Rhinocladiella mackenziei

Rhinocladiella mackenziei

Rhinocladiella mackenziei is a pigmented fungus.

Primary cerebral phaeohyphomycosis due to Rhinocladiella mackenziei is an extremely rare infection carrying more than 80% mortality, with most cases reported from the Middle East region. This darkly pigmented black yeast is highly neurotropic, aggressive and refractory to most antifungal agents.

Cerebral abscess due to pigmented moulds are a rare but usually fatal infection occasionally seen in transplant recipients.

Rhinocladiella mackenziei was believed to be endemic solely to the Middle East, due to the first cases of infection being limited to the region. However, cases of R. mackenziei infection are increasingly reported from regions outside the Middle East. The agent is dissimilar to typically opportunistic agents of fungal disease in that the majority of cases have been reported from immunologically normal people.

A 67 year old male of Iraqi origin underwent a deceased donation renal transplant for renal failure and 2 months later was diagnosed with an abscess in the left posterior frontal lobe of his brain. Subsequent biopsy proved this to be due to the mould Rhinocladiella mackenziei. Further interventions included two operations to aspirate the lesion, voriconazole, then liposomal amphotericin B, then a combination of posaconazole and flucytosine which he continued for over four years. He also suffered from right ankle pain and was diagnosed with septic arthritis; R. mackenziei was isolated from pus aspirated from the ankle joint. He responded well to the treatment and has had little loss of function, and on CT the cerebral lesion has stabilised. Beta-D-glucan, initially at very high levels proved useful to monitor response over the 5 years and the latest sample was negative (38 pg/mL). This case is notable for the first disseminated case of this infection, its favourable outcome on a novel antifungal combination and a new approach to monitoring the course of disease 1).

Barde et al. analyzed posaconazole concentrations in plasma and multiple CNS specimens taken from a patient who received posaconazole because of cerebral phaeohyphomycosis. Low posaconazole concentrations were obtained in CNS specimens, with sample-to-plasma ratios between 5% and 22%. This case highlights the role of neurosurgery during cerebral phaeohyphomycoses, even those caused by posaconazole-susceptible black fungi. 2).

Yusupov et al. presented an immunocompetent elderly male, presenting with multiple brain abscesses, with R. mackenziei confirmed by nuclear ribosomal repeat region sequencing, who was successfully treated by surgical debridement and intravenous voriconazole. To our knowledge this is the first case reported from the United Kingdom. We also present a review of all such cases so far reported in the English literature world-wide, which we believe is a step further to understanding the pathogenesis and establishing effective treatment of this rare, yet often fatal disease 3).

Cristini et al. described the case of a native Afghan woman living in France who presented with brain abscesses due to R. mackenziei 4).



Hardman N, Young N, Hobson R, Sandoe J, Wellberry-Smith M, Thomson S, Barton R. Prolonged survival after disseminated Rhinocladiella infection treated with surgical excision and posaconazole. Transpl Infect Dis. 2020 Feb 13:e13264. doi: 10.1111/tid.13264. [Epub ahead of print] PubMed PMID: 32053285.

Barde F, Billaud E, Goldwirt L, Horodyckid C, Jullien V, Lanternier F, Lesprit P, Limousin L, Cohen JF, Lortholary O. Low Central Nervous System Posaconazole Concentrations during Cerebral Phaeohyphomycosis. Antimicrob Agents Chemother. 2019 Oct 22;63(11). pii: e01184-19. doi: 10.1128/AAC.01184-19. Print 2019 Nov. PubMed PMID: 31427294; PubMed Central PMCID: PMC6811437.

Yusupov N, Merve A, Warrell CE, Johnson E, Curtis C, Samandouras G. Multiple brain abscesses caused by Rhinocladiella mackenziei in an immunocompetent patient: a case report and literature review. Acta Neurochir (Wien). 2017 Sep;159(9):1757-1763. doi: 10.1007/s00701-017-3141-0. Epub 2017 Apr 1. Review. PubMed PMID: 28365816.

Cristini A, Garcia-Hermoso D, Celard M, Albrand G, Lortholary O. Cerebral phaeohyphomycosis caused by Rhinocladiella mackenziei in a woman native to Afghanistan. J Clin Microbiol. 2010 Sep;48(9):3451-4. doi: 10.1128/JCM.00924-10. Epub 2010 Jun 30. PubMed PMID: 20592148; PubMed Central PMCID: PMC2937739.

