NORD gratefully acknowledges Sarah M. Nikkel, MD, FRCPC, FCCMG, Associate Professor, Pediatrics, University of Ottawa, Clinical Geneticist, Department of Genetics, Children’s Hospital of Eastern Ontario, for assistance in the preparation of this report.
Floating-Harbor syndrome (FHS) is an extremely rare genetic disorder characterized by a distinctive facial appearance, various skeletal malformations, delayed bone age, and expressive and receptive language delays. Children may be below average height for their age (short stature). Additional symptoms including mild to moderate intellectual disability have also been reported. The specific symptoms and severity FHS can vary greatly from one person to another. FHS is caused by mutations in the SRCAP gene. This mutation is inherited in an autosomal dominant manner, although most cases of FHS occur randomly (sporadically) as the result of a new (de novo) mutation. Treatment is symptomatic and supportive.
Floating-Harbor syndrome was named after the two hospitals where, during the 1970s, the first cases were identified and reported in the medical literature; namely, the Boston Floating Hospital and Harbor General Hospital in California.
Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent 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. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.
In some cases, delayed growth may occur before birth (prenatal growth retardation) resulting in low birth weight. Typically, growth deficiencies become apparent during the first year of life. Affected children may be below average height for their age (short stature), usually below the 5th percentile. The head size is typically in the average range. In addition to growth deficiencies, children with FHS have a delay in bone aging in the first decade of life, which means that the rate of growth and calcification of the bones is slower than normal.
Infants and children with FHS have distinctive facial features including a triangularly-shaped face; low-set ears; deep-set eyes with abnormally long eyelashes; thin lips; a broad, linear mouth; a prominent, triangular-shaped nose that is narrow at the root and broadens at the base; the bottom of the sheet of cartilage and bone (nasal septum) that separates the right and left nostrils (columella) may be low-hanging; the nostrils are large; and the groove that runs from the nose to the upper lip (philtrum) is short. These facial characteristics are the most distinctive features of FHS. Although they may change as an affected individual ages, the key features remain constant.
Speech and language deficits are common in children with FHS. Expressive language deficits are most common and often most severely affected. Expressive language is the ability of a person to ‘output’ language or how people express themselves such as through speech or writing. It also encompasses the use of gestures and facial expressions. Some affected children also have receptive language deficits, in which they are unable to understand words and gestures. Affected individuals may have difficulty speaking (dysarthria) and exhibit a distinct, high-pitched nasally voice. In some cases, speech may be absent. Children may be described as having verbal dyspraxia, which refers to the difficulty or inability to coordinate the precise movements required to produce clear speech despite the absence of damage to the nerves or muscles. The severity of expressive and receptive language abnormalities can vary widely.
Intellectual disability that is typically mild to moderate in degree has been reported. Learning disabilities are common as well.
Affected individuals exhibit various skeletal malformations including short fingers and toes (brachydactyly); broad fingertips that give the appearance of clubbing; short, broad thumbs; and prominent joints. The pinkies may be fixed or ‘locked’ in a bent position (clinodactyly). Some individuals may have abnormalities of the collarbones (clavicles) including underdevelopment (hypoplasia) of the collarbone or the development of a ‘false joint’ (pseudoarthrosis). A false joint is a bony structure that usually develops at the site of a poorly united fracture that allows abnormal movement of the affected bones.
Children with FHS may exhibit behavioral abnormalities including hyperactivity, impulsivity, short attention span, aggression, anxiousness, and obsessive behaviors such as repeated skin picking. Behavioral issues often improve in adulthood.
Additional symptoms have been reported in individuals with FHS including short bones in the hands (metacarpals); the presence of 11 pairs of ribs instead of 12; malformed (dysplastic) hips; abnormal curvature of the spine (kyphoscoliosis); seizures; backflow or leakage of the contents of the stomach into the esophagus (gastroesophageal reflux); farsightedness (hyperopia); crossed eyes (strabismus); recurrent middle ear infections (otitis media); and conductive hearing loss. Conductive hearing loss occurs when there is impaired transmission of sound from the outer or middle ear to the inner ear. Dental anomalies may also occur including extra (supernumerary) teeth, delayed loss of primary (“baby”) teeth, abnormally small teeth (microdontia), and malocclusion, a condition in which the upper teeth are improperly positioned in relation to the lower teeth.
