Investigation of Dental Health in Children With Neutrophil Defects: A Clinical Study
Investigation of Dental Health in Children With Neutrophil Defects: A Clinical Study
Title: Investigation of neutrophil defects associated with periodontal disease and tooth loss
 in children. A clinical study.

 Objectives: The primary objective of this study is:

 -  To investigate presence of periodontal disease and response to periodontal treatment in
 children affected by neutrophil defects

 The secondary objectives of this study are:

 -  To investigate presence of other dental diseases in children affected by neutrophil
 defects

 -  To assess oral microbiological and inflammatory parameters in children affected by
 neutrophil defects

 Primary outcomes: The primary outcomes are (a) presence of periodontal disease as assessed by
 clinical factors: probing pocket depth, attachment level, bleeding on probing and
 radiographic bone loss) (b) microbiological and host response factors: detected in
 periodontal pockets and gingival crevicular fluid and (c) response to treatment

 Study sample: Children affected by neutrophil defects and meeting outlined inclusion and
 exclusion criteria

 Number of participants: 50 children

 Study design: This is a longitudinal treatment study. All participants will attend for 4-7
 visits during the study as outlined below:

 -  Screening visit (visit 1): consent procedure, dental examination, saliva and plaque
 sampling

 -  Baseline visit (visit 2):, detailed periodontal examination, dental radiographs,
 sampling of gingival crevicular fluid and, if appropriate scaling, polishing and oral
 hygiene instructions

 -  Non-surgical periodontal treatment (visit 3A to 3D, max 4 sessions): oral hygiene
 instructions and supra- and sub-gingival debridement (under local anaesthesia if
 necessary)

 -  Follow-up Visit (visit 4, 4th to 7th visit) (six months following treatment): detailed
 dental examination, oral hygiene instructions, sampling of saliva, subgingival plaque
 and gingival crevicular fluid, tooth scaling and polishing.
1. BACKGROUND Primary immunodeficiency diseases (PIDs) are a group of rare inherited
 disorders that are estimated to affect approximately 1 in 2,000 children. In PIDs there
 is an intrinsic defect in the human immune system, such as a failure to produce enough
 antibodies to fight infection, or a failure in the cellular defences against infection .
 These conditions usually manifest themselves early in life and are often
 life-threatening. Rarer, severe forms of PIDs present in childhood with serious
 infections and are often associated with additional autoimmune and inflammatory
 complications. Periodontal diseases are inflammatory diseases of the gingivae (gums) due
 to an imbalance in the host response to subgingival bacteria and are associated with
 destruction of the supporting tissues of the teeth and early loss of the dentition and
 masticatory function. While periodontitis and its non-destructive partner condition,
 gingivitis (reversible plaque-induced gingival inflammation), are very common, the
 prevalence of periodontitis in the primary dentition and in the second decade of life
 appears very low, ranging from 0.1% to 1%. This prevalence increases dramatically in
 children affected by PIDs, to the point that periodontitis is considered a common
 feature of syndromic genetic conditions due to single gene defects affecting the host
 response, such as leukocyte adhesion deficiency (LAD), severe congenital neutropenia,
 cyclic neutropenia and Chediak-Higashi syndrome. Children with defects in neutrophil
 activity seem particularly susceptible to develop severe periodontitis, due to the
 important defensive role of neutrophils against periodontopathogenic bacteria. In such
 cases, both primary and permanent dentitions are affected, with a devastating effect on
 mastication, aesthetics and quality of life, also owing to the lack of reliable
 restorative solutions. Furthermore, oral diseases (in particular periodontitis) may also
 provide an additional systemic inflammatory burden for these subjects. This could occur
 since periodontal bacteria have been shown to enter the systemic circulation from
 inflamed gum tissues even during normal tooth brushing, have been found in atheromatous
 plaques and in the amniotic fluid of pregnant women.

