Microdeletion syndrome 22q11

22q11.2 deletion syndrome (DS) is a genetically induced multimorbidity syndrome (Malecki SL et al. 2019) with numerous congenital organic malformations and dysfunctions. These include: heart defects, palatal anomalies, facial dysmorphia, delayed or absent organ development, immunological disorders with recurrent infections and allergic diathesis. The clinical picture was described in the 1960s as DiGeorge syndrome (McDonald-McGinn DM et al. 2015).

CATCH-22 is a synonym of DiGeorge syndrome and reminds of the deletion on chromosome 22, as well as

• cardiac abnormality
• Abnormal facies
• Thymichypoplasia/aplasia
• Cleft palate
• hypocalcemia/hypoparathyroidism

22q11.2 deletion syndrome is considered the most common human chromosomal microdeletion syndrome and the second most common chromosomal cause of congenital heart disease (Hou HT et al. 2019). The worldwide prevalence in live births is estimated at 1/2,000-1/4,000.

The mutation is a new mutation in about 90% of cases (McDonald-McGinn DM et al. 2015). Children of affected individuals have a 50% risk of developing the disease.

In most cases, the syndrome is caused by a 3 million base pair (Mb) deletion on chromosomal region 22q11.2. The deletion is caused by non-allelic meiotic recombination during spermatogenesis or oogenesis. It is believed that the variable expression of the 22q11.2 phenotype is caused by genetic modifiers either in the other 22q11.2 allele or on other chromosomes.

Newborns

The 22q11.2-DS shows a variable clinical phenotype that can range from mild to severe. Congenital heart defects (77% of cases) include mainly conotruncal malformations such as truncus arteriosus, tetralogy of Fallot and ventricular septum defect (Hou HT et al. 2019).

> 75% of patients have palatal abnormalities (e.g. open cleft palate, cleft lip and palate, velo-pharyngeal incompetence) which can lead to hypernasal speech and feeding and swallowing problems.

Further developmental delays are often diagnosed. Many patients show mild facial dysmorphia (e.g. flat cheekbones, ptosis, hypertelorism, eyelid wrinkles, a protruding nasal root) and vertebral anomalies (e.g. butterfly vertebrae, hemivertebrae). 75% of those affected have an immunodeficiency due to aplasia or hypoplasia of the thymus, which makes them susceptible to various recurrent infections (34%), including chronic mucocutaneous candidiasis (Bernstock JD et al. 2019; Mahé P et al. 2019). Furthermore, selective T-cell lymphopenia is detectable in about half of the patients (Bernstock JD et al. 2019). In a larger French collective an increased allergy rate could be detected in 27% of the patients (Mahé P et al. 2019).

In about 13% of patients there is an increased risk of autoimmune diseases(Idiopathic thrombocytopenic purpura; Juvenile idiopathic arthritis - Mahé P et al. 2019). Neonatal hypocalcemia is observed in 50% of cases. Other possible clinical findings include gastrointestinal abnormalities (intestinal position abnormalities, anal atresia), hearing loss, renal abnormalities (renal agenesia), dental abnormalities (enamel hypoplasia), chronic mucocutaneous candidiasis, a wide range of psychiatric disorders such as ADHD (Guo Y et al. 2019), schizophrenia, epilepsy and Parkinson-like symptoms (Fanella M et al. 2019).

Clinical examination and detection of malformations (e.g., cardiac abnormalities by echocardiography, vertebral abnormalities by cervical radiographs) lead to diagnostic suspicion. Diagnosis is confirmed by detection of the 22q11.2 deletion by fluorescence in situ hybridization (FISH), MLPA, aCGH, or genome-wide SNP microarrays.

Smith-Lemli-Opitz Syndrome

CHARGE Syndrome

Alagille Syndrome

VATER syndrome

Goldenhar Syndrome

Isotretinoin Embryopathy

It is dependent on the accompanying malformations. A regular immunological control is necessary. In individual cases, both immunodeficiency and hypoparthyroidism could be corrected in athymic phenotypes by thymus transplantation (Kreins AY et al. 2019).

The prognosis varies and is determined by the severity of the disease. The mortality rate in infants is relatively low (about 4%); mortality in adults is slightly higher than in a healthy adult population.

Due to the wide range of clinical symptoms of 22q11.2 deletion syndrome, it has been divided into several clinical pictures in the past, such as:

• DiGeorge Syndrome
• the Velocardiofacial Syndrome
• the cardiofacial syndrome and others

Since these different phenotypes are genotypically identical, they were later collectively referred to as 22q11.2 DS.

1. Bernstock JD et al (2019) Recurrent microdeletions at chromosome 2p11.2 are associated with thymic hypoplasia and features resembling DiGeorge syndrome. J Allergy Clin Immunol pii: S0091-6749
2. Fanella M et al(2019) Myoclonic epilepsy, parkinsonism, schizophrenia and left-handedness as common neuropsychiatric features in 22q11.2 deletion syndrome. J Med Genet pii: jmedgenet-2019-106223.
3. Guo Y et al (2019) Association of a functional Claudin-5 variant with schizophrenia in femalepatients with the 22q11.2 deletion syndrome. Schizophr Res pii: S0920-9964
4. Hou HT et al (2019) Genetic characterisation of 22q11.2 variations and prevalence in patients with congenital heart disease. Arch Dis Child pii: archdichild 316634.
5. Kreins AY et al. (2019) Correction of both immunodeficiency and hypoparathyroidism by thymus transplantation in complete DiGeorge syndrome.On J Transplant doi: 10.1111/ajt.15668.
6. McDonald-McGinn DM et al (2015) 22q11.2 deletion syndrome. Nat Rev Dis Primers 1:15071.
7. Mahé P et al (2019) Risk factors of clinical dysimmune manifestations in a cohort of 86 children with 22q11.2 deletion syndrome: A retrospective study in France. At J Med Genet A 179:2207-2213.
8. Malecki SL et al(2019) A genetic model for multimorbidity in young adults. Genet Med doi: 10.1038/s41436-019-0603-1.