Hamartomas of the Tuber Cinereum Associated with X-Linked Deafness Show Signs of Pubertas Tarda Instead of Pubertas Praecox and No Gelastic Seizures—Long-Term Follow-Up of 12 Years

Abstract

Purpose Hamartomas of tuber cinereum present as ectopic tissue in the hypothalamic region. Clinically, the usual hypothalamic hamartomas manifest themself by gelastic seizures and pubertas praecox. We observed an increased coincidence of the presence of X-linked recessive deafness DFNX2 (DFN3) and a hamartoma of the tuber cinereum. Initially five patients presented with hearing loss in childhood, two additional were already adults, not showing any characteristic symptoms for a hamartoma but signs of delayed puberty.

Methods Seven patients who underwent computed tomography imaging due to a sensorineural hearing loss and had a hamartoma of the tuber cinereum in addition to X-linked deafness DFNX2 (DFN3) were included in a retrospective study. Patients underwent initial neurologic, endocrinologic, and genetic evaluation. Long-term follow-up was performed after 10 to 12 years.

Results The average age at the initial exam was 12.9 years (range 4–29). All patients genetically proven nonsyndromic, X-linked deafness associated with the POU3F4 gene. Three out of six patients presented signs of delayed puberty. None of all seven showed any evidence of pubertas praecox or gelastic seizures at mean age of 17 years (range 17–29 years) at any time.

Conclusion Hamartomas of tuber cinereum are often coincident with DFNX2. Clinically, half of the cases are—in contrary to the usual pubertas praecox—associated with growth hormone deficiency and delayed puberty, in the sense of pubertas tarda, when coincident. Clinicians' and radiologists' knowledge and awareness of this rare combination are crucial to identify children early enough for hormone-sensitive treatment.

Keywords

X-linked deafness - sensorineural hearing loss - pubertas tarda - hamartomas

^* These authors contributed equally to this work.

Long-Term Observational Study

The present study is based on a poster/abstract published as such in Clinical Neuroradiology in 2013. The correlation between the coexistence of hamartoma, X-linked deafness, and pubertas tarda described in the manuscript was thus first detected by us in 2013. As such, the present study is a continuation and a long-term observational study of the interplay of clinical symptoms observed at that time based on a common underlying genetic defect. (Compare also[18] [19]: Giesemann A, Hartmann H, Franke D, et al. Hamartome in Kombination mit X-chromosomaler Taubheit zeigen keine Epilepsie und keine Pubertas praecox. In: Clinical Neuroradiology. 2013; 0177).

Ethical Approval

Written consent for this retrospective analysis was waived by the local institutional ethics committee. All patients enrolled in this study agreed to their participation in this study in written form.

Authorś Contribution

Anja Giesemann: data sampling and analysis, writing, supervising; Katja Döring: data analysis, writing, editing; Friedrich Götz: data analysis, supervising. Hans Hartmann: clinical examination, supervising; Athanasia Warnecke: ENT data, supervising; Anja Schöner-Heinisch: genetic testing, writing genetic; Doris Steinemann: array CGH analyses.

