Bosma arhinia microphthalmia (BAM) syndrome is an extremely rare genetic congenital disorder characterized by severe hypoplasia of the nose and eyes, palatal abnormalities, deficient taste and smell, inguinal hernias, hypogonadotropic hypogonadism with cryptorchidism, bilateral colobomatous microphthalmia, arhinia, high arched palate, mild ear malformations, and hypogonadotropic hypogonadism, abnormal brain structure, and normal intelligence. It is defined by three major features: 1) complete absence of the nose, 2) eye defects, and 3) 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 with blindness. Boys with BAM syndrome may be born with underdeveloped genitals (small penis and/or testes that have not descended properly into the scrotum). If a girl with BAM syndrome has problems with her reproductive system, it will only become apparent in her teenage years when she does not develop breasts or have menstrual periods. The nose and eye problems typically require surgery, and the reproductive problems can be treated with hormones (testosterone or estrogen replacement). Despite the severe facial problems, patients typically have normal to above-average intelligence and live happy, productive lives. The only known genetic cause of BAM syndrome is a change in the gene SMCHD1. In the majority of cases, this change occurs spontaneously in the egg or sperm cell and is not inherited from the parents.
The complete absence of the nose from birth (congenital arhinia) was first described in French literature in the 1800s. A handful of additional patients with congenital arhinia, some with and some without eye defects, were reported in the early to mid-1900s. Dr. James Bosma, a pediatrician, and researcher at the National Institute of Dental Health, however, was the first to observe that these patients frequently had genital and reproductive hormone problems. In his 1981 report, he described two unrelated males (who were first reported by plastic surgeon Dr. George Gifford et al., (1972) with congenital arhinia, eye defects, and genital defects (small penis and undescended testes at birth, with no spontaneous sexual maturation). Nearly every patient with congenital arhinia has been the first and only one affected in his or her family. However, there have been several reports of multiple patients 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
Additional head and face abnormalities that can occur in people with BAMS include a high arch or opening in the roof of the mouth (high-arched or ), absence of the sinuses behind the nose (paranasal sinuses), blockage of the nasal passages (choanal atresia), narrowing of the tear ducts (nasolacrimal duct stenosis), or a small upper jaw (hypoplastic maxilla). Many of these abnormalities contribute to difficulty breathing, particularly in affected babies. Some affected individuals have abnormal external ears.
Although researchers have been able to delineate a recognizable syndrome with characteristic or “core” symptoms, 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. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below or may have symptoms that are not discussed. Every case 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.
Children with BAM syndrome are born with a very small (hypoplastic) nose or no nose at all. 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. Some, but not all, babies need oxygen and a breathing tube (oral airway or tracheostomy), at least temporarily. If the back part of the nasal airway is narrow or blocked (choanal atresia), this may also cause breathing problems, which 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.
Children with BAM syndrome may have problems with vision and their eyes. This includes missing eyes (anophthalmia), abnormally small eyes (microphthalmia), coloboma, cataracts, and absent or narrow tear ducts. In a study of nearly 40 patients with BAM syndrome, 77% of patients had anophthalmia or microphthalmia, 79% had coloboma, 53% had cataracts, and nearly all had missing or narrow tear ducts. Six patients had no vision problems. There can be a loss of vision with age.
- A coloboma is a cleft in or failure to close the eyeball during fetal development. This can result in a keyhole-shaped pupil (iris coloboma) and/or abnormalities in the retina, macula, or optic nerve. Coloboma of the retina or optic nerve may cause vision loss, including blind spots, problems with depth perception, or legal blindness. Many children with coloboma are sensitive to bright light. They may experience retinal detachment over time.
- A cataract is a clouding of the lens of the eye (which is normally clear) at birth. Cataracts can cause poor vision but eye doctors can do surgery to fix them.
- Tear ducts normally drain tears from the eyes to the nose. If tear ducts are absent, patients may have excessive tearing. If tear ducts are narrow, bacteria may collect in them, causing infections. Tear ducts can be opened up with surgery.
