Evaluation of the Relationship between Fascioscapulohumeral Dystrophy and Noonan Syndrome

Dear Editor, Facioscapulohumeral dystrophy (FSHD) is the third most common muscular dystrophy. Its prevalence is 4–12/100,000, and its prevalence is increasing compared with the 1990s.[1] It is inherited as autosomal dominant (OD) and affects skeletal muscles. Although the incidence is similar between different races, the penetrance in women is slightly less than in men.[2] Noonan syndrome (NS), on the other hand, defined by Jacqueline Noonan, is a genetic disease, inherited with OD, with a multisystem prevalence of 1/1000–2500. Men and women are affected equally.[3,4] In this article, we aimed to draw attention to the possible relationship between FSHD and NS by presenting a case where two rare hereditary diseases coexisted. A 30-year-old male patient was admitted to the neurology clinic with progressive weakness in both arms for several years. The patient had no known chronic disease history. In the patient’s family history, her older brother had similar symptoms but had no diagnosis, and her daughter had a history of surgery for pulmonary artery stenosis in the early postpartum period. There was no consanguinity between the patient’s parents, and they were completely healthy. In the neurologic examination of the patient, he could not squeeze his eyes fully bilaterally; his lips were prominently protruding forward. His shoulder and arm muscles were atrophic. Regarding muscle strength, his bilateral shoulder abduction was 4/5, and forearm flexion was 3/5, otherwise normal. Scapula alata was seen on the left side. There was no sensory defect, and cerebellar examination was normal. There was no pyramidal sign. In addition, the patient had scoliosis and thoracic deformities. No skin pathology was observed [Figures 1 and 2].Figure 1: The patient has scoliosis, thorax deformities, and atrophia at arm musclesFigure 2: The patient has scoliosis, thorax deformities, and atrophia at arm musclesIn the routine laboratory examinations of the patient, creatine kinase (CK) was slightly increased (396 U/L), and no pathologic finding was observed. Nerve conduction studies were found to be within normal limits in his electrophysiologic examination, and diffuse short-term polyphasic motor unit potentials and early interference were observed in the electromyography (EMG) examination, prominent in the upper extremity and proximal muscles. Spontaneous denervation was not observed. These findings were evaluated in relation to widespread myopathic involvement with dystrophy. No pathology was found in the other systemic examinations of the patient. When clinical and electrophysiologic findings were evaluated together, FSHD was considered in the patient, and genetic examination was requested. Muscle biopsy was not performed due to the clear clinical and electrophysiologic findings. As a result of the genetic examination of the patient, in the PTPN11 gene, an NM_002834.5 c.781>T(p.L261F) (p.Leu261Phe) (heterozygous) change was detected and evaluated as pathological. The patient was diagnosed as having NS because this change is a variant associated with NS in the Human Gene Mutation Database. The clinical presentation of FSHD may vary initially but is characterized by weakness of the facial, scapula, and arm muscles, which usually begins asymmetrically.[5] Extraocular, cardiac, and bulbar muscles are usually spared, and respiratory muscle involvement is observed in 15% of cases.[6] It occurs due to failure of suppression of the DUX4 gene, which is not normally expressed in skeletal muscle.[3] FSHD1 constitutes 95% of patients and is caused by heterozygous pathogenic contraction of the D4Z4 repeat sequence located in the subtelomeric region of 4q35. FSHD2, on the other hand, is formed by hypomethylation of the D4Z4 repeat sequence in the subtelomeric region of chromosome 4q35 and accounts for 5% of patients.[7] A slight CK elevation is expected in biochemical examinations. In electrophysiologic examinations, nerve conduction studies are within normal limits, and needle EMG examinations are consistent with myopathic changes in the muscles involved in accordance with the clinical findings of the patient. Nonspecific myopathic findings are also observed in pathologic examinations.[8] NS is a disease characterized by facial dysmorphism, cardiac conduction defects, skeletal anomalies, and cognitive deficits that vary in clinical presentation. Abnormalities in the PTPN11, SOS1, KRAS, RAF1, BRAF, and MEK1 genes are present in approximately 70% of patients. Congenital heart diseases, growth retardation, cryptorchidism, and skeletal deformities are seen in patients with a typical facial appearance.[9] The PTPN 11 gene, which was also seen pathologically in our patient, encodes the SH2 protein, which regulates cell migration, proliferation, survival, and differentiation, including RAS-MAPK signaling.[10] Although neurologic involvement is rare in NS, it is associated with retinitis pigmentosa, neurofibromatosis type 1, and Charcot–Marie–Tooth disease. In addition to these diseases, there are cases of Chiari type 2 malformation and Dandy–Walker syndrome reported in the literature.[11] Myopathic involvement was demonstrated by muscle biopsy in two patients with the NS phenotype and hypertrophic obstructive cardiomyopathy but without a PTPN11 mutation by de Boode et al.[12] In a study in which Hunter and Pinsky evaluated the relationship between NS and malignant hyperpyrexia, cardiomyopathy, mild serum CK elevation, and myopathic appearance in the upper extremities and face were reported in a patient with typical NS features.[13] Regarding its association with dystrophies, a case report with Becker muscular dystrophy and NS has been reported, but we found no cases with FSHD and NS in the association.[14] Although there are reported cases of NS and myopathic involvement in the literature, we present this patient because no case has been reported with the FSHD phenotype. Comprehensive studies are needed to examine the relationship between FSHD and NS. Author contributions Supervision – E.G.; Literature search – A.A; Writing – A.A. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.