A Case report: Co-occurrence of IMAGe syndrome and Rhabdomyosarcoma

Open AccessPublished:May 25, 2021DOI:https://doi.org/10.1016/j.cancergen.2021.05.006

      Abstract

      IMAGe syndrome is a rare congenital disorder, presenting with intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies (in males). So far only 17 individuals have been diagnosed molecularly with IMAGe syndrome, this patient is the first case of an individual diagnosed with IMAGe and concurrent rhabdomyosarcoma.
      The patient was born at 30 weeks’ gestation and received treatment for hyponatremia and hyperkalemia. At 4 9/12 years of age the patient showed a painless, non-mobile mass on the left thigh. In the biopsy performed a sarcoma weave with solid, nest-like growth, with characteristics of rhabdomyosarcoma was identified. The family history and physical examination indicated IMAGe syndrome so genetic testing was requested. A whole exome sequencing procedure with use of SureSelectXT Human ALL Exon V7, confirmed a single nucleotide variant NM_000076.2(CDKN1C):c.820G>A (p.Asp274Asn); identifying a missense mutation in the imprinted gene CDKN1C associated with IMAGe syndrome. Although tumours associated with CDKN1C are rare, deregulation of imprinted genes is increasingly being recognised as a mechanism of tumorigenesis in cancer; chromosomal region 11p15.5 contains a cluster of imprinted genes. This same region is the most consistent site of allele loss in rhabdomyosarcoma and is the same region altered in both IMAGe and Beckwith-Wiedemann syndrome. Molecular studies have found genetic changes in the 11p15 region in a variety of embryonal tumours like Wilms tumours which are commonly developed in Beckwith-Wiedemann syndrome and embryonal rhabdomyosarcoma.
      Through this case we aim to present the possibility of oncogenesis in patients with IMAGe syndrome, specifically rhabdomyosarcoma.

      Keywords

      Introduction

      IMAGe syndrome is an acronym of the major clinical findings of this disorder: intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies (in males) [
      • Bennett J
      • Schrier Vergano SA
      • Deardorff MA
      IMAGe syndrome.
      ]. It was described in 1991 [
      • Vilain E
      • Le Merrer M
      • Lecointre C
      • Desangles F
      • Kay MA
      • Maroteaux P
      • et al.
      IMAGe, a new clinical association of intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies.
      ] and it is an undergrowth developmental disorder with life-threatening consequences [
      • Bergada I.
      • et al.
      Familial occurrence of the IMAGe association: additional clinical variants and a proposed mode of inheritance.
      ]. No formal clinical diagnostic criteria for IMAGe have been defined; nevertheless, common findings reported in individuals with a clinical and/or molecular diagnosis include: intrauterine growth restriction, postnatal growth deficiency with variable growth hormone deficiency, adrenal hypoplasia congenita, genital abnormalities in males (including unilateral or bilateral cryptorchidism), micropenis, hypospadias and chordee.
      So far twenty-eight individuals from 16 families have been reported with features consistent with the clinical diagnosis of IMAGe syndrome. To date, only 17 of these individuals had the diagnosis confirmed molecularly [
      • Arboleba V.
      • et al.
      Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome.
      ]. The molecular diagnosis of IMAGe syndrome is established with suggestive findings or by identification of a heterozygous CDKN1C pathogenic variant in the PCNA binding domain of the maternally expressed allele.
      CDKN1C is located on chromosome 11 and encodes a protein known to have a key role in inhibiting cell-cycle progression. In most tissues, the paternal allele is repressed by distant imprinting control regions, such that expression of CDKN1C is primarily from the maternal allele [
      • Arboleba V.
      • et al.
      Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome.
      ,
      • Diaz-Meyer N.
      • et al.
      Silencing of CDKN1C (p75KIP2) is associated with hypomethylation at KvDMR1 in Beck-Wiedemann syndrome.
      ,
      • Shin J.Y.
      • Fitzpatrick G.V.
      • Higgins M.J.
      Two distinct mechanisms of silencing by the KvDMR imprinting control region.
      ].
      CDKN1C is located within an imprinted cluster of genes that regulates prenatal and postnatal growth and development. Genetic alterations in CDKN1C have been shown to give rise to Beckwith-Wiedemann syndrome (BWS), an overgrowth disorder [
      • Wiedemann HR
      Das EMG-Syndrom: Exomphalos, Makroglossie, Gigantismus und Kohlenhydratstoffwechsel-Störung [The EMG-syndrome: exomphalos, macroglossia, gigantism and disturbed carbohydrate metabolism].
      ,
      • Beckwith J.B.
      Macroglossia omphalocele, adrenal cytomegaly, gigantism, and hyperplastic visceromegaly.
      ]. In contrast, IMAGe syndrome is an undergrowth disorder. Missense mutations that are localised to a highly conserved region of the PCNA-binding domain of CDKN1C in IMAGe syndrome result in excess inhibition of growth and differentiation – a gain of function.
      For the first time in literature a case of a 5-year old paediatric patient, whose diagnosis of IMAGe syndrome has been molecularly confirmed and has been diagnosed with rhabdomyosarcoma (RMS) is presented. By presenting this patient's case we want to broaden the literature available in subjects with the rare IMAGe syndrome confirmed by molecular testing, as well as present a possible correlation between IMAGe syndrome and rhabdomyosarcoma, something that has not been reported in any previous published IMAGe syndrome cases.

