This 6 m/o child with recurrent infections, eczema and thrombocytopenia (petechiae and PLT count

<25,000) most likely has one of the syndromic primary immunodeficiencies.

Immunodeficiencies can be classified according to Etiology into Primary or secondary.

Secondary immunodeficiency: These are acquired later in life due to chemoradiation, drugs and
infections like HIV
Primary Immunodeficiency: These are mainly inherited or present congenitally due to genetic
defects.

Primary Immunodeficiencies can be classified according to which component of immune system is

being affected, which are innate system, phagocytes, adaptive system and regulatory system.

Defect in Innate system: Mostly concerned with recognition and quick response against pathogens
and barrier function. Pts predisposed to infection with particular pathogen or class.
• Defect in pathogen recognition:
◦ IRAK4 (IL-1 receptor associated kinase 4) or MyD88 (myeloid primary response
domain 88): Predispose to pyogenic bacterial infections like Osteomyelitis, meningitis,
pneumonia esp. with S.pneumo. a/w absent fever.
◦ CARD9 deficiency: Patients are predispose to fungal infections especially with candida.
◦ TLR3/UNC93B1 defect: Pts. Predisposed to severe HSV or VZV infections like Herpes
encephalitis
• Defect in Cytokine signalling: Defect in their receptors or secondary messenger signalling.
◦ Mendelian susceptibility to mycobacterial infections: Due to defect in IL-12 receptor
—IFN-gamma axis pts. Are predisopsed to Salmonella and Mycobacterial infections, Pts
especially have widespread infections from BCG strain. Tt-HSCT is curative, meanwhile
support with
◦ IL 17 receptor defect: Pts predisposed to mucocutaneous candidiasis.
◦ STAT1 defect: Severe invasive viral infecitons.
• Defect in barriers:
◦ Epidermodysplasia verruciformis:
▪ Due to EVER1/2 defects: These form complex with CIB at keratinocytes, defefct
here predisposes pts to HPV infections.
▪ WHIM syndrome: Standing for warts hypoimmunoglobulinemia and myelokathexis
(retention of neutrophils in marrow, Kathexis=retention)
◦ Atopic dermatitis
◦ Hidradenitis suppurativa.
Defects in phagocyte numbers function or both:
Granulocytopenias:
• Neutropenia: During infancy the absolute neutrophil count (ANC) is high but rapidly
decreases during 1st few days of life, the relative counts of them steadily increase with age
form 20-30% during infancy to 50% by 5y/o and to the adult levels by puberty.
C/c: Recurrent infections with Gram -ves and S.aureus, especially at body interfaces like
mouth (apthous stomatitis, gingivitis, periodontitis, Diarrhea, furunculosis, cellulitis,
perirectal inflammation,sinusitis & otitis media) as well as invasive infections like
pneumonia, deep abscess or sepsis.
Neutropenia can be classified based on onset (Acute or chronic) aetiology (Congenital or
acquired) or based on severity (Mild, moderate or severe).
Acute neutropenia (occuring within few days) usually occurs due to drugs or
chemoradiation or from viral infections like Influenzae, adenovirus, RSV, enteroviruses,
HHV6, rubella, varicella; viral causes have neutropenia within 24-48hrs persisting for a
week. Bacterial sepsis also causes acute neutropenia in infancy.
 Chronic neutropenia (>3 months) occurs from chronic infection, inflammation or
malnutrition.
Neutropenia can be divided into mild (ANC 1000-1500), moderate (ANC 500-1000), severe
(ANC <500) with ANC <200 termed agranulocytosis. Such division helps to prognosticate
risk of severe infection which occurs more commonly with severe neutropenia.
Neutropenia can be classified into acquired or congenital causes:
• Acquired neutropenia: Occurs most commonly with drugs, other major cause is
chemoradiation, less common cause is malnutrition and autoimmune.
◦ Drugs: Plenty of drugs cause Neutropenia, with various mechanisms ranging from
immune mediated, toxic, allergic or idiosyncratic.
◦ Immune mediated: Occurs abruptly with fever & lasting atleast a week from drug
discontinuation, It mainly invovles drugs like propylthiouracil or penicillin acting as
haptens or drugs like quinine stimulating Immune complex formations.
◦ Toxic mediated: Mainly caused by antipychotics esp. Phenothiazines.
◦ Idiosyncratic: chloramphenicol
◦ Hypersensitive: Mainly caused aromatic anticonvulsants like carbamazepine,
oxcarbazepine, lamotrigine, phenytoin or phenobarbital, pts C/c onset of fever, rash,
lymphadenopathy, hepatitis, nephritis, pneumonitis and aplastic anemia within a week of
drug continuation it resolves rapidly after discontinuation of offending drug. Its different
from DRESS syndrome which occurs weeks after drug regimen and is accompanied with
facial edema, fever and generalized rash.
◦ Tt: usually drug discontinuation is 1st step in all the causes, if no improvement and
patient symptomatic with infection subcutaneous filgastrim is given.
◦ Neutropenia from chemoradiation: neutropenia occurs predictably from
chemoradiation within 7-10 days of administration persisting for 1-2 weeks, during such
perids pts are susceptible to most severe forms of infection because marrow is directly
impacted and all arms of myeloid lineage (monocytes, lymphocytes etc.) are defunct. Tt:
Pts with post chemoradiation neutropenia should receive aggressive broad
spectrum antibiotics.
◦ Viruses: Esp. From ingluenza, adenovirus, RSV, HHV6, rubella, enteroviruses.
◦ Bacteria: Sepsis in infancy
◦ Immunologic causes:
▪ Alloimmune neutropenia of infancy: caused by transplacental transfer of maternal
IgG, infanfts C/cs of fever within 1st 2 wks of life with skin or umbilical infections,
pneumonia, by 7 wks the neutrophil count returns to normal, if it persists supportive
care with antibiotics and GCSF
▪ Autoimmune neutropenia: Caused by antineutrophil antibodies. Its rare benign. Total
ANC falls <500, and onset is within age of 8-11. C/c is asymptomatic rarely
infections, pts able to tolerate low neutrophil counts as they are able to generate
additional neutrophils from marrow. Tt GCSF may be required for infections or
wound healing.
