wordspicHistiocytosis a rare disease

Despite the misery it causes, histiocytosis is too rare a disease to have generated substantial research in medical circles.

Unfortunately, for every child or adult fighting for his or her life, the pain and suffering are just as severe for children and adults afflicted with other better known disorders receiving funding.

For the children and adults battling these illnesses, there is now reason to hope.
To ensure the research and information support work continues, we ask for your help, to complete the funding puzzle.

Our research programmes provide a beacon of hope for the many children and adults battling Histiocytosis, to ensure this research continues we ask you to pledge your support.


Histio Bear Hugs

Help us bring “hugs” to those suffering from Histiocytosis

Histio Bear does not hold a passport and so can only travel within the UK or to Eire and will not travel during 1st November to 30th January.

Histio bear hugs for patients of all ages - Do you know a child, young person or adult that would like a “Histio Bear” Hug? Then nominate them here:

Histio Bear Hugs – Nomination Form
Name & Contact Details of Person Making the Histio Bear Hug Request:

Your Name

Address & Postcode:



Your Email

Relationship to Patient:

Does the patient have brothers and sisters? (If we can we will include them in the Histio Bear Hugs nomination by sending them a mini bear PLEASE NOTE Mini Bears are not suitable for children under the age of 3 years).

Number of brothers and sisters.

PATIENT DETAILS (The person you wish to receive the Histio Bear Hug)

Patients Name

Patient Address & Postcode:


Patient Email

Patient Age

Type of Histiocytosis

Place of Treatment

Name of Consultant

Name of GP

GP Address & Postcode:

Name of Dentist (if applicable)

Dentist Address & Postcode: (if applicable)

Any other details you feel are relevant and would like to share:

Please answer the question:

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Histio UK. Litton House, Saville Road Peterborough PE3 7PR. Thank you for your participation.

If you can help us make “Histio Bear” Hugs go further please make your donation below.

Post your pictures of YOUR Histio Champions with their “Histio Bear Hugs” on Facebook @ Histio Champions UK or Tweet @ Histio UK.

Statement of Confidentiality: The information provided here is covered by the Data Protection Act and is for analytical and statistical research only and will not be shared with any other organisation.

Thank you for your help with our continued work.

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Your voice

HLH the impact on our family by Andrea & Paul Scholes.

Share your voice - Your story

The views expressed below are those of the writer and do not reflect views and or opinions of the charity.

Title: Young Person HLH – Our prefect daughter by Nicola Jackson…

Intro: Our perfect 20-year-old daughter was taken ill just before Christmas 2015…
We took her to our local GP, she had swollen glands and was just unwell, she had no sign of infection and so they sent us to the local Ear Nose & Throat outpatients to have it checked out.

Chelsea was diagnosed Glandular Fever, her white blood cell count was quite low, but they were not too concerned, 3 days later Chelsea’s throat was very sore, so we took her to the Emergency Doctors and they diagnosed Tonsillitis. Chelsea was prescribed a 10-day course of strong antibiotics.

After a few days the antibiotics did not seem to be working and Chelsea did not appear to be getting any better, she was struggling to speak and swallow. We took her to the Accident & Emergency and she was immediately admitted, her temperature was really high and she was subsequently transferred to the ENT ward for intravenous antibiotics.

After two days the Doctors said that she had been tested for CMV infection and that her liver and spleen were swollen, Chelsea was placed on antiviral medication and moved to another ward.
Over the next few days her breathing worsened and Chelsea was moved to Intensive Care. Her bloods were all over the place and her body was struggling to cope. Chelsea was placed into an Induced Coma and placed on a kidney machine due to the amount of acids in her blood.

A bone marrow test was taken and this is when the HLH was mentioned, Chelsea would be started on chemotherapy and steroids the next day. A biopsy was also taken on Chelsea’s neck.

We had a telephone call on Sunday 17th January 2016 to say that Chelsea’s organs were failing and that there was no brain function at all, it was just the machines that were keeping her alive.
The family had to make the agonising decision to let our beautiful girl pass on with all of her family around her.

We as a family, hope that we can help raise awareness of this condition in order that it can be investigated and tested for sooner to enable earlier diagnosis, timing is crucial in the treatment of this devastating disease.

Title: Young Person HLH – My Beautiful Daughter by Anne Goldring…

Intro: Anne Goldring shares the devastating story of the loss of her daughter Jo to HLH…
My beautiful 16-year-old daughter Jo took ill at the end of May 2015. She started with just a fever, no other symptoms at all. The fever started spiking to 39 degrees with no change for about two days despite having paracetamol cool baths etc. nothing would bring her temperature down.

