IllnessNeutropenia, congenital; differential diagnosis

NGS +

Severe congenital neutropenia renders affected individuals susceptible to recurrent infections. Neutropenia can occur in the perinatal period or lateron. The recurrent infections begin in infancy and include sinusitis, pulmonary and hepatic affections, which may be accompanied by fever, gingivitis and skin inflammation. Nearly half of these patients have osteopenia and may develop osteoporosis. Bone involvement may begin in infancy or as late as adulthood. Approximately 20% of these patients develop certain blood malignancies in adolescence, particularly myelodysplastic syndrome or leukemia. A few affected individuals have additional health problems such as seizures, developmental delays or cardiac and genital abnormalities. Congenital neutropenia can be caused by mutations in many different genes. These genes play a role in the maturation and function of neutrophils, which secrete e.g. immune molecules. The life span of neutrophils is shortened, and their function is impaired or the physiological maturation is impaired. About half of all cases of severe congenital neutropenia are caused by mutations in the ELANE gene, another 10% by mutations in the HAX1 gene. Mutations in other genes are each responsible for only a small percentage of all cases. In about one third of these patients, the cause remains unknown. Most cases of severe congenital neutropenia are classified as sporadic. When congenital neutropenia is caused by mutations in the ELANE gene, it is inherited in an autosomal dominant manner (as it is for mutations in other genes). If the disease is caused by alterations in the HAX1 gene, it is inherited in an autosomal recessive manner (like in other cases). Less commonly, severe congenital neutropenia is inherited in an X-linked recessive manner. A negative molecular genetic result by no means excludes the clinical diagnosis.

References: https://www.ncbi.nlm.nih.gov/books/NBK1533/

https://www.ncbi.nlm.nih.gov/books/NBK571103/

https://www.ncbi.nlm.nih.gov/books/NBK1756/

https://www.ncbi.nlm.nih.gov/books/NBK285321/

https://www.ncbi.nlm.nih.gov/books/NBK247162/

• Allelic: 3-methylglutaconic aciduria, type VIIB, AR (CLPB)
• Allelic: Aplastic anemia, susceptibility to (SBDS)
• Allelic: Blood group, Duffy system (AKCR1)
• Allelic: Cartilage-hair hypoplasia (RMRP)
• Allelic: Leukemia, acute myeloid (TERT)
• Allelic: Malaria, vivax, protection against (AKCR1)
• Allelic: Melanoma, cutaneous malignant, 9 (TERT)
• Allelic: Metaphyseal dysplasia without hypotrichosis (RMRP)
• Allelic: Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1 (TERT)
• Allelic: Pulmonary fibrosis and/or bone marrow failure, telomere-related, 3 (RTEL1)
• Allelic: Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4 (PARN)
• Allelic: Revesz syndrome (TINF2)
• Allelic: Thrombocytopenia with beta-thalassemia, XL (GATA1)
• Allelic: Thrombocytopenia, XL (WAS)
• Allelic: Thrombocytopenia, XL, intermittent (WAS)
• Allelic: Thrombocytopenia, XL, with/-out dyserythropoietic anemia (GATA1)
• Allelic: Wiskott-Aldrich syndrome (WAS)
• Anauxetic dysplasia 1 (RMRP)
• Anemia, XL, with/-out neutropenia +/- platelet abnormalities (GATA1)
• Ataxia-pancytopenia syndrome (SAMD9L)
• BM failure syndrome, AR [panelapp] (NAF1)
• Barth syndrome [3-methylglutaconic aciduria type II] (TAFAZZIN)
• Bone marrow failure syndrome 3 (DNAJC21)
• Bone marrow failure syndrome 5 (TP53)
• Cerebroretinal microangiopathy with calcifications + cysts (CTC1)
• Cerebroretinal microangiopathy with calcifications + cysts 2 (STN1)
• Chediak-Higashi syndrome (LYST)
• Cohen syndrome (VPS13B)
• Congenital disorder of glycosylation, type IIw (SLC37A4)
• Dursun syndrome (G6PC3)
• Dyskeratosis congenita [panelapp] (NAF1)
• Dyskeratosis congenita, AD (TINF2)
• Dyskeratosis congenita, AD 2 (TERT)
• Dyskeratosis congenita, AD 4 (RTEL1)
• Dyskeratosis congenita, AD 6 (ACD)
• Dyskeratosis congenita, AR 1 (NOP10)
• Dyskeratosis congenita, AR 2 (NHP2)
• Dyskeratosis congenita, AR 3 (WRAP53)
• Dyskeratosis congenita, AR 4 (TERT)
• Dyskeratosis congenita, AR 5 (RTEL1)
• Dyskeratosis congenita, AR 6 (PARN)
• Dyskeratosis congenita, AR 7 (ACD)
• Dyskeratosis congenita, XL (DKC1)
• Emberger syndrome (GATA2)
• Glycogen storage disease Ia (G6PC1)
• Glycogen storage disease Ib (SLC37A4)
• Glycogen storage disease Ic (SLC37A4)
• Griscelli syndrome, type 1 (MYO5A)
• Griscelli syndrome, type 2 (RAB27A)
• Griscelli syndrome, type 3 (MLPH)
• Hermansky-Pudlak syndrome 2 (AP3B1)
• Immunodeficiency 21 (GATA2)
• Immunodeficiency due to defect in MAPBP-interacting protein (LAMTOR2)
• Immunodeficiency, XL, with hyper-IgM (CD40LG)
• MIRAGE s.: Myelodysplasia, Infection, Restric. growth, Adrenal hypopl., Genital-/Enteropathy (SAMD9)
• Monosomy 7 myelodysplasia + leukemia syndrome 1 (SAMD9L)
• Monosomy 7 myelodysplasia + leukemia syndrome 2 (SAMD9)
• Myelokathexis, isolated (CXCR4)
• Neutropenia, alloimmune neonatal [panelapp] (FCGR3B)
• Neutropenia, cyclic (ELANE)
• Neutropenia, nonimmune chronic idiopathic, of adults (GFI1)
• Neutropenia, severe congenital 1, AD (ELANE)
• Neutropenia, severe congenital 2, AD (GFI1)
• Neutropenia, severe congenital 3, AR (HAX1)
• Neutropenia, severe congenital 4, AR (G6PC3)
• Neutropenia, severe congenital 5, AR (VPS45)
• Neutropenia, severe congenital 6, AR (JAGN1)
• Neutropenia, severe congenital 7, AR (CSF3R)
• Neutropenia, severe congenital 8, AD (SRP54)
• Neutropenia, severe congenital 9, AD (CLPB)
• Neutropenia, severe congenital XL (WAS)
• Osteopetrosis, AR 1 (TCIRG1)
• Osteopetrosis, infantile malignant (TCIRG1)
• Poikiloderma with neutropenia (USB1)
• Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PSTPIP1)
• Reticular dysgenesis (AK2)
• Shwachman-Diamond syndrome (SBDS)
• Shwachman-Diamond syndrome 2 (EFL1)
• T-cell immunodeficiency, recurrent infections, autoimmunity, cardiac malformations (STK4)
• Transcobalamin II deficiency (TCN2)
• WHIM [Warts, Hypogammaglobulinemia, Infections, Myelokathexis] syndrome 1 (CXCR4)
• White blood cell count QTL (AKCR1)