Knowledge on rare diseases and orphan drugs

The disease occurs predominantly in Southeast Asia. Prevalence at birth in this region is estimated to be between 1/200-2,000. Exact prevalence in other regions is not known.

Affected fetuses suffer from severe anemia in utero, causing severe tissue hypoxia, heart failure and a range of developmental abnormalities associated with hydrops fetalis (marked hepatosplenomegaly, urogenital and limb abnormalities). In survivors, the neonatal period is often stormy, and growth retardation and neurodevelopmental delay are the major adverse long-term outcomes. Maternal complications during pregnancy include preeclampsia, polyhydramnios or oligohydramnios, antepartum hemorrhage, and premature delivery. Although intrauterine transfusions and perinatal intensive care have resulted in increasing fetal survival to the perinatal period. Early therapeutic termination of at-risk pregnancies is usually recommended due to the severity of the syndrome and the risk of potentially serious maternal complications during pregnancy.

Bart's hydrops fetalis is caused by deletion or inactivation of all four alpha-globin alleles leading to a severe deficiency in alpha-globin chains of Hb, and to the production of gamma-4 tetramers (Hb Bart's) during fetal life, and beta-4 tetramers (HbH) postnatally. Hb Bart's and HbH have increased oxygen affinity resulting in ineffective tissue oxygen delivery. The disease is mostly the result of combined, biallelic deletions in the HBA1 and HBA2 genes (16p13.3).

The disease can be diagnosed on ultrasound as early as 10 weeks gestation, from ultrasonographic findings of hydrops fetalis followed by fetal DNA analysis and cord blood Hb electrophoresis revealing Hb Bart's.

The main differential diagnosis is hydrops fetalis without alpha-thalassemia, which is a common non-specific sign of numerous fetal or maternal disorders.

Prenatal genetic diagnosis is possible where the pathogenic variant has previously been identified in a family member.

The pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.

Death usually occurs in utero or shortly after birth, but fetuses can survive following intrauterine transfusions, and perinatal intensive care. Early intrauterine intervention leads to prolonged gestation, improved Apgar scores, and shortened neonatal mechanical ventilation, but with no clear additional benefits to long-term growth and neurodevelopment. After birth, patients require lifelong and intensive transfusion regimen, targeted at reducing HbH levels, and increasing functional HbA. Treatment is controversial since most treated infants surviving the immediate postnatal period subsequently show abnormal development. These patients may be considered for hematopoietic stem cell transplantation.

Most surviving infants experience a complicated perinatal course and a high prevalence of congenital urogenital and limb defects.

Last update: May 2021 - Expert reviewer(s): Dr Corinne PONDARRE