      Case Presentation

      The female patient is the sixth-born and the only living child of a healthy mother. The parents are unrelated and both are healthy with no family history of any chronic diseases. With regards to the five previous pregnancies, the first child, male, was born at 24th week of gestation (320gr birth weight) but died during the first day of life. The second child, also male, was born in the 35th week of pregnancy (1600gr birth weight), however the child died on the 10th day of life. The confirmed cause of death in both cases was adrenal agenesis. In addition, both children suffered from birth defects, namely shortened limbs, as well as hypospadias in the former and absence of corpus callosum in the latter one. After the death of the second child, the parents were referred to genetic counselling. A karyotyping from peripheral blood leukocytes was performed in both parents, showing no abnormalities. The third child was a male stillborn, born at 37th week of gestation (1550gr birth weight). The cause of death was once again confirmed in section to be adrenal agenesis. Similarly to previous births, this child also had shortened limbs. The fourth and fifth pregnancy were both miscarriages during the 10th and 12th week of pregnancy respectively. No genetic testing was performed in any of the first three children. In addition, all pregnancies were accompanied by symptoms of oedema, proteinuria and hypertension, also known as pre-eclampsia.
      Our patient was born at 30 week gestation to a healthy 41-year-old G6P4 mother, with a birth weight of 845g (<3rd percentile) and Apgar score of 3-5. No respiratory support was required.
      At the time of birth, the patient received a solution of NaCl 10% 0.5mL 4 times daily and on the seventh day of life she was treated with hydrocortisone on the grounds of hyponatremia and hyperkalemia. At 5 weeks of life, a therapy of Corhydron 3 × 2.5mg and Cortineff 100mg (½ tablet in the morning, ½ later in the day and ¾ in the evening) was initiated.
      During the first endocrinological evaluation at the age of 22 months, normal thyroid function was observed, however the physical examination revealed malnutrition and a Flocare FR 14 PEG (percutaneous endoscopic gastrostomy) was established. Subsequent endocrinological reviews at the age of 2 and 3 years old showed that euthyroidism was maintained (Table 1). At the age of 3 years 2/12, the patient was diagnosed with primary adrenal insufficiency (ACTH >1600pg.ml, cortisol 4.1ug/dl). During the same visit, hypertension, malnutrition and posture defects were also noted.
      Table 1Summary of laboratory testing
      DateACTH (Pead. Norms: 5-46 pg/ml)
      17.09.201447.1
      19.02.20159.4
      26.06.20155.4
      23.06.201615.9
      16.01.201711.9
      08.02.201815.6
      06.03.201815.6
      DateCortisol (Pead. Norms: 3.7-9.5 ng/ml)
      12.09.2014<10
      19.02.2015112
      26.06.201517
      23.06.2016204
      16.01.201771
      08.02.2018114
      06.03.201820
      06.03.201971
      10.05.2019114
      DateIgF-1 (Pead. Norms
      0-11 months: 14-192ng/mL
      ng/ml)
      09.02.201566
      22.07.201595
      09.10.2018229
      DateTSH (Pead. Norms: 0.92-4.38 uIU/ml)
      04.10.20181.438
      29.03.20192.056
      DateT4 (Pead. Norms: 6-16.4 ng/dl)
      04.10.20181.50
      29.03.20191.26
      1 year: 23-243 ng/mL
      2 years: 28-256 ng/mL
      3 years: 31-249 ng/mL
      4 years: 33-237 ng/mL
      1 0-11 months: 14-192ng/mL
      Developmental assessments revealed a language delay with only single words spoken by the age of 22 months, the patient started walking at the age of 2 years 4/12 with a tendency to fall forward.
      At age 4 years 9/12, she was admitted to our Paediatric Haematological and Oncological ward after a referral due to a tumour mass that had been present for a month. Upon first observation, there was a noticeable weight deficiency, dysmorphic features were noted, with small and low-set ears, prominent forehead and micrognathia (Fig 1). The patient had a short stature for her age and showed signs of global developmental delay with concurrent speech delay, although her understanding seemed to be appropriate for her age. On physical examination, RR 128/1, 113/87, 104/50 mm Hg with normal cardiac and pulmonary sounds. No abnormalities in the liver or spleen were found. The abdomen was painless on palpation without pathological resistance. No swelling was noted. A deep-seated mass was detected and located on the left thigh with a size of 5 × 3 × 4 cm, showing a hard consistency, non-mobile and painless features.
      Fig 1
      Fig 1Profile showing low-set ears, prominent forehead and micrognathia (a), frontal view showing short stature (b)
      The patient was on Corhydron 3 × 2.5mg, Cortineff ½ tablet of 0.1mg in the morning and ¾ tablet of 0.1mg in the evening, Enarenal ½ tablet of 5mg in the morning and Hydrochlorothiazide 1 × 6.25mg in the morning.
