Immunodeficiency in cartilage-hair hypoplasia : correlation with pulmonary disease, infections and malignancy

Cartilage-hair hypoplasia (CHH) is a rare chondrodysplasia with short stature, hair hypoplasia, variable degree of immunodeficiency and increased risk of malignancy. The non-coding RNA gene RMRP is mutated in CHH. The gene has multiple functions, including cell cycle regualtion. Several aspects of CHH remain inadequately explored, including the pathogenesis, detailed characteristics of immunologic phenotype, correlations of clinical and laboratory features, as well as disease course and prognosis. To address these questions, we recruited and carefully examined a large cohort of Finnish children and adults with CHH. We performed detailed immunologic evaluation, explored the prevalence of bronchiectasis and compared the diagnostic performance of lung high-resolution computed tomography (HRCT) and magnetic resonance imaging (MRI). We also conducted a prospective 30-year follow-up study to identify factors associated with adverse outcomes. In addition, we investigated the role of telomere machinery in the pathogenesis of CHH by measuring relative telomere length (RTL). Study patients (n=56) demonstrated specific abnormalities in B and T cell compartments: 1) decreased thymic naive, naive CD4+ and CD8+ T cells; 2) increased activated CD4+, central memory CD4+ and effector memory CD8+ T cells; 3) normal regulatory T cells; 4) decreased naive, transitional and memory B cells; and 5) increased activated B cells. Specific antibody deficiency was demonstrated in the majority of patients immunized with unconjugated pneumococcal vaccine. No significant correlations were observed between clinical and laboratory features. Children with CHH demonstrated significantly shorter median RTL compared with healthy controls. HRCT showed bronchiectasis in 10/34 patients (29%), justifying lung evaluation also in those without apparent immunodeficiency. Lung MRI was comparable to HRCT in the assessment of bronchiectasis and could be implemented in the follow-up of lung changes. In the prospective study of 80 subjects with CHH, in a significant proportion of patients (17/79, 22%) clinical features of immunodeficiency progressed over time, including six cases of adult-onset immunodeficiency. Of the 15 subjects with non-skin malignancy, eight demonstrated no preceding symptoms of immunodeficiency. These findings call for careful follow-up and screening for cancer even in asymptomatic patients. Altogether 20/80 patients had died during the follow-up, and causes of death included pneumonia (n = 4), malignancy (n = 7) and pulmonary disease (n = 4). Increased mortality was associated with severe short stature at birth, Hirschsprung disease, pneumonia, autoimmunity and symptoms of combined immunodeficiency. In addition, warts in adulthood and actinic keratosis were associated with the development of skin cancer. The study findings should be considered when establishing management guidelines for patients with CHH.Rusto-hiushypoplasia (RHH) on harvinainen luustosairaus, jonka oireisiin kuuluvat kasvuhäiriön lisäksi hiusten hentous, elimistön puolustuskyvyn heikkous ja lisääntynyt syöpäriski. Huolimatta vuosien tutkimustyöstä, monet sairauden piirteet tunnetaan edelleen puutteellisesti. Sairauden solutason mekanismit, puolustuskyvyn yksityiskohtaiset ominaisuudet ja niiden yhteys oireisiin, sekä taudin kulku ja ennuste ovat edelleen osin tuntemattomia. Saadaksemme näistä seikoista lisätietoa, tutkimme suomalaisia RHH:aa sairastavia lapsia ja aikuisia. Teimme yksityiskohtaisen puolustuskyvyn arvioinnin, tutkimme kroonisten keuhkomuutosten esiintyvyyttä ja vertasimme eri kuvantamistutkimusten - keuhkojen tietokonetomografia (TT) ja magneettikuvaus (MK) – tarkkuutta keuhkomuutosten diagnostiikassa. Suoritimme myös 30-vuotisen seurantatutkimuksen ennusteeseen liittyvien tekijöiden tunnistamiseksi. Lisäksi tutkimme telomeerien piirteitä RHH:ssa mittaamalla suhteellisen telomeeripituuden. Immunologisiin tutkimuksiin osallistuneilla 56 potilailla löydettiin runsaasti muutoksia puolustussolujen kokonaismäärässä ja alaryhmissä sekä poikkeavat rokotevasteet. Oireiden ja laboratorioarvojen välillä ei havaittu merkittäviä yhteyksiä. Telomeerien pituus oli RHH:aa sairastavilla lapsilla huomattavasti lyhyempi kuin verrokeilla, viitaten RHH:n taustalla olevan geenivirheen vaikuttavan telomeerien ylläpitoon. Merkittävällä osalla potilaista löytyi keuhkoputkien laajenemia (bronkiektasioita) (10/34, 29%) TT-kuvauksella. Keuhkojen MK-tulokset olivat verrattavissa TT-tuloksiin keuhkoputkien arvioinnissa ja MK:ta voidaan siten käyttää keuhko-muutosten seurannassa. Keuhkojen tilanteen arviointi on aiheellista myös niillä RHH-potilailla, joilla ei ole merkkejä häiriintyneestä puolustuskyvystä. Laajassa 80 potilaan pitkäaikaisessa (keskimäärin 30 vuotta) seurantatutkimuksessa merkittävällä osalla potilaista (17/79, 22 %) puolustuskyvyn heikkous paheni iän myötä; kuudelle näistä potilaista kehittyi myöhäinen puolustuskyvyn heikkous aikuisiässä. Yli puolella syöpään (ihosyöpä pois lukien) sairastuneista potilaista (8/15, 53 %) ei ollut edeltäviä merkkejä häiriintyneestä puolustuskyvystä. Nämä löydökset ovat peruste potilaiden tarkkaan seurantaan ja syövän seulontaan myös oireettomilla potilailla. Seurannan aikana 80 potilaasta kuoli yhteensä 20, mm. keuhkokuumeeseen (4), syöpään (7) ja keuhkosairauksiin (4). Useat tekijät lisäsivät varhaisen kuoleman riskiä, mukaan lukien lyhyempi syntymäpituus, Hirschsprungin tauti, keuhkokuume, autoimmuunitaudit ja tietyt puolustuskyvyn poikkeavuudet. Lisäksi aikuisiän syylillä ja aurinkokeratoosilla oli yhteyttä ihosyövän kehittymiseen. Tutkimustuloksemme antavat arvokasta tietoa RHH:an piirteistä ja ennusteesta ja tuloksia voidaan hyödyntää potilaiden hoitosuositusten laadinnassa

