A number sign (#) is used with this entry because of evidence that bone marrow failure and diabetes mellitus syndrome (BMFDMS) is caused by homozygous mutation in the DUT gene (601266) on chromosome 15q15.

Bone marrow failure and diabetes mellitus syndrome (BMFDMS) is an autosomal recessive disorder characterized by the onset of manifestations of bone marrow failure, such as anemia, thrombocytopenia, and dyserythropoiesis, in infancy or early childhood. White blood cell lineages may or may not be affected. Patients with BMFDMS also develop nonautoimmune insulin-dependent diabetes mellitus in the first or second decades, likely due to apoptosis of pancreatic beta cells. Many patients show pigmentary skin abnormalities and short stature. Bone marrow transplant is curative for the bone marrow failure, but does not have an effect on diabetes (Dos Santos et al., 2017).

Dos Santos et al. (2017) reported 4 patients from 2 unrelated consanguineous families of French (family 1) and Egyptian (family 2) descent with early-onset diabetes mellitus and variable degrees of bone marrow failure. The patients had variable hematologic findings including congenital macrocytosis, pancytopenia, dyserythropoiesis, bone marrow aplasia, anemia, increased erythrocyte volume, lymphopenia, and thrombocytopenia. All developed nonautoimmune insulin-dependent diabetes mellitus between 5 and 28 years of age. The patients in family 1 also had multiple nevi. Patient 2 (family 1) died at age 11 years from a brain hemorrhage due to thrombocytopenia, and patient 3 (family 2) died at age 21 years from graft-versus-host disease after a bone marrow transplant following a diagnosis of T-cell ALL (see 613065). Patient 1 (family 1) was alive at age 32; patient 4 (family 2) underwent bone marrow transplant and was alive at age 24.

Ghawil et al. (2022) reported 4 patients from 2 unrelated consanguineous Libyan families with BMFDMS confirmed by genetic analysis. The patients, who ranged from 12 to 15 years of age, presented in early childhood with evidence of bone marrow failure manifest as anemia, macrocytosis, and thrombocytopenia. White blood cell counts remained normal. All were diagnosed with insulin-dependent diabetes mellitus between 6.3 and 9.7 years of age. Other features included short stature and abnormal skin pigmentation. All patients underwent successful hematopoietic bone marrow transplantation, which normalized the hematologic parameters, but did not resolve the diabetes. Of note, family members who were heterozygous for the mutation also showed skin nevi, but did not have diabetes or bone marrow failure.

Tummala et al. (2022) restudied a consanguineous Sudanese family, originally reported by Dufour et al. (1998), with BMFDMS. The proband presented at age 5 years with pancytopenia, hypocellular bone marrow with dyserythropoiesis that progressed to myelodysplasia with monosomy 7 (see 252270). At age 10 years, he developed insulin-dependent diabetes mellitus. He had skin pigmentation abnormalities, but no nail dystrophy. Family history was significant for 3 older sibs who died of bone marrow failure associated with diabetes. Another older sib was alive and had the same phenotype, although genetic material was not available from this individual.

The transmission pattern of BMFDMS in the families reported by Dos Santos et al. (2017) was consistent with autosomal recessive inheritance.

In 2 probands from 2 unrelated consanguineous families of French (family 1) and Egyptian (family 2) origin with BMFDMS, Dos Santos et al. (2017) identified a homozygous missense mutation in DUT gene (Y142C; 601266.0001). Both probands had a similarly affected sib, but genetic material was not available and family segregation studies were not performed. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state at low frequencies in the dbSNP, Exome Variant Server, and ExAC databases. There was also evidence for an ancestral European founder effect. The mutation occurred near a conserved region of the protein and was predicted to result in conformational changes that would impact protein function. DUT is a key enzyme for maintaining DNA integrity by preventing misincorporation of uracil into DNA, which results in DNA toxicity and cell death. In vitro studies of siRNA-mediated DUT inhibition in rat and human pancreatic beta-islet cells resulted in increased apoptosis via a mitochondrial-mediated intrinsic pathway. The authors concluded that the disease results from disruption of the DNA damage repair and cell-cycle pathways. Sequencing the DUT gene did not identify any mutations in cohorts of over 113 individuals with diabetes and/or bone marrow failure, suggesting that DUT mutations are rare.

In 4 patients from 2 unrelated consanguineous Libyan families with BMFDMS, Ghawil et al. (2022) identified a homozygous Y142C mutation in the DUT gene that segregated with the disorder in both families. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of the variant in patient cells were not performed.

In a male patient, born of consanguineous Sudanese parents, with BMFDMS originally reported by Dufour et al. (1998), Tummala et al. (2022) identified a homozygous Y142C mutation in the DUT gene. The mutation, which was found by exome sequencing, was present in the heterozygous state in each unaffected parent. Functional studies of the variant were not performed. Tummala et al. (2022) also identified compound heterozygous missense mutations in the DUT gene (R173W and Y227C) in a 16-year-old boy, born of unrelated Scottish parents, who had bone marrow failure and nail dystrophy, but no diabetes. He was ascertained from a cohort of 189 patients with features of dyskeratosis congenita who underwent exome sequencing. Familial segregation studies and functional studies of these variants were not performed. The patient had anemia, lymphopenia, splenomegaly, and dyserythropoiesis. He also had abnormal facies with small jaw and crowded teeth, short stature, hypogonadism, and nail dystrophy.