Novel finding of paroxysmal tonic downgaze in Loeys-Dietz syndrome: expanding neurological phenotype

Raffaele Falsaperla; Vincenzo Sortino; Evelina Moliteo; Marco Andrea Nicola Saporito; Carla Cimino; Giovanni Cacciaguerra; Piero Pavone; Raffaele Falsaperla; Vincenzo Sortino; Evelina Moliteo; Marco Andrea Nicola Saporito; Carla Cimino; Giovanni Cacciaguerra; Piero Pavone

doi:10.3934/medsci.2025020

AIMS Medical Science

2025, Volume 12, Issue 3: 292-300. doi: 10.3934/medsci.2025020

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Case report

Novel finding of paroxysmal tonic downgaze in Loeys-Dietz syndrome: expanding neurological phenotype

1.
Department of Medical Science-Pediatrics, University of Ferrara, 44124 Ferrara, Italy
2.
Unit of Pediatrics and Pediatric Emergency, Azienda Ospedaliero-Universitaria Policlinico “Rodolico-San Marco”, San Marco Hospital, University of Catania, 95123 Catania, Italy
3.
National Council of Research, Institute for Research and Biomedical Innovation (IRIB), Unit of Catania, Catania, Italy
4.
Postgraduate Training Program in Pediatrics, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
5.
Unit of Neonatal Intensive Care and Neonatology, Policlinico “G. Rodolico-San Marco” University Hospital, University of Catania, 95100 Catania, Italy
6.
Unit of Clinical Pediatrics, AOU “Policlinico”, PO “G. Rodolico”, University of Catania, 95123 Catania, Italy

Received: 10 April 2025 Revised: 31 July 2025 Accepted: 06 August 2025 Published: 02 September 2025

Loeys-Dietz syndrome (LDS) is a rare connective tissue disorder caused by pathogenic or likely pathogenic variants in genes encoding the transforming growth factor beta (TGF-®) pathway components. The disease was originally characterized by a typical symptomatologic triad: Bifid uvula or cleft palate, hypertelorism and aortic aneurysm with tortuosity. However, the clinical manifestations are very varied, including vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, and cervical spine malformation and/or instability), craniofacial features (hypertelorism, strabismus, bifid uvula/cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Neurological involvement is very uncommon in LDS, although it has been reported that serial cases with 1q41 deletion encompassing TGF-® 2 ligand (TGFB2) are linked to neurodevelopment abnormalities. The association between LDS or 1q41 deletion and paroxysmal tonic downward gaze (PDT) has never been described in the literature. Here, we describe the case of a 4-month-old male with LDS type 4 caused by 1q41 deletion involving TGFB2 who has neurodevelopment abnormalities and paroxysmal ocular motor events (OPEs). Thanks to polygraphic video-EEG monitoring, such ocular paroxysms are classified as “paroxysmal tonic downward gaze” (PTD), a type of nonepileptic OPE. PTD has been described in most newborns as a benign phenomenon related to an immaturity of the extrageniculocalcarine visual pathway, so more often it concerns healthy and neurologically negative newborns, although associations with central nervous system pathology have been described. This is the first report of LDS with PDT as a novel clinical finding of the compatible syndrome.
- Loeys-Dietz syndrome,
- 1q41 deletion,
- video-EEG,
- paroxysmal tonic downgaze,
- neurodevelopment abnormalities,
- ocular motor events
Citation: Raffaele Falsaperla, Vincenzo Sortino, Evelina Moliteo, Marco Andrea Nicola Saporito, Carla Cimino, Giovanni Cacciaguerra, Piero Pavone. Novel finding of paroxysmal tonic downgaze in Loeys-Dietz syndrome: expanding neurological phenotype[J]. AIMS Medical Science, 2025, 12(3): 292-300. doi: 10.3934/medsci.2025020

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Abstract

Loeys-Dietz syndrome (LDS) is a rare connective tissue disorder caused by pathogenic or likely pathogenic variants in genes encoding the transforming growth factor beta (TGF-®) pathway components. The disease was originally characterized by a typical symptomatologic triad: Bifid uvula or cleft palate, hypertelorism and aortic aneurysm with tortuosity. However, the clinical manifestations are very varied, including vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, and cervical spine malformation and/or instability), craniofacial features (hypertelorism, strabismus, bifid uvula/cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Neurological involvement is very uncommon in LDS, although it has been reported that serial cases with 1q41 deletion encompassing TGF-® 2 ligand (TGFB2) are linked to neurodevelopment abnormalities. The association between LDS or 1q41 deletion and paroxysmal tonic downward gaze (PDT) has never been described in the literature. Here, we describe the case of a 4-month-old male with LDS type 4 caused by 1q41 deletion involving TGFB2 who has neurodevelopment abnormalities and paroxysmal ocular motor events (OPEs). Thanks to polygraphic video-EEG monitoring, such ocular paroxysms are classified as “paroxysmal tonic downward gaze” (PTD), a type of nonepileptic OPE. PTD has been described in most newborns as a benign phenomenon related to an immaturity of the extrageniculocalcarine visual pathway, so more often it concerns healthy and neurologically negative newborns, although associations with central nervous system pathology have been described. This is the first report of LDS with PDT as a novel clinical finding of the compatible syndrome.

Acknowledgments

We thank Dr Sergio Lombardo (Product Specialist Italia Linea Neurodiagnostica Nihon Kohden, Mi.Co.Medical Srl) for making the video.

Conflict of interest

Piero Pavone is an editorial board member for AIMS Medical Science and was not involved in the editorial review or the decision to publish this article. All authors declare that there are no competing interests.

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