J Clin Immunol (2014) 34:922–927 DOI 10.1007/s10875-014-0098-0
ASTUTE CLINICIAN REPORT
Pineal Germinoma in a Child with Interferon-γ Receptor 1 Deficiency. Case Report and Literature Review L. Taramasso & S. Boisson-Dupuis & M. L. Garrè & E. Bondi & A. Cama & P. Nozza & G. Morana & J. L. Casanova & M. G. Marazzi
Received: 15 July 2014 / Accepted: 2 September 2014 / Published online: 14 September 2014 # Springer Science+Business Media New York 2014
Abstract Interferon-γ receptor 1 (IFN-γR1) deficiency is one of the primary immunodeficiencies conferring Mendelian Susceptibility to Mycobacterial Disease (MSMD). Some cases of neoplasms have been recently reported in patients with MSMD, underlying the already known link between immunodeficiency and carcinogenesis. We report the first case of intracranial tumour, i.e. pineal germinoma, in a 11-year-old patient with complete IFN-γR1 deficiency. The first clinical presentation of the genetic immunodeficiency dates back to when the L. Taramasso (*) Infectious Disease Department, San Martino Hospital, University of Genova, 16100 Genoa, Italy e-mail: [email protected] S. Boisson-Dupuis : J. L. Casanova St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA M. L. Garrè : E. Bondi : A. Cama : P. Nozza : G. Morana Istituto Giannina Gaslini, Genoa, Italy J. L. Casanova Howard Hughes Medical Institute, Chevy Chase, USA J. L. Casanova Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Imagine Institute, Necker Hospital for Sick Children, Paris, France
child was aged 2 y and 10 mo, when he presented a multi-focal osteomyelitis caused by Mycobacterium scrofulaceum. The diagnosis of IFN-γR1 deficiency (523delT/523delT in IFNGR1 gene) was subsequently made. The child responded to antibiotic therapy and remained in stable clinical condition until the age of 11 years, when he started complaining of frontal, chronic headache. MRI revealed a solid pineal region mass lesion measuring 20 × 29 × 36 mm. Histological findings revealed a diagnosis of pineal germinoma. The patient received chemotherapy followed by local whole ventricular irradiation with boost on pineal site, experiencing complete remission, and to date he is tumor-free at four years follow-up. Four other cases of tumors have been reported in patients affected by MSMD in our knowledge: a case of Kaposi sarcoma, a case of B-cell lymphoma, a case of cutaneous squamous cell carcinoma and a case of oesophageal squamous cell carcinoma. In conclusion, in patients with MSMD, not only the surveillance of infectious diseases, but also that of tumors is important. Keywords Interferon-γ receptor 1 deficiency . interferon-γ receptor 2 deficiency . IL-12Rβ1 deficiency . MSMD . pineal germinoma
Introduction J. L. Casanova Paris Descartes University, Paris, France J. L. Casanova Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, Paris, France M. G. Marazzi Scuola di Scienze Mediche e Farmaceutiche, Università degli Studi di Genova, Genoa, Italy
Interferon-γ receptor 1 (IFN-γR1) deficiency is a primary immunodeficiency described nearly 20 years ago, in 1996, by Newport et al.  and by Jouanguy et al. . These first reports regarded, respectively, four Maltese children affected by severe dissemination of environmental mycobacteria (EM)  and a Tunisian child with fatal bacillus Calmette-Guerin (BCG) infection . These were the first descriptions of a
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genetic deficiency subsequently named Mendelian Susceptibility to Mycobacterial Disease (MSMD) . MSMD is characterized by an abnormal susceptibility to severe infection caused by BCG, EM and extra-intestinal non-typhoidal Salmonella infections. Also, severe Mycobacterium tuberculosis infections have been reported in patients with MSMD genetic etiologies . Other infections, viral, bacterial, fungal or parasitic, have also been described in individual patients. Four forms of IFN-γR1 deficiency are known, differentiated on the basis of mode of transmission (dominant or recessive), surface expression of receptor and total or partial effect on IFN-γ signaling . The autosomal dominant form (818del4/wt) is the commonest, and it has milder clinical expression, with greater long-term survival. The recessive forms are rare and burdened by high severity and lethality in the early years of life. In particular, complete IFN-γR1 deficiency has a severe clinical phenotype, resulting in susceptibility to recurrent infections, mostly caused by