Outcomes of Patients with Central Precocious Puberty Due to Loss-of-Function Mutations in the MKRN3 Gene after Treatment with Gonadotropin-Releasing Hormone Analog

Ramos, Carolina; Macedo, Delanie B.; Canton, Ana Pinheiro Machado; Cunha-Silva, Marina; Antonini, Sonir Roberto Rauber; Stecchini, Monica F; Seraphim, Carlos Eduardo; Rodrigues, Tânia Maria Barreto; Mendonca, Berenice B.; Latrônico, Ana Claudia; Brito, Vinícius Nahime

doi:10.1159/000504446

Cited by 18 publications

(10 citation statements)

References 37 publications

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“…Researchers have investigated the inter-relationship among obesity, CPP, and some of these genetic causes. Obesity has not been shown to be associated (positively or negatively) with MKRN3 mutations, the most common monogenic cause of CPP [ 113 , 114 ]. However, obesity is a common finding among children with DLK1 mutations [ 115-118 ].…”

Section: Areas Of Uncertainty and Future Directionsmentioning

confidence: 99%

An Approach to the Evaluation and Management of the Obese Child With Early Puberty

Tenedero

Oei

Palmert

2021

Journal of the Endocrine Society

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With the decline in age at onset of puberty and increasing prevalence of childhood obesity, early breast development in young, obese girls has become a more frequent occurrence. Here, we examine available literature to answer a series of questions regarding how obesity impacts the evaluation and management of precocious puberty. We focus on girls as the literature is more robust, but include boys where literature permits.Suggestions include: (1) Age cut-offs for evaluation of precocious puberty should not differ substantially from those used for non-obese children. Obese girls with confirmed thelarche should be evaluated for gonadotropin-dependent, central precocious puberty (CPP) to determine if further investigation or treatment is warranted. (2) Basal luteinizing hormone (LH) levels remain a recommended first-line test. However, if stimulation testing is utilized, there is a theoretical possibility that the lower peak LH responses seen in obesity could lead to a false negative result. (3) Advanced bone age (BA) is common among obese girls even without early puberty; hence its diagnostic utility is limited. (4) Obesity does not eliminate the need for MRI in girls with true CPP. Age and clinical features should determine who warrants neuroimaging. (5) BA can be used to predict adult height in obese girls with CPP to inform counselling around treatment. (6) Use of gonadotropin-releasing hormone analogues (GnRHa) leads to increased adult height in obese girls. (7) Obesity should not limit GnRHa use as these agents do not worsen weight status in obese girls with CPP.

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Section: Areas Of Uncertainty and Future Directionsmentioning

confidence: 99%

An Approach to the Evaluation and Management of the Obese Child With Early Puberty

Tenedero

Oei

Palmert

2021

Journal of the Endocrine Society

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“…Whether GnRH is effective for CPP patients with MKRN3 mutation has not been completely determined. A retrospective study revealed no significant differences in mean LH or target height between CPP patients with or without MKRN3 mutations after GnRH treatment[ 13 ]. In our study, after patient B was treated with three doses of GnRH analog (3.75 mg every 4 wk), LH, FSH and E2 decreased to normal levels, without any progression of puberty signs, suggesting that the GnRH analog is effective in the treatment of CPP patients with MKRN3 mutation.…”

Section: Discussionmentioning

confidence: 99%

Rare mutation in MKRN3 in two twin sisters with central precocious puberty: Two case reports

Jiang¹,

YanQiong²,

Yuan³

et al. 2021

WJCC

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BACKGROUND Caused by premature activation of the hypothalamic-pituitary-gonadal axis, there is increasing incidence of central precocious puberty (CPP), especially in girls. Makorin ring finger protein 3 ( MKRN3 ), a maternal imprinted gene with a highly conserved sequence, is the most common genetic etiology associated with CPP. Approximately 50 different mutations in MKRN3 have been found in CPP. CASE SUMMARY This case report involves identical twin sisters presenting with premature thelarche at the age of 6 years. The left hand bone age of both patients revealed advanced age (9 years). Pelvic B ultrasound indicated enlargement of the ovaries. Luteinizing hormone (LH) releasing hormone testing confirmed CPP. Whole-exome sequencing detected the c.841C>T mutation in MKRN3 , leading to a single base substitution, in the twins. This mutation was inherited from the father and paternal grandmother. After 3 mo of treatment with a gonadotropin-releasing hormone analog, levels of LH, follicle-stimulating hormone, and estradiol in the proband’s sister returned to normal levels. CONCLUSION Here, we report a rare mutation (c.841C>T) in MKRN3 in identical twin sisters with CPP.

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“…Patients with MKRN3 mutations have not been reported to manifest clinical characteristics other than pubertal advance. Similar to CPP caused by other etiologies, MKRN3-related CPP responds to pharmacological inhibition of the HPG axis by GnRH analogs [23].…”

Section: Mkrn3 Mutations In Patients With Cppmentioning

confidence: 95%

Makorin RING finger protein 3 and central precocious puberty

Maione

Naulé

Kaiser

2020

Current Opinion in Endocrine and Metabolic Research

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Makorin RING finger protein 3 (MKRN3) is a key inhibitor of the hypothalamic-pituitarygonadal axis. Loss-of-function mutations in MKRN3 cause familial and sporadic central precocious puberty (CPP), while polymorphisms are associated with age at menarche. To date, 115 patients with CPP carrying MKRN3 mutations have been described, harboring 48 different genetic variants. The prevalence of MKRN3 mutations in genetically screened populations with CPP is estimated at 9.0%. Girls are more commonly and more seriously affected than boys. MKRN3 is expressed in humans and rodents in the central nervous system. Circulating levels in humans and hypothalamic expression in rodents decrease during pubertal progression. Although some MKRN3 regulators have been identified, the precise mechanism by which MKRN3 inhibits the hypothalamic-pituitary-gonadal axis remains elusive. The role of makorins in developmental physiology and organ differentiation and the role of maternal imprinting are discussed herein.

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Outcomes of Patients with Central Precocious Puberty Due to Loss-of-Function Mutations in the MKRN3 Gene after Treatment with Gonadotropin-Releasing Hormone Analog

Cited by 18 publications

References 37 publications

An Approach to the Evaluation and Management of the Obese Child With Early Puberty

An Approach to the Evaluation and Management of the Obese Child With Early Puberty

Rare mutation in MKRN3 in two twin sisters with central precocious puberty: Two case reports

Makorin RING finger protein 3 and central precocious puberty

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