Summary

Pregnancy in the setting of metastatic paraganglioma is challenging, particularly in the context of tyrosine kinase use. We describe a 26-year-old female with a background of metastatic paraganglioma harboring a pathogenic SDHB variant, requiring sunitinib, which was withheld to facilitate the safe conception and delivery of a healthy baby. She required no alpha- or beta-blockade during her pregnancy and exhibited no signs of tumor progression or symptoms throughout this period. Historically, higher rates of fetal and maternal morbidity and mortality have been experienced in the setting of pregnancy. Although limited data exist on the management of metastatic paraganglioma in pregnant patients, this case suggests that careful treatment modifications, such as temporary tyrosine kinase therapy cessation and vigilant monitoring, can result in successful pregnancies without compromising maternal or fetal well-being.

Learning points

• Paraganglioma in pregnancy has been associated with poor fetal and maternal morbidity and mortality.

• Many of the treatment modalities for metastatic paraganglioma, including tyrosine kinase inhibitors, can affect fertility or cannot be utilized in pregnancy, necessitating the temporary suspension of these treatments.

• This case exemplifies that careful clinical and biochemical monitoring during pregnancy is required to avoid maternal and fetal harm while balancing the risk of disease progression off treatment.

Summary

RET mutations are implicated in 60% of medullary thyroid cancer (MTC) cases. The RET-selective tyrosine kinase inhibitor selpercatinib is associated with unprecedented efficacy compared to previous multi-kinase treatments. Langerhans cell histiocytosis (LCH) is a clonal histiocytic neoplasm usually driven by somatic BRAF mutations, resulting in dysregulated MAPK signalling. We describe a 22-year-old woman with metastatic MTC to regional lymph nodes, lung and liver. Tumour tissue harboured a somatic pathogenic RET variant p.(M918T) and selpercatinib was commenced. She experienced sustained clinical, biochemical and radiological responses. Two years later, she developed rapidly progressive apical lung nodules, prompting biopsy. Histopathology demonstrated LCH with a rare BRAF variant p.(V600_K601>D). The lung nodules improved with inhaled corticosteroids. We hypothesize that selective pressure from RET blockade may have activated a downstream somatic BRAF mutation, resulting in pulmonary LCH. We recommend continued vigilance for neoplasms driven by dysregulated downstream MAPK signalling in patients undergoing selective RET inhibition.

Learning points

• Patients with RET-altered MTC can experience rapid disease improvement and sustained disease stability with selective RET blockade (selpercatinib).

• LCH is a clonal neoplasm driven by MAPK activation, for which the most common mechanism is BRAF mutation.

• Both MTC and pulmonary LCH are driven by dysregulated MAPK signalling pathway activation.

• We hypothesise that the RET-specific inhibitor selpercatinib may have caused the activation of dormant LCH secondary to selective pressure and clonal proliferation.

Summary

A paired homeodomain transcription factor, PAX6 (paired-box 6), is essential for the development and differentiation of pancreatic endocrine cells as well as ocular cells. Despite the impairment of insulin secretion observed in PAX6-deficient mice, evidence implicating causal association between PAX6 gene mutations and monogenic forms of human diabetes is limited. We herein describe a 33-year-old Japanese woman with congenital aniridia who was referred to our hospital because of her uncontrolled diabetes with elevated hemoglobin A1c (13.1%) and blood glucose (32.5 mmol/L) levels. Our biochemical analysis revealed that her insulin secretory capacity was modestly impaired as represented by decreased 24-h urinary C-peptide levels (38.0 μg/day), primarily explaining her diabetes. Intriguingly, there was a trend toward a reduction in her serum glucagon levels as well. Based on the well-recognized association of PAX6 gene mutations with congenital aniridia, we screened the whole PAX6 coding sequence, leading to an identification of a heterozygous Gln135* mutation. We tested our idea that this mutation may at least in part explain the impaired insulin secretion observed in this patient. In cultured pancreatic β-cells, exogenous expression of the PAX6 Gln135* mutant produced a truncated protein that lacked the transcriptional activity to induce insulin gene expression. Our observation together with preceding reports support the recent attempt to include PAX6 in the growing list of genes causally responsible for monogenic diabetes. In addition, since most cases of congenital aniridia carry PAX6 mutations, we may need to pay more attention to blood glucose levels in these patients.

Learning points

• PAX6 Gln135* mutation may be causally associated not only with congenital aniridia but also with diabetes.

• Blood glucose levels may deserve more attention in cases of congenital aniridia with PAX6 mutations.

• Our case supports the recent attempt to include PAX6 in the list of MODY genes, and Gln135* may be pathogenic.

Learning points:

• Long-acting somatostatin analogues are effective in managing persistent CHI in BWS.

• UPD(11)pat genotype may be a pointer to persistent and severe CHI.

• Hepatoblastoma and Wilms’ tumour may have an onset within early infancy and early tumour surveillance is essential.

• Tumours associated with earlier onset may be resistant to recognised first-line chemotherapy.