Unique association of multiple endocrine neoplasia 2A and congenital anomalies of the kidney and urinary tract in a child with a RET mutation

Abstract

Pathogenic variants in the RET gene can cause isolated and multi-system diseases. We report a patient diagnosed prenatally with unilateral multicystic dysplastic kidney and genitourinary abnormality whose mother had multiple endocrine neoplasia type 2A (MEN2A). Targeted RET sequencing found the same pathogenic variant p.C618S in the child as her mother. The child is followed by paediatric nephrology for congenital anomalies of the kidney and urinary tract (CAKUT) and by endocrine oncology for surveillance for MEN2A-related endocrine tumours. While implicated in each of these conditions individually, RET variants have never been reported to cause MEN2A and CAKUT together. This child’s family history prompted RET sequencing, resulting in presymptomatic, personalised care for MEN2A. However, this case supports the idea that genetic screening of RET (and many other genes) in patients with CAKUT may lead to molecular diagnoses that potentially improve their health through precision care.

Background

Discovering congenital anomalies of the kidney and urinary tract (CAKUT) on a prenatal ultrasound may be the first indication that a child has a multi-system Mendelian disease whose signs and symptoms arise asynchronously. Thus, making a genetic diagnosis for an infant with CAKUT can improve their health by prompting multidisciplinary team care for extra-renal manifestations. However, genetic testing of infants born with CAKUT is not routinely obtained.

CAKUT can result from single gene (Mendelian) disorders as well as structural variation of the genome.¹ Some pathogenic variants in the RET proto-oncogene are a Mendelian cause of CAKUT.¹ Because it is a widely expressed receptor tyrosine kinase, pathogenic variants in RET can cause a number of other conditions, including Hirschsprung disease and multiple endocrine neoplasia type 2A (MEN2A).

We report an infant with a prenatal diagnosis of CAKUT who, because of a strong maternal history of MEN2A, underwent targeted sequencing of RET. This identified a known pathogenic variant previously implicated in MEN2A, leading to her now being closely followed for MEN2A surveillance. This variant may also be the cause of, or contributor to, her CAKUT. The case demonstrates the potential of genetic testing as a precision medicine strategy in children born with CAKUT.

Case presentation

A 32-year-old pregnant woman of middle class status living in a suburban locale underwent a prenatal ultrasound at 35 weeks, which identified a female fetus with a right multicystic dysplastic kidney (MCDK) as well as a possible left duplicated collecting system. There were normal amniotic fluid levels. She was a stay-at-home mom. Prior to and during her pregnancy, she did not have any exposures to lead, other heavy metals or toxins, did not have any infections or major illnesses and did not smoke, drink alcohol or use illicit substances. The pregnancy was overall uncomplicated, but the mother’s medical history was significant for having MEN2A, status-post thyroidectomy necessitating daily use of levothyroxine.

The infant was born at 39 weeks via uncomplicated C-section delivery for breech presentation. Birth weight was 2890 g and Apgar scores, which measure the health of a newborn, were 9 and 9. The infant urinated and stooled in the delivery room. Physical exam at the time of birth was significant for a round, protuberant cystic structure at the vaginal introitus. Following her exam, she was sent to the well-baby nursery. A renal-bladder ultrasound on day 0 of life did not appreciate a left duplicated collecting system, but confirmed a right MCDK and noted a right tubular structure that seemed to insert into the infant’s vagina and was thought to perhaps be an ectopic ureter.

With regards to her family history, there was no known history of kidney diseases or other congenital structural anomalies. However, two of her family members reported a diagnosis of MEN2A. Her mother was diagnosed with MEN2A at the age of 12 and underwent thyroidectomy at that time. Her maternal grandmother was diagnosed at the age of 40. Her mother and grandmother underwent targeted sequencing of RET, revealing a pathogenic RET variant (c.1853G>C; p.C618S) causing MEN2A.

Investigations

Given her CAKUT diagnosis, a chromosomal microarray test was performed using the Illumina CytoSNP-850K array. This was normal. Further CAKUT-motivated genetic testing (eg, CAKUT gene panel testing and whole exome sequencing) was not performed because of the known maternal history of a RET mutation and the recognition that the patient would first be sequenced for this variant. Indeed, due to the family history of MEN2A the patient was evaluated in the cancer genetics clinic and was found to carry the known familial pathogenic variant (RET c.1853G>C; p.C618S). If the patient had been negative for this pathogenic variant, CAKUT gene panel testing would have taken place.

Treatment

Her kidney function was normal since birth, but in the first 3 months of life there was metabolic acidosis and hyperkalaemia. There was concern about potential subtle abnormalities of her contralateral kidney that were not apparent on ultrasound or possible vesicoureteral reflux. However, a voiding cystourethrogram was not obtained and prophylactic antibiotics were not begun, opting instead for watchful waiting. The acidosis was managed with oral bicarbonate therapy.

The treatment plan for the patient with regards to the MEN2A diagnosis includes surveillance of calcitonin levels and discussion of either continued calcitonin level surveillance or even prophylactic thyroidectomy at age 5 as well as initiation of surveillance for pheochromocytoma and hyperparathyroidism starting in adolescence.²

Outcome and follow-up

The child continues to be followed by nephrology for her CAKUT. The renal ultrasound performed at 7 months of age showed new mild-moderate pelvocaliectasis and ureterectasis extending to the bladder. However, this was not observed on follow-up ultrasounds. The acidosis ultimately self-resolved by 1 year of age.

