Diamond-Blackfan Anemia 6

A number sign (#) is used with this entry because Diamond-Blackfan anemia-6 (DBA6) is caused by heterozygous mutation in the gene encoding ribosomal protein L5 (RPL5; 603634) on chromosome 1p22.

Description

Diamond-Blackfan anemia (DBA) is an inherited red blood cell aplasia that usually presents in the first year of life. The main features are normochromic macrocytic anemia, reticulocytopenia, and nearly absent erythroid progenitors in the bone marrow. Patients show growth retardation, and approximately 30 to 50% have craniofacial, upper limb, heart, and urinary system congenital malformations. The majority of patients have increased mean corpuscular volume, elevated erythrocyte adenosine deaminase activity, and persistence of hemoglobin F. However, some DBA patients do not exhibit these findings, and even in the same family, symptoms can vary between affected family members (summary by Landowski et al., 2013).

For a discussion of genetic heterogeneity of Diamond-Blackfan anemia, see DBA1 (105650).

Clinical Features

Aase and Smith (1969) observed 2 brothers with congenital anemia and triphalangeal thumbs. Ventricular septal defect was thought to be present in 1 brother. Alter (1978), Gorlin et al. (1990), and Hurst et al. (1991) considered the syndrome reported by Aase and Smith (1969) to be the same as Blackfan-Diamond syndrome. Alter (1978) and Gorlin et al. (1990) referred to it as Aase-Smith syndrome II.

Gazda et al. (2008) reviewed available medical records for 20 of the 24 RPL5 mutation-positive DBA patients and found that 14 of 20 had physical malformations, including craniofacial, thumb, and heart anomalies, and 11 of them had multiple, severe abnormalities. Thumb abnormalities were seen in 8 patients; cleft lip and/or palate or cleft soft palate was seen in 9 patients, isolated or in combination with other facial malformations, such as micrognathia, hypertelorism, or mandibular hypoplasia with retrognathia, and/or with other physical abnormalities of the heart or thumb. One patient had melanoma.

Gerrard et al. (2013) reported 5 patients, including a mother and daughter, with DBA6. A 4-year-old Caucasian boy was diagnosed at age 7 weeks. He had growth retardation, cleft palate, esophageal strictures, eosinophilic esophagitis, triphalangeal thumbs, and hepatic iron overload. He was transfusion-dependent. A 39-year-old mother was diagnosed at 5 years of age. She had growth retardation, osteoporosis, thumb abnormalities, and hepatic iron overload. Her 10-year-old daughter had intrauterine growth retardation and fetal distress, and was diagnosed at birth. She had Cathie facies, cleft palate, ventricular septal defect, vitamin D deficiency, and iron overload. Both had increased erythrocyte adenosine deaminase (ADA; 608958). The mother's disorder was steroid-responsive, whereas the daughter developed secondary steroid resistance. The 2 other patients also had cleft palate; one was more severely affected with autism spectrum disorder, growth retardation, and neutropenia.

Molecular Genetics

Gazda et al. (2008) screened 196 probands with Diamond-Blackfan anemia for mutations in 25 genes encoding ribosomal proteins and identified 15 different mutations in the RPL5 gene in 18 probands and 6 additional family members (see, e.g., 603634.0001-603634.0006); 3 of the mutation-positive patients were from the family with DBA originally described by Aase and Smith (1969) (see 603634.0005). The mutations segregated with disease in multiplex families and were not found in at least 150 controls. Functional studies demonstrated defects in the maturation of ribosomal RNAs associated with mutation in the RPL5 gene. Gazda et al. (2008) stated that RPL5 was the first ribosomal protein gene to be associated with cleft lip and/or cleft palate abnormalities in DBA patients, and that mutations in RPL5 appeared to cause a more severe phenotype than mutations in RPL11 (604175) or RPS19 (603474).

Gerrard et al. (2013) identified 4 different heterozygous truncating mutations in the RPL5 gene (see, e.g., 603634.0007 and 603634.0008) in 5 of 19 patients with DBA who were screened for mutations in 80 ribosomal protein genes.