Beneficial effect of gabapentin in two children with Noonan syndrome and early‐onset neuropathic pain

To the Editor: Chronic pain is not considered a key feature of Noonan syndrome (NS), although several studies have highlighted its high frequency among individuals affected by RASopathies (Smpokou, Tworog-Dube, Kucherlapati, & Roberts, 2012; Reinker, Stevenson, & Tsung, 2011; Vegunta et al., 2015). We reported two cases of pediatric patients diagnosed with NS who developed chronic extremity neuropathic pain, which benefited from a therapeutic trial with gabapentin. This study aims to describe the association between NS and neuropathic pain and suggests the opportunity of using a pain scoring system in the NS patients' assessment. A six-year-old girl was evaluated for a four-year history of bilateral, symmetrical diffuse pain in her legs and feet, leading to nocturnal arousals, occasionally associated with red and warming feet, without other symptoms. According to the parents' report, the pain occurred in the form of spontaneous paresthesia, associated with hyperalgesia and allodynia, and showed no response to NSAIDs. The girl scored the pain as severe, according to the age-appropriate Wong-Baker Faces Pain Scale (WBFPS). Laboratory tests (including complete blood count, C reactive protein, erythrocyte sedimentation rate, creatine phosphokinases, thyroid function, anti-transglutaminase antibodies, electrolytes, iron, ferritin, B12 vitamin, and folic acid) and magnetic resonance imaging (MRI) of the spine turned out to be negative. Since these pain episodes arose during sleep and benefited from massages, they were initially interpreted as growing pains, while for the subsequent discovery of mild hypomagnesemia, an oral supplementation was initiated but proved to be not useful. No other treatments were undertaken except for the occasional administration of NSAIDs, which, however, did not bring significant benefits. In the end, it was speculated that erythromelalgia was the cause of worsening pain during the warm months and associated cutaneous erythema. To exclude a familiar form, which could have been hypothesized due to the history of similar pain episodes within the maternal line (grandmother), the molecular analysis of SCN9A (Arthur et al., 2019) was performed, testing negative. By evaluating the peculiar facial gestalt with hypertelorism and low set ears, the borderline short stature, and the echocardiographic finding of diffuse aortic hypoplasia (despite the absence of valvular anomalies), we suspected a RASopathy. A Next-Generation Sequencing (NGS) specific panel, examining coding regions and splicing junctions of genes associated with Noonan syndrome and other RASopathies, was performed, showing the presence of the pathogenic de-novo variant c.1132A>G in SOS1 gene. Due to the increasing frequency of pain crises and negative impact on the child's quality of life (QoL), at the age of six, a therapeutic approach with gabapentin was undertaken. Starting from the dose of 100 mg per day, she received a maximum dose of 100 mg twice a day, obtaining a complete resolution of her pain episodes in around 1 month, without side effects. After 1 months of ongoing therapy, gabapentin was discontinued and there were no relapses. A six-year-old girl was diagnosed with Noonan syndrome at few months of life after a cardiologic finding of pulmonary valve stenosis; the NGS panel mentioned above, for the detection of RASopathies, showed a pathogenic variant in PTPN11 (c.1403C>T). From the age of three, she started complaining of bilateral pain in her legs and knees, starting as nocturnal crises of paresthesia and allodynia, which were more frequent during the cold months. According to the parents' report, the pain eventually worsened, also occurring during the day after physical activities and progressively extending to arms, wrists, and the back of the hands, without signs of cutaneous involvement. Laboratory tests (blood count, C reactive protein, erythrocyte sedimentation rate, creatine phosphokinases, thyroid function, anti-transglutaminase antibodies, electrolytes, iron, ferritin, B12 vitamin, and folic acid) and spine MRI proved negative. Based on the onset of the Received: 1 March 2020 Revised: 7 May 2020 Accepted: 22 May 2020