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NORD is very grateful to Professor Jozef Gecz, PhD, NH&MRC Principal Research Fellow, Head, Neurogenetics Laboratory, SA Pathology at the Women's and Children's Hospital, Adelaide, Australia and Dr. Matt Hunter, Clinical Genetics at the Genetics of Learning Disability (GOLD) Service in Newcastle, Australia, for their assistance in the preparation of this report.
Börjeson-Forssman-Lehmann syndrome (BFLS) is an extremely rare disorder characterized by intellectual disability, obesity, seizures, failure of the testes in males or the ovaries in females to produce hormones (hypogonadism), and distinctive facial features. Affected infants often experience delays in reaching developmental milestones. The exact symptoms vary from case to case, even among members of the same family.
BFLS is caused by disruptions or changes (mutations) of the PHF6 gene on the X chromosome. This mutation is usually transmitted as an X-linked recessive trait, which means the disorder is fully expressed predominantly in males. Females who carry a single copy of the disease gene (heterozygous carriers) may develop some variable features of the disorder, however, in some instances they can have features similar to the affected males (i.e. be considered as affected with the syndrome).
Börjeson-Forssman-Lehmann syndrome is usually fully expressed in males only, but there is at least one report of an effected female with the syndrome. Generally symptoms in females are less severe and more variable, but this cannot be predicted based on molecular studies. The symptoms associated with BFLS are variable even in males and even in individuals of the same family.
Most male cases of BFLS are characterized by mental retardation of varying severity. Affected infants may also have diminished muscle tone (hypotonia), a condition that indicates that the head circumference is smaller than would be expected for an infant's age and sex (microcephaly), and may experience feeding difficulties resulting in failure to thrive. As affected children age they may experience delays in reaching developmental milestones. Seizures may be present in some cases. Mild obesity is common in affected children even during infancy.
Affected individuals may have distinctive facial features including large, fleshy earlobes, deep-set eyes, heavy ridges above the eyes (prominent supraorbital ridge), and thickened connective tissue of the face, giving the face a coarse appearance. In some cases, affected individuals may have droopy upper eyelids (ptosis), rapid, involuntary eye movements (nystagmus), and abnormalities of the thin membrane that lines the back of the eyes (retina) and the main nerve that sends electrical impulses from the retina to the brain (optic nerve). Vision problems such as farsightedness (hyperopia) and cataracts may develop before the age of 30.
Individuals with BFLS may also have reduced function of the testes or ovaries (hypogonadism). The failure of the testes and ovaries to produces hormones may result in growth deficiencies resulting in short stature and delayed sexual development. In addition, affected males may have small genitalia and the testes may fail to descend into the scrotum (cryptorchidism). After puberty, some males may develop abnormally enlarged breasts (gynecomastia).
Skeletal abnormalities may occur in some cases including abnormal side-to-side or front-to-back curvature of the spine (scoliosis or kyphosis), a narrow cervical spinal canal, or underdevelopment (hypoplasia) of certain bones of the fingers or toes resulting long, tapered fingers and abnormally short toes especially the fourth and fifth toes.
As affected males age, the symptoms of the disorder may become milder and vary more between cases. Diabetes has occurred in some adults with BFLS.
Females who carry the disease gene for BFLS may develop some symptoms of the disorder. Females usually develop a milder form of BFLS than males and the specific symptoms are highly variable. For example, intelligence may be unaffected or intellectual disability may occur. Additional symptoms may include large ears, obesity, coarse facial appearance, and a variety of skeletal abnormalities. Some affected females may experience delayed development of secondary sexual characteristics. At least one female was reported so far in the medical literature with full features of the syndrome, similar to those of an affected male.
Börjeson-Forssman-Lehmann syndrome is caused by a mutation of the zinc finger protein 6 (PHF6) gene. This mutation is inherited as an X-linked recessive trait. The gene PHF6 contains instructions (encodes) for creating a specific type of protein. One of the functions of this protein is to prevent cancer, but the other functions are unknown.
Mutations in the PHF6 gene have been found in the cancer cells of people who have T-cell acute lymphoblastic leukaemia (T-ALL) or acute myelogenous leukemia (AML). These people do not have the BFLS syndrome. The mutations of PHF6 are found only in some cells in their blood. There has been at least one report of a male affected with both, BFLS and T-ALL. These cancers are thought to have occurred due to the role of PHF6 as a tumor suppressor gene, in other words a gene that prevents the development of cancer. It is obvious that PHF6 on its own is unlikely cause cancer, however, together with mutations in others genes it can contribute to cancer. While there might be a slightly increased risk of these forms of blood cancer to occur in people affected with BFLS (i.e. with germline PHF6 mutations), such risk is at the moment difficult to quantify. More studies are required to address the importance of the PHF6-cancer link for the BFLS patients.
X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the defective gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder is able to reproduce, he will pass the defective gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
Börjeson-Forssman-Lehmann syndrome is an extremely rare disorder that is fully expressed in males only. Some females who carry a single copy of the disease gene may develop some symptoms of the disorder. BFLS was originally described in the medical literature in 1962 in three related males as well as three of their more mildly affected female relatives. The exact incidence of BFLS is unknown. Approximately 20 unrelated families and various isolated cases have been reported in the medical literature with mutations in the PHF6 gene.
