.
In patients with immunodeficiency, lung disease such as BE or parenchymal changes contribute to poorer prognosis.6 Out of 8 previously reported patients with BE, 1 died from pneumonia at 58 years; ...others had significant respiratory symptoms and 6 suffered from pneumonia.1 BE was progressive in all those with longitudinal follow-up extending to adulthood.1 Another report described a young adult with CHH, frequent infectious exacerbations and rapid progression of BE, leading to fatal septicemic pneumonia within 2 years.9 We previously reported higher IgG levels in infection-prone patients with CHH.2 Here, we find the same trend, as well as higher white blood cells, total lymphocyte, and CD16/56+ cell counts in CHH patients with BE. Supplementary data Online Repository textFig E1 Characteristics Normal values for adultslow * Patients with BE Patients without BE P value Median age (y) (range)  59.5 (29-68) 36.5 (13-68) .023dagger Sex  F 70% (7 of 10)M 30% (3 of 10) F 88% (21 of 24)M 12% (3 of 24) .328 History of chronic cough  50% (5 of 10) 17% (4 of 24) .085 History of sinusitis  90% (9 of 10) 63% (15 of 24) .215 History of otitis media  70% (7 of 10) 75% (18 of 24) 1 History of pneumoniadouble dagger  30% (3 of 10) 21% (5 of 24) .666 History of physician-diagnosed asthma  30% (3 of 10) 29% (7 of 24) 1 History of allergic rhinitis  60% (6 of 10) 38% (9 of 24) .276 History of smoking  40% (4 of 10) 8% (2 of 24) .048 Previous or ongoing IVIG substitution  0% (0 of 10) 17% (4 of 24) .296 IgG (g/L) 6.8-15.0 13.0 (10.1-15.7) 10.6 (6.2-15.9) .013 IgG2 (g/L) 1.50-6.40 2.03 (0.27-4.01) 2.00 (0.55-4.52) .755 IgG3 (g/L) 0.20-1.10 0.43 (0.17-1.17) 0.45 (0.12-1.20) .724 IgG4 (g/L) 0.08-1.40 0.09 (0.00-0.82) 0.08 (0.00-0.47) .724 IgA (g/L) M 0.88-4.84F 0.52-4.02 2.82 (1.24-4.95) 1.83 (0.00-7.49) .086 IgM (g/L) M 0.36-2.59F 0.47-2.84 0.89 (0.28-2.47) 0.99 (0.20-3.06) .512 IgE (kU/L) 0-100 34 (10-98) 13 (2-254) .205 WBC (x109 cells/L) 3.4-8.2 6.8 (4.7-12.0) 4.8 (1.2-11.1) .034 Neutrophil count (x109 cells/L) 1.5-6.7 4.26 (2.22-8.40) 3.31 (0.28-7.88) .137 Total lymphocyte count (x109 cells/L) 1.3-3.6 1.76 (1.16-3.25) 1.21 (0.26-2.22) .008 CD3+ cell count (x109 cells/L) 0.85-2.28 1.24 (0.57-3.01) 0.90 (0.16-1.91) .051 CD4+ cell count (x109 cells/L) 0.458-1.406 0.711 (0.353-1.287) 0.524 (0.118-1.312) .123 CD8+ cell count (x109 cells/L) 0.24-0.98 0.52 (0.15-1.72) 0.30 (0.04-0.76) .068 CD3/CD4/CD45RA/CD31+ cell count (x109 cells/L) 0.05-2.4 0.011 (0.003-0.171) 0.030 (0.000-0.247) .269 CD16/56+ cell count (x109 cells/L) 0.08-0.57 0.25 (0.11-0.55) 0.14 (0.07-0.36) .008 CD19+ cell count (x109 cells/L) 0.12-0.43 0.11 (0.04-0.22) 0.11 (0.00-0.28) .524 CD27+ IgD+ B-cell count (cells/μL) 9-88 5,9 (2.9-13.3) 6.5 (0.0-20.9) .603 CD27+ IgD- B-cell count (cells/μL) 13-122 12.8 (3.9-59.6) 10.6 (0.0-63.8) .269 Antibodies to tetanus toxoid (IU/mL) >0.1 2.85 (0.07-4.60) 2.35 (0.05-8.90) .621 Good response to immunization with PPV (no. of serotypes)§ 7 4 (3-5) 6 (1-7) .773 Table I Comparison of clinical and laboratory characteristics of patients with and without BE Values for laboratory parameters are presented as median (range).
Abnormalities of dendritic cells (DCs) and STAT proteins have been reported in Crohn's disease (CD). Studies on JAK/STAT signaling in DCs are, however, lacking in CD. We applied a flowcytometric ...single-cell-based phosphoepitope assay to evaluate STAT1 and STAT3 pathways in DC subsets from CD patients. In addition, circulating DC counts were determined, together with the activation-related immunophenotype. We found that IL-6- and IFN-α-induced STAT3 phosphorylation and IFN-α-induced STAT1 phosphorylation were impaired in plasmacytoid DCs (pDCs) from CD patients (P = 0.005, P = 0.013, and P = 0.006, respectively). In myeloid DCs (mDCs), IFN-α-induced STAT1 and STAT3 phosphorylation were attenuated (P<0.001 and P = 0.048, respectively), but IL-10-induced STAT3 phosphorylation was enhanced (P = 0.026). IFN-γ-induced STAT1 signaling was intact in both DC subtypes. Elevated plasma IL-6 levels were detected in CD (P = 0.004), which strongly correlated with disease activity (ρ = 0.690, P<0.001) but not with IL-6-induced STAT3 phosphorylation. The numbers of pDCs and BDCA3+ mDCs were decreased, and CD40 expression on CD1c+ mDCs was increased in CD. When elucidating the effect of IL-6 signaling on pDC function, we observed that IL-6 treatment of healthy donor pDCs affected the maturation of and modified the T-cell priming by pDCs, favoring Th2 over Th1 type of response and the expression of IL-10 in T cells. Our results implicate DC signaling in human CD. Reduced IL-6 responsiveness in pDCs, together with the attenuated IFN-α-induced signaling in both DC subtypes, may contribute to the immunological dysregulation in CD patients.
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