 The treatment of periodontitis involves a non-specific reduction of the bacterial load
 below the gingival margin, achieved by oral hygiene instructions and non-surgical
 periodontal therapy (NSPT). More advanced cases need antibiotics, surgical treatment or
 extractions. In children with PID the response to this treatment is highly variable and
 the presence of periodontitis often leads to early tooth loss, adding to the poor
 quality of life of sufferers. Incorporation of periodontal screening has been advocated
 for early diagnosis and treatment of periodontal diseases in all children and especially
 for children with neutrophil defects, in order to prevent disease progression and tooth
 loss. However, most published papers on periodontitis in children with
 immunodeficiencies are case reports or familial observations or reviews. Therefore,
 there's a lack of well-designed studies investigating both the prevalence of
 periodontitis and oral diseases in general in children with neutrophil defects and their
 response to treatment. In particular, it is not clear which factors determine the onset
 of periodontitis in a subset of children with PID. Such factors may range from the
 composition of the subgingival microbiota, the immunological reaction against these
 bacteria, to the inflammatory response in the periodontium. A better understanding of
 the causative factors may help in early diagnosis and treatment, reducing the burden on
 affected children.

 2. AIMS AND OBJECTIVES

 The hypotheses behind this study are that:

 i) Specific microbiological and host response parameters dictate severity of periodontal
 diseases and associated risk of early tooth loss in children suffering from neutrophil
 defects ii) Periodontal treatment in children with neutrophil defects and periodontitis
 can lead to an improvement in their oral health (reduction in periodontal pockets and
 bleeding scores), which would reduce their risk of tooth loss and potentially improve
 their future quality of life.

 Therefore, the aims of this study are to offer specialist periodontal assessment and
 treatment to children with neutrophil defects, to determine the impact of neutrophil
 defects upon gingival health and to assess their response to periodontal therapy. This
 will facilitate the development of novel therapeutic management pathways specific for
 these conditions, and will determine whether there is a need for specific care protocols
 with a consequent improvement in tooth retention, quality of life and systemic health.

 -  The primary objective of this study is:

 - To investigate presence of periodontal disease and response to periodontal
 treatment in children affected by neutrophil defects

 -  The secondary objectives of this study are:

 -  To investigate presence of other dental diseases in children affected by
 neutrophil defects

 -  To assess oral microbiological and host response parameters in children
 affected by neutrophil defects.

 3. STUDY DESIGN 3.1 Overall study plan This is an exploratory longitudinal study. Fifty
 children affected by neutrophil defects potentially affecting the periodontium will be
 identified from subjects attending the Immunology and Haematology clinics at Great
 Ormond Street Hospital (GOSH), following a medical examination. All children will
 undergo a dental examination by a qualified dentist currently completing specialist
 training in periodontology. Children will also provide samples of gingival crevicular
 fluid (GCF) and subgingival plaque. Following the baseline, non-surgical periodontal
 therapy will be provided as necessary and participants will be followed-up and
 re-examined up to 6 months after treatment.

 4. STUDY POPULATION 4.1 Participant Selection Fifty children affected by neutrophil defects
 and under care at Great Ormond Street Hospital (GOSH) and meeting the inclusion criteria
 will participate in the study. Most children attend GOSH regularly (at least 6-monthly)
 for review/treatment planning appointments (seen by Dr Ancliff or Dr Worth). The
 parents/guardians of potentially suitable children will be initially contacted by letter
 prior to their attendance at GOSH. Every invitation will be followed up by a telephone
 call to discuss any issues and enquiry about willingness to participate. When possible,
 upon parents' agreement about study participation, patients could be enrolled and
 undergo the screening visit on the same day as their routine GOSH visit (this would save
 on extra travel for patients living outside London). Alternatively, they will be offered
 another appointment. All the study visits will take place at GOSH. QMULwill only serves
 as the sponsor and coordinating centre for this study. .

 5. STUDY VISITS Study visits include baseline, non-surgical periodontal therapy and
 follow-ups. All visits will be carried out at Great Ormond Street Hospital.

 5.1 Visit 1 (Screening) o Informed consent

 o Collection of data on clinical and laboratory diagnosis, time of diagnosis, previous
 and current systemic treatment and on any previous dental treatment

 o Basic Periodontal Examination (BPE) and assessment of caries (DMFT) and mucosal
 diseases

 o Saliva and plaque sample

 -  Clinical photographs

 -  Treatment plan All children found to have BPE scores of 1 (gingival bleeding), 2
 (presence of calculus), 3 or 4 (presence of gingival pockets) will be offered the
 possibility to enter the treatment phase of the study (from visit 2 onwards), which
 will be provided at GOSH. Children found not to be affected by periodontal diseases
 will be offered the possibility to be seen at GOSH for visit 2 only, if they wish
 so.