Now approximately 32 months old, she has never had a urinary tract infection and her kidney function has been normal based on creatinine-based estimated glomerular filtration rate. She is growing well (88%ile for height and 54%ile for weight) and achieving appropriate developmental milestones. She is normotensive and has no proteinuria. The most recent ultrasound confirmed the compensatory hypertrophy of the normally appearing left kidney, which has grown to 9.1 cm. The left MCDK is no longer visible. The ultrasound did not appreciate what had been previously thought to be an ectopic ureter. Because of the patient’s good growth, normotension, lack of proteinuria, normal kidney function and compensatory hypertrophy of the left kidney, she is now being seen once yearly by the nephrology team.

Calcitonin and carcinoembryonic antigen (CEA) levels have remained normal and continued surveillance versus prophylactic surgery are discussed in annual visits.³

Discussion

Here we present the case of a 32-month-old female child diagnosed prenatally with unilateral MCDK who, due to a family history of MEN2A, underwent targeted sequencing of RET and was found to have a pathogenic variant for MEN2A (c.1853G>C; p.C618S) which had not been previously implicated in CAKUT. CAKUT is a common condition, occurring in 1 in every 500 children and accounting for 50% of cases of chronic kidney disease (CKD).⁴ There is a substantial prevalence of genomic disorders in children with isolated CAKUT or as part of a multi-organ syndrome.⁵ For these syndromes, early recognition of a genomic disorder can allow a paediatrician to pre-emptively manage potential sequelae of the condition in their patients and/or refer the child to appropriate subspecialists.

MEN2A is a subtype of MEN, an autosomal dominant disorder that affects 1 in every 30 000 people.⁶ It is caused by pathogenic variants in the RET proto-oncogene.⁷ MEN2A-associated pathogenic variants are a rare example of inherited oncogenic hotspot mutations, which is in contrast to most inherited cancer syndromes, which are caused by inactivating mutations and subsequent loss of heterozygosity in associated tumours. MEN2A is associated with a high risk for medullary thyroid carcinoma (MTC), with nearly 100% of patients developing MTC as a result of their diagnosis. Fifty percent of patients develop pheochromocytoma.

The RET proto-oncogene, located on chromosome 10q11.2, encodes a widely expressed receptor tyrosine kinase that is integral to the normal development of kidneys and urinary tract via interaction with the ligand glial cell line-derived neurotrophic factor.⁸ Hypomorphic or loss of function RET variants are associated with renal agenesis, dysplasia and distal ureter insertion defects as well as Hirschsprung disease.⁹ Beyond CAKUT, and given its widespread expression, variants within the RET gene cause several diseases beyond CAKUT, with gain of function variants causing MEN2A.¹⁰ The main pathogenic variants within RET that cause MEN2A are located in codon 634 of exon 11 or codons 609, 611, 618 and 620 of exon 10. The most common pathogenic variant affects codon 634, accounting for 80% of MEN2A cases.¹¹ Extra-endocrine manifestations, including 13% of patients with kidney anomalies were also found in patients with MEN2B caused by the classical MEN2B associated pathogenic RET variant p.M918T.¹²

The potential association of RET variants with CAKUT and MEN2A/MTC in the same individual has been reported in three other families (p.C618R, C620S and C634R).^13–15 A critical distinction from the present case, however, is that in these previous reports, a CAKUT diagnosis was a secondary finding in an adult who presented clinically with cancer. This is in contrast with the present case, in which the family history of MEN2A prompted pre-symptomatic genetic testing in an infant who also had CAKUT. This early diagnosis of MEN2A allowed immediate connection with the cancer genetics clinic, providing long-term follow-up and management prior to any onset of cancer.

Based on established molecular genetics and the previous reports it is possible that the RET variant in the patient could be the cause of both MEN2A and CAKUT. The normal chromosomal microarray also helps to rule out a known pathogenic structural variant as the cause of CAKUT.^{16 17} However, we cannot state this unequivocally. Excluding other genetic forms of CAKUT in this patient through whole exome sequencing would increase the certainty of the association of the RET variant and CAKUT. Furthermore, while there were no obvious risk factors from the maternal and prenatal history, it is also possible that there were unidentified environmental factors that could have caused, or contributed to, the patient’s CAKUT diagnosis.

This case suggests that a prenatal or perinatal CAKUT diagnosis may be the first indicator of MEN2A in children with this condition. In the current era, it is highly likely that this infant would not have been routinely screened for a genetic cause of her MCDK without the positive family history. Making a genetic diagnosis allowed multidisciplinary care to be initiated to manage her presymptomatically for extra-renal manifestations. The potential specific association of RET variants with CAKUT and MEN2A may be individually rare. However, there are many other rare genetic causes of CAKUT that have extra-renal manifestations. By considering these individually rare genetic causes of CAKUT in aggregate across the population, a substantially greater percentage of patients than perhaps appreciated could benefit from making a genetic diagnosis.

Numerous other reports are emerging that highlight the value of more widespread genetic screening for patients with kidney diseases.^18–20 While it is certainly possible that the CAKUT in this patient was unrelated to the pathogenic RET variant, this case report perhaps provides another example of the value of performing principled clinical genetic testing in a wider range of nephrology cases than we have been doing previously.

Learning points.

• The p.C618S variant in RET may cause a syndrome of congenital anomalies of the kidney and urinary tract (CAKUT) and multiple endocrine neoplasia type 2A (MEN2A).

• A diagnosis of CAKUT in an infant or child should prompt physicians to obtain a more detailed and specific family history about MEN2A or endocrine malignancies in general.

• For infants and children diagnosed with CAKUT, early recognition of a genomic disorder can allow pre-emptive management of potential sequelae of the condition, including referral to appropriate subspecialists.