Arthrogryposis is a clinical feature defined by congenital joint contractures in two or more different body areas which occurs in between 1/3000 and 1/5000 live births. Variants in multiple genes have been associated with distal arthrogryposis syndromes. Heterozygous variants in MYH3 have been identified to cause the dominantly-inherited distal arthrogryposis conditions, Freeman-Sheldon syndrome, Sheldon-Hall syndrome, and multiple pterygium syndrome. In contrast, MYH3 variants underlie both dominantly and recessively inherited Contractures, Pterygia, and Spondylocarpotarsal Fusion syndromes (CPSFS) which are characterized by extensive bony abnormalities in addition to congenital contractures. Here we report two affected sibs with distal arthrogryposis born to unaffected, distantly related parents. Sequencing revealed that both sibs were homozygous for two ultra-rare MYH3 variants, c.3445G>A (p.Glu1149Lys) and c.4760T>C (p.Leu1587Pro). Sequencing and deletion/duplication analysis of 169 other arthrogryposis genes yielded no other compelling candidate variants. This is the first report of biallelic variants in MYH3 being implicated in a distal arthrogryposis phenotype without the additional features of CPSFS. Thus, akin to CPSFS, both dominant and recessively inherited distal arthrogryposis can be caused by variants in MYH3.

The MYH3 gene encodes the embryonic myosin heavy chain, which is crucial for the skeletal and muscular development. The MYH3 variants are associated with distal arthrogryposis type 2A (Freeman-Sheldon syndrome), distal arthrogryposis type 2B3 (Sheldon-Hall syndrome), CPSFS1A (Contractures, pterygia, and spondylocarpostarsal fusion syndrome 1A) and CPSFS1B, which have some shared characteristics and great variability of clinical phenotypes. In this study, we report two novel MYH3 missense variants c.1024T>G (p.Phe342Val) and c.3872A>C (p.Gln1291Pro), demonstrating different phenotypes in the prenatal setting. This study expands the spectrum of MYH3 variants and supports the domain-specific genotype-phenotype correlation of MYH3.

Background: Sheldon-Hall syndrome (SHS) or distal arthrogryposis 2B (DA2B) is a rare clinically and genetically heterogeneous multiple congenital contracture syndrome characterized by contractures of the distal joints of the limbs and mild facial involvement, due to pathogenic variants in genes encoding the fast-twitch skeletal muscle contractile myofiber complex (TNNT3, TNNI2, TMP2, and MYH3 genes). Patients and methods: A 16-year-old boy with a history of congenital distal arthrogryposis developed severe kyphoscoliosis and respiratory insufficiency. His mother and younger sister had phenotypes compatible with SHS but to a much lesser extent. Diagnostic work-up included physical examination and whole-body muscular MRI (WBMRI) in all three patients and electroneuromyography (ENMG) and paravertebral muscle biopsy in the proband. DNA sequencing was used to confirm the diagnosis. Results: Physical examination suggested the diagnosis of SHS. No muscle signal abnormalities were found in WBMRI. Large motor unit potentials and reduced recruitment suggestive of neurogenic changes were observed on needle EMG in distal and paravertebral muscles in the proband. DNA sequencing revealed a pathogenic variant in TNNT3 (c.187C>T), which segregated as a dominant trait with the phenotype. Discussion: This is the first report on neurogenic features in a patient with DA2B and a pathogenic variant in TNNT3 encoding the fast-twitch skeletal muscle contractile myofiber complex. A superimposed length-dependent motor nerve involvement was unexpected. Whether developmental disarrangements in number, distribution, or innervation of the motor unit in fetal life might lead to pseudo-neurogenic EMG features warrants further studies, as well as the role of genetic modifiers in SHS variability.

Freeman-Sheldon syndrome (FSS), also known as the distal arthrogryposis (DA) type 2A, is a rare congenital anomaly. We report a unique case of the DA type 2A with mixed clinical features and the unusual presentation of bilateral congenital dislocation of the knee but had unassisted stiff knee gait. A 5-year-old female child presented to the clinic with the complaint of inability to bend both knees since birth. She had an unassisted bipedal gait, but could not squat, cross-leg sit, run, and climb stairs without assistance. Her youngest brother had a similar presentation but succumbed to death at the age of 5 months due to respiratory distress. Clinical features were in the favor of FSS. Her serum creatinine kinase level was normal and the electromyography of bilateral tibialis anterior and abductor pollicis brevis was not suggestive of the myotonia. Radiograph of the skull showed cooper beaten skull appearance whereas bilateral pelvis with the hip showed following changes in the right hip; decrease femoral epiphysis height, horizontal proximal femoral physis, and the coxa brevia. She was initially managed conservatively by weekly stretching, manipulation, and casting. As a result, she could flex her knee up to 20°. Although the quadricepsplasty might be helpful for the persistent extension deformity, there was marked quadriceps weakness which could make it harder for the child to stand and walk. In addition, the abnormal muscle physiology in FSS may result in unfavorable outcomes after the surgery. Moreover, a consideration of the surgical aspect is not free of risks which include difficult endotracheal intubation, vein access, and malignant hyperthermia. FSS is a rare congenital anomaly that should be differentiated from another syndrome of the close resemblance, Sheldon Hall syndrome and Schwartz Jampel syndrome which are other rare autosomal recessive disorders characterized by myotonia and the chondrodysplasia. Conservative management has still a role in bilateral knee involvement especially if the patient is an independent walker.

To provide genetic testing and prenatal diagnosis for a woman with Sheldon-Hall syndrome. The woman was subjected to targeted capture and next-generation sequencing for variant of genes associated with skeletal disorders. And the result was verified in her parents and fetus. The woman was found to harbor a c.188G>A variant of the TNNT3 gene, which was also found in her affected mother and the fetus. Her grandmother and grandmother's brother had similar manifestations, which was in line with an autosomal dominant inheritance. The same variant was not found in her father. The c.188G>A variant of the TNNT3 gene probably underlay the distal joint contracture in this pedigree, based on which prenatal diagnosis was attained.