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Dr Frenkel WKZ                          Dr Swart WKZ                                Dr Wulffraat WKZ                             Dr Vastert WKZ                              Dr Legger Gronitis                         Dr Simon Radboud

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Dr Frenkel WKZ                          Dr Swart WKZ                                Dr Wulffraat WKZ                             Dr Vastert WKZ                              Dr Legger Gronitis                         Dr Simon Radboud

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Dr Swart, Dr Frenkel, Dr Vastert en Dr Wulffraat

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In het Wilhelmina kinderziekenhuis willen we kinderen die ziek zijn, beter maken. Ook worden er elk jaar 3000 baby's geboren. Omdat ieder mens de beste zorg verdient, legt het Wilhelmina Kinderziekenhuis de lat voortdurend hoog. Het resultaat: vernieuwende, toonaangevende behandelingen die beantwoorden aan de zorgbehoeften van nu en de toekomst

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Dr Legger

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De afdeling kinderreumatologie van het Beatrix Kinderziekenhuis is een onderdeel van het Universitair Medisch Centrum Groningen (UMCG)

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autoinflammatoire volwassen

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Overzicht van medewerkers binnen het afweercentrum

Patiëntenzorg volwassenen:

Prof.dr. P.M. van Hagen,
internist-immunoloog, sectiehoofd Klinische Immunologie

Dr. V.A.S.H. Dalm,
internist-immunoloog

Dr. P.L.A. van Daele,
internist-immunoloog

Dr. J.A.M. van Laar,
internist-immunoloog

Mw.drs. P. van Biezen,
internist, medisch coördinator afdeling 5 Noord (klinische afdeling)

Mw. M.W. van der Ent,
nurse practitioner

Patiëntenzorg kinderen:

Mw. Dr. A.M.C. (Annemarie) van Rossum,
kinderarts-infectioloog/immunoloog, subhoofd

Dr. G.J.A. (Gertjan) Driessen,
kinderarts-infectioloog/immunoloog

Dr. P.L.A. (Pieter) Fraaij,
kinderarts infectieziekten/immunologie

L.C. (Linda) van der Knaap,
verpleegkundig specialist

Drs. E.G. (Eline) Visser,
verpleegkundig specialist/onderzoekscoördinator

Diagnostiek & Onderzoek:

Prof.dr. J.J.M. van Dongen,
unithoofd Moleculaire Immunologie

Mw.Dr. M. van der Burg,
werkgroepleider Primaire Immuundeficiënties

Mw. H. IJspeert,
onderzoeker in opleiding

Mw. S.J. Posthumus,
researchanalist

Mw. I. Pico,
researchanalist

Mw. B.H. Barendregt,
researchanalist

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Overzicht van medewerkers binnen het afweercentrum Patiëntenzorg volwassenen: Prof.dr. P.M. van Hagen, internist-immunoloog, sectiehoofd Klinische Immunologie Dr. V.A.S.H. Dalm, internist-immunoloog Dr. P.L.A. van Daele, internist-immunoloog Dr. J.A.M. van Laar, internist-immunoloog Mw.drs. P. van Biezen, internist, medisch coördinator afdeling 5 Noord (klinische afdeling) Mw. M.W. van der Ent, nurse practitioner Patiëntenzorg kinderen: Mw.

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autoinflammatoire volwassen

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Anna Simon is internist, infectioloog en wetenschappelijk onderzoeker, verbonden aan het Radboud universitair medisch centrum in .

Zij heeft verschillende boeken gepubliceerd, waaronder een historische roman en een waargebeurd verslag over werken in een Ebola kliniek van tijdens de epidemie in Sierra Leone in 2014.

Daarnaast heeft zij tientallen ingesproken voor en , zowel in het Nederlands als in het Engels, die gratis te beluisteren zijn.

Ook heeft Anna een passie voor geschiedenis, waarbij ze onder andere actief is als vrijwilliger bij in Nijmegen.

Anna Simon is a physician, infectious disease specialist and scientist, working at the Radboud university medical center in Nijmegen, the Netherlands.

She has published several books, including a historical novel and a true account of working in an Ebola hospital of Doctors without Borders (MSF) during the epidemic in Sierra Leone in 2014.

Anna has recorded dozens of audiobooks for Librivox and Legamus, in Dutch as well as in English, that are available for free.

She also has a passion for history, and her activities include volunteering for a museum in Nijmegen, De Bastei.

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English translation below Anna Simon is internist, infectioloog en wetenschappelijk onderzoeker, verbonden aan het Radboud universitair medisch centrum in Nijmegen. Zij heeft verschillende boeken gepubliceerd, waaronder een historische roman en een waargebeurd verslag over werken in een Ebola kliniek van Artsen zonder Grenzen tijdens de epidemie in Sierra Leone in 2014.

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Dr. Erica Sermijn - Volgens arts - Raadplegingsgids - Professionals

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Dr Vito Sabato

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Dr Vandecasteele

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Spoedgevallen campus Henri Serruys 059 55 51 01

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Dr Patrick Lacor

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Service de Médecine Interne, Service de Rhumatologie et Médecine Physique Rhumatologie Adulte et Pédiatrique, Hôpital Erasme, Bruxelles

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Prik paspoort

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Tips en tricks kineret

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rarediseaseday US

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The main objective of Rare Disease Day 2018 is to raise awareness with policy makers and the public of rare diseases and of their impact on the lives of patients, and to reinforce their importance as a public health priority.

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zeldzameziektendag

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Tijdens de internationale Rare Disease Day - Zeldzameziektendag - wordt jaarlijks op 28 of 29 februari aandacht gevraagd voor mensen met zeldzame aandoeningen.

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zeldzamenziektedag

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Op zaterdag 27-2 is de Nederlandse Zeldzame Ziekten Dag. Ben je er bij? Aanmelden kan via http://www.zeldzameziektendag.nl/

Locatie: het Nederlands Instituut voor Beeld en Geluid te Hilversum.

Op deze dag organiseert de VSOP een boeiend beleidssymposium met als thema: 'Het geluid van zeldzaam goed in beeld!'.

Tijdens dit symposium is er een leuk kinderprogramma voor alle leeftijden.

In de middag kan met het hele gezin een bezoek worden gebracht aan het Nederlands Instituut voor Beeld en Geluid.

Aanmelden kan op de website van de zeldzameziektendag en daar staat ook alle informatie.

Nomineer jouw Zeldzame Engel!
Ook in 2016 kun je ook weer een patiënt of naaste van een patiënt en een medisch professional die zich bijzonder heeft ingezet voor een zeldzame aandoening, nomineren voor de Zeldzame Engel Award.
De Award wordt traditiegetrouw uitgereikt tijdens de Zeldzameziektendag op 27 februari 2016.

