Early-onset myopathy with fatal cardiomyopathy (EOMFC; OMIM 611705), generally known as Salih myopathy (SALMY; OMIM 611705), is a sporadic syndrome involving motor developmental delays caused by autosomal recessive inherited homozygous or compound heterozygous loss-of-function mutations in the TTN gene on chromosome 2q31.2. Affected patients exhibit muscle weakness, delayed motor development, joint and neck contractures, spinal rigidity, scoliosis, and cardiac dysfunction [1]. SALMY was initially described as Salih congenital muscular dystrophy beginning in 1998 [2] and later renamed as SALMY [3]. Its incidence rate is infrequent/sporadic and, therefore, unknown.

Feingold syndrome type 1 (FGLDS1; OMIM 164280) is a highly uncommon neurodevelopmental disorder caused by an autosomal dominant inherited heterozygous loss-of-function mutation in the MYCN gene on chromosome 2p24.3. Affected patients exhibit digit anomalies, microcephaly, facial dysmorphism, gastrointestinal atresia, cardiac and renal abnormalities, and developmental delay [4]. FGLDS1 was first described in 1971 [5]. While its incidence is unknown, there are reports of 69 families with 116 affected individuals demonstrating three or more of the condition’s core features [6-8].

This report describes a 19-month-old who presented with general hypotonia, a cardiac septal defect, distal arthrogryposis, and developmental delay. Whole genome sequencing (WGS) identified an inherited TTN mutation, c.46816_46820delinsCAATGGTTTT (p.Glu15606Glnfs*22) (p.E15606fs) and c.104724_104731dup (TTCCAGGT) (p.Tyr34911Phefs*7) (p.Y34911fs) and a de novo MYCN mutation, c.853C>T (p.Arg285Trp) (p.R285W). This is the first case report of concurrent SALMY and FGLDS1 caused by TTN and MYCN mutations.

This study was approved by the Institutional Review Board for Human Research of Asan Medical Center (IRB number 2021-0951). Written informed consent was obtained from the patient and patient’s parents for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

An Asian female neonate was born and referred to the Neonatal Intensive Care Unit at Asan Medical Center Children’s Hospital, Seoul, Korea, following resuscitation due to perinatal distress. She had no siblings and was the first child born at 40 weeks and 2 days of gestation to a 28-year-old mother without an abortion history. There was no family history of congenital heart disease or genetic disorders. Her birth weight was 2.97 kg (10-50th percentile), height was 48.5 cm (10-50th percentile), and head circumference was 36.3 cm (90th percentile). Syndromic features noted at admission included general hypotonia, macrocephaly, micrognathia, and distal arthrogryposis. We also detected a double outlet right ventricle with a subaortic ventricular septal defect and a large atrial septal defect.

At 3 months, she underwent surgery to address her cardiac septal defects. At 4 months, she was unable to control her head and body, and weak respiratory muscle tone prevented spontaneous breathing, necessitating a tracheostomy. Brain magnetic resonance imaging (MRI) showed prominent frontotemporal cerebrospinal fluid (CSF) spaces with suspected delayed myelination (Fig. 1). Her karyotype was 46, XX, and a chromosomal microarray revealed no significant copy number variants. Specific gene mutation tests for myotubular myopathy (MTM1 gene), spinal muscular dystrophy (SMN1/2 gene), and Prader–Willi syndrome (SNRPN gene) were unremarkable. By this time, she weighed 3.88 kg (<3th percentile), her height was 60 cm (50-90th percentile), and had a head circumference of 37 cm (10th percentile).

At 15 months, a muscle power test revealed central hypotonia, with grades of 1 in proximal muscles and 2-3 in distal muscles. Because of the patient’s multi-systemic clinical features, including general hypotonia, global developmental delay, macrocephaly, distal arthrogryposis, congenital heart defects, and normal chromosomal microarray results, WGS was performed. Observed variants were annotated by Ensembl Variant Effect Predictor (VEP) and filtered and classified using the RareVision system (Genome Insight).

WGS identified compound heterozygous mutations in the TTN gene: c.104724_104731dup (p.Y34911fs) and c.46816_46820delinsCAATGGTTTT (p.E15606fs) classified as “pathogenic” (PVS1, PM2, and PM3) [9]. Sanger sequencing confirmed that the c.104724_104731dup (p.Y34911fs) variant in the TTN gene was inherited from the father, and the c.46816_46820delinsCAATGGTTTT (p.E15606fs) variant in the TTN gene was inherited from the mother. Thus, we were able to diagnose SALMY.

WGS additionally revealed a novel mutation, c.853C>T (p.R285W), in the MYCN gene. An in silico analysis predicted that p.Arg285Trp would alter protein function; this variant, classified as “likely pathogenic” by ACMG guidelines (PS2, PM1, PM2, PP3), has not been previously reported in the general population [9]. Her parents did not carry the mutation, leading to diagnostic confirmation of FGLDS1 (Fig. 2).

The patient was admitted to the pediatric intensive care unit at 19 months with drowsiness, respiratory impairment, and hypotension. Transthoracic echocardiography revealed decreased left ventricular function. On hospital day 3, she experienced alternating episodes of ventricular arrhythmia and pulseless electrical activity and unfortunately expired the next day due to heart failure secondary to dilated cardiomyopathy.