intramacrophagic bacteria. It typically leads to early disseminated mycobacterial infections without mature granuloma formation, with a high rate of lethality within the 10th year of age in affected children [3, 6]. As well as IFN-γR1 deficiency, other genetic disorders can cause MSMD, when a mutation occurs in a key gene involved in the IFN-γ/IL-12 circuit. The genes involved are IFNGR1 and IFNGR2 (encoding IFN-γR1 and IFN-γR2, respectively), STAT1 (encoding STAT1), IL12P40 (encoding the IL12p40 subunit), IRF8 (encoding IFN regulatory factor), and IL12RB1 (encoding the IL-12Rβ1 chain) [3, 7]. An X-linked transmission of susceptibility to mycobacterial infection has also been reported, with mutations in NEMO (encoding NEMO) and CYBB (encoding gp91phox) genes . In the autosomal dominant form of IFN-γR1 deficiency, therapy with recombinant IFN-γ, associated to appropriate antibiotic treatment, may offer good response . In complete IFN-γR1 deficiency the only possible curative therapy is bone marrow transplantation, but the engraftment may be severely impaired by elevated IFN-γ plasma levels, and it is burdened by severe complications . Recently, some cases of neoplasms have been reported in patients with MSMD [10–13]. The link between immunodeficiency and carcinogenesis is already known in other forms of both acquired and primary immunodeficiencies such as HIV, organ or bone marrow transplantation, severe combined immunodeficiency, X-linked hyper-IgM syndrome, common variable immune deficiency, X-linked agammaglobulinemia, X-linked lymphoproliferative syndrome, autoimmune lymphoproliferative syndrome, ataxia telangiectasia and Wiskott-Aldrich Syndrome [14–17]. In our knowledge this is the first case of Central Nervous System (CNS) tumor (namely intracranial germinoma) described in a patient with IFN-γR1deficiency.
Case Description We report the case of pineal germinoma occurrence in an Italian boy with complete IFN-γR1 deficiency. The first clinical presentation of the genetic immunodeficiency dates back to when the child was aged 2 y and 10 mo. He presented to clinical observation with a multi-focal osteomyelitis, involving legs, feet and hands. He also had severe deficit of growth, with weight and height under the 5th percentile. Radiologic imaging revealed a lesion in the left lobe of the liver and multiple enlarged mesenteric and peripancreatic lymph nodes. The causative agent has been isolated from lymph node biopsy and was found to be Mycobacterium scrofulaceum. The child responded to therapy with rifampin, rifabutin, and clarithromycin, which he continued for ten months. Three months after the suspension of antibiotic treatment he had to restart it because a recrudescence of the infection occurred (high fever, pain, swelling and isolation of the same EM from a second lymph node biopsy). The recurrence of disseminated infection caused by EM brought the clinicians to investigate the possibility of a genetic immunodeficiency and to make the diagnosis of IFN-γR1 deficiency. The child had homozygous deletion of thymidine on exon 4 and position 523 in IFNGR1 gene. Such mutation is associated with a complete defect of IFN-γR1 expression and function and is inherited in autosomal and recessive mode . His parents were born in the same small town, yet consanguinity was not documented. The IFNγ plasmatic level at the moment of the diagnosis was 780 pg/ml. The child continued different combined antibiotic therapies for 10 years. The therapy has been later de-escalated to rifabutin and clarithromycin, which the patient is still tacking. The clinical conditions of the patient remained stable until the age of 11 y, when he started complaining of frontal, chronic headache. No abnormality was found on neurologic examination and fundus examination was normal. MRI was performed to clarify the origin of the symptom, and revealed a solid pineal region mass lesion measuring 20×29×36 mm, isointense on T1- and T2- weighted images, with marked enhancement after contrast administration. The mass also presented a small central calcification and extended caudally into the mesencephalic aqueduct and fourth ventricle, with consequent supratentorial hydrocephalus, effacement of cortical sulci, and periventricular edema (Fig. 1a, b). Based on imaging findings, pineal germinoma or pineoblastoma were suspected. Furosemide was promptly administered for the uncompensated hydrocephalus and total body MRI was performed, ruling out the presence of metastases. The patient was subjected to endoscopic biopsy and 3rd ventriculostomy. Neuropathological examinations disclosed a tumour composed of large cells with vacuolated, clear or eosinophilic cytoplasm and round nuclei with macronucleoli. Immunohistochemical stainings showed expression of PLAP and CD117. The labeling index was extremely high (70 %). Small
