Ophthalmic Manifestations of DiGeorge Syndrome

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Disease Entity

DiGeorge syndrome (DGS), as described by by Dr. Angelo DiGeorge in the 1960s, (1) refers to a set of symptoms that result from abnormal development of the pharyngeal pouches. Patients with DGS most commonly present with thymus hypoplasia resulting in immune deficits, parathyroid hypoplasia resulting in hypocalcemia, and cardiac abnormalities.

Disease

DiGeorge syndrome, otherwise known as 22q11. 2 deletion syndrome, is due to a microdeletion on chromosome 22. While DeGeorge syndrome has various symptoms, it usually causes a form of congenital heart issues, particular facial features, increased risk for infections, delayed development and learning, as well as a cleft palate. (1)

Etiology

Heterozygous deletions in chromosome 22q11.2 underlie most cases of DiGeorge syndrome (2, 3) and it is the most common microdeletion syndrome in the United States.(4) These chromosomal abnormalities are also normally found in patients with velocardiofacial syndrome. (5)

Risk Factors

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General Pathology

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Pathophysiology

Abnormal development of the embryonic pharyngeal pouches results in the clinical presentation of DGS, which involves various structures: thyroid gland, thymus, parathyroid glands, mandible, maxilla, conotruncal cardiac structures, and the ear.

Heterozygous 1.5 to 3 Mb gene deletions in the chromosome 22q11.2 region are most commonly associated with the development of DGS.(6) The gene encoding TBX1 has also been implicated in the development of DGS in humans, although this association remains to be further investigated.(6) Although genetics explain most cases, various teratogens are also linked to the development of DGS, such as maternal alcohol use(7, 8), maternal diabetes (9), and retinoic acid.(10)

Patients with DGS are categorized as having either partial or complete DGS based on their immune function and level of thymic hypoplasia. Complete DGS is often characterized by total absence of thymic tissue with severely reduced immune function; as a result, bone marrow transplant is required to restore cellular immunity. Meanwhile, partial DGS patients are less severely affected and may range from immunodeficient to normal.(11)


Diagnosis

It has been proposed that diagnosis of DiGeorge syndrome be stratified based on likelihood of the presence of actual disease. (12)

A definitive diagnosis of DGS is characterized by a reduced number of CD3+ T cells (<500/mm3) and 2 of the 3 following characteristics:

• Conotruncal cardiac abnormality, such as truncus arteriosus, tetralogy of Fallot, interrupted aortic arch, or anomalous right subclavian

• Hypocalcemia requiring therapy that lasts longer than 3 weeks

• Deletion of 22q11.2.

A probable diagnosis is characterized by a reduced number of CD3+ T cells (<1500/mm3) and deletion of 22q11.2.

A possible diagnosis is characterized by a reduced number of CD3+ T cells (<1500/mm3) and at least one of the following:

• Cardiac defect

• Hypocalcemia requiring therapy that lasts longer than 3 weeks

• Palatal abnormalities or dysmorphic facies.

Initial Presentation

The signs and symptoms of DGS are often recognized within the first few months of life when patients are evaluated for cardiac abnormalities implicated in 22q11.2 deletion syndromes. Patients may also present with hypocalcemic tetany and/or persistent viral or fungal infections. (12)

General Evaluation

General evaluation of DGS should include the following: (13)

• Cardiac evaluation with echocardiogram

• Complete blood cell count

• Endocrine studies (TSH, calcium, serum creatinine, phosphorus)

• Chest x-ray to assess thymic shadow. If diminished or absent, the following work-up should be obtained:

o Flow cytometry – T & B cell phenotyping

o Immunoglobulin levels

o TREC count

• Abdominal ultrasound to determine genitourinary tract abnormalities

• Genetic analysis, especially in those with symptoms or family history. Various testing modalities (FISH, MLPA, SNP, CGH) may assess the molecular basis of DGS.



Symptoms

Common Clinical Features (13-17)

The common clinical features of DGS include:

• Conotruncal cardiac abnormalities

• Hypoplastic parathyroids, resulting in hypocalcemia  tetany, seizures, jitters

• Hypoplastic or absent thymus, resulting in a range of immunodeficiencies

• Craniofacial abnormalities, including cleft palate and ocular hypertelorism

• Developmental delay

• Autoimmune disorders in older patients

• Ocular symptoms


Diagnostic procedures

Array comparative genomic hybridization (aCGH) is the preferable and most appropriate test for detecting the 22q11.2 deletion. It has the added benefit of detecting large or submicroscopic chromosomal deletions/duplications on all chromosomes in addition to the classic chromosome 22q11.2 deletion. (13)

Fluorescent in situ hybridization (FISH) is readily available with chromosome analysis but smaller deletions may not be detectable. The karyotype detects chromosome rearrangements and other chromosomal abnormalities. Multiplex ligation-dependent probe amplification (MLPA) appears to be equivalent to the FISH technique (14) and can be used for rapid diagnosis when the syndrome is suspected clinically or for confirmation of the deletion after aCGH analysis.

