Reticular Dysgenesis

A number sign (#) is used with this entry because of evidence that reticular dysgenesis is caused by homozygous or compound heterozygous mutation in the mitochondrial adenylate kinase-2 gene (AK2; 103020) on chromosome 1p35.

Clinical Features

Reticular dysgenesis is one of the rarest and most severe forms of combined immunodeficiency. It is characterized by congenital agranulocytosis, lymphopenia, and lymphoid and thymic hypoplasia with absent cellular and humoral immunity functions. De Vaal and Seynhaeve (1959) described newborn male twins who had normal numbers of erythrocytes and platelets but no blood leukocytes. They died at 5 and 8 days of age of sepsis. Postmortem examination showed absent myeloid elements from the bone marrow and absent lymphocytes from the thymus and spleen.

Seligmann et al. (1968) suggested that this may be generalized immunologic deficiency disorder. They also suggested that the case of Gitlin et al. (1964) may have been the same disorder. In that case the thymus was hypoplastic without Hassal corpuscles. Although few cases have been reported, only 2 affected females had been observed (Gitlin et al., 1964; Alonso et al., 1972).

Ownby et al. (1976) reported 2 affected nontwin male sibs who died at ages 3 and 50 days from congenital cytomegalovirus infection and pseudomonas sepsis, respectively. Ownby et al. (1976) excluded deficiency of adenosine deaminase (see 102700).

Espanol et al. (1979) reported 2 brothers who died at ages 12 and 8 days of infections. The thymus was very small. The lymph nodes were grossly small and histologically devoid of lymphocytes. The peripheral blood showed marked leukopenia and lymphopenia and the bone marrow showed lack of myeloid elements.

By 1983, 10 cases had been reported (Levinsky and Tiedeman, 1983). All died from overwhelming infections within a few days or weeks after birth. A child isolated in a sterile environment survived for 17 weeks (Haas et al., 1977).

Roper et al. (1985) reported the case of a premature male who died at age 30 days. They concluded that the defect is not failure to initiate stem cell differentiation along lymphoid and myelomonocytic lines but rather an abnormality that interferes with normal growth and maturation of immune cells committed to these pathways.

Clinical Management

Levinsky and Tiedeman (1983) used a bone-marrow transplant from an HLA-identical brother. Severe graft-versus-host disease (GVHD; see 614395) was responsive to high-dose methylprednisolone. At age 3 years, the child was thriving with full hematologic and immunologic reconstitution.

Mapping

Pannicke et al. (2009) studied 6 individuals with reticular dysgenesis from 5 independent families. In 3 of the families there was evidence of consanguinity. Assuming a recessive inheritance model, Pannicke et al. (2009) conducted a screening for homozygous chromosomal regions using genomewide SNP analysis with DNA obtained from the 6 individuals. In 4 families, including those with consanguineous parents, the analysis revealed a common region on chromosome 1p36.11-p34.3.

Molecular Genetics

Pannicke et al. (2009) noted that 80 genes within the reticular dysgenesis critical region on chromosome 1 are expected to be expressed in bone marrow. They used RT-PCR to examine the expression of these genes in bone marrow mononuclear cells derived from an index individual in a family with the disorder. When they compared the amplification products to those obtained from a healthy subject, they found that the cDNAs encoding adenylate kinase-2 revealed smaller products than the expected 815-bp amplimer. Pannicke et al. (2009) then sequenced the exons and splice junctions of the AK2 gene from genomic DNA of all affected individuals and detected 6 causative mutations in homozygous or compound heterozygous state (103020.0001-103020.0006). Pannicke et al. (2009) stated that reticular dysgenesis is the first example of a human immunodeficiency syndrome that is causally linked to energy metabolism and that can therefore be classified as a mitochondriopathy.

Lagresle-Peyrou et al. (2009) identified biallelic mutations in AK2 (103020.0007-103020.0013) in 7 individuals with reticular dysgenesis. These mutations resulted in absent or strongly decreased protein expression. The authors then demonstrated that restoration of AK2 expression in the bone marrow cells of individuals with reticular dysgenesis overcomes the neutrophil differentiation arrest, underlining its specific requirement in the development of a restricted set of hematopoietic lineages. Finally, Lagresle-Peyrou et al. (2009) established that AK2 is specifically expressed in the stria vascularis region of the inner ear, which provides an explanation for the sensorineural deafness in these individuals. Lagresle-Peyrou et al. (2009) concluded that their results identified a previously unknown mechanism involved in regulation of hematopoietic cell differentiation in one of the most severe human immunodeficiency syndromes.