foci of necrosis were seen and microcalcifcations were found. Few lymphocytes T (CD3+) and very few lymphocytes B (CD20+) were present. These features confirmed the diagnosis of germinoma. Levels of α-FP and BHCG in plasma and in liquor samples were normal. Biopsy cultures for fungi, mycobacteria and bacteria were negative. The patient received chemotherapy with the protocol SIOP GCTS’96 for intracranial germinoma (carboplatin+vepesid at 1st and 3rd cycle, ifosfamide+vepesid at 2nd and 4th cycle) , followed by whole ventricular irradiation 24 Gy+boost on pineal site up to 40 Gy. He experienced complete remission of the germinoma (Fig. 1 c, d), without secondary dissemination at four years follow-up. A prolonged phase of infectious complications with fever and doubtful pneumonia foci occurred after the end of irradiation therapy and recovery was prompt with liposomal amphotericin B therapy. The boy is now in stable clinical conditions, without active mycobacterial infection.
Discussion This is to our knowledge the first report of intracranial tumor, namely pineal germinoma, in a patient with complete IFN-γR1 deficiency and more generally with MSMD. Fig. 1 Pineal germinoma: preand post treatment MRI features. Figure legend: a, c: sagittal T2weighted images; b, d: post contrast T1-weighted images. Brain MRI performed for chronic headache demonstrates a solid mass lesion, isointense on T2weighted image (a) with marked enhancement following gadolinium injection (b), involving the pineal region. There is a small hypointense area on both T1- and T2-weighted images within the lesion, consistent with a central calcification (arrows). The lesion extends into the mesencephalic acqueduct and fourth ventricle, causing supratentorial hydrocephalus. At post treatment follow-up MRI performed 4 years later (c, d) showed complete remission. Note persistence of the small pineal gland calcification with physiological rim enhancement (arrows)
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Primary pediatric intracranial germ cell tumors are rare and usually localized in the pineal and suprasellar regions of the brain. They are divided into major histologic types: germinomas and non germinomatous germ cell tumors, that include choriocarcinoma, embryonal carcinoma, yolk sac tumors, and mixed germ cell tumors. Teratomas are often considered separate entities. These kinds of tumor have a peak incidence at 10–12 years of age , as happened in the case of our patient above described. Sporadic cases of germ cell tumors have been reported in other primary immunodeficiencies, however, they were all extra-cranial tumors, such as in ataxia-telangiectasia [21–25] and in Wiskott-Aldrich syndrome . More frequent are the cases reported in HIV  and the HIV itself has been recognized as a predisposing factor for testicular germ cell tumors . Differently than for HIV, not much is known about the onset of neoplasms in complete IFN-γR1 deficiency, perhaps because patients have poor prognosis and only a small proportion reach adult age [5, 6]. In vitro and murine cancer models have shown that lack of IFN-γR1 may be linked to higher rates of tumors . To date, 4 cases of tumors have been reported in patients affected by genetic deficiencies in IFN-γ/IL-12 axis: a case of Kaposi sarcoma, a case of B-cell lymphoma, a case of cutaneous squamous cell carcinoma and a case of oesophageal squamous
Recessive complete IFN-γ R1 deficiency
Complete IL-12Rβ1 deficiency
Recessive complete IFN-γ R2 deficiency
Recessive complete IFN-γ R1 deficiency
Recessive complete IFNγ R1 deficiency
Age at immunodeficiency diagnosis (years)
Disseminated 16 Mycobacterium avium at 1 year of age. Recurrent (9 episodes) Mycobacterium avium, fortuitum and porcium infections 4 Disseminated MAC at the age of 18 months, disseminated Mycobacterium abscessus 4 Disseminated Mycobacterium scrofulaceum at 2 years of age
9 From the age of 5 months recurrent disseminated BCG and Mycobacterium fortuitum 27 Recurrent enteric and extraintestinal salmonellosis from the age of 6 years. Oropharingeal candidiasis.