After two days we went to a local GP who did a urine sample and said she had a kidney infection gave antibiotics and said carry on with paracetamol.

After 3more days of this treatment she was no better and was transferred to our local hospital. She was taken for an MRI scan and was given multiple antibiotics by IV along with several other medications.

After 3 days she was discharged after having a test which showed glandular fever.

We returned home only for her to deteriorate even more so. After another trip to the local doctor we returned again to our local hospital. She was literally pumped full of more antibiotics paracetamol and was given enough IV protein, put on a strict fluid intake as her kidneys were failing but still they had no idea what they were treating her for.
After five days she had got so bad they had to transfer her to St. Thomas in London. Where she was admitted to intensive care.

The specialists told me that they had never seen such a sick child. By this time, she had fluid around her heart, kidney failure and was very very sick. She was attached to tubes 24 hours a day. She had been there 4 days when they decided that she needed to be on a 24-hour kidney dialysis machine as she had a high amount of ammonia in her blood.

At this point she was kept under complete sedation. From that day they finally found a specialist who took a bone marrow sample and Jo was diagnosed with HLH, by this time it was too late.
For another 4 days we had to watch her deteriorating it was the worst time of our life and I would do anything to make sure no one else suffers like we have.

Title: Paediatric HLH – our worst nightmare…

Intro: Debbie-Sue Price re-counts the terrible moment she found out her son, Aaron, had a life-threatening immune disease, HLH, and how all parents should listen to their gut instinct when it comes to a poorly child…

My son Aaron got chicken pox last year in May, two weeks after his twin sister. Five days later, when the spots had scabbed over, I thought he would be returning to nursery but that night Aaron spiked a fever of 39+. Despite giving him Calpol, his fever didn’t subside. We made numerous trips to our GP’s surgery and local hospital every day for a week until they finally admitted Aaron.

It was a good job that my husband and I did keep going back, as we soon learned that the chicken pox had sent Aaron’s immune system into overdrive and he had secondary Haemophagocytic Lymphohistiocytosis (HLH).

HLH is an immune disease and is most common in babies and toddlers; however, it can affect people of any age. It can become fatal rapidly and without effective treatment most patients will die.

The treatment for HLH is chemotherapy, high dose steroids and, in some cases, a bone marrow transplant. Thankfully, HLH is rare - there is a one in a million chance worldwide of getting it – but because of this doctors and parents might not spot the early signs so it’s important to raise awareness.

The initial symptoms of HLH mimic the flu and many parents’ stories begin the same way: “our child is sick, not getting better and we are being dismissed with “it’s just a virus, your child needs more antibiotics and time; they’ll be fine”. It’s important to keep in mind the most common symptoms of HLH are a fever, enlarged spleen, low blood counts and liver abnormalities.

Aaron was transferred to Birmingham Children’s Hospital (BCH) and stayed there for three months; with two months in Intensive Care and High Dependency. Our Christmas came early last year when Aaron was discharged in early October, albeit with a bag full of drugs that he had to take each day. We celebrated with a Halloween party.

My husband had to take Aaron to BCH twice a month for his chemo until he completed his course just recently this month.

I don’t want to cause panic but if you think something is seriously wrong or your child has a fever despite medication for over five days (a fever is classed as over 37.5). Speak up and trust your instincts. If your doctor hasn’t already done so, ask for blood tests (including a Ferritin test) and a complete blood count (CBC).

Aaron has been very lucky. If it wasn’t for our cousin, Shahenda, a paediatrician in the US, who spoke directly to our consultant in hospital and insisted on vital blood tests, Aaron might not be with us today.


Always listen to your gut instinct if you think something is seriously wrong with your child, especially as babies can deteriorate very quickly. Seek help if you need to and talk to your GP or midwife.

NCT’s helpline offers practical and emotional support: 0300 330 0700

Find out about our Early Days courses: www.nct.org.uk/early-days

Read more about life with a new baby: www.nct.org.uk/parenting

Title: Adult LCH – Did a common virus/bacteria trigger my LCH? by Clare Bacon.