◦ Malnutrition: Esp. With copper, folate and B12
◦ Hypersplenism: As ocurring with storage disease, myeloproliferative disorders
• Congenital neutropenias:
◦ Cyclic neutropenias/Severe congenital neutropenias (SCN): Cyclic neutropenia as
its namesake is characterized by neutropenia that ranges from normal to <200 occurring
in cycles, typically in a pattern of a 21 day period in which there is a 3-5 days of severe
neutropenic nadir, in which pts develop all typical C/cs of neutropenia. Major
complications a/w are Pneumonia, mastoiditis & intestinal perforation with peritonitis
leading to life threatening clostridial sepsis. Pathophys: Regulatory abnormality of early
haematopoietic precursor cells and is almost invariably a/w neutrophil elastase gene
ELANE mutations mostly inherited AD. Dx is made by demonstrating such oscillations
 by performing WBC counts every 3 times/wk for 6-8 weeks, which is IMP. Because
cyclic neutropenia shares a mutations with SCN (ELANE) and the latter is a risk of
progression to AML or MDS. Tt with GCSF that decreases the mean period of 21 days
to 15 days and neutropenic nadir to only 1 day, HSCT is curative.
SCN is characterized be severe neutropenia (ANC <500) since 1st few months of life
pts have all the typcial C/cs of neutropenia as mentioned above. Its caused by arrest of
maturation of myeloid cells into promyelocytic stage. Most commonly inherited AD that
is Mcly a/w ELANE mutations and X linked dominant is from WASP gene (wiskott-
aldrich), less common forms are inherited recessively like HAX 1(kostmann disease)
which is a/w neurological defect or G6PC3 a/w heart defects urogenital abnormalities &
venous angiectasia. Dx: CBC 3 times/wk for 6-9 wks; confirmed with marrow
aspiration. Tt GCSF with antibiotic prophylaxis of TMP-SMX, maintaining proper
hygiene, special orodental care. Few cases with ELANE mutations are refractory to
GCSF necessitating HSCT and some cases may develop AML due to gain of function
mutations of GCSF.
◦ Schawmann diamond & dyskeratosis congenita: Described in inherited bone marrow
failure syndromes
◦ Vesicular traficking disorders like Chediak higashi and griscelli syndromes: Described in
regulatory disorders.
◦ Metabolic disorders: In glycogen storage disease type 1b due to defect in glucose 6
phopshate transporter which inhibits gluose tranpsort in cells resulting in defective
neutrophil mobility and increased apoptosis. Tt with GCSF can manage neutropenia but
not the cellular defect.
Disorders of function
• Disorders of adhesion:
◦ Leukocyte adhesion defects(LAD): LADs are caused MCCly by Beta2 integrin
deficiency (LAD1), less commonly by selectin deficiency (LAD2) and kindlin 3 (which
activates beta integrins;LAD3). These present in infancy with features of omphalitis,
delayed cord separation (>3wks), and recurrent infections at body interfaces typical of
neutropenia (respiratory, GI, skin, genitals), major complication is early loss of primary
teeth due to severe gingivitis in kids. Patients have recurrent infections with common
bacterias involved in neutropenia like S.aureus, G-ve E.coli, Candida and Aspergillus.
O/E inflammation signs like swelling, erythema and warmth may be absent, Pus is
absent. Labs show neutrophillia despite the clinical findings. Dx confirmed with flow
cytometric measurements of CD11/18.
• Disorders of degranulation: Granulocytes have granules that contain chemotactic agents,
antibacterials and proteases which is necessary for migration and pathogen killing, disorders
of these groups also affect platelet functions as it is also dependent upon relasing its granule
which contians clotting factors and calcium. The disorders involved are Chediak higashi and
griscelli syndrome described in regulatory disorders
• Defects in motile responses against pathogens: Disorders affect chemotaxis, it involves
illnesses like LAD, IgG/C3 deficiency, Hyper-IgE syndrome, Illnesses with immune
complexes like SLE or RA and direct inhibitions with drugs like ethanol or glucocrticoids.
• Disorders of killing:
◦ Chronic Granulomatous disease: Is an XLR/AR inheritance involving defect of gp91phox
(XLR), gp47phox or gp61phox (AR) components that activate NADPH oxidase.
Granulocytes although able to phagocytose pathogens are unable to kill it due to defect
in NADPH oxidase preventing production of Hydrogen peroxide (which normally
becomes hypochlorite catalyzed by myeloperoxidase), In normal physiology bacteria
even if catalase positive do not have enough catalase to breakdown extra H2O2 from
granulocytes leading to demise, however in CGD the granulocytes are not making H2O2
and the catalase positive bacteria can sufficiently breakdown the H2O2 created by itself
 thus surviving but non-catalase positive cannot survive in phagosome without any H2O2
clearence. C/c recurrent deep space infections like subcutaneous or hepatic abscess,
osteomyelitis, lymphadenitis, GI infections like colitis, enteritis or gastric outlet or
ureteral obstruction. Pts have infections with catalase positive bacteria like S.Aureus,
B.Cepacia, Salmonella, Serratia, Nocardia, Mycobacteria (Esp. BCG) and fungals like
Aspergillus & Candida.
Complications: Granulomas can from due to granulocytes not effectively killing
microbes, these can cause obstruction at tracts of hollow organs like pyloric outlet
obstruction, bladder obstruction, ureter obstruction, rectal fistulas or granulomatous
colitis, >80% cases have crohn’s colitis. Persistent fever including splenomegaly and
cytopenia warrants investigation for macrophage activation syndromes.
Dx: Flowcytometry using dihydrorhodamine to measure oxidation by H2O2 is gold
standard. Nitroblue tetrazolium dye test can be used.
Tt: HSCT is curative, Daily oral TMP/SMX prophylaxis, if currently infected then it
requires longer antibiotic therapy of 6-8 wks esp. Parenteral, Cultures are frequently
negative (since other functions of phagocytes are nomral except killing there is exurbeat
inflammatory response) and hence response to antibiotics is measure by degree of
current inflammation using ESR, if pt does not have deep infection ESR is normal or
will normalize within few days with standard care, if it does not it warrants investigation
for deep infection(CECT sinus, chest or abdomen), if there is clear downward trend of
ESR over 3-10 days continue with current antibiotics, if not the case then IV
voriconazole should be added to cover Aspergillus. Unstable or very high fevers are
likely due to B.cepacia it is implicated in septic shock. Overall incidence of infection
decreases in 2nd decade of life as non neutrophil immunity matures.
Corticosteroids may be useful in children for treatment with antral and urethral
obstruction severe granulomatous colitis. Corticosteroids can also be used to shrink
pulmonary granulomas and ease their drainage.
◦ Myeloperoxidase (MPO) deficiency: Recurrent infections but milder than CGD as H2O2
production is unimpaired.
◦ G6PD deficiency: Aside from haemolysis it also causes defective immunity due to
depletion of NADPH for producing H2O2.
