SNP Shot: Genomic Insights

Histiocytosis-lymphadenopathy plus syndrome, also called SLC29A3 spectrum disorder, encompasses a group of related conditions affecting various body parts. This group includes H syndrome, pigmented hypertrichosis with insulin-dependent diabetes mellitus (PHID), Faisalabad histiocytosis, and familial Rosai-Dorfman disease (RDD). Previously considered distinct, these disorders are now understood to be part of a single spectrum due to shared genetic causes and overlapping symptoms. Individuals may exhibit symptoms characteristic of one specific condition or a combination of features from multiple conditions. The presentation can differ even within the same family.

A unifying characteristic of these disorders is histiocytosis, an overgrowth of immune cells called histiocytes. These cells accumulate abnormally in tissues, potentially causing organ or tissue damage. This buildup frequently occurs in lymph nodes, leading to their swelling (lymphadenopathy). Cell accumulation can also affect the skin, kidneys, brain and spinal cord (central nervous system), or the digestive tract.

The name "histiocytosis-lymphadenopathy plus syndrome" reflects the additional signs and symptoms that can accompany these disorders. H syndrome is characterized by abnormal skin patches (lesions), typically on the lower body. These lesions are unusually dark (hyperpigmented) and exhibit excessive hair growth (hypertrichosis). Histiocytes also accumulate within these skin lesions. Other features may include liver enlargement (hepatomegaly), heart problems, hearing loss, reduced levels of sex hormones (hypogonadism), and short stature.

Similar to H syndrome, PHID involves hyperpigmented skin patches with hypertrichosis. PHID is also defined by the development of type 1 diabetes (insulin-dependent diabetes mellitus), typically beginning in childhood. Type 1 diabetes results from insufficient insulin production, leading to blood sugar dysregulation.

Faisalabad histiocytosis typically presents with lymphadenopathy and eyelid swelling caused by histiocyte accumulation. Affected individuals may also experience joint deformities (contractures) in their fingers or toes and hearing loss.

The most common feature of familial RDD is lymphadenopathy, often affecting neck lymph nodes. Histiocytes can accumulate in other body areas as well. (Familial RDD is one of several forms of RDD; other forms are not included in histiocytosis-lymphadenopathy plus syndrome.)

Inheritance:

This condition follows an autosomal recessive inheritance pattern. This means that an individual must inherit two copies of the mutated gene, one from each parent, to develop the condition. The parents, who each carry only one copy of the mutated gene, usually do not show any signs or symptoms of the condition.