Lastenreumaa sairastavien ja elinsiirron saaneiden lasten ja nuorten luuston terveys

Osteoporosis is a skeletal disorder characterized by compromised bone strength that predisposes to increased fracture risk. Childhood and adolescence are critical periods for bone mass gain. Peak bone mass is mostly acquired by the age of 18 years and is an important determinant of adult bone health and lifetime risk for fractures. Medications, especially glucocorticoids (GCs), chronic inflammation, decreased physical activity, hormonal deficiencies, delayed puberty, and poor nutrition may predispose children and adolescents with a chronic disease to impaired bone health. In this work, we studied overall bone health, the incidence and prevalence of fractures in children and adolescents who were treated for juvenile idiopathic arthritis (JIA) or had undergone solid organ transplantation. The first study cohort included 62 patients diagnosed with JIA and treated with GCs. The epidemiology of fractures after transplantation was investigated in 196 patients and a more detailed analysis of bone health determinants was performed on 40 liver (LTx) and 106 renal (RTx) transplantation patients. Bone mineral density (BMD) and vertebral morphology were assessed by dual-energy x-ray absorptiometry. Standard radiographs were obtained to detect vertebral fractures and to determine bone age; BMD values were adjusted for skeletal maturity. Our study showed that median BMD values were subnormal in all patient cohorts. The values were highest in patients with JIA and lowest in patients with LTx. Age at transplantation influenced BMD values in LTx but not RTx patients; BMD values were higher in patients who had LTx before the age of two years. BMD was lowest during the immediate posttransplantation years and increased subnormally during puberty. Delayed skeletal maturation was common in all patient groups. The prevalence of vertebral fractures ranged from 10% to 19% in the cohorts. Most of the fractures were asymptomatic and diagnosed only at screening. Vertebral fractures were most common in LTx patients. Vitamin D deficiency was common in all patient groups, and only 3% of patients with JIA and 25% of transplantation patients were considered to have adequate serum vitamin D levels. The total cumulative weight-adjusted dose of GC was not associated with BMD values in JIA or LTx patients. The combination of female gender and age over 15 years, parathyroid hormone concentration over 100 ng/L, and cumulative weight-adjusted methylprednisolone dose over 150 mg/kg during the three preceding years were found to be important predictors for low lumbar spine BMD in RTx patients. Based on the high prevalence of osteoporosis in the study cohorts more efforts should be put to prevention and early diagnosis of osteoporosis in these pediatric patients.Lastenreumaa sairastavien ja elinsiirron saaneiden lasten ja nuorten luuston terveys Osteoporoosi on luuston sairaus, jossa luun lujuus on heikentynyt aiheuttaen lisääntyneen murtuma-alttiuden. Lapsuus ja nuoruus ovat merkittävimmät ajanjaksot luumassan kertymisen kannalta, sillä luun huippumassa saavutetaan 20-30 vuoden ikään mennessä. Mikä tahansa tekijä, joka estää normaalin luun huippumassan saavuttamisen, voi johtaa merkittävään osteoporoosiin jo lapsuudessa tai varhaisessa aikuisiässä. Lapsilla sekundaarinen osteoporoosi voi aiheutua perussairaudesta, sen hoidossa käytetyistä lääkkeistä, ravitsemusongelmista, liikuntakyvyn alenemisesta sekä sairauteen liittyvistä kasvun ja/tai murrosiän kehityksen ongelmista. Tässä tutkimuksessa selvitettiin luuston terveyttä ja murtumien esiintyvyyttä yli 4-vuotiailla lastenreumaa sairastavilla tai elinsiirron saaneilla lapsilla ja nuorilla sekä pyrittiin tunnistamaan luuston terveyteen vaikuttavat kliiniset ja hoidolliset tekijät. Luustontiheys määritettiin DXA-laitteella. Selkänikamien osteoporoottisten murtumien esiintyvyyttä tutkittiin selkärangan röntgenkuvien avulla. Tutkimukseen osallistui 62 glukokortikoidihoitoa saanutta lastenreumaa sairastavaa lasta. Murtumien epidemiologisessa tutkimuksessa oli 196 lapsena elinsiirron saanutta potilasta. Lisäksi 40 maksansiirron ja 106 munuaisen siirron saaneen lapsen ja nuoren luuston terveyttä kartoitettiin erillisissä tutkimuksissa. Luustontiheydet olivat normaalia matalammat kaikissa tutkituissa ryhmissä. Vähiten normaaliarvoista poikkesivat reumalasten tulokset ja matalimmat arvot todettiin maksansiirtolapsilla. Maksansiirron alle 2 vuoden iässä saaneiden luustontiheysarvot olivat paremmat kuin myöhemmällä iällä siirron saaneilla. Munuaisensiirron saaneiden kohdalla ei todettu eroa alle 2 vuoden iässä tai sen jälkeen siirron saaneilla. Luutontiheysarvot olivat matalimmat heti elinsiirron jälkeen, mutta ne paranivat vähitellen. Normaalisti murrosiässä luumassa lisääntyy voimakkaasti, mutta 80 %:lla maksansiirron saaneista nuorista luustontiheys normaalista poiketen pieneni murrosiässä; munuaisensiirron saaneista nuorista poikien luustontiheys nousi murrosiässä, mutta tytöillä heikkeni. Munuaisensiirtopotilailla yli 15-vuoden ikä ja naissukupuoli, korkea lisäkilpirauhashormonipitoisuus ja 150 mg/kg ylittävä metylprednisoloniannos edeltävän 3 vuoden aikana olivat matalan luustontiheyden riskitekijöitä. Reumalapsilla ja maksansiirtopotilailla kumulatiivinen painoon suhteutettu glukokortikoidiannos ei assosioitunut luustontiheysarvoihin. Oireettomat nikamamurtumat olivat huolestuttavan yleisiä kaikissa tutkimusryhmissä: reumalapsista 10%:lla ja maksansiirron saaneilla 19%:lla todettiin nikamamurtumia. D-vitamiinipitoisuudet olivat matalia suurella osalla potilaista, ainoastaan 3%:lla reumapotilaista ja noin 25%:lla elinsiirron saaneista D-vitamiinipitoisuus oli tavoitetasolla. Tulosten perusteella osteoporoosi on merkittävä ongelma lastenreumaa sairastavilla ja elinsiirron läpikäyneillä lapsilla ja nuorilla. Oireettomia nikamamurtumia esiintyy usein, mikä tulisi huomioida seurannassa. Murrosiän aikana elinsiirtopotilaiden osteoporoosiriski kasvaa ja näiden potilaiden luuston hoitoon tulisi kiinnittää erityistä huomiota. Riittävä kalsiumin ja D-vitamiinin saanti ovat tärkeitä ennaltaehkäisyssä. Lasten osteoporoosia on mahdollista myös hoitaa tehokkain lääkkein, minkä vuoksi on tärkeää löytää ajoissa ne potilaat, jotka hyötyisivät lääkityksestä jo kasvuiän aikana

