Melnick-Needles Syndrome: Synthesizing Current Knowledge on Etiology, Clinical Presentation, Diagnostic Methods, and...

Melnick-Needles syndrome (MNS) is a rare X-linked dominant skeletal dysplasia caused by pathogenic FLNA variants, primarily affecting females due to male lethality. Characterised by severe craniofacial and skeletal abnormalities, MNS exhibits marked phenotypic variability influenced by skewed X-inactivation, somatic mosaicism, and variant-specific functional consequences. Recent advances in next-generation sequencing and ACMG-based variant classification have refined diagnosis, particularly for pathogenic variants in exon 22, yet genotype-phenotype correlations remain incompletely defined. Differential diagnosis within the otopalatodigital spectrum, including OPD1, OPD2, and Frank-Ter Haar syndrome, remains challenging due to overlapping features, necessitating comprehensive radiological and molecular evaluation. Clinical manifestations span craniofacial dysmorphism, thoracic hypoplasia, respiratory compromise, and multisystem involvement. Management requires interdisciplinary coordination encompassing respiratory support, orthognathic surgery, dental reconstruction, and monitoring for complications such as glaucoma and psychiatric comorbidities. Evidence for the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) and mandibular distraction techniques highlights surgical adaptability, though altered bone metabolism in MNS necessitates modified approaches. Rare associations with periventricular nodular heterotopia and bipolar disorder suggest a broader neurodevelopmental impact of FLNA dysfunction. Despite expanding clinical insight, the rarity of MNS limits population-level studies, constraining understanding of natural history and long-term outcomes. Future research must prioritise elucidating modifier genes, therapeutic targets such as antisense oligonucleotides, and prenatal detection strategies. A synthesis of genetic, clinical, and surgical domains is essential to optimise care pathways, improve prognosis, and inform genetic counselling for families affected by this phenotypically diverse and medically complex disorder.