Myhre syndrome

Myhre syndrome is a very rare multisystem genetic disorder that affects connective tissue, skeletal development, and neurodevelopment. It is caused by specific changes in the SMAD4 gene, a key regulator of the transforming growth factor beta (TGF-β) signaling pathway that guides growth and tissue repair throughout the body. Signs usually become apparent in early childhood and affect individuals of all sexes. Fewer than one in a million people worldwide are thought to have the condition, so most clinicians encounter it only rarely.

The clinical picture of Myhre syndrome is distinctive but diverse. Early clues often include short stature, a muscular or stocky build, brachydactyly (short fingers and toes), and facial differences such as short palpebral fissures, a short philtrum, maxillary under-development, and forward-positioned lower jaw. Developmental challenges are common: many children have global developmental delay with speech articulation difficulties, and some experience intellectual or cognitive impairment of variable severity. As children grow, reduced joint mobility and joint stiffness tend to become more pronounced, sometimes leading to limitation of daily activities. Skeletal findings such as kyphosis or lumbar hyperlordosis, thickened skull bones, and enlarged vertebral pedicles can contribute to posture and back pain. Skin may feel unusually thick, and keratosis pilaris (rough skin bumps) has been reported. Mixed hearing loss is another frequent concern and may appear in childhood or adolescence. Additional features can accumulate over time, including hypertonia, highly arched eyebrows with long eyelashes, narrow mouth, and short palms or feet. Not all individuals experience all features, and severity varies considerably. Because the condition can affect multiple organ systems simultaneously, ongoing clinical observation is important to detect emerging issues early.

Myhre syndrome results from pathogenic variants in the SMAD4 gene. SMAD4 encodes a protein that transmits signals within the TGF-β pathway, helping cells coordinate growth and extracellular matrix production. When one copy of the gene is altered, signaling becomes dysregulated and leads to the skeletal, cutaneous, and developmental manifestations described above. The disorder follows an autosomal dominant inheritance pattern, meaning a person who carries the variant in one of their two SMAD4 copies can pass it to children with a 50 percent chance in each pregnancy. Many affected individuals represent a single occurrence in their family, but once a variant is present it can be transmitted to future generations. Even within the same family, the specific symptoms and their severity can vary considerably, an example of variable expressivity. Genetic counseling is recommended for families to understand testing options and reproductive considerations.

Currently, management focuses on supportive care tailored to each person’s needs, and no specific disease-modifying therapy has been approved. Because the condition can influence growth, joints, hearing, and development, care is usually coordinated by a multidisciplinary team that may include clinical geneticists, orthopedic specialists, audiologists, speech and physical therapists, and dermatologists. Regular surveillance helps monitor joint mobility, spinal alignment, skin health, and hearing so that interventions such as physical therapy, hearing aids, or orthopedic procedures can be offered when beneficial. Educational supports, speech therapy, and other developmental services play a central role in maximizing communication and learning. Families are encouraged to discuss evolving management strategies with specialists familiar with Myhre syndrome and to stay engaged with periodic monitoring to anticipate complications early.

Long-term outcomes for individuals with Myhre syndrome vary widely and depend on the severity of skeletal limitations, hearing loss, and developmental challenges. Many people live into adulthood, attend school, and participate in family and community life with appropriate medical and educational supports. Limitations in joint movement and progressive spinal changes can affect mobility over time, but early therapy and orthopedic follow-up may lessen their impact. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with expert centers and genetic counselors for guidance on future planning and available services.

Clinical trials are underway exploring new treatment approaches for Myhre syndrome. Individuals interested in research participation can search ClinicalTrials.gov or consult their care team about eligibility.