Symptoms of the following disorders can be similar to those of Börjeson-Forssman-Lehmann syndrome. Comparisons may be useful for a differential diagnosis.
Coffin-Lowry syndrome is a rare genetic disorder characterized by mental retardation; abnormalities of the head and facial (craniofacial) area; large, soft hands with short, thin (tapered) fingers; short stature; and/or various skeletal abnormalities. Characteristic facial features may include an underdeveloped upper jawbone (maxillary hypoplasia), an abnormally prominent brow, downslanting eyelid folds (palpebral fissures), widely spaced eyes (hypertelorism), large ears, and/or unusually thick eyebrows. Skeletal abnormalities may include abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis) and unusual prominence of the breastbone (sternum) (pectus carinatum). Coffin-Lowry syndrome is caused by mutations in the RSK2 gene and is inherited as an X-linked dominant trait. Males are usually more severely affected than females. (For more information on this disorder, choose "Coffin Lowy syndrome" as your search term in the Rare Disease Database.)
Bardet-Biedl syndrome is a rare genetic disorder characterized by intellectual disability, obesity, delayed sexual development or underdeveloped reproductive organs, progressive pigmentary degeneration of the retinas of the eyes, kidney abnormalities in structure or function, and/or abnormal or extra fingers and/or toes (polydactyly). A primary feature of Bardet-Biedl syndrome is progressive pigmentary degenerative changes of the retina (retinal dystrophy), similar to retinitis pigmentosa. Additional visual abnormalities may include night blindness; loss of side (peripheral) vision (tunnel vision); nearsightedness (myopia); abnormal alignment of one eye in relation to the other (strabismus); abnormal, involuntary, rapid eye movements (nystagmus). Bardet-Biedl syndrome is inherited as an autosomal recessive trait. Many genes have been identified to cause Bardet-Biedl syndrome. (For more information on this disorder, choose "Bardet-Biedl" as your search term in the Rare Disease Database.)
Prader-Willi syndrome is a genetic disorder characterized in infancy by diminished muscle tone (hypotonia), feeding difficulties, and failure to grow and gain weight (failure to thrive). In childhood, features of the disorder include short stature, genital abnormalities and an excessive appetite. Progressive obesity results because of a lack of feeling satisfied after completing a meal (satiety) that leads to overeating. Without appropriate treatment, individuals with severe progressive obesity may have an increased risk of cardiac insufficiency, diabetes or other serious conditions that may lead to potentially life-threatening complications. All individuals with Prader-Willi syndrome have some cognitive impairment that ranges from borderline normal with learning disabilities to mild mental retardation. Behavior problems are common and can include temper tantrums, obsessive/compulsive behavior, and skin picking. Prader-Willi syndrome occurs when the genes in a specific region of chromosome 15 do not function. The abnormal genes usually result from random errors in development, but are sometimes inherited. (For more information on this disorder, choose "Prader-Willi" as your search term in the Rare Disease Database.)
Wilson-Turner syndrome (WTS) is a rare genetic disorder characterized by X-linked inheritance of mild to moderate intellectual disability, obesity, gynaecomastia (breast development in males), tapered fingers, small feet, and mood swings. The differences from BFLS include: no distinctive facial appearance, normal growth, normal (or small) genitals. In infancy there is global developmental delay with speech more severely involved, low tone and excessive drooling. Males with WTS are said to be quiet with a cheerful temperament, although some males have been easily upset, tearful or aggressive. Stuttering is common. Mild disturbances of the male hormones (androgens) have been reported, similar to BFLS. The genetic cause for WTS has not been identified.
Chudley-Lowry syndrome (CLS) is a genetic disorder characterized by X-linked inheritance of moderate to severe intellectual disability, obesity, low tone and genital underdevelopment. There is a distinctive facial appearance which is different to BFLS with almond shaped eyes, depressed nasal bridge, large open mouth with arched upper lip, short philtrum, and high palate. There can be shortening and tapering of the fingers. Testes are small or not fully descended but the male hormones (androgens) are normal. Growth is below average for height and head circumference but weight is above average. In early childhood there is global developmental delay. Short attention span and hyperactivity has been reported. CLS is caused by mutations in the ATR-X gene.
A diagnosis of Börjeson-Forssman-Lehmann syndrome is made based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic features. X-rays of the skeletal (skeletal radiography) may be used to detect the presence and assess the severity of potential skeletal defects and support a diagnosis of BFLS.
Molecular genetic testing for mutations in the PHF6 gene is available to confirm the diagnosis.
The treatment of BFLS 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, eye specialists (ophthalmologists), and specialists in treating skeletal disorders (orthopedists), and other healthcare professionals may need to systematically and comprehensively plan an affected child's treatment.
Early developmental intervention is important in ensuring that affected children with BFLS reach their potential. Special services that may be beneficial to affected children may include special remedial education and other medical, social, and/or vocational services. Genetic counseling may be of benefit for affected individuals and their families.
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Report last updated: 2012/04/03 00:00:00 GMT+0