 5.2 Visit 2 (Baseline and first treatment session- ± 28 days) o Recording of any adverse
 events (AE or concomitant medication)

 -  Full periodontal examination including collection of periodontal measurements (and
 dental radiographs if appropriate)

 -  Gingival crevicular fluid (GCF) sample

 -  Session of tooth scaling, oral hygiene and polishing

 All children found to require further treatment will need to attend an additional 1 to 4
 treatment sessions at GOSH as detailed below:

 5.3 Visit 3A to 3D (treatment, within 2 months of visit 1, from 1 to 4 visits) Update
 medical history, check adverse events, non-surgical periodontal therapy (maximum 4
 sessions): oral hygiene instructions and supra- and sub-gingival debridement.

 5.4 Visit 4 (last follow-up, 6 months after last treatment visit ± 21 days) Update
 medical history, check adverse events, dental examination and collection of periodontal
 measurements, perform oral hygiene instructions, sampling of saliva, subgingival plaque
 and gingival crevicular fluid, tooth scaling and polishing (if needed).

 5.5 Medical and dental history A complete medical and dental history will be obtained
 during screening and confirmed during the baseline visit. Information on previous
 medical tests and status of current treatment will be obtained by the treating GOSH
 physician. The histories will include demographic background information, ethnicity,
 systemic and dental status information.

 5.6 Concomitant medications All concomitant medications will be recorded throughout the
 study.

 5.7 Periodontal examination At the screening visit, a Basic Periodontal Examination
 (BPE) will be performed, consisting of gentle probing between teeth and gums on index
 teeth (UR6, UR1, UL6, LL6, LL1 and LR6 or URd,URc,ULd,LLD,LLc,LRd) to identify presence
 of gum disease. A number between 0 (health) and 4 (gingival pocket>5mm) will be recorded
 for each quadrant. The dmft/ DMFT (decayed missing filled teeth) index will be used for
 recording caries experience. Mucosal status will be investigated by recording presence
 of ulcers, blisters, white patches, speckled areas and masses. Saliva samples and plaque
 samples will be collected. At the baseline visit, a calibrated dental examiner will
 perform a more detailed assessment, consisting of collection of full-mouth measurements
 of probing pocket depth (PPD), clinical attachment level (CAL), gingival bleeding on
 probing gingival crevicular fluid sampling and assessment of plaque levels (simplified
 visible biofilm index).

 5.8 Dental sampling A series of samples will be collected from the patients' oral cavity
 (sample of saliva, GCF and subgingival plaque biofilm). GCF will be taken by gentle
 insertion of 4 paper-strips in the gingival crevice of the mesio-buccal aspect of 4
 teeth (3 first molars and 1 incisor). Subgingival plaque will be collected by the
 examiners following gentle insertion of a curette at the base of 3 first molars and 1
 first incisor sites (one in each quadrant). In case of absence of permanent molars, the
 samples will be collected from the second deciduous molars. The 4 subgingival samples
 will be pooled together.

 5.9 Definition of periodontal disease

 Following the periodontal examination, children will be diagnosed as:

 - Healthy: no attachment loss (measured as no CAL>3mm or CAL>3mm in <2 non-adjacent
 teeth) and no/minimal gingival inflammation (measured as <15 sites bleeding on probing)

 - Gingivitis: no attachment loss (measured as no CAL>3mm or CAL>3mm in <2 non-adjacent
 teeth) and presence of gingival inflammation (≥15 sites bleeding on probing)

 - Periodontitis: attachment loss (measured as CAL>3mm in ≥2 non-adjacent teeth)

 5.10 Dental radiographs If a BPE code 3 or more is detected, bite-wings or long cone
 parallel periapical radiographs (more indicated for a BPE of 4) using Rinn holders will
 be taken to detect marginal bone levels, according to clinical needs. The distance
 between coronal and apical bone levels and cemento-enamel junction will be analysed as
 described previously, also taking into account age of the patient, tooth eruption stage
 and presence of primary, mixed or permanent dentition. Radiographs will then be
 digitized for future analysis using an image-analysis software.

