Lenz–Majewski syndrome

Overview

Lenz–Majewski syndrome (LMS) is an extremely rare genetic disorder characterized by a unique combination of skeletal abnormalities, intellectual disability, and distinctive facial and skin features. The most prominent feature is progressive skeletal dysplasia, including hyperostosis (excessive bone growth), short stature, and craniofacial malformations. LMS affects multiple organ systems and is evident from infancy or early childhood. Due to its rarity, only a few cases have been documented worldwide.

Causes

Lenz–Majewski syndrome is caused by a gain-of-function mutation in the PTDSS1 gene, which encodes the enzyme phosphatidylserine synthase 1. This enzyme plays a role in membrane phospholipid biosynthesis. The mutation leads to abnormal phospholipid metabolism, which is thought to contribute to the excessive bone growth and other systemic manifestations of the syndrome. The condition follows an autosomal dominant inheritance pattern, but most cases appear to result from de novo (new) mutations with no prior family history.

Symptoms

Individuals with Lenz–Majewski syndrome exhibit a wide range of clinical features, most of which affect the skeletal system. Common signs and symptoms include:

• Hyperostosis – abnormal thickening of bones, especially in the skull and long bones

• Short stature – due to skeletal dysplasia

• Craniofacial abnormalities – including a prominent forehead, hypertelorism (widely spaced eyes), broad nasal bridge, and dental anomalies

• Intellectual disability – typically moderate to severe

• Skin abnormalities – such as hyperpigmentation, skin thickening, or laxity

• Syndactyly or brachydactyly – webbing or shortening of the fingers and toes

• Joint stiffness or contractures

• Delayed motor milestones – and difficulties with coordination

Diagnosis

Diagnosis of Lenz–Majewski syndrome is based on clinical findings and confirmed through genetic testing. The diagnostic process may include:

• Clinical examination – to identify characteristic skeletal, facial, and skin features

• Radiographic imaging – X-rays or CT scans to assess bone thickening and structural anomalies

• Developmental and neurological evaluation – to assess intellectual and motor delays

• Genetic testing – identification of a pathogenic variant in the PTDSS1 gene confirms the diagnosis

Due to its rarity, LMS may be misdiagnosed or confused with other forms of skeletal dysplasia or syndromic intellectual disability without genetic confirmation.

Treatment

There is no cure for Lenz–Majewski syndrome, and treatment is symptomatic and supportive. A multidisciplinary approach is essential, involving specialists in orthopedics, neurology, dermatology, and developmental pediatrics. Management strategies include:

• Orthopedic care – to address skeletal deformities, joint stiffness, and mobility issues

• Physical and occupational therapy – to improve motor function and independence

• Special education services – for children with intellectual disabilities

• Dermatologic care – for management of skin abnormalities

• Speech and feeding therapy – if oral-motor dysfunction is present

• Regular monitoring – of bone growth, neurological function, and development

Prognosis

The prognosis for individuals with Lenz–Majewski syndrome depends on the severity of symptoms and access to comprehensive care. While the condition is lifelong and progressive, especially in terms of skeletal abnormalities, quality of life can be improved with early intervention and supportive therapies. Intellectual disability and physical limitations may restrict independence, but many patients can achieve developmental progress with appropriate support. Due to the rarity of the syndrome, long-term outcomes are not well documented.