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Doe mee met de Zeldzameziektendag! - Zeldzame Ziekten Fonds

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Op zaterdag 27-2 is de Nederlandse Zeldzame Ziekten Dag. Ben je er bij? Aanmelden kan via http://www.zeldzameziektendag.nl/ Locatie: het Nederlands Instituut voor Beeld en Geluid te Hilversum. Op deze dag organiseert de VSOP een boeiend beleidssymposium met als thema: 'Het geluid van zeldzaam goed in beeld!'.

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KPN KlasseContact

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Infoboekje PFAPA

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KPN KlasseContact

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Ziezon infoboekje

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KAISZ

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Autoinflammatie website

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autoinflammatory.org

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cryopyrin associated periodic fever syndrome

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The Autoinflammatory Alliance is a non-profit dedicated to increasing awareness, care and treatment for patients with Cryopyrin-Associated Periodic Syndromes, including: NOMID/CINCA, Muckle-Wells (MWS) Familial Cold Autoinflammatory Syndromes (FCAS), and other autoinflammatory diseases.

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Rareconnect

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A safe, easy to use platform where rare disease patients, families and patient organizations can develop online communities and conversations across continents and languages. RareConnect partners with the world's leading rare disease patient groups to offer global online communities allowing people to connect around issues which affect them while living with a rare disease.

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SAID support blog

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Systemic Autoinflammatory Disease (SAID) Support

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Pain. Hurt. Fire. Needles. Burning. Knives.

Those are the words used by children and adults who have a systemic autoinflammatory disease (SAID). From diseases with sporadic attacks of inflammation, such as PFAPA, to the more chronic and damaging autoinflammatory diseases like CANDLE, NOMID and SAVI, it's clear these are painful diseases.

Those affected by a SAID (also called periodic fever syndromes) go through periods of time referred to as "flares" or "attacks" where their disease is highly active and debilitating.

Flare symptoms can include fever, rash, mouth ulcers, joint swelling, inflammation in or around organs, and other systemic inflammatory symptoms. Depending on which autoinflammatory syndrome it is, flares may last days, weeks, or months. Some may have periods of decreased severity, but never get full relief of their symptoms. And some of the more chronic SAIDs can cause permanent damage to bones, tissues or organs if untreated. (Learn more about these diseases and symptoms here.)

Although we can read and know the symptoms of a periodic fever disease from medical literature, for those of us who do not suffer from it, it's hard to image what it actually feels like to have these flares. So we asked our community to describe what a flare physically feels like to them.

The answer most everyone gave, from kids to adults was "pain." Flares are painful, and the entire body, inside and out, can hurt.

I feel really, really sick and don't want to do anything but sleep. I get a headache and everything hurts. -D.C., age 4 diagnosed with uSAID/SURFS

It feels like my bones are all broken. My brain hurts. My eyes are on fire. My throat feels all krinkly. My heart beats hard and fast and I can't breathe. -R.A., age 5, diagnosed with uSAID

-A.V., age 8, diagnosed with It makes me feel weak and like I can't move at all. Sometimes I feel like I can't wait to go to heaven so my body won't hurt anymore. TRAPS

My brain and body are at odds. I feel like I'm walking through water and my head is full of cotton wool. I want to run away from my body, but I'm too busy hiding in my bed and focusing on just breathing when the pain becomes overwhelming. -S.K., age 40, diagnosed with FMF and neuro-Behcet's disease

If pain were noise, my body isn't loud anymore. (Stated after getting on effective treatment.) -M.C., adult diagnosed with MWS

It feels like my eyes, my knees... it feels like my whole body is in pain. It makes me tired. It makes me weak. When my bones are crackly and the pain is starting up and stairs make me cry, that's when I know a flare is starting. -L.J., age 5, diagnosed with variant CAPS/MWS

It feels like a dragon is spraying fire on me! -O.G., age 7, diagnosed with FMF

Badness...my whole body feels bad and it means I have to get a shot. I'm scared of my shots and don't like them. -E.E.C., age 4, diagnosed with HIDS

My body hurts. I'm always cold. -T.T., child diagnosed with FMF

It feels really bad. It feels like tons of stuff hit my head and tummy. All of my mouth hurts. My whole body hurts. Tons of knives are poking my feet and legs. -I.B., age 5, diagnosed with uSAID

My body feels very tired and I say "Owww." My knees feel like they have bumps in them and my skin looks like a spider web. -G.S., age 5, diagnosed with uSAID

When I have a headache, it's like I have a metal ball inside my head. My throat has fireworks inside. My legs are too tired and shaky. My tummy is like rotten eggs. My muscles are too big and it hurts. -S.B, age 5, diagnosed with uSAID with IFIH1 mutation

Sore- I feel sore, more sore than normal, my throat blisters. I feel different. I don't like it. -C.D., age 10, diagnosed with CAPS

It's an unwanted visitor that I can't wait for it to leave. Never the same, but familiar. Always, always stops me from living normally and robs me of special occasions, social gatherings and days and nights out. It doesn't just leave without a footprint- it leaves fatigue and an aching. And once it's gone, it's the mental preparation for it returning. It is unpredictable, and as such life can't be planned counting on it to arrive at a set time and place. Sometimes it arrives out of punishment for getting to bed late, for allowing yourself to be stressed, for getting cold. These are the worst kind because you take the blame. But it's not really our fault- it would come anyways! -M.D., age 37, diagnosed with CAPS

It feels like multiple pains at one time. Very painful pain. The pain is everywhere. -Q.T., age 8, diagnosed with HIDS

Doesn't feel really good, my body hurts so bad. I wish they [the flares] would go away with a hug and kiss. -O.G., age 5, diagnosed with uSAID

It feels like I'm very burning everywhere and my head hurts so bad. -P.R., age 5, diagnosed with Majeed syndrome

All I want to do is sleep. My stomach hurts. My whole body hurts. I can't hold down anything. -A.O., age 21, diagnosed with NOMID

It's like having a bad flu. I told my doctor I can see why people die from dysentery, because that's what it's like for me: very painful everywhere, nauseating, disgusting, and I feel like curling up into a ball and rocking. I'm only getting half of my life done. -C.M., adult diagnosed with FMF

It's like the worst flu you've ever had. -N.S., adult diagnosed with HIDS

It burns when people touch me! Or when things touch me! - child diagnosed with PFAPA

So easy to sleep! Just about the only time I don't have insomnia. Heavy eyes, SUPER fatigued, screaming legs. Sometimes I still gotta go to school. That's the worst. I used to be very nauseous and vomit frequently. I often lose my appetite and have lost weight because of it. Stomach pains. Throat feels like needles are stabbing it. -J.J., age 13 diagnosed with uSAID