Defect of adaptive system
Combined immunodeficiency syndromes: These disorders are caused by receptor or metabolic
defects affecting the T helper cells, which leads to both cellular and humoral defects as helper cells
regulate both of these arms. Most of CIDs can be screened at neonatal period using guthrie test
showing low number of T cell receptor excision circles (TRECs)
• Severe combined immunodeficiency (SCID): This syndrome is the most severe form of
combined immunodeficiencies that pts typically do not survive past 1 year of age. It is
caused by profound block in T cell development leading to complete absence of these cells,
pts present with invasive bacterial infections, severe viral infections (due to HMI and CMI
defects) and fungal infections (Th17 impaired). Most cases caused by gamma chain defect,
less common causes are defective Rag gene, Adenosine deaminase defect (leading to
cytotoxicity of precursors) or adenylate kinase 2 defect leading to reticular dysgenesis (c/c:
SCID+Severe neutropenia+Sensorineural deafness).
Dx: Flow cytometric measurement of CD3+ (T cells) CD19+ (b cells) and CD56+ cells (NK
cells) cells
Complications: Graft v/s host disease from maternal T cells transfused during labour with
c/c of rash, diarrhea, hepatosplenomegaly.
Omenn syndrome from expansion of Immature T cells in infants with c/c of erythrodermal
rash, alopecia, severe infections, hepatosplenomegaly & FTT. Labs show T cell
lymphocytosis, eosinophilia and low B-cell counts.
Tt: HSCT is curative. Pts with ADA defect can receive pegylated-ADA injections.
 • Combined immunodeficiency (CID): Generally less profound than SCID, most commonly
caused by hyper IgM disorders due to CD40 ligand deficiency, Zap-70 protein defects. C/c
pts do not die within 1 year and have higher numbers of T cells and T cell function,
recurrent infections are present though not that severe. Tt: HSCT is curtive.
Combined Immunodeficiency syndromes with syndromic features
• CID with congenital cytopenias
◦ Wiskott aldrich syndrome: Caused by WASP gene defect inherited in AR fashion,
WASP binds with actin filaments and regulates their organization, which if impaired
leads to issues in degranulation. Pts typically have recurrent infections from capsular
bacteria like S.pneumo causing otitis media, pneumonia, meningitis and sepsis, later
infections also include P.jiroveci & herpes viruses, associated features include eczema,
skin (petechiae) & mucosal bleeding (bloody diarrhea) from thrombocytopenia &
autoimmune manifestations like autoimmune hemolysis, glomerulonephritis, vasculitis,
erythema nodosum and arthritis. WAS can be complicated by Lymphoma which can be
virally induced (e.g by EBV or Kaposi sarcoma by HHV)
Labs show severe thrombocytopenia going <30,000 and abnormally small platelets on
PS, low serum IgM but elevated IgA or IgE, Dx confirmed by Intracellular
immunofluorescence analysis of WASP expression in blood cells. Tt: HSCT is curative.
Supportive measures include prophylactic antibiotics, IgG supplementation and careful
topical treatment of eczema.
◦ WIP (WASP interacting protein) deficiency: Similar features to WAS and similar
management.
• CID with DNA repair defects: Aside from recurrent infection due to CIDs, pts also have
features of radiosensitivity (replace CT with MRI/USG and RT with proton beam therapy),
predisposition to cancers, craniofacial deformities due to DNA repair defects.
◦ Ataxia telengectasia : Occurs from defect in ATM gene (encodes a protein for DNA
repair), pts have cerebellar ataxia, oculocutaneous telengectasia, chronic sinopulmonary
infections & high incidence of malignancy. Ataxia is evident when child begins walking
and progresses to wheelchair confinement by 10-12y/o.Telengectasia begin to develop
by 3-6 y/o, most frequent humoral immunologic defect is that of IgA deficiency, IgG2 or
total IgG may be deficient. Pts carry a high risk of leukaemia, lymphoma and
carcinomas.
Complications: Fatal Varicella.
Labs: karyotyping show excessive chromosomal rearrangements esp. That of
chromosome 7 and 14.
Tt: Supportive with physical rehabilitation & antibiotic prophylaxis.
◦ Nijmegan breakage syndrome: Caused by defect in nibrin, involved in involved in
DNA repair, which if absent causes chromosomal instability, pts have severe T and B
Cell CID with AR inheritance, O/E pts have microcephaly and bird like face.
◦ Immunodeficiency with centromeric and facial anomalies (ICF):Complex syndrome
of AR inheritance caused by defects in DNA methyltransferase, pts have mild T cell
immunodeficiency with more Severe B cell Immunodeficiency, coarse face, digestive
disease and mild mental retardation. Dx: Cytogenetic analysis showing multiradial
aspects in multiple chromosomes (frequently 1,9 & 16) corresponding to abnormal DNA
structure secondary to DNA methylation.
◦ Bloom syndrome: Caused by defect in BLM gene encoding for DNA Helicase. Pts have
c/c of pre and postnatal growth deficiency, craniofacial abnormalities (keel shaped head,
malar hypoplasia, nasal prominence and protuberant ear), A high pitched voice and
absent upper lateral incisors are also present, Lupus like characteristics (UV induced
malar rash, erythrodermal rash of sun exposed areas like hands and feet), Telangiectasia
and poikiloderma occur early in 1st or 2nd year of life in response to sun exposure. Small
clusters of telangiectasia appear in rash or sclera of eye, other features are mouth
 fissures, cafe-au-lait spots, and well demarcated area of dyschromia (hypo- or
hyperpigmentation). Endocrine abnormalities like male hypogonadism, female early
menopause, intellectual disability and late onset, non-insulin dependent diabetes,
recurrent infections in sinopulmonary areas in infancy due to reduced levels of Igs like
IgA, IgM and occasionally IgG. Severe dehydration can occur in infancy from
vomiting, diarrhea and GE reflux, aspiration from reflux may contribute to increased risk
for pneumonia and development of chronic lung disease in pts. Pts. Are predisposed to
malignancy, mainly leukemias and NHL.
Dx: confirmed with cytogenetic analysis showing increased no. Of sister chromatid
exchange and quadriradial configurations in lymphocytes and fibroblasts.
Tt: fluid support in infancy, gastrostomy or feeding tube for nutrition, IVIG supplement
for immunodef., Avoiding sun exposure, Growth hormone not used because it is
ineffective to stimulate growth and may instead increase the risk of cancers.
• CID due to Thymic defects
◦ Digeorge syndrome: Caused by 22q11.2 deletion, leading to absent development of 3rd
and 4th pharyngeal pouches, which normally develops thymus and parathyroid glands.
Pts have T cell immunodeficiency, hypocalcemia (presents as seizures during infancy),
conotruncal, atrial and ventricular cardiac defects, great vessel abnormalities, esophageal
atresia, bifid uvula. Due to Absent T cells pts are susceptible to recurrent and
opportunistic infections resembling SCID, including fungi, viruses, and P.jiroveci and to
GVHD from nonirradiated blood transfusions, pts can slo develop omenn syndrome.
