Severe combined immunodeficiency (SCID) is a genetically heterogeneous group of diseases with a common clinical phenotype. SCID represents the most severe form of primary inherited immunodeficiency (PID) . SCID is characterized by an absence of T lymphocytes, leading to a lack of cellular and humoral immune responses [70]. Some variations of SCID also include B cell deficiency and/or natural killer cell deficiency. The severe lack in immunity leads to serious health consequences, mostly infectious in etiology, usually presenting in the first months of life. The variable clinical presentation seen with SCID is attributed to the multiple genetic loci that have been discovered to be related to SCID. Multiple genes have been associated with SCID, including Adenosine Deaminase and IL-2RG (X-linked recessive) [71].

SCID was first described in 1950 by Glanamann and Rinker, in a Swiss case series of children dying of infectious etiologies by their first birthdays [72]. The first enzyme found to be responsible for SCID, adenosine deaminase, was described in the literature in 1972. The gene for the most common form, X-linked, was described in the literature in 1993 [73].

Various reports regarding the incidence and prevalence of SCID have been published. Most report a prevalence of 1:5000 to 1:100,000 per live births. Prevalence varies depending on the population, with reports of increased prevalence among the Hispanic population [74].

Infants generally appear well at the time of birth. The disease usually manifests during the first few months of life, commonly presenting due to inability to fight infection. Bacterial infections are less common in newborns, due to residual circulating maternal IgG antibodies. Recurrent respiratory and gastrointestinal infections are common. Progressive respiratory disease can also occur and hyperinflation and interstitial pneumonitis is frequently seen on chest x-rays due to Pneumocytis jirovecii . Eventually the patient demonstrates failure to thrive with an inability to gain weight due to intestinal villi atrophy, leading to malabsorption. Omenn syndrome , an autosomal recessive type of SCID, presents with thickening erythematous rash of a leathery consistency, commonly accompanied by eyebrow and eyelash loss [75].

SCID patients have an increased susceptibility to opportunistic infections; most ocular manifestations are a direct result of this. The most common ocular manifestation of SCID, especially during immune reconstitution after a bone marrow transplant, is cytomegalovirus (CMV) [76]. CMV manifests in the eyes in many ways and results from a disseminated infection. Typically, CMV will involve the retina causing chorioretinitis. Patients may also present with optic neuritis [77] or viral endophthalmitis [78]. Patients with CMV retinitis can develop retinal necrosis, leading to retinal tears and detachments.

Pediatric patients with CMV retinitis or optic neuritis may have symptoms of flashes floaters and a decrease in vision. However, preverbal children may not be able to express these symptoms. For that reason, these patients should be screened if disseminated CMV is found. Findings on examination can be retinal whitening and edema, hemorrhages, vascular sheathing, or optic nerve pallor. Long term, these patients can have permanent decrease in vision, even with adequate treatment [79].

After immune reconstitution, patients with healed CMV retinitis who are no longer receiving CMV prophylaxis medication can develop immune recovery uveitis , an inflammatory response within the eye. This has complications of vitritis, macular edema, epiretinal membrane, macular hole, retinal detachment associated with proliferative vitreoretinopathy, and cataract [80, 81].

In addition to CMV , other opportunistic infectious could potentially affect the eyes in patients with SCID . These include toxoplasmosis, fungal keratitis and/or endophthalmitis, and Pneumocystis jirovecii presenting as conjunctivitis and chorioretinitis [82]. More details about these ocular infections—including diagnosis and treatment—can be found in the infectious disease chapter.

SCID is diagnosed with flow cytometric immunophenotyping of lymphocyte subsets in peripheral blood. Lack of T cells is essential to the diagnosis. It is important to rule out HIV as a cause of the immunodeficiency . A few states, such as Wisconsin and California, have enacted universal screening for SCID as part of the routine newborn screening. Currently, this has been widely adopted.

The treatment of choice for SCID is a stem cell transplant, preferably early in life. Survival is now reported at 92 % if the transplant is within first month of life. Patients should avoid live attenuated viral vaccines, which could cause illness in the child. Prophylactic antimicrobials are frequently given to avoid previously mentioned infectious manifestations, such as Peumocystis jirovecii . Breastfeeding should be discontinued if the mother is CMV positive to reduce risk of transmission and subsequent infection [75].

X-linked Agammaglobulinemia (XLA) is an X-linked recessive immunodeficiency characterized by a lack of B cells , plasma cells and all subtypes of antibodies. It is caused by a defect in the non-receptor Bruton tyrosine kinase (BTK) [83, 84]. The defect leads to a block in B cell development in the pre-B cell phase. This subsequently leads to the absence of plasma cells and the inability to form secondary lymphoid follicles [85]. Given the genetic inheritance, it is clinically seen almost exclusively in males and usually presents in early childhood with recurrent bacterial infections.