A flare feels like a really bad flu bug - rash, fever, swollen glands, sores in my mouth and throat with a pain throughout my bones. However, because it doesn't have a name and because I can't find a doctor who understands how to diagnose this, I am expected to continue preform my life as if I am a healthy person. Worse, as a business woman, I have to keep my illness hidden from my male colleagues so that I do not appear weak and inferior. -C.E., age 42 diagnosed with uSAID
A flare is fatigue so bad you can't sleep. It's bone pain in your arms and legs. It's every joint screaming at you when you try to move. It's skin so sensitive you can't bear the thought of a shirt. It's constant GI issues, such as debilitating nausea. It's having a sudden bout of diarrhea in the drop-off line at your child's school, causing you to sacrifice another pair of underwear and pants to the cause. It's the excruciating twist of pain in your gut. It's the realization that after 15 bouts of diarrhea in 4 hours, you're going to have to face the ER. It's always knowing more about your disorder than any doctor you encounter aside from your specialist. It's knowing you've failed most known treatments for this, and waiting for the last one that you're currently on to lose effectiveness. It's being a walking time bomb because your disorder has attacked almost every organ in your body at some point EXCEPT for your heart and lungs, but you know it's coming for you.
My tummy feels like out tightens then un-tightens. I hurt all over. My head feels like it will explode. I can't open my eyes and it feels like glass is in my throat. -J.R., age 7, diagnosed with uSAID

-A.L.M, age 42, diagnosed with It feels like being attacked from within; my whole body was shaking, throbbing, in pain, and unable to walk, unable to use a knife and fork or drive; having uncontrollable temperatures; having a rash that is all over and intensely itchy at times and a sore throat and glands up so bad that your jaw can't open properly; stomach pain and chest pain. Still's disease (AOSD)

Today's rash is like poison ivy over a second degree burn. -M.S., adult diagnosed with uSAID

I want to know what not having a flare feels like. What does it feel like to be completely and totally healthy? What does not having fatigue, bloodshot eyes, joint pain, hearing loss, stomach and abdominal cramps, chest pain, chills, headaches, and hives feel like?! -K.R., adult diagnosed with MWS

I never knew what "normal" was supposed to feel like until I went on treatment for CAPS. I am free-I am no longer a prisoner of pain. -A.C., diagnosed in adulthood with CAPS

The feeling that a patient "never knew what normal felt like" before being on the right medication for their disease is one of the most common statements that we have heard from a number of patients with various forms of autoinflammatory diseases. For many of these syndromes there is effective treatment, but because these are rare diseases, it can take many years to get to a diagnosis. For some there is not yet a highly effective treatment. This is why the Autoinflammatory Alliance is dedicated to promoting awareness, proper diagnosis and treatment, and improved care for people with autoinflammatory diseases. You can help us by making a donation here.

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Systemic Autoinflammatory Disease (SAID) Support - Welcome to the Autoinflammatory Alliance blog for discussing all things involving awareness, advocacy, care and thriving with SAID

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Those are the words used by children and adults who have a systemic autoinflammatory disease (SAID). From diseases with sporadic attacks of inflammation, such as PFAPA, to the more chronic and damaging autoinflammatory diseases like CANDLE, NOMID and SAVI, it's clear these are painful diseases.

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Website Reumatische aandoeningen

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acuut reuma en post-streptokokken reactieve artritis

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mevalonaat kinase deficientië (mkd) (of hyper igd syndroom)

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periodieke koorts met afteuze faryngitis en adenitis (pfapa)

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tumornecrosefactor receptor geassocieerd periodiek syndroom (traps) of familiale ierse koorts

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Informatie over reumatische aandoeningen op de kinderleeftijd

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Deze website is het resultaat van samenwerking tussen de Paediatric Rheumatology InterNational Trials Organisation (PRINTO) en de Paediatric R...

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CRMO

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CRMO is a "diagnosis of exclusion." This means that other diseases must be ruled out before the diagnosis can be made. Generally, many tests are required, such as blood tests, X-rays, bone scans, MRI, and often a bone biopsy. What causes CRMO? The cause of CRMO is unknown.

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Informatieve site

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Jongeren Binnenboord - Onderwijs aan jongeren met chronische klachten

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Iedereen binnenboord, alle jongeren een diploma en/of toegang tot vervolgonderwijs. Dit is het motto van het innovatieproject 'Liever een karrenspoor', dat speciaal voor jongeren met een chronische ziekte of stoornis is ontwikkeld op het Esdal College in Emmen. Deze jongeren ondervinden door hun kwetsbare gezondheid belemmeringen om het onderwijs te volgen.

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KPN KlasseContact

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Dankzij KlasseContact kunnen langdurig en ernstig zieke kinderen die niet naar school kunnen toch actief meedoen in de les. Met behulp van een laptop thuis en een slimme ICT-set in de klas werden meer dan duizend chronisch zieke leerlingen de afgelopen jaren geholpen.

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Ziek Zijn Ziezon

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Een op zeven leerlingen heeft een chronische ziekte. Voor zieke leerlingen is het belangrijk dat het onderwijs doorgaat. Om dit mogelijk te maken, kunnen scholen van het primair en voortgezet onderwijs, en in sommige gevallen het mbo, de hulp inroepen van een consulent onderwijsondersteuning zieke leerlingen. Ruim 120 consulenten zijn werkzaam bij de onderwijsadviesbureaus en bij de educatieve voorzieningen van de zeven universitair medische centra in Nederland. Samen vormen zij het Landelijk dekkend Netwerk Ziek zijn en Onderwijs (Ziezon).

Op woensdag 1 november vond het mini-symposium Verzuim door ziekte?! in Sittard plaats. De organisatie was in handen van Jan Bogie, Marjo Delboeuf en Maren Hendriks (AB Adelante), Haske Willemars (EV UMC Maastricht) en Charlotte de Vrede en Wiel Zautsen (OZL Midden- en Zuid-Limburg).
Op deze geslaagde bijeenkomst waren zo'n 100 deelnemers uit de regio met [...]

Op 1 november a.s. organiseren Ambulante maatwerkexpertise Adelante, OZL Midden- en Zuid-Limburg en de Educatieve voorziening van het MUMC het mini-symposium Verzuim door ziekte?!
Het symposium wordt om 13.00 uur geopend door Marc Dullaert, voormalig Kinderombudsman, Bart van Kessel (Gedragswerk) treedt op als dagvoorzitter. Een serie interessante presentaties volgen door professionals die in hun praktijk met [...]

We zoeken voor het nieuwe platform 'Onderwijs dat past!' naar jongeren tussen de 10 en 16 jaar met een chronische aandoening. We brengen in beeld hoe leerlingen/studenten (en hun ouders) hun school of opleiding doorlopen. Wat ze daarbij belangrijk vinden, waar ze behoefte aan hebben, en wat volgens hen beter kan. Wil je jouw ervaringen [...]

