Moebius syndrome and hypopituitarism: a case of multiple pituitary hormone deficiency and revision of the literature

Silvia Molinari; Maria Laura Nicolosi; Angelo Selicorni; Chiara Fossati; Martina Lattuada; Iacopo Bellani; Federica Arcuti; Riccardo Carnevale; Andrea Biondi; Adriana Balduzzi; Alessandro Cattoni

doi:10.1515/jpem-2024-0494

Article

Moebius syndrome and hypopituitarism: a case of multiple pituitary hormone deficiency and revision of the literature

Silvia Molinari , Maria Laura Nicolosi , Angelo Selicorni , Chiara Fossati , Martina Lattuada , Iacopo Bellani , Federica Arcuti , Riccardo Carnevale , Andrea Biondi , Adriana Balduzzi and Alessandro Cattoni

Published/Copyright: January 24, 2025

Published by

Become an author with De Gruyter Brill

Submit Manuscript Author Information Explore this Subject

From the journal Journal of Pediatric Endocrinology and Metabolism Volume 38 Issue 4

Abstract

Objectives

Moebius syndrome (MS) is a rare congenital non-progressive rhombencephalic disorder mostly characterised by abducens and facial nerve palsy, but with a multifaceted clinical presentation. Isolated or multiple pituitary hormone deficiencies in the setting of MS have been occasionally reported, but the simultaneous involvement of three or more hypothalamic-pituitary axes has never been described. We hereby report the case of a girl with MS that showed a co-occurrence of GH-, TSH- and ACTH-deficiency. In addition, we provide a systematic revision of all the published cases of hypopituitarism among patients with MS.

Case presentation

A 6-year-old patient with a MS was referred to our outpatient clinic for faltering growth. The combination of stature below −3.0 SDS, impaired height velocity and pathological response to two GH-stimulation tests prompted the diagnosis of GH deficiency and therefore recombinant human GH was undertaken. Brain MRI highlighted a thin infundibular stalk. By the age of 10 years, she started to complain progressive fatigue and the co-occurrence of remarkably decreased fT4 levels in the setting of non-increased TSH led to diagnose central hypothyroidism. Accordingly, she was started on levothyroxine replacement therapy with timely clinical improvement. At the age of 11.3 years, recurrent symptoms consistent with morning hypoglycaemia prompted the prescription of a low-dose ACTH test, that confirmed an ACTH deficiency, in the setting of a multiple pituitary hormonal impairment.

Conclusions

Patients with MS are potentially at risk for either isolated or multiple pituitary hormones deficiency. Clinicians should lower the threshold for prescribing a dedicated endocrine assessment.

Keywords: GH deficiency; central hypothyroidism; adrenal insufficiency; hypopituitarism; combined pituitary hormone deficiency; hypogonadism

Corresponding author: Silvia Molinari, Department of Pediatrics, Fondazione IRCCS San Gerardo Dei Tintori, Via Pergolesi 33, 20900, Monza (MB), Italy, E-mail: silvia.molinari@irccs-sangerardo.it

Acknowledgments

The authors would like to thank the Fondazione Mariani and the Comitato Maria Letizia Verga. These no profit-foundations support the assistance and care to ensure a better quality of life to children and adolescents with neuro-metabolic diseases, genetic disorders and hemato-oncological diseases.

Research ethics: The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).
Informed consent: Informed consent was obtained from the parents of the patient included in this study.
Author contributions: SM and AC developed the idea of the study, participated in its design and coordination and draft the manuscript. SM, RC, ML, IB, FA contributed to the acquisition and interpretation of data. SM, AC, CF, AS, MLN, AB and Abi were involved in critically reviewing the manuscript. All authors read and approved the final manuscript.
Use of Large Language Models, AI and Machine Learning Tools: None declared.
Conflict of interest: The authors state no conflict of interest.
Research funding: None declared.
Data availability: Not applicable.

Appendix 1

List of genes implicated in hypopituitarism assessed by next generation sequencing: ACAN, ALMS1, ANKRD11, ARID1A, ARID1B, ARNT2,ATR, ATRIP, BLM, BRAF, CBL, CCDC8, CENPJ, CEP152, CEP63, CHD7, COL2A1, COL9A1, COL9A2, COL9A3, COL10A1, COMP, CREBBP, CRIPT, CUL7, DNA2, DVL1, EP300, ERCC8, FGD1, FBN1, FGF8, FGFR1, FGFR3, GH1, GHR, GHRHR, GLI2, GLI3, GNAS, GPR161, HDAC8, HESX1, HMGA2, HRAS, HSPG2, IGF1, IGF1R, IGF2, IGFALS, IGSF1, IHH, KDM6A, KRAS, LARP7, LHX3, LHX4, LMNA, MATN3, MLL2, NIPBL, NPR2, NRAS, NSMCE2, OBSL1, OTX2, PAPPA2, PCNT, PDE4D, PITX2, POC1A, POU1F1, PRKAR1A, PROK2, PROKR2, PTPN11, RAD21, RAF1, RBBP8, RIT1, RNPC3, ROR2, SHH, SHOC2, SHOX, SMARCA4, SMARCAL1, SMARCB1, SMARCE1, SMC1A, SMC3, SOCS1, SOS1, SOX2, SOX 3, SOX9, SOX11, SRCAP, STAT5b, TRAIP, TRIM37, WDR11, WNT5A, XRCC4.

