MDP syndrome

Overview

MDP syndrome, short for Mandibular hypoplasia, Deafness, and Progeroid features syndrome, is an extremely rare genetic disorder characterized by a combination of craniofacial anomalies, progressive loss of subcutaneous fat (lipodystrophy), sensorineural deafness, and signs resembling premature aging (progeroid features). First described in the early 2000s, MDP syndrome is part of a broader category of disorders known as lipodystrophies, which involve abnormal fat distribution in the body.

Individuals with MDP syndrome often present with a distinct appearance, including a small lower jaw (mandibular hypoplasia), prominent eyes due to fat loss, and tight, thin skin. The condition typically manifests in early childhood and progressively worsens over time. While MDP syndrome shares features with other progeroid and lipodystrophic disorders, it is considered a clinically and genetically distinct entity.

Causes

MDP syndrome is caused by mutations in the POLD1 gene, which is located on chromosome 19 (19q13.33). This gene encodes the catalytic subunit of DNA polymerase delta, an enzyme essential for DNA replication and repair.

Mutations in POLD1 disrupt the normal function of this enzyme, leading to defects in cellular proliferation and tissue maintenance. This dysfunction contributes to the characteristic features of MDP syndrome, such as impaired fat storage, accelerated aging phenotypes, and organ dysfunction.

The syndrome is inherited in an autosomal dominant manner, meaning one copy of the mutated gene in each cell is sufficient to cause the disorder. However, most reported cases have been sporadic, resulting from new (de novo) mutations with no family history.

Symptoms

MDP syndrome presents with a variety of physical and systemic features, often recognizable in early childhood. Common symptoms and signs include:

Craniofacial Abnormalities

• Mandibular hypoplasia: Small or underdeveloped lower jaw

• Prominent eyes: Due to loss of facial fat

• Beaked nose and tight facial skin: Contributing to aged appearance

• High-pitched or weak voice

Progeroid and Lipodystrophic Features

• Loss of subcutaneous fat (generalized lipodystrophy): Especially in the face, limbs, and trunk

• Thin, wrinkled skin: Particularly over the hands and feet

• Muscle wasting and visible veins: Due to fat loss

Auditory and Skeletal Features

• Sensorineural deafness: Progressive, bilateral hearing loss starting in early life

• Osteopenia or osteoporosis: Leading to increased fracture risk

• Joint stiffness or contractures

Metabolic and Endocrine Issues

• Insulin resistance or diabetes mellitus (may develop in adolescence or adulthood)

• Hypertriglyceridemia: Elevated levels of triglycerides in the blood

• Low levels of leptin and adiponectin due to fat loss

Despite the progeroid appearance, many affected individuals have normal intellectual development and cognitive function.

Diagnosis

The diagnosis of MDP syndrome is based on clinical evaluation, imaging studies, metabolic assessments, and genetic testing. The following steps are typically taken:

• Clinical examination: Identification of key physical features such as lipodystrophy, mandibular hypoplasia, and signs of premature aging

• Hearing assessment: Audiometry to detect sensorineural hearing loss

• Imaging studies:

  • X-rays to assess bone density and detect osteoporosis or skeletal abnormalities

• Laboratory tests:

  • Fasting glucose and insulin levels to evaluate insulin resistance

  • Lipid profile for triglycerides and cholesterol

  • Leptin and adiponectin levels, typically reduced in lipodystrophy

• Genetic testing:

  • Sequencing of the POLD1 gene to confirm the diagnosis

Differential diagnoses include other progeroid syndromes (e.g., Hutchinson–Gilford progeria, Werner syndrome), congenital generalized lipodystrophy, and mandibuloacral dysplasia.

Treatment

There is no cure for MDP syndrome, so treatment is supportive and focused on managing symptoms, preventing complications, and improving quality of life. Management includes:

Hearing Management

• Hearing aids or cochlear implants to address sensorineural deafness

• Regular audiological follow-ups

Metabolic and Endocrine Management

• Insulin therapy or oral hypoglycemics for diabetes

• Lipid-lowering medications for hypertriglyceridemia

• Leptin replacement therapy (e.g., metreleptin) may be considered on a case-by-case basis

Orthopedic and Physical Therapy

• Physical therapy to improve muscle strength and joint mobility

• Treatment of fractures or joint abnormalities

Nutrition and Lifestyle

• Balanced diet to support growth and manage metabolic issues

• Regular exercise tailored to individual capabilities

Psychological Support

• Counseling and social support for body image, hearing impairment, and coping with a chronic disorder

Regular monitoring by a multidisciplinary team including endocrinologists, geneticists, audiologists, dermatologists, and orthopedic specialists is essential.

Prognosis

The prognosis for individuals with MDP syndrome varies depending on the severity of symptoms and the presence of complications such as insulin resistance and cardiovascular disease. Key points include:

• Intellectual development is usually unaffected

• Hearing impairment is progressive but manageable with assistive devices

• Metabolic issues like diabetes and hyperlipidemia require lifelong management

• Progeroid appearance does not necessarily correlate with accelerated aging of internal organs

With early diagnosis and proper care, many individuals with MDP syndrome can lead fulfilling lives, although they may face significant medical and psychosocial challenges. Genetic counseling is recommended for affected families to discuss inheritance patterns and reproductive options.