DiGeorge syndrome (DGS) is a congenital disorder caused by a microdeletion on the long arm of chromosome 22 (22q11.2 deletion). It was first reported by Dr. Angelo DiGeorge in the 1960s. Based on abnormal development of the pharyngeal pouches, it presents with a wide range of clinical features including heart malformations, hypoparathyroidism, thymic hypoplasia, and craniofacial abnormalities.
The incidence is 1 in 3,000 to 6,000 births, making it the most common microdeletion syndrome1)2). About 90% of cases are de novo mutations, while approximately 10% are inherited from a parent in an autosomal dominant manner5)6). 85% of affected individuals have a deletion of about 2.54 Mb, containing approximately 40 genes5).
Over 180 clinical symptoms have been described in DGS, showing extremely wide phenotypic variability6). Ophthalmic signs are also diverse, including retinal vascular tortuosity, posterior embryotoxon, eyelid abnormalities, strabismus, refractive errors, and anterior segment developmental anomalies. All patients diagnosed with this condition require ophthalmic evaluation.
QCan it be diagnosed in adulthood?
A
Diagnosis in adulthood is not uncommon. Patients born before the widespread availability of genetic testing in the late 1990s, or those with only hypocalcemia without heart malformations, are prone to delayed diagnosis5). The oldest reported case in the literature was first diagnosed at age 719). It has been reported that about 60% of adult DGS cases are discovered through the diagnosis of a child5).
The ocular symptoms perceived by patients with DGS depend on the type and severity of the associated ocular findings.
Decreased vision: Due to structural abnormalities of the anterior and posterior segments, such as cataracts, coloboma, and microphthalmia.
Diplopia and abnormal eye position: May be observed with strabismus (occurring in 15–18% of cases).
Eye pain and redness: Can occur when uveitis is present.
The following systemic symptoms are characteristic:
Symptoms due to hypocalcemia: tetany, seizures, muscle cramps. Common in the neonatal period, but may also become apparent during adolescence or pregnancy6).
Increased susceptibility to infections: due to immunodeficiency from thymic hypoplasia, leading to recurrent respiratory and fungal infections8).
Developmental delay: observed in about 90% of patients, affecting both motor and language development1).
Clinical Findings (Findings Confirmed by Physician Examination)
Cataract: May occur secondary to hypocalcemia due to hypoparathyroidism9).
Posterior segment findings
Retinal vascular tortuosity: Observed in 24–75% of patients with 22q11.2 deletion syndrome, it is the most common posterior segment finding 7). No correlation with cardiovascular disease has been identified.
Retinal vascular malformation: Cases of intraretinal hemorrhage and vitreous hemorrhage arising from malformed vessels have been reported 7).
Optic disc abnormalities: Tilted disc, disc edema (secondary to hypocalcemia), and epipapillary fibrosis.
Telecanthus and infraorbital discoloration: recognized as part of facial abnormalities.
QWhen should an eye examination be performed?
A
A comprehensive eye examination should be performed at the initial diagnosis of 22q11.2 deletion syndrome, with follow-up based on individual findings. Patients with characteristic findings such as posterior embryotoxon, tortuous retinal vessels, and eyelid hooding who remain undiagnosed should be considered for referral for genetic evaluation.
Most cases of DGS are caused by a heterozygous deletion of 1.5 to 3 Mb in the 22q11.2 region of chromosome 22. This region contains low-copy repeats (LCRs), and non-allelic homologous recombination (NAHR) is the main cause of the deletion 4).
The TBX1 gene, located within the deleted region, is considered the most important responsible gene. TBX1 controls the migration of neural crest cells and is involved in the morphogenesis of structures derived from the pharyngeal arches (craniofacial bones, thymus, parathyroid glands, and cardiac outflow tract) 1)4). Cases involving TBX1 deletion are reported to have more pronounced cardiac malformations and immune deficiencies 8).
In addition to genetic causes, teratogenic factors (maternal alcohol consumption, maternal diabetes, retinoic acid) are also associated with the development of DGS.
de Wallau et al. (2024) examined the association between the parental origin of the deletion (maternal origin 48%, paternal origin 52%) and clinical features in 61 patients with 22q11.2 deletion syndrome 4). Patients with maternally derived deletions had significantly more seizures (p=0.0455) and scoliosis (p=0.0200), and truncus arteriosus and pulmonary atresia were only seen in the maternal origin group. Congenital heart disease and endocrine abnormalities were also slightly more frequent, suggesting that maternally derived deletions may result in a more severe phenotype.
