Table 1.
Genetic associations of inborn errors of thymic stromal cells. References are cited within the main text
| Condition | Genetic defect | Inheritance | Other names | Immunological features | Associated features |
|---|---|---|---|---|---|
| 22q11 deletion syndrome | Del22q11.2 |
De novo (90–95%) AD (5-10%) |
DGS Velocardiofacial syndrome |
• Variable DGS features*: • cDGS +/- atypical features/OS • pDGS • Mild T lymphopaenia with improvement over time • T cell proliferation may be impaired • Thymus: present/normal, hypoplastic or absent • Ab production may be impaired • Can be asymptomatic • Immunology may be normal • Autoimmunity, atopy |
• CHD • Hypoparathyroidism • Other endocrinopathies • Facial dysmorphism • Palatal abnormalities • Feeding difficulties • Genitourinary abnormalities • Developmental delay • Psychiatric disorders |
| TBX1 deficiency | TBX1 | AD | • Variable DGS features (see above)* |
• CHD • Hypoparathyroidism • Other endocrinopathies • Facial dysmorphism • Palatal abnormalities • Deafness • Psycho-developmental abnormalities |
|
| TBX2 deficiency | TBX2 | AD | • Variable DGS features (see above)* |
• Craniofacial dysmorphism • CHD • Hypoparathyroidism • Other endocrinopathies • Cleft lip/palate • Skeletal malformations • Developmental delay |
|
| Partial monosomy 10p | Del10p13-14 |
De novo (1 familial deletion reported) |
HDR DGS2 |
• Variable DGS features (see above)* |
• Hypoparathyroidism • Sensorineural hearing loss • Renal anomalies • Craniofacial dysmorphism • Developmental delay • Growth retardation |
| CHARGE syndrome |
CHD7 (?SEMA3E) |
Most de novo | • Variable DGS features (see above)* |
• Coloboma • CHD • Atresia choanae • Retarded growth/development • Genital hypoplasia • Ear anomalies/deafness • Cranial nerve dysfunction • Feeding difficulties • Anosmia • Trachea-oesophageal anomalies • Hypoparathyroidism |
|
| 2p11.2 microdeletions | Del2p11.2 |
AD (4/5 kindreds) De novo (1/5 kindreds) |
• Variable DGS features (see above)* |
• (Transient) hypocalcaemia • Asymmetric crying face • Skeletal and palatal abnormalities (1 patient) • Hearing impairment |
|
| FOXN1 deficiency | FOXN1 | AR | Nude SCID |
• T-/lowB+NK+ SCID +/- OS • Athymia • Absent/severely naïve T cells, RTEs, TRECs • Impaired T cell proliferation • Impaired Ab production |
• Congenital alopecia totalis • Nail dystrophy |
| FOXN1 |
CH AD |
Hypomorphic FOXN1 deficiency |
• Wide spectrum: T-/lowB+NK+ SCID to mild T cell lymphopaenia with improvement over time • Low TRECs • Can be asymptomatic |
• +/-Nail dystrophy | |
| OTFCS2 | PAX1 | AR |
• T-/B+NK+ SCID +/- OS • Athymia • Absent/severely naïve T cells, RTEs, TRECs • Impaired T cell proliferation • Impaired Ab production |
• Facial dysmorphism • Ear anomalies, preauricular pits, deafness • Branchial cysts/fistulas • Vertebral & shoulder girdle malformations • Mild intellectual impairment |
|
| EXTL3 deficiency | EXTL3 | AR | Immunoskeletal dysplasia with neuro-developmental abnormalities |
• Variable • T-B+NK+SCID, +/- OS • Milder T cell lymphopaenia with improvement over time • Or normal immunology |
• Short limbed skeletal dysplasia: platyspondyly, brachydactyly, short stature, kyphoscoliosis, cervical spinal stenosis, pelvic anomalies. • Craniofacial dysmorphism • Motor delay, hypotonia, seizures • Hepatic cysts |
| AIRE deficiency | AIRE | AR |
APS1 APECED |
• Early onset multisystem autoimmunity • Classical triad = CMC, hypoparathyroidism, Addison’s • Auto-Abs including anticytokine Abs • Asplenia |
• Ectodermal dystrophy |
| AIRE | AD | • Delayed onset, attenuated autoimmune phenotypes, incomplete penetrance | • Ectodermal dystrophy |
Ab Antibody; AD autosomal dominant; APECED autoimmune polyendocrinopathy candidiasis ectodermal dystrophy; APS1 autoimmune polyglandular syndrome 1; AR autosomal recessive; CH compound heterozygous; CHD congenital heart disease; CMC chronic mucocutaneous candidiasis; DGS DiGeorge syndrome; cDGS complete DGS; pDGS partial DGS; OS Omenn syndrome; OTFCS2 otofaciocervical syndrome type 2; RTEs recent thymic emigrants; SCID severe combined immune deficiency; TRECs T cell receptor excision circles.