The disease was first described by Bruton in 1952. Bruton described the case of an 8 year old male with recurrent bacterial infections with agammaglobulinemia [86]. The BTK genetic etiology of the disease was described in 1993 [83, 84]. Even with antibiotics, the outcome of patients was very poor until the development of intravitreal immunoglobulin (IVIG) in the 1980s.

Prevalence of XLA is reported to be between 5–10:100,000 [87]. No reported ethnic variability has been reported. Family history and consanguinity are risk factors that dramatically increase prevalence in certain populations.

XLA is characterized clinically with recurrent bacterial respiratory and cutaneous infections, commonly with encapsulated organisms. Patients can also develop serious parasitic and gastrointestinal viral infections [88]. 90 % of patients are symptomatic by 18 months [89] with a mean diagnosis around 3 years of age. Respiratory infections continue to be the main cause of mortality [88].

X-linked agammaglobulinemia patients can have a myriad of ocular manifestations of infectious diseases since these patients lack mature B cells and plasma cells. Patients may present with bacterial conjunctivitis . One case report by Al Ghonaium, et al. discussed a patient who presented with bilateral chlamydial conjunctivitis confirmed with culture. Patients with XLA may not present with follicular conjunctivitis that is highly suggestive of Chlamydia since B cells are necessary for follicle formation [90]. Bilateral conjunctivitis from Haemophilus influenza can also occur patients with XLA [91]. These patients with severe bacterial conjunctivitis can have significant sequelae of profound cornea scarring that can lead to vision impairment [91]. There has also been a reported case of sectoral iris atrophy from presumed viral infection [92].

Patients with XLA can develop unusual malignancies in unusual places in the pediatric population, which can present as ocular symptoms. There is one case report of a patient who presented with epiphora secondary to a non-Hodgkin lymphoma mass at the inferior portion of the nasolacrimal duct [93].

Laboratory tests that demonstrate a lack of circulating B cells (Cd-19+) along with a lack of all antibody classes are used to make a diagnosis. Classically, serum IgG levels are less than 200 mg/dL, IgM less than 10 mg/dL and complete lack of IgA. Circulating B cells are usually less than 0.5 % of lymphocytes. Confirmation of XLA occurs with western blot confirmation of BTK protein mutation.

With the development of IVIG in the 1980s, improvement in the clinical outcomes has been seen. While there is still a high associated morbidity and mortality rate, survival has improved. Immunoglobulins have also been formulated to be given subcutaneously, though IVIG still remains the standard of care [94]. One case report of the development of neutropenia in a patient with XLA reports successful treatment with granulocyte colony stimulating factor Filgrastim [87].

Patients are to avoid live attenuated vaccines due to inability to mount proper immune response and increased probability of infection.

Combined Variable Immunodeficiency (CVID) is the term used to describe a genetically and clinically heterogeneous group of diseases with similar characteristics of agammaglobulinemia. It is the most common symptomatic primary immunodeficiency in adults [95]. As opposed to X-linked recessive agammaglobulinemia, which is congenital and affects males, CVID affects males and females at an equal rate. This normally manifests in the second or third decade of life. CVID is similar to XLA in its characteristic agammaglobulinemia and persistent bacterial infections. CVID does not have one genetic marker like XLA, but is a group of diseases characterized by hypogammaglobulinemia with IgG levels two standard deviations below the mean, impaired vaccine response, or absent isohemagglutinins without another identified etiology of the hypogammaglobulinemia [96]. It is thought to be due to defective T cell and B cell interaction with defective antibody formation, due to abnormal B lymphocyte differentiation commonly termed late-onset antibody failure.

CVID was first reported in 1953 by Janeway [97]. This study led to the differentiation of XLA and CVID due to its description to an immunodeficiency similar to XLA with a different onset and inheritance pattern.

Prevalence is estimated to be 1:50,000 to 1:100,000 [98]. There appears to be ethnic variation, with a reported prevalence of 1:25,000 in Australia and lower prevalence rates in the North East Asia region [96].

Similar to other primary immunodeficiencies affecting humoral immunity, the clinical presentation of CVID commonly consists of recurrent pyogenic sinopulmonary infections. Severe enteroviral infections can also occur and lead to chronic meningo-encephalitis. GI infections with bacteria such as Giardia lamblia and Cambylobacter jejuni are also common. CVID can also present with granulomatous disease, not unlike sarcoid, with ocular and pulmonary manifestations.

In addition to the multiple infectious complications associated with CVID, there is a well-studied phenomenon of non-infectious comorbidities. There is an increased incidence of autoimmune disorders including colitis, Sjogren’s, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, inflammatory bowel disease, celiac disease, and Guillan- Barre syndrome. 22 % of patients have an autoimmune diagnosis at time of CVID diagnosis. This prevalence increases to 36 % in patients followed over an extended period of time. The autoimmune relationship is more common in women and patients with granulomatous disease [99]. This association with immunodeficiency and autoimmune disease illustrates the complexity of the immune system.