      From the patient's previous medical history, in combination with the physical characteristics and clinical symptoms noted during the admission, concerns were raised of a possible diagnosis of IMAGe syndrome. As a result, both the patient and her parents were referred for genetic testing. The results of the patient's genetic testing (Whole exome sequencing (WES) procedure with use of SureSelectXT Human ALL Exon V7 - Agilent), confirmed a single nucleotide variant c.820G>A of CDKN1C, amino acid change p.Asp274Asn; identifying a missense mutation in the imprinted gene CDKN1C associated with IMAGe syndrome. As of the time of writing this case report, the variant C.820G>A has not yet been reported in the Leiden Open Variation Database (LOVD). Following Human Genomic Variant Society recommendations for the naming of genetic mutations, this mutation is named NM_000076.2(CDKN1C):c.820G>A (p.Asp274Asn) and was determined using the reference sequence NC_000011.10:g.2884670C>T [
      • Dunnen Den
      • et al.
      HGVS recommendations for the description of sequence variants: 2016 update.
      ].
      The paternal genetic testing showed no genetic mutations in the tested region, whereas the maternal testing showed the same mutation of CDKN1C gene as in our patient. Due to a suspected rhabdomyosarcoma on the left lower limb, the patient was sent for biopsy of the tissue mass and referred to MRI and CT imaging.
      The MRI scan across the entire left limb showed a large limited polynuclear lesion in the vastus intermedius with high signal in T2-dependent images and STIR sequences; and low signal in T1-dependent images. The change irregularly intensified when contrast was given, with maximum dimensions of 8.6 × 5.2 × 3.3 cm (Fig. 2).
      Fig 2
      Fig 2MRI scans: frontal T1-weighted and fat saturated T2-weighted images (a,b), axial frontal T1-weighted and fat saturated T2-weighted images (c,d), all images illustrate a left sided muscle tumour adjacent to femur bone
      The MRI of the head revealed focal lesions both over and under the subarachnoid, with pathological enhancements. The ventricular system was not extended nor displaced. The base tanks were normal. The middle and inner ear structures were also normal. Finally, the bone structures appeared normal without any features of pathological reconstruction.
      The CT scan of the chest showed no focal changes in the lungs and no fluid in the pleural space. Scoliosis was present. The abdominal CT scan revealed that the liver, spleen and pancreas were not enlarged and were uniformly enhanced with contrast. The adrenal glands were very poorly visible. The right kidney (7.8cm) showed features of a filled capillary-pelvic system; left kidney 8.2cm without stasis. In the upper chalice of the right kidney and in the lower chalice of the left kidney deposits of 3mm and 4mm respectively were noted. Ureters were not dilated. Finally, a double arterial vascularization of the left kidney was visible with an additional artery reaching the lower pole of the kidney. Scoliosis was again confirmed on this scan.
      In the biopsy performed, sarcoma weave with solid, nest-like growth, with characteristics of rhabdomyosarcoma, possibly in alveolar form was identified. In the performed IHC reactions: Vimentin (+), Desmin (+), MyoD1 (+) nuclear reaction, present in approximately 50% of the growth cells, Myogenin (+) present in > 90% of the growth cells, Caldesmon (-), WT1 (+) spilled, cytoplasmic, CD99 (-), CD56 (+) spilled, S-100P (-), wall positive, Ki67 (+), nuclei positive in about 40% of the growth cells. FISH test with the Vysis FOX01 BreakApart probe - after recalculating 100 cells no FOX01 gene translocation was found. The microscopic image indicated the lack of FOX01 gene translocation (translocations t(2,13)(q35,q14) or (1,13)(p36,q14)) FOX01 (13.q14). The microscopic image in correlation with IHC was ambiguous, corresponding to RMS embryonal (G3), but did not allow to explicitly exclude a solid, undifferentiated form of RMS alveolar (G3).
      Empirical chemotherapy was initiated as per the treatment guidelines for rhabdomyosarcoma with a combination of vincristine, actinomycin, ifosfamide and cyclophosphamide (according to CWS-guidance for risk adapted treatment of soft tissue sarcoma and soft tissue tumours in children, adolescents, and young adults Version 1.6.1. from 24.05.2014).
      An MRI performed 2 months after initiation of chemotherapy showed a decrease in size of the tumour (Fig. 3, B). Administration of contrast still lead to an increase in attenuation on the left lower limb lateral to the femur. Based on the imaging, the dimensions of the tumour was estimated to be no more than 7.4 × 1.9 × 0.7cm. After four months of chemotherapy and with imaging showing reduction in size of the tumour, a decision was taken to surgically excise the remains of the mass (Fig 3, C). Several months later and after the excision of the mass, no signs of relapse were seen on imaging (Fig 3. D).
      Fig 3
      Fig 3MRI scans: initial frontal T1-weighted image during diagnosis (a), frontal T1-weighted image at the second and fourth month into chemotherapy (b,c), frontal T1-weighted image after surgical excision (d)
      As of writing this case report, the patient remains in full remission and under the care of an oncologist, nephrologist, cardiologist and endocrinologist.

