medwireNews: Familial central precocious puberty (CPP) caused by mutations in the makorin RING finger protein 3 gene (MKRN3) is phenotypically similar to idiopathic forms, although it can vary with the severity of the mutation, a study shows.

MKRN3 loss-of-function mutations represent the most common genetic cause of familial CPP”, write the researchers in The Journal of Clinical Endocrinology & Metabolism.

“They have been described in children from multiple countries and may account for a substantial proportion of inherited CPP cases (33–46%).”

From a multiethnic cohort of 716 patients with CPP, Ana Claudia Latronico (Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil) and study co-authors identified 45 girls and 26 boys from 36 unrelated families who had pathogenic MKRN3 mutations. The children were all seen at a centre in Brazil, but just 40 were Brazilian, with other nationalities including North American, Turkish, Norwegian, Israeli and Australian.

Between them, these children had a total of 18 rare inactivating MKRN3 mutations, eight of which were classed as severe.

The severe mutations were the most common, affecting 75% of all patients (or 72% of the 36 index cases), and they comprised six frameshift variants and one stop gain variant, plus one promoter region deletion. The other 10 mutations were missense variants.

Seven of all the variants identified were novel, and included two frameshift mutations and five missense variants.

The children with MKRN3 mutations displayed the first signs of puberty at an average age of 6.2 years for the girls and 7.1 years for the boys, and their bone was advanced by an average of 2.0 and 1.8 years, respectively.

“Both female and male patients carrying MKRN3 mutations exhibited classical clinical and biochemical features of premature reactivation of the reproductive axis”, say Latronico and team.

When the researchers compared the girls in their cohort with 156 girls who had idiopathic CPP, they found that those with MKRN3 mutations had their first clinical examination at a significantly earlier average age (7.2 vs 8.4 years) and at a shorter time since first onset of symptoms (0.8 vs 2.4 years). Girls with MKRN3 mutations also had a smaller height standard deviation score (1.2 vs 1.7) at this time.

However, the team say that 51% of the children with MKRN3 mutations had a family history of CPP, suggesting heightened awareness from parents and doctors, although they note that the shorter time to first examination remained even for those without a family history, at 1.1 years versus 2.4 years for the idiopathic CPP cohort.

Girls with MKRN3 mutations had somewhat higher average follicle-stimulating hormone levels than those with idiopathic CPP (4.9 vs 3.8 IU/L) but the ranges for the two groups overlapped.

Although children with MKRN3 mutations had broadly “classical” CPP phenotypes, the researchers did find that “severe defects have a greater impact on phenotype when compared to pathogenic missense variants.”

Specifically, children with severe mutations had significantly more advanced bone age than those with missense variants, by an average of 2.3 versus 1.6 years, and they also had significantly higher average basal luteinising hormone levels, at 2.2 versus 1.1 IU/L.

By Eleanor McDermid

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J Clin Endocrinol Metab 2020; doi:10.1210/clinem/dgaa955

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