Other means of diagnosis are being evaluated, including a rapid polymerase chain reaction (PCR) assay–based method.

Laboratory test

There are no specific laboratory values that diagnose patients with DGS, however specific labs that should be conducted include: 1. Complete Blood Count (CBC) A CBC with an elevated mean platelet volume above 10 fL may be a useful screening test.

2. Calcium and parathyroid hormone studies Hypocalcemia may occur in DGS secondary to hypoparathyroidism. Measure the ionized serum calcium level to evaluate parathyroid function. If the level is low, obtain simultaneous ionized serum calcium and parathyroid hormone levels. An endocrinology consultation may be necessary. Latent or subclinical hypoparathyroidism can be unmasked by performing a diagnostic ethylenediaminetetraacetic acid (EDTA) challenge test. Despite occasional normal calcium and parathyroid hormone levels, the secretory reserve for parathyroid hormone is usually diminished in patients with 22q11.2DS.


Differential diagnosis

• CHARGE syndrome, which shares features such as cardiac and craniofacial abnormalities (3, 18)

• Opitz G/BBB syndrome

• Zellweger syndrome

• SCID

• Teratogen exposure



Ophthalmology

Every patient diagnosed with DiGeorge Syndrome requires Ophthalmologic evaluation. The ophthalmic manifestations of DGS can vary. Tortuous retinal vessels, posterior embryotoxin, eyelid hooding, strabismus, refractive errors, and ptosis are the most commonly reported ocular symptoms of DGS. Ophthalmologists should pay particular attention to these symptoms during the evaluation of patients with DGS. (13, 16, 19, 20)


Ocular Symptoms

A comprehensive list of symptoms is included below, with percentages representing previously reported frequencies in cohorts of patients with DGS: (13, 16, 19, 20)

• Strabismus (15-18%)

• Refractive errors

• Amblyopia (4%)

• Extraocular

o Eyelid hooding (20%)

o Ptosis

o Distichiasis

o Telecanthus

o Infraorbital discoloration

o Canthal dystopia

• Anterior segment

o Posterior embryotoxon (49%)

o Sclerocornea

o Peters anomaly

o Iris remnants

o Cataracts

o Uveitis

o Colobomas

o Keratoconus21

o Microopthalmia & general anterior segment dysgenesis

o Case report of retrolental persistent fetal vasculature (PVF) stalk & orbital cyst due to failed closure of orbital fissure.  Current standard of care is observation of orbital cysts until it reaches adult volume & subsequent surgical removal

• Posterior segment

o Tortuous retinal vessels (34%)

o Possible genetic locus for exudative vitreoretinopathy

o Tilted optic nerves

Ophthalmic Physical Examination

Ophthalmic evaluation of DGS patients should include various tools. Slit lamp examination may be used to assess for common ocular findings in DGS patients, including tortuosity of retinal vessels, posterior embryotoxin, and colobomas. The foveal light reflex may be examined to determine the presence of retinopathy. Appropriate imaging modalities include fundoscopic imaging and optical coherence tomography (OCT). OCT imaging may be used to determine changes to the photoreceptor inner segment-outer segment junction and retinal pigment epithelium.(22)

Management & General Treatment

Patients with DGS are subcategorized as having either partial or complete DGS based on their immune function and level of thymic hypoplasia. Complete DGS is often characterized by total absence of thymic tissue with severely reduced immune function; as a result, bone marrow transplant is required to restore cellular immunity. Meanwhile, partial DGS patients are less severely affected and may range from immunodeficient to normal. (11)

Medical follow up

After initial evaluation, patients should receive genetic counseling as appropriate and regular follow-up with primary care and specialists to monitor for common sequelae; these include but are not limited to immunology, cardiology, neurology, psychiatry, endocrinology, oral and maxillofacial surgery, and ophthalmology. (13)

Ophthalmologic evaluation should include a comprehensive eye exam on initial diagnosis of chromosome 22q11.2 deletion syndrome and subsequent follow-up based on individual presentation. Patients with common ocular findings (posterior embryotoxon, tortuous retinal vessels, eyelid hooding) who do not yet have a confirmed diagnosis of DiGeorge syndrome may be appropriate candidates for referral for genetic evaluation. (20)

Complications

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Prognosis

Infants with complete DGS who don’t undergo transplantation have a life expectancy of less than one year. However, even those who undergo transplantation generally have a life expectancy less than 5 years. The oldest reported indivuals with complete DGS have survived into their 20s.

Patients with partial DGS may expect varied prognoses depending on the extent of systemic involvement. Cardiac complications are the most common cause of death in this patient population. (23)


References

1. Lischner HW, Dacou C and DiGeorge AM. Normal lymphocyte transfer (NLT) test: negative response in a patient with congenital absence of the thymus. Transplantation 1967; 5: 555-557.

2. de la Chapelle A, Herva R, Koivisto M, et al. A deletion in chromosome 22 can cause DiGeorge syndrome. Hum Genet 1981; 57: 253-256. DOI: 10.1007/BF00278938.