Outcomes of 42 pregnancies in 14 women with cartilage-hair hypoplasia : a retrospective cohort study

Background Cartilage-hair hypoplasia (CHH) is a rare skeletal dysplasia characterized by disproportionate short stature, immunodeficiency, anemia and risk of malignancies. All these features can affect pregnancy and predispose to maternal and fetal complications. This study aimed to evaluate obstetric history and maternal and fetal outcomes in women with CHH. Methods Among 47 Finnish women with CHH, we identified 14 women with ICD codes related to pregnancies, childbirth and puerperium in the National Hospital Discharge Registry and obtained detailed data on gynecologic and obstetric history with a questionnaire. Offspring birth length and weight were collected and compared with population-based normal values. Results There were altogether 42 pregnancies in 14 women (median height 124 cm, range 105-139 cm; 4 ' 1 '', range 3 ' 5 ''-4 ' 7 ''). Twenty-six pregnancies (62%), including one twin pregnancy, led to a delivery. Miscarriages, induced abortions and ectopic pregnancies complicated 9, 5, and 2 pregnancies, respectively. Severe pregnancy-related complications were rare. All women with CHH delivered by cesarean section, mostly due to evident cephalo-pelvic disproportion, and in 25/26 cases at full-term. In the majority, the birth length (median 48 cm, range 45.5-50 cm; 1 ' 7 '', range 1 ' 6 ''-1 ' 8 '') and weight (3010 g, range 2100-3320 g; 6.6 lb, range 4.6-7.3 lb) of the offspring in full-term singleton pregnancies was normal. Conclusions Despite CHH mothers' significant short stature and other potential CHH-related effects on pregnancy outcome, most pregnancies lead to a term cesarean section delivery. Since fetal growth was generally unaffected, cephalo-pelvic disproportion was evident and planned cesarean section should be contemplated in term pregnancies.Peer reviewe