Dit najaar organiseert Buro Puur weer verschillende bijeenkomsten rond het thema eetstoornissen.
Op maandag 9 oktober vindt een trainingsdag plaats. Het doel van deze trainingsdag is professionals leren een eetstoornis eerder te herkennen en leren hoe ze de juiste hulp kunnen bieden. Op dinsdag 21 november is de training Speeddaten met ervaringsdeskundigen. Het doel is professionals [...]

Deze literatuurlijst bevat leesboeken, informatieboeken en websites over het thema chronische ziekten. De lijst is samengesteld door Marijke Smienk en Saskia Meijer, consulenten OZL van de educatieve voorziening van het AMC-VUmc, en wordt elk jaar geactualiseerd.
Boeken en websites chronisch zieke leerlingen PO 2016
Boeken en websites chronisch zieke leerlingen VO 2016

3FM Tussenuur, het online channel voor middelbare scholieren, uitgerold via de kanalen van NPO 3FM is op zoek naar jongeren met een chronische aandoening tot 20 jaar die hun verhaal willen vertellen. Dit verhaal komt dan op de website van 3FM Tussenuur.

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Ziezon - Landelijk Netwerk Ziek Zijn en Onderwijs

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Een op zeven leerlingen heeft een chronische ziekte. Voor zieke leerlingen is het belangrijk dat het onderwijs doorgaat. Om dit mogelijk te maken, kunnen scholen van het primair en voortgezet onderwijs, en in sommige gevallen het mbo, de hulp inroepen van een consulent onderwijsondersteuning zieke leerlingen.

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Mee

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MEE ondersteunt mensen met een beperking. U kunt bij MEE terecht met uw vragen over opvoeding & ontwikkeling, leren & werken,...

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Wet passend onderwijs

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Steun kinderen met ontwikkelingsproblemen bij: lezen, schrijven, rekenen, bewegen, plannen, organiseren en contact maken. KIES NU VOOR BALANS.

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Pediatric rheumatologist Ann Reed, M.D., of Mayo Clinic Children's Center in Rochester, Minnesota, speaks about the symptoms and treatment options for pediatric autoinflammatory disorders which can also be referred to as periodic fevers. To make an appointment at the Mayo Clinic Children's Center please call 1 (800) 533-1564.

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Periodic fever syndromes

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Animated infographic on periodic fever syndromes - rare, long-term inflammatory diseases characterized by repeated bouts of fever in recognizable patterns. They are caused by gene mutations which affect certain proteins that subsequently cause inflammation. Symptoms can include rash, fever, abdominal pain and joint pain.

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a lifelong periodic fever syndrome

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A lifelong challenge: periodic fever syndromes

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Dr Lachmann, medical expert in periodic fever syndromes (PFSs), a group of rare childhood autoinflammatory diseases, discusses the symptoms of PFSs and their impact on a child's quality of life as well as on the child's caregiver. For more information, please visit http://www.novartis.com/corporate-responsibility/access-to-healthcare/r-d.shtml © 2012 Novartis AG

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IL-1

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The Role of Interleukin-1 (IL-1) in Two Rare Autoinflammatory Diseases

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National Human Genome Research Institute

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Adventures in the Genomics of Inflammation - Daniel Kastner

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September 7, 2012 - Genomics in Medicine Lecture Series More: http://www.genome.gov/27549874

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Dr Kastner

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Demystifying Medicine 2017: Inflammation: One Gene at a Time

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Demystifying Medicine 2017: Inflammation: One Gene at a Time Air date: Tuesday, February 14, 2017, 4:00:00 PM Category: Demystifying Medicine Runtime: 01:48:03 Description: The Demystifying Medicine Lecture Series is designed to help bridge the gap between advances in biology and their applications to major human diseases.

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Quin and Nomid

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If there was a disease out there so rare that only about 40 people in the entire country were affected, would you still do all you could to help fight it? If you were Colleen Paduani, or the parent of one of the other 39 or so...

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living with CAPS

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Earlier in January we had the pleasure of speaking with Ian Stedman-a lawyer, a father of two, and a rare disease patient and advocate from Toronto. He has Muckle Wells Syndrome, which is a variant of Cryopyrin-Associated Periodic Syndrome, or CAPS.

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living with FMF

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Ariella's Story - Living with familial Mediterranean fever

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Ariella shares her experiences in trying to get a diagnosis for her condition. She talks about what it is like living with FMF and how treatable the condition is. Ariella feels strongly that awareness of Jewish genetic disorders like FMF, and the availablity of genetic testing are really important in getting an accurate diagnosis and effective treatment for patients.

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living with CRMO

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CRMO: Chronic Recurrent Multifocal Osteomyelitis

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This video has info about CRMO, as well as my personal story. Please feel free to comment on this or to email me to add your story to the video. ALSO... if you are looking for support, info, or advice, there is a facebook group called CRMO: Chronic Recurrent Multifocal Osteomyelitis, which is open to family, friends, and those with CRMO.

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Living with HIDS

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Rare Disease Day 2017- Living with HIDS in the UK

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I created this video with the YouTube Slideshow Creator (https://www.youtube.com/upload)

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Informatie over CAPS (FCAS, MWS ,ENCA/ NOMID)

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Website Periodic Fevers

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

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Familial Mediterranean fever mutations are hypermorphic mutations that specifically decrease the activation threshold of the Pyrin inflammasome. - PubMed - NCBI

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Clinical and Molecular Phenotypes of Low-Penetrance Variants of NLRP3: Diagnostic and Therapeutic Challenges. - PubMed - NCBI

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Christian M Hedrich 1 Email author ,

Sigrun R Hofmann 1,

Jessica Pablik 2,

Henner Morbach 3 and

Hermann J Girschick 4

Received: 6 October 2013

Accepted: 14 December 2013

Published: 23 December 2013

Abstract

Sterile bone inflammation is the hallmark of autoinflammatory bone disorders, including chronic nonbacterial osteomyelitis (CNO) with its most severe form chronic recurrent multifocal osteomyelitis (CRMO). Autoinflammatory osteopathies are the result of a dysregulated innate immune system, resulting in immune cell infiltration of the bone and subsequent osteoclast differentiation and activation. Interestingly, autoinflammatory bone disorders are associated with inflammation of the skin and/or the intestine. In several monogenic autoinflammatory bone disorders mutations in disease-causing genes have been reported. However, regardless of recent developments, the molecular pathogenesis of CNO/CRMO remains unclear.

Here, we discuss the clinical presentation and molecular pathophysiology of human autoinflammatory osteopathies and animal models with special focus on CNO/CRMO. Treatment options in monogenic autoinflammatory bone disorders and CRMO will be illustrated.