Intro: Clare Bacon shares her story from initial illness through diagnosis and treatment to the current day
Sept 2012 busy at work, busy at home, living the usual juggle of a working mum. I had a cold which developed into tonsillitis, something I had become prone to since the arrival of our children. After a couple of weeks, several rounds of antibiotics the infection faded away. I was back at home but still feeling very under the weather, headache, sinus pain bad cough....GP wasn't keen to prescribe more antibiotics so I plodded on. I was extremely fatigued and one night having gone to bed early, a large lump appeared on top of my forehead.
I could feel the swelling moving across my head and tracking down across my brow. I felt quite panicked, my husband told me not to worry - Mr Calm! Somehow I slept.

The next day my face was still swollen, my head and neck were stiff and painful, I managed to get a GP appt for that day. My husband came with me and I explained my symptoms, and previous infection. The swelling was clear for the doctor to see, I stressed the sinus pain.
The GP was fairly swift in telling me to go to A and E, so off we went.

It is about now desperation, and frustration started to rear their heads, feelings that have only grown over the last three years.

Our local A and E decided I needed to go to another hospital as they had an ENT dept.
Arrived at next A and E, went through the usual process eventually got to speak to a member of medical profession - not convinced an actual Doctor. His opinion was that I was allergic to shampoo and had suffered a reaction. My history of infection and sinus pain were discounted. I was sent away with steroids and some general antibiotics. I knew I did not have a shampoo allergy and could feel inflammation, swelling and pain all around my head. I returned home very worried.

The next couple of weeks passed in a blur of pain, weird brain sensations and feeling unwell. I decided to take matters into my own hands and requested my GP to refer me to an immunologist.

Saw the immunologist who actually listened to me and agreed to run a CT scan of my sinuses/head. I started to feel better and the only ongoing issue was pinpoint pain on my skull.
The immunologist asked for me to return on 24th December. The day came I trundled up to the hospital in amongst Christmas mayhem with relatives at home and children beyond excited.
The Dr wasted no time in telling me I had multiple lesions on my skull, he advised me not to think this was the worst news ever. Clearly that advise fell on deaf ears.
Thoughts of Bone/brain cancer, sudden death, last Christmas, 3 months to live filled my head.
The DR busied himself with form filling in and told me I needed multiple urgent tests.

I returned to my car where I collapsed in sobbing fear, telephoned my brother in a crying state and blurted out I was dying. - my poor brother. I had to go home and tell my husband and then get back for all the tests. Walking past smiling at my mum and father in law I had a large sherry and told them I had a routine scan later that day. How I pretended I will never know.

The day was one of the worst I have experienced, scans and bloods followed. No opinion proffered until the last MRI where a radiologist suggested it could be severe infection. Was this a glimmer of hope that I wasn't about to lose my life ?

Returning home, I staggered through Christmas Eve. The immunologist DR rang about 8 pm and told me he was trying to arrange urgent surgery for me as one of the lesions was close to penetrating my brain. The effort to pretend I was ok dissolved., although I still could not say anything to family. At 10pm it was confirmed by telephone that a surgeon would see me Boxing Day morning at St Georges. OH MY GOD.

Needless to say Christmas was a walking blur, my husband was suffering from a peritonsillar abscess and was really unwell and I was beyond distressed. I often think that the virus/bacteria infection that caused our tonsillitis kick started LCH. (of course I am alone in that)

I was admitted into St Georges and various tests were carried out, I waited about 10 hours before being taking to surgery. I was forcing myself to be calm and disconnected from what was going to happen. That is, until I was on a trolley outside theatre and a guy in scrubs approached, he started putting stickers on my head, and asked if he could shave my hair. The look on my face, made him mumble "maybe later" and he retreated. Seconds before oblivion the surgeon introduced himself and said whatever he finds he is going to cut out. Brilliant!

I come round in some holding pen for post op patients and feel grateful I can see and have normalish thoughts. I leave hospital with no information but a lot of heavy staples in my skull.

It turns out bone biopsy takes a number of days/weeks. A section of skull measuring 4 by 4 cm was removed and a piece a mesh inserted. I was advised to avoid bumps on the head - helpful!

After a few weeks I finally got a call from the much pestered Doctor at St Georges. I had Langerhans Cells Histiocytosis. His thinking was, I would live, but would be ill for a long time.
Its going to be manageable I thought, I can carry on with my life. What a phenomenal relief.

Now, it is still a relief and from where this all started I am a very lucky woman.

Unfortunately, what I and other patients struggle with is medical care, support, treatment and understanding. The illness is understood in part but not what causes it, and not its behaviour.