 5.11 Non-surgical periodontal treatment All children will be offered an oral hygiene and
 tooth scaling and polishing session. For children affected by periodontal disease,
 subgingival debridement will also be performed according to needs, with the aim to
 disrupt the subgingival biofilm responsible for the onset and progression of the
 periodontal pathology. This can be accompanied, when appropriate, by the use of local
 anaesthesia and adjunctive antimicrobials (systemic or locally applied subgingivally),
 according to the clinical presentation and the child's medical conditions. In addition,
 when required, nitrous oxide sedation (NOS) could be used before treatment. NOS is a
 safe and widely-used technique in paediatric dentistry. It is administered by inhalation
 via a nasal mask and is used to reduce dental anxiety along with behaviour management
 techniques. There are very few contra-indications. It is not suitable for patients who
 have nasal congestion or severe dental anxiety. NOS will be conducted following the
 guidelines by Standards for Conscious Sedation in the Provision of Dental Care and
 appropriate clinical consent forms will be obtained before its use.

 Accurate supra- and sub-gingival removal of calculus and dental plaque will be performed
 both with ultrasonic and/or manual instruments. The necessary sub-gingival debridement
 will be performed in 1 to 4 visits (either full mouth treatment, half-mouth treatment or
 quadrant-wise treatment) depending on patient preference and practical considerations,
 using manual (Gracey curettes, Hu-Friedy) and ultrasonic devices (EMS). Caries will be
 treated as necessary (shared care with the general dental practitioners / community
 dental services). Children with mucosal lesions requiring treatment will be given a
 letter for their GDP suggesting referral to a collaborating expert in Oral Medicine
 (Prof. Stephen Porter).

 6. Missing data The inclusion of very young subjects in the present study introduces the
 risk of missing data, owing to the difficulty in data and sample collection in some
 children (due to their unwillingness to be examined or sampled). The Investigators will
 endeavor to complete data and sample collection with minimal discomfort to each subject.
 However, should dental and periodontal examination not be achievable, the subjects will
 be exited from the study. Once the main variable outcome of the study (presence of
 periodontal disease by means of collection of BPE) is recorded, the subject will not be
 excluded from analysis, even if some of the other data are not collected. For example,
 if a child tolerated periodontal probing (hence collection of BPE) but refuses to
 provide a plaque sample, he/she will still be included in the study until the last
 visit. The final study analyses and report/publications will take into account possible
 missing data and reasons why they were not collected.

 5.7 Repeatability Prior to initiation of the study, the designated examiner will participate
 in a training and repeatability exercise. For the repeatability exercise, the examiner will
 score 5 subjects for PPD and REC and then perform repeated examinations of the same subjects
 on the same day after at least 15 minutes separation. Upon completion of all measurements,
 intra-examiner repeatability for PPD measurements will be assessed. The reproducibility of
 the examiner will be tested using the Bland-Altman approach and by calculating Lin's
 concordance correlation coefficient. A co-efficient of repeatability less than ± 2 mm in 95%
 of the cases is considered acceptable.

 5.8 Laboratory analyses Samples will initially be stored at -70° to -80° for analysis.
 Microbiological analysis will involve next generation sequencing of the 16S rRNA metagenome
 at QMUL. GCF samples will be eluted and will undergo analysis of inflammatory markers as
 described before.

 9. PARTICIPANTS' COMPLETION AND WITHDRAWAL 9.1Reasons for withdrawal

 Participants will be informed that they have the right to withdraw from the study at any time
 for any reason, without prejudice to their medical care. The investigator also has the right
 to withdraw participants from the study for any of the following reasons:

 -  Occurrence of an unacceptable adverse event/illness

 -  Participant/parent/guardian request

 -  Protocol violations

 -  Administrative reasons

 -  Failure to return for follow-up

 -  General or specific changes in the Participant's condition unacceptable for further
 treatment in the judgment of the investigator

 9.2 Completion/Withdrawal Procedures At the time of withdrawal, all study procedures outlined
 for the end of study visit should be concluded. The primary reason for a participant's
 withdrawal from the study is to be recorded on the CRF.

 10. ADVERSE EVENT REPORTING 7.1 Adverse Events (AEs) An adverse event includes any noxious,
 pathological or unintended change in anatomical, physiological or metabolic functions as
 indicated by physical signs, symptoms and/or laboratory changes occurring in any phase of the
 clinical study, whether associated with the study or not. This includes exacerbation of
 pre-existing conditions or events, inter-current illnesses, drug interaction or the
 significant worsening of the disease under study. For all adverse events, the investigator
 must pursue and obtain information adequate both to determine the outcome of the adverse
 event and to assess whether it meets the criteria for classification as a serious adverse
 event requiring immediate notification to the sponsor or its designated representative. For
 all adverse events, sufficient information should be obtained by the investigator to
 determine the causality of the adverse event.

