Diffuse midline glioma H3 K27M-mutant

Diffuse midline glioma H3 K27M-mutant

Diffuse midline glioma (DMG), H3 K27M-mutant, is a new entity in the World Health Organization Classification of Tumors of the Central Nervous System 2016 grouping together diffuse intrinsic pontine gliomas and infiltrating glial neoplasms of the midline harboring the same canonical mutation at the Lysine 27 of the histone H3 tail.

In the past, pediatric diffuse gliomas were grouped with their adult counterparts, despite known differences in behavior between pediatric and adult gliomas with similar histological appearances. Information on the distinct underlying genetic abnormalities in pediatric diffuse gliomas is beginning to allow the separation of some entities from histologically similar adult counterparts.

One narrowly defined group of tumors primarily occurring in children (but sometimes in adults too) is characterized by K27M mutations in the histone H3 gene H3F3A, or less commonly in the related HIST1H3B gene, a diffuse growth pattern, and a midline location (e.g., thalamus, brain stem, and spinal cord). This newly defined entity is termed diffuse midline glioma, H3 K27M–mutant and includes tumors previously referred to as diffuse intrinsic pontine glioma (DIPG). The identification of this phenotypically and molecularly defined set of tumors provides a rationale for therapies directed against the effects of these mutations.

Epidemiology

Diffuse H3 K27M-mutant gliomas occur primarily in children but can also be encountered in adults.

Diagnosis

see Diffuse midline glioma H3 K27M-mutant diagnosis.

Differential diagnosis

After the start of the era of biopsy, Diffuse intrinsic pontine gliomas (DIPG)s bearing Histone H3K27 mutations have been reclassified into a novel entity, diffuse midline glioma, based on the presence of this molecular alteration. However, it is not well established how clinically diagnosed DIPG overlap with H3 K27-mutated diffuse midline gliomas, and whether rare long-term survivors also belong to this group 1).

Treatment

see Diffuse midline glioma H3 K27M-mutant treatment.

Outcome

Prognosis remains poor, with a 2-year survival of less than 10%

Research

Contemporary survival endpoints: an International Diffuse Intrinsic Pontine Glioma Registry study 2).


Eight patient-derived orthotopic xenograft models were obtained after direct stereotactic injection of a mixed cell suspension containing tumor cells and stromal cells in the brainstem or thalamus of nude mice and serially passaged thereafter. In parallel, we developed 6 cell-derived xenograft models after orthotopic injection of tumor-initiating cells cultured from stereotactic biopsies. Cells were modified to express luciferase to enable longitudinal tumor growth monitoring, and fluorescent reporter proteins to trace the tumor cells in the brain.These models do not form a tumor mass, they are invasive, show the H3K27 trimethylation loss in vivo and the tumor type diversity observed in patients in terms of histone H3 mutations and lineage markers. Histological and MRI features at 11.7 Tesla show similarities with treatment naïve human DIPG, and in this respect, both direct and indirect orthotopic xenograft looked alike. These DIPG models will therefore constitute valuable tools for evaluating new therapeutic approaches in this devastating disease 3).

Case series

Diffuse midline glioma H3 K27M-mutant case series.

Case reports

A 36-year-old man presented with subacute progressive cognitive and visual deterioration, and hydrocephalus requiring ventricular shunting. MRI revealed a diffusely infiltrating lesion with a gliomatosis cerebri growth pattern, multiple foci of contrast enhancement, and diffuse leptomeningeal involvement. Suboccipital craniotomy with exploration of the posterior fossa revealed a subtle capsular lesion infiltrating into the choroid plexus. Although histologically low-grade, the tumor was found to have an H3K27 M mutation establishing the diagnosis.

In spite of diverse clinicopathologic characteristics, H3K27M-mutant diffuse midline gliomas are incurable, WHO grade IV lesions with poor prognosis. Yekula et al. discussed the case in the context of a review of published reports of H3K27-mutant diffuse midline gliomas in adults. Findings late in the disease course may mimic inflammatory or infectious pathologies radiographically, and low-grade infiltrative neoplasms histologically.

The diverse clinical, radiographic and molecular features of H3K27M-mutant diffuse midline gliomas in adults remain to be completely characterized. A high index of suspicion is required to avoid missing the diagnosis. Early biopsy and detailed molecular characterization are critical for accurate diagnosis and patient counseling 4).

References

1)

Porkholm M, Raunio A, Vainionpää R, Salonen T, Hernesniemi J, Valanne L, Satopää J, Karppinen A, Oinas M, Tynninen O, Pentikäinen V, Kivivuori SM. Molecular alterations in pediatric brainstem gliomas. Pediatr Blood Cancer. 2017 Aug 9. doi: 10.1002/pbc.26751. [Epub ahead of print] PubMed PMID: 28792659.
2)

Cooney T, Lane A, Bartels U, Bouffet E, Goldman S, Leary SES, Foreman NK, Packer RJ, Broniscer A, Minturn JE, Shih CS, Chintagumpala M, Hassall T, Gottardo NG, Dholaria H, Hoffman L, Chaney B, Baugh J, Doughman R, Leach JL, Jones BV, Fouladi M, Warren KE, Monje M. Contemporary survival endpoints: an International Diffuse Intrinsic Pontine Glioma Registry study. Neuro Oncol. 2017 Sep 1;19(9):1279-1280. doi: 10.1093/neuonc/nox107. PubMed PMID: 28821206.
3)

Plessier A, Dret LL, Varlet P, Beccaria K, Lacombe J, Mériaux S, Geffroy F, Fiette L, Flamant P, Chrétien F, Blauwblomme T, Puget S, Grill J, Debily MA, Castel D. New in vivo avatars of diffuse intrinsic pontine gliomas (DIPG) from stereotactic biopsies performed at diagnosis. Oncotarget. 2017 Feb 2. doi: 10.18632/oncotarget.15002. [Epub ahead of print] PubMed PMID: 28178670.
4)

Yekula A, Gupta M, Coley N, U HS. Adult H3K27M-mutant diffuse midline glioma with gliomatosis cerebri growth pattern: Case report and review of the literature. Int J Surg Case Rep. 2020 Feb 28;68:124-128. doi: 10.1016/j.ijscr.2020.02.046. [Epub ahead of print] PubMed PMID: 32145563.