For me the last couple of years have been full of doctor’s appointments, tests for unexplained symptoms, reoccurrence of skull and immune issues, scaring the life out of me that more holes are appearing in my body.
Doctors can only see what they can see and will only treat what they can clearly identify. Sadly, that does not help LCH sufferers.

I cannot explain my illness to my employer, GP and LCH Doctors do not react to the eternal roll of infections and symptoms. It is hard to be positive and think that I might be well for more than a week or two at a time.

That said, so far one hole in the head, significant unexplained hearing loss and poor health, perhaps I am one of the fortunate ones.

Title:LCH Paediatric - Sebbie’s Story by Mum,Kristina Smith.

In May 2015, my beautiful little boy was diagnosed with a very rare cancer like condition called LCH (Langerhans’s Cell Histiocytosis). He was two and a half.
He had lost two kilos in two months. His left eye was partially closed from a skull tumour. His scalp was a bloody mess. His skin was covered in spots. his ears were oozing with infection. He had an insatiable thirst to the point of drinking rain water from the trampoline. He had lost his wonderful zest for life.
After almost two years of repeated GP visits, seeing dermatology and ENT at the hospital and advice from all quarters we finally got diagnosed on Northbrook Ward in Winchester hospital.
Only 50 kids a year get this wicked illness in the UK. Nobody knows why, or how. It's so rarely seen that its diagnosis is often missed by doctors for some time.
Within three days, our little Sebbie had been through hell. He'd had cannulas, scans, prodding and poking, general anaesthetic, a central line fitted in his chest, and was away from his home and new baby brother. We were transferred to the excellent Piam Brown paediatric oncology ward at Southampton Hospital. Sebbie was put on chemo immediately.
Sebbie is on chemo for one year. His pituitary gland has been damaged for life so he has to take tablets three times a day every day to stop his body weeing to death. His skull tumours are all reducing in size. His skin now looks amazing. He now has his old mop of blonde hair back. We visit Northbrook Ward in Winchester every 3 weeks for chemo with the wonderful Dr Ian Rodd. Every three sessions we return to Piam Brown FOR the excellent Dr Ramya to check on progress.
So that's our story. My child happens to be that one in a million. Luckily I have been on maternity leave this year so Sebbie has had Mummy to hand (albeit with a new baby in tow). He is SO incredibly brave. He still doesn't know he's ill. He gets frustrated that he can’t go to soft play or playgroup, go for a swim or dig for mud in the garden, but his immunity is low and his central line has to be protected.
Sebbie's preschool, 'Rainbows Playgroup' have been amazing. They keep him feeling 'normal', beavering in the background to give him separate sand play, water play and snacks; being trained by the community nurse on dealing with any emergency; and keeping everything super clean. They are also abseiling with me. They’ll be raising money for the preschool.
Hopefully Sebbie will recover. There are many more children around the world that are being diagnosed with LCH. All with similar stories I'm sure. So please give generously to fund more research. LCH doesn't have the public's awareness, or support, like other childhood cancers but it can be just as devastating.

Share your story with the media

By raising awareness of histiocytosis in the national and local press we can reach more people. We rely on personal stories to help us engage readers around our cause and bring our stories to life.

If you are interested in sharing your story on our website or in a magazine, newspaper or on TV please send a 100-word summary of your story along with your name, contact details and a recent photo to Histio@histiouk.org. We regret that we are unable to respond to everyone, but we really appreciate you getting in touch.

Why should I share my story?
We want to help as many people as possible during their histiocytosis experience – patients, carers, families and communities. By raising awareness of what we do in national newspapers, magazines, on TV and in the local press we can reach more people.

We rely on personal stories to help us do this as they engage the reader and bring the story to life. For example, if we provide research for a newspaper showing that histiocytosis can affect people financially it has more of an impact if it’s accompanied by an emotive quote or story of someone who has been directly affected and helped by us.

Your story can encourage those who see it to get help if they are worried they have the symptoms of histiocytosis or may inspire them to donate or fundraise for us. Some people who have shared their story find it a cathartic experience. It makes them feel good to give something back.

Where would my story appear?
As well as our website, we work with a range of media from broadcasters like the BBC, national newspapers like The Times, Daily Mail and Guardian and women’s magazines like Woman’s Own and Good Housekeeping.

They all have different requirements for their stories so we would approach those which we think are most appropriate, depending on your story.

Do I have to be identified/pictured?
Yes, all of the magazines and newspaper ask that the people they interview are pictured. Some ask you to send/email them photos to use while others send a photographer to take photos.