Keywords

PAPA DIRA Majeed CNO CRMO Bone Inflammation IL-10 TNF-α TLR4 Treatment

Background

Autoinflammatory disorders are characterized by seemingly unprovoked systemic inflammation in the absence of auto-reactive T cells or high-titer auto-antibodies [ 1]. Sterile bone inflammation is the hallmark of autoinflammatory bone disorders, including pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, the deficiency of IL-1 receptor antagonist (DIRA), familial chronic multifocal osteomyelitis which is also referred to as Majeed syndrome, sporadic chronic recurrent multifocal osteomyelitis (CRMO), and synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome [ 2, 3].

Autoinflammatory bone disorders are the result of a disturbed regulation of the innate immune system, resulting in immune cell infiltration of the bone and subsequent osteoclast differentiation and activation, osteolysis and bone remodeling. Though bone biopsies usually remain sterile, lesions mimic infectious osteomyelitis in histology and on radiographs [ 2- 5]. Interestingly, autoinflammatory bone disorders are associated with inflammation of the skin (palmoplantar pustulosis, acne, psoriasis, Sweet syndrome) and/or the intestine (Crohn's disease, ulcerative colitis, coeliac disease) [ 2- 5]. In several so-called monogenic autoinflammatory bone disorders mutations in disease-causing genes have been reported [ 1, 6- 8]. Regardless of recent developments, the molecular pathogenesis of sporadic CRMO, however, remains to be determined.

In the following, we discuss the clinical presentation and molecular pathophysiology of human autoinflammatory osteopathies and animal models with special focus on CNO/CRMO. Currently available treatment options in monogenic autoinflammatory bone disorders and CRMO will be illustrated.

Review

Monogenic autoinflammatory bone disorders

Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA)

PAPA segregates with mutations in the threonine phosphatase-interacting protein (PSTPIP)1 that is also referred to as CD2 binding protein (CD2BP)1 on chromosome 15 and follows an autosomal-dominant inheritance [ 8]. Interactions of the PSTPIP1 protein with the protein tyrosine phosphatase PEST results in phosphorylation of PSTPIP1 that in turn prevents its binding to pyrin, a negative regulator of the NLRP3 inflammasome. Mutations in PSTPIP1 result in impaired phosphorylation and subsequently prolonged interactions with pyrin, resulting in enhanced activation of the NLRP3 inflammasome [ 10- 12] (Figure 1A). Alternatively it has been suggested that mutated PSTPIP1 may allow pyrin to oligomerize with adaptor proteins and form a pyrin inflammasome [ 11]. In both models, mutated PSTPIP1 mediates increased inflammasome activation and IL-1 (and IL-18) release, resulting in down-stream pro-inflammatory signaling through IL-8, IL-6, and TNF-α.

Diagnosis can be made based on the clinical picture and family history. Genomic testing for mutations in the PSTPIP1 gene is available in order to prove the clinical diagnosis. Treatment with corticosteroids, TNF-α inhibitors, and IL-1 blocking strategies bring clinical benefit. However, disease flares even occur in patients on high doses of IL-1 blockers, suggesting that IL-18, which is also cleaved by activated caspase-1, can sufficiently drive systemic inflammation in the absence of IL-1 [ 1, 13]. Alternatively, an even more complex pathomechanistic role of PSTPIP1 in the molecular pathogenesis of PAPA may be discussed [ 11]. Waite et al. suggested that pyrin may be recruited into aggregations of apoptosis-associated speck-like protein containing a CARD (ASC), another pyrin-binding protein, which are then referred to as ASC specks. In the authors' pathophysiological model ASC specks mediate particularly increased inflammasome activation and pro-inflammatory cytokine release [ 11].

Deficiency of IL-1 receptor antagonist (DIRA)

DIRA manifests in the first days of life with a pustular skin rash, joint swelling, painful resorptive bone lesions, and periostitis. Bone lesions usually affect distal ribs and long bones. In contrast to individuals suffering from cryopyrinopathies, DIRA patients usually do not present with fever. A subset of patients develop additional symptoms of central nervous system (CNS) vasculitis and interstitial lung disease [ 14].

Majeed syndrome

Familial inherited cases of chronic osteomyelitis, also referred to as Majeed syndrome, have been described four consanguineous families. Affected family members present with early-onset osteomyelitis within the first two years of life, a skin rash resembling Sweet syndrome, and a microcytic dyserythropoietic anemia. Usually, Majeed syndrome is more severe when compared with sporadic CRMO and may be accompanied by recurrent fevers [ 16, 17].

Majeed syndrome follows an autosomal-recessive inheritance and has been linked with mutations in the LPIN2 gene, encoding for the Lipin2 protein [ 7]. Lipin2 is expressed in the liver, the kidneys, the gastrointestinal system, lymphoid tissues and the bone marrow. Interestingly, carriers of heterozygous LPIN2 mutations on one allele develop psoriatic skin lesions underscoring the potential pathophysiological linkage between skin involvement and bone inflammation [ 5, 7, 16- 18]. Lipin2 is a phosphatidate phosphatase that plays a role in lipid metabolism. The exact function of Lipin2, however, remains to be established. Interestingly, Lipin2 shares sequence homology with Lipin1 that has been documented to carry polymorphisms and mutations in lipodystrophy in humans and mice. However, to date the involvement of Lipin2 in fatty acid metabolism cannot completely explain the inflammatory effects of mutations in Majeed syndrome [ 19- 21]. Even though the phosphatase activity of Lipin2 is completely abolished in Majeed patients carrying the LPIN2 p.S73L mutation, its role in the control of inflammatory responses is less clear. Based on findings in the field of obesity-induced chronic inflammation, it has been suggested that fatty acids may induce a pro-inflammatory phenotype by toll-like receptor (TLR)2 and 4 stimulation that result in the activation of Mitogen Activated Protein (MAP) Kinases, particularly Jun Kinase (JNK)1, and the induction of NLRP3 inflammasomes (Figure 1C) [ 4, 20, 21]. This is of special interest, since patients with sporadic CNO/CRMO also present anomalies in the MAP kinase pathways of monocytes (see below). Lipopolysaccharide (LPS) treatment of human or murine monocytes that either expressed increased or reduced amounts of Lipin2 produced altered levels of TNF-α, IL-6 and the chemokine C-C motif ligand (Ccl-)2. Cells with increased Lipin2 expression failed to produce pro-inflammatory cytokines, whereas reduced Lipin2 expression mediated increased expression of TNF-α, IL-6, and Ccl-2. Thus, Lipin2 may be a negative regulator of fatty acid induced pro-inflammatory signaling in monocytes and macrophages [ 2- 4].

