Kostman’s syndrome

• Autosomal recessive disorder
• Mutation of HAX 1 gene and neutrophil elastase 2 gene.
• Neutropenia at birth - <0.2x10⁹/L
• Hemoglobin and platelet counts are normal
• Bone marrow- Promyelocyte maturation arrest with abundant promyelocytes but a selective reduction in myelocytes, metamyelocytes & neutrophils
• Present with severe infections. Skin abscesses are common.
• Treatment
  • G CSF- 5-10microgm/kg- SC- OD to maintain ANC of 1000/cmm. 90% patients respond to this.
  • Bisphosphonates for G-CSF induced osteoporosis
  • Stem cell transplantation - For those who become refectory to G-CSF and those who develop MDS or AML.

Cyclical neutropenia

• 19-23 days periodicity with peak neutropenia for 3-4 days
• Autosomal dominant
• Locus on chromosome 19p 13.3
• Mutation of gene encoding neutrophil elastase (ELANE) which is expressed in promyelocyte stage & is important in neutrophil development.
• Associated with recurrent mouth infections
• Treatment- G-CSF- Daily/ thrice a week

Neutropenia and exocrine pancreas dysfunction

(Shwachman-Diamond syndrome)

• AR- Mutation in SBDS gene on 7q11
• Associated with short stature, pancreatic exocrine deficiency
• Treatment: G-CSF for correction of neutropenia
• HSCT if there is development of MDS or AML

Cartilage hair hypoplasia

• Neutropenia and disordered cellular immunity
• AR- 9p13- Endoribonuclease gene mutation
• Associated with short stature, hyperextensible digits and very fine hairs
• Treatment- HSCT

Cohen syndrome

• Autosomal recessive inheritance
• Chromosome 8q22-q23- VPS13B/COH1 gene mutation
• Associated with pigmentary retinopathy, mental retardation, skeletal abnormalities (microcephaly, facial dysmorphism)

X-Linked cardio skeletal myopathy and neutropenia (Barth syndrome)

• X linked recessive disorder
• Alteration of cardiolipin remodeling which is a component of inner mitochondrial membrane
• Associated with cardiomyopathy, underdeveloped skeletal musculature, exercise intolerance, growth delay
• BM shows maturation arrest at myelocyte stage
• Electron microscopy- Concentric, tightly packed cristae within mitochondria.
• Treatment- G-CSF for correction of neutropenia

Myelokathexis

• Autosomal dominant disorder
• Characterized by degenerative changes in granulocytes which include pyknotic nuclear lobes, fine chromatin filaments and hypersegmentation
• BM- Hypercellular with granulocytic hyperplasia
• There is decreased expression of BCL-X gene which leads to accelerated apoptosis
• Treatment- G-CSF for correction of neutropenia

Warts, hypogammaglobulinemia, infection, myelokathexis (WHIM) syndrome

• Autosomal dominant inheritance
• Mutation in chemokine receptor gene CXCR4
• BM- Hypercellular with retention of increased number of mature neutrophils
• Treatment- 
  • G-CSF
  • IVIg therapy
  • Removal of dysplatic skin or mucosal HPV related lesions
  • Plerixafor is being tried

Dursun syndrome

• Autosomal recessive inheritance
• Biallelic mutation of G6PC3 which codes for glucose 6 phosphate catalytic subunit 3
• There is increased apoptosis of neutrophils
• Associated anomalies include- structural heart defects, urogenital abnormalities, venous angiectasia on trunk and extremities

Griscelli syndrome

• Autosomal recessive inheritance.
• Gene on chromosome 15q21 is affected
• Type 1- MYO5A gene mutation- Neurological dysfunction, partial (oculo-cutaneous) albinism
• Type 2- RAB27A- Same as type 1, but has high incidence of hemophagocytosis.
• There is pigmentary dilution 
• Have associated cellular immunodeficiency
• Treatment- HSCT

Glycogen storage disease- Type 1b

• Mutation of G6PT1 gene
• Deficiency of glucose 6 phosphate translocase
• Associated with fasting hypoglycemia, lactic acidosis, hepatomegaly, poor linear growth, delayed pubertal development
• BM- Maturation at myelocyte stage
• Treatment- G-CSF for correction of neutropenia

