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A novel likely pathogenic germline variant in CDKN1B in a patient with MEN4 and medullary thyroid cancer

Fernández Mercè1,2, Queralt Asla3,4, Francisco J Illana5

  • 1Department of Endocrinology and Nutrition, Institut de Recerca Sant Pau (IR SANTPAU), Endo-ERN. Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. mfmiro79@gmail.com.

Familial Cancer
|February 26, 2025
PubMed

Insights

Multiple Endocrine Neoplasia type 4 (MEN4) is linked to CDKN1B gene variants. This case highlights a novel CDKN1B variant causing MEN4 and medullary thyroid cancer, emphasizing genetic testing for rare endocrine conditions.

Area of Science:

  • Endocrinology
  • Genetics
  • Oncology

Background:

  • Multiple Endocrine Neoplasia type 4 (MEN4) is a rare genetic disorder caused by germline variants in the CDKN1B gene, encoding the tumor suppressor p27Kip1.
  • MEN4 shares clinical similarities with MEN1, necessitating genetic confirmation for diagnosis.
  • p27Kip1 plays a crucial role in cell cycle regulation and tumor suppression.

Purpose of the Study:

  • To report a unique clinical case of a patient presenting with medullary thyroid cancer (MTC) and Cushing's disease.
  • To identify the genetic basis of the patient's rare endocrine conditions.
  • To characterize the identified genetic variants and their potential impact on tumor development.

Main Methods:

  • Clinical case presentation and detailed patient history.
  • Germline and somatic genetic variant analysis using Next-Generation Sequencing (NGS) panels (Oncomine Comprehensive Assay v3).
  • Immunohistochemical analysis of p27/Kip1 expression in tumor tissues.
  • Evaluation of Loss of Heterozygosity (LOH).

Main Results:

  • A novel heterozygous germline CDKN1B frameshift variant (c.536del) was identified, confirming a diagnosis of MEN4.
  • The patient had MTC without a germline RET variant and subsequently developed Cushing's disease.
  • A pathogenic somatic HRAS variant (c.182A>G, p.(Gln61Arg)) was found in the MTC, alongside the germline CDKN1B variant. Weak p27/Kip1 nuclear expression was observed in tumors.

Conclusions:

  • This study reports a novel CDKN1B germline variant associated with MEN4, presenting with MTC and Cushing's disease.
  • The coexistence of MTC, Cushing's disease, and a novel CDKN1B variant underscores the importance of comprehensive genetic evaluation in patients with rare endocrine tumors.
  • The findings contribute to understanding the genetic landscape of MEN4 and its phenotypic variability.
Keywords:
CDKN1B variantMedullary thyroid cancerMultiple endocrine neoplasia type 4p27Kip1

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