Fragile X Syndrome in Practice: A Clinical Dysmorphology Guide for Diagnosis without Genetic Testing

Abstract

Background: Fragile X syndrome is one of the most common inherited causes of mental retardation and a leading monogenic cause of autism spectrum disorder. Despite its well-established genetic basis, diagnosis in many low-and middle-income countries remains limited due to restricted access to molecula testing. Historically, the condition was first described by James Purdon Martin and Julia Bell in 1943, with subsequent cytogenetic characterization by Herbert Lubs. Later clinical delineation highlighted a recognizable pattern of craniofacial dysmorphism and neurodevelopmental impairment. In resource- limited settings, reliance on clinical features remains essential for diagnosis. Objectives: The objective of the study was to describe the clinical characteristics and diagnostic features of three Iraqi male patients presenting with neurodevelopmental impairment and phenotypic findings suggestive of Fragile X syndrome, emphasizing the role of phenotype-based diagnosis in the absence of genetic confirmation. Methods: This case series includes three male patients evaluated in 2025 in a clinical setting. Diagnosis  was based on detailed clinical assessment, including developmental history, behavioral profile, and physical examination focusing on dysmorphic features. Data collected included age at presentation, neurodevelopmental status, behavioral characteristics, growth parameters, and craniofacial morphology. Results: The patients (ages 6, 8, and 16 years) demonstrated variable neurodevelopmental impairment: (1) One patient exhibited severe autism, absent eye contact, stereotypic behaviors, and growth failure. (2) One patient presented with marked speech delay and hyperactivity without clear autistic features. (3) One patient showed mental retardation with less prominent behavioral abnormalities. All patients shared consistent craniofacial features, including: (1) Long, narrow face, (2) Prominent or protruding ears, (3) Forehead prominence (in two patients), (4) Variable mandibular changes (micrognathia or prognathism). Additional findings included slender body habitus in two patients and absence of major congenital anomalies in all cases. Notable phenotypic variability was observed, particularly in behavioral manifestations and severity of cognitive impairment. Conclusion: Fragile X syndrome can be diagnosed with reasonable clinical confidence based on characteristic craniofacial features and neurodevelopmental profile, even in the absence of genetic testing. This case series highlights the importance of clinician awareness and careful phenotypic. Early clinical recognition may facilitate timely intervention, appropriate management, and genetic counseling, thereby reducing underdiagnosis and improving patient outcomes.