Symbolic illustration of genetic inheritance and support in Sheldon-Hall Syndrome

Unlocking Sheldon-Hall Syndrome: A Family's Genetic Journey

Elliot Brynn in Health & Wellness December 2025 • 4 min read.

"Exploring a rare TPM2 mutation and its impact on distal arthrogryposis"

Sheldon-Hall syndrome (SHS), also known as distal arthrogryposis type 2B, is a rare genetic condition characterized by congenital joint contractures, primarily affecting the limbs. Unlike other forms of arthrogryposis, SHS doesn't involve primary neurological issues. Common features include contractures in the distal limb joints, leading to camptodactyly (弯曲指), clubfeet, a triangular face, distinct facial features such as downslanting palpebral fissures, a small mouth, prominent nasolabial folds, and a high arched palate.

SHS is a genetically heterogeneous disorder, meaning it can be caused by mutations in different genes. It's distinguished from Freeman-Sheldon syndrome (FSS) by the absence of severe orofacial muscle contractures, making SHS generally a less severe condition. While the prevalence of arthrogryposis is estimated at 1 in 3,000 births, SHS remains exceptionally rare, with fewer than 100 cases reported in medical literature.

This article presents the first documented case of a Korean family spanning two generations affected by SHS resulting from a rare mutation in the TPM2 gene. We'll explore the clinical presentation of this family, the diagnostic journey, and the implications of this genetic finding.

The TPM2 Mutation and Its Impact

Symbolic illustration of genetic inheritance and support in Sheldon-Hall Syndrome

The affected individuals in this family, a mother and her daughter, exhibit typical features of SHS. The daughter was referred to the Seoul National University Children's Hospital as a one-month-old, for evaluation of multiple congenital contractures of both hands and feet. Prenatal ultrasounds had already indicated bilateral clenched hands and talipes equinovarus (clubfoot).

Upon examination after birth, the infant presented with camptodactyly, overlapping fingers, and adducted thumbs in both hands. Her feet showed calcaneovalgus deformity with congenital vertical talus on the right and equinovarus deformity on the left. Subtle facial dysmorphism was also noted. The mother's history revealed similar features, including multiple congenital contractures of distal limbs, camptodactyly with ulnar deviation of all fingers, and bilateral talocalcaneal coalition.

Clinical Presentation: Triangular face, downslanting palpebral fissures, small mouth, high arched palate, prominent nasolabial folds.
Limb Deformities: Camptodactyly (bent fingers), clubfoot, talocalcaneal coalition (fusion of bones in the ankle).
Genetic Confirmation: The family's SHS was confirmed through genetic testing, which revealed a rare TPM2 mutation (p.R133W) in both the mother and daughter.

Genetic analysis pinpointed the TPM2 gene as the culprit. TPM2 encodes β-tropomyosin, a protein crucial for regulating muscle contractions. While mutations in MYH3 are more commonly associated with SHS, this family's case highlights the role of TPM2, mainly expressed in slow-twitch muscle fibers. Electromyography (EMG) in the mother revealed generalized myopathy with relative sparing of the slow-twitch muscle fibers. Further studies suggest that certain mutations in TPM2 cause changes in the actin-myosin interaction and modify the contractile speed. The p.R133W mutant tropomyosin caused a slower actin-myosin attachment rate and a faster detachment rate.

Implications and Future Directions

This case underscores the importance of considering TPM2 mutations in individuals presenting with SHS, especially when MYH3 mutations are absent. Accurate diagnosis is crucial for appropriate management and genetic counseling. Given the autosomal dominant inheritance pattern, families have a 50% chance of recurrence.

Although SHS is rare, the potential for progressive motor weakness and associated feeding difficulties, as seen in the infant patient, necessitates close monitoring and proactive intervention. The family received genetic counseling, and the mother is considering prenatal genetic diagnosis in future pregnancies.

Further research is needed to fully elucidate the mechanisms by which TPM2 mutations lead to congenital contractures and to develop targeted therapies for individuals with SHS. Long-term follow-up of affected individuals is essential to monitor the progression of muscle weakness and address any associated complications.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

Everything You Need To Know

What is Sheldon-Hall Syndrome (SHS), and what are its primary characteristics?

Sheldon-Hall Syndrome (SHS), also known as distal arthrogryposis type 2B, is a rare genetic condition marked by congenital joint contractures primarily in the limbs. It differs from other arthrogryposis forms by not involving primary neurological issues. The key implications of SHS include the physical limitations caused by joint contractures, which can affect mobility and fine motor skills. It's crucial to recognize this condition for proper medical care and to provide suitable genetic counseling to families. The features of SHS are commonly distinguished by a triangular face, downslanting palpebral fissures, a small mouth, prominent nasolabial folds, and a high arched palate. Limb deformities, such as camptodactyly and clubfoot, are also typical. This is a genetically heterogeneous disorder and the severity can vary.

What is the role of the TPM2 gene, and how does a mutation in this gene affect the body?

The TPM2 gene provides instructions for creating the β-tropomyosin protein. This protein plays a vital role in regulating muscle contractions. The particular mutation observed in this family, p.R133W, influences the interaction between actin and myosin, which are crucial for muscle contraction. The mutation causes the actin-myosin attachment rate to slow down, and the detachment rate to quicken. This ultimately affects how the muscles function. Electromyography (EMG) studies in the mother revealed a generalized myopathy, with the slow-twitch muscle fibers being relatively spared. The identification of the TPM2 mutation highlights the significance of considering this gene in diagnosing individuals with SHS, especially if mutations in MYH3 are not present.

How do camptodactyly and clubfoot relate to Sheldon-Hall Syndrome (SHS), and what are their implications?

Camptodactyly is a condition where fingers are bent or curved, and clubfoot, also known as talipes equinovarus, refers to a condition where the foot is twisted out of shape. These are both major physical characteristics associated with Sheldon-Hall Syndrome (SHS). In the context of this condition, these deformities are due to congenital joint contractures that primarily affect the limbs. The presence of camptodactyly and clubfoot can have significant impacts on mobility and daily activities, making early diagnosis and treatment essential for management and improving the quality of life for those affected by SHS.

What was the role of the Seoul National University Children's Hospital in the diagnosis of this genetic condition?

The Seoul National University Children's Hospital played a significant role in the case by evaluating a one-month-old daughter referred for multiple congenital contractures of both hands and feet. Diagnostic assessments included a physical examination and a review of prenatal ultrasound findings, which had already indicated bilateral clenched hands and talipes equinovarus (clubfoot). Upon examination after birth, the infant presented with camptodactyly, overlapping fingers, and adducted thumbs in both hands. Her feet showed calcaneovalgus deformity with congenital vertical talus on the right and equinovarus deformity on the left. These diagnostic measures and the hospital's expertise were crucial in the early identification and assessment of the condition. The diagnostic journey included the use of genetic testing, which confirmed the presence of a rare TPM2 mutation in both the mother and the daughter, helping to provide a definitive diagnosis of SHS.

What does the autosomal dominant inheritance pattern mean for families with Sheldon-Hall Syndrome (SHS)?

The autosomal dominant inheritance pattern means that only one copy of the mutated gene is sufficient to cause the condition. For families affected by Sheldon-Hall Syndrome (SHS), this implies that each child has a 50% chance of inheriting the mutated gene from an affected parent. This inheritance pattern makes genetic counseling and testing essential for families. The implications of this understanding include the need for proactive screening and monitoring. Family members can take steps to understand their risk and the possibility of passing the condition to future generations. Healthcare professionals can also provide guidance on managing the condition and preparing for potential challenges related to the genetic inheritance.