QIs it hereditary?
A
About 90% of cases are de novo mutations, with unaffected parents. However, about 10% are inherited from a parent via autosomal dominant inheritance5)6). Children of an affected individual have a 50% chance of inheriting the deletion. In some cases, a mildly affected parent may remain undiagnosed until the child is diagnosed6).
A definitive diagnosis of DGS is established when the CD3-positive T cell count is decreased (<500/mm³) and at least two of the following three criteria are met.
aCGH (array CGH): Detects copy number changes across all chromosomes and is currently the most recommended test.
FISH (fluorescence in situ hybridization): The traditional gold standard using the TUPLE1 probe, but may not detect atypical small deletions1)6).
CMA (chromosomal microarray analysis): Has sensitivity equal to or greater than aCGH and can detect smaller deletions than FISH6).
MLPA: Considered equivalent to FISH and used for confirmation after aCGH or for rapid diagnosis5).
Newborn screening: TREC (T-cell receptor excision circle) analysis can screen for T-cell development abnormalities5).
DGS is a disease that is often diagnosed late, and cases with only hypocalcemia without heart malformations may be missed until adulthood2)5)6).
Wylazlowska et al. (2023) reported a boy first diagnosed with DGS at age 13 2). The patient underwent aCGH testing for suspected muscular dystrophy due to elevated creatine kinase, and a 22q11.2 deletion was incidentally discovered. Past medical records showed at least two episodes of hypocalcemia, which had been overlooked.
There is no curative treatment for DGS; management is based on symptomatic treatment for complications in each organ and multidisciplinary collaboration.
Hypocalcemia due to hypoparathyroidism is observed in 50–70% of DGS patients2). The mainstay of treatment is oral administration of calcium preparations and active vitamin D preparations.
Calcium supplementation: Oral administration of calcium preparations2)9).
Active vitamin D: Because the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D is impaired under parathyroid hormone deficiency, active vitamin D preparations such as alfacalcidol or calcitriol are used2).
Magnesium supplementation: Used in combination as needed2).
Advanced cases of cataract secondary to hypocalcemia are surgical indications. Papilledema resolves in about 1 to 5 months with improvement of hypocalcemia.
Partial DGS: Presents with mild to moderate immunodeficiency. Prophylactic antibiotics may be used for recurrent infections8).
Complete DGS: Characterized by complete absence of thymic tissue and severe immunodeficiency, requiring thymus transplantation or hematopoietic stem cell transplantation8).
Immunoglobulin replacement (IVIG): Used in cases with low immunoglobulin levels 8).
Orbital cyst: Observe until the orbit reaches adult size (approximately 90% of adult size by age 5) to promote orbital growth, then perform surgical excision 3).
Vitreous hemorrhage: Observe for spontaneous absorption; if not absorbed, consider intravitreal anti-VEGF injection and vitrectomy7).
Strabismus: Surgical correction is performed as needed.
Refractive errors and amblyopia: Early detection and correction are important.
QHow is hypoparathyroidism treated?
A
The mainstay of treatment is oral administration of calcium preparations and active vitamin D preparations (such as alfacalcidol and calcitriol)2). Since activation of inactive vitamin D is impaired under PTH deficiency, active forms must be used. Lifelong monitoring of calcium and PTH levels is necessary, and hypocalcemia may worsen under stress such as infection, surgery, or pregnancy6).
The underlying pathology of DGS is abnormal development of the third and fourth pharyngeal pouches during embryogenesis. The third pharyngeal pouch forms the thymus and inferior parathyroid glands, while the fourth pharyngeal pouch forms the superior parathyroid glands1). Hypoplasia of these structures is the main cause of immunodeficiency, hypocalcemia, and cardiac malformations.
The 22q11.2 region contains 44 known protein-coding genes 4). Among them, the TBX1 gene is expressed in cells within the pharyngeal arches and controls the migration of neural crest cells. Neural crest cells are involved in the formation of many structures, including the craniofacial skeleton, thymic capsule, and vascular architecture of the aortic arch 4). Dosage imbalance of TBX1 causes abnormal neural crest migration, leading to the diverse clinical features of DGS.
