Parathyroid carcinoma (PC) is usually diagnosed in the fifth decade of life and has an equal frequency of occurrence in both sexes . But since our patient presented in her second decade, we had to strongly suspect a familial syndrome causing PC. Hyperparathyroidism jaw tumor syndrome is an autosomal dominant disease which is known to cause parathyroid carcinoma. It consists of mutations in the CDC 73 gene, primary hyperparathyroidism due to parathyroid tumours, ossifying fibroma (usually in the maxilla or mandible) and a variety of uterine and renal abnormalities. We suspect this familial syndrome in our patient because she had a CDC 73 gene mutation, parathyroid carcinoma and possible ossifying fibroma in the right maxillary sinus, but no evidence of uterine or renal abnormalities. Unfortunately, we couldn’t biopsy the right maxillary lesion to confirm the ossifying fibroma .
There are several clinical, diagnostic, and therapeutic problems with parathyroid carcinoma when it occurs in pregnancy. A palpable rapidly enlarging neck mass (30 – 70%) and recurrent laryngeal nerve palsy are important clinical signs which suggest PC rather than benign hyperparathyroidism . During pregnancy our patient presented with a rapidly enlarging neck lump suggestive of parathyroid carcinoma. PHPT in pregnancy could be linked with adverse complications. Analysis of outcome of 40 pregnant patients with PHPT, there was a 27.5% incidence of foetal deaths and a neonatal tetany incidence of 19% . Major maternal complications identified were nephrolithiasis, acute pancreatitis, and bone disease.
Fibrous bands with trabecular architecture, capsular and vascular invasion and a high mitotic index in the parathyroid histology are suggestive of PC. Some have used atypical adenoma for lesions which has PC features but questionable invasion. But with the use of immunohistochemistry, now parathyroid adenoma and carcinoma can be clearly differentiated. The main immunohistochemistry features suggestive of PC are, loss of expression of parafibromin, Rb, p27, Bcl-2a, mdm -2 and APC with the positivity of galectin and overexpression of P53 and Ki index of > 5% . Our patient, following initial surgery had a high mitotic index, questionable invasion, overexpression of P53 with Ki index of 12 are more suggestive of parathyroid carcinoma rather than atypical adenoma. Parafibromin staining is very important for immunohistopathological diagnosis of PC, as CDC – 73 gene is responsible for expression of parafibromin protein. In our patient, staining of parafibromin and B catenin proteins were not done due to its unavailability.
In our patient, the Whole exome sequencing was done in blood, and not in parathyroid tissue, and it was performed by Illumina® NovaSeq® 6000 Next Generation Sequencer using the SureSelectXT ® Human (Mouse) All Exon V6 5190–8864 kit. With the in-house bioinformatics pipeline, the genetic analysis was performed. Mapping the paired end sequences to GrCh37 human reference genome and variant calling was done using BWA-mem algorithm and Genome Analysis Tool Kit (GATK). Generated variant calling format file (VCF) was annotated using SNP‐eff with Refseq, population and clinical database information. A virtual gene panel was created including the genes responsible for Multiple Endocrine Neoplasia (MEN) and Hyperparathyroidism, which was then used to identify the variant associated with the phenotype and the clinical features of the proband. Benign variants were filtered out according to the standard American College of Medical Genetics (ACMG) guidelines .
of the remaining variants revealed a novel heterozygous single base deletion (NM_024529.5:
c.584delC) in the exon 07 of the CDC73 gene which may create a frameshift (p.
Ser195Leufs*7) and a premature protein truncation. This variant is predicted to
be pathogenic, when analysed using the MutationTaster software .
this single base deletion causes the loss of the C- terminal domain of theparafibromin
protein. Hence the interaction of the C- terminal domain of the parafibromin protein
with the RNA polymerase II-associated factor 1 homolog protein (PAF1) and DNA-directed
RNA polymerase II subunit RPB1(POLR2A) is lost. Moreover, the premature protein
lost during the interaction with Catenin beta-1 protein, which is a key
downstreamcomponent of the canonical Wnt signalling pathway .
When parathyroid carcinoma occurs in pregnancy, the main cause for increase maternal and foetal mortality is Hypercalcemia. Hypercalcemia can be managed medically or surgically. Both approaches have its own benefits and risks. Patient symptoms, severity of disease and age at gestation at the time of diagnosis are main factors which will decide therapeutic option. If the patient was diagnosed during the 1st or 2nd trimesters in pregnancy with severe hypercalcemia (Ionized calcium > 2.85 mg/dl), second trimester surgery is generally preferred over medical management . According to Carella and Gossain  there are higher foetal complications in 3rd trimester surgery when compared to the second trimester. In our patient, we suspected an underline parathyroid carcinoma, before the second surgery. But at that time, she was pregnant at 16 weeks of POA. Even though en bloc resection with thyroidectomy was considered, we had to consider the duration of surgery and the harmful effects of prolong anesthesia to the fetus as well as mother, as en block resection will take a considerable time, compared to focal removal of the parathyroid mass. Therefore, after discussing the benefits and risks with the patient, we decided to go ahead with focal removal of the parathyroid mass.
Medical management is mainly indicated in mild hypercalcemia, and it consist of volume expansion, loop diuretics, bisphosphonates, denosumab, calcimimetics and calcitriol. But in pregnancy, most of the above are contraindicated. But calcimimetics and calcitriol have been used successfully without any foetal mortality. However, they have not shown to alter the natural progression of the disease, and data on long term efficacy of calcimimetics are lacking .
Parathyroid carcinoma has a high recurrence rate (23 – 51%). So, patients with parathyroid carcinoma should be followed up throughout their lifetime with serum calcium and intact PTH, every 6 months for the initial 5 years following surgery, and then annually. They should also undergo ultrasound scans of the neck annually with biochemical monitoring as above.
This case shows the importance of stringent follow up with atypical parathyroid adenoma patients, benefit of second trimester surgery in management of hypercalcemia due to parathyroid carcinoma during pregnancy and importance of identifying the novel mutations of CDC73 gene.