The mechanism of autoimmunity of CVID is unclear. Hypotheses include lack of removal of autoimmune of B cells due to ineffective B cell receptor signaling, abnormal ligand interaction due to reduced CD40 expression on B cells, accelerated expansion of auto reactive B cells and increased levels of BAFF/April [99]. There is also a higher reported incidence of malignancies, specifically lymphoma and gastric adenocarcinoma, which are a significant contributor to mortality [100].

Patients with CVID are susceptible to recurrent infections and autoimmune disorders, both of which can manifest in the eyes, although this is rare. Ocular infections can include all aspects of the eye. Patients with CVID can present with significant bacterial conjunctivitis with S. pneumoniae, H. influenzae, Staphylococcus epidermidis, Staphylococcus aureus, and other multidrug-resistant bacteria [101–103]. Cornea involvement in the form of keratitis has also been reported [103], and there have been reported cases of dacryocystitis, an infection within the lacrimal sac, in patients with CVID [104].

The ocular features of CVID-associated uveitis can include granulomatous inflammation, retinal vasculitis, choroiditis, and optic nerve involvement [105, 106]. The granulomatous uveitis in CVID can manifest as mutton-fat keratic precipitates on the corneal endothelium, snowball vitreous opacities, or optic disc granulomas. The granulomatous inflammation seen in CVID could also be due to the association with sarcoidosis or a sarcoid-like syndrome. Patients with CVID can have an anterior granulomatous or non-granulomatous uveitis [107, 108]. A case report of three patients with CVID developed retinal vasculitis with optic nerve and macular edema. Two of the three patients in this case report also developed neovascularization of the retina. No signs of retinal ischemia or infectious etiology were found, therefore the etiology was presumed to be CD4+ T-cell -mediated autoimmunity [104]. Patients can present with a multifocal choroiditis [109, 110] or birdshot-like chorioretinopathy [111, 112]. Bilateral optic neuritis has also been reported as an autoimmune complication of CVID [113].

Other rare ocular diseases have been reported as case reports in the setting of CVID. These ocular diseases are also thought to be secondary to some autoimmune response. One patient with CVID, who presented with proptosis and limitation of extraocular motility, developed orbital inflammation with a mass infiltrating the lacrimal gland. Biopsy of this mass revealed a non-granulomatous, lymphocytic infiltration. There was no evidence of infection. His condition improved significantly on oral steroids [114]. Another patient presented with sterile cornea thinning resulting in perforation [115]. An acquired Brown’s syndrome with tenderness in the area of the superior oblique tendon resulting in diplopia has also been reported [116]. There has also been the suggestion of the link of CVID with retinitis pigmentosa based on a case series of three generations that carry both diseases. Retinitis pigmentosa is a retinal degeneration characterized by night blindness and peripheral visual field constriction. On examination, these patients have a pigmentary retinopathy with bony spicules seen in the retina, vascular attenuation, and a waxy pallor to the optic nerve [117].

CVID is a diagnosis of exclusion and thus can be difficult. There is current discussion in the field regarding the exact diagnostic criteria. The European Society of Immune deficiencies established criteria with the pan American group for Immune Deficiency in 1999 and gave an update in 2014. The updated diagnostic criteria includes marked decrease in IgG and IgA, poor response to vaccines with low switched memory B cells developed after 4 years of age, with no evidence of profound T cell deficiency and a lack of secondary cause of hypogammaglublinemia .

Patients also must have one of the following: increased susceptibility to infection, autoimmune manifestations, granulomatous disease, unexplained polyclonal lymphoproliferation, or an affected family member with antibody deficiency. Ameratunga et al. propose a different criteria . Though similar, it puts more emphasis on clinical manifestations with recurrent infections combined with laboratory testing [96].

The current gold standard is either IVIG of subcutaneous immunoglobulin to address the hypogammaglobulinemia . Antibiotics are used appropriately to treat infections. Corticosteroids and cyclosporine A can be used to treat granulomatous manifestations and concomitant autoimmune diseases.

Selective IgA deficiency is the most common primary immunodeficiency . Though it is much more common than CVID , many patients remain asymptomatic. The defect is presumed to result from impaired switching or a maturational failure of IgA producing lymphocytes. The clinical course is widely heterogeneous as is the inheritance pattern [98].

IgA deficiency was first described in 1963 in children with ataxia-telangiectasia [118, 119]. The deficiency was soon found to be in the general asymptomatic population along with increased numbers in those with recurrent respiratory and gastrointestinal infections and those with autoimmune diseases.

Selective IgA deficiency is the most common primary immunodeficiency . Studies vary on prevalence rates as there have been differing opinions on laboratory diagnostic values along with ethnic variability. Reported values range from 1:173 in a study in Sweden to 1:22,500 in a Japanese study [98, 120]. This is consistent with various studies that report higher numbers in Caucasian populations and lower prevalence rates in East Asian ethnicities [121].