Pohjavesialueiden suojelusuunnitelma Peltosalmi-Ohenmäki, Honkalampi ja Haminamäki-Humppi

Tämä suojelusuunnitelma on laadittu kolmelle pohjavesialueelle, jotka sijaitsevat Iisalmen kaupungin ja Lapinlahden kunnan alueella. Pohjavesialueet sijoittuvat etelä-kaakosta Lapinlahden ja Iisalmen kautta luoteeseen suuntautuvalle pitkittäisharjujaksolle. Eteläisin suojelusuunnitelmaan sisältyvistä pohjavesialueista on Haminamäki-Humppi, jonka pohjoispuolella on Honkamäen pohjavesialue. Peltosalmi-Ohenmäen pohjavesialue sijaitsee Iisalmen kaupungin eteläosassa. Suojelusuunnitelma on laadittu turvaamaan Ylä-Savon Vesi Oy:n vedenhankintaa. Suojelusuunnitelmaan sisältyviltä pohjavesialueilta otetaan lähes puolet Ylä-Savon Vesi Oy:n tuottamasta vedestä. Suojelusuunnitelmassa on selvitetty alueen geologisia ja hydrogeologisia olosuhteita, vedenottamoita ja pohjaveden laatua. Lisäksi on kartoitettu pohjavesialueilla olevia riskitoimintoja ja arvioitu riskien vaikuttavuutta. Mahdollisiksi riskiä aiheuttaviksi toiminnoiksi on luokiteltu asutus, liikenne ja tienpito, rautatieliikenne, yritystoiminta, maa-ainestenotto, muuntamot, maa- ja metsätalous sekä pilaantuneet tai mahdollisesti pilaantuneet maa-alueet (pima-alueet). Selvityksessä on myös huomioitu pohjavesien ennakoiva suojelu maankäytön ja kaavatilanteen suhteen. Toimenpidesuosituksia on esitetty maankäytön suunnitteluun antamalla rajoituksia ja suosituksia pohjavesialueille tulevaisuudessa sijoitettaville toiminnoille. Lisäksi suojelusuunnitelma sisältää toimenpideohjelman ja esityksen seurannan järjestämisestä. Tässä suojelusuunnitelmassa hyödynnetään suojelusuunnitelmamenettelystä tähän mennessä saatuja käytännön kokemuksia ja sovelletaan vesipuitedirektiivin asettamia vaatimuksia pohjaveden suojelulle. Tavoitteena on käyttää tätä nyt laadittua suojelusuunnitelmaa esimerkkinä tulevaisuudessa uusia suojelusuunnitelmia laadittaessa