Immunodeficiency in cartilage-hair hypoplasia : Pathogenesis, clinical course and management

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 theRMRPgene, 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.Peer reviewe

Gynecologic assessment of 19 adult females with cartilage-hair hypoplasia - high rate of HPV positivity

BackgroundPatients with cartilage-hair hypoplasia (CHH), a rare metaphyseal chondrodysplasia, manifest severe growth failure, variable immunodeficiency and increased risk of malignancies. The impact of CHH on gynecologic and reproductive health is unknown. Vulnerability to genital infections may predispose CHH patients to prolonged human papillomavirus (HPV) infections potentially leading to cervical, vaginal and vulvar cancer.MethodsWe carried out gynecologic evaluation, pelvic ultrasound and laboratory assessment in 19 women with genetically confirmed CHH. All patients were clinically examined and retrospective data were collected from hospital records.ResultsThe women ranged in age from 19.2 to 70.8years (median 40.8years) and in height from 103 to 150cm (median 123cm). All women had undergone normal pubertal development as assessed by breast development according to Tanner scale and by age of menarche (mean 12.5yrs., range 11-14yrs). Despite significant short stature and potentially small pelvic diameters, a well-developed uterus with fairly normal size and shape was found by pelvic ultrasound in mostof the patients. Ovarian follicle reserve, assessed by ultrasound was normal in relation to age in all premenopausal women it could be assessed (12 cases). Anti-Mullerian hormone was normal in relation to age in 17 women (89%). HPV was detected in 44% (8/18) and three women carried more than one HPV serotype; findings did not associate with immunological parameters. Three patients had a concurrent cell atypia in Pap smear.ConclusionsPubertal development, reproductive hormones and ovarian structure and function were usually normal in women with CHH suggesting fairly normal reproductive health. However, the immunodeficiency characteristic to CHH may predispose the patients to HPV infections. High prevalence of HPV infections detected in this series highlights the importance of careful gynecologic follow up of these patients.Peer reviewe

Outcome of children with ESBL-E. coli acute pyelonephritis treated with cephalosporins

Non peer reviewe

Gynecologic assessment of 19 adult females with cartilage-hair hypoplasia – high rate of HPV positivity

Abstract Background Patients with cartilage-hair hypoplasia (CHH), a rare metaphyseal chondrodysplasia, manifest severe growth failure, variable immunodeficiency and increased risk of malignancies. The impact of CHH on gynecologic and reproductive health is unknown. Vulnerability to genital infections may predispose CHH patients to prolonged human papillomavirus (HPV) infections potentially leading to cervical, vaginal and vulvar cancer. Methods We carried out gynecologic evaluation, pelvic ultrasound and laboratory assessment in 19 women with genetically confirmed CHH. All patients were clinically examined and retrospective data were collected from hospital records. Results The women ranged in age from 19.2 to 70.8 years (median 40.8 years) and in height from 103 to 150 cm (median 123 cm). All women had undergone normal pubertal development as assessed by breast development according to Tanner scale and by age of menarche (mean 12.5 yrs., range 11–14 yrs). Despite significant short stature and potentially small pelvic diameters, a well-developed uterus with fairly normal size and shape was found by pelvic ultrasound in most of the patients. Ovarian follicle reserve, assessed by ultrasound was normal in relation to age in all premenopausal women it could be assessed (12 cases). Anti-Müllerian hormone was normal in relation to age in 17 women (89%). HPV was detected in 44% (8/18) and three women carried more than one HPV serotype; findings did not associate with immunological parameters. Three patients had a concurrent cell atypia in Pap smear. Conclusions Pubertal development, reproductive hormones and ovarian structure and function were usually normal in women with CHH suggesting fairly normal reproductive health. However, the immunodeficiency characteristic to CHH may predispose the patients to HPV infections. High prevalence of HPV infections detected in this series highlights the importance of careful gynecologic follow up of these patients

