MKRN3 gene deletion can cause central precocious puberty without PWS

medwireNews: Whole-gene deletion of MKRN3 can cause central precocious puberty (CPP) without any features of Prader–Willi syndrome (PWS), researchers report.

“[O]ur findings suggest that CPP patients undergoing genetic testing with negative MKRN3 sequencing results, and suspected non-maternal inheritance (as paternal inheritance may be masked due to imprinting), should be tested for whole gene deletions for completeness of the genetic investigation”, say Angela Delaney (St Jude Children’s Research Hospital, Memphis, Tennessee, USA) and colleagues.

The researchers explain that MKRN3 is located in an imprinted region on chromosome 15, and paternal deletions in this area are known to cause PWS.

Yet the team identified two unrelated girls, from among 16 with idiopathic CPP, who had whole-gene deletions of MKRN3 but no symptoms or features of PWS.

Indeed, one patient had a paternally inherited 584 kb deletion encompassing the genes MKRN3MAGEL2 and NDN, all of which fall into the region associated with PWS.

The only clinical feature present in this girl suggestive of PWS was obesity (BMI 23.4 kg/m2; 99th percentile for age). However, there was a paternal family history of obesity, and the researchers say that “[u]pon careful questioning, she does not have any evidence of hyperphagia or any other signs or symptoms of PWS in her history or presentation.”

This “raises the question of which areas of the [PWS imprinting region] are critical for development of the typical features of PWS”, write Delaney and team in The Journal of Clinical Endocrinology & Metabolism.

This girl came to medical attention at the age of 6 years, with episodes of vaginal bleeding, and was found to have Tanner stage 4 breasts and stage 1 pubic hair, and laboratory findings consistent with CPP. Both parents had normal pubertal timing.

The other patient experienced thelarche and pubarche at the age of 7 years, and was found to have Tanner stage 4 breast and stage 3 pubic hair at the age of 8 years. She had a MKRN3 deletion, inherited from her paternal grandmother, who experienced menarche between the age of 8 and 9 years. She had no symptoms suggestive of PWS.

Looking at previous publications, the researchers found another report of a patient with deletion of MKRN3MAGEL2 and NDN who had CPP but not PWS. Conversely, they identified PWS patients with deletions including MKRN3 who did not have CPP; pubertal timing in these patients ranged from normal to delayed.

“Thus, MKRN3 and other microdeletions centromeric to the [PWS imprinting region] may not be sufficient to cause PWS alone, and PWS patients with deletions that include MKRN3 do not necessarily develop CPP”, say Delaney and study co-authors.

They add: “We speculate that there is a more specific critical region of the PWS locus beyond MKRN3MAGEL2, and NDN that is responsible for the PWS phenotype.”

By Eleanor McDermid

medwireNews is an independent medical news service provided by Springer Healthcare. © 2020 Springer Healthcare part of the Springer Nature Group

J Clin Endocrinol Metab 2020; doi:10.1210/clinem/dgaa331
Martin Savage
Programme Director
Sign up for eAlerts
Be the first to hear about new resources and content by signing up to receive our eAlerts.

We'd love your feedback!

Please complete this short 5-question survey to help improve the content offered on this website.
Please rank the following aspects of the program from best [1] to worst [4].