Approx. 1/3rd are also A/w CHARGE syndrome
Dx: All infants with neonatal hypocalcemia,CHARGE syndrome and conotruncal
cardiac anomalies should have their T cells counted to confirm the Dx.
Prognosis: The 3 manifestations of Highest morbidity in early infancy are
Hypocalcemic seizures, severe cardiac anomaly and severe immunodeficiency.
Necessitating an early focus on these issues even before confirmation of Dx. Pts also at a
risk of autoimmune cytopenia, JIA, atopy and malignancies (Lymphomas).
Tt: Cultured unrealted Thymic tissue transplants. Unfractionated marrow or a
peripheral blood transplant from HLA identical individual can also be done. Supportive
management includes, Hygiene, prophylactic antibiotics, Ig replacement.
◦ CHARGE syndrome: Standing for coloboma of eye, heart defects, choanal atresia,
growth retardation, genital and ear abnormality is caused by CHD7. O/E patients have
vestibular areflexia due to semicircular canal hypoplasia, cranial nerve abnormalities
like anosmia, facial palsy, impaired hearing and difficulty swallowing has been seen.
Cryptorchidism, hypogonadism, orofacial clefts, developemental delay and TE fistula
have also been seen.
Dx: Mainly clinical, which includes 3 major criterias (Which are 4 Cs, coloboma, cranial
nerve defects, choanal atresia and typical CHARGE ear) & 3 minor criterias (includes
heart defects, cleft lip & palate, genital anomalies, kidney anomalies, esophageal atresia,
typical CHARGE face and hand), Confirmation done by CHD7 analysis.
Prognosis: Most common emergency is cyanosis due to congenital heart defects, or B/L
posterior choanal atresia, hence all CHARGE pts, should have cardiology consult.
Tt: Needs management of cardiac defects, feeding tube or gastrostomy, intubation,
artifical tears for corneal scarring due to facial palsy, hearing ais should be regularly
used with regular remodeling due to ear growth, sex steroid therapy for endocrine issues,
Surgical correction of cleft lip and palate.
◦ FOXN1 deficiency: FOXN1 is responsible for differentiation of thymic epithelium into
cortical and medullary epithelium, defects of which leads to severe loss of T cell
resulting in severe recurrent infections with viral, bacterial and fungal infections, O/E pts
have congenital alopecia, nail dystrophy and skin involvement (eczema).
• Immuno-osseous dysplasias
 ◦ Cartilage hair hypoplasia (CHH): It is a syndrome which is in a spectrum with 3 other
types, seen typically in Amish or Finnish population, its typically caused by defects in
RMRP (RNase MRP) gene, which codes for RNA endoribonuclease involved in
cleavage of RNA in mitochondrial DNA synthesis and nucleolar pre RNA, hence it
leads to defective protein formation of multiple types, involving multiple organ systems.
C/c: Disproportionately short limbed short stature from birth (even detected prenatal),
hypotrichosis (sparse, thin and silky hair), hyper-extensible joints except elbows which
don’t extend completely, redundant skin, kyphoscoliosis, lordosis, bowed tibiofemur,
bullet shaped distal phalanges, atlantoaxial instability, cone epiphyses & premature
epiphyseal fusion, Immunodeficiency due to T cell arrest in G1 phase from defective cell
cycle regulator proteins, Hirschprung disease from defective migration of neural crest
cells that require specific proteins involved in migration like BMN7 (bone
morphogenetic), RhoB and Slug proteins, Autoimmunity, Defective erythropoesis
causing anemia, Malignancies mostly NHL.
Dx: Suggested by radiographic findings of short & thick tubular bones with metaphyseal
dysplasia most prominent at knees, Distal metaphyses are wide, flared, and occasionally
scalloped with cystic areas and poor ossification with trabeculation. Treatment of
underlying infections based on their type, location and severity
Confirmation done with molecular genetic testing.
Tt: Management is specific to particular issues arising from syndrome. For cervical
spinal instability, special care for GA or surgery done to fuse unstable cervical vertebrae
and/or to treat progressive kyphoscoliosis compromising lung function. Corrective
osteotomies may be required for progressive varus deformity of the lower extremity, Tt
underlying infections & prophylactic immunosuppressants or Ig replacement, immediate
high dose acyclovir for varicella, SCID and/or severely depressed erythropoesis requires
HSCT, physiotherapy for bronchiectasis, RBC transfusions for severe anemia with iron
chelation as needed. Routine growth monitoring by charts, clinical and radiographic
examination of joints, clinical and radiographic monitoring of spine, lab monitoring for
anemia.
Other diseases in spectrum are metaphyseal dysplasia without hypotrichosis (MDWH) or
Anauxetic dysplasia (AD). In MDWH clinical manifestations are similiar to CHH except
that pts hair is normal and without additional GI defects or Anemia, there may not be
immunodeficiency initially but develop by adulthood. AD is the most severe form in the
spectrum characterized by pronounced skeletal phenotype like prenatal onset of short
limbed short stature, barrel chest, hip dislocations, facial deformities (midfacial
hypoplasia, macroglossia and dental abnormalities) & cognitive defects, major
complication is atlantoaxial subluxation in newborn.
• Hyper IgE syndromes:
◦ T cell primary immunodeficiency with hyper IgE (Autosomal recessive Hyper IgE):
Caused by deficiency of DOCK8 gene, patients c/c of severe primary immunodeficiency
from absent T cells with severe viral infections with CMV,EBV, poxvirus (molluscum)
and Papillomavirus, they also have severe cryptosporidiosis. Severe allergic
response is also common. Labs show low T cell counts and absent proliferative
function. Pts have poor survival with many complications, hence necessitating HSCT
early in life.
◦ Autosomal dominant Hyper IgE syndrome: Caused by heterozygous dominant
mutation in gene encoding STAT3 which is a transcription factor required in no. of
signalling pathway following cytokine binding, it also results in partially defective
antibody production because of defective IL-21 signaling.
Pts, C/c of Severe recurrent bacterial infections esp. Of S. Aureus causing deep skin
abscesses, joint infections, visceral infections and pneumonias which develops into
pneumonoceles, severe infections with C. Albicans are also present, Pts have h/o
 sinusitis or mastoiditis, pts have pruritic dermatitis. Facial deformities with broad
forehead, deep-set wide-spaced eyes, a broad nasal bridge, a wide fleshy nasal tip, mild
prognathism, facial asymmetry and hemihypertrophy, all of these most prominently seen
in adulthood. Pts also have loss of primary teeth, Scoliosis, hyperextensibility and
osteoporosis (recurrent fractures). In labs IgE levels are exceptionally high (IgE levels
>2000IU/ml was used to confirm Dx) along with high IgD. IgG,IgA,IgM levels are
normal. There is blood and sputum hypereosinophilia. Poor antibody and CMI resposne
to antigens. T cell, B cell and NK cell counts are normal although the memory
phenotype of T Cells and Th17 cell counts are low. Most patients have normal T
lymphocyte proliferative response to mitogens but very low or absent responses to
antigens or allogenic cells form family members. Blood, sputum and histologic sections
of lymph nodes, spleen and lung cysts show striking eosinophilia.
