Severe congenital neutropenia is a chronic blood disorder due to an accumulation of granulocyte precursors in the bone marrow, resulting in recurrent fever and recurrent infections, including respiratory, skin and oropharyngeal infections, most often due to staphylococci and streptococci. Neutropenia is apparent soon after birth and can lead to osteoporosis or even leukaemia, affecting about 1 in a million worldwide. While the cause of severe congenital neutropenia is unknown for about one-third of the people with the disorder, mutations in different genes are known to be responsible for the rest; about 50% of the cases are due to mutations in the neutrophils elastase (ELANE)gene while 10% are due to mutations in the HS-1-associated protein X-1 (HAX1) gene. Mutations in other genes such as the Wiskott-Aldrich syndrome (WAS) gene, that encodes for the WAS protein (WASP), may also result in severe congenital neutropenia. Mutations in the ELANEgene cause misfolding in the 3D structure of the protein. This results in the accumulation of the neutrophil elastase protein within the neutrophils, eventually leading to the death of the neutrophils. HAX1 is a protein required for regulating apoptosis. Mutations in the HAX1 gene results in premature death of the neutrophils. These mutations are often isolated, sporadic cases. However, mutations in the ELANEgene are inherited in an autosomal dominant manner, while mutations in the HAX1gene are autosomal recessive.
Here is a case of three-year-old Shama (name changed), who presented to the ICU at Lilawati Hospital at Mumbai with fever, vomiting and rashes on the thighs and around the mouth. Dr. K. N. Shah, the consulting paediatrician, observed that the child had tachycardia and tachypnea with a palpable liver that was soft and non-tender, but no palpable spleen and lymph nodes. Laboratory tests revealed that her white blood counts, CRP, PCT and ESR were high. However, her neutrophil count was low, and the monocyte count was high. Previous history of the child showed that she had frequent hospitalizations in which all the reports showed low neutrophil counts. The patient was then referred to Dr. Swati Kanakia, the paediatric hemato-oncologist at Lilawati Hospital. She performed a bone marrow aspiration and biopsy to understand the cause of the neutropenia. Bone marrow biopsy showed a reactive marrow with a mild maturation arrest in myeloid series and mild erythroid hyperplasia. This observation, along with the history of neutropenia, suggested a diagnosis of severe congenital neutropenia. Genetic analysis revealed the child to have a homozygous HAX1mutation. The family was also tested. Both parents were heterozygous for the mutation and one sibling tested heterozygous for the same mutation.
Severe congenital neutropenia is typically treated symptomatically with antibiotic treatment during each recurring infection and recombinant granulocyte colony stimulating factor (G-CSF) which can promote granulopoiesis and release neutrophil reservoirs from the bone marrow. Recombinant G-CSF treatment can increase the circulating neutrophil count by 10-12 folds.
In accordance with international guidelines, Shama was given antibiotics and G-CSF. She requires higher than normal doses of G-CSF (10 mcg/kg) to document a small rise in neutrophil counts. Shama did well with the treatment. However, she continues to suffer from fever and respiratory infections every 2-3 months. A G-CSF injection has to be given to her as treatment each time. A definitive treatment option for severe congenital neutropenia is bone marrow transplantation. In recent years, bone marrow transplants have become available in many bigger cities of India. The challenges are the availability of a matched donor, the cost of the procedure, and the availability of suitable expertise. Often siblings are suitable matched donors. While Shama’s brother also carries a copy of the mutation, it may be possible to use him as a donor. Shama’s parents are currently considering bone marrow transplantation, and one of the key deciding factors would be whether Shama’s brother could be a potential donor. This is the only known curative treatment for this potentially life-threatening disease.