Hypoparathyroidism in Complex Disorders - DiGeorge Syndrome

Type 1 (DGS1, OMIM phenotype number #188400)

Type 2 (DGS2, (OMIM phenotype number %601362)

DiGeorge Syndrome (OMIM phenotype number #188400) is the most frequent form of hypoparathyroidism associated with multiorgan impairment due to abnormalities in transcription factors, autoimmune dysregulation or mitochondrial alterations.
DiGeorge syndrome type 1 (DGS1, also referred to as chromosome 22q11.2 deletion syndrome or hypoplasia of thymus and parathyroids or third and fourth pharyngeal pouch syndrome) is the most frequent human disorder due to a DNA microdeletion. The birth prevalence is high, being 1:2000-4000 newborns. Since multiple organ abnormalities can be present in various combinations, the syndrome is also referred to as CATCH22, namely Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, and Hypocalcaemia with microdeletion of chromosome 22. These developmental abnormalities involve the derivatives of the third and fourth parhyngeal pouches, such as the parathyroids and the thymus. It is characterized by a T-cell and a B-cell deficiency, craniofacial abnormalities (such as cleft palate, with other mouth, nose and eye alterations), anomalies of the heart and the great vessels and growth defects and hypoparathyroidism. Hypoparathyroidism can be present at birth, in the case of parathyroid aplasia, or manifest later in life if only hypoplasia occurs. It can be inherited in an autosomal dominant fashion or, more commonly, rather occur as a sporadic disease. Indeed, the 22q11.2 microdeletions causing DGS1 usually derive from meiotic non-allelic homologous recombination events between low-copy repeats. The deleted chromosomal region encompasses almost 60 genes comprising Tbx1. The absence of Tbx1, a transcription factor essential for embryonic patterning and development, is likely to play a key role in the pathogenesis of the syndrome. Indeed, in some cases of DGS negative for 22q11.2 microdeletions, loss-of-function mutations of Tbx1 have been detected. Cases of DGS negative for 22q11.2 mutations may display heterozygous deletion in chromosome 10p13-14, and therefore being referred to as DSG type 2 (DSG2, OMIM phenotype number %601362).
People of the disease show various grades of disease severity and combination of abnormalities and no genotype-to-phenotype correlation exists, although cases of late onset DGS1 tend to display similar cytogenetic defects. Interactions of Tbx1 with other factors coded by regions other than the 22q11.2 have been postulated to cause the wide variability of the phenotypes of DGS. Alternatively, it is possible that specific microRNA signatures or other environmental factors may modulate the expression of the genetic abnormality. Recently, a study in mice has demonstrated that the loss of Tbx1 induces a phenotype similar to cleidocranial dysplasia. No systematic assessment of bone in patients with DSG has been performed, yet.

Genes

Microdeletions in 22q11.2 region (DGS1) or 10p13-14 region (DGS2).

Phenotype

Thymic hypoplasia with T-cell deficiency, often early-onset, congenital hypocalcemia, with cardiac defects, craniofacial deformities, short stature.

Main biochemical alterations:

Neonates: low serum calcium; adults: low serum calcium in 65 % of cases, low serum PTH.

Images

Figure: two affected siblings from a family where DGS is inherited with an autosomal dominant pattern (Tbx1 loss-of-function mutation).

Reproduced from BMC Res Notes. 2014 Nov 5;7:783 under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) License.

Other resource

VCFS and 22q11 Foundation (DiGeorge Syndrome)

 

References:

  1. Cianferotti L. and Brandi M.L.: The Molecular Genetics of Hypoparathyroidism. In: The Parathyroids: Basic and Clinical Concepts, Third Edition, Academic Press, 2015.
  2. Tarsitano M., Vitale A., Tarsitano F.: DiGeorge Syndrome. In: Hypoparathyroidism, Springer, 2015.
  3. Funato N, Nakamura M, Richardson JA, Srivastava D, Yanagisawa H. Loss of Tbx1 induces bone phenotypes similar to cleidocranial dysplasia. Hum Mol Genet. 2015 Jan 15;24(2):424-35.
  4. Ogata T, Niihori T, Tanaka N, Kawai M, Nagashima T, Funayama R, Nakayama K, Nakashima S, Kato F, Fukami M, Aoki Y, Matsubara Y. TBX1 mutation identified by exome sequencing in a Japanese family with 22q11.2 deletion syndrome-like craniofacial features and hypocalcemia. PLoS One. 2014 Mar 17;9(3):e91598.
  5. Aggarwal VS, Morrow BE. Genetic modifiers of the physical malformations in velo-cardio-facial syndrome/DiGeorge syndrome. Dev Disabil Res Rev 2008;14:19–25.
  6. Papangeli I, Scambler P. The 22q11 deletion: DiGeorge and velocardiofacial syndromes and the role of TBX1. Wiley Interdiscip Rev Dev Biol 2013;2:393–403.
  7. www.omim.org