Cleidocranial dysostosis

Cleidocranial dysostosis

Cleidocranial dysplasia is a rare genetic condition that affects teeth and bones, such as the skullfacespine, collarbones, and legs. The bones in people with CCD might be formed differently or might be more fragile than normal, and certain bones such as collarbones may be absent.


Runx2, also known as Cbfa1, is a multifunctional transcription factor essential for osteoblast differentiation. It also plays a major role in chondrocyte maturation, mesenchymal stem cell differentiation, cleidocranial dysplasia, and the growth and metastasis of tumors.

A review encountered several cases of orthodontic implications but a few cases on cranial defect approach.

The articles present literature that is unanimous on the recommendation of expectant conduct in children since the cranial block can occur spontaneously, even if the delayed form 1).

Hypophosphatasia (HPT) and cleidocranial dysplasia (CCD) are characterized by both defective ossification and bone mineralization. Patients usually present with craniosynostosis and cranial defects which in many cases require surgical repair.


There re only 2 reported case of combined HPT and CCD in the literature.

The reported case of Blionas et al. involves a 3.5-year-old girl with concomitant homozygous CCD and heterozygous HPT. The child had an extended cranial defect since birth which improved with the administration of Strensiq and was followed until preschool age. Bone defects were relatively minor on revaluation. Due to the limited final defect, we decided not to intervene. In HPT-CCD patients, bone defects are overestimated due to osteomalacia, and thus, management strategy should be less aggressive. They should undergo surgical repair with cranioplasty with the use of cement and/or titanium meshes in case of extended final defects 2).


A case of posterior fossa subdural hematoma (PFSDH) after vaginal delivery in a neonate with CCD, which presented with several clinical symptoms such as apnea, vomiting, and bradycardia. Our patient, who had a family history of CCD, developed apnea and vomiting shortly after birth; PFSDH was detected by head computed tomography, and the patient recovered well following standard medical treatment.

The prognosis of intracranial hemorrhage in neonates with CCD is generally poor. In neonates, PFSDH occurs by the following mechanism: the distortion of the infant’s cranium during delivery, by the strong force, causes elongation of the falx and angulation of the tentorium that leads to tears in the posterior fossa venous structures, which then cause bleeding into the subdural space. In CCD, the forces occurring during vaginal delivery may cause excessive distortion of the fragile skull. An awareness of CCD is hence important to avoid vaginal delivery in prenatally diagnosed CCD cases with a family history of CCD 3).


A 40-yr-old woman presented with sensory disturbance on the left side of the body. Magnetic resonance imaging (MRI) revealed cerebellar tonsil herniation into the foramen magnum with cervical syringomyelia, and computed tomography additionally revealed skull anomalies: fontanel closure insufficiencies, cranial dysraphism, thin cranial bone, and dentition abnormalities. We diagnosed as symptomatic CM1 with syringomyelia associated with cleidocranial dysplasia, which is a dominantly inherited autosomal bone disease. Cerebral angiography revealed a developed right occipital sinus and hypoplasia of the bilateral transverse sinus. We performed FMD, paying special attention to the developed occipital sinus using ICG-VA to ensure a safe duraplasty. The angiography clearly highlighted a right-sided occipital sinus with a high contrast ratio, and no left-sided occipital sinus was visible. After a dural incision in a unilateral curvilinear fashion was safely completed, expansive duraplasty was performed. The sensory disorders experienced by the patient disappeared postoperatively. Postoperative MRI revealed elevation of the cerebellar tonsil and decreasing of the syringomyelia.

Conclusion: Additional assessment using intraoperative ICG-VA provides useful information for a safe FMD, particularly in patients with complicated cerebral venous circulation anomalies 4).


A rare case of successful cranioplasty using a modified split calvarial graft technique in a patient with cleidocranial dysplasia 5).


