Reticular dysgenesis (RD) is the most severe and rarest form of severe combined immunodeficiency (SCID), a group of genetic disorders causing a near-total lack of immune function. This condition is dangerous for newborns because it compromises the earliest stages of blood cell formation. Unlike other forms of SCID, RD affects both the myeloid lineage (including neutrophils) and the lymphoid lineage (comprising T cells, B cells, and NK cells). This dual impact leaves infants defenseless against overwhelming infections, and its rapid progression makes it a medical emergency.
The Genetic Roots of Reticular Dysgenesis
Reticular dysgenesis is an inherited genetic disorder, with most cases caused by mutations in the adenylate kinase 2 (AK2) gene. The condition is passed down in an autosomal recessive pattern, meaning an infant must inherit two mutated copies of the gene, one from each parent. Parents who carry one copy of the mutated gene are carriers and have a 25% chance with each pregnancy of having a child with RD.
The AK2 gene provides instructions for making the AK2 protein, which is found in the mitochondria. This protein maintains energy balance within hematopoietic stem cells, the precursors to all blood cells. When the AK2 protein is non-functional, this energy balance is disrupted, leading to the death of myeloid and lymphoid precursor cells and halting the formation of a mature immune system.
Identifying Early Warning Signs
Symptoms of reticular dysgenesis appear within the first few days or weeks of life, much sooner than other forms of SCID. Affected infants suffer from severe, recurrent infections caused by bacteria, fungi, and viruses, which can manifest as sepsis, pneumonia, skin abscesses, and persistent oral thrush. Infants with RD will not develop visible lymphoid tissues like tonsils or lymph nodes.
A defining characteristic is a failure to thrive, marked by poor weight gain, stunted growth, and persistent diarrhea. Blood tests reveal low counts of white blood cells, specifically severe congenital neutropenia (a lack of neutrophils) and lymphopenia (a lack of lymphocytes). A distinctive feature associated with AK2 mutations is bilateral sensorineural deafness, or hearing loss, present from birth.
Path to Diagnosis
An initial suspicion of reticular dysgenesis arises from the early and severe onset of symptoms, especially with a family history of immunodeficiency. The first diagnostic step is a complete blood count (CBC) with a differential. This test reveals the characteristic combination of severe neutropenia, monocytopenia, and lymphopenia that distinguishes RD from other immunodeficiencies.
Immunophenotyping by flow cytometry is then used to confirm the severe deficiency or absence of T cells, B cells, and NK cells, as well as myeloid progenitor cells. A definitive diagnosis requires genetic testing to identify mutations in the AK2 gene. Newborn screening for SCID can help flag these infants early, but the combined myeloid and lymphoid defects in RD require further investigation to differentiate it from other SCID forms.
Lifesaving Treatment: Stem Cell Transplantation
The only curative treatment for reticular dysgenesis is a hematopoietic stem cell transplantation (HSCT), which replaces the infant’s defective stem cells with healthy ones from a donor. A successful transplant allows the infant to develop a new, functional immune system. Performing the transplant as early as possible is important, as infants who receive one before three months of age have a better chance of survival.
Donor stem cells can come from a matched sibling, a matched unrelated donor (MUD) from a bone marrow registry, or a haploidentical (half-matched) family member. Before the transplant, the infant undergoes a conditioning regimen with chemotherapy to clear the existing bone marrow. After the stem cell infusion, the infant requires intensive supportive care, including isolation to prevent infections, prophylactic medications, and immunoglobulin replacement therapy for temporary immunity.
Navigating Life After Treatment
A successful and early HSCT can lead to a normal immune system and a good quality of life, with one study showing a 68% survival rate. Life after transplant requires continuous medical monitoring to manage potential complications like graft-versus-host disease (GVHD), where donor immune cells attack the recipient’s tissues. Long-term follow-up is also needed to monitor immune system reconstitution and manage any late effects from chemotherapy.
HSCT corrects the blood and immune defects but does not reverse the sensorineural deafness associated with AK2 mutations. This hearing loss requires separate management, such as hearing aids or cochlear implants. Genetic counseling is recommended for affected families to discuss risks for future pregnancies and explore diagnostic options.