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Clinical Diagnostic Techniques for Rare Genetic Diseases in Children: Current...
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Clinical Diagnostic Techniques for Rare Genetic Diseases in Children: Current Status, Advances, and Thoughts

A Special Issue of Children (ISSN 2227-9067) belonging to the section "Pediatric Neurology & Neurodevelopmental Disorders".

Deadline for manuscript submissions: closed (25 August 2026) | Viewed by 2825

Editors

Dr. Raquel Medina-Ramírez

E-Mail Website
Guest Editor
Soc-Dig Research Group, University of Las Palmas de Gran Canaria, 35001 Las Palmas, Spain
Interests: sleep; neuroscience; rehabilitation; pain; education; neuromodulation; sport; physiotherapy
Dr. Laura Mordillo-Mateos

E-Mail Website
Guest Editor
1. Faculty of Health Sciences, University of Castilla-La Mancha, Avda. Real Fábrica de Seda, s/n, 45600 Talavera de la Reina, Spain
2. Technological Innovation Applied to Health Research Group (ITAS Group), Faculty of Health Sciences, University of Castilla-La Mancha, 45600 Talavera de la Reina, Spain
Interests: neuroscience; nursing; physical therapy

Special Issue Information

Dear Colleagues,

Rare genetic diseases in children often present with heterogeneous clinical manifestations, delayed diagnosis and complex care pathways. Beyond genetic alterations, many of these conditions are associated with autonomic nervous system dysfunction and multisystem physiological imbalances that significantly impact development, sleep, cardiovascular regulation, pain and overall health. Early and accurate diagnosis is therefore essential to identify not only the underlying genetic cause but also the functional and physiological alterations that influence clinical outcomes.

In recent years, advances in clinical diagnostic techniques, including functional assessment, physiological biomarkers, autonomic nervous system evaluation, imaging and non-invasive monitoring, have contributed to a more comprehensive understanding of rare pediatric diseases. This Special Issue aims to highlight current and emerging diagnostic approaches that integrate genetic, physiological and clinical perspectives to support early identification and personalized management of children with rare and complex conditions. 

Dr. Raquel Medina-Ramírez
Dr. Laura Mordillo-Mateos
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Children is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2400 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • rare genetic diseases
  • pediatric diagnosis
  • clinical assessment
  • diagnostic techniques
  • child health

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Published Papers (3 papers)

