Molecular Characteristics

HDR syndrome is primarily caused by mutations in GATA3 located on chromosome 10p (10p14) (OMIM 146255). GATA3 belongs to a family of dual zinc-finger transcription factors involved in vertebrate embryonic development of the parathyroid glands, auditory system, kidney as well as the thymus and CNS. The mechanism underlying the role of these mutations in the etiology of HDR has been well illustrated by functional studies of GATA3 mutations associated with the syndrome. The HDR GATA3-causing mutations expand the spectrum of genetic defects and consist of mutations that disrupt ZnF2 leading to loss of DNA binding, mutations that disrupt ZnF1 destabilizing DNA binding and/or its interaction ZnF1 and ZnF2 and encodes the 444-amino-acid protein GATA3. In addition, Bernandini et al. (2009) reported an overexpression of GATA3 resulting from gene duplication in association with this syndrome.  The spectrum of defects in patients with the HDR triad includes in coding and non-coding regions that lead to haploinsufficiency, disruption of the wild type protein (dominant negative), and point mutations. In 2017, Kim et al. described a newborn female infant with the largest deletion of chromosome 10p reported to date. The infant had the defect on 10p14 responsible for HDR and 10p13–14, which is another cause of DiGeorge anomaly defined as DGS2. The fact that identifiable GATA3 mutations are not present in all patients with clinical features compatible with HDR syndrome may be explained by genetic heterogeneity or by the fact that genetic syndromes have overlapping phenotypic components. Given the fact that GATA3 defects were not detected in 9.4% of the reported patients, and 22% were not studied, leaves open the possibility of the presence of other gene defects associated with this disorder. The phenotypic heterogeneity of the Barakat syndrome is due to variability of expression and incomplete penetrance of GATA3 mutations.

Though the syndrome is phenotypically defined by the triad of “H”, “D” and “R” the literature identifies cases with different components consisting of “HD,” “DR,” “HR,” “R,” and “D” with, or without, GATA3 defects making the definition of the syndrome difficult.  “HDR” was found in 64.4% of reported patients with the syndrome, “HD” in 27.2%, “DR” in 4.4%, “R” in 1.7%, “HR” in 1.7%, and “D” in 0.6%.

Belge et al. (2017) reported eight patients with this syndrome, one of whom had only “D” but had a new heterozygous substitution c.856A>G(p.N286D) involving a highly conserved amino acid within the zinc-finger transcription factor 1 motif (ZnF1). The other components of the syndrome may have been overlooked in this patient and some of the other reported patients. In the 16 patients reported by Muroya et al. (2001), hearing was not evaluated in two of their patients with “HR” and one with isolated “R.” In two patients with “R”, the “H” and “D” were not evaluated. Yet, GATA3 defects were found in the two “HR” patients and two of the “R” patients who were not evaluated for “H” and “D.” Hasegawa et al. (1997) reported a patient with HDR and terminal deletion of chromosome 10 with the break point at p13 [46,XX,del (10)(p13)]. The authors suggested that the HDR syndrome may be a contiguous gene syndrome and clinical variations may be caused by the extent of the deletions. In most patients, the syndrome is primarily caused by GATA3 haploinsufficiency and is associated with a wide phenotypic spectrum; however, some patients with the typical HDR phenotype do not have the GATA3 defect. Fujimoto et al. (1999) reported a Japanese boy with cerebral infarctions in the basal ganglia. Chromosome analysis demonstrated a de novo deletion of 10p15.1-p14, suggesting that the putative gene responsible for HDR syndrome is located at 10p15. Hasegawa et al. (1997) reviewed 14 patients with deletions in 10p13. Among these patients, five had “H” and four of them were considered partial De George syndrome, six had CAKUT, and two had “D.” None of these patients had the triad of “HDR.” According to Nesbit et al. (2004), greater than 90% of patients with the syndrome have “HD,” and over 80% have “R.” GATA3 mutations are usually identified in patients with two or three of the HDR triad features, suggesting a genotypic heterogeneity.  Familial studies of probands with typical HDR syndrome have shown GATA3 mutations in patients with isolated “D”. Chiu et al. (2006) described 12 Chinese patients with mutations in GATA3 associated with “HD.” There have been no reports of normal phenotype in individuals with GATA3 mutations. According to Ali et al. (2007) a search for GATA3 mutations would be worthwhile mainly in patients with either two or three of the phenotypic manifestations but not in those with only one of the clinical features. However, GATA3 abnormalities were found in one patient with isolated “D” and two patients with “R” where “H” and “D” were not evaluated. Some patients were found to have early “D” and “H” appeared later. “H” and “R” have been diagnosed many years, even decades, after the diagnosis of “D”.  GATA3 testing revealed abnormalities in some of these patients but not in others. Patients with isolated “D” then, should have abnormal GATA3 to be diagnosed with the syndrome. The three affected individuals had asymptomatic “H,” and one of them had unilateral renal agenesis. The authors suggested the mechanism of genetic anticipation, the phenomenon in which successive generations exhibit earlier onset or greater severity of the disease.  

GATA3 is primary expressed in breast and urothelial tissue. The protein functions in immune regulation by regulating T-cell development. Missense mutations, nonsense mutations, silent mutations, frameshift insertions and deletions, and in-frame insertions and deletions have been observed in lymphomas, sarcomas and cancers of the skin, head, neck, brain, ovary, biliary tract, breast, lung, intestines, pancreas and bladder. GATA3 has also been shown to play a role in allergic diseases, atopic disease, inflammatory diseases, glomerular disease, Paget disease, Parkinson’s disease, and others.