Childhood T-cell lymphopenia: With growth, IL-7-driven homeostatic proliferation of T cells occurs, and peripheral T-cell counts appear to normalize 8).
IgM deficiency: Qualitative T-cell abnormalities lead to insufficient B-cell help, potentially causing immunoglobulin deficiency (especially IgM) in adulthood 8).
Complete DGS
Thymic aplasia: Characterized by complete absence of thymic tissue, accounting for approximately 1.5% of DGS patients 8).
Severe immunodeficiency: Cell-mediated immunity is markedly impaired, with a high risk of opportunistic infections.
Prognosis: Without transplantation, the average life expectancy is less than one year, requiring thymus transplantation or hematopoietic stem cell transplantation.
Animal studies have shown that deficiency of the VEGF164 isoform causes congenital anomalies similar to DGS in mice 7). VEGF164 is also involved in normal retinal vascular development, and abnormalities in this pathway are speculated to cause retinal vascular tortuosity and vascular malformations.
Kozak et al. (2022) first reported retinal vascular malformations, peripapillary, intraretinal, and vitreous hemorrhages in children with DGS 7). Fluorescein angiography showed no dye leakage from the malformed vessels, and the hemorrhages were attributed to vascular fragility due to VEGF dysregulation.
Hypocalcemia due to parathyroid hypoplasia can cause cataracts and papilledema. Papilledema is observed in approximately 18% of patients with idiopathic hypoparathyroidism and resolves with improvement of hypocalcemia.
7. Latest Research and Future Perspectives (Investigational Reports)
de Wallau et al. (2024) examined the association between parental origin of the deletion and clinical symptoms in 61 patients with 22q11.2DS4). Patients with maternal deletions had slightly higher frequencies of congenital heart disease (66% vs 53%), endocrine abnormalities (21% vs 9%), and skeletal abnormalities (66% vs 47%). Seizures and scoliosis were observed only in those with maternal deletions (p<0.05). Although statistical significance was not reached for many items, it was suggested that maternal deletions may lead to a more severe phenotype.
VEGF Pathway and Molecular Mechanisms of Ocular Vascular Abnormalities
Since deficiency of the VEGF164 isoform causes DGS-like phenotypes in mice, the VEGF pathway has been proposed as a disease modifier in DGS7). Elucidation of the molecular basis of retinal vascular abnormalities may lead to future preventive therapeutic strategies targeting VEGF.
Hare et al. (2022) reported the occurrence of malignancies in patients with DGS8). In a multicenter study of 687 children, the incidence of malignancies in DGS patients under 14 years of age was approximately 900 per 100,000, which is markedly higher than the 3.4 per 100,000 in the general pediatric population. T-cell deficiency, chronic infection/inflammation, and deletions of the COMT gene and SMARCB1 tumor suppressor gene are thought to be involved.
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Chandramohan A, Sears CM, Huang LC, et al. Microphthalmia and orbital cysts in DiGeorge syndrome. J AAPOS. 2021;25(6):358-360.
de Wallau MB, Xavier AC, Moreno CA, et al. 22q11.2 deletion syndrome: influence of parental origin on clinical heterogeneity. Genes. 2024;15(4):518.
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Liarakos AL, Tran P, Rao R, Murthy N. Late maternal diagnosis of DiGeorge syndrome with congenital hypoparathyroidism following antenatal detection of the same 22q11.2 microdeletion syndrome in the fetus. BMJ Case Rep. 2022;15:e250350.
Kozak I, Ali SA, Wu WC. Novel retinal observations in a child with DiGeorge (22q11.2 deletion) syndrome. Am J Ophthalmol Case Rep. 2022;27:101608.
Hare H, Tiwari P, Baluch A, Greene J. Infectious complications of DiGeorge syndrome in the setting of malignancy. Cureus. 2022;14(6):e26277.
Chen X, Yang L, Li J, Tan H. Hypoparathyroidism and late-onset hypogonadism in an adult male with familial 22q11.2 deletion syndrome: a case report with 3-year follow-up and review of the literature. BMC Endocr Disord. 2022;22:278.
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