What dysmorphic features are common in children with Diamond‑Blackfan anemia and how should they be screened and managed?

Dysmorphic Features in Diamond-Blackfan Anemia

Children with Diamond-Blackfan anemia (DBA) present with craniofacial dysmorphisms in approximately 50% of cases, most commonly including hypertelorism, flat nasal bridge, cleft lip/palate, micrognathia, and low-set ears, along with upper limb malformations such as triphalangeal or bifid thumbs and radial hypoplasia. 1, 2, 3

Common Dysmorphic Features

Craniofacial Abnormalities

• Facial dysmorphisms occur in roughly half of DBA patients and include hypertelorism (wide-set eyes), flat or broad nasal bridge, micrognathia (small jaw), cleft lip and/or palate, and low-set or malformed ears 1, 2
• These craniofacial features may be subtle and require careful examination by a clinician experienced in dysmorphology 1

Upper Limb Malformations

• Radial ray defects are the hallmark skeletal abnormality, including triphalangeal thumbs, bifid (duplicated) thumbs, absent or hypoplastic thumbs, and radial hypoplasia or aplasia 3
• Upper limb malformations occur in approximately 40% of patients with congenital anomalies 1, 3

Growth Abnormalities

• Short stature is present in a significant proportion of DBA patients, often related to both the underlying condition and growth hormone deficiency 2

Other Associated Anomalies

• Cardiac defects, genitourinary malformations, and eye abnormalities may occur but are less common than craniofacial and limb defects 1, 3

Screening Approach

Initial Clinical Assessment

• Examine all infants presenting with macrocytic anemia and reticulocytopenia for the characteristic dysmorphic features, even if subtle, as 25% of DBA cases have no obvious physical anomalies 1, 4
• Document presence or absence of: thumb abnormalities (triphalangeal, bifid, hypoplastic, or absent), radial abnormalities, facial features (hypertelorism, flat nasal bridge, micrognathia, cleft palate), and short stature 1, 3

Laboratory Confirmation

• Elevated erythrocyte adenosine deaminase (eADA) is present in approximately 85% of DBA patients and supports the diagnosis 5
• Complete blood count reveals macrocytic anemia with reticulocytopenia and normal white blood cell and platelet counts in classic cases 1, 4
• Bone marrow examination shows selective reduction or absence of erythroid precursors 4

Genetic Testing

• Genetic screening for ribosomal protein gene mutations should be performed in all suspected cases, as mutations in RPS19 account for 25% of cases, with other ribosomal protein genes accounting for an additional 25% 1, 4, 3
• Genomic analysis is particularly valuable in patients with nonclassical presentations (normocytic anemia, mild transfusion-independent anemia) where the diagnosis may not be immediately apparent 5
• Test both the patient and parents, as approximately 45% of cases are familial with autosomal dominant inheritance, though 55% are sporadic de novo mutations 1, 4

Management Considerations

Multidisciplinary Surveillance

• Involve pediatric endocrinology early to monitor for growth hormone deficiency and manage short stature 2
• Cardiac evaluation with echocardiography should be performed at diagnosis given the association with congenital heart defects 2
• Ophthalmology and audiology assessments are warranted if craniofacial anomalies are present 2

Hematologic Management

• Glucocorticoid therapy is first-line treatment, with approximately 80% of patients responding initially 2
• Chronic red blood cell transfusions are required for steroid-refractory patients, necessitating iron chelation therapy 2
• Allogeneic hematopoietic stem cell transplantation remains the only curative option for the hematologic phenotype 2

Cancer Surveillance

• Lifelong monitoring for malignancy is essential, as DBA patients have increased predisposition to myelodysplastic syndrome, acute myeloid leukemia, and solid tumors 1, 2

Clinical Pitfalls

• Do not exclude DBA based on absence of congenital anomalies, as approximately 50% of patients have no physical malformations and present solely with anemia 1
• Do not dismiss the diagnosis in patients with normocytic rather than macrocytic anemia, as nonclassical presentations occur and require genomic analysis for confirmation 5
• Recognize that the phenotype is highly variable even within families carrying the same mutation, requiring individualized assessment 1, 4