medwireNews: Cases of neonatal severe hyperparathyroidism (NSHPT) fall into two distinct categories determined by the number of causative genetic variants, which can be distinguished simply by measuring maximal calcium levels, say researchers.
“Our findings reveal for the first time that serum calcium measurements can serve as a biomarker for robust and very early genetic diagnosis among NSHPT cases”, the study authors write in The Journal of Clinical Endocrinology & Metabolism.
“Therefore, in the future, robust detection of extreme hypercalcemia in most homozygotes could promote individualized and very early total [parathyroidectomy], the definitive management for homozygous cases of NSHPT.”
When Stephen Marx (Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA) and Ninet Sinaii (National Institutes of Health Clinical Center, Bethesda, Maryland, USA) searched the literature for reports of this extremely rare condition, they found that “the vast majority” of cases were caused by variants of the CASR gene, although they note that this could partly reflect a bias against reporting cases where no obvious mutation was identified.
There were also three cases of NSHPT caused by a heterozygous variant of the AP2S1 gene, but the researchers excluded these from the main analysis.
From the 57 CASR cases, they created a “partly speculative” distribution of genotype/phenotype pairings, ranging from a wild-type CASR genotype and normal parathyroid function up to homozygous pathogenic variants that could be lethal in utero. They believe that severely affected patients with NSHPT are likely to carry two copies of mildly pathogenic CASR variants, supported by the fact that they frequently have heterozygous relatives with high-normal or slightly elevated calcium.
Less affected patients, on the other hand, are likely to carry one copy of a strongly pathogenic CASR variant, almost always inherited from the father. These patients had similar phenotypes to people with familial hypocalciuric hypercalcaemia, which is also underpinned by CASR variants in around 60% of cases, says the team.
Several of these milder NSHPT cases were managed without the need for parathyroidectomy, they note. Some patients were born with additional reversible secondary hyperparathyroidism caused by disturbances in materno–foetal calcium fluxes.
In total, there were 21 patients who were heterozygous for CASR variants, and they had an average maximal calcium value of 3.20 mM, with a 95% confidence interval of 3.08–3.32 mM.
But the 36 patients who were homozygous (two variant alleles, including five compound heterozygous) had a significantly higher average value of 5.83 mM, with a 95% confidence interval of 5.31–6.35. Likewise, the maximal parathyroid hormone values were 8.14 versus 17.42 for heterozygous and homozygous patients, respectively, with 95% confidence intervals of 4.06–12.23 and 13.41–21.44, respectively.
“Hypercalcemia values above 3.7 mM were seen only in the CASR homozygotes”, say Marx and Sinaii.
They suggest extreme hypercalcaemia, above a cutoff of 4.5 mM, as a “highly conservative” and specific definition, which “comfortably excludes all heterozygotes”, although they stress that lower values “should be interpreted with caution”, as they included six patients with homozygous mutations.
These maximal values “occurred during presentation at initial testing as early as at 1–6 days of life”, in the majority of patients, says the team, although they note that “prospective experience with extreme hypercalcemia may not be identical to retrospective experience.”
The researchers also identified an additional group of patients – 11 from nine families – with homozygous CASR variants but a mild phenotype who were not identified during infancy. The age of diagnosis ranged from 3 to 59 years of age, and it was not clear if this represented late onset or delayed diagnosis.
By Eleanor McDermid
medwireNews is an independent medical news service provided by Springer Healthcare. © 2019 Springer Healthcare part of the Springer Nature group
J Clin Endocrinol Metab 2019; doi:10.1210/clinem/dgz233