Diamond–Blackfan anemia (DBA) is a congenital erythroblastopenia with various malformations (40%). DBA inheritance is usually sporadic (55%). In ≈70% of DBA cases, mutations have been identified in various ribosomal protein (RP) genes. Most of the DBA cases are diagnosed in early infancy (median age at diagnosis: 2 months). Only 16% of the DBA cases have been diagnosed at birth and the diagnosis of most of these cases is due to careful follow-up of the newborn of a DBA pregnant mother. Hydrops fetalis is even more rare in DBA with only eight reported cases [1-6]. Five had a family history of DBA while the three others were diagnosed after birth. In none of these eight cases, the molecular basis for hydrops fetalis was explored. The case reported hitherto (EERB-RD, no. 2012/005 ethical committee approval) is the first DBA fetus identified with a mutation in RPS19 gene and hydrops fetalis. This is the first child of unrelated healthy Caucasian parents without family history of DBA. The first sign of anemia was noted at 32 weeks of amenorrhea with an increased Doppler velocity in the fetal middle cerebral artery, but without any edema. No malformations, infection, nor immunologic causes have been documented. The fetus was small for the gestational age (5th to 10th percentile). In utero, death was discovered few days later. The fetus weight, height, and cranial perimeter were compatible with a gestational age of 34 weeks. The fetus exhibited short arm extremities and extensive edema in almost all the tissues with the exception of the kidneys and the thymus, which was hypoplastic. The bone marrow examination of a fetal rib exhibited erythroblastopenia (Supporting Information Fig. 1A). Strikingly, we identified a nonsense heterozygous mutation in exon 2 of the RPS19 gene, designated as c.13dup; p.Thr5AsnfsX46 (Supporting Information Fig. 1B). This allelic variation has not been identified either in 600 controls chromosomes or in all the Single Nucleotide Polymorphism (SNP) websites available. Threonine 5 is a highly conserved amino acid from archeobacteria to plants, and mammals. Normal erythrocyte Adenosine DeAminase (eADA) activity and the absence of mutations in RPS19 gene (sporadic mutation) in both parents implies that neither of them are silent DBA.
In conclusion, we report the first case of a mutation in a ribosomal protein gene resulting in hydrops fetalis in DBA. The present finding implies that DBA can occur during fetal development. It is likely that the DBA cases diagnosed after birth may be the less severe ones, the severely affected DBA fetus likely die due to hydrops fetalis and result in undiagnosed miscarriages. The present case validates the importance of the measurement of blood flow velocity in the middle cerebral artery as a gold standard during the pregnancy and the necessary regular follow-up. The identification of a mutation and the confirmation of the DBA diagnosis in case of a hydrops fetalis may be very helpful in the genetic counseling. DBA may be one of the causes of hydrops fetalis and this possibility needs to be taken into account for evaluations of anemia during fetal development.