Scapuloperoneal Phenotypes in Three Genetically Distinct Patients: Diagnostic and Electrophysiological Implications

To the Editor, Scapuloperoneal syndrome (SPS) refers to a clinical phenotype, characterized by weakness in the scapular and peroneal muscles, often presenting with scapular winging and foot drop. This constellation of symptoms may arise from either myopathic or neurogenic origins and can be associated with a wide array of genetic disorders. We present three genetically distinct patients exhibiting the SPS phenotype to highlight the clinical, electrophysiologic, and molecular heterogeneity of this presentation. The first patient, a 36-year-old male with a longstanding history of gait disturbances, presented with bilateral scapular winging, proximal upper limb weakness, pes cavus, and steppage gait [Figure 1]. There was no family history of neuromuscular disease. Needle electromyography (EMG) revealed short-duration, polyphasic motor unit potentials in the bilateral serratus anterior and left deltoid muscles, whereas the abductor pollicis brevis, first dorsal interosseous, and tibialis anterior muscles were electrophysiologically normal [Figure 2]. Nerve conduction studies were within the normal limits. Cervical spinal magnetic resonance imaging (MRI) showed straightening of the cervical lordosis without spinal cord signal abnormalities, mass lesions, or foraminal compromise. Genetic testing identified a heterozygous pathogenic variant in the DHTKD1 gene, consistent with Charcot-Marie-Tooth disease type 2Q (CMT2Q). These findings support a mixed-pattern pathology, combining both myopathic and neurogenic elements.[1]Figure 1: Prominent bilateral scapular winging observed in Case 1Figure 2: Short-duration, low-amplitude myopathic motor unit potentials observed in the right serratus anterior muscle (needle electromyography)The second patient, a 21-year-old female, presented with progressive proximal muscle weakness since early childhood, accompanied by scapular winging, facial muscle involvement, and calf pain. A neurologic examination revealed hypotonia of the facial muscles, shoulder girdle atrophy, and difficulty rising from the floor. Creatine kinase levels were elevated (1774 U/L). Needle EMG showed short-duration, low-amplitude polyphasic motor unit potentials in the biceps, deltoid, rectus femoris, and tibialis anterior muscles, consistent with a generalized myopathic pattern. A muscle biopsy revealed chronic myopathic changes without necrosis or inflammatory infiltration, and with increased endomysial connective tissue. Genetic testing identified a pathogenic variant in the CAPN3 gene, confirming a diagnosis of limb-girdle muscular dystrophy R1 (LGMD R1; calpainopathy).[2] Although LGMD typically presents with symmetric limb girdle weakness, scapuloperoneal involvement with facial weakness has been previously described. The third patient, a 44-year-old male, reported longstanding proximal upper extremity weakness, facial muscle involvement, and prominent scapular winging. He had been followed since childhood with progressive shoulder girdle atrophy and difficulty raising his arms above his head. A neurologic examination revealed periscapular muscle wasting, facial muscle weakness, and preserved distal strength. Needle EMG showed myopathic motor unit potentials in the deltoid, biceps, and triceps muscles without neurogenic features. Nerve conduction studies were normal. Genetic testing revealed a heterozygous variant in the GAA gene, classified as a variant of uncertain significance. Although facioscapulohumeral dystrophy (FSHD) is classically associated with D4Z4 repeat contraction, the clinical and electrophysiologic findings in this case were most consistent with an atypical FSHD phenotype.[3] The Lamminen MRI scoring system is increasingly used to quantify fatty infiltration and aid in the diagnosis.[4] The clinical, electrophysiological, and genetic correlations of all three cases are summarized in Table 1.Table 1: Correlation of clinical, electrophysiological, and genetic data in three distinct scapuloperoneal syndrome casesOur case series underscores the diagnostic complexity of SPS. Although all three patients shared similar clinical findings, they were ultimately diagnosed as having distinct genetic disorders: CMT2Q, LGMD, and FSHD. SPS may also resemble conditions such as long thoracic or dorsal scapular neuropathies, motor neuron diseases, or congenital myopathies. Importantly, variants in genes such as DHTKD1 and TRPV4 have been associated with overlapping neurogenic and myopathic features, further complicating the differential diagnosis.[1,5] Xu et al. demonstrated that DHTKD1 deficiency in mouse models resulted in muscle damage and neuromuscular junction dysfunction.[6] Similarly, TRPV4 mutations have been linked to both CMT2C and scapuloperoneal spinal muscular atrophy, reflecting the dual neurogenic-myopathic pathogenesis.[7,8] This duality has prompted the terms such as “neurogenic SPSs,” as suggested by Mathis et al., to describe this diverse clinical entity.[9] Given this complexity, a comprehensive approach combining detailed clinical assessment, electrophysiologic testing and targeted genetic analysis is crucial. Especially when EMG findings are inconclusive or suggest mixed pathology, genetic testing can be decisive. Objective tools such as the Charcot-Marie-Tooth Neuropathy Score may aid in classifying phenotypes and tracking disease progression.[10] In conclusion, the scapuloperoneal phenotype should prompt physicians to consider a broad range of neuromuscular disorders. Our report highlights the necessity of early, multidisciplinary evaluation – including electrophysiology and molecular genetics – to establish accurate diagnoses and guide management in patients presenting with this uncommon but diagnostically challenging presentation. Author contributions NT: Study concept, patient acquisition, manuscript drafting SB, ÖB: Electrophysiological evaluation and patient data analysis YED: Critical revision and genetic interpretation. All authors approved the final manuscript. Ethical approval Informed consent was obtained from all the participants. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.