In some cases, affected individuals may exhibit kidney abnormalities such as cysts on the kidneys or swelling (distention) of the kidneys due to the abnormal accumulation of urine (hydronephrosis). Hydronephrosis develops because of blockage within the urinary tract that prevents urine from being evacuated through the bladder. In some cases, there may be absence of the kidneys (agenesis).
In some cases, the onset of puberty may occur earlier than normal. Males may have undescended testicles (cryptorchidism) and hypospadias, a condition in which the tube that is connected to the bladder and discharges urine from the body (urethra) opens on the underside of the penis instead of the tip. Other conditions that have been reported in individuals with FHS include Celiac disease, congenital heart defects, mild underactivity of the thyroid (hypothyroidism), and, in adulthood, high blood pressure (hypertension).
Floating-Harbor syndrome is caused by a mutation in the SRCAP gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
Investigators have determined that the SRCAP gene is located on the short arm (p) of chromosome 16 (16p11). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered.
In FHS, mutations in the SRCAP gene often occur as a new (sporadic or de novo) mutation, which means that in nearly all cases the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. There are no silent carriers of FHS (i.e. if one carries a mutation in SRCAP, he/she will show signs of FHS).
Although most cases are due to sporadic mutations, dominant inheritance (where a trait is transmitted from either an affected mother or father to a child) has been documented in a few families. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the 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 affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
The SRCAP gene creates (encodes) a protein that has several functions in the body. This protein is a cofactor (i.e. a substance required for a protein’s biological activity) for the CREB-binding protein (CREBBP). Mutations in the gene that produces CREB-binding protein cause Rubinstein-Taybi syndrome, a rare disorder with many overlapping symptoms to FHS.
Floating-Harbor syndrome affects males and females in equal numbers. The exact incidence and prevalence of the disorder is unknown. Because cases may go undiagnosed or misdiagnosed, determining the true frequency of FHS in the general population is difficult. As of 2014, approximately 100 cases have been reported in the medical literature. However, some of these individuals do not fit the classical description of FHS and were found not to carry mutations in the SRCAP gene.
A diagnosis of Floating-Harbor syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. The distinctive facial features that characterize FHS can be subtle and difficult to recognize during infancy. Additionally, many of the other symptoms are nonspecific to FHS, making it difficult to diagnose the disorder on clinical grounds alone.
Molecular genetic testing can confirm a diagnosis of FHS. Molecular genetic testing can detect mutations in the SRCAP gene, but is available only on as a diagnostic service at specialized laboratories.
Prenatal diagnosis may also be possible for families with a known mutation of the SRCAP gene. Deoxyribonucleic acid or DNA taken from fetal cells obtained through amniocentesis or chorionic villus sampling (CVS) can be studied for the disease-causing mutation. During amniocentesis, a sample of fluid that surrounds the developing fetus (amniotic fluid) is removed and studied. CVS involves the removal of tissue samples from a portion of the placenta.
In cases where a parent has a known genetic abnormality, pre-implantation genetic diagnosis (PGD) may be an option. PGD can be performed on embryos created through in vitro fertilization. PGD refers to testing an embryo to determine whether it has the same genetic abnormality as the parent. Families interested such an option should seek the counsel of a certified genetics professional.
The treatment of FHS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, specialists who assess and treat skeletal problems (orthopedists), specialists who asses and treat hearing problems (audiologists), specialists who assess and treat vision problems (ophthalmologists), dental specialists, speech pathologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with FHS.
Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Additional medical, social, and/or vocational services including special remedial education may also be beneficial. Ongoing counseling and support for parents is beneficial as well. Genetic counseling will also be of benefit for affected individuals and their families.
Growth hormone (GH) therapy has been used to treat some individuals with FHS. Referral to a specialist who deals with the system of glands that secrete hormones into the bloodstream (endocrinologists) is recommended for those considering GH therapy. However, there is limited information as to the effectiveness and side effects of GH therapy in children with FHS.
Additional therapies for specific symptoms follow standard treatment guidelines. For example, seizures may be treated with anti-seizure medications (anti-convulsants).
According to the medical literature, affected individuals, in general, often remain in good overall health and have a good quality of life.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
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