Will I have a say over what’s written?
By sending us your story you agree to its publication on our website or on or in any publication that may collect news feeds or create editorial content.

Request by journalist for contact details will be agreed with you in advance of disclosuer.

Please be aware that whilst some journalists offer to read your story before it goes to print to check facts it depends on the publication and this cannot be guaranteed.

What happens next?
The journalist will try tell you when your story will appear so you can get a copy and tell all your friends. We ask the journalists to include information about Histiocytosis UK Support’s campaigns and services and you can feel proud that you’ve helped deliver our message.

If you are interested in sharing your story in a magazine, newspaper or on TV please send a 100-word summary of your story along with your name, contact details and a recent photo to Histio@histiouk.org. We regret that we are unable to respond to everyone, but we really appreciate you getting in touch.

Help ensure that we can continue to bring you this vital informational material, make a donation today

News Stories and Articles
Some of the articles presented on this website are accessed through RSS feeds from third-party sources that are not necessarily sourced by or part of Histio UK. While we try to select appropriate feeds to prevent objectionable content from being displayed, the presence of any article does not indicate endorsement or recommendation by Histio UK.

(SOURCES. http://www.ncbi.nlm.nih.gov)

pubmed: histiocytosis[mesh t...

NCBI: db=pubmed; Term=histiocytosis[MeSH Terms]

Related Articles

Tracheobronchial Involvement of Rosai-Dorfman Disease: Case Report and Review of the Literature.

Medicine (Baltimore). 2016 Feb;95(7):e2821

Authors: Boissière L, Patey M, Toubas O, Vella-Boucaud J, Perotin-Collard JM, Deslée G, Lebargy F, Dury S

Rosai-Dorfman Disease (RDD) is a rare non-neoplastic entity, also known as sinus histiocytosis with massive lymphadenopathy (SHML), characterized by a benign proliferation of histiocytes in lymph nodes. Localized forms of RDD involving the tracheobronchial tree are very rare. There is no consensus regarding the management of central airway forms and recurrence is frequent. We report the case of an 81-year-old Caucasian woman admitted in 2014 for chronic cough. Her main medical past history included a diagnosis of sinonasal RDD in 1996 with recurrent obstructive rhinosinusitis requiring repeated sinonasal surgery, and a diagnosis of tracheal RDD in 2010 with 2 asymptomatic smooth lesions (5 and 7 mm) on the anterior tracheal wall. Physical examination was normal in 2014. Pulmonary function tests showed an obstructive pattern. Computed tomographic scan revealed a mass arising from the anterior wall of the trachea that projects into the tracheal lumen. Fiberoptic bronchoscopy showed a hypervascular multilobular lesion (2 cm) arising from the anterior tracheal wall and causing 50% obstruction of the tracheal lumen. Mechanical resection with electrocoagulation of the tracheal mass was performed by rigid bronchoscopy with no complication. Histological examination demonstrated tracheal RDD. One year after endotracheal resection, the patient presented no recurrence of cough and the obstructive pattern had resolved. Reports on tracheobronchial involvement are scarce. Symptomatic tracheobronchial obstruction requires mechanical resection by rigid bronchoscopy or surgery. Recurrence is frequent, justifying long-term follow-up.

PMID: 26886634 [PubMed - indexed for MEDLINE]

Related Articles

Cutaneous manifestations of Erdheim-Chester disease (ECD): Clinical, pathological, and molecular features in a monocentric series of 40 patients.

J Am Acad Dermatol. 2016 Mar;74(3):513-20

Authors: Chasset F, Barete S, Charlotte F, Cohen-Aubart F, Arnaud L, Le Pelletier F, Emile JF, Francès C, Amoura Z, Haroche J

BACKGROUND: Erdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis with possible cutaneous-specific involvement.
OBJECTIVES: We sought to describe the clinical, pathological, and molecular features of the cutaneous manifestations of 40 patients with ECD identified from a cohort of 123 patients.
METHODS: Confirmed cases of patients with ECD were included in a single-center retrospective observational study. Clinical and pathological cutaneous features were analyzed and BRAF(V600E) mutation was determined.
RESULTS: The most frequent ECD cutaneous manifestations were xanthelasma-like lesions (XLL), which occurred in 31 (25%) patients. Other ECD cutaneous lesions were patches or papulonodular lesions. Mixed form of ECD and cutaneous Langerhans cell histiocytosis presented with crusty papules of the folds in some patients. Compared with classic xanthelasma palpebrarum, ECD XLL pathology more frequently involved the reticular dermis, displayed more multinucleated or Touton cells, and showed less extensive fibrosis. BRAF(V600E) mutation was more frequently detected in patients with cutaneous involvement than in those without (76% vs 52%; P = .005) and constantly found in 10 XLL.
LIMITATIONS: Some clinical data were not available because of the retrospective design of the study.
CONCLUSIONS: XLL are the most frequent cutaneous ECD manifestations and might be targeted both for pathology and determination of BRAF mutational status.

