Hajdu-Cheney syndrome is a rare disorder that can affect many parts of the body, particularly the bones. Loss of bone tissue from the hands and feet (acro-osteolysis) is a characteristic feature of the condition. The fingers and toes are short and broad, and they may become shorter over time as bone at the tips continues to break down. Bone loss in the fingers can interfere with fine motor skills, such as picking up small objects.

Bone abnormalities throughout the body are common in Hajdu-Cheney syndrome. Affected individuals develop osteoporosis, which causes the bones to be brittle and prone to fracture. Many affected individuals experience breakage (compression fractures) of the spinal bones (vertebrae). Some also develop abnormal curvature of the spine (scoliosis or kyphosis). Hajdu-Cheney syndrome also affects the shape and strength of the long bones in the arms and legs. The abnormalities associated with this condition lead to short stature.

Hajdu-Cheney syndrome also causes abnormalities of the skull bones, including the bones of the face. The shape of the skull is often described as dolichocephalic, which means it is elongated from back to front. In many affected individuals, the bone at the back of the skull bulges outward, causing a bump called a prominent occiput. Distinctive facial features associated with this condition include widely spaced and downward-slanting eyes, eyebrows that grow together in the middle (synophrys), low-set ears, a sunken appearance of the middle of the face (midface hypoplasia), and a large space between the nose and upper lip (a long philtrum). Some affected children are born with an opening in the roof of the mouth called a cleft palate or with a high arched palate. In affected adults, the facial features are often described as "coarse."

Other features of Hajdu-Cheney syndrome found in some affected individuals include joint abnormalities, particularly an unusually large range of joint movement (hypermobility); dental problems; hearing loss; a deep, gravelly voice; excess body hair; recurrent infections in childhood; heart defects; and kidney abnormalities such as the growth of multiple fluid-filled cysts (polycystic kidneys). Some people with this condition have delayed development in childhood, but the delays are usually mild.

The most serious complications of Hajdu-Cheney syndrome, which occur in about half of all affected individuals, are abnormalities known as platybasia and basilar invagination. Platybasia is a flattening of the base of the skull caused by thinning and softening of the skull bones. Basilar invagination occurs when the softened bones allow part of the spine to protrude abnormally through the opening at the bottom of the skull, pushing into the lower parts of the brain. These abnormalities can lead to severe neurological problems, including headaches, abnormal vision and balance, a buildup of fluid in the brain (hydrocephalus), abnormal breathing, and sudden death.

The signs and symptoms of Hajdu-Cheney syndrome vary greatly among affected individuals, even among members of the same family. Many of the disorder's features, such as acro-osteolysis and some of the characteristic facial features, are not present at birth but become apparent in childhood or later. The risk of developing platybasia and basilar invagination also increases over time.

The features of Hajdu-Cheney syndrome overlap significantly with those of a condition called serpentine fibula-polycystic kidney syndrome (SFPKS). Although they used to be considered separate disorders, researchers discovered that the two conditions are associated with mutations in the same gene. Based on these similarities, many researchers now consider Hajdu-Cheney syndrome and SFPKS to be variants of the same condition.

Hajdu-Cheney syndrome is associated with mutations in the NOTCH2 gene. This gene provides instructions for making a receptor called Notch2. Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. When a ligand binds to the Notch2 receptor, it triggers signals that are important for the normal development and function of many different types of cells. Studies suggest that signaling through the Notch2 receptor is important for the early development of bones and later for bone remodeling, a normal process in which old bone is removed and new bone is created to replace it. Notch2 signaling also appears to be involved in the development of the heart, kidneys, teeth, and other parts of the body.

Mutations in a specific area near the end of the NOTCH2 gene are associated with Hajdu-Cheney syndrome. These mutations lead to a version of the Notch2 receptor that cannot be broken down normally. As a result, the receptor continues to be active even after signaling should stop. Researchers are unsure how excessive Notch2 signaling is related to the varied features of Hajdu-Cheney syndrome. They suspect that the skeletal features of the disorder, including acro-osteolysis, osteoporosis, and distinctive facial features, likely result from abnormal bone development and remodeling. Excess signaling through the overactive Notch2 receptor may increase the removal of old bone, reduce the formation of new bone, or both. It is less clear how the overactive receptor contributes to the other signs and symptoms of this condition.

