DiGeorge syndrome: consider the diagnosis (2024)

Abstract

DiGeorge syndrome (DGS) is caused by a chromosomal microdeletion at 22q11.2 that results in impaired development of the pharyngeal pouch system. Patients with DGS may have developmental abnormalities of craniofacial structures, parathyroid glands, thymus and cardiac outflow tract. Doctors have been routinely testing for DGS in newborns with conotruncal cardiac anomalies since the late 1990s; before then, however, they relied on complex diagnostic criteria and the disease was often missed. Adults born with conotruncal defects before the late 1990s may have undiagnosed DGS. We present one such case: a 35-year-old woman with a cardiac diagnosis of tetralogy of Fallot and unilateral absence of a pulmonary arter who was found to have DGS. Identifying DGS in adults is important both for disease management and genetic counselling. Our case emphasises the importance of screening for DGS in adults who were born with conotruncal cardiac abnormalities before widespread neonatal testing became common.

Keywords: dermatology, immunological products and vaccines, infections

Background

DiGeorge syndrome (DGS) involves a constellation of features that arise due to a heterozygous microdeletion of chromosome 22q11.2 that leads to impaired development of the pharyngeal pouch system. Clinical manifestations can be traced back to developmental abnormalities of these structures, which contribute to development of craniofacial structures, parathyroid glands, thymus and cardiac outflow tract.¹ Variations in the length and specific genetic makeup in the deletion mean people with DGS can have a broad range of phenotypes.¹ The most common clinical manifestations include conotruncal cardiac abnormalities, immunodeficiency from impaired thymus development, palatal abnormalities, hypoparathyroidism and intellectual disability.²

Case presentation

Our patient was a 35-year-old woman who was initially referred to a cardiologist at 6 months of age after a heart murmur was noticed. Catheterisation and aortogram were performed and confirmed the diagnosis of tetralogy of Fallot (TOF) and revealed an absent left pulmonary artery. She had infundibular and valvar pulmonic stenosis accompanied by a single malalignment ventricular septal defect. A single right coronary artery was found to arise anteriorly. Surgery was performed at 9 months of age. A single right coronary artery was found to arise anteriorly. Surgery was performed at 9 months of age. The patient’s other past medical history was notable for cleft lip and cleft palate, frequent respiratory infections, thoracolumbar scoliosis, hypothyroidism and mild learning disability. Of note, the patient has no known family history of congenital heart disease or DGS.

She did well clinically with intermittent cardiac follow-up. At the age of 35, she presented for a cardiology follow-up appointment for routine testing.

Investigations

Echocardiogram that showed worsening pulmonary stenosis with a right ventricular systolic pressure of 136 mm Hg. CT scan showed known unilateral absence of the left pulmonary artery and a patent right pulmonary artery (figure 1).

Differential diagnosis

Pulmonary stenosis is most frequently associated with congenital heart disease. Pulmonary stenosis is usually accompanied by other congenital heart anomalies, most commonly as part of TOF. TOF is frequently associated with DGS, but other syndromic associations include Down syndrome and Alagille syndrome (a disorder of biliary drainage), neither of which were suspected in our patient.

Treatment

Catheterisation was performed with placement of two bare metal stents in the right ventricular outflow tract followed by an 18 mm Melody valve. At the postprocedure appointment, the physician discussed the possibility of DGS and recommended genetic testing. Fluorescent in situ hybridisation (FISH) was positive for 22q11.2 microdeletion. The patient’s mother and father were tested and were both found not to be carriers.

Outcome and follow-up

Despite her condition, our patient leads a productive life, living independently and working as a professional photographer.

Discussion

DGS involves a constellation of features that arise due to a heterozygous microdeletions of chromosome 22q11.2 and is found in 1 in 4000–6000 live births.^{3 4} The majority of affected individuals (85%) have a 2.54 Mb deletion encompassing approximately 40 genes; a subset of individuals have a smaller atypical or ‘nested’ deletion.⁵ Approximately 5% of individuals will have a smaller, recurrent 1.5 Mb deletion, and 7% will have one of two recurrent smaller microdeletions within this region.⁵ DGS may be passed down in an autosomal dominant manner, though 90% of cases of cases are attributable to de novo microdeletions.⁶ DGS was first identified in 1968 and the underlying genetics were determined in 1981. In the absence of widely available genetic testing, a complex set of diagnostic criteria were used to establish the diagnosis. In 1982, FISH was discovered and, over the next 10–20 years, became widely available for use.⁷ By the late 1990s, doctors were routinely using FISH to screen newborns with conotruncal cardiac anomalies for DGS.⁷ FISH is now replaced by comparative genomic hybridisation (CGH) to interrogate the entire genome rather than just 22q11.2 region.⁸ Regardless of the testing modality, most patients in high-resource countries who were born in the last 20–25 years who had conotruncal cardiac anomalies or other concerning features of DGS had genetic testing available to them at birth. However, there remains an entire generation of adults, like our patient, who were born before genetic screening for DGS was available. Adults over 53 in 2021 were born before the disease had even been described. Without the simple diagnostic tool of genetic studies, the disease was often missed. Genetic testing has shown that DGS was underdiagnosed during the 1980s and 1990s.⁹

