, Volume 60, Issue 8, pp 813–820 | Cite as

Rhinencephalon changes in tuberous sclerosis complex

  • Renzo ManaraEmail author
  • Davide Brotto
  • Samuela Bugin
  • Maria Federica Pelizza
  • Stefano Sartori
  • Margherita Nosadini
  • Sara Azzolini
  • Giorgio Iaconetta
  • Cecilia Parazzini
  • Alessandra Murgia
  • Angela Peron
  • Paola Canevini
  • Francesca Labriola
  • Aglaia Vignoli
  • Irene Toldo
Paediatric Neuroradiology



Despite complex olfactory bulb embryogenesis, its development abnormalities in tuberous sclerosis complex (TSC) have been poorly investigated.


Brain MRIs of 110 TSC patients (mean age 11.5 years; age range 0.5–38 years; 52 female; 26 TSC1, 68 TSC2, 8 without mutation identified in TSC1 or TSC2, 8 not tested) were retrospectively evaluated. Signal and morphological abnormalities consistent with olfactory bulb hypo/aplasia or with olfactory bulb hamartomas were recorded. Cortical tuber number was visually assessed and a neurological severity score was obtained. Patients with and without rhinencephalon abnormalities were compared using appropriate parametric and non-parametric tests.


Eight of110 (7.2%) TSC patients presented rhinencephalon MRI changes encompassing olfactory bulb bilateral aplasia (2/110), bilateral hypoplasia (2/110), unilateral hypoplasia (1/110), unilateral hamartoma (2/110), and bilateral hamartomas (1/110); olfactory bulb hypo/aplasia always displayed ipsilateral olfactory sulcus hypoplasia, while no TSC patient harboring rhinencephalon hamartomas had concomitant forebrain sulcation abnormalities. None of the patients showed overt olfactory deficits or hypogonadism, though young age and poor compliance hampered a proper evaluation in most cases. TSC patients with rhinencephalon changes had more cortical tubers (47 ± 29.1 vs 26.2 ± 19.6; p = 0.006) but did not differ for clinical severity (p = 0.45) compared to the other patients of the sample.


Olfactory bulb and/or forebrain changes are not rare among TSC subjects. Future studies investigating clinical consequences in older subjects (anosmia, gonadic development etc.) will define whether rhinencephalon changes are simply an imaging feature among the constellation of TSC-related brain changes or a feature to be searched for possible implications in the management of TSC subjects.


Tuberous sclerosis complex Olfactory bulb Olfactory sulcus MRI 


Compliance with ethical standards


No funding was received for this study.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in the studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required.

Informed consent

For this type of retrospective study formal consent is not required.

Supplementary material

234_2018_2045_Fig6_ESM.png (1.3 mb)
e-Fig. 1

MRI of normal olfactory bulbs and sulci in tuberous sclerosis complex patients; magnifications of rhinencephalon and forebrain details are on the right. A) coronal T2-weighted image disclosing the oval shape of the anterior rhinencephalon (short arrows) within the olfactory grooves; the olfactory sulci indent the inferior surface of the frontal lobes about one centimeter from the midline (arrowheads); several cortical tubers are recognizable, especially in the right frontal lobe B) axial image at the level of the upper portion of the orbits showing the olfactory sulci (arrowheads) separating the giri recti from the remaining orbitofrontal cortex; the crista galli (*) is also recognizable; C) Parasagittal T2-weighted image disclosing the cigar-like olfactory bulb (short arrows). Subependymal nodules and giant astrocytoma are evident close to Monro’s foramina. (PNG 1341 kb)

234_2018_2045_MOESM1_ESM.tif (5.4 mb)
High resolution image (TIF 5564 kb)