Fatigue and disturbances of sleep in patients with osteogenesis imperfecta - a cross-sectional questionnaire study

Background: Persisting fatigue has been reported to be a common complaint by individuals with connective tissue disorders, including Osteogenesis imperfecta (OI). This controlled study evaluated in an adult OI population the subjective experience of fatigue, affecting daily life. Sleep disturbances and chronic pain were examined as hypothesized underlying factors. Methods: This cross-sectional study analyzed the answers of 56 OI patients and 56 matched healthy controls to a questionnaire, designed to evaluate levels of experienced fatigue and bodily pain, as well as the presence or absence of symptoms related to sleep disturbances or sleep apnea. The relationships between fatigue, pain, and sleep disturbances were evaluated with correlation analysis and regression analysis. Results: Fatigue was reported by 96%, and daily pain by 87% of the individuals with OI. Notably, the level of fatigue was similarly experienced by patient respondents and controls. In total, 95% of the patients and 77% of the controls reported one to several sleep disturbance symptoms. These symptoms as well as previously diagnosed sleep apnea were statistically significantly more prevalent in the patient group than in the controls (p <0.05). Likewise, the experienced bodily pain was statistically highly significantly more severe among the respondents with OI (p <0.001), and correlated with the reported fatigue. Conclusions: In comparison with age-matched controls, adults with OI do not differ in experienced fatigue, unlike hypothesized. Therefore, sleep disturbances, which based on the frequency of reported related symptoms and previous sleep apnea diagnoses appear to be common in OI patients, may remain undiagnosed.Peer reviewe

Polyostotic Fibrous Dysplasia With and Without McCune-Albright Syndrome-Clinical Features in a Nordic Pediatric Cohort

Objective: Fibrous dysplasia (FD) presents as skeletal lesions in which normal bone is replaced by abnormal fibrous tissue due to mosaic GNAS mutation. McCune-Albright syndrome (MAS) refers to FD combined with skin (cafe-au-lait) and endocrine manifestations. This study describes the clinical childhood manifestations of polyostotic FD and MAS in a Nordic cohort. Patients and design: We retrospectively reviewed a cohort of pediatric patients (n = 16) with polyostotic FD with or without MAS diagnosed and followed in two Nordic Pediatric tertiary clinics between 1996 and 2017. Results: Half of the 16 patients with polyostotic FD presented with MAS. All patients with MAS (n = 8) had cafe-au-lait spots, and either gonadotropin-independent precocious puberty (PP) (girls; n = 5) or abnormal testicle structure (boys, n = 3). None manifested hyperthyroidism or growth hormone excess. Mild hypophosphatemia was common (11/16), but none had signs of hypophosphatemic rickets. Craniofacial bone involvement was found in 12 patients (75%); in 5 of these, skeletal lesions were limited to craniofacial area. One child with craniofacial disease had lost vision due to optic nerve damage. Eleven (69%) patients had sustained a fracture at FD lesion, over half of them requiring surgical fixation of the fracture, most commonly in the proximal femur. The first symptoms leading to FD/MAS diagnosis included skull/facial asymmetry (n = 4), PP (n = 3), abnormal gait (n = 3), pathologic fracture (n = 3), wide-spread cafe-au-lait spots (n = 1), headache (n = 1), and vision loss (n = 1). Conclusion: Polyostotic FD and MAS remain diagnostic and therapeutic challenges because of the broad clinical spectrum. Recurrent fractures, pain, and even vision loss may impair the quality of life in children with FD.Peer reviewe

