DiGeorge syndrome (22q11.2 deletion syndrome)
DiGeorge syndrome (22q11.2DS), is the most common microdeletion syndrome in humans, with a prevalence of approximately 1 in 4,000 live births.
It is an autosomal dominant condition caused by a microdeletion on the long arm of chromosome 22 at band q11.2, which typically involves the loss of 30-40 genes, including TBX1.
This gene is a key transcription factor for the development of the pharyngeal arches and is thought to be responsible for many of the syndrome’s characteristic features.
While it is an inherited condition with a 50% chance of transmission from an affected parent, over 90% of cases are due to a de novo mutation.
Clinical Features and Diagnosis
The clinical presentation is highly variable, even among family members, but a classic triad is often described:
Cardiac anomalies: The most common and often life-threatening feature, present in up to 85% of cases. Conotruncal heart defects are most frequent, including Tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus.
Hypocalcaemia: Resulting from hypoparathyroidism, this can lead to seizures and tetany, especially in the neonatal period.
Thymic hypoplasia: Leading to T-cell immunodeficiency and a predisposition to recurrent infections.
Other common features include:
Palatal abnormalities: Such as a submucous cleft palate or velopharyngeal insufficiency, which can lead to hypernasal speech and feeding difficulties.
Dysmorphology: Subtle facial features (e.g., hooded eyelids, bulbous nose, small ears), though these are not always present.
Developmental and neuropsychiatric issues: Learning disabilities, developmental delay, and an increased risk of attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), anxiety, and schizophrenia in later life.
Renal anomalies: Structural abnormalities are common.
Diagnosis is confirmed by a genetic test, such as chromosomal microarray analysis or fluorescence in situ hybridisation (FISH), to detect the 22q11.2 deletion. In the UK, a referral to the NHS Genomic Medicine Service is the standard pathway for testing.
Management
Management is multidisciplinary and lifelong. Key aspects include:
Initial Neonatal Assessment: Urgent management of cardiac defects and hypocalcaemia is paramount. Blood products for transfusion should be irradiated, CMV-negative, and leukocyte-reduced to prevent transfusion-associated graft-versus-host disease in severely immunocompromised patients.
Immunology: For the rare but life-threatening severe immunodeficiency (complete DiGeorge syndrome, cDGS), which occurs in ~1% of patients, management involves isolation, prophylactic antibiotics, and potential thymic or hematopoietic stem cell transplant. For the majority with partial immunodeficiency, the immune function improves with age. Live vaccines are typically avoided in patients with severely reduced T-cell counts.
Cardiology: Regular echocardiograms are necessary. Patients may require early surgical intervention for congenital heart defects.
Endocrinology: Regular monitoring of serum calcium and parathyroid hormone levels. Hypocalcaemia is managed with calcium and vitamin D supplementation.
ENT/Speech and Language Therapy: A referral to a cleft and maxillofacial service is essential for palatal abnormalities. Speech therapy is crucial for communication development.
Developmental Paediatrics: Early intervention services and educational support are vital to address developmental delays and learning difficulties.
Recent Developments
Updated Clinical Practice Recommendations: Recent systematic reviews, such as those published in Genetics in Medicine in 2023, have updated management guidelines for both children and adults with 22q11.2DS, highlighting the need for ongoing surveillance for a wide range of conditions, including psychiatric illnesses and autoimmune diseases.
Novel Therapies and Research: There is a growing focus on targeted therapies. Researchers are exploring gene-editing technologies like CRISPR to correct the underlying genetic deletion and stem cell-based therapies to restore thymus function.
Pharmacological Treatments: Drug development is ongoing, particularly for neuropsychiatric symptoms. For example, a small-molecule metabotropic glutamate receptor (mGluR) modulator, NB-001, has received Orphan Drug Designation from the FDA for treating these symptoms.
Improved Diagnosis: The use of advanced diagnostic technologies like Next-Generation Sequencing (NGS) and chromosomal microarray analysis, often combined with AI and machine learning algorithms, is improving diagnostic sensitivity and allowing for earlier and more precise management.