Diagnosing DGS in adults is important both for disease management and for genetic counselling. Optimal long-term management of patients with DGS requires careful monitoring for syndromic manifestations such as immunodeficiency, parathyroid insufficiency and psychiatric conditions.^10–12 Although regular prophylactic antibiotics are not specifically indicated for patients with DGS, knowledge of the diagnosis can help providers have a low threshold for early intervention if signs of infection are present.¹⁰ The medical team should be aware that patients with DGS are at higher risk for opportunistic organisms and consider this when selecting an antibiotic and determining duration of therapy.¹¹ Making the diagnosis of DGS is also important for the purposes of genetic counselling. The parents and siblings of affected patients may also be offered genetic testing, especially if they have symptoms of DGS.⁹ In a retrospective review of 126 adults diagnosed with DGS, 60% were only diagnosed after their children had the diagnosis established.¹³ Patients should be counselled that their children will have a 50% chance of inheriting the condition and diagnostic discussions, including prenatal and preimplantation options should be reviewed with them.¹³

The task of making the diagnosis in adults falls to doctors of all specialties. Among 50 adults diagnosed with DGS, initial referral for genetic testing came from primary care doctors, cardiologists, craniofacial surgeons, endocrinologists, neurologists and psychiatrists.¹³ In order to help identify patients for whom genetic testing would be appropriate physicians should familiarise themselves with the widely ranging clinical presentation of adults with DGS.

The most common symptoms of DGS include immune dysregulation, craniofacial abnormalities, hypoparathyroidism, learning disability, psychiatric disorders and cardiac anomalies.⁵ Roughly 75% of patients with DGS have some degree of immune dysfunction, which can present with recurrent, severe respiratory infections.⁵ Immune dysregulation also leads to autoimmune disease in 10% of patients, the most common being juvenile rheumatoid arthritis, vitiligo and Grave’s disease.¹⁴ Common craniofacial abnormalities include palatal malformations, velopharygeal insufficiency, prominent nasal bridge, micrognathia, asymmetric facies and bulbous nose.⁵ Learning disabilities occur in the majority of patients: 75% have some form of intellectual disability.¹⁵ In 50%–60% of people with DGS, dysgenesis of the parathyroid glands leads to hypoparathyroidism and chronic hypocalcaemia.^{10 11} Patients are also at high risk of psychiatric disorders including anxiety, depression and ADHD.^{12 16} Schizophrenia is common: 25% of patients receive the diagnosis at some point.¹⁷ As many as 75% of people with DGS are born with some form of cardiac defects.¹⁸ The most common findings are ventricular and atrial septal defects, truncus arteriosus, interrupted aortic arch, vascular rings and TOF.^{15 18}

We agreed that the discussion of genetic testing should be expanded. We have expanded the discussion section to include the following information: in high-income countries, nearly all infants are screened at birth for disorders of T cell development by analysing T cell receptor excision circles (TRECS).¹⁹ This test may be abnormal in patients with DGS and triggers expanded testing.^{19 20} In patients with clinical symptoms suggestive of DGS who have normal TRECS, physicians may order tests specifically aimed at identifying DGS.¹⁹ Testing has traditionally been performed with FISH; however, more sensitive tools of analysis have emerged in recent years.²¹ CGH and single-nucleotide polymorphism are increasingly replacing FISH, as they are both more sensitive and have the advantage of evaluating the entire genome.²¹ Another option is multiplex ligation-dependent probe amplification, which is a variant of PCR which uses a single primer pair to identifying multiple targets.²⁰ Although most cases of DGS are sporadic, parents should be referred for genetic testing.

Our patient was tested at a cardiology clinic because a physician recognised that her cardiac abnormalities and craniofacial abnormalities might be part of a larger syndrome. Through the 2018 Guidelines for the Care of the adult congenital heart disease patient, the American Heart Association and American College of Cardiology state that testing for DGS is reasonable for adults with congenital conotruncal heart defects.²² Other physicians can help diagnose DGS by recognising symptomatology and ordering genetic testing when appropriate.

Footnotes

Ethics statements

References