References

1. Carta, A, Favilla, S, Calzetti, G, Casalini, MC, Ferrari, PF, Bianchi, B, et al.. The epidemiology of Moebius syndrome in Italy. Orphanet J Rare Dis 2021;16:162. https://doi.org/10.1186/s13023-021-01808-2. [Internet] Available from: https://ojrd.biomedcentral.com/articles/10.1186/s13023-021-01808-2.Search in Google Scholar PubMed PubMed Central

2. Picciolini, O, Porro, M, Cattaneo, E, Castelletti, S, Masera, G, Mosca, F, et al.. Moebius syndrome: clinical features, diagnosis, management and early intervention. Ital J Pediatr 2016;42:56. https://doi.org/10.1186/s13052-016-0256-5. [Internet] Available from: http://ijponline.biomedcentral.com/articles/10.1186/s13052-016-0256-5.Search in Google Scholar PubMed PubMed Central

3. Verzijl, HTFM, Van der Zwaag, B, Cruysberg, JRM, Padberg, GW. Möbius syndrome redefined: a syndrome of rhombencephalic maldevelopment. Neurology 2003;61:327–33. https://doi.org/10.1212/01.wnl.0000076484.91275.cd.Search in Google Scholar PubMed

4. Bell, C, Nevitt, S, McKay, VH, Fattah, AY. Will the real Moebius syndrome please stand up? A systematic review of the literature and statistical cluster analysis of clinical features. Am J Med Genet Part A 2019;179:257–65. https://doi.org/10.1002/ajmg.a.60683. [Internet] Available from: https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.60683.Search in Google Scholar PubMed

5. Bavinck, JNB, Weaver, DD, Opitz, JM, Reynolds, JF. Subclavian artery supply disruption sequence: hypothesis of a vascular etiology for Poland, Klippel-Feil, and Möbius anomalies. Am J Med Genet 1986;23:903–18. https://doi.org/10.1002/ajmg.1320230405. [Internet] Available from: https://onlinelibrary.wiley.com/doi/10.1002/ajmg.1320230405.Search in Google Scholar PubMed

6. Pirmez, R, Freitas, MET, Gasparetto, EL, Araújo, APQC. Moebius syndrome and holoprosencephaly following exposure to misoprostol. Pediatr Neurol 2010;43:371–3. https://doi.org/10.1016/j.pediatrneurol.2010.05.026. [Internet] Available from: https://linkinghub.elsevier.com/retrieve/pii/S0887899410002754.Search in Google Scholar PubMed

7. Kadakia, S, Helman, SN, Schwedhelm, T, Saman, M, Azizzadeh, B. Examining the genetics of congenital facial paralysis–a closer look at Moebius syndrome. Oral Maxillofac Surg 2015;19:109–16. https://doi.org/10.1007/s10006-015-0485-6. [Internet] Available from: http://link.springer.com/10.1007/s10006-015-0485-6.Search in Google Scholar PubMed

8. Olson, WH, Bardin, CW, Walsh, GO, Engel, WK. Moebius syndrome: lower motor neuron involvement and hypogonadotrophic hypogonadism. Neurology 1970;20:1002. https://doi.org/10.1212/wnl.20.10.1002. [Internet] Available from: http://www.neurology.org/cgi/doi/10.1212/WNL.20.10.1002.Search in Google Scholar PubMed

9. Koide, Y, Yamashita, N, Kurusu, T, Kugai, N, Kuzuhara, S, Fujita, T, et al.. Association of isolated adrenocorticotropin deficiency with a variety of neuro-somatic abnormalities in congenital facial diplegia (Moebius) syndrome. Endocrinol Jpn 1983;30:499–507. https://doi.org/10.1507/endocrj1954.30.499.Search in Google Scholar PubMed

