Phenotypic variability in two siblings with Poretti-Boltshauser syndrome

Abstract

Introduction Poretti-Boltshauser Syndrome (PBS) is a rare neuro-ophthalmological disorder with autosomal recessive inheritance. It is characterized by non-progressive cerebellar ataxia, delay in neuropsychomotor development, intellectual disability, and vision abnormalities. PBS is caused by mutations in the LAMA1 gene, resulting in cerebellar abnormalities, including cerebellar cysts in most cases.

Case presentation We present two siblings with LAMA1 mutations and distinct phenotypic presentation, with one of them showing no evidence of cerebellar cysts on magnetic resonance imaging (MRI).

Conclusion This study highlights intrafamilial variability in patients with Poretti-Boltshauser Syndrome (PBS). Patient 1 exhibits more pronounced cerebellar dysplasia (with cysts) and oculomotor apraxia, while Patient 2 shows milder cerebellar dysplasia (without cysts) and a macular hole. These findings underscore the importance of comprehensive evaluation and genetic testing for accurate diagnosis and management of PBS.

Keywords

Rare Diseases / Cerebellum / Genetics / Vision Disorders / Magnetic Ressonance Imaging

Patient consent

The family of the patients gave written informed consent to publish this article.

Conflict of interest

None declared.

References

[1] L. Powell, D. DeMille, H. Alwazzan, et al., Identification of LAMA 1 mutations ends diagnostic odyssey and has prognostic implications for patients with presumed Joubert syndrome, Brain Commun. 3 (3) (2021), https://doi.org/10.1093/braincomms/fcab163.

[2] A. Micalizzi, M. Batalha, A. Morales, et al., Clinical, neuroradiological and molecular characterization of cerebellar dysplasia with cysts (Poretti-Boltshauser syndrome), Eur. J. Hum. Genet 24 (9) (2016) 1262-1267, https://doi.org/10.1038/ejhg.2016.19.

[3] A.S. Alahmadi, A. Al-Rubaish, A. Al-Shehri, et al., Poretti-Boltshauser syndrome: a rare differential diagnosis to consider in pediatric high myopia with retinal degeneration, Ophthalmic Genet. 42 (1) (2020) 96-98, https://doi.org/10.1080/13816810.2020.1849316.

[4] K.A. Aldinger, X. Wang, M. McDonald, et al., Mutations in LAMA 1 cause cerebellar dysplasia and cysts with and without retinal dystrophy, Am. J. Hum. Genet. 95 (2) (2014) 227-234, https://doi.org/10.1016/j.ajhg.2014.07.007.

[5] M. Elmas, B. Gogus, M. Solak,Understanding what you have found: a family with a mutation in the LAMA1 gene with literature review, 117954762094866, Clin. Med. Insights Case Rep. 13 (2020), https://doi.org/10.1177/1179547620948666.

[6] L.M. Huisman, T.A.G.M. Huisman, World-renowned “Swiss” pediatricians, their syndromes, and matching imaging findings: a historical perspective, Children 10 (10) (2023) 1668, https://doi.org/10.3390/children10101668.

[7] T. Vilboux, S. Riazuddin, T. Sultan, et al., Cystic cerebellar dysplasia and biallelic LAMA 1 mutations: a lamininopathy associated with tics, obsessive compulsive traits and myopia due to cell adhesion and migration defects, J. Med. Genet. 53 (5) (2016) 318-329, https://doi.org/10.1136/jmedgenet-2015-103416.

[8] E. Marlow, H.B. Al-Kouatly, O.M. Durrani, et al., Retinal avascularity and neovascularization associated with LAMA 1 (laminin1) mutation in Poretti-Boltshauser syndrome, JAMA Ophthalmol. 136 (1) (2018) 96, https://doi.org/10.1001/jamaophthalmol.2017.5060.

[9] P. Wang, Y. Zhao, J. Lu, et al., An early diagnostic clue for COL18A1- and LAMA1-associated diseases: high myopia with alopecia areata in the cranial midline, Front. Cell Dev. Biol. 9 (2021) 644947, https://doi.org/10.3389/fcell.2021.644947.

[10] M. Kamate, N. Goudar, V. Hattiholi, Antenatal presentation and supratentorial brain abnormalities in a child with Poretti-Boltshauser syndrome, Brain Dev. 44 (2) (2022) 139-141, https://doi.org/10.1016/j.braindev.2021.09.010.

[11] R Masson, E Piretti, S Pellegrin, E Gusson, A Poretti, EM Valente, G Cantalupo, Early-onset head titubation in a child with Poretti-Boltshauser syndrome, Neurology 88 (15) (2017 Apr)1478-1479, https://doi.org/10.1212/WNL.0000000000003823.

[12] A. Poretti, T.A.G.M. Huisman, G. Schroth, et al., Ataxia, intellectual disability, and ocular apraxia with cerebellar cysts: a new disease? Cerebellum 13 (1) (2013) 79-88, https://doi.org/10.1007/s12311-013-0521-8.

[13] S. Schröder, M. Hönig, S. Zuchner, et al., The genetic spectrum of congenital ocular motor apraxia type Cogan: an observational study, continued, Orphanet. J. Rare Dis. 18 (1) (2023) 107, https://doi.org/10.1186/s13023-023-02706-5.

[14] M. Chen, M. Velez, D. Scott, et al., Identification of a likely pathogenic structural variation in the LAMA 1 gene by Bionano optical mapping, Npj Genom Med. 5 (1) (2020) 15, https://doi.org/10.1038/s41525-020-0138-z.

[15] C. Geerts, J. Smith, J. Van Houdt, et al., Phenotypic spectrum of patients with Poretti-Boltshauser syndrome: patient report of antenatal ventriculomegaly and esophageal atresia, Eur. J. Med. Genet. 66 (2) (2023) 104692, https://doi.org/10.1016/j.ejmg.2022.104692.

[16] A. Banerjee, S. Vyas, N. Sankhyan, Cerebellar cysts and dysplasias: more diagnoses to consider, Pediatr. Neurol. 98 (2019) 91-92, https://doi.org/10.1016/j.pediatrneurol.2019.02.021.

[17] F. D’Abrusco, S. Bianchi, S. Vermeer, et al., Get your molar tooth right: Joubert syndrome misdiagnosis unmasked by whole-exome sequencing, Cerebellum 21 (6) (2021) 1144-1150, https://doi.org/10.1007/s12311-021-01350-8.

[18] K. Ikeda, T. Ogata, Y. Goto, et al., Case report: an adult case of Poretti-Boltshauser syndrome diagnosed by medical checkup, Cerebellum 23 (1) (2024) 1-10, https://doi.org/10.21203/rs.3.rs-3892643/v1.

[19] S. Richards, N. Aziz, S. Bale, et al., Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, Genet. Med. 17 (5) (2015) 405-424, https://doi.org/10.1038/gim.2015.30.

[20] N. Faizi, S. Mahmood, A. Ali Shah, et al., High myopia and vitreal veils in a patient with Poretti-Boltshauser syndrome due to a novel homozygous LAMA 1 mutation, Ophthalmic Genet. 43 (5) (2022) 653-657, https://doi.org/10.1080/13816810.2022.2068045.

[21] E.R. Schiff, K.M. Cavuoto, P. Wang, et al., Variability of retinopathy consequent upon novel mutations in LAMA1, Ophthalmic Genet. 43 (5) (2022) 671-678, https://doi.org/10.1080/13816810.2022.2076283.