Sporadic chronic recurrent multifocal osteomyelitis (CRMO)

Chronic nonbacterial osteomyelitis (CNO) is a non-infectious inflammatory disorder of yet to be determined etiopathology. It represents a clinical spectrum with self-limited mono- or oligo-focal inflammatory bone involvement on one end and chronic recurrent courses on the other end of the spectrum, which are then referred to as CRMO [ 2- 4].

Children and adolescents are most commonly affected. Symptoms at disease onset can be mild with bone pain with or without local swelling and warmth, or acute with more severe pain, malaise, (usually mild) fevers and even fractures. While, as aforementioned, in some patients inflammation can be self-limited and mono- or oligo-focal, a subset of patients develop chronic disease with ongoing inflammation over years and may suffer from sequelae, such as vertebral fractures and gibbus formation. Bone lesions can occur at any site of the skeleton except for the neurocranium. Additional organs can be involved, including the skin, the eyes, the gastrointestinal system, and the lungs. Skin inflammation can manifest as palmoplantar pustulosis, psoriasis, and occasionally as pyoderma gangrenosum [ 3, 4]. This is of special interest, since most of the skin manifestations of CNO/CRMO also occur in the aforementioned monogenic autoinflammatory disorders. Furthermore, CNO can be part of the so-called SAPHO syndrome (Synovitis, acne, pustulosis, hyperostosis, and osteitis), which manifests in adolescence or adulthood. Whether CRMO in juvenile patients and SAPHO syndrome are the same disorder in different age groups remains to be determined [ 2- 4]. Up to 60% of (usually adolescent or adult) patients may resemble or evolve into spondylarthropathies [ 23].

The precise pathophysiology of CNO/CRMO remains unknown. However, recent findings from our group and others indicate that an imbalance between pro- (IL-6, TNF-α) and anti-inflammatory (IL-10) cytokines may be centrally involved in the molecular pathology of CNO. In the serum of newly diagnosed and untreated CRMO patients, levels of IL-6 and TNF-α were elevated while IL-10 was not detectable in a single patient included in our study [ 24]. Furthermore, monocytes from CRMO patients failed to produce IL-10 under resting conditions and after stimulation of TLR4 with lipopolysaccharide (LPS) [ 24]. Since IL10 is regulated on the transcriptional level by promoter haplotypes influencing recruitment capacities of the transcription factor specificity protein (Sp-)1 to its binding elements [ 25], we asked whether such promoter variants may be responsible for the failure to produce IL-10 by CRMO monocytes. Interestingly, in CRMO patients such IL10 promoter haplotypes that encode for "high" (GCC) rather than "low" (ATA) IL-10 expression were enriched [ 24, 26]. The failure to express IL-10 was linked with reduced activation of the MAP kinases Extracellular Signal Regulated kinase (ERK)1 and ERK2 which in turn results in reduced recruitment of the transcription factor Sp-1 to the IL10 proximal promoter and impaired histone H3 serin 10 phosphorylation (H3S10P), an activating epigenetic mark that had previously been demonstrated to be central for IL-10 expression in monocytes and macrophages (Figure 1D) [ 24, 27]. Activating epigenetic patterns allow for transcription factor recruitment and the initiation of transcriptional complex formation by the rearrangement of nucleosomes. However, at this point, it remains to be determined which exact molecular defect results in the failure to activate ERK1/2 in response to TLR4 stimulation. Interestingly, the expression of pro-inflammatory cytokines IL-6 and TNF-α is not affected by this molecular defect, which is most likely caused by the fact that the induction of the p38 MAPK and JNK was not affected, resulting in an imbalanced activation of p38 and JNK on the one and ERK1/2 on the other hand [ 24, 27]. This is of particular interest, since imbalanced MAPK induction can also be caused by an increased activation of JNK in response to TLR2/4 activation. This mechanism subsequently contributes to increased NFkB recruitment and pro-inflammatory cytokine expression. Therefore, this mechanism may be of central relevance for the molecular pathology of inherited familial osteomyelitis, since decreased expression of LPIN2, which is the cause of Majeed syndrome, results in increased expression of proinflammatory cytokines including TNF-α and IL-6. Conversely, forced expression of LPIN2 resuls in reduced inflammatory responses [ 4]. In this context it may also be of interest that infections with Propionibacterium acnes or other bacterial pathogens (Bartonella) have been suspected to trigger CNO/CRMO [ 28, 29]. Next to TLR9, P. acnes may also activate TLR2 and TLR4 signaling, resulting in MAP kinase activation. Thus, we hypothesize that the imbalance between the expression of IL-10 and pro-inflammatory cytokines may be central to the pathophysiology of CRMO [ 30, 31]. TNF-α and IL-6 contribute to bone resorption and remodeling by inducing the receptor activator of NFkB (RANK) ligand on stromal cells favoring osteoclast differentiation and activation, while IL-10 can suppress RANK-induced effects on osteoclasts [ 3, 30, 32- 36].

Familial clusters with affected siblings and parents together with an increased prevalence of other inflammatory diseases, such as inflammatory bowel disease, in patients and first-degree relatives, suggest a genetic component to CNO/CRMO. Still, to date no single gene variant has been linked to the onset of sporadic CRMO [ 3- 5]. A CRMO susceptibility locus has been mapped to chromosome 18q21.3-22 [ 37] and the aforementioned enrichment of "GCC" IL10 promoter haplotypes that encode for "high" IL-10 expression further suggests a genomic component to CNO [ 24, 26]. However, both findings remain to be established in larger cohorts from other backgrounds. Polymorphisms in genes that co-segregate with related inflammatory conditions were not present in CNO/CRMO (PSTPIP1, PSTPIP2, LPIN2, IL1RN, CARD15), indicating that CRMO and those inflammatory disorders may be related and share key symptoms but are still distinct from one another [ 38- 40]. Identifying common pathways and differences in pro-inflammatory signaling may prove helpful in the search for molecular mechanisms of cytokine deregulation in CNO/CRMO.

Sporadic CNO/CRMO is a diagnosis of exclusion, since the clinical presentation and laboratory findings are not disease-specific and vary between affected individuals. Differential diagnoses include infections (mycobacteria, septic osteomyelitis, etc.), malignancies (bone tumors, metastases, leukemia or lymphoma), benign tumors (osteoid osteoma, bone cysts, fibrosis), further autoinflammatory disorders (PAPA, DIRA, Majeed syndrome, etc.), osteonecrosis, osteopetrosis, and others. Laboratory findings include (slightly) elevated inflammation markers (CrP, ESR, IL-6, TNF-α) in the absence of high-titer auto-antibodies. A subset of patients, however, do not exhibit any serological prove of systemic inflammation. Genomic markers are not available for the diagnosis of CNO/CRMO, since no HLA-associations or single gene mutations have been reported. At this point, no specific biomarkers for the diagnosis and/or measurement of disease activity are available [ 2- 4].

