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Conditions

Diamond-Blackfan anaemia syndrome

Diamond-Blackfan anaemia syndrome is a rare congenital hypoplastic anaemia that often presents in infancy. A significant proportion of patients also have congenital malformations and growth deficiency. It is associated with an increased risk of malignancy.

Overview

Diamond-Blackfan anaemia syndrome (DBA syndrome or DBAS) is a clinically variable and genetically heterogenous condition resulting from disordered ribosome biogenesis and function. It often presents in the first year of life with clinically significant anaemia requiring red blood cell transfusion, but can also manifest in later childhood or in adult life, usually with anaemia. Around 50% of patients have congenital malformations (craniofacial, thumb, cardiac and/or urogenital).

Clinical features

DBAS is a variable condition and patients may present with a combination of anaemia, growth failure and congenital anomalies.

Anaemia usually presents in the first year of life (median age of three months) and typical features include:

  • pallor, weakness, failure to thrive;
  • macrocytic anaemia with reticulocytopaenia.

Growth deficiency is observed in 30% of those affected.

Congenital malformations are observed in 30%–50% and can include:

  • craniofacial: microcephaly, wide set eyes (hypertelorism), small chin (micrognathia), low frontal hairline, low set ears, small ears (microtia), cleft palate, cleft lip, short neck, webbed neck;
  • skeletal: thumb/radial anomalies, pectus excavatum;
  • cardiac: ventricular septal defects, atrial septal defects, coarctation of aorta, other complex cardiac anomalies;
  • urogenital tract: hypospadias, absent kidney, horseshoe kidney;
  • eyes: squint (strabismus), congenital cataract, congenital glaucoma; and/or
  • neurodevelopmental/learning difficulties.

In some cases congenital abnormalities without anaemia occur. In the most severe cases, DBAS presents in pregnancy, with non-immune hydrops fetalis requiring in-utero transfusion.

DBAS can also present in later childhood or adulthood, usually with anaemia of variable severity.

Genomics

DBAS is a heterogeneous condition with pathogenic variants in over 25 genes known to be associated with the condition. Most cases are autosomal dominant, but there are also two known X-linked genes and one autosomal recessive gene that can be causative.

In the autosomal dominant form of the disease, the genes encode ribosomal proteins. The most commonly affected gene is RPS19: 20%–25% of people with DBAS have pathogenic variants in this gene. Autosomal dominant variants can be inherited from a parent, or arise for the first time in an individual due to a de novo variant. Other genes linked with autosomal dominant DBAS include RPL11, RPL15, RPL31, RPL35A, RPL5, RPS10, RPS17, RPS24, RPS26 and RPS7.

In the X-linked form of the disease, pathogenic variants are seen in GATA1, an erythroid transcription factor, or TSR2, a ribosomal maturation factor.

Biallelic pathogenic variants in HEATR3 are associated with autosomal recessive DBAS.

Genomic variants include single nucleotide changes (start codon, nonsense, indels or splice-site mutations), missense mutations (especially in RPS genes) and genomic deletions (exonic, whole gene or multigenic), leading to haploinsufficiency and defective ribosome assembly.

In 20% of classical cases, the underlying genetic cause has not yet been identified. Additional causative gene variants or other types of genomic variants (such as non-coding regulatory variants) may be discovered.

Diagnosis

Typical findings

Features typically seen, but not mandatory for diagnosis, include:

  • disease onset under the age of one;
  • reticulocytopaenia and macrocytosis;
  • elevated erythrocyte adenosine deaminase activity (before first transfusion, in patients who have not received a transfusion, or in parents of patients);
  • elevated foetal haemoglobin HbF (reliably assessed in patients older than six months);
  • positive family history or unexplained history of anaemia during infancy or childhood;
  • congenital anomalies; and
  • abnormal ribosomal RNA processing in cells.

Diagnostic criteria

  • A pathogenic or likely pathogenic variant in a DBAS-associated gene (see Wlodarski and others, appendix p 4); or
  • haematological features consistent with DBAS: macrocytic anaemia with reticulocytopaenia and bone marrow erythroblastopaenia; absence of dysplasia, dyserythropoiesis, and sideroblasts.

Note that a diagnosis should only be made following the exclusion of known differential diagnoses.

Differential diagnosis

  • Transient erythroblastopaenia of childhood.
  • Other inherited bone marrow failure syndromes, such as Shwachman-Diamond syndrome, Fanconi anaemia, Pearson syndrome.
  • Adenosine deaminase 2 deficiency.
  • EPO dysfunction.
  • Acquired causes, such as drugs or other toxins.
  • Infections, such as parvovirus B19, HIV, Epstein-Barr virus or cytomegalovirus.
  • Immune-mediated diseases.
  • Thymoma with pure red cell aplasia.
  • In adults, pregnancy, or malignancies including myelodysplastic syndrome.