Hermansky Pudlak syndrome

• Autosomal recessive inheritance.
• Gene on chromosome 5q14.1affected
• Decreased IgG
• Platelet dysfunction

Poikiloderma with neutropenia

• Autosomal recessive inheritance.
• C160RF57 gene on chromosome 16q13 is mutated
• Associated with rash, short stature, dystrophic nails

P14 deficiency

• Autosomal recessive inheritance.
• MAPBPIP gene on chromosome 1q22 is mutated
• Associated with immunodeficiency and hypopigmentation

Charcoat-Marie-Tooth syndrome- type 2

• Autosomal dominant inheritance.
• DMN2 gene on chromosome 19p13.2 is affected
• Associated with axonal demyelinating neuropathy

Pure white cell aplasia

Introduction:

• It is an acquired disorder in which there is immune suppression of neutrophil production
• Immune suppression can be both antibody mediated and cell mediated

Precipitating causes:

• Drugs: Ibuprofen, chlorpropamide, imipenum-cilastatin
• Excess of zinc
• Thymoma
• Various infections and inflammatory states

Bone marrow examination:

• Total absence of myeloid precursors/ arrest at promyelocyte stage

Treatment

• Immunosuppressive therapy with ATG, Cyclosporine and steroids
• Azathioprine with G-CSF
• Stop offending drug
• Thymectomy

Chronic idiopathic neutropenia

• Commonly affects women aged 18-35 years
• Diagnosis of exclusion
• Splenomegaly is often present
• No genetic abnormalities or presence of antibodies
• Bone marrow- Normal/ selective hypoplasia of neutrophil series
• Treatment: For patients with significant recurrent infections- GCSF and supportive care

Neonatal neutropenia associated with maternal hypertension

• It is associated with increased risk of early onset sepsis
• Inhibitor produced from placenta causes decreased neutrophil production
• Treatment- G-CSF

Autoimmune neutropenia

• Etiology-
  • Primary- Antibodies against  Fc gamma RIIIb on NA1 and NA2, ND1, ND2 and NB1
  • Secondary- SLE, Rheumatoid arthritis, Sjogren syndrome, ALPS etc
• Seen in children aged 5-15 months
• Antibodies can be detected by agglutination or cytotoxicity tests
• BMA- Hypercellular with late maturation arrest picture
• Spontaneous remissions occur especially in children
• Treatment of primary cases- 
  • G-CSF
  • Prednisolone- PO- 1mg/kg- may be needed in some cases
  • If no response- Rituximab +/- IVIg
• For secondary cases- Treatment of underlying disorder

Alloimmune neonatal neutropenia

• It occurs due to transplacental transfer of maternal IgG antibodies that bind to infant’s neutrophil specific antigens (derived from father) such as Fc-gamma-RIIIb
• Other antigens are
  • NB1glycoprotein
  • HNA-3a
  • HLA antigens
• Incidence- 1 in 2000 neonates
• Lasts for 2-4 months, until passively acquired immunity is lost
• Severity varies- Most present with omphalitis
• BM- Hypercellular with decreased mature neutrophils
• Treatment
  • Antibiotics
  • IVIg and GCSF
  • Rarely- Exchange transfusion to decrease antibody titers

Drug induced neutropenia

• Drugs causing neutropenia are enlisted in approach to diagnosis section
• Definition excludes known cytotoxic agents and requires that the drug have been administered within four weeks of the onset of neutropenia
• Mechanism- Usually immune mediated destruction of neutrophils (drugs act as haptens)
• Case fatality rate – approximately 5%
• Neutropenia is seen usually within 3 months of starting the offending drug
• Presentation- 
  • Fever with pharyngitis
  • Sepsis and pneumonia- Seen in 10%-30% cases
• Recovery occurs by10 days if offending medication is stopped
• Treatment
  • Prompt withdrawal of offending drug
  • Broad spectrum antibiotics
  • G-CSF- No much benefit