BBB Syndrome - Clinical Features, Types, Cause, and Diagnosis

Introduction:

BBB syndrome, also known as Opitz G syndrome is a genetic disorder that causes defects in the midline of the body. “BBB and G” denote the first letters of the surnames of the families that were first diagnosed with this disorder and “Opitz” is the doctor who described the features of this disorder. There are two types of BBB syndrome that occur due to mutation in the genes or by alteration in the chromosome such as deletions. In some cases, there can be new mutations without any family history which can cause this condition. The prognosis of BBB syndrome depends on the severity of the condition, some infants may die because of aspiration due to defects in the esophagus, larynx, or trachea.

What Is BBB Syndrome?

BBB syndrome is a genetic disorder that causes midline malformations. There is no cure for BBB syndrome but involves a multispecialty team of pediatricians, cardiologists, craniofacial surgeons, urologic surgeons, ENT (ear, nose, and throat) surgeons, neuropsychologists, speech therapist, and a medical geneticist.

What Are the Clinical Features of BBB Syndrome?

The clinical features of both forms of BBB syndrome are similar except for their genetic cause and inheritance pattern. The clinical features include:

• Ocular hypertelorism (increased distance between the two eyes).

• Defects in the trachea (windpipe), larynx (voice box), or esophagus (food pipe) due to which there can be a problem in swallowing and breathing. These can result in recurrent pneumonia (infection in the air sacs of the lungs and these episodes recur at least two to three times in a year) and other severe breathing problems.

• Laryngeal cleft is an abnormal opening between the esophagus and larynx which can result in the passage of food in the lungs. This can cause breathing problems and infants have difficulty breathing while feeding.

• Genital abnormalities such as hypospadias (a birth defect where the urethral opening is not located at the tip), cryptorchidism (undescended testes), and a bifid or underdeveloped scrotum (a male reproductive system that is present under the penis).

• Defects in the urinary tract due to genital abnormalities.

• Developmental delay occurs in half of the cases.

• Mild intellectual disabilities also occur in half of the cases.

• Delayed motor skills such as speech and language difficulties, and difficulty in walking.

• Autistic spectrum disorders (developmental disorder that causes difficulty in social interaction, communication, and repetitive behaviors).

• Cleft lip (split in the lip) with or without cleft palate (opening in the top portion of the mouth) occurs in half of the cases.

Facial features can vary among individuals including family members. The features include:

• Prominent forehead.

• Flat nasal bridge.

• Thin upper lip.

• Low-set ears.

• Widow's peak hairline (the shape of hair which is pointed at the center of the forehead).

Features that occur less commonly are:

• Imperforate anus (absence of anal opening).

• Minor heart defects.

• Brain defects such as absent or small corpus callosum (a region in the brain that defects the right and left side of the brain).

What Are the Types of BBB Syndrome?

There are two types of BBB syndrome which are:

• X-Linked Opitz G or BBB Syndrome: This occurs due to a mutation in the MID1 (midline 1) gene which is located on X-chromosome. This type is inherited in an X- linked pattern because the mutated gene is located on X-chromosome. Features of this inheritance pattern are:

  • Males carry one X and one Y chromosome, and the presence of the mutated gene in that one X chromosome is sufficient to cause this condition.

  • Fathers cannot pass down the condition to their sons.

  • Females who have two X chromosomes are unlikely to have two mutated genes in both chromosomes, but a female with one mutated gene in one X chromosome presents with no symptoms or with hypertelorism which is the only symptom of this condition in females and is called a carrier.

• Autosomal Dominant Opitz G or BBB Syndrome: This occurs due to a deletion in the small part of chromosome 22 or due to mutation in the SPECC1L (sperm antigen with calponin homology and coiled-coil domains 1-like) gene which is located on chromosome 22. This condition is inherited in an autosomal dominant pattern in which the presence of one single gene from one parent is enough to cause this disorder. Both males and females have the same symptoms.

What Is the Cause of BBB Syndrome?

The different forms of BBB syndrome occur due to different variations in the genes. X-linked BBB syndrome occurs due to mutations in the MID1 gene. The features of this gene include:

• This gene is located on X-chromosome.

• MID1 gene is a part of the tripartite motif (TRIM) gene family which plays an important role in cellular activities and in recycling unwanted proteins by attaching them to ubiquitin protein so that they can be reused. These ubiquitin proteins transfer the unwanted proteins into proteasomes (a protein complex that causes selective hydrolysis of the proteins).

• The MID1 gene provides information in the production of a protein called midline-1.

• Midline-1 attaches to microtubules which are the component of the cytoskeleton (cell’s structural framework) that helps in maintaining the shape of the cells, cell division, and cell migration.

• A mutation in the MID1 gene causes failure in protein recycling and the accumulation of unwanted proteins interferes with the microtubule function, cell migration, and cell division, therefore causing the features of BBB syndrome.

Autosomal dominant BBB syndrome occurs due to variation in chromosome 22. The variations can include a small part of deletion in chromosome 22 and the specific location is called 22q11. This condition is also referred to as 22q11.2 deletion syndrome. In some individuals, this condition occurs due to a mutation in the SPECC1L gene which is located in the 22q11.2 region. The features of the SPECC1L gene include:

• This gene provides information in the production of a protein called cytospin-A.

• This protein helps in stabilizing microtubules of cytoskeletons and in cell migration.

• During embryonic development, these proteins help in the migration of neural crest cells (stem cells that give rise to the peripheral nervous system, pigment cells, smooth muscle cells, and cartilage tissue) and help in the development of the face such as the lower jaw, forehead, and nasal bridge.

• Mutation in the SPECC1L gene can result in an inactive protein that fails to interact with the microtubules causing facial anomalies. Therefore, individuals with this mutation develop cleft palate and cleft lip.

What Is the Diagnosis of BBB Syndrome?

The diagnosis of BBB syndrome includes:

• Prenatal diagnosis with the help of ultrasound which is done at 19 weeks of gestation shows hypospadias and hypertelorism.

• Prenatal molecular genetic testing reveals a mutation in the MID1 gene or other variations like deletions in chromosome 22. There can be de novo mutations, too, without any family history.

• Diagnosis can be made based on clinical features such as hypotelorism, imperforated anus, hypospadias, defects in the larynx, trachea, and esophagus, laryngeal cleft, and cleft lip or palate.

What Is the Treatment of BBB Syndrome?

BBB syndrome is a complex medical condition that currently has no cure. It requires a multidisciplinary approach that aims to address the various aspects of the syndrome and provide comprehensive care to affected individuals. The treatment includes:

• Surgery is performed as needed to treat hypospadias.

• In cases of medically significant laryngotracheoesophageal (LTE) abnormalities, surgical treatment is required. Sometimes, an initial tracheostomy is necessary to ensure a proper airway.

• Affected individuals may require neuropsychological support and may require special educational programs.

• Surgery is used to manage cleft lip or palate and other craniofacial anomalies, while therapy helps address speech issues caused by these conditions.

• Surgery is performed as needed to repair heart defects.

Conclusion:

Individuals with BBB syndrome should undergo genetic counseling since it can be X-linked, where the female carriers can pass down the condition to male offspring and have a 50 percent of risk developing this condition and female offspring have a 50 percent of risk becoming carriers. This condition is also inherited in an autosomal dominant manner where the offspring has a 50 percent chance of developing this condition.