A number sign (#) is used with this entry because of evidence that Shwachman-Diamond syndrome-2 (SDS2) is caused by homozygous or compound heterozygous mutation in the EFL1 gene (617538) on chromosome 15q25.

Shwachman-Diamond syndrome-2 (SDS2) is characterized by exocrine pancreatic dysfunction, hematopoietic abnormalities, short stature, and metaphyseal dysplasia (Stepensky et al., 2017).

For a discussion of genetic heterogeneity of Shwachman-Diamond syndrome, see SDS1 (260400).

Stepensky et al. (2017) reported a 6-year-old Mexican boy and his 4-year-old sister (family A) who had short stature, mild global developmental delay, severe myopia, exocrine pancreatic insufficiency, and bilateral genu varum. Skeletal survey showed metaphyseal widening and irregularity, especially in the ribs and femurs. Both sibs had neutropenia, which was intermittent in the sister and persistent in the brother, who also had an unspecified antibody deficiency with poor immune memory and was hospitalized multiple times with severe respiratory infections. In addition, the brother had hypotonia, subglottic stenosis, posterior laryngeal cleft, and laryngomalacia, with poor feeding and poor growth in infancy as well as diarrhea and constipation. The authors also studied 3 affected sibs (family B) and 1 affected girl (family C) from 2 unrelated consanguineous Palestinian Muslim families. All 3 exhibited severe failure to thrive in the first year of life. They had diarrhea and steatorrhea due to exocrine pancreatic insufficiency, with low stool elastase levels, low blood lipase and elastase, decreased vitamin E, and abnormal coagulation tests. Other features included hypotonia, severe neurodevelopmental delay, microcephaly, low-set ears, high-arched palate, rhizomelic shortening of the limbs, and short fingers. Two of the sibs and the unrelated girl died between 7 months and 15 months of age, whereas the remaining sib, who received pancreatic enzyme replacement from early infancy, was alive at age 15 months. Laboratory evaluation in the Palestinian patients showed progressively profound neutropenia, progressive normocytic anemia with low reticulocyte count, and fluctuating thrombocytopenia. Abdominal ultrasound showed hyperechogenic pancreas, consistent with fatty infiltration. Skeletal x-rays revealed irregular metaphyses of the long bones and cupping of anterior ribs. Brain MRI was performed in 1 of the patients and was normal.

Tan et al. (2018) reported a patient with a history of intrauterine growth restriction and neonatal thrombocytopenia. She presented at 22 months of age with failure to thrive, short stature, and transaminitis. Liver biopsy showed periportal bridging and centrilobular fibrosis. She had mild intermittent thrombocytopenia from 2 to 5 years of age and an episode of neutropenia with fever at 9 years of age. Bone marrow biopsy showed low cellularity. Skeletal survey at 6 years of age demonstrated scoliosis and metaphyseal dysplasia of the corner fracture type (184255). She had recurrent hematuria at 4 and 7 years of age with hypercalciuria. She was diagnosed with learning disabilities in the second grade. At 14 years of age she was diagnosed with mild pancreatic insufficiency.

Tan et al. (2019) reported 3 patients with SDS. Patient 1, aged 31 years, presented with thrombocytopenia at 17 years of age and developed pancytopenia at 30 years of age. Bone marrow biopsy at 28 years of age showed a neutrophil segmentation defect. He had evidence of pancreatic insufficiency at 27 years of age and pancreatic lipomatosis detected on MRI. He also had portal hypertension and splenomegaly with evidence of fibrosis on CT scan. Skeletal abnormalities included metaphyseal chondrodysplasia identified at 29 years of age and abnormal tooth enamel. Patient 2, aged 14 years, presented at 1.5 years of age with failure to thrive. She had severe neutropenia, and a bone marrow biopsy at 8 years of age showed a neutrophil segmentation defect. She had evidence of pancreatic dysfunction at 5 years of age. She did not have skeletal abnormalities but she had short stature and growth hormone deficiency. She also had severe myopia, nystagmus, and low visual acuity. Patient 3, aged 8 years, presented at 1.2 months of age with anemia and failure to thrive. She had evidence of pancreatic insufficiency at 6 months of age and hyperechogenicity on ultrasound. She also had metaphyseal dysplasia and short stature with growth hormone deficiency.

Lee et al. (2021) reported 3 unrelated patients, aged 3, 9, and 25 years, with SDS2. All 3 patients had pancreatic lipomatosis, and 2 patients had exocrine pancreatic insufficiency. Two patients had anemia and neutropenia, and all 3 had thrombocytopenia. All 3 patients had metaphyseal chondrodysplasia, osteopenia or osteoporosis, and developmental delay.

The transmission pattern of SDS2 in the families reported by Stepensky et al. (2017) was consistent with autosomal recessive inheritance.

In 2 Mexican sibs (family A) and 3 sibs and 1 unrelated girl from 2 Palestinian Muslim families (B and C) with exocrine pancreatic dysfunction, hematopoietic abnormalities, short stature, and metaphyseal dysplasia, Stepensky et al. (2017) performed whole-exome sequencing that excluded mutation in the SBDS gene (260400) and identified 2 different homozygous missense mutations in the EFL1 gene that segregated with disease in the respective families: an M882K substitution (617538.0001) in the Mexican family, and an R1095Q substitution (617538.0002) in the Palestinian Muslim families.

Tan et al. (2018) identified a homozygous mutation in the EFL1 gene (617538.0003) in a 14-year-old girl with SDS2. The mutation, which was identified by trio whole-exome sequencing, was present in heterozygous state in the parents. Functional studies were not performed.

By whole-exome sequencing followed by Sanger sequencing, Tan et al. (2019) identified mutations in the EFL1 gene in 3 patients with SDS2: compound heterozygous mutations (617538.0004-617538.0005) in patient 1, a homozygous mutation (617538.0006) in patient 2, and a single heterozygous mutation (617538.0007) inherited from the father in patient 3. There was near absence of detectable mRNA transcripts from the maternal allele in patient 3, suggesting a noncoding mutation in the maternal allele affecting EFL1 expression. Tan et al. (2019) demonstrated that the EFL1 mutations resulted in impaired eIF6 release from the late 60S cytoplasmic subunit, causing defective ribosomal subunit joining and reduced global protein synthesis.

In 3 Korean patients with SDS2, Lee et al. (2021) identified compound heterozygous mutations in the EIF1 gene (617535.0008-617535.0010); one of the mutations (T1069A; 617538.0008) occurred in all 3. All 3 patients also had somatic partial loss of heterozygosity (LOH) of chromosome 15, including the EIF1 gene, in bone marrow-derived cells, resulting in homozygosity for the T1069A allele in some cells. In patients I-1 and III-1, this loss of heterozygosity was not observed in non-bone marrow-derived cells. Lee et al. (2021) concluded that the LOH on chromosome 15 and homozygosity for a relatively milder mutation resulted in avoidance of catastrophic consequences. EFL1 -/- HeLa cells exhibited a partial rescue of ribosome assembly when transfected with EFL1 with the T1069A mutation, suggesting that this mutation is hypomorphic.