1)

Azevedo Almeida LC, Faraj de Lima FB, Matushita H, Valença MM, Ferreira Castro TL, de Mendonça RN. Cleidocranial dysplasia, a rare skeletal disorder with failure of the cranial closure: case-based update. Childs Nerv Syst. 2020 Dec;36(12):2913-2918. doi: 10.1007/s00381-020-04831-z. Epub 2020 Jul 30. PMID: 32734401.
2)

Blionas A, Friehs GM, Zerris VA. Hypophosphatasia and cleidocranial dysplasia-a case report and review of the literature: the role of the neurosurgeon. Childs Nerv Syst. 2021 Jun 15. doi: 10.1007/s00381-021-05261-1. Epub ahead of print. PMID: 34131769.
3)

Nagasaka S, Suzuki K, Saito T, Tanaka K, Yamamoto J. Posterior fossa subdural hematoma in a neonate with cleidocranial dysostosis after a spontaneous vaginal delivery: a case report. Childs Nerv Syst. 2021 Feb;37(2):683-686. doi: 10.1007/s00381-020-04689-1. Epub 2020 Jun 5. PMID: 32504170.
4)

Omoto K, Takeshima Y, Nishimura F, Nakagawa I, Motoyama Y, Park YS, Nakase H. Additional Assessment of Developed Occipital Sinus Using Intraoperative Indocyanine Green Videoangiography for a Safe Foramen Magnum Decompression-Technical Case Report. Oper Neurosurg (Hagerstown). 2020 Oct 15;19(5):E533-E537. doi: 10.1093/ons/opaa125. PMID: 32421802.
5)

Jung YT, Cho JI, Lee SP. Cranioplasty Using a Modified Split Calvarial Graft Technique in Cleidocranial Dysplasia. J Korean Neurosurg Soc. 2015 Jul;58(1):79-82. doi: 10.3340/jkns.2015.58.1.79. Epub 2015 Jul 31. PMID: 26279819; PMCID: PMC4534745.

Optic Pathway Glioma MRI

Optic Pathway Glioma MRI

Usually showing low T1 and high central T2 signal on MRI images, enhancement is variable.

MR imaging is optimal for showing the relationship of the mass to the hypothalamusoptic chiasm, and infundibulum as well as the intraorbital and intracanalicular components of the mass. Large tumours are typically heterogeneous with cystic and solid components.

T1: enlargement, often iso to hypointense compared to the contralateral side

T2: hyperintense centrally

thin low-signal at the periphery representing the dura 1).

FLAIR: hyper intense

T1 C+ (Gd): enhancement is variable

Patients with chiasmatic-hypothalamic low-grade glioma (CHLGG) have frequent MRIs with gadolinium-based contrast agents (GBCA) for disease monitoring. Cumulative gadolinium deposition in the brains of children is a potential concern. The purpose of a study of Malbari et al. was to evaluate whether MRI with GBCA is necessary for determining radiographic tumor progression in children with CHLGG.

Children who were treated for progressive CHLGG from 2005 to 2019 at Texas Children’s Cancer Center were identified. Pre- and post-contrast MRI sequences were separately reviewed by one neuroradiologist who was blinded to the clinical course. Three-dimensional measurements and tumor characteristics were evaluated. Radiographic progression was defined as a 25% increase in size (product of two largest dimensions) compared with baseline or best response after initiation of therapy.

A total of 28 patients with progressive CHLGG were identified with a total of 683 MRIs with GBCA reviewed (mean 24 MRIs/patient; range, 11-43 MRIs). Radiographic progression was observed 92 times, 91 (99%) on noncontrast and 90 (98%) on contrast imaging. Sixty-seven progressions necessitating management changes were identified in all (100%) noncontrast sequences and 66 (99%) contrast sequences. Tumor growth > 2 mm in any dimension was identified in 184/187 (98%) noncontrast and 181/187 (97%) with contrast imaging. Metastatic tumors were better visualized on contrast imaging in 4/7 (57%).

MRI without GBCA effectively identifies patients with progressive disease. When imaging children with CHLGG, eliminating GBCA should be considered unless monitoring patients with metastatic disease 2)


Gadolinium might not be needed for these exams to inform management decisions. Secondary benefits of a non-contrast follow-up protocol include decreased cost and risk to the patient 3).


MR examinations of 91 patients with OPG (47 with NF and 44 without) were reviewed at presentation and during follow-up. The images were evaluated for size and extension of tumor, and imaging parameters. Statistical bivariate analysis was used to compare the patients with and those without NF, and Pearson correlation was used to evaluate the correlation between the different imaging parameters and prognosis. Kappa values were calculated to determine intraobserver and interobserver variability.

