Malouf syndrome

Overview

Malouf syndrome is an extremely rare genetic disorder characterized by a combination of dilated cardiomyopathy and hypergonadotropic hypogonadism. First described by Malouf et al. in 1985, the syndrome has been identified primarily in females, although male cases have been reported. The condition typically manifests during adolescence or early adulthood with symptoms related to heart failure and delayed or absent sexual development due to gonadal dysfunction.

Malouf syndrome is part of a group of disorders caused by mutations in the Lamin A/C gene, which encodes proteins critical for maintaining nuclear structure and function. These proteins are involved in many cellular processes, and their dysfunction leads to a spectrum of diseases collectively known as laminopathies. Because of its rarity, much of the understanding of Malouf syndrome is based on isolated case reports, and clinical management remains largely symptomatic and supportive.

Causes

Malouf syndrome is caused by mutations in the LMNA gene, which encodes lamin A and lamin C—proteins that are essential components of the nuclear lamina. The nuclear lamina provides structural support to the nucleus and plays a role in regulating gene expression, cell cycle progression, and chromatin organization.

The condition follows an autosomal dominant inheritance pattern, meaning one copy of the altered gene is sufficient to cause the disorder. However, de novo (new) mutations not inherited from either parent have also been reported. LMNA mutations are known to be pleiotropic, meaning the same mutation can cause different phenotypes, including cardiomyopathies, lipodystrophies, muscular dystrophies, and progeroid syndromes.

Symptoms

The two core features of Malouf syndrome are:

• Dilated cardiomyopathy (DCM):

  • Progressive enlargement and weakening of the heart’s ventricles

  • Symptoms of heart failure such as shortness of breath, fatigue, palpitations, and edema

  • Risk of arrhythmias and sudden cardiac death

• Hypergonadotropic hypogonadism:

  • Underdeveloped or absent secondary sexual characteristics

  • Primary amenorrhea in females or delayed puberty in males

  • Elevated levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) with low estrogen or testosterone

  • Infertility

Other possible features reported in some cases include:

• Intellectual disability or developmental delay

• Mild facial dysmorphism (e.g., broad nasal bridge, long face)

• Short stature

• Muscle weakness or mild myopathy

Due to the variability in presentation, not all patients will exhibit every symptom, and the severity may differ even among affected family members.

Diagnosis

Diagnosing Malouf syndrome requires a multidisciplinary approach and involves several steps:

• Clinical evaluation: Detailed history and physical examination to identify features of delayed puberty and heart failure.

• Cardiac assessment:

  • Echocardiography to evaluate ventricular size and function

  • Electrocardiogram (ECG) to detect arrhythmias

  • Cardiac MRI for detailed imaging in complex cases

• Hormonal testing:

  • Elevated LH and FSH with low sex steroid levels

  • Gonadotropin-releasing hormone (GnRH) stimulation tests to confirm primary gonadal failure

• Genetic testing:

  • Sequencing of the LMNA gene to identify causative mutations

  • May be performed as part of a panel for laminopathies or cardiomyopathy-related genes

• Family history evaluation: To identify potentially affected relatives and assess inheritance patterns

Because of the overlap with other LMNA-related disorders, accurate genetic confirmation is essential for distinguishing Malouf syndrome from similar syndromes.

Treatment

There is no cure for Malouf syndrome, and treatment focuses on managing the cardiac and endocrine manifestations of the disease. Key components of treatment include:

• Cardiac management:

  • Use of standard heart failure medications such as ACE inhibitors, beta-blockers, diuretics, and aldosterone antagonists

  • Implantable cardioverter defibrillator (ICD) placement in cases with high arrhythmia risk

  • Regular cardiac monitoring and echocardiography

  • Consideration of heart transplantation in end-stage heart failure

• Hormone replacement therapy (HRT):

  • Estrogen and progesterone therapy in females to induce and maintain secondary sexual characteristics and menstrual cycles

  • Testosterone replacement in males with delayed puberty or hypogonadism

• Fertility counseling: Most patients will be infertile due to gonadal failure; reproductive endocrinology consultation is recommended.

• Psychosocial support: Addressing emotional, developmental, and social challenges associated with delayed puberty and chronic illness.

A multidisciplinary team including cardiologists, endocrinologists, geneticists, and psychologists is essential for optimal care.

Prognosis

The prognosis for individuals with Malouf syndrome varies depending on the severity of cardiac involvement and the timing of diagnosis and intervention. Dilated cardiomyopathy can progress to life-threatening heart failure or sudden cardiac death, especially if untreated or undiagnosed. Early cardiac surveillance and proactive management significantly improve outcomes.

Endocrine symptoms such as hypogonadism can be effectively managed with hormone replacement, though fertility is usually not achievable. Patients who receive timely cardiac care and hormone therapy can lead functional lives, but lifelong monitoring is required.

Because Malouf syndrome is so rare, long-term data are limited. Continued documentation of new cases and further research into LMNA-related conditions may help clarify the natural history and improve diagnostic and therapeutic approaches in the future.