Nicolaides-Baraitser syndrome is a condition that affects many body systems. Affected individuals can have a wide variety of signs and symptoms, but the most common are sparse scalp hair, small head size (microcephaly), distinct facial features, short stature, prominent finger joints, unusually short fingers and toes (brachydactyly), recurrent seizures (epilepsy), and moderate to severe intellectual disability with impaired language development.

In people with Nicolaides-Baraitser syndrome, the sparse scalp hair is often noticeable in infancy. The amount of hair decreases over time, but the growth rate and texture of the hair that is present is normal. Affected adults generally have very little hair. In rare cases, the amount of scalp hair increases over time. As affected individuals age, their eyebrows may become less full, but their eyelashes almost always remain normal. At birth, the hair on the face may be abnormally thick (hypertrichosis) but thins out over time.

Most affected individuals grow slowly, resulting in short stature and microcephaly. Sometimes, growth before birth is unusually slow.

The characteristic facial features of people with Nicolaides-Baraitser syndrome include a triangular face, deep-set eyes, a thin nasal bridge, wide nostrils, a pointed nasal tip, and a thick lower lip. Many affected individuals have a lack of fat under the skin (subcutaneous fat) of the face, which may cause premature wrinkling. Throughout their bodies, people with Nicolaides-Baraitser syndrome may have pale skin with veins that are visible on the skin surface due to the lack of subcutaneous fat.

In people with Nicolaides-Baraitser syndrome, a lack of subcutaneous fat in the hands makes the finger joints appear larger than normal. Over time, the fingertips become broad and oval shaped. Additionally, there is a wide gap between the first and second toes (known as a sandal gap).

Most people with Nicolaides-Baraitser syndrome have epilepsy, which often begins in infancy. Affected individuals can experience multiple seizure types, and the seizures can be difficult to control with medication.

Almost everyone with Nicolaides-Baraitser syndrome has moderate to severe intellectual disability. Early developmental milestones, such as crawling and walking, are often normally achieved, but further development is limited, and language development is severely impaired. At least one-third of affected individuals never develop speech, while others lose their verbal communication over time. People with this condition are often described as having a happy demeanor and being very friendly, although they can exhibit moments of aggression and temper tantrums.

Other signs and symptoms of Nicolaides-Baraitser syndrome include an inflammatory skin disorder called eczema. About half of individuals with Nicolaides-Baraitser syndrome have a soft out-pouching around the belly-button (umbilical hernia) or lower abdomen (inguinal hernia). Some affected individuals have dental abnormalities such as widely spaced teeth, delayed eruption of teeth, and absent teeth (hypodontia). Most affected males have undescended testes (cryptorchidism) and females may have underdeveloped breasts. Nearly half of individuals with Nicolaides-Baraitser syndrome have feeding problems.

Nicolaides-Baraitser syndrome is caused by mutations in the SMARCA2 gene. This gene provides instructions for making one piece (subunit) of a group of similar protein complexes known as SWI/SNF complexes. These complexes regulate gene activity (expression) by a process known as chromatin remodeling. Chromatin is the network of DNA and proteins that packages DNA into chromosomes. The structure of chromatin can be changed (remodeled) to alter how tightly DNA is packaged. Chromatin remodeling is one way gene expression is regulated during development; when DNA is tightly packed, gene expression is lower than when DNA is loosely packed. To provide energy for chromatin remodeling, the SMARCA2 protein uses a molecule called ATP.

The SMARCA2 gene mutations that cause Nicolaides-Baraitser syndrome result in the production of an altered protein that interferes with the normal function of the SWI/SNF complexes. These altered proteins are able to form SWI/SNF complexes, but the complexes are nonfunctional. As a result, they cannot participate in chromatin remodeling. Disturbance of this regulatory process alters the activity of many genes, which likely explains the diverse signs and symptoms of Nicolaides-Baraitser syndrome.

Normal Function

The SMARCA2 gene provides instructions for making one piece (subunit) of a group of similar protein complexes known as SWI/SNF complexes. These complexes regulate gene activity (expression) by a process known as chromatin remodeling. Chromatin is the network of DNA and proteins that packages DNA into chromosomes. The structure of chromatin can be changed (remodeled) to alter how tightly DNA is packaged. Chromatin remodeling is one way gene expression is regulated during development; when DNA is tightly packed, gene expression is lower than when DNA is loosely packed. SWI/SNF complexes help with chromatin remodeling by moving parts of chromatin called nucleosomes, which makes DNA more accessible for gene expression. To provide energy for chromatin remodeling, the SMARCA2 protein uses a molecule called ATP.