Type of bacterial infection associated
Disseminated cutaneous squamous cell carcinoma
Oesophageal squamous cell carcinoma
Kind of tumor Age at neoplastic disease diagnosis (years)
Table 1 Clinical features of patients with IFNγ/IL12 axis deficiency and reported neoplastic diseases
Disseminated Mycobacterium abscessus
At the age of 17 years, he still had generalized lymphoadenopathy. Infection well controlled.
Protocol GCTS’96 and radiotherapy
Radiotherapy and esophagectomy, followed by chemotherapy with taxotere, cisplatin, and 5FU Surgical excision
IFNα and taxol
Mycobacterium fortuitum isolated in pleural fluid
Active infectious diseases at time of tumor diagnosis
EBV detected by hybridisation in atypical lymphoid cells
Deceased at 20 years of age
Alive after 4 years follow up
Deceased at 20 years of age
Deceased at 29 years of age
None (HPV-DNA negativity on tumor biopsy)
Deceased at 12 years of age
Outcome after neoplastic disease diagnosis
Viral infection associated (tumorrelated)
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cell carcinoma [10–13]. General features of the cases reported in the literature are showed in Table 1. In two of the abovementioned reports a viral activation has been detected: HHV8 positivity in the case of Kaposi sarcoma and EBV positivity in B-cell lymphoma. Our present findings further suggest a link between immunodeficiency and susceptibility to neoplasms. The 4 cases of cancer reported in the literature occurred in patients with severe homozygous forms, with complete deficit of IFN-γR1 in two of them, complete deficiency of IFN-γR2 in one and complete deficiency of IL-12Rβ1 in the last case. Of note, the diagnosis of the genetic immunodeficiency disorder was made after the diagnosis of neoplasm in one case  and after the tenth year of age in two cases [12, 13]. This emphasizes the difficulty of making an early diagnosis in the setting of these rare diseases. All 4 patients reported died between 2 and 4 y after the diagnosis of neoplasm. Our patient is still alive 4 y after the diagnosis of pineal germinoma and his clinical situation is tumor-free to date. The good outcome obtained in our case may be favored by the overall good prognosis of pineal germinoma  and to the fact that an appropriate therapy was possible despite immunodeficit. The therapy caused more toxicity than usual with this protocol, and it was solved also thanks to a strong multidisciplinary approach. Furthermore, the baseline clinical situation of the patient allowed us to make an effective chemotherapy, because the EM infection was kept dormant by antibiotic prophylaxis. In other cases, some patients with immunodeficiencies have a prognosis that may be affected by the inability to perform aggressive chemotherapies for the simultaneous presence of infections in phase of activity, as in the case described by Bax and colleagues  (see Table 1). In conclusion, in patients with MSMD and inherited deficit of the IFN-γ/IL-12 circuit, not only the surveillance of infectious diseases, but also that of tumors is important. Acknowledgments We are grateful to “Fondazione Berlucchi” and “Associazione per la ricerca sui tumori cerebrali del bambino”, which support the assistance to patients with cerebral tumors. We are also grateful to Manuela Rescali for her secretarial assistance. Conflict of Interest The authors declare that they have no conflict of interest.
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