IgA is the most abundant immunoglobulin in the body. It is found in tissues and secretions, specifically the respiratory and gastrointestinal tract. IgA has a role in mucosal immunity, defense against mucosal pathogens and development of immune tolerance. Clinically there is wide variability in clinical presentation for patients with IgA deficiency. The majority remain a symptomatic. Those with clinical presentation frequently have recurrent sinopulmonary infections. Recurrent respiratory and gastrointestinal infections are due to lack of IGA in serum and mucosal secretions [121].

IgA deficiency is more common in patients with chronic lung disease. Additionally, there is an association between IgA deficiency and the development of CVID, suggesting a similar underlying pathogenesis [121].

There is a well-established relationship between IgA deficiency and an increased incidence of autoimmune diseases. One study reports a 25 % incidence of autoimmune disease in patients with IgA deficiency [122]. Autoimmune diseases that have shown to have an association with IgA deficiency include: autoimmune hemolytic anemia, systemic lupus erythematosus, juvenile idiopathic arthritis, sclerosing cholangitis, celiac disease, vitiligo, psoriasis, ulcerative colitis, Sjogren’s disease, polyarteritis nodosa, sarcoidosis, Kawasaki disease, and Behcet’s disease [120]. The exact reason for the close association is unknown though Jacobs (2008) proposes a mechanism involving IgA and its receptor leading to a phosphorylation cascade that results in deactivating immune-activating pathway, furthering the idea that IgA has a role in protecting against autoimmunity [123].

Most vaccines are considered to still be effective, though with a muted immune response. The CDC currently considers the oral polio vaccine, Bacillus Calmette-Guérin (BCG) , and yellow fever vaccines to be the only contraindicated vaccines for patients with IgA deficiency [124].

The lacrimal gland and the conjunctiva are parts of the ocular immune system which produce IgA. In patients with IgA deficiency, not many ocular diseases have been reported. However, the disease has been reported to in the conjunctiva as conjunctivitis [125].

Given the association with autoimmune diseases, patients with IgA deficiency may develop an uveitide, though this is more likely due to the underlying autoimmune disease as opposed to a manifestation of the IgA deficiency.

Prevalence studies have used varying cutoff, but the standard definition suggests using a 0.05 g/L of serum IgA as the upper limit for diagnosis in adults with a concomitant lack of secretory IgA. Values above this level, but lower than normal, should be considered partial IgA deficiency. During diagnosis, it is important to rule out secondary reasons for the selective hypogammaglobulinema and for specific medicines that have been found to be associated with IgA depletion, such as anti-rheumatic and anti-epileptic drugs [126].

No treatment is needed for the majority of patients, as they are asymptomatic. Infections should be treated with appropriate antimicrobials, though prophylactic antibiotics are not considered standard of care .

Patients should be warned of the potential complications with blood transfusions. Some patients with IgA deficiency develop anti-IgA antibodies, which can react to IgA in blood products and produce an anaphylactic reaction.

Additionally, patients should be counseled on the increased risk of progression to CVID .

Selective IgM deficiency is a relatively uncommon selective primary agammaglobulinemia . It is characterized by a complete or partial lack of IgM circulating antibodies. IgM deficiency is characterized with heterogeneous lab and clinical findings. Lab results can range from complete absence to partial deficiency with normal to complete absence of circulating B cells . There can also be normal to severely impaired specific antibody responses against pneumococcal polysaccharides with a wide variety of chromosomal associations.

The first case of IgM deficiency was described by Hobbs in 1967 in a case report of two male children with fulminant meningococcal septicemia that were found to have low levels of IgM on lab work [127].

The prevalence of primary selective IgM deficiency is reported to be 0.03 % in the general population. The prevalence of partial deficiency is reported to be from 0.1 to 3.8 % in hospitalized patients [128]. There does not seem to be a gender predilection.

80 % of patients with IgM deficiency present with recurrent infections [129]. Infections range from benign to life-threatening meningitis and sepsis. Reported recurrent infections from intracellular bacteria, protozoan, viruses and fungi have been reported. Patients commonly have recurrent upper respiratory infections. Atopic diseases are common with an association with allergic rhinitis and 25 % of patients have a concurrent diagnosis of asthma [130].

Similar to other antibody deficiencies, there is an association with autoimmune diseases. Reports have shown an association with systemic lupus erythematous, vitiligo, autoimmune glomerulonephritis, rheumatoid arthritis, and celiac disease [128]. It is thought that the association is due to IgM- autoantigen complex crosslinks with B -cell receptors to auto reactive B cells and trigger their deletion/anergy [128].

Patients with selective IgM deficiency also may present with a number of skin manifestations including recurrent abscesses, impetigo, pyoderma, molluscum contageosum, and epidermal dysplasia verrucifomis [129, 131–134].

Also similar to other select agammaglobulinemia deficiencies, there is an association with malignancies. In IgM deficiency, clear cell carcinoma is the most commonly associated malignancy [135], along with leukemia [136].

Few ophthalmic manifestations of selective IgM deficiency have been reported. IgM deficient patients have been reported to have recurrent hordeola, conjunctivitis , and blepharitis due to Staphalococcus aureus [137].