Results: The most common site of involvement in the NF group was the orbital nerve (66%), followed by the chiasm (62%). In the non-NF group, the chiasm was the most common site of involvement (91%); the orbital nerves were involved in only 32%. Extension beyond the optic pathway at diagnosis was uncommon in the NF group (2%) but frequent in the non-NF group (68%). In the NF group, the tumor was smaller and the original shape of the optic pathways was preserved (91% vs. 27% in the non-NF group). The presence of cystic components was significantly more common in the non-NF patients (66% vs. 9% in the NF group). During follow-up, half the NF patients remained stable, in contrast to 5% of the non-NF group. No statistical correlation was found between imaging features and biological behavior of the tumor.

Conclusion: NF-OPG is a separate entity from non-NF-OPG, with different imaging features and prognosis, thereby warranting a specific diagnostic, clinical, and therapeutic approach 4).


1)

Müller-Forell WS, Boltshauser E. Imaging of Orbital and Visual Pathway Pathology. Springer Verlag. (2005) ISBN:3540279881.
2)

Malbari F, Chintagumpala MM, Wood AC, Levy AS, Su JM, Okcu MF, Lin FY, Lindsay H, Rednam SP, Baxter PA, Paulino AC, Orzaiz GA, Whitehead WE, Dauser R, Supakul N, Kralik SF. Gadolinium is not necessary for surveillance MR imaging in children with chiasmatic-hypothalamic low-grade glioma. Pediatr Blood Cancer. 2021 Jun 16:e29178. doi: 10.1002/pbc.29178. Epub ahead of print. PMID: 34133064.
3)

Maloney E, Stanescu AL, Perez FA, Iyer RS, Otto RK, Leary S, Steuten L, Phipps AI, Shaw DWW. Surveillance magnetic resonance imaging for isolated optic pathway gliomas: is gadolinium necessary? Pediatr Radiol. 2018 Sep;48(10):1472-1484. doi: 10.1007/s00247-018-4154-4. Epub 2018 May 22. PMID: 29789890.
4)

Kornreich L, Blaser S, Schwarz M, Shuper A, Vishne TH, Cohen IJ, Faingold R, Michovitz S, Koplewitz B, Horev G. Optic pathway glioma: correlation of imaging findings with the presence of neurofibromatosis. AJNR Am J Neuroradiol. 2001 Nov-Dec;22(10):1963-9. PMID: 11733333; PMCID: PMC7973845.

Medulloblastoma classification

Medulloblastoma classification

The diagnosis of medulloblastoma incorporates the histologic and molecular subclassification of clinical medulloblastoma samples into wingless (WNT)-activated, sonic hedgehog (SHH)-activated, group 3 and group 4 subgroups. Accurate medulloblastoma subclassification has important prognostic and treatment implications.

Harmony alignment reveals novel MB subgroup/subtype-associated subpopulations that recapitulate neurodevelopmental processes, including photoreceptor and glutamatergic neuron-like cells in molecular subgroups GP3 and GP4, and a specific nodule-associated neuronally-differentiated subpopulation in subgroup molecular SHH. Riemondy et al. definitively chart the spectrum of MB immune cell infiltrates, which include subpopulations that recapitulate developmentally-related neuron-pruning and antigen presenting myeloid cells. MB cellular diversity matching human samples is mirrored in subgroup-specific mouse models of MB 1)

Medulloblastoma, WNT-activated

Sonic hedgehog medulloblastoma.

Medulloblastoma, SHH-activated, and TP53-mutant.

Medulloblastoma, SHH-activated, and TP53-wildtype

Medulloblastoma non-WNT/non-SSH

Group 3 medulloblastoma

Group 4 medulloblastoma

Medulloblastoma histologically defined:

Classic medulloblastoma

Desmoplastic nodular medulloblastoma

Medulloblastoma with extensive nodularity

Medulloblastoma, large cell/anaplastic

Medulloblastoma, NOS.

see Cerebellar medulloblastomas

see Cerebellopontine angle medulloblastoma

see Multifocal medulloblastoma.

