Wilms tumor with Mulibrey Nanism: A case report and review of literature

Abstract Background Mulibrey‐Nanism (Muscle‐liver‐brain‐eye Nanism = dwarfism; MUL) is a rare genetic syndrome. The underlying TRIM37 mutation predisposes these children to develop tumors frequently. In the largest published series of MUL, 8% patients were reported to develop Wilms tumor (WT). The published literature lacks data regarding the best treatment protocol and outcome of this cohort of children with WT and MUL. We report here a 2‐year‐old boy with WT and MUL and present a review of literature on WT in MUL. Case Our patient had associated cardiac problems of atrial septal defect, atrial flutter and an episode of sudden cardiac arrest. We managed him successfully with chemotherapy, surgery and multi‐speciality care. He is alive and in remission at follow‐up of 6 months. Conclusion A total of 14 cases (including present case) of WT have been reported in MUL and treatment details were available for six cases. They were managed primarily with surgery, chemotherapy with/without radiotherapy, and all achieved remission. The outcome data is available only for two cases, one has been followed up till 15 years post treatment for WT and other is our patient.

congestion secondary to constrictive pericarditis and yellowish dots in fundi. They have an increased tendency to develop cystic and benign adenomatous lesions in various parts of the body, cutaneous nevi flammi, gonadal dysfunction especially in females, type II diabetes mellitus, fibrous dysplasia and malignancy, mainly Wilms tumor (WT). 5,6 There are very few reports of WT in MUL and the published literature lacks data regarding the best treatment protocol and outcome of this cohort. Here we report a child of WT with MUL and provide a review of literature.

| METHOD
We reviewed medical records of our case of a child with MUL and WT and looked at treatment details, complications and outcome. We  and 0, Z score as per WHO growth chart) and length of 49 cm (between À2 and 0, Z score as per WHO growth chart). On examination, child had a triangular face, low nasal bridge, high broad forehead, low set ears, a high-pitched voice, distended abdomen, left sided ballotable renal mass and hepatomegaly. Neurological examination revealed mild hypotonia and normal higher mental functions. His present height was 87 cm (15th-50th centile as per WHO growth chart) and weight was 10 kg (third centile as per WHO growth chart). Echocardiography showed moderate size secundum atrial septal defect (ASD) with bidirectional shunt predominantly left to right and restrictive filling of right ventricle as evidenced by tissue doppler imaging. Final diagnosis was considered WT stage 4 due to multiple nodules seen in liver. He was started on neo-adjuvant chemotherapy as per SIOP2001 protocol.

| RESULTS
He received five doses of weekly injection vincristine and one dose of injection actinomycin-D. Doxorubicin was not given in view right ventricular dysfunction and was replaced with cyclophosphamide. After week 5 of chemotherapy child was admitted with febrile neutropenia and started on intravenous antibiotics. On the second day of this admission he complained of restlessness, vomiting and hypotension, closely followed by generalized tonic-clonic seizures and went into sudden cardiac arrest. Child was revived after cardiopulmonary resuscitation. As he was still in coma and had jerky respiration so was intubated and ventilated. His condition improved over next 48 h and he was extubated. Electroencephalogram was normal.
Magnetic resonance imaging of brain was normal except for presence of a choroid plexus/xanthogranulomatous cyst in left lateral ventricle and a shallow and J shaped Sella turcica. He developed hoarseness of voice which was possibly due to vincristine and intubation. Subsequently, he developed an episode of paroxysmal tachycardia with heart rate >220/min, diagnosed as atrial flutter (AF) on electrocardiogram. It was aborted with injection amiodarone. Gradually his voice returned and he could swallow food. In view of cough, he was tested for SARS-COV-2 by PCR and it was detected to be positive. He was shifted to COVID-19 care ward where he had a second episode of atrial flutter and required to be shifted to intensive care unit again. He was managed successfully for AF and his cardiac rhythm reverted to normal. Once he was negative for COVID-19 he was discharged.
In view of child not tolerating chemotherapy well, having abnormal facies, cardiac anomaly, hepatomegaly and abnormal findings in MRI brain; it was suspected that child has some underlying syndrome.
So, a karyotyping with standard 400-450 G banding technique was performed and it was reported as normal. Mitomycin C sensitivity testing was done on 72 h PHA stimulated unsynchronized cultures to rule of Fanconi Anemia and was reported as normal. Finally a clinical exome sequencing using selective capture and sequencing of the protein coding regions of the genome/genes was performed. The library was sequenced to mean >80-100Â coverage on Illumina sequencing platform. The sequences obtained was aligned to human reference genome (GRCh38.p13) using Sentieon aligner and analyzed using Sentieon for removing duplicates, recalibration and re-alignment of indels. 7 Sentieon haplotype caller was used to identify variants which are relevant to the clinical indication. Gene annotation of the variants was performed using VEP program 8 against the Ensembl release 99 human gene model. 9 In addition to SNVs and small indels, copy number variants (CNVs) were detected from targeted sequence data using the Exome Depth (v1.1.10) method. 10

