Novel germline variants of CDKN1B and CDKN2C identified during screening for familial primary hyperparathyroidism

We report three novel CDKIs germline variants in three different patients with PHPT identified during the course of screening for FHPT causes: (1) two likely pathogenic variants of CDKN1B gene (cases 1 and 2) and (2) one VUS of CDKN2C gene (case 3).

As stated above, CDKIs germline mutations have been proposed as a cause of MEN1-like syndromes without MEN1 mutation. This situation is called MEN4 when a CDKN1B germline mutation is found. However, the clinical course of patients affected by mutations in CKDIs is still poorly understood since few cases have been reported until now. We reviewed medical literature and genetic databases (ClinVar, HGMD) and found that a few more than 100 cases with MEN4, including 52 different variants of CDKN1B, have been reported to date [12, 16, 20, 29, 36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54]. As supplementary material, we added a table with the total number of CDKIs pathogenic/likely pathogenic/VUS germline variants thus far reported along with the type of parathyroid lesion or other tumours found (if reported) and pathogenicity level of the variants, which was assessed following the ACMG guidelines [26] (see supplementary material Appendix 1). It should be noted that 34 of these CDKN1B variants have been reported from a single submitter as criteria provided and 10/55 are classified as VUS. All these facts support that so very little knowledge about the clinical implications of CDKIs pathogenic variants is available to date. In addition, four other variants of CDKN1B have been reported in patients with medulloblastoma, paraganglioma, acute lymphoblastic leukaemia and familial colorectal cancer [30, 55,56,57].

Germline mutations in three other CDKI genes (CDKN2B, CDKN2C, and CDKN1A) were found in MEN1-like cases without detectable MEN1 mutations [16]. Afterall, a reliable prevalence of CDKIs mutations in MEN1-like patients or patients with PHPT is difficult to estimate as genetic screening of these genes has not been widely established. We report three novel CDKIs germline mutations in three different patients with PHPT. The possibility of including these cases within the term MEN4 or MEN1-like states should be assessed.

MEN4–PHPT affects approximately 80–90% of the reported MEN4 cases to date [7, 53]. This finding is in accordance with MEN1 classical presentation [58]. On the contrary, in most MEN4 cases, the clinical course of PHPT seems to be less severe than in patients with MEN1 syndrome and exhibits a female predominance. Only one case of MEN4 presented recurrent PHPT after subtotal parathyroidectomy [39, 53]. All cases that we reported agree with this as all of them showed remission of PHPT after surgery to date (at least nine years follow-up). However, moderate to severe hypercalcemia was seen in our three cases in contrast to other cases of PHPT associated with CDKIs mutations [53] (Table 1). Considering that most of these patients presented remission after surgery, differing from many MEN1 cases, a minimally invasive parathyroid surgery could be contemplated. Regarding endocrine histology, most of the cases of PHPT-related to CDKIs mutations described to date were caused by a single parathyroid adenoma [53], except for a few cases of MGD [16, 39]. To our knowledge, we report for the first time two cases of APA and one case of cystic parathyroid adenoma related to CDKIs germline mutations (Table 1).

Regarding pituitary neoplasms, up to now, some cases of these tumours were described in patients with MEN4 (43%) [12, 38, 45, 47, 49, 50, 52, 53]. These findings agree with the estimated prevalence of pituitary tumours in patients with MEN1 (40%). Recently, in a large cohort of 211 patients (mostly paediatric) with Cushing disease, five germline CDKN1B variants were identified (2.6%) [50]. In addition, three germline CDKN1B variants were detected in three paediatric patients with pituitary adenomas, with no other manifestations related to MEN4 [47]. In addition, one case of macroprolactinoma was described in a case with germline CDKN1A mutation [16]. Somatotroph, corticotroph, and non-functioning pituitary adenomas have been found to be the most frequent pituitary tumours in MEN4 cases. On the contrary, prolactinomas seem less frequent in MEN4 patients [45, 52]. Non-functioning microadenomas are usual in the general population, and it remains challenging to distinguish between incidentalomas and MEN-related pituitary tumours [53]. In this regard, a non-functioning microadenoma was detected in case 3. The age of onset of pituitary tumours in MEN4 is still unclear due to the few number of cases reported until now.

Concerning NETs, we did not find any radiological image or analytical alteration suggestive of tumour in our cases. That finding fits with the last data about MEN4 cases, which indicates a lower prevalence of NETs than in MEN1 [53].

Other tumours, such as meningiomas, liver haemangiomas, skin tumours, adrenal nodes, colon cancer, breast cancer, and genitourinary neoplasms, have been described in patients with germline mutations of CDKIs [12, 16, 20, 36, 38, 53]. We describe a colon adenoma with low-grade dysplasia and atypical lipomas in case 1 and a colon neoplasia in her mother who carried the same variant in CDKN1B. In addition, we report a malignant hemopathy (aberrant T-cell population) in a CDKN1B carrier (case 2).

In the firsts two cases (cases 1 and 2), genetic analysis of tumour samples showed nor LOH neither CNV for CDKN1B, findings that agree with those in the literature. We reviewed recent data of MEN4 published cases describing CDKN1B pathogenic variants that have analysed tumour tissue to assess the presence of a possible LOH. In most of the cases, tumour testing failed to demonstrate a second somatic event in the wildtype allele. Therefore, in contrast to MEN1 syndrome, haploinsufficiency for CDKN1B appears to be enough for tumours to occur in MEN4 syndrome [41, 53, 59]. Conversely, in case 3, genetic tumour testing showed uniparental disomy of chromosome 1, including CDKN2C gene, which could support a pathogenic role of this variant. Another germline variant of CDKN2C with LOH was described in a patient with parathyroid adenoma [33]. In addition, some reports propose the contribution of CDKN2C as tumour suppressor gene in different neoplasms [60,61,62,63]. However, further studies are required to establish whether CDKN2C germline pathogenic variants cause genetic predisposition to FHPT or multiple endocrine neoplasms. In addition, immunohistochemistry testing for p18 (not available in our laboratory) could be of interest in future studies of similar cases to determine the protein expression in tumour tissue.

To summarize, we report two novel likely pathogenic variants of CDKN1B gene in patients with suspected familial PHPT. The first one was found in a patient with atypical parathyroid adenoma, atypical lipomas, and a colon tubule-villous adenoma with low-grade dysplasia. His mother, who carried the same variant, died from colon neoplasia and once presented with non-studied hypercalcemia. The second one found in a patient with PHPT is associated with aberrant T-cell population and other comorbidities, such as obesity, subclinical hypothyroidism, and chronic idiopathic axonal polyneuropathy. In addition, we describe a novel variant in CDKN2C gene with uniparental disomy in tumour sample that was classified as uncertain significance in a patient with PHPT and a non-functional pituitary adenoma. Although the case 3 variant was classified as VUS, we would like to highlight its clinical relevance since both the proband and her mother, who carried the same variant, presented PHPT.

As a reflection, we would like to point out that genetic screening of FHPT could be considered in patients with features such as APA or in the presence of other tumours apart from PHPT. Considering all reported cases of MEN1-like patients with CDKIs germline mutations with PHPT as the predominant feature, we theorize that patients with mutations in different CDKIs apart from CDKN1B (such as CDKN2C) may be encompassed in the nomenclature of MEN4. However, further studies should be done for a better understanding of this entity, and development of specific guidelines for these patients should be established. New germline variants described in this study can be added to the current knowledge. In conclusion, we can say that germline mutations in CDKIs may represent an etiology of FHPT. Therefore, these genes should be included in gene panels for screening this disease.

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