3. McDonald-McGinn DM, Hain HS, Emanuel BS, et al. 22q11.2 Deletion Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al. (eds) GeneReviews((R)). Seattle (WA), 1993.

4. Botto LD, May K, Fernhoff PM, et al. A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics 2003; 112: 101-107. DOI: 10.1542/peds.112.1.101.

5. Swillen A, Feys H, Adriaens T, et al. Early motor development in young children with 22q.11 deletion syndrome and a conotruncal heart defect. Dev Med Child Neurol 2005; 47: 797-802. DOI: 10.1017/S0012162205001696.

6. Du Q, de la Morena MT and van Oers NSC. The Genetics and Epigenetics of 22q11.2 Deletion Syndrome. Front Genet 2019; 10: 1365. 20200206. DOI: 10.3389/fgene.2019.01365.

7. Sulik KK, Johnston MC, Daft PA, et al. Fetal alcohol syndrome and DiGeorge anomaly: critical ethanol exposure periods for craniofacial malformations as illustrated in an animal model. Am J Med Genet Suppl 1986; 2: 97-112. DOI: 10.1002/ajmg.1320250614.

8. Ammann AJ, Wara DW, Cowan MJ, et al. The DiGeorge syndrome and the fetal alcohol syndrome. Am J Dis Child 1982; 136: 906-908. DOI: 10.1001/archpedi.1982.03970460036008.

9. Dentici ML, Placidi S, Francalanci P, et al. Association of DiGeorge anomaly and caudal dysplasia sequence in a neonate born to a diabetic mother. Cardiol Young 2013; 23: 14-17. 20120306. DOI: 10.1017/S1047951112000194.

10. Coberly S, Lammer E and Alashari M. Retinoic acid embryopathy: case report and review of literature. Pediatr Pathol Lab Med 1996; 16: 823-836.

11. Muller W, Peter HH, Wilken M, et al. The DiGeorge syndrome. I. Clinical evaluation and course of partial and complete forms of the syndrome. Eur J Pediatr 1988; 147: 496-502. DOI: 10.1007/BF00441974.

12. Conley ME, Notarangelo LD and Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol 1999; 93: 190-197. DOI: 10.1006/clim.1999.4799.

13. Bassett AS, McDonald-McGinn DM, Devriendt K, et al. Practical guidelines for managing patients with 22q11.2 deletion syndrome. J Pediatr 2011; 159: 332-339 e331. 20110512. DOI: 10.1016/j.jpeds.2011.02.039.

14. Moss EM, Batshaw ML, Solot CB, et al. Psychoeducational profile of the 22q11.2 microdeletion: A complex pattern. J Pediatr 1999; 134: 193-198. DOI: 10.1016/s0022-3476(99)70415-4.

15. McDonald-McGinn DM, Kirschner R, Goldmuntz E, et al. The Philadelphia story: the 22q11.2 deletion: report on 250 patients. Genet Couns 1999; 10: 11-24.

16. Motzkin B, Marion R, Goldberg R, et al. Variable phenotypes in velocardiofacial syndrome with chromosomal deletion. J Pediatr 1993; 123: 406-410. DOI: 10.1016/s0022-3476(05)81740-8.

17. Ryan AK, Goodship JA, Wilson DI, et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet 1997; 34: 798-804. DOI: 10.1136/jmg.34.10.798.

18. Hsu P, Ma A, Barnes EH, et al. The Immune Phenotype of Patients with CHARGE Syndrome. J Allergy Clin Immunol Pract 2016; 4: 96-103 e102. 20151107. DOI: 10.1016/j.jaip.2015.09.004.

19. Chandramohan A, Sears CM, Huang LC, et al. Microphthalmia and orbital cysts in DiGeorge syndrome. J AAPOS 2021; 25: 358-360. 20210929. DOI: 10.1016/j.jaapos.2021.06.001.

20. Forbes BJ, Binenbaum G, Edmond JC, et al. Ocular findings in the chromosome 22q11.2 deletion syndrome. J AAPOS 2007; 11: 179-182. 20061130. DOI: 10.1016/j.jaapos.2006.08.006.

21. Saffra N and Reinherz B. Keratoconus in an adult with 22q11.2 deletion syndrome. BMJ Case Rep 2015; 2015 20150116. DOI: 10.1136/bcr-2014-203737.

22. De Niro JE, Randhawa S and McDonald HR. Retinal vascular tortuosity in DiGeorge syndrome complicated by solar retinopathy. Retin Cases Brief Rep 2013; 7: 343-346. DOI: 10.1097/ICB.0b013e3182919cb2.

23. Janda A, Sedlacek P, Honig M, et al. Multicenter survey on the outcome of transplantation of hematopoietic cells in patients with the complete form of DiGeorge anomaly. Blood 2010; 116: 2229-2236. 20100607. DOI: 10.1182/blood-2010-03-275966.

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