| REVIEW OF LITERATURE
On review of literature, we found a total of 14 cases including one case of ours. 6,[15][16][17][18][19] The algorithm used for review of literature is shown in Figure 2. Table 1 show details of all the cases.
The mean age of the subjects was 19 months (Male: Female ratio 1:1). Other than our case, histopathology detail was available for only one other case which was cystic partially differentiated nephroblastoma. Staging details were available for three patients.
Two were classified as stage 1 and one as stage IV and managed accordingly. Largest series of eight patients of Wilms tumor has been reported from Finland in a cohort of 101 cases of MUL but it lacked details of treatment and outcome. 19 The treatment details were available for six cases. They were managed mainly Children with WT should be assessed for possible syndromic association and be managed accordingly.
Two out of 14 patients initially treated for WT, required pericardiectomy several years later. Our case also has early signs of pericardial thickening and may later require cardiac intervention. Although cardiac affliction is known, arrhythmia as a predominant symptom seen in our patient has not been described previously. Other features seen in patients associated with MUL and WTs included bone dysplasia, constrictive pericarditis requiring pericardiectomy, and massive ascites requiring repeated abdominocentesis.

| DISCUSSION
Our patient presented with WT. In view of child not tolerating chemotherapy well, having abnormal facies, cardiac anomaly, hepatomegaly and abnormal findings in MRI brain; it was suspected that child has some underlying syndrome thus genetic testing was performed. Our patient showed three major signs (small for gestational age lacking catchup growth, craniofacial features, shallow and J-shaped Sella turcica) and two minor signs (peculiar high-pitched voice and hepatomegaly) as described by Karlberg   could be a way for the cell to survive the loss of TRIM37. 24 In several non-MUL cancers, TRIM37 has been found to be overexpressed.
TRIM37 plays a critical role in cell proliferation and, therefore its overexpression has been detected in a variety of human tumors. 25 The decrease in TRIM37 results in loss of ubiquitinated H2A and therefore a decrease in tumor growth, while its overexpression induces tumorigenesis. 26 Although WT has been previously reported in MUL patients, cases of familial WT associated with TRIM37 outside of MUL have not been documented.
The missense variation in exon 2 of the TRIM37 gene variant c.80T>A noted in our patient was novel and has not been reported previously. 25 This mutation was also found in the father and hence possibly can be considered to confer pathological attributes. The other mutation found in the patient in exon 15 of the TRIM37 gene variant c.1336C>T is a reported pathogenic variant and is probably de novo acquired in our patient.
The coexisting liver lesion which was initially considered as hepatic metastasis and was later diagnosed as benign liver hamartomas, emphasizes the need to look out for associated benign tumors. These patients are highly prone to tumorigenesis and careful diagnosis can help in assigning the correct stage and formulating relevant treatment protocol.
Heart is the most frequently affected organ in MUL with constrictive pericarditis, myocardial hypertrophy and variable myocardial fibrosis constituting the main components of Mulibrey heart disease.
Mariata et al. reported 49 adults with MUL heart disease, noted these patients to be highly susceptible to develop congestive cardiac failure and need for pericardiectomy in one third of the patients. 27 ASD similar to our case have been reported in MUL. 28,29 Our patient had two episodes of AF and an episode of sudden cardiac arrest which has not been reported previously in children with MUL. Structural heart defect, particularly ASD especially ostium primum is known to be associated with arrhythmias, with increasing frequency with age. 30  WT although rare in children with MUL, is treatable. Our case highlights the need to watch out for cardiac arrhythmia in these patients. Although a lot could not be gathered form review of literature regarding treatment protocol, but it appears that these children tolerate standard treatment protocol well and can achieve remission.
T A B L E 2 Diagnostic criteria for Mulibrey Nanism and the diagnostic findings in our patient

ETHICAL STATEMENT
Institutional approval N/A. Informed consent of parent obtained.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.