Congenital Dyserythropoietic Anemia Type I

CLINICAL CHARACTERISTICS

Congenital dyserythropoietic anemia type I (CDA I) is characterized by moderate-to-severe macrocytic anemia presenting occasionally in utero as severe anemia associated with hydrops fetalis but more commonly in neonates as hepatomegaly, early jaundice, and intrauterine growth restriction. Some individuals present in childhood or adulthood. After the neonatal period, most affected individuals have lifelong moderate anemia, usually accompanied by jaundice and splenomegaly. Secondary hemochromatosis develops with age as a result of increased iron absorption even in those who are not transfused. Distal limb anomalies occur in 4%-14% of affected individuals.

DIAGNOSIS/TESTING: The diagnosis of CDA I is suspected based on hematologic findings and established with identification of biallelic pathogenic variants in or .

MANAGEMENT

Intramuscular or subcutaneous injections of interferon IFN-α2a or IFN-α2b are given two or three times a week or peginterferon-α2b once a week to increase hemoglobin and decrease iron overload. Allogeneic bone marrow transplantation should be considered only in transfusion-dependent persons who are resistant to IFN therapy. Treatment of iron overload using iron chelation as necessary; laparoscopic cholecystectomy for biliary stones; treatment of scoliosis per orthopedist; calcium and vitamin D supplementation for osteoporosis; treatment of extramedullary hematopoiesis including regular blood transfusions, surgical debulking, or low-dose radiation; treatment of vision issues per ophthalmologist. Measurement of hemoglobin every three to six months and more frequently at the time of infections, measurement of bilirubin, iron, transferrin, and serum ferritin concentration every six to 12 months starting at age ten years to monitor anemia and iron overload; annual myocardial and liver T-weighted MRI starting at age ten years (if available). Annual abdominal ultrasound beginning at age five years; examination for scoliosis with orthopedist as needed; bone densitometry for osteoporosis as recommended by bone specialist; annual assessment of visual acuity and fundoscopic examination by ophthalmologist beginning at age 40 years or earlier if symptomatic. Any preparation containing iron.

GENETIC COUNSELING

CDA I is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CDA I-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.