Although the syndrome is phenotypically defined by this triad, the literature identifies cases with different components, consisting of “HD,” “DR,” “HR,” “R,” and “D” with, or without, GATA3 defects. Patients may present with congenital anomalies of the kidney and urinary tract (CAKUT) detected on routine prenatal ultrasound, hearing loss diagnosed by routine neonatal hearing screen, or signs and symptoms of hypocalcemia (non-febrile seizures, tetany, myalgia, neuromuscular irritability).
Hypoparathyroidism occurs in about 93% of patients. The parathormone is usually low or inappropriately normal for the degree of hypocalcemia, reflecting the absence of adequately functioning parathyroid tissue as a primary hormonal deficiency. There seems to be no published cases of isolated, nonsurgical hypoparathyroidism with GATA3 mutations. However, these patients should be evaluated for deafness and renal disease, since hypoparathyroidism is caused only by few other disorders
Sensorineural hearing loss is the most consistent feature of the syndrome. Affecting about 96% of patients, it is usually bilateral, moderate to severe, slightly worse at the higher end of the frequency spectrum, peripheral in origin, and presents with early onset. The higher frequency sensorineural hearing loss progressively worsens with age. Although hearing loss occurs with other hereditary kidney disorders, none of these is associated with hypoparathyroidism (OMIM 146255).
Renal involvement is heterogeneous and occurs in about 72% of cases. Forty percent of renal disease in these patients is due to CAKUT including hypoplastic, aplastic, dysplastic, and cystic kidneys, vesicoureteral reflux, and pelvicalyceal abnormality. Nephrotic syndrome, hematuria, proteinuria, proximal and distal renal tubular acidosis, and chronic kidney disease have also been described. Experiments have shown that GATA3 is indispensable for kidney development especially for urinary bud formation. About 28% of reported patients had no renal disease, suggesting variable expression of renal anomalies in GATA3 haploinsufficiency.
Similar to most phenotypic syndromes, several additional features have been described in association with the syndrome including hypergonadotropic hypogonadism, polycystic ovaries, congenital heart disease, facial abnormalities, cerebral infarctions, retinitis pigmentosa, basal ganglia calcifications, severe cognitive disability, autism, neuropsychological, behavioral abnormalities and others. Although some of these conditions could be coincidental, they underscore the clinical diversity of this syndrome, suggesting the phenotypic heterogeneity and variable penetrance.
Although this syndrome is phenotypically defined by this triad, 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 and the criteria for its diagnosis difficult.
Barakat et al. (2018) suggested that the syndrome could be diagnosed in patients who have all three components, and those who have two components with a positive family history. Because of the cost and unavailability of genetic testing in many countries, GATA3 testing is not necessary for the diagnosis in this group of patients. Patients with isolated non-neurogenic sensorineural deafness and those with isolated renal disease should be suspected of having the syndrome, especially in the presence of a family history of any of the other components of the syndrome. In these instances, confirmatory GATA3 testing is necessary to confirm the diagnosis.
GATA3 studies, when available, should be performed on every suspected patient, and family members should be checked for the presence of “H”, “D”, and “R”, as well as GATA3 abnormalities. In patients with isolated “H” where “D” and “R” have been conclusively ruled out no GATA3 studies are needed, as none of these patients had shown GATA3 haploinsufficiency.
GATA3