Trigonocephaly

Trigonocephaly

In this pathology different degrees of dysmorphia of the anterior cranial fossa and the presence of associated anomalies of the skull might enable specific subgroups to be identified.

Neurosurgeons, maxillofacial and plastic surgeons will be increasingly concerned with trigonocephaly because of the increase in prevalence observed over the last two decades. Cytogenetic alterations are probably underestimated in this craniosynostosis, considering the high rate of neurodevelopmental retardation compared to other single-suture synostoses. Genetic counseling is, therefore, more and more effective in this pathology. An objective method to evaluate the cosmetic results of both endoscopic and open surgeries is necessary, as some under-corrections have been reported with minimally invasive surgery 1).

Epidemiology

The cause of trigonocephaly is attributed to premature closure of the metopic suture.

Trigonocephaly is a relatively uncommon form of craniosynostosis, with an incidence of 0.3 per 1000 live births.

The prevalence of trigonocephaly increased during the last two decades both in Europe and in the United States, but no clear contributing factors have yet been identified 2).

Etiology

Chromosomal abnormalities described in metopic synostosis comprised deletion of chromosome 11q24, deletion or trisomy of 9p and deletion of 7p, deletions of 3q, 13q, 12pter, 22q11, and duplication of 15q25. SMAD6 mutations should be systematically screened for in familial cases. 3).

Diagnosis

Trigonocephaly diagnosis.

Review

The aim of a review of Mocquard et al. was to report on recent advances in trigonocephaly since the last report on craniosynostosis published in 2006.

The review was conducted in accordance with the PRISMA guidelines. Research focused on four main topics: epidemiology, neurodevelopmental disorders, genetics and surgical techniques.

Forty reports were included. The prevalence of trigonocephaly increased during the last two decades both in Europe and in the United States, but no clear contributing factors have yet been identified. Neurodevelopmental disorders are frequent in syndromic trigonocephaly and not particularly rare in non-syndromic cases (up to 34%). Developmental retardation (speech, motor or global) was almost always present in children exposed to valproic acid. Chromosomal abnormalities described in metopic synostosis comprised deletion of chromosome 11q24, deletion or trisomy of 9p and deletion of 7p, deletions of 3q, 13q, 12pter, 22q11, and duplication of 15q25. SMAD6 mutations should be systematically screened for in familial cases. Recent advances in surgical techniques have mainly concerned endoscopic-assisted procedures, as they significantly reduce perioperative morbidity.

Neurosurgeons, maxillofacial and plastic surgeons will be increasingly concerned with trigonocephaly because of the increase in prevalence observed over the last two decades. Cytogenetic alterations are probably underestimated in this craniosynostosis, considering the high rate of neurodevelopmental retardation compared to other single-suture synostoses. Genetic counselling is therefore more and more effective in this pathology. An objective method to evaluate the cosmetic results of both endoscopic and open surgeries is necessary, as some under-corrections have been reported with minimally invasive surgery 4).

Treatment

Trigonocephaly treatment.

Case series

Trigonocephaly case series.

Case reports

A patient with microcephaly and trigonocephaly, moderate intellectual disability, speech and language delay, and poor social interaction in addition to minor but atypical dysmorphic features. This report provides further insight into the pathogenicity of the Xp22.31 duplication by extending knowledge of its clinical features. This case, in association with those reported in the literature, indicates that the Xp22.31 duplication may contribute to cause pathological phenotypes with minor facial dysmorphisms, microcephaly, and intellectual disability as main features 5).


The diagnosis of a combination of both Sturge-Weber syndrome and trigonocephaly has been reported. Ristow et al., presents a patient with the unusual findings of a Sturge-Weber syndrome and simultaneous trigonocephaly induced by premature metopic synostosis. Thus, the rare combination of a port-wine stain involving the first division of the trigeminal nerve with the diagnosis of a craniosynostosis justifies the indication of a prophylactic magnetic resonance imaging acquisition before craniofacial surgeries, in order to prevent seizures and stroke-like episodes triggered by the surgical intervention 6).

References

1) , 2) , 3) , 4)

Mocquard C, Aillet S, Riffaud L. Recent advances in trigonocephaly. Neurochirurgie. 2019 Nov;65(5):246-251. doi: 10.1016/j.neuchi.2019.09.014. Epub 2019 Sep 27. Review. PubMed PMID: 31568780.
5)

Pavone P, Corsello G, Marino S, Ruggieri M, Falsaperla R. Microcephaly/Trigonocephaly, Intellectual Disability, Autism Spectrum Disorder, and Atypical Dysmorphic Features in a Boy with Xp22.31 Duplication. Mol Syndromol. 2019 Jan;9(5):253-258. doi: 10.1159/000493174. Epub 2018 Oct 2. PubMed PMID: 30733660; PubMed Central PMCID: PMC6362926.
6)

Ristow O, Freudlsperger C, Berger M, Bächli H, Hoffmann J, Engel M. Combination of Sturge-Weber Syndrome and Trigonocephaly. J Craniofac Surg. 2016 Aug 24. [Epub ahead of print] PubMed PMID: 27557468.

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