Rusto-hiushypoplasiaa sairastavat tarvitsevat tarkkaa seurantaa : immuunivaje keskeinen sairastavuutta ja kuolleisuutta lisäävä tekijä

Vertaisarvioitu.Rusto-hiushypoplasia (RHH) on peittyvästi periytyvä syndroominen immuunivaje, johon kuuluvat luuston kasvuhäiriö, lyhytkasvuisuus, hennot hiukset, vaihteleva immuunihäiriö, syöpäalttius sekä suurentunut anemian ja Hirschsprungin taudin ilmaantuvuus. RHH aiheutuu RMRP-geenin mutaatioista. Geenin koodaama RNA-molekyyli on osa endoribonukleaasikompleksia ja osallistuu mitokondriaalisen RNA:n prosessointiin, solunjakautumisen säätelyyn ja telomeerien ylläpitoon. Immuunivajeen kliiniset ominaisuudet ovat vaihtelevia ja eteneviä. Immuunivaje lisää kuolleisuutta erityisesti infektioiden, keuhkosairauden ja syöpäalttiuden myötä. Suomalaisessa RHH-kohortissa tunnistettiin useita varhaisen kuoleman riskitekijöitä, ja näitä havaintoja voidaan hyödyntää hoidosta päätettäessä. Hematopoieettisten kantasolujen siirto saattaa parantaa immuunivajeen, mutta on vielä epävarmaa, onko siitä hyötyä vähäoireisille RHH-potilaille. Moniammatillinen säännöllinen immuunivajeen seuranta pitäisi kohdistaa kaikkiin, myös vähäoireisiin, RHH-potilaisiin.Peer reviewe

Metaphyseal dysplasia without hypotrichosis' can present with late-onset extraskeletal manifestations

Peer reviewe

Lymphomas in cartilage-hair hypoplasia - A case series of 16 patients reveals advanced stage DLBCL as the most common form

BackgroundPatients with cartilage-hair hypoplasia (CHH) have an increased risk of malignancy, particularly non-Hodgkin lymphoma and basal cell carcinoma. The characteristics, clinical course, response to therapy and outcome of lymphomas in CHH remains unexplored. MethodsWe assessed clinical features of lymphoma cases among Finnish patients with CHH. Data were collected from the Finnish Cancer Registry, hospital records, the National Medical Databases and Cause-of-Death Registry of Statistics Finland. ResultsAmong the 160 CHH patients, 16 (6 men, 10 women) were diagnosed with lymphoma during 1953-2016. Lymphoma was diagnosed in young adulthood (median age 26.4 years, range from 6.4 to 69.5 years), mostly in advanced stage. The most common lymphoma type was diffuse large cell B-cell lymphoma (DLBCL) (6/16, 38%). Eight patients received chemotherapy (8/16, 50%), and two of them survived. Standard lymphoma chemotherapy regimens were administered in the majority of cases. Altogether, eleven CHH patients died due to lymphomas (11/16, 69%). In almost all surviving lymphoma patients, the diagnosis was made either during routine follow-up or after evaluation for non-specific mild symptoms. Search for CHH-related clinical predictors demonstrated higher prevalence of recurrent respiratory infections, in particular otitis media, and Hirschsprung disease in patients with lymphoma. However, three patients had no clinical signs of immunodeficiency prior to lymphoma diagnosis. ConclusionDLBCL is the most common type of lymphoma in CHH. The outcome is poor probably due to advanced stage of lymphoma at the time of diagnosis. Other CHH-related manifestations poorly predicted lymphoma development, implying that all CHH patients should be regularly screened for malignancy.Peer reviewe

A Wide Spectrum of Autoimmune Manifestations and Other Symptoms Suggesting Immune Dysregulation in Patients With Cartilage-Hair Hypoplasia

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 (X-(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.Peer reviewe