Barakat syndrome diagnosed decades after initial presentation

Abstract

Summary: Barakat syndrome, also called HDR syndrome, is a rare genetic disorder encompassing hypoparathyroidism (H), sensorineural deafness (D) and renal disease (R). A 64-year-old woman was referred to our endocrinology clinic for a switch in treatment (from dihydrotachysterol to calcitriol). She had progressive sensorineural deafness since the age of 18 and idiopathic hypoparathyroidism diagnosed at age of 36. Her medical history included osteoporosis with hip/spine fractures, nephrolithiasis and a family history of hearing loss, osteoporosis and kidney disease. The patient's clinical presentation indicated Barakat syndrome. Genetic analysis found a GATA3:c.916C>T nonsense variant. Further tests such as audiometry, labs and renal imaging supported the diagnosis. Due to rarity and manifold symptoms, diagnosis can be challenging. Optional GATA3 testing was suggested in 2018, except in cases of isolated sensorineural deafness or renal disease with pertinent family history. In isolated 'H' cases without 'D' and 'R', GATA3 studies are not required, as no haploinsufficiency cases were reported. Given the rise in genetic disorders, physicians should consistently consider rare genetic disorders in patients with suggestive symptoms, even decades after onset. Although diagnosis might not always impact management directly, it aids patients in accepting their condition and has broader family implications.

Learning points: There is currently an important increase in genetic and clinical characterization of new orphan diseases and their causative agents. Unbiased re-evaluation for possible genetic disorders is necessary at every consultation. It is essential to recognize the differential diagnosis of idiopathic hypoparathyroidism. The patient's clinical presentation and family history can be important to establish the correct diagnosis. Physicians should not hesitate to search a patient's signs and symptoms online.

Figure 1

Family pedigree supporting an autosomal dominant inheritance pattern with varying penetrance.

Figure 2

Pure tone audiogram showing air and bone conduction threshold for each ear in decibels (dB) of hearing loss (normal hearing at 0 dB) and frequency in kilohertz (kHz). There is a severe hearing loss of about 80 dB on the right and 85 dB on the left more pronounced at higher frequencies.

Figure 3

Direct sequencing identifies the heterozygous variant, substitution of cytosine for thymine in complementary DNA (cDNA).

Figure 4

(A) GATA 3 protein structure showing the location of the reported mutation. (B) Protein homology of GATA 3 between Homo sapiens (human), Mus musculus (mouse), Bos taurus (bovine), Danio rerio (danre), and Gallus gallus (chick) and the location to the reported mutation.