Tt: antibiotic prophylaxis and Ig replacement.
Predominantly Antibody deficiencies: Most frequent cause of primary immunodeficiencies. Most
Kids are unaffected 1st 6-9 months of life due to presence of maternal antibodies. IgG antibdoies
spread freely extravascularly, IgA & pentameric IgM antibodies line the mucosa, Hence defective
antibody production leads to onset of invasive pyogenic bacterial infections (due to IgG deficiency),
as well as recurrent sinus and pulmonary infections (IgA deficiency) by S.pneumo, H.influenzae,
M.catarrhalis, which progresses to bronchiectasis & further into cor pulomanle. Diagnostics involve
B cell counts, measuring Ig levles after tetanus toxoid or nonconjugated pneumococcal
polysaccharide antigen or B cell phenotype determination.
• Bruton’s agammaglobulinemia: Caused by defect involving bruton’s tyrosine Kinase (btk)
involved in conversion of pre B cell stage into mature b cells resulting in a partial blockade
of this process.
C/c of chronic sinus and respiratory infections, infections with mycoplasma are also
common, chronic fungal infections are seen, Viral infections like hepatitis and enteroviruses
are common. Pts have paralysis with live polio vaccine and chronic, eventually fatal CNS
infections due to various echovirus and coxsackieviruses. An enterovirus associated
myositis, resembling dermatomyositis has been observed. Neutropenia, typically seen when
infected can be a/w pseudomonas or Staph. Infections.
Dx: Suspected with lymphoid hypoplasia O/E, confirmed with absence of all antibodies or
with flow cytometry showing absent B cells.
• Common variable immunodeficiency (CVID): Most common immunodeficiency in
adolescents and young adults, its characterized by hypogammaglobulinemia. Pts have C/c of
recurrent infections with encapsulated bacterias causing sepsis, meningitis or repeated
pulmonary infections leading to bronchiectasis, pts may develop, granulomatous lesions,
colitis, lymphoproliferation (characterized by splenomegaly), autoimmune disease (like
alopecia areata, hemolytic anemia or pernicious anemia) and lymphomas signifying poor
outcomes. CVID pts may also develop spruelike enteropathy with or without nodular
hyperplasia of intestines. All male pts with CVID should be also suspected for X linked
lymphoproliferative disease, esp. If more than 1 male family members have CVID and
particularly with SH2D1A mutations.
Dx: Confirmed with presence of hypogammaglobulinemia (reduction in atleast 2 serum Ig
isotypes) and excluding the presence of hypomorphic mutations a/w agammaglobulinemia
or more subtle T cell defects. B cell number can be low or normal.
Hypogammaglobulinemia can be a/w neutropenia and lymphopenia in the WHIM
syndrome.
Tt: Antibiotic prophylaxis for recurrent infections, Ig supplementation.
• Hyper IgM syndromes: In these syndromes, the characteristic feature is failure of class
switching from IgM class antibody to a different one, as a consequence very ineffective
immune response against pathogens occurs leading to recurrent infections. It can be caused
by 4 types of mutations, 1 of which is on X chromosome and other 3 are autosomal, all are
 inherited recessively. There are some characteristic differences b/w X linked and autosomal
hyper IgM syndromes:
◦ X linked recessive Hyper IgM: It occurs from defects on CD40 Ligand gene on X
chromosome, its expressed on T helper cells and it interacts with CD 40 receptors on B
cells enabling cross talk b/w them which helps in 2 things, Isotype switching from IgM
class and upregulation of CD80/86 on B cells or monocytes that interacts with
CD28/CTLA4 leading to secretion of cytokines promoting B cell conversion to plasma
cells and their multiplication, absence of these features presents in pts clinically as
lymphoid hypoplasia (small tonsils, absent lymph nodes) mimicking
agammaglobulinemia, recurrent sinopulmonary infections esp. Susceptibility to PJP,
verruca vulgaris lesions, cryptosporidium enteritis, liver diseases and neutropenia. Lab
findings of Lymph node histology shows only abortive germinal center formation with
severe depletion and phenotypic abnormality of dendritic cells, Bcell numbers are
normal but have a decrement in memory cell subtype. Tt is HSCT transplant at an early
age, alternatively monthly infusion of IVIG can be done, In severe neutropenia GCSF
can be administered.
◦ Autosomal recessive Hyper IgM: It’s caused by mutations at 3 locations, 50% cases are
caused the Activation induced cytosine deaminase (AID) or the Uracil DNA glycosylase
gene (UNG) & the other 50% accounts for mutations of CD40 receptors on chromosome
20. AID deaminates cytosine into uracil followed by its removal by UNG, these pts
unlike the other mutations of Hyper IgM, are relatively resistant to recurrent infections
hence recurrent sinopulmonary infections are less common, PJP, cryptosporidiosis are
also less likely, instead pts suffer form autoimmune & inflammatory disorders like
Diabetes mellitus, polyarthritis, autoimmune hepatitis, hemolytic anemia, ITP, crohn’s
disease and chronic uveitis, O/E these cases have lymphoid hyperplasia (enlarged
lymphoid organs, lymph nodes, spleen or tonsils). CD 40 deficiency mimics CD40L
deficiency.
• Selective Ig deficiency: only of 2 notable types IgA and IgG subclass defect:
◦ Selective IgA defect: belong to same continuum as CVID with similar mutations,
Patients have recurrent sinopulmonary and GIT infections, family h/o of CVID can also
be found, Selective IgA deficiency may evolve into CVID later in life, pts also
susceptible to celiac disease other autoinflammtory disorders, Selective IgA deficiency
pts should only receive blood transfusion only with washed erythrocytes (routine in BT)
or from other IgA deficient individuals, because of presence of anti serum IgA antibodies
which can cause nonhemolytic transfusion reactions, IVIGs are also contraindicated due
to the same reason. Some case of IgA deficiency are also a/w IgG2 subclass deficiency.
◦ Selective IgG subclass deficiency: 1 or more of IgG subclasses are deficient, most
commonly its IgG2, some cases are a/w IgA deficiency and CVID. In these cases there is
deficiency of antibodies against protein and polysaccharide components making children
susceptible to infections with encapsulated bacteria even in normal concentrations of all
Ig subclasses. IVIG is avoided.