Diagnosis is confirmed with a lab test showing IgM levels <30 mg/dL in children, which is less than two standard deviations below adult values.

Treatment includes appropriate antimicrobials for recurrent infections. Recent case reports suggest that immunoglobulin therapy is helpful and beneficial to patients, even if all other immunoglobulins are normal [128, 138, 139].

Chronic Granulomatous Disease (CGD) is an uncommon inherited immunodeficiency disorder. The disease is caused by an inability for phagocytic cells such as neutrophils and macrophages to kill catalase-positive organisms. Phagocytic cells use a respiratory burst, consisting of a rapid release of reactive oxygen species, to help degrade bacteria. Defects in the phagocyte NADPH oxidase results in low levels of NADPH activity and leads to CGD. More than two-thirds of the cases of CGD are X-linked recessive, though autosomal dominant and recessive patterns may occur [140].

CGD was first described by Janeway in 1954 [141]. Over the ensuing years, researchers learned that the disease was caused due to a lack of oxidative burst. In 1967, the use of reduction of nitroblue tetazolium by phagocytes from patients with CGD during phagocytosis was introduced as diagnostic testing, which helped distinguish the disease process from other immunodeficiencies [142].

CGD prevalence is reported to be between 1:200,000 to 1:250,000 [143].

CGD is commonly associated with recurrent bacterial and fungal infections for which aggressive antibiotics are needed. Recurrent abscesses are common in early childhood, although presentation can be later. Patients with CGD are particularly susceptible to catalase-producing organisms, such as S. aurea, E. coli, Serratia, Klebsiella, Pseudomonas aeruginosa , and various fungi. Aspergillus infections are also a common cause of morbidity and mortality.

Patients can develop multiple granulomatous lesions in the lungs, liver, lymph nodes, and gastrointestinal and genitourinary tract, which can cause obstruction. Patients can also have suppurative lymphadenitis, hepatosplenomegaly, and colitis. Pneumonia is a common cause of mortality.

As CGD affects the phagocytic cell function, these patients are susceptible to infections that can manifest within the eye. Anterior segment conditions such as blepharokeratoconjunctivitis , which includes inflammation or infection of the eyelid, cornea and conjunctiva, have been reported [144, 145]. These patients can develop severe keratitis [146] leading to ulceration [147] or thinning [148]. There is a case report of a patient presenting with anterior segment uveitis demonstrated by anterior synechiae, mutton fat keratic precipates, and anterior segment inflammation [149].

These patients can also have chorioretinal lesions, that have been described as being perivascular and sparing the macula [144, 150–152]. These lesions have also been described in female carriers [153]. There has been speculation that the cause of these scars may be from previous bacterial infections [154]. Some patients with CGD have chorioretinal lesions in the peripapillary region and associated with optic nerve pallor [155]. These lesions have been described as well-circumscribed scars in the retina and choroid with areas of atrophy involving the choroid, retinal pigment epithelium, and retina. The chorioretinal lesions are also sometimes associated with retina pigment clumping [156].

Chorioretinal lesions have been visualized in the absence of visual symptoms or signs of active uveitis . Some patients with these retinal findings can have severe visual impairment when associated with vitreous hemorrhage, neovascular membrane, peripheral retinal ischemia, and macular edema [156]. There have been reported cases of severe vision loss, pain and photophobia with presumed progression of chorioretinal lesions to anterior chamber inflammation , posterior synechiae, vitritis, vitreous hemorrhage, and exudative retinal detachment. These enucleated eyes showed multiple foci of granulomatous inflammation with an absence of an organism [157]. Exudative retinal detachment can also be associated with a granulomatous subretinal mass [158].

Originally diagnosis of CGD was performed with reduction of nitroblue tetazolium by phagocytes. This has been replaced in clinical practice by the dihydrorhodamine-1,2,3 (DHR) oxidation test (a flow-cytometry study) due to its ease of use [159]. Confirmation of CGD is performed with a positive test with genetic testing of known mutations.

The cornerstone of clinical care of CGD patients is lifelong preventative treatment. This includes prophylaxis of antibiotics, antifungals and immunomodulatory therapy [160]. Management of infection is also important which includes appropriate antimicrobials, excisions of liver abscesses, steroids for management of CGD colitis, and granulocyte transfusion in certain situations. Definitive treatment of CGD includes stem cell transplant . There is much research into gene therapy, but this is not currently approved [140, 160].

Chediak-Higashi syndrome (CHS) is a rare autosomal recessive immunodeficiency caused by an abnormal granule formation in neutrophils and melanocytes. The abnormal accumulation of granules causes a form of oculocutaneous albinism combined with immunodeficiency and recurrent infections. The alterations in neutrophils can lead to neutropenia, impaired chemotaxis and delayed phagolysosomal fusion resulting in decreased bactericidal activity. Lymphocytes can also contain large cytoplasmic granules and function poorly. Reduced natural killer cell activity can also be seen [161].

