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We present a family in which four individuals have been identified with the same likely pathogenic genetic alteration in the PIK3CA gene at the germinal level; specifically, c.1145G>A p.(Arg382Lys) missense type. The index case patient was diagnosed with multinodular goiter and breast cancer at 61 years old. Among the other three carrier relatives: one has been diagnosed with serous cystadenoma of the ovary and a thyroid nodule with no radiological suspicion of malignancy; the other two present multinodular goiter. Additionally, a sister of three of the carriers suffered from an ovarian teratoma, follicular thyroid carcinoma on multinodular goiter, and high-grade serous ovarian carcinoma. No direct mutation study was performed on her as she had died due to ovarian carcinoma. This finding suggests that the PIK3CA gene should be considered in Cowden-like families when no other gene mutations have been found. Furthermore, this report contributes to characterization of the clinical phenotype caused by mutations in PIK3CA , which may be shared with other hereditary breast and ovarian cancer syndromes.

Purpose: To determine the rate of genetic testing for familial hyperaldosteronism (FH) in the SPAIN-ALDO Registry and to describe the clinical characteristics of patients with FH. In addition, a literature review of reports of FH cases was performed., Methods: A retrospective multicenter study of primary aldosteronism (PA) in patients followed in 35 Spanish tertiary hospitals (SPAIN-ALDO Registry)., Results: Twenty-five of the 855 patients (3%) with PA included in the registry underwent genetic testing for FH, with complete results available in only 24 patients. However, we found that there were 57 patients who met the criteria for performing a genetic study of PA. Only 8 out of these 57 patients were genetically tested (14.0%), while the reasons to perform a genetic study in the remaining 9 genetically studied cases were quite heterogeneous. A positive result for FH was found only in one case for FH type III (KCNJ5 pathogenic variant). A systematic review of the literature was performed and identified a total of 25 articles reporting 246 patients with FH type I; 12 articles reporting 72 patients with FH type II; 14 articles reporting 29 cases of FH type III and 3 articles reporting 12 patients with FH type IV., Conclusion: The genetic study of familial hyperaldosteronism is often scarce in real-world clinical practice, as 86% of patients with criteria to undergo genetic study were not evaluated in our cohort. Nevertheless, FH is an uncommon cause of PA, representing only 0.2% of cases in the SPAIN-ALDO Registry, although its prevalence may be as high as 4% among suspected cases might be studied., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Purpose: To evaluate the rate of recurrence among patients with pheochromocytomas and sympathetic paragangliomas (PGLs; together PPGLs) and to identify predictors of recurrence (local recurrence and/or metastatic disease)., Methods: This retrospective multicenter study included information of 303 patients with PPGLs in follow-up in 19 Spanish tertiary hospitals. Recurrent disease was defined by the development of local recurrence and/or metastatic disease after initial complete surgical resection., Results: A total of 303 patients with PPGLs that underwent 311 resections were included (288 pheochromocytomas and 15 sympathetic PGLs). After a median follow-up of 4.8 years (range 1-19), 24 patients (7.9%) had recurrent disease (3 local recurrence, 17 metastatic disease and 4 local recurrence followed by metastatic disease). The median time from the diagnosis of the PPGL to the recurrence was of 11.2 months (range 0.5-174) and recurrent disease cases distributed uniformly during the follow-up period. The presence of a pathogenic variant in SDHB gene (hazard ratio [HR] 13.3, 95% CI 4.20-41.92), higher urinary normetanephrine levels (HR 1.02 per each increase in standard deviation, 95% CI 1.01-1.03) and a larger tumor size (HR 1.01 per each increase in mm, 95% CI 1.00-1.02) were independently associated with disease recurrence., Conclusion: The recurrence of PPGLs occurred more frequently in patients with SDHB mutations, with larger tumors and with higher urinary normetanephrine levels. Since PPGL recurrence may occur at any time after the initial PPGL diagnosis is performed, we recommend performing a strict follow-up in all patients with PPGLs, especially in those patients with a higher risk of recurrent disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Araujo-Castro, García Sanz, Mínguez Ojeda, Hanzu, Mora, Vicente, Blanco Carrera, de Miguel Novoa, López García, Lamas, Manjón-Miguélez, del Castillo Tous, Rodríguez de Vera, Barahona San Millán, Recasens, Tomé Fernández-Ladreda, Valdés, Gracia Gimeno, Robles Lazaro, Michalopoulou, Álvarez Escolá, García Centeno, Barca-Tierno, Herrera-Martínez and Calatayud.)

Objective: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants., Methods: CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path&#95;MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path&#95;MMR carriers who were first- or second-degree relatives of Lynch syndrome probands., Results: In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path&#95;MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path&#95;MSH2 50% and 39%; for path&#95;MSH6 13% and 17% and for path&#95;PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups., Conclusions: Prospectively observed CRC incidences (PLSD) in path&#95;MLH1 and path&#95;MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path&#95;MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path&#95;PMS2 carriers subjected to colonoscopy, but not significantly so., (© 2022. The Author(s).)