PMID: 26785805 [PubMed - indexed for MEDLINE]

Related Articles

Multiple aneurysms and Rosai-Dorfman disease: association or coincidence?

BMJ Case Rep. 2015;2015

Authors: Ganesh Y, Yadala V, Vemula B, Kammela NY

PMID: 26396129 [PubMed - indexed for MEDLINE]

Related Articles

Longitudinal changes in cerebellar and subcortical volumes in adult-onset Niemann-Pick disease type C patients treated with miglustat.

J Neurol. 2015 Sep;262(9):2106-14

Authors: Bowman EA, Walterfang M, Abel L, Desmond P, Fahey M, Velakoulis D

Niemann-Pick disease type C (NPC) is a rare neurovisceral disorder resulting in impaired intracellular lipid trafficking. The only disease-modifying treatment available to date is miglustat, an iminosugar inhibiting the accumulation of lipid by-products in neurons. This study explored how changes in cerebellar grey and white matter volumes, and in subcortical volumes, related to patient treatment status and disability and ataxia ratings. Nine adult-onset NPC patients and 17 matched controls underwent T1-weighted MRI. One patient was not receiving miglustat, and pre-treatment data were available for a further patient. Semi-automated cerebellar and subcortical segmentation was undertaken, and the rates of change in putamen, hippocampal, thalamic and caudal volumes, and grey and white matter cerebellar volumes, were compared to rates of change in Iturriaga disability score, Brief Ataxia Rating Scale (BARS), and horizontal saccadic gain. Untreated NPC patients appeared to lose cerebellar grey and white matter, bilateral thalamic volume, and right caudate volume faster than treated patients. Cerebellar grey matter volume loss and volume loss in the left thalamus were significantly correlated with Iturriaga disability scale changes. Change in both cerebellar grey and white matter was correlated with decrease in horizontal saccadic gain, but not with change in BARS. This is the first study to examine longitudinal treatment effects of miglustat on cerebellar and subcortical volumes in patients with adult-onset NPC, and is evidence that miglustat may have a protective effect on cerebellar and subcortical structure and function.

PMID: 26092521 [PubMed - indexed for MEDLINE]

Related Articles

A novel pathogenic variant in PRF1 associated with hemophagocytic lymphohistiocytosis.

J Clin Immunol. 2015 Jul;35(5):501-11

Authors: Romero CA, Sánchez IP, Gutierrez-Hincapié S, Álvarez-Álvarez JA, Pereañez JA, Ochoa R, Muskus-López CE, Eraso RG, Echeverry C, Arango C, Restrepo JL, Trujillo-Vargas CM

Familial Hemophagocytic Lymphohistiocytosis type 2 (FHL2) results from mutations in PRF1. We described two unrelated individuals who presented with FHL, in whom severely impaired NK cytotoxicity and decrease perforin expression was observed. DNA sequencing of PRF1 demonstrated that both were not only heterozygous for the p.54R > C/91A > V haplotype but also presented with the novel variant p.47G > V at the perforin protein. Perforin mRNA was found to be increased in a individual with that genotype. A carrier of the novel variant also demonstrated altered perforin mRNA and protein expression. Phylogenetic analysis and multiple alignments with perforin orthologous demonstrated a high level of conservation at Gly47. PolyPhen-2 and PROVEAN predicted p.47G > V to be "probably damaging" and "deleterious", respectively. A thermodynamic analysis showed that this variant was highly stabilizing, decreasing the protein internal energy. The ab initio perforin molecular modeling indicated that Gly47 is buried inside the hydrophobic core of the MACPF domain, which is crucial for the lytic pore formation and protein oligomerization. After the in silico induction of the p.47G > V mutation, Val47 increased the interactions with the surrounding amino acids due to its size and physical properties, avoiding a proper conformational change of the domain. To our knowledge, this is the first description supporting that p.47G > V is a pathogenic variant that in conjunction with p.54R > C/91A > V might result in the clinical phenotype of FHL2.

PMID: 25975970 [PubMed - indexed for MEDLINE]

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