◦ Deficiency of heavy or light chain.
• Transient hypogammaglobulinemia of infancy: Common lab finding due to delayed
production of Igs, occurs in 1:1000 kids, most infants begin production of IgG within 1st
3months of life, which progresses throughout infancy, for unknown reasons a small no. O
infants either begin production late or do not have turn overs expected for age. It can be
differentiated from genuine PIDs by measuring response to vaccination, which is normal in
this case and low in pathologic cases.

Disorders of Immune dysregulation

• Haemophagocytic lymphohistiocytosis (HLH) syndromes: These disorders lie in a
spectrum of histiocytosis syndromes, which also includes langerhans cell histiocytosis,
HLH syndromes can be primary (familial), Secondary (from underlying inflammation),
HLH a/w albinism and HLH in response to EBV infection (XLP). HLH is characterised
pathologically by presence of haemophagocytosis (phagocytosis of RBC by macrophages in
marrow specimen) and histiocytosis, clinically its characterized by severe systemic
symptoms like fever, maculopapular &/or petechial rash, weight loss or irritability and
lymphoproliferation (hepatosplenomegaly,lymphadenopathy), Acute presentations may
include septic shock, ARDS, serizures, meningitis and coma, associated feateures occur
from marrow invovlvement, hepatic failure (jaundice) and pancytopenia. Dx requires
fulfilment of 5 out of 8 clinical & lab findings which are presence of fever, splenomegaly,
cytopenias of 2 cell lines, hypertriglyceridemia, hyperferritenmia(>500, typically >10,000),
hypofribrinogenemia, extremely elevated soluble CD25, reduced or absent NK cell activity
and marrow, CSF or lymph node e/o hemophagocytosis. MRI may show T2 weighted/FLAR
hyperintensities in gray and white matter in supratentorial and infratentorial regions:
◦ Primary (familial) HLH: Caused by mutations in perforin and granzyme genes leading
to defect in fx of Cytotxic T cells and NK cells, familial HLH is inherited in Autosomal
recessive fashion, FHLH and Secondary HLH have similar features except FHLH
doesn’t occur in setting of an underlying infection and it is a/w severe
immunodeficiency. Dx involves mutation analysis at PRF1 (perforin gene) or the
MUNC13-4 gene.
◦ Secondary HLH: Occurs in setting of severe systemic inflammation which typically
occurs in severe infections but can also be of noninfectious nature like drugs (phenytoin,
HAART), HSCT, Chemo., Autoimmune diseases, IBD, Cancers and immunodeficiency
states. Its clinically differentiated from FHLH by presence of an already documented
underlying pathology and its acute presentation.
◦ HLH a/w albinism: This group involves mainly 3 diseases, Chediak-Higashi syndrome,
Griscelli syndrome and Hermansky Pudlak-2, these group of disorders are characterised
by presence of oculocutaneous albinism:
▪ Chediak Higashi Syndrome: It occurs from mutations in lysosome trafficking
regulator gene LYST, which causes defects in degranulation, pts have
immunodeficiency with recurrent skin and URT infections, Oculocutaneous
albinism, neurological defects in form of neuropathy and cerebellar ataxia, mild
bleeding tendency(easy bruising, petechiae, mucosal bleeds and prolonged Bleeding
time), The syndrome may evolve into accelerated phase in the setting of ineffective
treatment in form of a HLH manifestation. Pts surviving childhood may develop
cerebellar atrophy, peripheral neuropathy and cognitive delay. Labs show large
melanosomes but reduced in number and Large peroxidase positive lysosomes in a
granulocyte on a PS. Tt is HSCT, if currently Pts in HLH then that is managed 1st
before HSCT, its managed similar to FHLH
▪ Griscelli syndrome: Pts have characterstic HLH and albinism features, neurological
defects are less common. Labs show melanosome clumping in hair shafts and center
of melanocytes. . Tt is HSCT.
▪ Hermansky-Pudlak syndrome: Pts have features of albinism and HLH, they are
also characterised by bleeding tendency. Tt is HSCT.
◦ X linked lymphoproliferative disease or EBV asso. HLH: In this disorder there is
defect in SH2D1A gene encoding for SAP (SLAM associated protein), SLAMs are
adhesion molecules upregulated on T and B cells with infections and other stimulation,
their absence leads to several problems in immune interactions, mainly, uncontrolled
cytotoxic T cell response to EBV, Impaired 2B4 mediated NK cell activation, defective
antigen induced T cell death & defective T helper cell mediated B cell activation.
C/c: Pts are usually asymptomatic till they get infected by EBV after which they present
typically with 3 characteristic features, 1) Fulminant, often Fatal Infectious
mononucleosis, 2) B cell lymphomas and 3) Acquired hypogammaglobulinemia, less
 commonly CNS vasculitis is also present, there is marked decrease in production of
antibodies against EBV nuclear antigen, whereas titres of antibody against viral capsid
may range from absent to greatly elevated, XLP has very poor prognosis because in
absence of family h/o they are very difficult to detect as pts are asymptomatic in
beginning. Mutation causing XLP SH2D1A is also a/w CVID phenotype, hence all male
members of CVID should be suspected for XLP, particularly if more than 1 male
members have CVID phenotype. Tt is HSCT.
◦ Management of FHLH involves therapy of Etoposide, cyclsoporine, Dexamethasone or
other steroids and Intrathecal methotrexate. Mangement of secondary HLH involves
control of underlying inflammation
• Autoimmune lymphoproliferative syndrome: Caused by mutations in Fas gene leading to
abnormal apoptosis of T cells which results in polyclonal populations of T cells which lack
CD4 & CD8 co-receptors and only express CD3 and ɑ/β antigen receptors (called CD4-CD8-
CD3+ ɑ/β+ TCR Tcells), they respond poorly to antigens and mitogens and do not produce
growth or survival factors(IL-2). Persistent survival of these polyclonal lymphocytes leads
to immune dysregulation and autoimmunity.
C/c: Pts present within 1st 1-5 years of life with chronic inflammation and generalized
lympahdenopathy, hepatosplenomegaly & Hypergammaglobulinemia (IgA & IgG),
Autoimmunity produces anaemia (coombs positive hemolytic anaemia), thrombocytopenia
or neutropenia, lymphoproliferation may regress later in life but autoimmunity doesn’t and
its a/w freuqent exacerbations and recurrences, e.g of autoimmune conditions may include
urticaria, glomerulonephritis, uveitis, hepatitis, vasculitis, panniculitis, arthritis and CNS
involvement(seizures, headaches, encephalopathy). Malignancies are also common and it
includes Hodgkin and non hodgkin lymphomas and solid tissue tumors of thyroid, skin,
heart or lung. ALPS is also a cause of Evan syndrome (immune thrombocytopenia and
immune hemolytic anemia).
