A number sign (#) is used with this entry because of evidence that bone marrow failure syndrome-3 (BMFS3) is caused by homozygous mutation in the DNAJC21 gene (617048) on chromosome 5p13.

Bone marrow failure syndrome-3 is an autosomal recessive disorder characterized by onset of pancytopenia in early childhood. Patients may have additional variable nonspecific somatic abnormalities, including poor growth, microcephaly, and skin anomalies (summary by Tummala et al., 2016).

BMFS3 has a distinct phenotype and may include features that overlap with Shwachman-Diamond syndrome (SDS1; 260400), such as pancreatic insufficiency and short stature, and with dyskeratosis congenita (see, e.g., DKCA1, 127550), such as dental and hair abnormalities and shortened telomeres. In addition, some patients may have joint and skeletal abnormalities, impaired development, and retinal dysplasia (summary by D'Amours et al., 2018).

For a discussion of genetic heterogeneity of BMFS, see BMFS1 (614675).

Tummala et al. (2016) reported 4 unrelated children with a bone marrow failure syndrome. All children were born of consanguineous parents, and none had a family history of the disorder. Beginning in early childhood, all had global bone marrow failure associated with a reduction in all cell lineages in the peripheral blood. Additional features included intrauterine growth failure and/or short stature; 2 had microcephaly. Three patients had other variable abnormalities, including microdontia, hyperkeratosis, retinal dystrophy with poor vision, skin pigmentation anomalies, and dysphagia with oral ulceration. One patient developed acute myeloid leukemia at age 12 years, suggesting that the disorder is associated with cancer predisposition. Patient cells did not show increased chromosome breakage, and telomere lengths were within the normal range.

Dhanraj et al. (2017) reported 4 patients from 3 unrelated families with a bone marrow failure syndrome suggestive of Shwachman-Diamond syndrome. Two families were consanguineous of Afghan and First Nations Canadian descent, respectively, whereas the third family was of Indian descent. The patients presented in infancy or early childhood with pancytopenia and a hypocellular bone marrow. All had pancreatic exocrine dysfunction with decreased serum levels of pancreatic enzymes and abnormal echogenic findings on pancreatic ultrasound. Additional features included poor growth, short stature, evidence of metaphyseal dysplasia, and variably impaired cognitive and/or motor development. Two unrelated patients had retinal dystrophy, although 1 patient had another genetic defect (C2ORF71; 613425), which could have contributed to the eye phenotype. Two patients underwent bone marrow transplantation, but 1 died posttransplantation. Another patient died of infection at age 18 months; postmortem examination of that patient showed an atrophic pancreas with preservation of the endocrine tissue. Less common features observed in 1 or 2 patients included seizures, eczema, mild facial dysmorphism, and abnormal dentition.

D'Amours et al. (2018) reported 5 additional patients with BMFS3. All presented in infancy or early childhood with failure to thrive, postnatal growth retardation, and pancytopenia or aplastic anemia associated with bone marrow failure. Additional features included short stature (-2 to -4 SD), global developmental delay, recurrent infections, and ectodermal anomalies, such as fine hair, nail dysplasia, eczema, pigmented spots, amelogenesis imperfecta, carious teeth, and microdontia. Some patients had retinal abnormalities, myopia, astigmatism, pancreatic insufficiency, liver cirrhosis (1 patient), cryptorchidism, decreased bone mineral density, and skeletal abnormalities, including metaphyseal dysplasia, 11 pairs of ribs, pectus abnormalities, congenital hip dysplasia, and joint hypermobility. Three patients had mild hearing impairment, and 3 had mild progressive microcephaly. Variable dysmorphic facial features were also noted, including downslanting palpebral fissures, epicanthus, hypertelorism, and micrognathia. Some patients had spontaneous improvement of the bone marrow hypocellularity with age. All 4 patients who were tested had short telomeres compared to controls. Noting the multisystemic involvement, D'Amours et al. (2018) provided management guidelines for patients with biallelic DNAJC21 mutations.

The transmission pattern of BMFS3 in the families reported by Tummala et al. (2016) was consistent with autosomal recessive inheritance.

In 4 unrelated children with BMFS3, Tummala et al. (2016) identified homozygous mutations in the DNAJC21 gene (617048.0001-617048.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Three of the mutations were predicted to result in a truncated protein with a loss of function; the fourth was a missense mutation. In vitro functional expression studies of 1 of the truncating mutations (R173X; 617048.0001) showed that it did not interact with 60S ribosome maturation factors, consistent with a loss of function. Studies of the missense mutation (P32A; 617048.0003) showed that it failed to interact with HSPA8 (600816). T cells from 1 patient with a truncating mutation (617048.0004) showed a growth impairment after mitogenic stimulation, decreased cell viability in response to actinomycin D, and decreased levels of rRNA subunits compared to controls. The findings suggested that the mutations resulted in defects in ribosome biogenesis rRNA.

In 4 patients from 3 unrelated families with BMFS3, Dhanraj et al. (2017) identified homozygous mutations in the DNAJC21 gene, including a nonsense (Q174X; 617048.0005) and a missense (K34E; 617048.0006) mutation and an intragenic deletion. The mutations, which were found by a combination of whole-exome sequencing and homozygosity mapping and confirmed by Sanger sequencing, segregated with the disorder in the families. Patient cells showed decreased levels of DNAJC21 protein, consistent with a loss of function. Additional functional studies of the variants were not performed.

In 5 unrelated patients with BMFS3, D'Amours et al. (2018) identified the same homozygous K34E mutation in the DNAJC21 gene. Functional studies of the variant were not performed.