SWI/SNF complexes regulate genes that are involved in many processes, including repairing damaged DNA; copying (replicating) DNA; and controlling the growth, division, and maturation (differentiation) of cells. The SMARCA2 protein and other SWI/SNF subunits are thought to act as tumor suppressors, which keep cells from growing and dividing too rapidly or in an uncontrolled way.

Health Conditions Related to Genetic Changes

Nicolaides-Baraitser syndrome

At least 50 mutations in the SMARCA2 gene have been found to cause Nicolaides-Baraitser syndrome. This condition is characterized by multiple abnormalities, primarily sparse scalp hair, small head size (microcephaly), distinctive facial features, short stature, abnormal fingers, recurrent seizures (epilepsy), and moderate to severe intellectual disability with impaired language development. Almost all SMARCA2 gene mutations that cause Nicolaides-Baraitser syndrome change single protein building blocks (amino acids) in the protein. These mutations are located within an area of the protein that attaches to ATP and is responsible for providing energy to the SWI/SNF complexes. These altered proteins are able to form SWI/SNF complexes, but these complexes are nonfunctional and cannot participate in chromatin remodeling. Disturbance of this regulatory process alters the activity of many genes, which likely explains the diverse signs and symptoms of Nicolaides-Baraitser syndrome.

Cancers

Common DNA variants (polymorphisms) that affect the SMARCA2 gene have been found in certain types of cancer, particularly lung cancer in tobacco smokers and head and neck cancer. The changes that are associated with these cancers are described as germline, meaning that they are present from birth and found in all of the body's cells. (While the mutations that cause Nicolaides-Baraitser syndrome, which is described above, are also germline, there is no increased risk for cancer in individuals with that condition.) Two specific SMARCA2 gene polymorphisms have been found to be associated with the development of these cancers. These changes occur in an area near the SMARCA2 gene called the promoter region, which controls the production of the SMARCA2 protein. One change adds seven building blocks of DNA (nucleotides) at position -741 (insTATTTTT); the other adds six nucleotides at position -1321 (insTTTTAA) of the promoter. The incidence of lung cancer and head and neck cancer is increased only when both of these polymorphisms are present in both copies of the SMARCA2 gene in each cell.

These polymorphisms impair the function of the promoter and reduce the expression of the SMARCA2 gene. The reduced gene activity likely decreases or alters protein production, which would lead to changes in SWI/SNF complexes. These changes may impair normal cell differentiation, which leads to the overgrowth of certain cell types, causing cancer. Alternatively, abnormal SWI/SNF complexes may disrupt the regulation of genes that help control the growth and division of cells, which leads to cancer. It is unclear why these changes in the promoter region of the SMARCA2 gene seem to be associated only with head and neck cancer and lung cancer in smokers.

Other Names for This Gene

• ATP-dependent helicase SMARCA2
• BAF190
• BAF190B
• BRG1-associated factor 190B
• BRM
• global transcription activator homologous sequence
• hBRM
• hSNF2a
• protein brahma homolog
• SNF2
• SNF2-alpha
• SNF2/SWI2-like protein 2
• SNF2L2
• SNF2LA
• Sth1p
• sucrose nonfermenting 2-like protein 2
• SWI/SNF-related matrix-associated actin-dependent regulator of chromatin a2
• SWI2

Genomic Location

Nicolaides-Baraitser syndrome follows an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

All cases of this condition result from new (de novo) mutations in the gene that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. These cases occur in people with no history of the disorder in their family.

• Scalp hair is usually sparse at birth and usually becomes increasingly sparse with age, particularly in the second decade of life. However in some, the sparseness improves with time.
• Facial characteristics typically become more pronounced with increasing age. In some affected adults, the lower third of the face becomes markedly broad.
• As people with NCBRS age, the amount of subcutaneous fat tissue tends to decrease, making the skin below the eyes sagging and wrinkled, especially at the cheeks when smiling. However, some affected people retain full cheeks.
• The distal phalanges widen with age, becoming oval shaped and broad. Increasing space between the first and second toes can also occur over time.
• At first, finger mobility is normal (maybe even hypermobile). Later on mobility often decreases, and some older people dislike passive movements of their fingers.
• Osteoporosis is not uncommon and affected people may develop fractures in puberty or thereafter.
• Although psychomotor regression is not typical, the high incidence of seizures that progressively worsen has been associated with loss of speech.

Nicolaides-Baraitser syndrome is likely a rare condition; approximately 75 cases have been reported in the scientific literature.