Immunohistochemistry (IHC)-based and nanoString-based subgrouping methodologies have been independently described as options for medulloblastoma subgrouping, however, they have not previously been directly compared. D’Arcy described the experience with nanoString-based subgrouping in a clinical setting and compare this with our IHC-based results. Study materials included FFPE tissue from 160 medulloblastomas. Clinical data and tumor histology were reviewed. Immunohistochemical-based subgrouping using β-catenin, filamin A and p53 antibodies and nanoString-based gene expression profiling was performed. The sensitivity and specificity of IHC-based subgrouping of WNT and SHH-activated medulloblastomas was 91.5% and 99.54%, respectively. Filamin A immunopositivity highly correlated with SHH/WNT-activated subgroups (sensitivity 100%, specificity 92.7%, p < 0.001). Nuclear β-catenin immunopositivity had a sensitivity of 76.2% and specificity of 99.23% for the detection of WNT-activated tumors. Approximately 23.8% of WNT cases would have been missed using an IHC-based subgrouping method alone. nanoString could confidently predict medulloblastoma subgroup in 93% of cases and could distinguish group 3/4 subgroups in 96.3% of cases. nanoString-based subgrouping allows for a more prognostically useful classification of clinical medulloblastoma samples 2).


Molecular subgrouping was performed by immunohistochemistry (IHC) for beta cateninGAB1 and YAP1FISH for MYC amplification, and sequencing for CTNNB1, and by NanoString Assay on the same set of MBs. A subset of cases was subjected to 850k DNA methylation array.

IHC + FISH classified MBs into 15.8% WNT, 16.8% SHH, and 67.4% non-WNT/non-SHH subgroups; with MYC amplification identified in 20.3% cases of non-WNT/non-SHH. NanoString successfully classified 91.6% MBs into 25.3% WNT, 17.2% SHH, 23% Group 3 and 34.5% Group 4. However, NanoString assay failure was seen in eight cases, all of which were > 8-years-old formalin-fixed paraffin-embedded tissue blocks. Concordant subgroup assignment was noted in 88.5% cases, while subgroup switching was seen in 11.5% cases. Both methods showed prognostic correlation. Methylation profiling performed on discordant cases revealed 1 out of 4 extra WNT identified by NanoString to be WNT, others aligned with IHC subgroups; extra SHH by NanoString turned out to be SHH by methylation.

Both IHC supplemented by FISH and NanoString are robust methods for molecular subgrouping, albeit with few disadvantages. IHC cannot differentiate between Groups 3 and 4, while NanoString cannot classify older-archived tumors, and is not available at most centres. Thus, both the methods complement each other and can be used in concert for high confidence allotment of molecular subgroups in clinical practice 3).


The maturation of medulloblastoma into a ganglion cell-rich lesion is very rare, with few well-characterized previous reports. Given the rare nature of this entity, it would be of great value to understand the process of posttreatment maturation and the genetic and treatment factors which contribute to this phenomenon 4).


1)

Riemondy KA, Venkataraman S, Willard N, Nellan A, Sanford B, Griesinger AM, Amani V, Mitra S, Hankinson TC, Handler MH, Sill M, Ocasio J, Weir SJ, Malawsky DS, Gershon TR, Garancher A, Wechsler-Reya RJ, Hesselberth JR, Foreman NK, Donson AM, Vibhakar R. Neoplastic and immune single cell transcriptomics define subgroup-specific intra-tumoral heterogeneity of childhood medulloblastoma. Neuro Oncol. 2021 Jun 2:noab135. doi: 10.1093/neuonc/noab135. Epub ahead of print. PMID: 34077540.
2)

D’Arcy CE, Nobre LF, Arnaldo A, Ramaswamy V, Taylor MD, Naz-Hazrati L, Hawkins CE. Immunohistochemical and nanoString-Based Subgrouping of Clinical Medulloblastoma Samples. J Neuropathol Exp Neurol. 2020 Jan 30. pii: nlaa005. doi: 10.1093/jnen/nlaa005. [Epub ahead of print] PubMed PMID: 32053195.
3)

Kaur K, Jha P, Pathak P, Suri V, Sharma MC, Garg A, Suri A, Sarkar C. Approach to molecular subgrouping of medulloblastomas: Comparison of NanoString nCounter assay versus combination of immunohistochemistry and fluorescence in-situ hybridization in resource constrained centres. J Neurooncol. 2019 May 18. doi: 10.1007/s11060-019-03187-y. [Epub ahead of print] PubMed PMID: 31104222.
4)

Mullarkey MP, Nehme G, Mohiuddin S, et al. Posttreatment Maturation of Medulloblastoma into Gangliocytoma: Report of 2 Cases [published online ahead of print, 2020 Sep 3]. Pediatr Neurosurg. 2020;1-10. doi:10.1159/000509520
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