CHS is due to mutations in the lysosomal trafficking (LYST) regulator gene [162]. It is thought that defects of the lysosomal trafficking regulator protein lead to decrease MHC class II molecules reaching endosomes, inhibiting antigen presentation [163].

CHS was first described by Bequez-Cesar in 1943. Ultimately the disease was further characterized by Chediak (1952) and Higashi (1954), from which the disease’s eponym originates [164].

CHS is a very rare condition with approximately 500 cases reported in the literature [161].

CHS is accompanied by oculocutaneous albinism (OCA) due to melanosome dysfunction. CHS patients have all the findings that would be expected in OCA. This includes decreased pigmentation in skin, hair, choroid, and iris [165]. There have been reported cases of hyperpigmentation in sun-exposed areas [165].

Immunodeficiency due to neutrophil dysfunction leads to recurrent pyogenic infections, most commonly on the skin and in the gastrointestinal tract [166]. Coagulation defects are also seem to be due to platelet dysfunction. There are normal amounts of platelets, but due to the presence of dense platelet bodies, the platelets do not function properly, and bruising and bleeding times are increased [167].

If patients survive past the initial barrage of infections, approximately half will develop neurologic symptoms including progressive neuropathy, paresthesias, stroke, coma or convulsions [161]. Patients can also enter into an accelerated phase of the illness. This is characterized by lymphohistiocytic infiltration leading to a lymphoma-like infiltration of the major organs. There are various hypotheses related to the etiology of this accelerated phase, and there appears to be an association with the Epstein Barr Virus [166, 167]. Regardless of the exact etiology, this is a devastating stage with infiltration of visceral organs and a major cause of mortality [161].

Similar to other forms of albinism, patients can have photophobia due to iris transillumination defects and fundus hypopigmentation [168]. Nystagmus can be present, thought to be a result of misrouting of optic fibers [169]. Exam can reveal a lack in pigmentation of iris, choroid, RPE and/or ciliary body. There have been case reports of hyperpigmentation of the iris with choroidal hyperpigmentation and concomitant RPE hypopigmentation [165]. Patients can experience foveal hypoplasia and papilledema [170]. Systemic manifestations and microscopic diagnostics are important for confirmed diagnosis given similar ocular findings to other the forms OCA. In addition to aforementioned ocular findings, HPS is associated with strabismus complications, cataract and posterior embryotoxon, which are generally not found with CHS [171].

The diagnosis of CHS is definitively made with pathognomonic intracytoplasmic giant granules in leukocytes or gene testing [161].

Prophylactic antibodies are frequently given due to the recurrent infections. A review of 25 patients with CHS showed a survival rate 62 % at 5 years of HLA-matched allogeneic transplantation [172]. Survival was more likely if patients had no symptoms of the accelerated lymphoproliferative stage. Another review showed long-term neurocognitive sequelae in patients after stem cell transplants, presumably due to post-transplant chimerism [173].

Blau Syndrome (BS) is a rare autoinflammatory, autosomal dominant disease characterized by the triad of granulomatous inflammation that affects joints, eyes and skin. The onset is almost always under 4 years of age. There is considerable overlap with juvenile sarcoidosis. Early onset sarcoidosis (EOS) and Blau Syndrome have defects from the same CARD15/NOD2 gene mutation [174]. There is same uncertainty in the difference between the two, although it is generally accepted that Blau syndrome refers to the familial form and EOS refers to de novo mutations. The gene is a caspase recruitment gene involved in immune and inflammatory functions. The defects cause an over-activation that leads to increased inflammation, although how this specifically leads to Blau Syndrome remains unclear [175].

Blau Syndrome was first described by Blau in 1985. He describes granulomatous arthritis, iritis, and rash in 11 family members in four different generations [176].

The disease is rare, with a review in 2012 noting 193 reported cases. This, however, is confounded by the incomplete distinction between diagnosis of BS and EOS [177]. There have been reported cases in the Caucasian, African-American, Spanish, and Asian populations. In a study of the Danish pediatric population, juvenile sarcoidosis in Denmark reported an incidence of 0.06 per 1,000,000, though that study did not distinguish between familial versus de novo presentations [178].

Presentation is usually in childhood with the majority of cases presenting between 3 and 4 years old [179]. Polyarthritis is the most common presenting symptoms, and can be commonly confused for juvenile idiopathic arthritis. Patients also have joint swelling and erythema. If the arthritis is severe, patients can develop camptodactyly. Skin manifestations are common with two distinct dermatologic presentations possible.

The first is a papulonodular tender brownish rash and the second is the multiple firm subcutaneous nodules [177]. Ocular inflammation is also common, which will be detailed in the next section. Various case reports have also described different cranial neuropathies [180, 181]. Granulomas of liver and kidneys along with large vessel vasculitis have also been described [181].