      Discussion

      We present the first case captured in literature of a patient with genetically diagnosed IMAGe syndrome and rhabdomyosarcoma. This provides an opportunity to broaden the literature available for this rare syndrome as well as shine a light on a potential increased risk of developing rhabdomyosarcoma in these patients.
      Previous studies have shed light on the similarities between IMAGe and Beckwith-Wiedemann syndromes, both derived from mutations in the CDKN1C gene (11p15.5 region).
      Beckwith-Wiedemann syndrome (BWS), a syndrome of overgrowth that presents with congenital abnormalities and an increased risk of childhood cancer, has been well described in medical literature and its mechanisms are well understood. The cause of the syndrome has been pinpointed to mutations and DNA methylation defects along the chromosomal region 11p15.5, specifically two regions: ICR1 and IC2. ICR1 contains two genes, a noncoding growth-suppressing RNA called H19 and the gene for the fetal growth factor IGF2 (insulin-like growth factor 2) [
      • Eggermann Thomas
      • Binder Gerhard
      • Brioude Frédéric
      • Maher Eamonn R.
      • Lapunzina Pablo
      Maria Vittoria Cubellis et al. CDKN1C mutations: two sides of the same coin.
      ]. Deletions within the maternally inherited ICR1 as well as hypermethylation of the paternally inherited ICR1 causes elevated IGF2 levels and BWS in humans [
      • Eggermann Thomas
      • Binder Gerhard
      • Brioude Frédéric
      • Maher Eamonn R.
      • Lapunzina Pablo
      Maria Vittoria Cubellis et al. CDKN1C mutations: two sides of the same coin.
      ]. IC2 contains, as well as regulates the expression of the gene CDKN1C, a gene responsible for negatively regulating cell proliferation during the G1 phase of the cell. Loss-of-function mutations or hypomethylation of IC2 lead to underactivity of CDKN1C and dysregulation of the cell cycle at the G1 phase. It is this underactivity of CDKN1C that results in the BWS phenotype [
      • Eggermann Thomas
      • Binder Gerhard
      • Brioude Frédéric
      • Maher Eamonn R.
      • Lapunzina Pablo
      Maria Vittoria Cubellis et al. CDKN1C mutations: two sides of the same coin.
      ]. Paternal uniparental disomy for chromosome 11p15, which usually presents with mosaicism, has also been detected in patients diagnosed with BWS and confers a severe phenotype [
      • Milani Donatella
      • Pezzani Lidia
      • Tabano Silvia
      • Miozzo Monica
      Beckwith-Wiedemann and IMAGe syndromes: two very different diseases caused by mutations on the same gene.
      ].
      The consensus on oncologic risk in patients diagnosed with BWS is that it varies depending on the heterogeneity of the genetic and epigenetic abnormalities as well as the duration of observation. Patients with abnormalities contained exclusively within the centromeric domain (IC2 hypomethylation and CDKN1C mutations) carry a lower risk of embryonal tumors (especially Wilm's tumor) compared to patients with abnormalities within the telomeric domain (ICR1 hypermethylation) and 11p15 paternal uniparental disomy, which have an increased risk of such tumors [
      • Milani Donatella
      • Pezzani Lidia
      • Tabano Silvia
      • Miozzo Monica
      Beckwith-Wiedemann and IMAGe syndromes: two very different diseases caused by mutations on the same gene.
      ].
      Another syndrome characterised by abnormalities within the 11p15 chromosome is Silver-Russell syndrome (SRS), a rare condition presenting with prenatal and postnatal growth restriction among a multitude of other symptoms. Characteristic features of SRS such as: relative macrocephaly (defined as a head circumference at birth ≥1.5 SD score (SDS) above birth weight and/or length SDS), prominent forehead, body asymmetry and feeding difficulties; enables it to be distinguished from idiopathic intrauterine growth restriction and those born small for gestational age [
