Bosma Arhinia Microphthalmia Syndrome

Bosma Arhinia Microphthalmia Syndrome

Overview

Bosma arhinia microphthalmia (BAM) syndrome is an extremely rare genetic disorder defined by three major features: 1) complete absence of the nose (arhinia) 2) eye abnormalities and 3) lack of typical sexual development during puberty (absent sexual maturation).  

The specific symptoms and severity of the disorder can vary from one person to another. For example, eye problems can range from absent tear ducts (the small tubes that carry tears from the eyes to the nose) to very small eyes and/or blindness.  

In males, BAM syndrome may cause underdeveloped genitalia at birth, including a small penis and/or testes that do not descend properly into the scrotum. In females, reproductive differences are usually not noticeable until adolescence when she does not develop breasts or have menstrual periods.  

The only known genetic cause of BAM syndrome is a change (variant) in the SMCHD1 gene. In most cases, this genetic change occurs spontaneously in the egg or sperm cell and is not inherited from either parent. 

Fewer than 100 people worldwide have been reported with BAM syndrome over the past century, making it an exceptionally rare condition.  

Treatment focuses on managing symptoms. Surgery is often needed to address the absence of the nose and eye-related differences. Hormone replacement therapy (testosterone or estrogen replacement) can help support sexual typical development during adolescence.  

Despite significant facial differences, most people with BAM syndrome typically have normal to above average intelligence and live happy, productive lives. 

Nearly every person with congenital arhinia has been the first and only one affected in their family. However, there have been several reports of multiple affected people within the same family, the first by Klaus Ruprecht and Frank Majewski (1978) describing two German sisters with congenital arhinia and eye defects. Several terms have been used in the past for this syndrome to acknowledge the work of Drs. Gifford, Bosma, Ruprecht and Majewski. 

Symptoms

BAM syndrome is a recognizable syndrome with characteristic or “core” symptoms, but much about this disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies and other factors have prevented physicians from developing a complete picture of associated symptoms and prognosis (how a condition is expected to affect a person over time). Therefore, it is important to note that affected individuals may not have all the symptoms discussed below, or they may have symptoms that are not discussed. Every person is unique, and the disorder can be different in one child when compared to another. Parents should talk to their child’s physicians and medical team about their specific case, associated symptoms and overall prognosis.  

The main features of BAM syndrome include: 

Absent or small nose: Children with BAM syndrome are born with a very small (hypoplastic) nose or with no nose at all (arhinia). They cannot smell because they are also missing the internal parts of the smell (olfactory) system, but they may be able to detect very strong, irritating odors.  

Babies who are born without a nose often have trouble breathing because it takes some time for them to learn how to breathe through their mouth and how to breathe and eat at the same time.  

The back part of the nasal airway can be narrow or blocked (choanal atresia) which can also cause breathing problems.  

Eye and vision problems: Children with BAM syndrome may have problems with vision and their eyes, including missing eyes (anophthalmia), abnormally small eyes (microphthalmia), coloboma (an area of missing tissue in the eye present at birth), cataracts and absent or narrow tear ducts. There can be loss of vision with age.   

A coloboma is a cleft in or failure to close the eyeball during fetal development, which can result in a keyhole-shaped pupil (iris coloboma) and/or abnormalities in the retina (light-sensitive layer of tissue in the back of the eye), macula (oval-shaped yellow spot in the center of the retina at the back of the eye), or optic nerve (a bundle of nerve fibers that carries visual information from the retina to the brain).  

Coloboma of the retina or optic nerve may cause vision loss, including blind spots, problems with depth perception or legal blindness, and sensitivity to bright light.  

People with coloboma may experience retinal detachment (a medical emergency where the light-sensitive tissue at the back of the eye peels away from its normal position, requiring immediate treatment to prevent permanent vision loss) over time. 

A cataract is a clouding of the lens of the eye (which is normally clear) at birth and can cause poor vision. 

Absence of tear ducts, the ducts that normally drain tears from the eyes to the nose.  

If tear ducts are absent, patients may have excessive tears.  

If tear ducts are narrow, bacteria may collect in them, causing infections.  

In a study of 40 patients with BAM syndrome, 77% of patients had anophthalmia (absence of one or both eyes) or microphthalmia (one or both eyes are abnormally small), 79% had coloboma (an area of missing tissue in the eye), 53% had cataracts (cloudy lens of the eye), and nearly all had missing or narrow tear ducts. 6 patients had no vision problems., 

 Other common facial problems include cleft lip or cleft palate, abnormal external ears (too large or too small) and crowded or missing teeth. 

 Problems with sexual development: It is very common for affected children to have differences in the genitals and difficulty producing (or inability to produce) sex hormones. This is most likely because a part of the brain that plays a key role in regulating puberty and reproductive function, called the hypothalamus, does not make the hormone GnRH (gonadotropin-releasing hormone). This hormone is required for the reproductive system to develop and function normally. Most boys have a small penis and undescended testes (cryptorchidism).  

Causes

BAM syndrome is caused by a change (variant) in the SMCHD1 gene. The gene variant is usually a spontaneous (de novo) change in SMCHD1 that occurs in the egg or sperm cell. De novo means it is a new, spontaneous change that is not inherited from a parent. Rarely, an SMCHD1 gene variant can be inherited from a parent. 