Ophthalmic manifestation is extremely important in the diagnosis and management of Blau disease, given the high morbidity associated with its complications and sequelae. Anterior and posterior uveitides, frequently seen together in panuveitis, are the most common presenting features. In a review by Carreno, all patients developed anterior chamber inflammation and posterior segment involvement was present in 77 % of patients [182]. An international review by Rose also showed anterior segment inflammation as the most common presentation [183]. Choroidal lesions have been reported, with one review reporting 94 % of patients developed panuveitis with multifocal choroidal and were identified as the most common ocular presentation in that case series [184–186].

Other ocular complications include cataracts [180, 183, 186, 187], glaucoma [180, 183, 188], corneal opacities [187, 189], band keratopathy [183], peripheral retinitis [176], and retinal detachment [183]. In a review by Carreno, optic disc changes were common, specifically optic disc nodular excrescens at the margin and pallor [182]. Carreno argues that disc changes should be more closely analyzed as a common manifestation of BS.

Diagnosis is initially made with a clinical exam with family history and confirmed with genetic testing demonstrating a NOD2 mutation. Electron microscopy can also be used, as there can be characteristic common shaped bodies in epithelioid cells [181].

Steroids are usually first line, especially for acute-phase inflammation. Immunomodulators can also be used to control inflammation long-term. There have been case reports of biologic anti-cytokine agents such as infliximab, TNF-alpha inhibitor and anakinra, Il-1 receptor antagonist [190, 191].

Neonatal onset multisystem inflammatory disorder (NOMID) or Chronic Infantile Neurologic Cutaneous and Articular syndrome (CINCA) is a rare autosomal dominant condition that is considered as part of the family of cryopyrin-associated periodic fever (CAP) syndromes. CAP includes a spectrum of diseases and includes familial cold autoinflammatory syndrome, Muckel-wells syndrome , and neonatal multisystem inflammatory disorder. All the CAP diseases are caused by a mutation in the CIAS gene on chromosome 1, which encodes NLRP3, an inflammasome and component of IL-1 beat and IL-18 activating platform. The genetic mutations lead to over-activation of NLRP3 leading to overexpression of inflammatory pathways [192, 193].

NOMID was first described by Prierur and Grischelli in 1981 with the report of three children with papilledema, arthritis and chronic rashes that flared with periodic fevers and lymphadenopathy [194].

Formal studies have not been completed, but the estimated prevalence is 1–10:1,000,000 with Caucasians affected more than other racial groups. There does not appear to be any gender predilection [195].

NOMID, as the name implies, is a multisystem autoinflammatory disease that presents in the neonatal period. The most distinguishing characteristics include rash, arthropathy, hearing loss, ocular inflammation and CNS damage. The rash is usually a nonpruritic, neutrophilic, urticarial-like rash, which can progress to skin erythema and exuberant skin. The arthropathy affects large joints, can be severe, and is caused by bony overgrowth [196]. Progressive hearing loss results from chronic cochlear inflammation. CNS damage can occur from aseptic meningitis or increased intracranial pressure (ICP) , and includes cognitive delays, seizures and strokes [192]. Patients generally have high inflammatory markers on laboratory work and can develop secondary sarcoidosis from prolonged systemic inflammation. However, this mechanism is not well understood [192]. Patients classically also have macrocephaly, saddle nose, and finger clubbing.

Ophthalmic manifestations in NOMID can vary with a wide variety of ocular pathology presented in the literature. Dollfus et al. (2013) gave the most extensive review to date on ocular manifestations with a report of 31 patients. They reported 85 % with optic nerve head (ONH) changes, commonly pallor or swelling. 55 % had chronic non-granulomatous anterior uveitis and 42 % of patients suffered from chronic conjunctivitis [197]. Other manifestations reported include corneal abnormalities (42 %) such as stromal scarring, band keratopathy and corneal neovascularization [197]. Vitritis, retinal vasculitis, focal chorioretinitis, cystoid macular edema, and cataracts have also been reported [197, 198]. One report of retinal dystrophy in association with NOMID has been reported [199]. ONH appearance can vary with some reports of optic nerve head pallor and sheathing of peripappillary vessels [200]. There are also reports of pseudopapilledema thought to represent a neutrophil-based infiltrative etiology [201]. Other reports of papilledema and eventual pallor are thought to arise from increased ICP [202].

The diagnosis of NOMID is confirmed with NLRP2 mutation detected by genetic testing.

Historically, anti-inflammatory medicines, including steroids, have been the mainstay of therapy to decrease systemic inflammation . However, there are currently three IL-1 antagonists on the market, Anakinra, Rilonacept, and Canakumab, which are gaining popularity and usage in regards to NOMID treatment [195].

Ataxia-telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disorder. It classically consists of cerebellar ataxia, progressive neurologic impairment, immunodeficiency , and oculocutaneous telangiectasia [203]. It has been shown to be associated with mutation in the ATM gene (11 q22-23). ATM encodes for protein kinase ataxia telangietctasia mutated (ATM) , which responds to double-stranded DNA damage [204]. The ATM protein also assists with cell cycle checkpoint pathways [205].