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19 pages, 2014 KB  
Article
Frequency-Following Responses for Objective Neurophysiological Monitoring in Pediatric Fetal Alcohol Spectrum Disorder: A Proof of Concept Case Study During Non-Invasive Neuromodulation
by Sheila Templado, Raquel Medina-Ramirez, Guillermo Savio, María Teresa Almela and Francisco J. García-Purriños
Children 2026, 13(8), 1116; https://doi.org/10.3390/children13081116 - 20 Aug 2026
Viewed by 494
Abstract
Background/Objectives: Fetal Alcohol Spectrum Disorder (FASD) is a preventable neurodevelopmental condition associated with dysfunction of fronto-subcortical networks affecting attention, executive function, and behavioral regulation. Central auditory processing difficulties frequently persist despite preserved peripheral hearing, complicating clinical evaluation when behavioral testing is limited or [...] Read more.
Background/Objectives: Fetal Alcohol Spectrum Disorder (FASD) is a preventable neurodevelopmental condition associated with dysfunction of fronto-subcortical networks affecting attention, executive function, and behavioral regulation. Central auditory processing difficulties frequently persist despite preserved peripheral hearing, complicating clinical evaluation when behavioral testing is limited or unreliable, and objective markers that do not depend on behavioral cooperation are therefore needed. This exploratory observational case study investigated whether Frequency-Following Responses (FFRs) can capture measurable within-subject change in speech-evoked neural encoding in a pediatric patient with FASD. Methods: FFRs were recorded at two time points bracketing an eight-session period of non-invasive superficial neuromodulation (NESA®) in an 8-year-old girl with FASD, using speech syllables (/da/, /ba/, /ga/) presented monaurally at 80 dB SPL. Two-tailed block-level Mann–Whitney U tests with rank-biserial correlations compared peak latencies, sustained pitch-tracking metrics (pitch strength, pitch error), onset stimulus–response correlation, and signal-to-noise ratio. Results: Sustained pitch-tracking metrics differed between time points, with increased pitch strength and reduced pitch error, whereas onset peak latencies, onset cross-correlation, and signal-to-noise ratio remained stable. Peak C, marking the transition to the sustained portion of the response, occurred earlier at the post-assessment in all six stimulus–ear combinations. The differences were therefore selective to sustained encoding rather than to onset timing or recording quality. Conclusions: FFR-derived pitch-encoding metrics detected measurable within-subject change, providing proof of concept for the feasibility of FFRs as a candidate objective tool for longitudinal monitoring of speech-evoked neural encoding in pediatric FASD. This single-case observation does not evaluate diagnostic accuracy, sensitivity, specificity, or discrimination from typically developing children, and therefore does not establish FFR as a validated diagnostic technique. The findings are hypothesis-generating and motivate controlled longitudinal studies. Full article
(This article belongs to the Special Issue Clinical Diagnostic Techniques for Rare Genetic Diseases in Children: Current Status, Advances, and Thoughts)
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7 pages, 182 KB  
Case Report
Delayed Diagnosis of Mild GLUT1 Deficiency Syndrome Caused by an Apparently De Novo SLC2A1 p.(Phe445del) Variant in a Child with a History of Severe Neonatal Hyperkalemia
by Simona Ivančan, Maruša Debeljak, Tanja Loboda and Štefan Grosek
Children 2026, 13(7), 883; https://doi.org/10.3390/children13070883 - 30 Jun 2026
Viewed by 402
Abstract
Background/Objectives: Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a rare neurometabolic disorder with an expanding clinical spectrum, including mild and non-classical presentations. We report a boy with severe transient neonatal hyperkalemia, bilateral congenital cataracts, and later subtle neurological and neurocognitive symptoms, in [...] Read more.
Background/Objectives: Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a rare neurometabolic disorder with an expanding clinical spectrum, including mild and non-classical presentations. We report a boy with severe transient neonatal hyperkalemia, bilateral congenital cataracts, and later subtle neurological and neurocognitive symptoms, in whom genomic testing supported the diagnosis of mild GLUT1DS. Methods: This single-patient case report describes clinical follow-up from birth to nine years of age, including neurological, metabolic, neuropsychological, imaging, and genetic investigations. Whole-exome sequencing using next-generation sequencing technology was performed. Results: The patient required intensive care immediately after birth because of severe transient hyperkalemia of unclear etiology. Bilateral congenital cataracts were surgically corrected during infancy. Later, he developed two brief seizure episodes, reduced exercise tolerance, episodic fatigue, attentional difficulties, motor restlessness, and mild graphomotor impairment. Neuropsychological assessment showed overall average intellectual functioning, below-average verbal abilities, low-average non-verbal abilities, and attention-deficit/hyperactivity disorder. Repeated metabolic investigations, electroencephalography, and brain magnetic resonance imaging were unrevealing. Whole-exome sequencing identified an apparently de novo heterozygous SLC2A1 variant, NM_006516.4.1333_1335del, p.(Phe445del), supporting the diagnosis of mild GLUT1DS. Because of the mild phenotype and preserved everyday functioning, ketogenic diet therapy was not initiated. Conclusions: This case highlights the diagnostic challenges of mild GLUT1DS and the value of genomic testing in children with unexplained neurological or neurocognitive symptoms despite normal routine investigations. Although neonatal hyperkalemia and GLUT1DS coexisted in this patient, current evidence is insufficient to establish a causal relationship. Full article
(This article belongs to the Special Issue Clinical Diagnostic Techniques for Rare Genetic Diseases in Children: Current Status, Advances, and Thoughts)
12 pages, 1967 KB  
Case Report
Studying Familial Bainbridge–Ropers Syndrome Due to a Novel ASXL3 Germline Variant and Expanding the Clinical Spectrum
by Daiana Mariano, Valentina Petrone, Francesca Madia, Mariasavina Severino, Luca Basso, Valeria Capra, Maria Stella Vari, Antonio Marras, Giacomo Tantari and Giuseppe d’Annunzio
Children 2026, 13(5), 599; https://doi.org/10.3390/children13050599 - 27 Apr 2026
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Abstract
Background/Objectives: Bainbridge–Ropers syndrome (BRPS) is a rare neurodevelopmental disorder caused by truncating and splicing pathogenic variants in the additional sex combs-like 3 (ASXL3) gene. It is primarily characterized by neurodevelopmental delay and craniofacial dysmorphism. Most reported cases involve de novo [...] Read more.
Background/Objectives: Bainbridge–Ropers syndrome (BRPS) is a rare neurodevelopmental disorder caused by truncating and splicing pathogenic variants in the additional sex combs-like 3 (ASXL3) gene. It is primarily characterized by neurodevelopmental delay and craniofacial dysmorphism. Most reported cases involve de novo mutations in the ASXL3 gene, whereas inherited mutations have been rarely described. The present report aims to describe the clinical and molecular presentation of a familial case of BRPS and to highlight the potential role of parental mosaicism. Methods: We describe the clinical and molecular presentation of a 12-year-old boy and his 20-month-old half-brother, both affected by Bainbridge–Ropers syndrome. Trio-exome sequencing (ES) was performed in the family to identify variants in the ASXL3 gene, and targeted Sanger sequencing was also performed for segregation analysis. Results: Genetic analysis identified a previously unreported heterozygous frameshift variant in the ASXL3 gene (c.1648_1649del; p.Met550Aspfs*5) shared by both siblings. The variant was inherited from their clinically unaffected mother, who carries the mutation in the mosaic state with a variant allele fraction of approximately 15% in peripheral blood DNA. Conclusions: This observation highlights parental mosaicism as a potential mechanism underlying the familial recurrence of BRPS and emphasizes the importance of considering mosaic variants during the genetic evaluation and counseling of affected families. Full article
(This article belongs to the Special Issue Clinical Diagnostic Techniques for Rare Genetic Diseases in Children: Current Status, Advances, and Thoughts)
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