Shwachman-Diamond Syndrome 2

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

Description

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).

Clinical Features

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.

Molecular Genetics

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.