Dx: Flow cytometric coutns of characteristic T cells, mutation analysis.
Tt: Rapamycin (sirolimus) to control Lymphadenopathy and autoimmune cytopenias.
Malaginancies cna be controlled as per usual protocols. HSCT is alternate option.
• Primary immunodeficiencies a/w autoimmune conditions and Enteric inflammation:
◦ Immune dysregulation polyendocrinopathy, enteropathy X linked syndrome
(IPEX): It is caused by FOXP3 gene mutation (also by Gain-of-function at STAT1)
which encodes a transcription factor involved in growth and functioning of CD4+ and
CD25+ regulatory T cells, the mutation leading to their absence may be responsible for
abnormal activation of effector T cells. C/c: Its characterized by widespread
inflammatory enteropathy presenting as watery diarrhea, villous atrophy accompanies
this presenting as failure to thrive & food intolerance, Cutaneous manifestations of
widespread eczema, psoriasiform and icthyosiform rash are also seen, insulin
dependent diabetes mellitus, autoimmune disorders (like coombs positive hemolysis,
thrombocytopenia,neutropenia) are also present, severe hypersensitive reactions are
seen, hyperthryoidism or hypothyroidism are asso. Features. Serious invasive bacterial
infections like that of meningitis, sepsis, pneumonia and osteomyelitis may be related to
severe neutropenia, malnutrition or immune dysregulation.
Labs: Absent CD25+ and CD4+ T cells, elevated IgE but normal other Igs. Dx
confirmed by mutational analysis of FOXP3.
Tt: Inhibition of T cell activation by cyclosporine, sirolimus, tacrolimus or with
corticosteroids, with specific care of endocrinopathy and other manifestations of
autoimmunity, these agents are only a bridge to definitive Tt, that is HSCT.
◦ Autoimmune candidiasis ectodermal dysplasia (APECED) syndrome: Caused by
defect in Autoimmune regulator (AIRE) gene inherited autosomal recessively resulting
in decreased expression of self antigens in medullary thymus consequently resulting in
impaired negative selection of T cells causing autoimmunity. C/c are mulitple
 autoimmune manifestations and endocrine disorders, mild chronic candidiasis is also
associated with this syndrome.
◦ PLCγ2-associated antibody deficiency and immune dysregulation (PLAID or APLAID):
A combination of hypogammaglobulinemia, autoantibody production, cold induced
urticaria or skin granulomas or auto-inflammation
◦ CTLA-4 recessive mutations in gene encoding LRBA as well as gain of function
mutation in STAT3 cause a multifaceted lymphoproliferative and autoimmune syndrome
frequently causing IBD a/w hypogammaglobulinemia. Dx: Molecular analysis. Tt:
targeted therapy.
Inherited Bone marrow failure syndromes
• Fanconi Anemia: Caused by mutations in FANC gene which is involved in DNA repair
and cross linking, this leads to increased chromosomal fragility. Pts have C/c of
Congenital anomalies, marrow failure & chemoradiosensetivity, which presents as
anatomic abnormality consisting of absent radii, absent or hypoplastic,
bifid/supernumerary thumb, feet anomalies, congenital hip dislocation & leg
abnormalities, skin hyperpigmentation of trunk, neck, and intertriginous areas, cafe-
au-lait spots, and vitiligo, Facial anomalies consisting of epicanthal folds,
hypertelorism, almond shaped eyes, low set ears, broad nasal base, micrognathia and
microcephaly, Short stature is common & in some cases aggravated from Subnormal
Growth hormone secretion or hypothyroidism, Male pts have Underdeveloped penis,
undescended, atrophic or absent testes and hypospadiasis or phimosis & all are
infertile. Females can have malformations of vagina, uterus, and ovary and all have
reduced fertility. Kidneys may be ectopic, horseshoe shaped, hypoplastic or absent,
CVS and GI malformations may occur. Approx. 10% cases are cognitively delayed.
Neonates with FA have IUGR and Low birth weight with malformations like
VACTERL/VACTERL-H.
Bone marrow failure appears within 1st decade of life initially as thrombocytopenia,
RBC macrocytosis & increased hemoglobin F, at these stages bone marrow aspirate and
biopsy show a hypoplastic specimen subsequently pts develop neutropenia and then
anemia. Severe aplasia in most cases, usually over years.
Complications: Pts are susceptible to Squamous cell cancers, especially of Head & Neck,
upper esophagus and vulva, and./or anus, cervix and lower esophagus, which also occur
earlier than in general population. Benign and malignant liver tumors can occur as a side
effect of androgen therapy for marrow failure, which is additionally responsible for peliosis
hepatitis (blood filled hepatic sinusoids) that can be reversed with androgen
discontinuation. Clonal marrow cytogenetic abnormality are common whih can be stable,
interminttantly detected or progressive. Pts can progress to clonal myeloid transformation
by young adult age into MDS or AML.
Dx: Should be considered in all children with unexplained pancytopenia, abnormal
hematologic finding and congenital anomalies. It is confirmed with lymphocyte
chromosomal breakage study, done with or without addition of
DEB(diepoxybutane)/MMC(mitomycin C) which shows increased chromosomal fragility
indicated by spontaneous chromatid breakage, rearrangements, gaps, chromatid exchanges
in blood lymphocytes cultrued with phytohemagglutinin or skin fibroblasts. Abnormal
chromosomal breakage analysis can also be done prenataly on amniotic fluid or chorionic
villi samples. NO other inherited pancytopenias shows this much hypersensitivity to
DEB/MMC as seen in fanconi, Some cases of FA have somatic mosaicism in which some
populations of lymphocytes in body have one abnormal allele instead of 2, which occurs
when some cells from lymphoid lineage in marrow undergo spontaneous somatic gene
correction o the allele, in that case there is less hypersensitivity to DEB/MMC. Skin
fibroblast testing is performed additionally if blood lympocyte testing was negative.
Other method is to induce complementation in which a Pts cells are hypridized with known
 genetic complement or wild type FANC gene resulting in correction of chromosomal
fragility caused by DEB/MMC. Next generation sequencing as replaced the former for Dx,
if it is also negative then high resolution copy number variation analysis techniques can be
employed f/b genome wide search for novel associated genes. Extensive screening for
medical rpblems should be done after Dx of FA is established, imaging with radiation is to
be minimized due to carcinogenic risk, MRI should replace CT as investigation of choice,
USG of abdomen & Echo to r/o congenitla anomalies. If growth velocity is low than
endocrine workup, blood work for thyroid, renal liver, metabolic and immune should be
included.