 Clinically significant symptoms following NSPT include those that are outside a normally
 accepted range (as judged by the clinician). This would include:

 -  Excessive or progressively increasing pain or discomfort

 -  Excessive swelling

 -  Signs of infection (e.g. suppuration)

 -  Excessive bleeding

 Moreover we shall record if the participants take any drugs as a result of these adverse
 events.

 7.2 Serious Adverse Events definition

 A serious adverse event or serious adverse drug reaction is any untoward medical occurrence
 at any dose which:

 -  results in death

 -  is life-threatening (immediate risk of death)

 -  requires participant hospitalization or prolongation of existing hospitalization

 -  results in persistent or significant disability/incapacity

 -  results in congenital anomaly/birth defect.

 Medical and scientific judgment should be exercised in determining whether an event is an
 important medical event. An important medical event may not be immediately life-threatening
 and/or result in death or hospitalization. However, if it is determined that the event may
 jeopardize the participant and may require intervention to prevent one of the other outcomes
 listed in the definition above, the important medical event should be reported as serious.

 7.3 Reporting of Serious Adverse Events Because of the need to report to health authorities
 all suspected unexpected serious adverse reactions (SUSARs) in a timely manner, it is vitally
 important that the investigator reports immediately any adverse events which would be
 considered serious. Any serious adverse event (including death) due to any cause, which
 occurs during the course of this clinical study, whether or not related to the study, must be
 reported immediately to the Principal Investigator or its designee.

 7.4 Reporting period The nature of each individual adverse event, date and time of onset,
 duration, severity and relationship to treatment and corrective treatment must be established
 by the investigator and recorded in the CRF. Adverse events will be recorded following
 signing of the first consent form up to the last study visit. Any serious adverse event
 occurring any time after the reporting period must be promptly reported if a causal
 relationship to the investigational product is suspected and all SUSARs will be followed up
 until resolution.

 8 STATISTICAL PROCEDURES 6.1 Sample size estimation A convenience sample of 50 children
 (based on current estimation of numbers of children with neutrophil defects seen yearly at
 GOSH) is proposed for this study, since no formal power calculation could be performed owing
 to the lack of similar studies in the literature. However, hypothesising that subgingival
 presence of bacterium A.actinomycetemcomitans at baseline could discriminate between
 responders and non-responders to periodontal treatment (difference 0.5mm ± 0.5 mm mean
 clinical attachment gain), 41 children (including 20% drop-outs) who undergo periodontal
 therapy would give 80% power to prove or disprove this hypothesis.

 6.2 Statistical analysis All data derived from the study will be anonymised and entered in a
 dedicated database. The initial plan of analysis will describe the prevalence of periodontal
 diseases in the study cohort (divided by medical diagnosis). Appropriate summary statistics
 will be determined separately for affected and non-affected subjects. Differences in
 demographic and systemic parameters (diagnosis, current treatment) between affected and
 non-affected subjects will be assessed by the two-sample t-test or Mann-Whitney test as
 appropriate. Explorative logistic regression analyses will be performed to detect the effect
 of microbiological and inflammatory parameters (e.g. presence of periodontopathogenic
 bacterium A.actinomycetemcomitans or cytokine concentrations in the GCF) on groups, taking
 into account that many children may be on long-term antimicrobial therapy. Response to
 therapy will be assessed by comparing clinical periodontal parameters at baseline and
 follow-ups by random effects analysis taking time points as repeated measures. This will be
 then associated to patients' demographics, compliance and microbiological and inflammatory
 factors.

 7 ADMINISTRATIVE REQUIREMENTS 9.1 Good clinical practice The study will be conducted in
 accordance with the International Conference on Harmonisation (ICH) for Good Clinical
 Practice (GCP) and the appropriate regulatory requirement(s). Essential clinical documents
 will be maintained to demonstrate the validity of the study and the integrity of the data
 collected. Master files should be established at the beginning of the study, maintained for
 the duration of the study, and retained according to the appropriate regulations.

 9.2 Ethical considerations The study will be conducted in accordance with ethical principles
 founded in the Declaration of Helsinki. The Research Ethics Committee will review all
 appropriate study documentation in order to safeguard the rights, safety, and well-being of
 the participants. The study will be conducted only at sites where Research Ethics Committee
 approval has been obtained. The protocol, informed consent, advertisements (if applicable),
 written information given to the participants, safety updates, progress reports, and any
 revisions to these documents will be provided to the Research Ethics Committee by the
 investigator.

