Aug 2026· Frontiers in Psychiatry· Vol 17· 0 citations· 10 references
Medicine
TL;DR
This case underscores that the genetic and neuropsychological identification of a neurodevelopmental disorder, together with the integration of tailored psychomotor interventions and contextual adaptations, can improve psychiatric management and daily functioning, and mitigate behavioral decline in adulthood, even following a prolonged diagnostic delay.
Abstract
This report describes the diagnostic and treatment course of an adult woman with the ultra-rare Au-Kline syndrome (AUKS). Since the age of 32 years, when the syndrome was yet undiagnosed, the patient suffered from behavioral decline coinciding with changes in living conditions. At the age of 38, following a bladder infection, she presented with a delirium for which antipsychotic medication was started. The delirium resolved but, while the medication was continued, the pre-existing behavioral symptoms persisted. Clinicpal genetic evaluation revealed a history of congenital hypotonia, developmental delay, and multiple (craniofacial) dysmorphisms. Subsequent trio-based genetic testing demonstrated a novel pathogenic variant in the HNRNPK gene, causative for AUKS. Clinical neuropsychological assessment showed moderate intellectual disability, slow information processing speed, restricted verbal expression, and limited comprehension. Registration of sensory information was severely hampered and there was difficulty in self-modulating the sensory information to be processed. Contextual adaptations and individual psychomotor therapy were then implemented to optimize sensory and motor information processing, to promote daily functioning, and reduce behavioral decline. These interventions, along with the long-term psychotropic medication, had beneficial effects on her functioning, which subsequently returned to near premorbid levels by the age of 45. Overall, this case underscores that the genetic and neuropsychological identification of a neurodevelopmental disorder, together with the integration of tailored psychomotor interventions and contextual adaptations, can improve psychiatric management and daily functioning, and mitigate behavioral decline in adulthood, even following a prolonged diagnostic delay.
KBG syndrome is a rare autosomal dominant neurodevelopmental disorder caused by pathogenic variants
in the ANKRD11 gene. The clinical presentation is highly variable and may include characteristic craniofacial
features, developmental delay, learning disabilities, behavioral abnormalities, and growth impairment. Here
we describe a Lebanese female patient who was followed for 11 years because of failure to thrive,
developmental delay, attention deficit, behavioral difficulties, and persistent learning disabilities. Longitudinal follow-up documented gradual neurocognitive improvement with multidisciplinary interventions and
pharmacological treatment for attention and behavioral difficulties. Whole Exome Sequencing (WES),
performed at the age of 11 years, identified a novel heterozygous frameshift pathogenic variant in the
ANKRD11 gene (p.Tyr808fs), confirming the diagnosis of KBG syndrome. To our knowledge, this is the first
reported Lebanese patient carrying this specific ANKRD11 variant. This case expands the molecular
spectrum of KBG syndrome and highlights the importance of genomic testing in children presenting with
developmental delay, learning difficulties, and subtle dysmorphic features, particularly when the diagnosis
remains uncertain during early childhood.
A novel homozygous missense variant in RNF216 gene c.1055T>G (p.(Phe352Cys)) in three siblings with Gordon Holmes syndrome is reported, contributing to the limited knowledge of GHS and highlighting the importance of hypogonadotropic hypogonadism treatment and close observation of neurological symptoms that may develop over time.
Pathogenic variants in KIF11 are linked to autosomal dominant syndromes with microcephaly, chorioretinopathy, lymphedema, and intellectual disability (MCLID), though adult presentations remain underreported. We report a 42-year-old female presenting with a de novo single-amino acid in-frame deletion in the KIF11 gene (c.1294_1296del; p.Glu432del), who exhibited severe intellectual disability, microcephaly, hypotonia, seizures, and self-injurious behavior. There was evidence of developmental delays, ophthalmologic findings, and impairments in speech and adaptive functioning in her clinical history. Trio whole exome sequencing identified a diagnostic pathogenic variant in KIF11 and a maternally inherited SCN3A variant of uncertain significance. The presentation of the case offers an unusual longitudinal perspective of over four decades, illustrating the variable expressivity and long-term outcome of KIF11 disorders. This report calls for the consideration of KIF11 variants in the differential diagnosis of syndromic developmental delay and microcephaly in adults and underlines the diagnostic as well as the prognostic importance of detailed genetic and phenotypic analysis, particularly in cases with de novo variants.