The disease was first described in 1926, by Syllaba and Henner, with a report of three adolescent Czech siblings with progressive choreoatheotsis and ocular telangiectasias [206]. The disease is also known as Louis-Bar disease due a description of the disease by Louis-bar in 1941 [207]. The association with chromosome 11 was described in 1988 [208].

The disease has an estimated prevalence of 1:88,000 live births in the USA [209].

Symptoms of A-T usually do not manifest until early childhood when the child is learning to walk (around 12 to 18 months of age). There is a persistent, unsteady gait with progressive development of hypotonia, intention tremor, and decreased deep tendon reflexes. This has been correlated to cerebellar atrophy on MRI and associated in pathology to a loss of Purkinje cells [203]. The disease is normally neurodegenerative with a decline in neurologic status with time. Patients frequently develop dysarthria and increased extra-pyramidal symptoms with Parkinson-like symptoms.

Clinically, one-third of patients will have severe immune deficiency, one-third will have mild immunodeficiency , and one-third have no immune dysfunction [210]. The immunodeficiency frequently leads to sinopulmonary infections and chronic obstructive pulmonary disease. It is commonly associated with a lymphocytopenia.

There is an increased predisposition to malignancies, cells with increased radiosensitivity, sterility with poor secondary sex characteristics, and short stature [211]. There is commonly mild hepatic dysfunction with decreased excretion of 17-ketosteroids, likely related to the underlying hypogonadism [211].

In addition to ocular telangiectasias, which are discussed in the next section, patients frequently have cutaneous telangiectasia in sun-exposed areas such as the face.

The most characteristic ocular finding in A-T is ocular telangiectasia. The telangiectasias can be found on both bulbar and palpebral conjunctiva, and reported to be most common in canthal regions. The telangiectasias do not extend past the limbus and have been confirmed to be of venous origin [211]. The vessels normally appear between 3 and 6 years of age and, in-and-of themselves, cause no ocular dysfunction.

There are numerous reports of eye motility abnormalities. Boder and Sedgwick report an 84 % prevalence of apraxic eye movements and 83 % prevalence of gaze nystagmus [212]. There is a reported 50 % prevalence of saccadic intrusions including square wave jerks and runs of back-to-back saccades without an intersaccadic interval [213]. Other studies report 100 % abnormal saccade movements including smooth pursuit and initiating saccades [214, 215].

Patients shows abnormal vestibular and optokinetic nystagmus fast phase. Approximately half of patients may have defective gaze holding. There is also a 95 % reported prevalence of extended interval of voluntary horizontal and vertical saccades [213]. Abnormal head thrust movements and strabismus, specifically esodeviations, have been reported [213, 216].

A large majority have abnormal convergence [214]. Farr et al. report mild decreased visual acuity in patients, likely secondary to the ocular motility abnormalities and abnormal convergence [217].

Three laboratory findings frequently used to determine an A-T diagnosis include elevated alpha feto-protein, karytotyping of immune status of B and T cell compartments, along with assessing radiosensitivity of cells. Mutations in ATM can be sought [210].

Treatment generally consists of medical management of complications including infection control. Neurorehabilitation is important to optimize the patient’s neurologic capabilities. Neurologic medicines are commonly given to help improve neurologic symptoms , but there is no definitive treatment at this time [210].

Bloom syndrome is a rare autosomal recessive DNA breakage disorder that results in short stature, photosensitive rash, immunodeficiency , and malignancy. It is caused by disruption of the BLM gene , which encodes the protein RecQl3 helicase, an enzyme that restores malfunctioning replication forks during DNA replication. The protein binds to recombination intermediates and Holliday junctions, which normally assist with homologous DNA recombination [218]. The mutated gene causes a tenfold increase in DNA exchange between sister chromatids and prevents the removal of Holliday junctions, which results in elongated, segmented and entangled sister chromatids [219].

The syndrome was first described by Bloom in 1954 with a case series of three patients with short stature and systemic lupus erythematous–like facial rash [220].

The syndrome is most common in Ashkenazi Jews in Eastern Europe and Israel, accounting for one-third of reported cases [221]. Over 170 cases have been reported in the literature in the USA with a male to female ration of 1.3:1 [222].

The systemic manifestations of Bloom Syndrome include short stature, erythematous facial skin with malar hypoplasia, beaked nose, micrognathia and dolichocephaly [223]. Patients can also have hyper and hypopigmented skin lesions. Immunodeficiency is common, leading to pulmonary infections and chronic lung disease. Patients usually have hypogonadism, leading to infertility. Although there have been a few reported successful pregnancies in affected females [224]. Patients have a high incidence of diabetes and decreased intelligence [222]. Due to replication malfunctioning, patients experience an increased incidence of malignancies of lower and upper gastrointestinal tract, genitalia, urinary tract and skin.

Before the age of 20, leukemia is the most common malignancy, while after the age of 20, sarcomas and carcinomas are more common [222]. Other syndromes with increased rates of malignancies generally have specific malignancies but the wide variation of malignancies seen is a distinct characteristic of Bloom syndrome [223].