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.

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.



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 1).

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 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.

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.

Hair collar sign

Hair collar sign

The “hair collar sign”, a designation introduced by Commens et al. in 1989, is characterized by the presence of a ring of terminal hairs around any cutaneous lesion. It has been described as a relatively specific marker of neuroectodermal defects.

Infants with Hair collar sign (HCS) and hair tuft of the scalp (HTS) are at high risk for underlying neurovascular anomalies. Magnetic resonance imaging scans should be performed in order to refer the infant to the appropriate specialist for management 1).

Kuemmet et al. investigated the risk of cranial central nervous system dysraphism in children presenting with aplasia cutis congenita of the head, who presented between 1/1/2000 and 6/15/2016. Inclusion criteria were subjects with aplasia cutis congenita of the head who received CT or MR imaging of the head.

They identified a total of 69 subjects with aplasia cutis congenita affecting the head and who received imaging. The most common location of the aplasia cutis congenita lesion was the vertex scalp (49.3%). The hair collar sign was present in 27.5% of patients. Twelve of 69 patients (17.4%) demonstrated abnormalities of the bone, vasculature, or brain on head imaging. Only one patient had a diagnosis of encephalocele that required neurosurgical intervention. There was a statistical association between the hair collar sign and the presence of abnormal imaging findings (P = .029), with a negative predictive value of 89.4%.

The incidence of central nervous system dysraphism in patients with aplasia cutis congenita of the head appears below, and it may not be necessary to image the head of each child presenting with this skin lesion. The hair collar sign may be a marker of underlying defects 2).

Takayama et al. reported two cases of aplasia cutis congenita associated with hair collar signs and hemangioma simplex in their parietal regions. A hair collar sign and a hemangioma are known to suggest the possibility of underlying neural tube defects. However, no obvious bone defects or heterotopic neural tissue were observed in the imaging and histopathological examinations. Nevertheless, some pathological observations similar in both cases suggested abnormalities in the process of ectodermal fusion. A flat epidermis and a lack of appendages were recognized. Both cases also exhibited the presence of melanocytes in a portion of the superficial dermal layer. An increase in the number of macrophages was observed in the dermal area with neither elastic fibers nor normal collagen fibers. The peripheral hair follicles grew horizontally 3).

Hair-Collar-and-Tuft-Sign Associated with an Atretic Cephalocele and a Persistent Primitive Falcine Sinus 4).



Bessis D, Bigorre M, Malissen N, Captier G, Chiaverini C, Abasq C, Barbarot S, Boccara O, Bourrat E, El Fertit H, Eschard C, Hubiche T, Lacour JP, Leboucq N, Mahé E, Mallet S, Marque M, Martin L, Mazereeuw-Hautier J, Milla N, Phan A, Plantin P, Picot MC, Puzenat E, Rigau V, Vabres P, Fraitag S, Boralevi F; Groupe de Recherche Clinique en Dermatologie Pédiatrique. The scalp hair collar and tuft signs: A retrospective multicenter study of 78 patients with a systematic review of the literature. J Am Acad Dermatol. 2017 Mar;76(3):478-487. doi: 10.1016/j.jaad.2016.08.046. Epub 2016 Oct 11. Review. PubMed PMID: 27742172.

Kuemmet TJ, Miller JJ, Michalik D, Lew SM, Maheshwari M, Humphrey SR. Low risk of clinically important central nervous system dysraphism in a cohort study of 69 patients with isolated aplasia cutis congenita of the head. Pediatr Dermatol. 2020 Feb 13. doi: 10.1111/pde.14117. [Epub ahead of print] PubMed PMID: 32053222.

Takayama E, Harada A, Ikura Y, Seto H. Two cases of aplasia cutis congenita with hair collar signs and macrophage hyperplasia. J Dermatol. 2019 Aug;46(8):734-738. doi: 10.1111/1346-8138.14946. Epub 2019 Jun 10. PubMed PMID: 31180149.

Gagliardo T, Diplomatico M, Sordino D, Aliberti F, Esposito F, De Bernardo G. Hair-Collar-and-Tuft-Sign Associated with an Atretic Cephalocele and a Persistent Primitive Falcine Sinus. J Pediatr. 2018 Jan;192:263-263.e1. doi: 10.1016/j.jpeds.2017.08.027. Epub 2017 Sep 28. PubMed PMID: 28964426.
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