 9.3 Participant Information and Informed Consent During the first screening session and the
 enrolment visit, written informed consent will be obtained from all
 participants/guardians/parents. The method of obtaining and documenting the informed consent
 and the contents of the consent will comply with ICH-GCP and all applicable regulatory
 requirement(s).

 9.4 Participant confidentiality In order to maintain participant privacy, all CRFs, study
 reports and communications will identify the participant by initials and the assigned
 participant number. The participant's confidentiality will be maintained and will not be made
 publicly available to the extent permitted by the applicable laws and regulations.

 9.5 Protocol compliance The investigator will conduct the study in compliance with the
 protocol and given approval/favorable opinion by the Research Ethics Committee and the
 appropriate regulatory authority(ies). Changes to the protocol will require written Research
 Ethics Committee approval/favourable opinion prior to implementation, except when the
 modification is needed to eliminate an immediate hazard(s) to participants.

 9.6 Study monitoring Monitoring and auditing procedures developed by the investigator will be
 followed, in order to comply with GCP guidelines. On-site checking of the CRFs for
 completeness and clarity, cross-checking with source documents, and clarification of
 administrative matters will be performed. The study will be monitored by a clinical trial
 coordinator or its designee.

 9.7 Case report form completion Case report forms will be completed for each study
 participant. It is the investigator's responsibility to ensure the accuracy, completeness,
 and timeliness of the data reported in the participant's CRF. Source documentation supporting
 the CRF data should indicate the participant's participation in the study and should document
 the dates and details of study procedures, adverse events and participant status.

 The investigator, or designated representative, should complete the CRF pages as soon as
 possible after information is collected, preferably on the same day that a study participant
 is seen for an examination, treatment, or any other study procedure. Any outstanding entries
 must be completed immediately after the final examination. An explanation should be given for
 all missing data. The investigator must sign and date the Investigator's Statement at the end
 of the CRF to endorse the recorded data.

 9.8 Premature closure of the study This study may be prematurely terminated, if in the
 opinion of the investigator there is sufficient reasonable cause. Written notification,
 documenting the reason for study termination, will be provided to the investigator by the
 terminating party.

 Circumstances which may warrant termination include, but are not limited to:

 -  Determination of unexpected, significant, or unacceptable risk to participants

 -  Failure to enter participants at an acceptable rate

 -  Insufficient adherence to protocol requirements

 -  Insufficient data

 9.9 Complaints and indemnity

 -  Complaints. In the event of complaint about the conduct of the study, the hosting NHS-
 Great Ormond Street Hospital for Children NHS Foundation - complaints policy should
 apply as the research subject is recruited through an NHS Trust.

 -  Indemnity QMUL holds insurance against claims from participants for harm caused by their
 participation in this clinical study. Participants may be able to claim compensation if
 they can prove that QMUL has been negligent. However, if this clinical study is being
 carried out in a hospital, the hospital continues to have a duty of care to the
 participant of the clinical study. QMUL does not accept liability for any breach in the
 hospital's duty of care, or any negligence on the part of hospital employees. This
 applies whether the hospital is an NHS Trust or otherwise.
Inclusion Criteria

 Each participant must meet the following inclusion criteria to be enrolled in the study:

 1. Age 4-16 years

 2. Diagnosis of one of the following neutrophil defects (as confirmed by the treating
 physician):

 -  Disorders of neutrophil numbers

 -  Cyclic neutropenia

 -  Congenital neutropenia

 -  Severe Congenital Neutropoenia

 -  X-linked Neutropoenia

 -  Disorders of neutrophil function

 -  Leucocyte Adhesion Defect s

 -  Other neutrophil disorders/ undefined neutrophil disorders (functional
 defects demonstrated on testing but genetic basis not yet known)

 -  Combined immunodeficiency syndromes

 -  Wiskott Aldrich Syndrome

 -  Hyper IgM Syndrome

 -  Chediak Higashi Syndrome

 -  Undefined combined immunodeficiency (functional defects demonstrated on
 testing but genetic basis not yet known)

 3. Participants/parents/guardians willing to sign the informed consent Exclusion Criteria
 Participants will not be eligible for participation in the study if unwilling to be
 examined or unable to return for follow-up appointments.