Marfanoid–progeroid–lipodystrophy syndrome

Overview

Marfanoid–progeroid–lipodystrophy syndrome (MPLS) is a very rare genetic disorder characterized by a combination of physical features resembling Marfan syndrome, signs of premature aging (progeroid features), and generalized or partial loss of subcutaneous fat (lipodystrophy). First described in the medical literature in recent decades, MPLS presents in early infancy or childhood and has been reported in only a small number of patients worldwide. It is also referred to by some as marfanoid–lipodystrophy syndrome or LMNA-related MPLS.

The syndrome results from mutations in the LMNA gene, which encodes proteins crucial for the structural integrity of the nuclear envelope. LMNA mutations are known to cause a spectrum of disorders called laminopathies, which include muscular dystrophies, cardiomyopathies, lipodystrophies, and premature aging syndromes. MPLS shares overlapping features with some of these disorders but presents a unique triad of marfanoid habitus, aging-like appearance, and fat loss.

Causes

MPLS is caused by heterozygous mutations in the LMNA gene, located on chromosome 1q22. The LMNA gene encodes two major nuclear envelope proteins—lamin A and lamin C—which are important for maintaining nuclear structure, chromatin organization, and gene expression regulation.

Most identified mutations in MPLS involve aberrant splicing or cryptic splice sites in the LMNA gene, leading to the production of abnormal forms of lamin A protein. One such variant is progerin, a truncated form of lamin A also associated with Hutchinson–Gilford progeria syndrome (HGPS). In MPLS, however, the phenotype differs significantly from classic progeria and includes distinct marfanoid features and lipodystrophy.

The disorder follows an autosomal dominant inheritance pattern, though most cases appear to result from de novo mutations with no family history.

Symptoms

The clinical features of Marfanoid–progeroid–lipodystrophy syndrome emerge in infancy or early childhood and include a unique constellation of signs affecting multiple systems. Common symptoms include:

• Marfanoid habitus:

  • Tall, slender build with long limbs (dolichostenomelia)

  • Arachnodactyly (long, thin fingers and toes)

  • Scoliosis or kyphosis

  • Pectus excavatum or pectus carinatum (chest wall deformities)

• Progeroid appearance:

  • Aged facial appearance with prominent eyes and thin nose

  • Poor subcutaneous fat leading to sunken cheeks and visible veins

  • Thin skin, fine hair, and wrinkling

• Lipodystrophy:

  • Generalized or partial loss of subcutaneous fat

  • Fat loss most noticeable in limbs and face

  • Fat may accumulate abnormally in other areas

• Metabolic disturbances:

  • Insulin resistance

  • Hypertriglyceridemia

  • Diabetes mellitus (in adolescence or adulthood)

• Other features:

  • Delayed puberty or hypogonadism

  • Joint hypermobility or stiffness

  • Cardiovascular issues such as aortic root dilation (in some cases)

Despite the progeroid features, intellectual development is usually normal in affected individuals, although some may experience psychosocial challenges due to physical differences.

Diagnosis

The diagnosis of MPLS is based on a combination of clinical evaluation and genetic testing. The key diagnostic steps include:

• Clinical evaluation:

  • Identification of marfanoid body habitus, lipodystrophy, and premature aging features

  • Family and developmental history to assess onset and progression

• Imaging studies:

  • Echocardiography to evaluate the heart and aorta

  • DEXA scans or MRI to assess body fat distribution

• Metabolic workup:

  • Blood glucose levels

  • Lipid profile (triglycerides, cholesterol)

  • Hormone assays for insulin resistance or hypogonadism

• Genetic testing:

  • Sequencing of the LMNA gene to detect pathogenic variants

  • Testing may be performed via whole-exome sequencing or targeted gene panels

MPLS must be distinguished from related laminopathies such as Hutchinson–Gilford progeria syndrome, familial partial lipodystrophy, and Marfan syndrome. Genetic confirmation is essential for an accurate diagnosis.

Treatment

There is no cure for Marfanoid–progeroid–lipodystrophy syndrome. Treatment is symptomatic and multidisciplinary, aiming to manage metabolic issues, physical complications, and psychological well-being. Key aspects of management include:

• Endocrinological management:

  • Insulin sensitizers (e.g., metformin) for insulin resistance

  • Lipid-lowering agents (e.g., statins or fibrates) for dyslipidemia

  • Monitoring and management of diabetes if present

• Cardiovascular monitoring:

  • Regular echocardiograms to detect aortic dilation or cardiomyopathy

  • Beta-blockers or other medications if indicated

• Orthopedic support:

  • Bracing or surgery for scoliosis or chest wall deformities

  • Physical therapy to support mobility and posture

• Nutritional and metabolic care:

  • Specialized diet plans to optimize energy and prevent complications

  • Monitoring of fat-soluble vitamin levels

• Psychosocial support:

  • Psychological counseling and social integration support

  • Educational support where needed

Regular follow-up with a multidisciplinary team, including genetics, endocrinology, cardiology, orthopedics, and psychology, is essential for comprehensive care.

Prognosis

The prognosis for individuals with MPLS varies depending on the severity of symptoms, especially metabolic and cardiovascular complications. Unlike Hutchinson–Gilford progeria syndrome, which is associated with a significantly shortened lifespan, individuals with MPLS may live into adulthood, particularly with proper medical management.

Major concerns include the risk of early-onset diabetes, atherosclerosis, and other cardiovascular complications due to lipodystrophy and metabolic abnormalities. Skeletal deformities and physical differences may lead to reduced mobility or social challenges, but cognitive function is typically preserved.

Early diagnosis, consistent monitoring, and proactive treatment can greatly improve quality of life and long-term outcomes. As more cases are documented and studied, the understanding of MPLS and potential therapeutic strategies will continue to evolve.