Oligogenic Inheritance of Monoallelic TRIP11, FKBP10, NEK1, TBX5, and NBAS Variants Leading to a Phenotype Similar to Odontochondrodysplasia

Skeletal dysplasias are often well characterized, and only a minority of the cases remain unsolved after a thorough analysis of pathogenic variants in over 400 genes that are presently known to cause monogenic skeletal diseases. Here, we describe an 11-year-old Finnish girl, born to unrelated healthy parents, who had severe short stature and a phenotype similar to odontochondrodysplasia (ODCD), a monogenic skeletal dysplasia caused by biallelic TRIP11 variants. The family had previously lost a fetus due to severe skeletal dysplasia. Exome sequencing and bioinformatic analysis revealed an oligogenic inheritance of a heterozygous nonsense mutation in TRIP11 and four likely pathogenic missense variants in FKBP10, TBX5, NEK1, and NBAS in the index patient. Interestingly, all these genes except TBX5 are known to cause skeletal dysplasia in an autosomal recessive manner. In contrast, the fetus was found homozygous for the TRIP11 mutation, and achondrogenesis type IA diagnosis was, thus, molecularly confirmed, indicating two different skeletal dysplasia forms in the family. To the best of our knowledge, this is the first report of an oligogenic inheritance model of a skeletal dysplasia in a Finnish family. Our findings may have implications for genetic counseling and for understanding the yet unsolved cases of rare skeletal dysplasias.Peer reviewe

Compromised Peak Bone Mass in Patients with Inflammatory Bowel Disease-A Prospective Study

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Timing of dental development in osteogenesis imperfecta patients with and without bisphosphonate treatment

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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

Is sleep apnea underdiagnosed in adult patients with osteogenesis imperfecta? -a single-center cross-sectional study

BackgroundPatients with Osteogenesis imperfecta (OI) suffer from increased bone fracture tendency generally caused by a mutation in genes coding for type I collagen. OI is also characterized by numerous co-morbidities, and recent data from questionnaire studies suggest that these may include increased risk for sleep apnea, a finding that lacks clinical evidence from cohort studies. In this cross-sectional study, 25 adults with OI underwent clinical otorhinolaryngology examination as well as overnight polysomnography to address the question. The participants were aged between 19 and 77years, and ten of them had mild clinical OI phenotype, seven had a moderately severe phenotype, and eight had a severe phenotype.ResultsWe found obstructive sleep apnea (apnea hypopnea index 5/h) in as many as 52% of the OI patients in the cohort. Unexpectedly, however, no correlation was present between sleep apnea and daytime sleepiness, experienced bodily pain, severity of OI, Mallampati score, or neck circumference.ConclusionsSeeing that the usual predictors showed no association with occurrence of sleep apnea, we conclude that obstructive sleep apnea may easily be left as an undetected disorder in individuals with OI. Recurrent nocturnal hypoxia due to episodes of apneas can even affect bone metabolism, thereby further aggravating bone fragility in patients with OI.Peer reviewe

Novel variants in natriuretic peptide receptor 2 in unrelated patients with acromesomelic dysplasia type Maroteaux

Acromesomelic dysplasia are a heterogeneous group of disorders with variable spectrum and severity of skeletal anomalies in the affected individuals. Acromesomelic dysplasia type Maroteaux (AMDM) is characterized by extreme shortening of the forelimbs and disproportionate short stature. Several homozygous inactivating mutations in NPR2 have been identified in different AMDM patients. We report five novel variants in affected individuals in four different families. These include two nonsense and three missense variants. This study broadens the genotypic spectrum of NPR2 mutations in individuals with AMDM and also describes the intra- and inter-familial phenotypic variability due to NPR2 variants.Peer reviewe