10. Kawai, M, Momoi, T, Fujii, T, Nakano, S, Itagaki, Y, Mikawa, H. The syndrome of Möbius sequence, peripheral neuropathy, and hypogonadotropic hypogonadism. Am J Med Genet 1990;37:578–82. https://doi.org/10.1002/ajmg.1320370432. [Internet] Available from: https://onlinelibrary.wiley.com/doi/10.1002/ajmg.1320370432.Search in Google Scholar PubMed

11. Engler, RJ, Oetgen, WJ, Hyman, LR. Congenital facial diplegia (Mobius syndrome) and diabetes insipidus: case report. Mil Med 1979;144:117–20. https://doi.org/10.1093/milmed/144.2.117. [Internet] Available from: http://www.ncbi.nlm.nih.gov/pubmed/106335.Search in Google Scholar

12. Abid, F, Hall, R, Hudgson, P, Weiser, R. Moebius syndrome, peripheral neuropathy and hypogonadotrophic hypogonadism. J Neurol Sci 1978;35:309–15. https://doi.org/10.1016/0022-510x(78)90011-4. [Internet] Available from: https://linkinghub.elsevier.com/retrieve/pii/0022510X78900114.Search in Google Scholar PubMed

13. Rubinstein, AE, Lovelace, RE, Behrens, MM, Weisberg, LA. Moebius syndrome in Kallmann syndrome. Arch Neurol 1975;32:480–2. https://doi.org/10.1001/archneur.1975.00490490084010. [Internet] Available from: http://archneur.jamanetwork.com/article.aspx?articleid=573829.Search in Google Scholar PubMed

14. Amouyal, M, Bouvagnet, P, Rochette, G, de Roux, N. The association of Moebius syndrome and kallman syndrome is due to a specific mutation of TUBB3, 53rd annual meeting of the European society for paediatric endocrinology (ESPE). Dublin, Ireland, September 18–20, 2014: abstracts. Horm Res Paediatrs 2014;82:1–507. [Internet] Available from: https://www.karger.com/Article/FullText/365775.10.1159/000365775Search in Google Scholar PubMed

15. Omar, AM, Shahar, MA, Ab Wahab, N, Mustafa, N, Sukor, N, Kamaruddin, NA. Moebius and Kallmann syndromes with diabetes insipidus : a phenotype of fibroblast growth factor (FGF) 8 mutation Moebius and Kallmann syndromes with diabetes insipidus. J Endocrinol Metab 2016;4:44–8.Search in Google Scholar

16. Chora̧zy, M, Leśniewicz, R, Posmyk, R, Halicka, D, Zalewska, A, Wincewicz-Pietrzykowska, A, et al.. The natural history of Möbius syndrome in a 32-year-old man. Neurol Neurochir Pol 2011;45:74–9. https://doi.org/10.1016/s0028-3843(14)60063-3.Search in Google Scholar PubMed

17. McCabe, MJ, Gaston-Massuet, C, Tziaferi, V, Gregory, LC, Alatzoglou, KS, Signore, M, et al.. Novel FGF8 mutations associated with recessive holoprosencephaly, craniofacial defects, and hypothalamo-pituitary dysfunction. J Clin Endocrinol Metab 2011;96:E1709–18. https://doi.org/10.1210/jc.2011-0454. [Internet] Available from: https://academic.oup.com/jcem/article-lookup/doi/10.1210/jc.2011-0454.Search in Google Scholar PubMed PubMed Central

18. López de Lara, D, Cruz-Rojo, J, Sánchez del Pozo, J, Gallego Gómez, ME, Lledó Valera, G. Moebius-Poland syndrome and hypogonadotropic hypogonadism. Eur J Pediatr 2008;167:353–4. https://doi.org/10.1007/s00431-007-0473-4. [Internet] Available from: https://link.springer.com/10.1007/s00431-007-0473-4.Search in Google Scholar PubMed PubMed Central

19. Jennings, JE, Costigan, C, Reardon, W. Moebius sequence and hypogonadotrophic hypogonadism. Am J Med Genet 2003;123A:107–10. https://doi.org/10.1002/ajmg.a.20500. [Internet] Available from: https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.20500.Search in Google Scholar PubMed

20. Petrus, M, Rhabbour, M, Clouzeau, J, Bat, P, Bildstein, G, Ibanez, MH, et al.. [Association of Moebius syndrome and hypopituitarism due to a midline anomaly. A case report]. Ann Pediatr (Paris) 1993;40:376–8. [Internet] Available from: http://www.ncbi.nlm.nih.gov/pubmed/8352501.Search in Google Scholar