      • Wakeling Emma L.
      • et al.
      Diagnosis and management of Silver-Russell syndrome: first international consensus statement.
      ]. Currently in ~60% of patients diagnosed with SRS an underlying molecular cause can be identified. The most common identified causes are loss of methylation on chromosome 11p15 (30-60% of patients) and maternal uniparental disomy for chromosome 7 (upd(7)mt; seen in ~5-10% of patients). Rare familial cases of SRS caused by a maternal CDKN1C gain-of-function mutation have been reported [
      • Wakeling Emma L.
      • et al.
      Diagnosis and management of Silver-Russell syndrome: first international consensus statement.
      ].
      A molecular etiology cannot currently be determined in ~40% of patients diagnosed with SRS. The Netchine-Harbison clinical scoring system (NH-CSS) has been developed to aid in diagnosis of SRS by basing the diagnosis on characteristic clinical features seen in the syndrome. SRS was part of the differential diagnosis in this patient, but was excluded as the patient did not sufficiently meet the NH-CSS criteria.
      The inheritance of IMAGe syndrome is complex. The condition is described as having an autosomal dominant inheritance pattern. However, because this gene is paternally imprinted, IMAGe syndrome results only when the mutation is present on the maternally inherited copy of the gene. In contrast to BWS, IMAGe syndrome is caused by so-called gain-of-function mutations in the PCNA-binding domain of CDKN1C. All of the reported CDKN1C pathogenic variants in individuals with IMAGe syndrome are missense variants in the maternally inherited allele that fall within an eight amino-acid region of the PCNA (proliferating cell nuclear antigen)-binding domain. Point mutations leading to single amino acid changes confer increased stability, decreased degradation and thereby increased overall activity of the CDKN1C protein. Higher activity of this protein leads to inhibition and ultimately dysregulation of the cell cycle and cell growth. Paradoxically, decreased cell growth does not necessarily result in a decreased likelihood of malignancy as dysregulation of the cell cycle can lead to unforeseen effects on the organism.
      Therefore, underactivity of CDKN1C, and its role in the development of malignancy cannot be discounted; nor its role in BWS and development of Wilm's tumour [
      • Debaun MD, MPH, Michael R.
      • Tucker MD, Margaret A.
      Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome.
      ]. Although overactivity of CDKN1C, as in IMAGe syndrome, is not that well described in literature, it has been observed in hepatoblastoma as well as in head and neck cancers [
      • Hartmann W.
      • et al.
      P57(KIP2) is not mutated in hepatoblastoma but shows increased transcriptional activity in a comparative analysis of the three imprinted genes p57(KIP2), IGF2 and H19.
      ,
      • Lai S
      • Goepfert H
      • Gillenwater AM
      • Luna MA
      • El-Naggar AK.
      Loss of imprinting and genetic alterations of the cyclin-dependent kinase inhibitor p57KIP2 gene in head and neck squamous cell carcinoma.
      ]. Children with BWS are at risk of developing cancer by approximately 7.5% and although tumours associated with CDKN1C are rare, they have been reported in such patients [
      • Li M.
      • Squire J
      • Shuman C
      • et al.
      Imprinting status of 11p15 genes in Beckwith-Wiedermann syndrome patients with CDK1N mutations.
      ]. Therefore, there is a possibility that IMAGe syndrome patients who share mutations on the same gene CDKN1C (11p15 region) can be at risk of cancer.  In addition, dysregulation of imprinted genes is increasingly being recognised as a mechanism of tumorigenesis in cancer. Chromosomal region 11p15.5 contains a cluster of imprinted genes and is the most consistent site of allele loss in rhabdomyosarcoma, a main embryonal muscle cancer most commonly occurring in children [