Other common facial problems include cleft lip or cleft palate, abnormal external ears (too large or too small), and crowded or missing teeth.
It is very common for affected children to have genital abnormalities and/or an inability to make sex hormones. This is most likely because a part of the brain, 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). Most boys and girls require hormone therapy to go through puberty. A pediatric endocrinologist can help with this treatment.
Causes
BAMS is usually caused by mutations in the SMCHD1 gene. Other, unknown genes may be rare causes of the condition.
The SMCHD1 gene provides instructions for making a protein involved in regulating gene activity by altering the structure of DNA. Specifically, the SMCHD1 protein plays a role in turning off (silencing) certain genes. Among other functions, the SMCHD1 protein appears to be important for the development of the nose, eyes, and other structures of the head and face.
Researchers are unsure how SMCHD1 gene mutations affect the protein’s function and lead to the development problems characteristic of BAMS. Changes in this gene may lead to abnormal silencing of genes involved in the development of the head and face, which could underlie arhinia, microphthalmia, and other characteristic facial abnormalities of BAMS. Problems with nasal development may affect gonadotropin-releasing hormone (GnRH) neurons, which are nerve cells that control the release of reproductive hormones. GnRH neurons originate in the developing nose and then move to the brain. Impaired development of these neurons could explain hypogonadotropic hypogonadism in affected individuals.
In 2017, two independent teams of researchers discovered that the gene that is altered in most patients with BAM syndrome is the SMCHD1 gene. BAM syndrome is usually caused by a spontaneous (de novo) change in SMCHD1 that occurs in the egg or sperm cell. In such situations, it is not inherited from the parents. Rarely, the abnormal gene can be inherited as an autosomal dominant trait.
Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Researchers believe that having a change in SMCHD1 is necessary but not sufficient to develop BAM syndrome. This is because there are families, for example, where a child with BAM inherited a change in SMCHD1 from his mother who has a very mild form of BAM (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, in this example, the father. 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.
The SMCHD1 protein is a gene repressor. This means it can turn other genes off. The changes that occur in SMCHD1 in patients with BAM syndrome may cause other genes that are important for developing a normal nose and eyes to be turned off at the wrong time. 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 have also been shown to cause a rare form of muscular dystrophy, called facioscapulohumeral muscular dystrophy type 2 (FSHD2; see NORD database). FSHD2 patients have not been reported to have any nose, eye, or reproductive problems, and researchers are still trying to understand if some BAM patients will develop signs of FSHD2 as adults, since FSHD2 is an adult-onset condition, with an average age of onset of 26 years.
There are no known environmental exposures during pregnancy that cause BAM. However, studies in animals have suggested that high blood sugar, alcohol, and retinoic acid may cause holoprosencephaly, a severe congenital disorder whose features may overlap with those of BAM (e.g., absent nose, anophthalmia or microphthalmia, cleft lip or cleft palate, hormone problems).
Diagnosis
Arhinia is apparent at birth and can sometimes be suspected prenatally. A medical geneticist, pediatrician, or another pediatric subspecialist should do a complete physical exam and order tests to look for the two other major features of BAM, eye defects and genital/hormone defects. Molecular genetic testing for changes in the SMCHD1 gene that are associated with BAM is available at specialized laboratories.
Treatment
Although children with BAM may require intensive medical support early in life because of difficulty breathing and feeding, they usually become healthy and productive citizens with normal life spans. Many of the structural abnormalities (choanal atresia, cleft palate, etc.) can be surgically corrected and new technologies are allowing surgeons to create much more cosmetically appealing nasal prostheses for these children. Two groups have published papers on a custom-made nasal implant made with a 3D printer. Most patients will require ongoing medical care from a team of medical and surgical sub-specialists, including plastic or maxillofacial surgeons, ophthalmologists (eye doctors), and endocrinologists (hormone doctors). Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families. Due to the rarity of BAM, there are no standardized treatment protocols or guidelines for affected individuals.
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