Patients with the DiGeorge syndrome (DGS) typically suffer from hypoparathyroidism, immunodeficiency, cardiac outflow tract mal formations; facial dysmorphia and palatal dysfunction. DGS has been reported in up to 60% of children with familial or idiopathic forms of hypoparathyroidism, and has a wide spectrum of se verity. Most commonly, hypoparathyroidism associated with DGS presents in the neonatal period with marked hypocalcaemia, which may cause laryngospasm or seizures. However, the hypoparathyroidism may be transient and characterized by serum calcium concentrations that normalize during infancy and early childhood. Some individuals with DGS may only develop hypocalcaemic symptoms in adolescence or adulthood. Most cases of DGS are sporadic but an autosomal dominant inheritance of DGS has been observed in up to 28% of cases. DGS is most commonly caused by a heterozygous 3 Mb microdeletion of chromosome 22q11.2, which is referred to as DGS type 1 (DGS1). The deleted region encompasses the TBX1 gene, which encodes a T- box transcription factor that regulates histone modification and is involved in para thyroids and thymic development (Figure 1). TBX1 mutations have been identified in some DGS patients who did not have deletions of chromosome 22q11.2, and demonstrated to lead to all of the major phenotypes of DGS. Furthermore, transgenic mice with deletion of Tbx1 have been reported to have a phenotype that is similar to that of DGS1 patient.
Fig1. Transcription factors involved in parathyroid gland development and function. In humans, the parathyroid glands are derived from the endoderm of the third and fourth pharyngeal pouches. Whereas, in mice, the parathyroid glands develop with the thymus from the third pharyngeal pouch endoderm. A network of transcription factors such as the EYA1, HOXA3, TBX1, PAX1/ PAX9, SIX1/ SIX4, and GATA3 proteins mediate patterning of the third pharyngeal pouch and formation of the common parathyroid- thymus primordia. These transcription factors act in a spatiotemporal manner, for example, TBX1 is expressed in the pharyngeal endoderm and required for the development of the third pharyngeal pouch; whereas GATA3 is expressed in the common parathyroid- thymus primordia and mediates the differentiation of parathyroid and thymus progenitor cells. Moreover, GATA3 regulates the expression of GCM2, which is expressed in the parathyroid domain of the common primordia and mediates the initial stages of parathyroid organogenesis. MAFB is also expressed in the parathyroid domain and facilitates separation of the parathyroid glands from the thymus, and also the migration of the parathyroids towards the thyroid gland. GATA3, GCM2, and MAFB also act synergistically to upregulate PTH expression. Adapted with permission from Mannstadt M, Bilezikian JP, Thakker RV, Hannan FM, Clarke BL, et al. Hypoparathyroidism. Nat Rev Dis Primers. 2017;3:17055. Copyright © 1992, Springer Nature. (ref 1).
Chromosome 10p deletions have been detected in some DGS patients [58] and this is referred to as DGS type 2 (DGS2). The nebulette (NEBL) gene, located on chromosome 10p, has been reported to be deleted in DGS2 patient cell lines, and thus may be the responsible gene for DGS2 (Table 1). Moreover, some DGS patients have features of the CHARGE syndrome, which is characterized by coloboma, heart abnormalities, choanal atresia, growth retardation, and genitourinary and/ or ear anomalies; and is caused by heterozygous mutations of the CHD7 gene (Table1). CHD7 encodes the chromodomain helicase DNA binding protein 7, which is expressed within the pharyngeal ectoderm, and may play a role in pharyngeal region development.
Table1. Inherited forms of hypoparathyroidism and their chromosomal locations
