Chromosomal Abnormalities and Hydrocephalus: Could There Be an Association between Klinefelter's Syndrome and Idiopathic Normal-Pressure Hydrocephalus?

Abstract

Idiopathic normal-pressure hydrocephalus shows a typical clinical triad consisting of gait disturbance, dementia, and urinary incontinence, often combined with ventriculomegaly. Fortunately, these clinical manifestations are potentially reversible by adequate surgical treatment. Men affected by Klinefelter's syndrome can present cognitive problems. These include impairments in both verbal and nonverbal memory and in executive functions, which could be related to idiopathic normal-pressure hydrocephalus in these patients. In this study, we describe the case of a 62-year-old-man genetically diagnosed with Klinefelter's syndrome with a history of gait ataxia resulting in recurrent falls. Direct associations between idiopathic normal-pressure hydrocephalus and Klinefelter's syndrome and clinical pathophysiologic and potential molecular implications are discussed.

Keywords

Klinefelter's syndrome - idiopathic normal-pressure hydrocephalus - dementia

Authors' Contributions

Conception or design of the work was done by A.Pe. and G.T. Data collection was done by S.C., R.C., and S.E. Data analysis and interpretation were done by G.P. Drafting the manuscript was done by G.T., A.Pe., and M.P. Critical revision of the article was done by G.T., G.P., and A.Po. All the authors reviewed the results and approved the final version of the manuscript.

Ethical Approval

All procedures performed in studies involving human participants were done 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.

Consent to Participate/to Publication

Informed consent for surgery was obtained from the patient's caretaker. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.

We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, concerning intellectual property. In so doing, we confirm that we have followed the regulations of our institutions concerning intellectual property. We further confirm that any aspect of the work covered in this manuscript that has involved either experimental animals or human patients has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript. We understand that the corresponding author is the sole contact for the editorial process (including the editorial manager and direct communications with the office). He is responsible for communicating with the other authors about progress, submissions of revisions, and final approval of proofs. We confirm that we have provided a current, correct email address that is accessible by the corresponding author and that has been configured to accept email.