Thrishna Chathurvedula, Juvy L. Rabelas, Kareem Touleimat et al.· American Journal of Medical...· 0 citations
Noonan syndrome (NS) is a clinically heterogeneous condition caused by pathogenic variants in genes of the RAS/MAPK signaling pathway, presenting as a spectrum of phenotypic features rather than a single uniform disorder. We report two unrelated female pediatric patients evaluated for LZTR1‐related NS following whole‐exome sequencing. The first patient presented with isolated short stature, subtle dysmorphic features, and normal neurodevelopment. The second displayed multisystem involvement including developmental delay, skeletal abnormalities, and auditory processing disorder. A heterozygous pathogenic variant in LZTR1 was confirmed in the first patient, while the second carried a heterozygous LZTR1 variant of uncertain significance, rendering her diagnosis provisional. Neither patient had congenital heart defects. These cases illustrate the marked phenotypic variability of LZTR1‐related NS and underscore that, while cardiac defects may be absent in some individuals, appropriate cardiac surveillance remains necessary.
Karolina J Skrzynska, B. Kalina-Faska, Ewa Błaszczyk et al.· Clinical Genetics· 0 citations
We present a family of five siblings who came to our attention with a clinical and radiological diagnosis of familial hypomyelinating leukodystrophy. Despite brain white matter abnormalities being present in all siblings, the clinical phenotype was variable: the three brothers presented with a clear-cut late-onset spastic paraplegia, whereas the two sisters displayed only mild pyramidal signs. Molecular analysis revealed a single relevant variant shared by all affected siblings, namely the likely pathogenic variant c.659C>T (p.Ser220Phe) in the GJA1 gene. Variants in this gene are generally associated with oculodentodigital dysplasia (ODDD), an autosomal dominant condition characterized by distinctive facial features and anomalies of the eyes, teeth, and digits. Neurological features are reported in about 30% of cases. In this family, ODDD manifested as a predominantly neurological phenotype. Although a clear explanation for this uncommon presentation is lacking, shared genetic modifiers, the effect of the specific variant, and a possible patient-population bias may have contributed. This case highlights the wide phenotypic spectrum of CX43-related disorders and suggests the importance of testing the GJA1 gene in individuals with atypical presentations, including predominant or isolated neurological phenotypes such as late-onset spastic paraplegia. MRI findings may also provide a useful diagnostic clue when ODDD is suspected.
Irene Ambrosetti, Flavia Palombo, Diego D'Angeli et al.· International Journal of Mol...· 0 citations
Background.
neurofibromatosis type 1 is a common hereditary autosomal dominant disorder caused by pathogenic genetic variants in the NF1 gene located on chromosome 17q11.2. the disease is characterized by high allelic heterogeneity and the absence of clear genotypic correlations, with the exception of large deletions associated with a more severe phenotype. Clinically, neurofibromatosis is characterized by the presence of multiple (>6) "café-au-lait” spots, neurofibromas of any type or plexiform neurofibromas, freckles in the axillary or inguinal areas, hamartomatous Lisch nodules of the iris, optic glioma, and bone dysplasia. therefore, the description of each new genetic variant is essential for expanding the spectrum of known variants and improving molecular diagnostics.
Case Report
. the article describes a clinical and molecular genetic study of a 10-year-old boy. since early childhood, the patient has had multiple “café-au-lait” spots, speech impairment, grade 1 hypotrophy, rickets, sequelae of perinatal CNs damage, myotonic syndrome, and a delay in motor development. Magnetic resonance imaging of the brain revealed signs of focal damage to both hemispheres, the cerebellar vermis, and the left subcortical nuclei, and a glioma of the right optic nerve was detected. Neurofibromatosis type 1 was diagnosed based on clinical criteria. Whole-genome DNA sequencing was performed, followed by bioinformatics analysis and confirmation of the results by direct sanger sequencing. A previously undescribed complex, likely pathogenic variant NM_001042492.3:c.40 60_4068delinsC of the NF1 gene was identified in the heterozygous state. this variant leads to a reading frameshift and premature translation termination after the synthesis of 23 amino acids (p.ser1354Leufs*23). this variant is not present in available population genetic variant databases.
Conclusion.
thus, wholegenome sequencing identified a new pathogenic variant in the NF1 gene associated with the development of neurofibromatosis type 1. the obtained data expand the range of variants for this pathology and can be used in medical genetic counseling, as well as in algorithms for molecular genetic diagnostics of patients with suspected neurofibromatosis type 1.
I. Z. Zhalsanova, E. Fonova, D. N. Erburova et al.· Siberian journal of oncology· 0 citations