What is the clinical presentation of a novel mutation in Hemojuvelin (HJV) causing Juvenile Hemochromatosis (JH), a rare genetic disorder characterized by excessive iron accumulation?

From the Guidelines

Juvenile Hemochromatosis (JH) caused by a novel mutation in Hemojuvelin (HJV) typically presents with rapid iron accumulation, leading to excessive iron storage in the body.

Clinical Presentation

The clinical presentation of JH due to HJV mutation is characterized by:

• Rapid iron accumulation, which can lead to various symptoms and complications, including liver disease, heart problems, and endocrine disorders 1
• The disease often manifests at a younger age, typically in the second or third decade of life, with a more severe phenotype than hereditary hemochromatosis caused by HFE mutations 1
• Patients may present with symptoms such as fatigue, weakness, abdominal pain, and skin hyperpigmentation, which are similar to those seen in hereditary hemochromatosis, but often more severe and at a younger age 1

Pathophysiology

The HJV gene plays a crucial role in regulating iron metabolism by controlling the production of hepcidin, a hormone that down-regulates iron absorption 1

• Mutations in the HJV gene lead to decreased hepcidin production, resulting in increased iron absorption and accumulation in the body 1
• The resulting iron overload can cause damage to various organs, including the liver, heart, and pancreas, leading to complications such as cirrhosis, cardiomyopathy, and diabetes 1

From the Research

Clinical Presentation of Juvenile Hemochromatosis

The clinical presentation of Juvenile Hemochromatosis (JH) due to a novel mutation in the Hemojuvelin (HJV) gene is characterized by:

• Severe iron overload leading to organ damage, typically before the age of 30 years 2
• Classical clinical findings include:
  • Hypogonadotropic hypogonadism 3, 4
  • Cardiomyopathy 3, 2
  • Liver fibrosis 3, 5, 4
  • Glycemic changes, such as insulin-dependent diabetes mellitus 3, 4
  • Arthropathy 3
  • Skin pigmentation 3, 4
• Atypical clinical features may include:
  • Secondary hypothyroidism 3
  • Hypophysis hypothyroidism 4
• Patients may present with a range of symptoms, including:
  • Diabetic ketoacidosis 3
  • Arthralgia 3
  • Abdominal pain 3
  • Adynamia 3
  • Hair loss 3
  • Amenorrhea 3
  • Dyspnea and lower limb edema 3

Genetic Mutations

The HJV gene mutations associated with JH are:

• Novel homozygous mutation, c.697delC 3
• Novel heterozygous mutations, such as g.3659_3660insG and g.2297delC 5
• Compound heterozygous mutations, such as c.863G>A (p.R288Q) and c.962_963delGCinsAA (p.C321*) 4
• Missense substitutions affecting highly conserved residues 2

Diagnosis and Treatment

Diagnosis of JH is based on:

• Clinical presentation and family history
• Biochemical tests, such as serum ferritin and transferrin saturation
• Genetic analysis, including targeted exome sequencing and Sanger sequencing 4 Treatment of JH involves:
• Intensive phlebotomy therapy to reduce serum ferritin levels 4
• Regular monitoring of iron stores and organ function
• Management of related conditions, such as diabetes and hypogonadism 3, 4