Publication History

Received: 03 December 2023

Accepted: 06 February 2024

Article published online:
05 August 2025

• References

• 1 Adams RD, Fisher CM, Hakim S, Ojemann RG, Sweet WH. Symptomatic occult hydrocephalus with “normal” cerebrospinal-fluid pressure. A treatable syndrome. N Engl J Med 1965; 273: 117-126
• 2 Jaraj D, Rabiei K, Marlow T, Jensen C, Skoog I, Wikkelsø C. Prevalence of idiopathic normal-pressure hydrocephalus. Neurology 2014; 82 (16) 1449-1454
• 3 Gavrilov GV, Gaydar BV, Svistov DV. et al. Idiopathic normal pressure hydrocephalus (Hakim-Adams syndrome): clinical symptoms, diagnosis and treatment. Psychiatr Danub 2019; 31 (Suppl. 05) 737-744
• 4 Bräutigam K, Vakis A, Tsitsipanis C. Pathogenesis of idiopathic normal pressure hydrocephalus: a review of knowledge. J Clin Neurosci 2019; 61: 10-13
• 5 Klinefelter HF, Reifenstein EC, Albright F. Syndrome characterized by gynecomastia, aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone. J Clin Endocrinol Metab 1942; 2 (11) 615-627
• 6 Mehmet B, Gillard S, Jayasena CN, Llahana S. Association between domains of quality of life and patients with Klinefelter syndrome: a systematic review. Eur J Endocrinol 2022; 187 (02) S21-S34
• 7 Groth KA, Skakkebæk A, Høst C, Gravholt CH, Bojesen A. Clinical review: Klinefelter syndrome: a clinical update. J Clin Endocrinol Metab 2013; 98 (01) 20-30
• 8 Marano M, Pompucci A, Motolese F. et al. Normal pressure hydrocephalus in down syndrome: the report of two cases. J Alzheimers Dis 2020; 77 (03) 979-984
• 9 Anile C, De Bonis P, Albanese A. et al. Selection of patients with idiopathic normal-pressure hydrocephalus for shunt placement: a single-institution experience. J Neurosurg 2010; 113 (01) 64-73
• 10 Nakajima M, Yamada S, Miyajima M. et al. Research Committee of Idiopathic Normal Pressure Hydrocephalus. Guidelines for Management of Idiopathic Normal Pressure Hydrocephalus (Third Edition): endorsed by the Japanese Society of Normal Pressure Hydrocephalus. Neurol Med Chir (Tokyo) 2021; 61 (02) 63-97
• 11 Boltshauser E, Meyer M, Deonna T. Klinefelter syndrome and neurological disease. J Neurol 1978; 219 (04) 253-259
• 12 Funakawa I, Miyao S, Takayanagi T. Klinefelter syndrome with communicating hydrocephalus: a case report. Rinsho Shinkeigaku 1985; 25 (08) 960-964
• 13 Turliuc MD, Cucu AI, Perciaccante A. et al. Hydrocephalus of King Charles II of Spain, the bewitched king. Eur Neurol 2019; 81 (1–2): 76-78
• 14 Tatum IV WOT, Passaro EA, Elia M, Guerrini R, Gieron M, Genton P. Seizures in Klinefelter's syndrome. Pediatr Neurol 1998; 19 (04) 275-278
• 15 Sasaki R, Ohta Y, Takahashi Y. et al. A rare case of Klinefelter syndrome accompanied by spastic paraplegia and peripheral neuropathy. Intern Med 2019; 58 (03) 437-440
• 16 Skakkebæk A, Gravholt CH, Rasmussen PM. et al. Neuroanatomical correlates of Klinefelter syndrome studied in relation to the neuropsychological profile. Neuroimage Clin 2013; 4: 1-9
• 17 Foland-Ross LC, Gil M, Shrestha SB, Chromik LC, Hong D, Reiss AL. Cortical gray matter structure in boys with Klinefelter syndrome. Psychiatry Res Neuroimaging 2021; 313: 111299
• 18 Hong DS, Hoeft F, Marzelli MJ. et al. Influence of the X-chromosome on neuroanatomy: evidence from Turner and Klinefelter syndromes. J Neurosci 2014; 34 (10) 3509-3516
• 19 Ji W, Tang Z, Chen Y. et al. Ependymal cilia: physiology and role in hydrocephalus. Front Mol Neurosci 2022; 15: 927479
• 20 Serra R, Simard JM. Adherens, tight, and gap junctions in ependymal cells: a systematic review of their contribution to CSF-brain barrier. Front Neurol 2023; 14: 1092205
• 21 Condorelli RA, Calogero AE, La Vignera S. Different profile of endothelial cell apoptosis in patients with Klinefelter's syndrome. J Endocrinol Invest 2013; 36 (02) 84-91
• 22 Haymana C, Aydogdu A, Demirci I. et al. Increased endothelial dysfunction and insulin resistance in patients with Klinefelter syndrome. Endocr Metab Immune Disord Drug Targets 2018; 18 (04) 401-406
• 23 Al-Dosari MS, Al-Owain M, Tulbah M. et al. Mutation in MPDZ causes severe congenital hydrocephalus. J Med Genet 2013; 50 (01) 54-58
• 24 Baltzegar DA, Reading BJ, Brune ES, Borski RJ. Phylogenetic revision of the claudin gene family. Mar Genomics 2013; 11: 17-26
• 25 Tully HM, Dobyns WB. Infantile hydrocephalus: a review of epidemiology, classification and causes. Eur J Med Genet 2014; 57 (08) 359-368
• 26 Walsh FS, Barton CH, Putt W. et al. N-cadherin gene maps to human chromosome 18 and is not linked to the E-cadherin gene. J Neurochem 1990; 55 (03) 805-812
• 27 Feldner A, Adam MG, Tetzlaff F. et al. Loss of Mpdz impairs ependymal cell integrity leading to perinatal-onset hydrocephalus in mice. EMBO Mol Med 2017; 9 (07) 890-905
• 28 Wyss L, Schäfer J, Liebner S. et al. Junctional adhesion molecule (JAM)-C deficient C57BL/6 mice develop a severe hydrocephalus. PLoS One 2012; 7 (09) e45619