Inflammatory bone lesions may be detected in plain radiographs presenting as radiolucent, osteolytic or sclerotic lesions, depending on the disease stage. However, in early phases of CNO/CRMO radiographs may remain normal. Whole-body imaging techniques, including MRI and Tc-99 m labeled methylene bone scintigraphy, have become widely available and represent novel and valuable diagnostic tools. Since CNO/CRMO reconstitutes a systemic disease with potentially multiple inflammatory lesions, whole-body imaging techniques should be performed at least at the time of diagnosis to exclude asymptomatic lesions e.g. in the vertebral column. MRI is especially sensitive during early stages, since it can detect bone edema even before erosions and/or sclerosis become apparent. Furthermore, MRI techniques allow an assessment of adjacent tissues. At the time of diagnosis, gadolinium-enhanced T1 or strongly T2 weighted sequences (Turbo Inversion Recovery Measurement; TIRM) with fat saturation can be used and are superior to conventional radiographs or scintigraphy. However, diagnoses can be complicated by low specificity of radiological findings, especially during phases of clinical remission in children. For follow-up non-enhanced sequences may be sufficient [ 41, 42].

In unclear cases; especially such with monofocal bone lesions in untypical sites, fevers, highly elevated inflammatory markers (CrP, ESR) and/or pathological white blood cell differentiation patterns, or elevated levels of uric acid or LDH; bone biopsies should be performed to exclude the aforementioned differential diagnoses. In CNO/CRMO, cellular infiltrates are highly dependent on the disease stage. In early phases, neutrophils are the predominant cell subset (Figure 2A). Monocytes, macrophages, lymphocytes, and plasma cells can be detected during later stages of the disease (Figure 2B). Osteolyses and concomitant slcerosis and/or fibrosis can be seen in late phases of CNO/CRMO (Figure 2C). The cellular distribution in inflammatory lesions reflects the immunological reaction at the time. Innate immune activation in early disease stages may be reflected by neutrophils, macrophages and monocytes, while subsequent activation of the adaptive immune system may be reflected by the presence and later predominance of lymphocytes and plasma cells [ 43]. Unfortunately, very little is known about the kinetics of inflammatory responses. Based on our preliminary data from biopsies collected from 12 CRMO patients [ 43], we conclude that early inflammation may last for approximately six months, followed by the lymphocytic/plasma cellular phase that may last for several months or years. The fibrosing end-stage may be reached after several years of active bone inflammation [ 43].

Treatment in CNO/CRMO is empiric, since placebo controlled randomized trials have not been performed [ 3, 4, 39, 43]. NSAID are commonly used as first-line treatment of CNO/CRMO in less to moderately severe cases. NSAIDs provide pain control in most cases and most likely alter the disease course, since prostaglandins are centrally involved in osteoclast activation and bone remodeling. Recently, we reported a cohort of CNO/CRMO patients treated with naproxen over one year. In over half of our patients, a symptom free status was achieved after 12 months. However, complete clinical remission in the absence of radiographic proof of inflammation was only achieved in 27% of patients [ 44]. In a recent study, response rates to NSAIDs were reported lower (13%) [ 45]. Differences between this US American and our study may be due to the collection of retrospective data from charts in two independent sites over a 24-year interval, and the incomplete availability of results from imaging techniques. For the same reasons, patients with more severe and treatment-resistant forms of CNO/CRMO may be over-represented in this cohort. In our prospective study, predictors of incomplete response to NSAIDs were arthritis and/or vertebral involvement at diagnosis [ 44]. Over 40% of our patients developed radiographic signs of recurring bone inflammation after the discontinuation of naproxen, 67% of which remained clinically silent [ 44]. Over all, our data suggest a favorable response to NSAIDs in most patients. The discrepancy between clinical and radiographic remission raises the questions of when NSAID treatment can be discontinued safely and whether treatment is necessary in the absence of clinical symptoms. Both questions are of special relevance, since it appears likely that CNO/CRMO is largely under-diagnosed. This may be secondary to the absence of subjective complains in a subset of patients, which only get diagnosed after vertebral fractures that may be prevented by early treatment. In our study and according to other reports, a significant fraction of CNO/CRMO patients require more aggressive treatment regimens [ 4, 44, 46]. Second line options include corticosteroids, sulfasalazine, methotrexate (MTX), anti-TNF agents (usually etanercept or infliximab), or bisphosphonates (usually pamidronate) [ 3, 4]. Case reports and our clinical experience suggest favorable effects of corticosteroids in a majority of patients (60%) reviewed in [ 3, 5]. Unfortunately, prospective studies are not available and safety concerns need to be considered [ 3, 4]. Thus, we recently proposed a therapeutic escalation regimen based on (the limited) published data on treatment response in CNO/CRMO and our own experience (Figure 3) [ 47]. In NSAID refractory cases, authors apply corticosteroids in high-dose regimens (up to 2 mg/kg/d) for two weeks or continuously in lower doses (0.1-0.2 mg/kg/day). Sulfasalazine has been reported beneficial in case reports and case series. Recently, Borzutzky et al. reported limited effects in most patients (clinical remission in 18%) [ 45]. However, the authors' personal experience suggests higher efficacy in selected CNO/CRMO subsets, particularly HLA-B27 positive patients and in patients with concomitant inflammatory bowel disease [ 3, 4, 48]. MTX is a relatively common treatment choice for CNO/CRMO in North America. However, two recent reports suggest the induction of clinical remission in only a subset of patients (up to 20%) [ 45, 49]. Given the imbalance between pro- (IL-6 and TNF-α) and anti-inflammatory cytokines in CNO/CRMO, TNF-α blockers have proven useful in a subset of patients (up to 65%) [ 4, 44, 46]. However, a significant fraction of treated individuals do not fully respond. Though most CNO/CRMO patients receiving anti-TNF treatment were resistant to standard treatment, more than one third did also not completely respond to TNF inhibitors. Given the off-label character and the high cost of TNF-α blocking agents, together with safety concerns, they should be reserved for complicated cases with structural damage and/or steroid refractory courses [ 3, 44, 46]. Intravenous application of bisphosphonates has proven effective in pain reduction and bone-inflammation (up to 80% have been reported to experience improvement) and some patients reach complete remission after a single dose reviewed in [ 3, 5, 50- 53]. However, most individuals require repeated infusions to reach and sustain remission. Usually three to four courses are applied in four-weeks intervals reviewed in [ 3, 5, 50- 53]. Given potential safety concerns during long-term treatment in children and adolescents, bisphosphonates should be reserved for severe cases (with structural damage, e.g. vertebral fractures) or in otherwise treatment-resistant patients.

CNO/CRMO in animals

Genetically determined CNO has been reported in animals which function as disease models, helping to understand molecular requirements and immunological patterns of bone inflammation.

