Barakat syndrome diagnosed decades after initial presentation

Genetic background

Our case of Barakat syndrome is an excellent example of the phenotypic variability of heterozygous GATA3 variants.

The identified heterozygous variant GATA3 c.916C>T in exon 4 is a scarce nonsense variant (not found in the population database GnomAD) and results in a premature stop codon (p.(Arg306*)) located in the flexible linker between the two zinc finger domains of the protein.

Thus, the variant might lead to a truncated protein lacking the C-terminal zinc finger domain, or loss or reduced DNA binding affinity by conformational changes causing developmental anomalies. Similar nonsense variants have already been reported as pathogenic (3).

When writing the initial report, this variant was neither listed in the databases ClinVar, HGMD, nor in the scientific literature. Earlier this year, the variant was entered with a single submission as pathogenic in the ClinVar database; however, no functional data are available. According to the ACMG/ACGS criteria, this variant should be classified as likely pathogenic (class 4) (3).

Similar to our study, Van Esch et al. identified a nonsense variant resulting in a stop codon in exon 4 of GATA3 (c.828C>T, p.(Arg277*), heterozygote) in patients with hypoparathyroidism and bilateral sensorineural deafness but without renal anomalies, suggesting a reduced penetrance for renal anomalies of nonsense variants (4).

Ali et al. grouped GATA3 variants into three classes based upon their functional consequences on DNA binding (2). The first class leads to, particularly truncated variants resulting in loss of DNA binding due to loss of the carboxyl-terminal zinc finger and accounts for more than 90% of all variants. The second class reduces DNA binding affinity, and the third class does not alter DNA binding or affinity but is probably associated with conformational alterations (2). Our nonsense variant should be considered part of the first class; however, functional studies would be needed to confirm this.

In general, genetic syndromes raise the question whether treatment should be different from similar, more common non-genetic manifestations.

Primary hypoparathyroidisms and calcium disorders

HDR syndrome alongside other genetic diseases comprises 10% of all cases of hypoparathyroidism. Under physiological conditions, hypocalcaemia leads to a reduction in occupancy of calcium-sensing receptors triggering an increase in the synthesis and secretion of parathormone (5).

On the other hand, hypocalcaemia causes neuromuscular irritability, seizures, tetany or paraesthesia (5). Our patient experienced paraesthesia, abdominal pain accompanied by vomiting and diarrhoea at serum calcium levels below 1.5 mmol/L (reference range, 2.15–2.5 mmol/L).

Management of hypoparathyroidism is based on substitution with calcium and an active form of vitamin D. Another possibility is the use of recombinant human parathormone rh-PTH 1-84 once daily (5).

Besides symptomatic hypocalcaemia, prolonged insufficient treatment of hypoparathyroidism may lead to structural and morphological skeletal changes (6). In a review of the literature, we did not find evidence for an increased risk for cardiovascular disease and malignancy, but possibly a slightly increased risk for upper extremity fractures (7). Our patient has a history of osteoporosis with numerous fractures (e.g. ribs, radius, spine). Antiresorptive therapy with denosumab was established for 10 years, and we recommended a change to a bisphosphonate for an additional year to mitigate the risk of rebound bone loss after stopping denosumab. We are not aware of any studies investigating osteoporosis under treatment with parathormone, for example teriparatide or abaloparatide in hypoparathyroidism, but given the clear therapeutic benefit in osteoporosis, its use in hypoparathyroidism is even more appealing (5).

In our patient, the initial serum calcium concentration was above the reference range (i.e. ≥2.8 mmol/L), due to the overly aggressive substitution with dihydrotachysterol and calcium carbonate. After switching to calcitriol 0.25 mg twice daily and adding 12.5 mg hydrochlorothiazide once daily – to increase serum calcium, decrease hypercalciuria and subsequent nephrocalcinosis – calcium levels stabilized in a tolerable range (see Table 1) (5).

Mitchell et al. corroborated the relationship between hypoparathyroidism and kidney disease in a cross-sectional study of more than 100 patients with hypoparathyroidism. They showed that 40% of patients had chronic renal disease and up to one-third had evidence of renal calcification in ultrasound and/or computed tomography imaging (8).

Kidney

The renal penetrance of HDR syndrome is variable. Reports indicate that up to 41% of patients have either aplasia, hypoplasia, or dysplasia; 16% have vesicoureteral reflux; and 11% have cysts or pelvicalyceal deformities (9). Although our patient had CKD stage 3 renal insufficiency, there were no pathological findings in imaging studies and kidney function was stable over time. We did not measure the albumin–creatinine ratio in urine. However, Barakat syndrome can present itself as a steroid-resistant nephrotic syndrome which was already recognized in the initial case description (1).

GATA3 is strongly expressed in two major progenitor populations, ureteric bud and stroma cells, and plays a crucial role in kidney development which explains the occurrence of renal dysplasia. Additionally, human fetal and adult kidneys demonstrated a strong GATA3 expression in mesangial progenitor cells as well as in mature mesangial cells, respectively (10). Heterozygous GATA3 knockout mice showed reduced proliferation rates of mesangial cells possibly leading to defective repair processes and GATA3 was shown to be increased in rodent models of mesangioproliferative glomerulonephritis and in patients with IgA nephropathy (9, 10). These observations may indicate that GATA3 plays a critical role to maintain glomerular homeostasis.

Hypomagnesaemia can be a subtle part of syndrome’s renal presentation. In our case, hypomagnaesemia was not a predominant finding, since we did not measure the fractional excretion of magnesium. However, Alkaissi et al. demonstrated that patients with HDR syndrome can have fractional excretion of magnesaemia up to 9% compared to 2–4% as in the normal population (11).

As the prognosis of affected patients usually depends on the severity of renal disease, early diagnosis and close follow-up are crucial in improving the prognosis.

Deafness

While renal penetrance is varying, penetrance of sensorineural deafness seems to be high, progressively increasing over the years, and more pronounced at higher frequencies.

A study reported detailed auditory and vestibular phenotypes of six patients with GATA3 mutations (12). While all patients present with early-onset sensorineural hearing loss and absent distortion product otoacoustic emissions (DPOAEs) in both ears, their auditory brainstem responses were normal, supporting a cochlear site of lesion with a lack of evidence for a vestibular dysfunction.

GATA3 is involved in the early morphogenesis of the pro-sensory domain of the inner ear and regulates the apoptosis of spiral ganglion neurons during maturation of the auditory system. A knockout in GATA3 leads to a limited genesis of hair cells and therefore causes severe inner ear defects (12).