      • Anderson John
      • Gordon Anthony
      • McMAnus Aidan
      • Shipley Janet
      • Pritchard-Jones Kathy
      Disruption of imprinted genes at chromosome region 11p15.5 in peadiatric rhabdomyosarcoma.
      ].
      Both BWS and RMS, have been noted to have alterations in the 11p15 chromosomal region. Similarly, molecular studies have found genetic changes in the 11p15 region in a variety of embryonal tumours like Wilms tumour and embryonal rhabdomyosarcoma. It is noted that embryonal RMS is the most frequent subtype of RMS, accounting for 50% of the tumours, while alveolar RMS accounts for 30% [
      • Schwienbacher C
      • Angioni A
      • Scelfo R
      • Veronese A
      • Calin GA
      • Massazza G
      • Hatada I
      • Barbanti-Brodano G
      • Negrini M.
      Abnormal RNA expression of 11p15 imprinted genes and kidney developmental genes in Wilms' tumor.
      ].  Although the above is derived from the only four cases reported by the year 2001, Adam C. Smith et al. reported three additional cases of BWS and RMS, all showing histological consistency of alveolar RMS. It is important to note that the cytogenetic analysis of those tumours did not detect the t(2;13) or t(1;13) translocation that generate the PAX3- or the PAX7FKHR fusion proteins common for alveolar RMS [
      • Schwienbacher C
      • Angioni A
      • Scelfo R
      • Veronese A
      • Calin GA
      • Massazza G
      • Hatada I
      • Barbanti-Brodano G
      • Negrini M.
      Abnormal RNA expression of 11p15 imprinted genes and kidney developmental genes in Wilms' tumor.
      ]. The findings of this analysis are important to our case, as a similar lack of detection of the t(2;13) or t(1;13) translocation has been reported on the tissue biopsy that was performed on our patient diagnosed with IMAGe and RMS, with the ambiguous results of embryonal type and without exclusion of alveolar RMS.
      To the best of our knowledge, this is the first reported case of a molecularly diagnosed IMAGe syndrome patient with RMS. However, it is difficult to determine and with certainty say that there is an increased risk of malignancies in such patients diagnosed with IMAGe syndrome, compared with the general population, due to the rarity of this disease and the resulting difficulty in finding patients to conduct further studies on. Nevertheless, we hope the above will increase the focus on further testing and better prognosis on IMAGe syndrome patients with malignancies.

      Conclusion

      By presenting this case of IMAGe syndrome with concurrent rhabdomyosarcoma; we intend to start the discussion for not only the underactivity of CDKN1C carrying malignant potential, but overactivity as well, as in the case of IMAGe syndrome. Whenever a patient presents with dysmorphic features, small and low-set ears, prominent forehead, micrognathia and abnormal values of ACTH and cortisol, IMAGe syndrome should be on the differential and the patient should be referred for genetic testing. Upon diagnosis of the disease, the patient should be considered for further screening for any malignancies including hepatoblastoma, neck tumours as well as rhabdomyosarcoma.
      Until now, there have not been any reports on the IMAGe syndrome with concurrent RMS, and little is known about a possible link between RMS and IMAGe syndrome. However, the increasing number of articles concerning the role of mutations in the CDKN1C gene and tumorigenesis, indicates that there should be a higher level of suspicion in patients with IMAGe syndrome. We believe this case is a step forward in understanding the possibilities of cancer in such patients and suggest that further research should be conducted to determine any possible correlations.

      Declarations of Competing Interest

      None.

      Acknowledgements

      The authors thank Dr Anna Materna-Kiryluk and Prof. Rafał Płoski for the genetic examination.

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