Tt: Definitive is HSCT, Androgen therapy can be used as a bridge to HSCT as a way to
increase marrow production, with the mechanism of increase in erythropoeitin production
and upregulating its receptors of cells with consequence of increase progenitor cell division,
its response is heralded by reticulocytosis and rise in Hgb lvls in 1-2 months, pts gradually
loose response to androgens when marrow failure progresses or pts develop MDS/AML. If
hematologic abnormalities are mild to moderate and stable then no there is no blood
transfusion requirement,
Screening: pts can be observed with PS every 3 monthly and marrow aspiration
surveillance annually for MDS/AML, Blood sugar screened annually or biannually,
Hypothyroid screening annually, Assessment for solid tumors annually, Fluroscopic
examination of orolaryngeal cavity or FOBT after a 10y/o or after HSCT transplant,
begining menarche females should screen for gynecologic cancers. Chromsome fragility
test for close family memebers should be offered.
• Schawmann-Diamond syndrome: It is a ribosomopathy caused by AR inheritence of
defective genes involved in ribosome assembly or maturation esp. SDBS, DNAJC21,
EFL1, with the former 2 involved in maturation and assembly of 60s ribosomal subunit,
with the consequence of multisystem disease involving marrow failure cahracterized by
dysfunctional HSCs, accelerated apoptosis of progenitors and defective marrow
microenviornement & pancreatic exocrine failure characterized by acinar development
failure and fatty replacement of pancreatic tissues.
C/c: Pts present with pancreatic insufficiency since birth causing malabsorption but
steatorrhea is not prominent initially which may improve in 50% cases with age, pts have
deficiency of fat soluble vitamins A,D,E and K. Pts have pancytopenia, among which
neutropenia is most predominant with the consequence of recurrent severe bacterial &
fungal infections, pts have short stature but normal growth velocity. Pts may skeletal
abnormality Importantly metaphyseal dysplasia, osteopenia, delayed appearence of 2ndary
ossification centers, short or flared ribs & thoracic dystrophy, some patients have
hepatomegaly and elevation of liver enzymes, most pts have dental abnormalities and poor
oral health, many have neurocognitive problems and poor social skills.
Complication: Severe infections, MDS/AML, isochromosome 7q and deletion 20q are
associated with low risk of progression to MDS/AML
Dx: Age adjusted trypsinogen and isoamylase measurement in infants (as these are
physiologically low in 1st few months of life) are reduced, fecal elastase can be measured,
Fat soluble vitamins can be measured, fat malabsorption can be proven on assay on a 72
hour stool collection, USG& CT to visualize fatty replacement of pancreatic tissue. CBC
and PS for pancytopenia and marrow aspiration and biopsy to confirm failure. Mutation
analysis of all 3 genes confirm the diagnosis of SDS. SDS does not show chromosomal
breakage with DEB/MMC as seen with FA. Pearson syndrome presentes similiarly to SDS
with marrow and pancreatic failure, but sideroblastic anemia is more prominent than
neutropenia and it cna be confirmed with mutational analaysis of mitochondrial DNA
Tt: HSCT is a definitive Tt, Daily subcutaneous GSCF can be given for neutropenia
although it may increase the risk of conversion to MDS/AML, Oral pancreatic enzyme
replacement & supplemental vitamins for pancreatic failure.
 Periodic CBC (every 3 monthly) and marrow aspiration (annual) to look for early evidence
of myeloid transformation.
• Diamond Blackfan syndrome: It is a ribosomopathy caused by mutations in RPS19 gene
involved in 40s subunit maintenance and GATA-1 defect (X-linked). It is characterized by
Marrow failure and congenital anomalies.
C/c: Congenital aplastic anemia is main feature, can present with hydrops in fetal age, other
features are congenital anomalies of craniofacial bones (snub nosed and high arched palate),
hands (flat thenar, triphalangeal thumb, absent radial pulse) etc. GATA-1 is esp. a/w
neutropenia.
Labs: Show macrocytic anemia and reticulocytopenia without megaloblasts or neutrophil
segments, Increased concentration of “i” antigens in RBCs and HbF, increased activity of
eADA (erythrocyte ADA) esp. Helpful in Dx in very young infacts as fetal RBCs have very
low eADA activity.
Complications: predisposition to tumours like AML, MDS, Colon cancer, osteogenic
sarcomas & female gynaecological cancers. Chronic transfusion may cause
haemochromatosis.
Tt: Corticosteroids are mainstay but may cause delayed growth and neurocognitive
development hence initiation is delayed after 1 y/o, response is seen within 1-3 weeks by
increase in RBC precursors and Hgb reaches normal lvls by 4-6 wks. Chronic RBC
transfusion is needed for cases who are steroid non responders, steroid refractory or stable
on low dose of steroids. HSCT is curative.
• Dyskeratosis Congenita: Caused by defects in telomerase complex genes like TERT,
DKC1,, which leads to accelerated telomere shortening affecting cell division and
senescence. It can be X linked (DKC1 on Xq28), AD (TINF and TERT), AR (PARN and
TERT)
C/c: Classic triad of Dyskeratotic nails (longitudinal ridging, splitting or pterygium
formation), oral leukoplakia (may also occur in eyes, anal, uretheral or genitals) and
reticular pigmentation, however not present in all, if it occurs skin and nails findings
appears in 1st decade of life earlier than leukoplakia. In addition pts are susceptible to
aplastic anemia, pulmonary and hepatic fibrosis, congenital anomalies and a predisposition
to solid tumours like AML or MDS. Marrow failure usually occurs in last 2 decades of life.
MC of complaints are reticular markings which worsens with ageing and can involve whole
skin, there may also be telangiectatic component. Excessive tearing (epiphora) cna occur
from nasolacrimal duct obstruction, cognitive delays may be present, hyperhidrosis of
palms & soles, hair loss & graying, dental caries or loss, esophageal strictures, pulmonary
disease with restrictive airflow limitation and diffusion limitation, short stature may be
seen.
Ocular abnormalities can be conjunctivitis, blepharitis, eyelash losses, strabismus, cataracts
and optic atrophy.
Skeletal abnormalities include osteoporosis, avascular necrosis of hip and shoulders,
abnormal bone trabeculation, mandibular hypoplasia, scoliosis. Genitourinary abnormalities
like hypoplastic testes, hypospadias, phimosis, urethra stenosis, and horseshoe kidney. GI
findings like vascular lesions causing bleeding, hepatomegaly, peptic ulceration, and
fibrosis.
Labs: Predominant finding of pancytopenia & macrocytosis.
Complications: MDS/AML, SCCs.
Tt: Androgens to stimulate haematopoiesis, HSCT as a definitive treatment.
Outcomes: Major cause of death is marrow failure, HSCT complciations, cancer, fatal
pulmonary problems and GI bleed.