Severe CRMO with systemic inflammation occurs in mice with mutations in the proline serine threonine interacting protein 2 (Pstpip2) gene. Two strains have been reported: Chronic multifocal osteomyelitis (CMO) mice carry a spontaneous mutation in Pstpip2 (p.L98P) [ 54], in lupo mice a Pstpip2 mutation was chemically induced (p.I282N) [ 55]. Both mice develop phenotypes that are similar to severe human CRMO with multiple sites of bone inflammation. Since both total (in CMO mice) and partial (in lupo mice) PSTPIP2 deficiency result in a pro-inflammatory phenotype, PSTPIP2 has been suggested to exert anti-inflammatory functions. Unlike most human CRMO patients, CMO and lupo mice exhibit additional signs of systemic inflammation, including hepatosplenomegaly, extramedullary hematopoiesis, and elevated serum inflammatory parameters (MIP-1a, RANKL, both osteoclastogenic factors, IL-1α, IL-1β, TNF-α, and IL-6) [ 54, 55]. Cross breeding with RAG −/− mice demonstrated disease expression independent from adaptive immune cells [ 55]. Macrophage depletion or treatment with inhibitors of the M-CSF receptor (c-FMS), decreased circulating MIP-1a and diminished extramedullary hematopoiesis and inflammation. Furthermore, osteoclast precursor cells in CRMO-prone mice exhibit increased osteoclastogenesis in vitro. This suggests that cytokine imbalance in CRMO-prone mice drives osteoclast generation and activation, resulting in sterile inflammation and bone loss [ 54]. Taken together, over-responsive myeloid cells and subsequent osteoclast generation and activation have been suggested to be major contributors to the pro-inflammatory phenotype of CMO and lupo mice. This is of special interest, since this mechanism may also be central to the molecular pathogenesis in human CRMO.

Another form of CRMO in animals is referred to as hypertrophic osteodystrophy (HOD), which is prevalent in large breed dogs. HOD usually presents in young dogs with fevers and bone pain. Similar to human CRMO, vertebral bodies and the metaphyses of long bones are most commonly affected. Osteolytic and sclerotic lesions can be detected in radiographs. In biopsies sterile osteomyelitis and osteonecrosis can be seen. Extra osseous manifestations include skin rashes and diarrhea [ 56, 57]. Even though self-limiting in most cases, sometimes HOD can take a life-threatening course. Affected animals respond to NSAIDs but corticosteroids show better efficacy. The etiopathology of HOD remains unclear. Since specific large breeds are most commonly affected and familial cluster have been reported, an autosomal-recessive inheritance or dominant traits with incomplete penetrance are most likely. One study in affected Weimaraner dogs documented an association of HOD with DLA-DRB1*01501 that was not reproduced in follow-up investigations [ 56, 57].

Conclusions

Over the past decade, significant progress has been made in understanding the pathophysiology of autoinflammatory bone disorders in humans and animals. Regardless of the identification of disease-causing genes in some monogenic disorders, the exact pathophysiology remains largely elusive for most of them (with the exception of DIRA). In the light of in vivo and in vitro studies, together with favorable response to cytokine blocking strategies, an imbalance between pro- and anti-inflammatory cytokines appears to be central for disease expression in all of them.

In the (most probably) polygenic human disorder CNO/CRMO, progress has been made targeting molecular pathomechanisms and molecular disturbances. Defective MAP kinase pathways result in impaired anti-inflammatory cytokine expression. Disease-causing mutations in one or multiple genes, however, remain to be determined. The clinical picture and outcomes in CRMO are highly variable, complicating the identification of patients who require treatment on top of NSAIDs to control disease activity and prevent complications. Thus, the development of clinical scoring systems and biomarkers will prove essential in order to select patients at risk for fractures and/or prolonged disease courses.

Declarations

Authors' original submitted files for images

Competing interests

Authors' contribution

All authors contributed to the drafting of the manuscript and approved the final version. JP provided histologies from bone biopsies of CNO patients.

The authors declare that they have no competing interests.

Below are the links to the authors' original submitted files for images.

Authors' Affiliations

(1)

Division of Pediatric Rheumatology and Immunology, Children's Hospital Dresden, University Medical Center Carl Gustav Carus, TU Dresden

(2)

Division of Pathology, University Medical Center Carl Gustav Carus, TU Dresden

(3)

Department of Pediatrics, University of Würzburg

(4)

Children's Hospital, Vivantes Klinikum-Friedrichshain

References

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2. Stern SM, Ferguson PJ: Autoinflammatory bone diseases. Rheum Dis Clin North Am. 2009, 360: 735-749.

3. El-Shanti H, Ferguson P: Majeed syndrome. GeneReviews™ [Internet]. Edited by: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K. Seattle (WA): University of Washington, Seattle, 1993-2013. 2008

4. Beck C, Girschick HJ, Morbach H, Schwarz T, Yimam T, Frenkel J: Mutation screening of the IL-1 receptor antagonist gene in chronic non-bacterial osteomyelitis of childhood and adolescence. Clin Exp Rheumatol. 2011, 29: 1040-1043.

5. Jansson A, Renner ED, Ramser J, Mayer A, Haban M, Meindl A: Classification of non-bacterial osteitis: retrospective study of clinical, immunological and genetic aspects in 89 patients. Rheumatology (Oxford). 2007, 46: 154-160. 10.1093/rheumatology/kel190.

© 2017 BioMed Central Ltd unless otherwise stated. Part of Springer Nature.

# data[].attributes.attachment_link.title
Autoinflammatory bone disorders with special focus on chronic recurrent multifocal osteomyelitis (CRMO)

# data[].attributes.attachment_link.description
Sterile bone inflammation is the hallmark of autoinflammatory bone disorders, including chronic nonbacterial osteomyelitis (CNO) with its most severe form chronic recurrent multifocal osteomyelitis (CRMO). Autoinflammatory osteopathies are the result of a dysregulated innate immune system, resulting in immune cell infiltration of the bone and subsequent osteoclast differentiation and activation.

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wat is WES..Whole Exon Screening

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Deze website toont video's van o.a. YouTube. Dergelijke partijen plaatsen cookies (third party cookies). Als u deze cookies niet wilt kunt u dat hier aangeven. U kunt dan geen video's op deze website zien. Wij plaatsen zelf ook cookies om onze site te verbeteren. Deze gegevens worden niet aan derden verstrekt.

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Gentische testen bij kinderwens

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OnlineSeminar | Webinar: Genetische testen bij een kinderwen

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Webinar bekijken:(27-11-2017) Genetische testen bij een kinderwens. Wat kan er? Hoe ver willen we gaan van UMC Utrecht

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autoinflammatoire volwassen

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autoinflammatoire volwasse