This is the first documented case of concurrent SALMY and FGLDS1, identified through WGS and revealing mutations in TTN and MYCN genes. Our case’s clinical manifestations were consistent with previous reports of SALMY and some features of FGLDS1 (Table 1). Specifically, our patient presented with macrocephaly, micrognathia, distal arthrogryposis, and cardiac anomalies, including double outlet right ventricle with subaortic ventricular septal defect and large atrial septal defect. General hypotonia and developmental delay were the predominant symptoms. Brain MRI showed prominent frontotemporal CSF spaces with suspected prolonged myelination (Table 1) [10-14].

Previous studies, including Roggenbuck et al. [15], highlighted overlapping features in patients with TTN gene microdeletion, including facial weakness, neck flexor weakness, decreased muscle bulk, and predominant proximal muscle weakness. Other researchers found that patients with contiguous gene deletions_—including MYCN and adjacent genes_—may present with duplicated features such as micrognathia and structural cardiac defects [10,16,17].

The TTN gene on chromosome 2q31.2 encodes titin, a colossal muscle protein spanning half the sarcomere length from the Z line to the M line. Titin is crucial in cardiac and skeletal muscle cells for muscle assembly, force transmission at the Z line, and maintaining resting tension in the I band region. Bang et al. [18] found that titin interacts with various sarcomere proteins at the Z line, I band, and M line regions. Pathogenic TTN mutations typically lead to loss of function, reduced titin-binding of sarcomere proteins, and disruptions in the C-terminal residues and sarcomere M line protein complex, ultimately affecting sarcomere function [19]. Hypertrophic cardiomyopathy, dilated cardiomyopathy, tardive tibial muscular dystrophy, and myofibrillar myopathy-9 with early respiratory failure are associated with a single heterozygous mutation of the TTN gene [20-25]. SALMY and autosomal recessive limb-girdle muscular dystrophy-10 are linked to compound heterozygous and homozygous mutations [19,22,26,27].

The MYCN gene on chromosome 2p24.1 encodes a Myc family transcription factor, pivotal for regulating neurogenesis and differentiation [28]. MYCN gene expression is critical during embryonic development and involves morphogenesis and development [28,29]. Pathogenic MYCN mutations also lead to loss of function, reducing c-Myc and n-Myc activity. This disruption can affect pulmonary subdivision morphogenesis, neuroepithelial development, and the development of the mesonephric tubules, sensory ganglia, limb, gut, and heart [30]. FGLDS1 is associated with a single heterozygous and compound heterozygous mutation of the MYCN gene [6,7,31,32]. Megalencephaly-polydactyly syndrome is linked to a single heterozygous mutation of the MYCN gene [33,34].

SALMY typically presents with muscle weakness at birth or early infancy, leading to delayed motor milestones. These children can usually walk independently between 20 months and 4 years. During the first decade of life, a child’s motor skills may remain stable or improve. Moderately severe contractures in the joints, neck, and spinal rigidity may appear within the first 10 years but generally worsen by the second decade of life. Scoliosis commonly develops after age 11. Cardiac issues frequently emerge between 5 and 16 years, progressing rapidly and typically resulting in death due to heart rhythm abnormalities between age 8 and 20 years [35].

Optimal care for individuals with SALMY is multidisciplinary. It includes stretching exercises, physical therapy, assistive mechanical devices for sitting and ambulation according to the patient’s needs, and appropriate technical support in educational settings. Prompt treatment for heart failure and cardiac arrhythmias is crucial, with cardiac transplantation as an option for those with progressive dilated cardiomyopathy and heart failure unresponsive to medical therapy. Annual influenza vaccines and other respiratory infection-related immunizations are recommended to prevent secondary complications, and aggressive treatment of lower respiratory tract infections is advised. Surveillance should include electrocardiograms (EKG) (including 24-hours Holter EKGs), echocardiograms every 6 months starting at age 5 years, and annual respiratory function evaluations beginning by age 10. Clinical examinations and X-rays should be conducted for patients with orthopedic complications such as foot and spinal deformities and joint contractures. Additionally, ibuprofen should be avoided in individuals with congestive heart failure [35].

If managed appropriately, FGLDS1 is not typically life-threatening. Comprehensive medical examinations are essential for detecting potential heart or kidney anomalies. Managing FGLDS1 primarily involves surgical correction of specific congenital anomalies, such as certain cardiac malformations and tracheoesophageal fistula, during the immediate postnatal period, followed by ongoing medical management of sequelae. Developmental or educational interventions are crucial for children with developmental delays or intellectual disabilities. Surveillance should include monitoring developmental progress and academic needs and regularly assessing hearing loss by an audiologist. Cochlear implants may be considered in some instances [4]. We believe that our patient’s concurrent diseases explain her unusually severe presentation.

In conclusion, this is the first documented instance of concurrent SALMY and FGLDS1 attributed to an inherited TTN mutation, c.[46816_46820delinsCAATGGTTTT]; [104724_104731dup] (p.[Glu15606Glnfs*22]; [Tyr34911Phefs*7]) and a de novo MYCN mutation, c.853C>T (p.Arg285Trp). Further identification of similar cases will enhance our understanding of this rare genetic condition and improve patient care.

We thank the patient and her family for sincerely participating in this study.

This study was supported in part by the Bio and Medical Technology Development Program of the National Research Foundation (NRF), funded by the Korean government (grant number: NRF-NRF-2022R1A2C2091689) and the Asan Institute for Life Sciences (Seoul, Republic of Korea) (2022IP0017).

Conception and design: BHL. Acquisition of data: ES, DK, SH. Analysis and interpretation of data: JYK, YSJ, GHK. Drafting the article: ES. Critical revision of the article: ES. Final approval of the version to be published: BHL.