  1. 1.
    Randle SC (2017) Tuberous sclerosis complex: a review. Pediatr Ann 46(4):e166–e171CrossRefPubMedGoogle Scholar
  2. 2.
    Curatolo P, Moavero R, de Vries PJ (2015) Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol 14:733–745CrossRefPubMedGoogle Scholar
  3. 3.
    Northrup H, Krueger DA, on behalf of the International Tuberous Sclerosis Complex Consensus Group: Tuberous Sclerosis Complex Diagnostic Criteria Update (2013) Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 49:243–254CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Kingswood C, Bolton P, Crawford P, Harland C, Johnson SR, Sampson JR, Shepherd C, Spink J, Demuth D, Lucchese L, Nasuti P, Gray E, Pinnegar A, Magestro M (2016) The clinical profile of tuberous sclerosis complex (TSC) in the United Kingdom: a retrospective cohort study in the Clinical Practice Research Datalink (CPRD). Eur J Paediatr Neurol 20(2):296–308CrossRefPubMedGoogle Scholar
  5. 5.
    Boer K, Troost D, Jansen F, Nellist M, van den Ouweland AM, Geurts JJ, Spliet WG, Crino P, Aronica E (2008) Clinicopathological and immunohistochemical findings in an autopsy case of tuberous sclerosis complex. Neuropathology 28(6):577–590PubMedGoogle Scholar
  6. 6.
    Boronat S, Shaaya EA, Auladell M, Thiele EA, Caruso P (2014) Intracranial arteriopathy in tuberous sclerosis complex. J Child Neurol 29:912–919CrossRefPubMedGoogle Scholar
  7. 7.
    Tortori-Donati P, Rossi A (2005) Pediatric neuroradiology brain. Springer-Verlag, Berlin, pp 785–800CrossRefGoogle Scholar
  8. 8.
    Sarnat HB, Flores-Sarnat L (2017) Olfactory development, part 2: neuroanatomic maturation and dysgeneses. J Child Neurol 32(6):579–593CrossRefPubMedGoogle Scholar
  9. 9.
    Manara R, Salvalaggio A, Favaro A, Palumbo V, Citton V, Elefante A, Brunetti A, Di Salle F, Bonanni G, Sinisi AA (2014) Kallmann syndrome neuroradiological study group. Brain changes in Kallmann syndrome. AJNR Am J Neuroradiol 35(9):1700–1706CrossRefPubMedGoogle Scholar
  10. 10.
    Quinton R, Duke VM, de Zoysa PA, Platts AD, Valentine A, Kendall B, Pickman S, Kirk JM, Besser GM, Jacobs HS, Bouloux PM (1996) The neuroradiology of Kallmann’s syndrome: a genotypic and phenotypic analysis. J Clin Endocrinol Metab 81(8):3010–3017PubMedGoogle Scholar
  11. 11.
    de León GA, Zaeri N, Foley CM (1988) Olfactory hamartomas in tuberous sclerosis. J Neurol Sci 87(2–3):187–194CrossRefPubMedGoogle Scholar
  12. 12.
    Feliciano DM, Quon JL, Su T, Taylor MM, Bordey A (2012) Postnatal neurogenesis generates heterotopias, olfactory micronodules and cortical infiltration following single-cell Tsc1 deletion. Hum Mol Genet 21(4):799–810CrossRefPubMedGoogle Scholar
  13. 13.
    Wong AM, Wang HS, Schwartz ES, Toh CH, Zimmerman RA, Liu PL, Wu YM, Ng SH, Wang JJ (2013) Cerebral diffusion tensor MR tractography in tuberous sclerosis complex: correlation with neurologic severity and tract-based spatial statistical analysis. AJNR Am J Neuroradiol 34:1829–1835CrossRefPubMedGoogle Scholar
  14. 14.
    Ottaviano G, Cantone E, D'Errico A, Salvalaggio A, Citton V, Scarpa B, Favaro A, Sinisi AA, Liuzzi R, Bonanni G, Di Salle F, Elefante A, Manara R, Staffieri A, Martini A, Brunetti A (2015) Sniffin’ Sticks and olfactory system imaging in patients with Kallmann syndrome. Int Forum Allergy Rhinol 5(9):855–861CrossRefPubMedGoogle Scholar
  15. 15.
    Cabrera SM, Rogol AD (2013) Testosterone exposure in childhood: discerning pathology from physiology. Expert Opin Drug Saf 12(3):375–388CrossRefPubMedGoogle Scholar
  16. 16.
    Manara R, Bugin S, Pelizza MF, Sartori S, Nosadini M, Labriola F, Canevini P, Vignoli A, Toldo I (2018) Genetic and imaging features of cerebellar abnormalities in tuberous sclerosis complex: more insights into their pathogenesis. Dev Med Child Neurol 60(7):724-725Google Scholar
  17. 17.
    Boronat S, Thiele EA, Caruso P (2017) Cerebellar lesions are associated with TSC2 mutations in tuberous sclerosis complex: a retrospective record review study. Dev Med Child Neurol 59(10):1071–1076CrossRefPubMedGoogle Scholar
  18. 18.
    Au KS, Williams AT, Roach ES, Batchelor L, Sparagana SP, Delgado MR, Wheless JW, Baumgartner JE, Roa BB, Wilson CM, Smith-Knuppel TK, Cheung MY, Whittemore VH, King TM, Northrup H (2007) Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet Med 9:88–100CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Renzo Manara
    • 1
    Email author
  • Davide Brotto
    • 2
  • Samuela Bugin
    • 3
  • Maria Federica Pelizza
    • 3
  • Stefano Sartori
    • 3
  • Margherita Nosadini
    • 3
  • Sara Azzolini
    • 4
  • Giorgio Iaconetta
    • 5
  • Cecilia Parazzini
    • 6
  • Alessandra Murgia
    • 7
  • Angela Peron
    • 8
    • 9
  • Paola Canevini
    • 10
  • Francesca Labriola
    • 11
  • Aglaia Vignoli
    • 10
  • Irene Toldo
    • 3
  1. 1.Neuroradiology, Department of Medicine and Surgery, Sezione di NeuroscienzeUniversity of SalernoBaronissiItaly
  2. 2.Otolaryngology Unit, Department of NeuroscienceUniversity Hospital of PadovaPadovaItaly
  3. 3.Pediatric Neurology and Neurophysiology Unit, Department of Woman and Child HealthUniversity Hospital of PadovaPadovaItaly
  4. 4.Pediatric Endocrinology Unit, Department of Woman and Child HealthUniversity Hospital of PadovaPadovaItaly
  5. 5.Neurosurgery, School of Medicine “Scuola Medica Salernitana”University of SalernoFiscianoItaly
  6. 6.Department of Pediatric Radiology and NeuroradiologyChildren’s Hospital V. BuzziMilanItaly
  7. 7.Molecular Genetics of Neurodevelopment Laboratory, Department of Women’s and Children’s HealthUniversity Hospital of PadovaPadovaItaly
  8. 8.Child Neuropsychiatry Unit - Epilepsy Center, San Paolo Hospital, Department of Health SciencesUniversity of MilanoMilanItaly
  9. 9.Department of Pediatrics, Division of Medical GeneticsUniversity of Utah School of MedicineSalt Lake CityUSA
  10. 10.Epilepsy Center, Health Sciences DepartmentUniversity of MilanoMilanItaly
  11. 11.Epilepsy and Sleep Medicine Center - Neuropsychiatric Unit - ASST Santi Paolo CarloMilanItaly

Personalised recommendations