21. Hashimoto, N, Sakakihara, Y, Miki, Y, Kagawa, J, Egi, S, Kamoshita, S. Moebius syndrome associated with pituitary dwarfism and hypoplastic optic disc. Pediatr Int 1993;35:144–7. https://doi.org/10.1111/j.1442-200x.1993.tb03026.x. [Internet] Available from: https://onlinelibrary.wiley.com/doi/10.1111/j.1442-200X.1993.tb03026.x.Search in Google Scholar PubMed

22. Brackett, LE, Demers, LM, Mamourian, AC, Ellenberger, C, Santen, RJ. Moebius syndrome in association with hypogonadotropic hypogonadism. J Endocrinol Invest 1991;14:599–607. https://doi.org/10.1007/bf03346879. [Internet] Available from: http://link.springer.com/10.1007/BF03346879.Search in Google Scholar PubMed

23. Pierce, M, Madison, L. Evaluation and initial management of hypopituitarism. Pediatr Rev 2016;37:370–5. https://doi.org/10.1542/pir.2015-0081.Search in Google Scholar PubMed

24. Procter, AM, Phillips, IIIJA, Cooper, DN. The molecular genetics of growth hormone deficiency. Hum Genet 1998;103:255–72. https://doi.org/10.1007/s004390050815. [Internet] Available from: http://link.springer.com/10.1007/s004390050815.Search in Google Scholar PubMed

25. Carrière, C, Gleiberman, A, Lin, CR, Rosenfeld, MG. From panhypopituitarism to combined pituitary deficiencies: do we need the anterior pituitary? Rev Endocr Metab Disord 2004;5:5–13. https://doi.org/10.1023/b:remd.0000016120.84792.54. [Internet] Available from: http://link.springer.com/10.1023/B:REMD.0000016120.84792.54.10.1023/B:REMD.0000016120.84792.54Search in Google Scholar PubMed

26. De Rienzo, F, Mellone, S, Bellone, S, Babu, D, Fusco, I, Prodam, F, et al.. Frequency of genetic defects in combined pituitary hormone deficiency: a systematic review and analysis of a multicentre Italian cohort. Clin Endocrinol (Oxf) 2015;83:849–60. https://doi.org/10.1111/cen.12849.Search in Google Scholar PubMed

27. Crisafulli, G, Aversa, T, Zirilli, G, De Luca, F, Gallizzi, R, Wasniewska, M. Congenital hypopituitarism: how to select the patients for genetic analyses. Ital J Pediatr 2018;44:1–4. https://doi.org/10.1186/s13052-018-0484-y.Search in Google Scholar PubMed PubMed Central

28. Giordano, M. Genetic causes of isolated and combined pituitary hormone deficiency. Best Pract Res Clin Endocrinol Metab 2016;30:679–91. [Internet] Available from: https://doi.org/10.1016/j.beem.2016.09.005.Search in Google Scholar PubMed

29. Parkin, K, Kapoor, R, Bhat, R, Greenough, A. Genetic causes of hypopituitarism. Arch Med Sci 2020;16:27–33. https://doi.org/10.5114/aoms.2020.91285. [Internet] Available from: https://www.termedia.pl/doi/10.5114/aoms.2020.91285.Search in Google Scholar PubMed PubMed Central

30. Emmanuel, M, Bokor, BR. Tanner stages. StatPearls 2021. [Internet] Available from: http://www.ncbi.nlm.nih.gov/pubmed/29262142.Search in Google Scholar

31. Moebius syndrome-axonal neuropathy-hypogonadotropic hypogonadism syndrome, ORPHA:2560 [Internet]. Available from: https://www.orpha.net/en/disease/detail/2560.Search in Google Scholar

32. Chew, S, Balasubramanian, R, Chan, WM, Kang, PB, Andrews, C, Webb, BD, et al.. A novel syndrome caused by the E410K amino acid substitution in the neuronal β-tubulin isotype 3. Brain 2013;136:522–35. https://doi.org/10.1093/brain/aws345.Search in Google Scholar PubMed PubMed Central

33. Xatzipsalti, M, Voutetakis, A, Stamoyannou, L, Chrousos, G, Kanaka-Gantenbein, C. Congenital hypopituitarism: various genes, various phenotypes. Horm Metab Res 2019;51:81–90. https://doi.org/10.1055/a-0822-3637. [Internet] Available from: http://www.thieme-connect.de/DOI/DOI?10.1055/a-0822-3637.Search in Google Scholar PubMed

Received: 2024-10-16

Accepted: 2025-01-10

Published Online: 2025-01-24

Published in Print: 2025-04-28

You are currently not able to access this content.

Articles in the same Issue

https://doi.org/10.1515/jpem-2024-0494

Keywords for this article

GH deficiency; central hypothyroidism; adrenal insufficiency; hypopituitarism; combined pituitary hormone deficiency; hypogonadism