The SMCHD1 protein is a gene repressor. This means it can turn other genes off. It is possible that the changes that occur in SMCHD1 in patients with BAM syndrome cause other genes that are important for developing a normal nose and eyes to be turned off at the wrong time.  A recent paper also suggested that in BAM syndrome, loss of SMCHD1 protein activity may lead to the production of a toxic protein (called DUX4) that kills the precursors of the human nose.  However, more research is needed to understand how changes in SMCHD1 activity cause BAM syndrome. 

Several of the same changes in SMCHD1 that cause BAM syndrome can cause  a rare form of muscular dystrophy, called facioscapulohumeral muscular dystrophy, specifically facioscapulohumeral dystrophy type 2 (FSHD2). FSHD2 patients have not been reported to have any nose, eye, or reproductive problems, and researchers are still trying to understand if some BAM syndrome patients will develop signs of FSHD2 as adults, since FSHD2 is an adult-onset condition, with an average age of onset of 26 years. 

BAM syndrome follows autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. 

Researchers think that having a variant in the SMCHD1 gene is necessary but not sufficient to develop BAM syndrome. This is because there are families, for example, where a child with BAM syndrome inherited a variant in SMCHD1 from his mother who has a very mild form of BAM syndrome (for example, no sense of smell but no other defects) or has no medical problems at all. This suggests that the child has a change in a second critical gene, which may have occurred spontaneously or may have been inherited from the other parent. This type of inheritance, called digenic inheritance, occurs when a change in more than one gene is required to cause disease. Researchers are still trying to identify these other genes. 

There are no known environmental exposures during pregnancy that cause BAM syndrome. However, studies in animals have suggested that high blood sugar, alcohol, and retinoic acid may cause holoprosencephaly, a severe congenital (from birth) disorder with features that may overlap with those of BAM (e.g., absent nose, anophthalmia or microphthalmia, cleft lip or cleft palate, hormone problems). 

Affected populations

BAM syndrome is an extremely rare disorder that is known to affect patients from many different ethnic groups. As with many rare disorders, the exact incidence or prevalence of this disorder is unknown. The disorder probably goes misdiagnosed or undiagnosed, making it difficult to determine the true frequency in the general population. Fewer than 100 people have been reported in the medical literature. 

Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of BAM syndrome. 

Kallmann syndrome 

frontonasal dysplasia 

craniofrontonasal dysplasia 

frontofacionasal dysplasia 

holoprosencephaly 

Treacher Collins syndrome 

Diagnosis

Arhinia is apparent at birth and can sometimes be suspected prenatally. A medical geneticist, pediatrician, or other pediatric subspecialist should do a complete physical exam and order tests to look for the two other major features of BAM syndrome: eye defects and genital/hormone defects. Molecular genetic testing for variants in the SMCHD1 gene that are associated with BAM syndrome is available at specialized laboratories. 

Standard Therapies

Treatment

Children with BAM syndrome may require intensive medical support early in life because of difficulty breathing and feeding, but they usually become healthy and productive citizens with normal life spans. Many of the structural abnormalities (choanal atresia where a tissue blocks the nasal airway, cleft palate, etc.) can be surgically corrected, and new technologies are allowing surgeons to create much more cosmetically appealing nasal prostheses (artificial noses) for these children.  

Some babies need oxygen and a breathing tube (oral airway or tracheostomy), at least temporarily. Choanal atresia (a tissue blocking the nasal airway) may result in breathing problems and can be corrected with surgery. Babies who aren’t growing well may need a feeding tube (gastrostomy or G-tube). Plastic surgeons can help to build an external nose.  

Achieving the best possible results in nasal reconstruction involves carefully balancing how the nose functions with how it looks. Traditional surgical methods, such as using cartilage grafts and skin flaps, have improved greatly over the years and have helped many patients. However, these approaches can still present challenges, including discomfort and/or scarring at the tissue donor site (the area of the body where tissue is taken to be used for nose reconstruction), difficulty maintaining long-term structural support, and preserving normal nasal function over time. 

Recent advances in custom-made nasal implants using three-dimensional (3D) imaging and 3D printing have brought important improvements to this area of care.  

Eye problems such as cataract, coloboma (an area of missing tissue in the eye present at birth), and tear ducts may need surgery. 

Many boys and girls with BAM syndrome require hormone replacement therapy to go through puberty. A pediatric endocrinologist (a specialized doctor who diagnoses and treats disorders of the glands and organs that produce hormones) can help with this treatment. 

Most patients will require ongoing medical care from a team of medical and surgical sub-specialists, including plastic or maxillofacial (head, neck, face and jaw) surgeons, ophthalmologists (eye doctors) and endocrinologists (hormone doctors). Psychosocial support for the entire family is essential as well. Genetic counseling is recommended for affected individuals and their families. Due to the rarity of BAM syndrome, there are no standardized treatment protocols or guidelines for affected individuals. 

Type of Doctor Department :  A medical geneticist or pediatrician, otolaryngologists (ENT), ophthalmologists, endocrinologists, and craniofacial surgeons