KCNJ10 encodes the inward-rectifying potassium channel (Kir4.1) that is expressed in the brain, inner ear, and kidney. Loss-of-function mutations in KCNJ10 gene cause a complex syndrome consisting of epilepsy, ataxia, intellectual disability, sensorineural deafness, and tubulopathy (EAST/SeSAME syndrome). Patients with EAST/SeSAME syndrome display renal salt wasting and electrolyte imbalance that resemble the clinical features of impaired distal tubular salt transport in Gitelman's syndrome. A key distinguishing feature between these two conditions is the additional neurological (extrarenal) manifestations found in EAST/SeSAME syndrome. Recent reports have further expanded the clinical and mutational spectrum of KCNJ10-related disorders including non-syndromic early-onset cerebellar ataxia. Here, we describe a kindred of three affected siblings with early-onset ataxia, deafness, and progressive spasticity without other prominent clinical features. By using targeted next-generation sequencing, we have identified two novel missense variants, c.488G>A (p.G163D) and c.512G>A (p.R171Q), in the KCNJ10 gene that, in compound heterozygosis, cause this distinctive EAST/SeSAME phenotype in our family. Electrophysiological characterization of these two variants confirmed their pathogenicity. When expressed in CHO cells, the R171Q mutation resulted in 50% reduction of currents compared to wild-type KCNJ10 and G163D showed a complete loss of function. Co-expression of G163D and R171Q had a more pronounced effect on currents and membrane potential than R171Q alone but less severe than single expression of G163D. Moreover, the effect of the mutations seemed less pronounced in the presence of Kir5.1 (encoded by KCNJ16), with whom the renal Kir4.1 channels form heteromers. This partial functional rescue by co-expression with Kir5.1 might explain the lack of renal symptoms in the patients. This report illustrates that a spectrum of disorders with distinct clinical symptoms may result from mutations in different parts of KCNJ10, a gene initially associated only with the EAST/SeSAME syndrome.

SHOX and SHOX2 transcription factors are highly homologous, with even identical homeodomains. Genetic alterations in SHOX result in two skeletal dysplasias; Léri-Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LMD), while no human genetic disease has been linked to date with SHOX2. SHOX2 is, though, involved in skeletal development, as shown by different knockout mice models. Due to the high homology between SHOX and SHOX2, and their functional redundancy during heart development, we postulated that SHOX2 might have the same transcriptional targets and cofactors as SHOX in limb development. We selected two SHOX transcription targets regulated by different mechanisms: 1) the natriuretic peptide precursor B gene (NPPB) involved in the endochondral ossification signalling and directly activated by SHOX; and 2) Aggrecan (ACAN), a major component of cartilage extracellular matrix, regulated by the cooperation of SHOX with the SOX trio (SOX5, SOX6 and SOX9) via the protein interaction between SOX5/SOX6 and SHOX. Using the luciferase assay we have demonstrated that SHOX2, like SHOX, regulates NPPB directly whilst activates ACAN via its cooperation with the SOX trio. Subsequently, we have identified and characterized the protein domains implicated in the SHOX2 dimerization and also its protein interaction with SOX5/SOX6 and SHOX using the yeast-two hybrid and co-immunoprecipitation assays. Immunohistochemistry of human fetal growth plates from different time points demonstrated that SHOX2 is coexpressed with SHOX and the members of the SOX trio. Despite these findings, no mutation was identified in SHOX2 in a cohort of 83 LWD patients with no known molecular defect, suggesting that SHOX2 alterations do not cause LWD. In conclusion, our work has identified the first cofactors and two new transcription targets of SHOX2 in limb development, and we hypothesize a time- and tissue-specific functional redundancy between SHOX and SHOX2.

We report the clinical and molecular characteristics of 12 Spanish families with multiple members affected with Léri-Weill dyschondrosteosis (LWD) or Langer mesomelic dysplasia (LMD), who present the SHOX (short stature homeobox gene) mutation p.A170P (c.508G>C) in heterozygosity or homozygosity, respectively. In all studied families, the A170P mutation co-segregated with the fully penetrant phenotype of mesomelic limb shortening and Madelung deformity. A shared haplotype around SHOX was observed by microsatellite analysis, confirming the presence of a common ancestor, probably of Gypsy origin, as 11 of the families were of this ethnic group. Mutation screening in 359 Eastern-European Gypsies failed to identify any carriers. For the first time, we have shown SHOX expression in the human growth plate of a 22-week LMD fetus, homozygous for the A170P mutation. Although the mutant SHOX protein was expressed in all zones of the growth plate, the chondrocyte columns in the proliferative zone were disorganized with the chondrocytes occurring in smaller columnal clusters. We have also identified a novel mutation at the same residue, c. 509C>A (p.A170D), in two unrelated Spanish LWD families, which similar to A170P mutation impedes nuclear localization of SHOX. In conclusion, we have identified A170P as the first frequent SHOX mutation in Gypsy LWD and LMD individuals.