Publikationsverlauf

Eingereicht: 30. Januar 2024

Angenommen: 10. Juli 2024

Artikel online veröffentlicht:
31. Juli 2024

• References

• 1 Arimura H, Askoro R, Fujio S. et al. A thyroid-stimulating hormone (TSH) producing adenoma in a patient with severe hypothyroidism: thyroxine replacement reduced the TSH level and tumor size. NMC Case Rep J 2019; 7 (01) 17-21
• 2 Arita K, Ikawa F, Kurisu K. et al. The relationship between magnetic resonance imaging findings and clinical manifestations of hypothalamic hamartoma. J Neurosurg 1999; 91 (02) 212-220
• 3 Martin DD, Seeger U, Ranke MB, Grodd W. MR imaging and spectroscopy of a tuber cinereum hamartoma in a patient with growth hormone deficiency and hypogonadotropic hypogonadism. AJNR Am J Neuroradiol 2003; 24 (06) 1177-1180
• 4 Hall JG, Pallister PD, Clarren SK. et al. Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus and postaxial polydactyly–a new syndrome? Part I: clinical, causal, and pathogenetic considerations. Am J Med Genet 1980; 7 (01) 47-74
• 5 Tsugu H, Fukushima T, Nagashima T, Utsunomiya H, Tomonaga M, Mitsudome A. Hypothalamic hamartoma associated with multiple congenital abnormalities. Two patients and a review of reported cases. Pediatr Neurosurg 1998; 29 (06) 290-296
• 6 Smith RJ, Bale Jr JF, White KR. Sensorineural hearing loss in children. Lancet 2005; 365 (9462): 879-890
• 7 Warnecke A, Giesemann A. Embryology, malformations, and rare diseases of the cochlea. Laryngorhinootologie 2021; 100 (S 01): S1-S43
• 8 Phelps PD, Reardon W, Pembrey M, Bellman S, Luxom L. X-linked deafness, stapes gushers and a distinctive defect of the inner ear. Neuroradiology 1991; 33 (04) 326-330
• 9 Olson NR, Lehman RH. Cerebrospinal fluid otorrhea and the congenitally fixed stapes. Laryngoscope 1968; 78 (03) 352-360
• 10 de Kok YJ, van der Maarel SM, Bitner-Glindzicz M. et al. Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4. Science 1995; 267 (5198): 685-688
• 11 Bitner-Glindzicz M, Turnpenny P, Höglund P. et al. Further mutations in Brain 4 (POU3F4) clarify the phenotype in the X-linked deafness, DFN3. Hum Mol Genet 1995; 4 (08) 1467-1469
• 12 Wallis C, Ballo R, Wallis G, Beighton P, Goldblatt J. X-linked mixed deafness with stapes fixation in a Mauritian kindred: linkage to Xq probe pDP34. Genomics 1988; 3 (04) 299-301
• 13 Corvino V, Apisa P, Malesci R, Laria C, Auletta G, Franzé A. X-linked sensorineural hearing loss: a literature review. Curr Genomics 2018; 19 (05) 327-338
• 14 Hildebrand MS, de Silva MG, Tan TY. et al. Molecular characterization of a novel X-linked syndrome involving developmental delay and deafness. Am J Med Genet A 2007; 143A (21) 2564-2575
• 15 Prat Matifoll JA, Wilson M, Goetti R. et al. A case series of X-linked deafness-2 with sensorineural hearing loss, stapes fixation, and perilymphatic gusher: MR imaging and clinical features of hypothalamic malformations. AJNR Am J Neuroradiol 2020; 41 (06) 1087-1093
• 16 Oza AM, DiStefano MT, Hemphill SE. et al . ClinGen hearing loss clinical domain working group. Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss. Hum Mutat 2018; 39 (11) 1593-1613
• 17 Myhre SA, Ruvalcaba RHA, Kelley VC. Congenital deafness and hypogonadism: a new X-linked recessive disorder. Clin Genet 1982; 22 (06) 299-307
• 18 Hoffmann GF, Lentze ML, Spranger J, Zepp F, Berner R. Pädiatrie: Grundlagen und Praxis. 4th ed.. Berlin: Springer; 2014
• 19 Wester JL, Merna C, Peng KA. et al. Facial nerve stimulation following cochlear implantation for X-linked stapes gusher syndrome leading to identification of a novel POU3F4 mutation. Int J Pediatr Otorhinolaryngol 2016; 91: 121-123
• 20 Giesemann A, Hartmann H, Franke D. et al. Hamartome in Kombination mit X-chromosomaler Taubheit zeigen keine Epilepsie und keine Pubertas praecox. In: Clinical Neuroradiology. 2013
• 21 Debeneix C, Bourgeois M, Trivin C, Sainte-Rose C, Brauner R. Hypothalamic hamartoma: comparison of clinical presentation and magnetic resonance images. Horm Res 2001; 56 (1–2): 12-18
• 22 Arita K, Uozumi T, Kuwabara S. et al. A case of pituitary adenoma producing both growth hormone (GH) and adrenocorticotropic hormone (ACTH). Endocrinol Jpn 1991; 38 (03) 271-278
• 23 Naranjo S, Voesenek K, de la Calle-Mustienes E. et al. Multiple enhancers located in a 1-Mb region upstream of POU3F4 promote expression during inner ear development and may be required for hearing. Hum Genet 2010; 128 (04) 411-419
• 24 Castaño De La Mota C, Martín Del Valle F, Pérez Villena A, Calleja Gero ML, Losada Del Pozo R, Ruiz-Falcó Rojas ML. Hypothalamic hamartoma in paediatric patients: clinical characteristics, outcomes and review of the literature [in Spanish]. Neurología 2012; 27 (05) 268-276
• 25 Wu HM, Jie HQ, Wang H. et al A novel POU domain class 3 transcription factor 4 mutation causes X-linked non-syndromic hearing loss in a Chinese family. Chin Med J (Engl) 2019; 132 (28) 2251-2253
• 26 Jiang Y, Wu L, Huang S. et al Study of complex structural variations of X-linked deafness-2 based on single-molecule sequencing. Biosci Rep 2021; 41 (06) BSR20203740 DOI: 10.1042/BSR20203740.
• 27 Richard EM, Santos-Cortez RLP. et al Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss. Human Mutation 2019; 40: 53-72