For information on genetic testing, see Presentation: Child with anaemia.

This condition may be identified before any symptoms appear, for example through the Generation Study. Confirmation of the diagnosis will require referral to haematology. Please refer to the local pathway for your region for this condition.

Inheritance and genomic counselling

DBAS is a rare congenital disorder with an incidence of seven per million live births. Most often DBAS is inherited in an autosomal dominant manner; however, there are two known X-linked causes and one autosomal recessive cause.

Clinical severity can vary even with the same variant in the same family. Generally penetrance is high, especially for loss-of-function variants.

For autosomal dominant inheritance:

  • Individuals affected by an autosomal dominant condition have one working copy of the gene, and one with a pathogenic variant.
  • The chance of a child inheriting the gene with the variant from an affected parent is 1 in 2 (50%).
  • Incomplete penetrance can occur when not everyone who has the variant develops the disease.

In about 45% of autosomal dominant DBAS cases, the patient will have inherited the causative genetic variant from a parent, while in 55% of cases it will have arisen de novo.

For autosomal recessive inheritance (typically only HEATR3):

  • If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:
    • 1-in-4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected;
    • 1-in-2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
    • 1-in-4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.

For X-linked recessive inheritance (typically GATA1 or TSR2):

  • X-linked recessive conditions are usually only present in males.
  • Males with X-linked conditions cannot pass the variant on to their sons, but they always pass their affected X chromosome to their daughters. If the condition is recessive, their daughters will be carriers for the condition.
  • Female carriers of X-linked recessive conditions have a second, working copy of the gene and are therefore usually unaffected, or affected only mildly.
  • Sons of female carriers of X-linked recessive conditions have a 1-in-2 (50%) chance of being affected by the condition, and their daughters have a 1-in-2 (50%) chance of being carriers.

Genetic testing in early pregnancy or pre-implantation genetic testing (an IVF-based technique) are available. Pre-conception genetic counselling is recommended. Pregnancy management for people with DBAS should involve both obstetrics and haematology.

The underlying genetic aetiology of 20% of cases of DBAS has not yet been found, so a negative genetic test does not rule out a clinical diagnosis. Reproductive counselling in these cases would need to cover all known mechanisms.

Management

The management of patients with DBAS is complex and should be delivered via a multidisciplinary team; detailed suggested approaches have been published by several authors. Broadly, management may include those listed below.

For the treatment of anaemia:

  • blood transfusions are usually needed for children before one year of age;
  • corticosteroids are recommended for children over one year old (steroids may be continued for a prolonged period of time if there is a response, but steroid toxicities should be monitored);
  • in those who are resistant to steroids, they will need regular blood transfusions and management of iron overload with chelation; or
  • allogeneic hematopoietic stem cell transplantation, which is the only curative option for DBAS, is recommended for patients who are steroid resistant and need regular blood transfusions, if there is a match with a related or unrelated donor.

After initial diagnosis, patients will require a comprehensive work-up to manage known complications of the condition as well as monitoring for future complications. This might include:

  • orthopaedic review, if there is a known skeletal anomaly;
  • ophthalmology review, for risk of congenital glaucoma and cataract;
  • echocardiogram, as DBAS patients have a higher risk of congenital heart disease, including ventricular septal defect, atrial septal defect and coarctation of the aorta;
  • renal ultrasound, as a proportion of patients have an absent kidney or horseshoe kidney;
  • endocrinology review, for those who are steroid or transfusion dependent; and/or
  • referral to genetics services, for genetic counselling to cover reproductive advice and potential testing of first-degree relatives.

Patients with DBAS are at increased risk of malignancy, such as acute myeloid leukaemia, myelodysplastic syndrome, and solid tumours including colorectal cancer and osteogenic sarcoma. Full blood count should be monitored closely to check for additional cytopaenias. Patients should also be made aware of signs to look out for and when to seek medical attention.

A diagnosis of DBAS puts a huge strain on patients and their families. People should therefore be directed towards support groups, such as those listed under ‘Resources for patients’ below.

This condition may be identified before any symptoms appear, for example through the Generation Study. Management of these individuals may differ to management of patients who present symptomatically.

Resources

For clinicians

References

For patients

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  • Last reviewed: 23/02/2026
  • Next review due: 23/02/2028
  • Authors: Dr Yashashree Gupta
  • Reviewers: Dr Eleanor Hay, Dr Deena Iskander, Dr Anne Kelly, Dr Joanna Kennedy, Dr Hannah Massey