Normal Function

The NOTCH2 gene provides instructions for making a protein called Notch2, a member of the Notch family of receptors. Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. Attachment of a ligand to the Notch2 receptor sends signals that are important for normal development and function of many tissues throughout the body, both before and after birth. In particular, research indicates that Notch2 signaling is important for the development of cells destined to be part of the heart, liver, kidneys, teeth, bones, and other structures in a growing embryo. After birth, Notch2 signaling is involved in immune system function, tissue repair, and a process called bone remodeling, in which old bone is removed and new bone is created to replace it.

The Notch2 receptor has several major parts. A region of the receptor called the extracellular domain extends from the surface of the cell and binds to ligands. This binding triggers the part of the receptor inside the cell, known as the intracellular domain or NICD, to be cut (cleaved) from the rest of the protein. The NICD then moves into the cell's nucleus, where it interacts with other proteins to regulate the activity of specific genes. The very end of the NICD contains a region known as a proline-, glutamic acid-, serine-, and threonine-rich (PEST) domain. The PEST domain is necessary for the NICD to be broken down, which stops Notch2 signaling at the appropriate time.

Health Conditions Related to Genetic Changes

Alagille syndrome

NOTCH2 gene mutations appear to be a relatively uncommon cause of Alagille syndrome, a condition that can affect the liver, heart, and other parts of the body. At least 10 mutations in the NOTCH2 gene have been associated with the condition. These mutations can affect either the intracellular or extracellular domain of the Notch2 receptor. The genetic changes probably lead to the production of a receptor that is abnormally small or folded into the wrong 3-dimensional shape. These mutations are described as "loss-of-function" because the defective receptor is unable to bind to its ligands and trigger signaling within the cell. Disrupted Notch2 signaling is believed to affect the development of numerous organs and tissues, resulting in the signs and symptoms of Alagille syndrome.

Hajdu-Cheney syndrome

Several mutations in the NOTCH2 gene have been associated with Hajdu-Cheney syndrome, a rare disorder that can affect many parts of the body, particularly the bones. Affected individuals have acro-osteolysis, which is a loss of bone tissue that affects the hands and feet most severely. Most people with this condition also have osteoporosis, which causes the bones to be brittle and prone to fracture; distinctive facial features; spinal abnormalities; and short stature. Additionally, Hajdu-Cheney syndrome can affect the joints, teeth, heart, kidneys, and other parts of the body.

The mutations associated with Hajdu-Cheney syndrome all occur near the end of the NOTCH2 gene in a region called exon 34. These mutations lead to an abnormally shortened version of the Notch2 receptor that is missing the PEST domain. Without this domain, the receptor cannot be broken down normally, and Notch2 signaling within the cell continues after it should stop. Because the NOTCH2 gene mutations related to Hajdu-Cheney syndrome lead to abnormally increased Notch2 signaling, they are described as "gain-of-function" mutations.

Researchers are unsure how excessive Notch2 signaling is related to the varied features of Hajdu-Cheney syndrome. They suspect that the skeletal features of the disorder, including acro-osteolysis, osteoporosis, and distinctive facial features, likely result from abnormal bone development and remodeling. Excess signaling through the overactive Notch2 receptor may increase the removal of old bone, reduce the formation of new bone, or both. It is less clear how the overactive receptor contributes to the other signs and symptoms of this condition.

Cancers

Mutations in the NOTCH2 gene have also been found in certain forms of lymphoma, which is a group of cancers that arise from immune system cells. These mutations are somatic, which means that they are not inherited. Somatic mutations are acquired during a person's lifetime and are present only in certain cells. The NOTCH2 gene mutations associated with lymphomas are described as "gain-of-function" because they increase the activity (expression) of the NOTCH2 gene in certain immune system cells. In some affected cells, extra copies of the mutated gene have been found, further increasing gene activity. Overexpression of this gene may lead to uncontrolled cell growth and cell division in immune system cells, which can result in the development of lymphoma.

Other Names for This Gene

• hN2
• NOTC2_HUMAN
• Notch (Drosophila) homolog 2
• notch 2 preproprotein
• Notch homolog 2 (Drosophila)

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered NOTCH2 gene in each cell is sufficient to cause the disorder. Most cases result from new mutations in the gene and occur in people with no history of the disorder in their family. Less commonly, an affected person inherits the mutation from one affected parent.

Hajdu-Cheney syndrome is a rare disease; its prevalence is unknown. Fewer than 100 affected individuals have been described in the medical literature.