NORD gratefully acknowledges Professor Jozef Gecz, PhD, NH&MRC, Senior Principal Research Fellow, Head, Neurogenetics Laboratory, Robinson Research Institute, The University of Adelaide, Adelaide, Australia; Dr. Mark Corbett, PhD, MS, Neurogenetics Laboratory, Robinson Research Institute; and Dr. Mike Field, Genetics of Learning Disability (GOLD) Service of NSW, Sydney, 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 has been considered to be fully expressed only in males given the X-chromosome localization of the responsible gene (see below). However, there have been several reports of affected females with the syndrome. Generally, the symptoms of females vary dramatically, from no clinical presentations to fully affected status. The symptoms associated with BFLS are variable even in males and even in individuals of the same family.
Most males affected by BFLS are characterized by mental retardation of varying severity. Affected infants may also have diminished muscle tone (hypotonia), a smaller head circumference 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 were considered to be much less severely affected and develop only some symptoms of the disorder, generally a milder form of BFLS seen in the affected males. However, this assumption was based on females from larger families with primarily affected men. With the advent of new DNA sequencing technologies many singleton patients are tested and with those it has recently been revealed that de novo mutations (not present in the parents of the child) in PHF6 in singleton females result in a specific clinical phenotype, which might have been under-recognized so far. These female patients are affected with variable level of intellectual disability, characteristic facial features, underdeveloped nails, some dental anomalies, sparse hair and linear skin hyperpigmentation. A few females have been reported to develop epilepsy, which may be associated with signs of a generalized neuronal migration disorder resembling a subcortical band heterotopia on MRI. Interestingly while this female clinical phenotype shows overlap with BFLS, it also includes additional clinical features, thus adding a new facet to the disorder. These affected females (in particular when young) seem to resemble another genetic syndrome, Coffin-Siris syndrome. Their clinical presentations overlap, but are not identical, with typical BFLS phenotype only later in life, ie. in adolescence and adult life.
Börjeson-Forssman-Lehmann syndrome is caused by a mutation of the plant homeodomain 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 at least in some blood cells (T-lymphocytes important in immunity), but the other functions are not that well understood. More recent findings suggest that PHF6 protein is important for movement (migration) and function of neurons in the brain.
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 BFLS because the mutations are just in the cancer cells (in some cells in their blood) and not in the whole body. These cancers are thought to have occurred because PHF6 is a tumor suppressor gene, in other words a gene that normally prevents the development of cancer. Mutation of PHF6 on its own is unlikely cause cancer, but it is ought to be considered as a risk factor. There has been at least one report of a male affected with both, BFLS and T-ALL. Overall, there have been more males than females diagnosed with T-ALL when a mutation in PHF6 is involved. 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 disease 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. However, new research shows that female carriers can also be fully affected while having mutation in the PHF6 gene only on one of their X chromosomes. Why some carrier women of PHF6 gene mutations are not affected and others are is not yet clear. It can be speculated that the outcome (ie affected or not) can be due to the choice of the X chromosome in the cells of these female carriers to be active, the one with PHF6 mutation against the one with normal PHF6, which can drive the presentation of disease in these females. As females have two X chromosomes in each cell, one of them needs to be inactivated. In case the normal X chromosome is chosen for an unknown reason to be inactivated, the only active chromosome the females have is the one with the PHF6 mutation and as such they become affected. At the moment we cannot predict or control which of the two X chromosomes of such females will be active and which inactive. As such we cannot predict accurately the affected status of females with PHF6 mutation.
Generally, 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. These numbers need to be interpreted with caution in view of the findings of affected carrier females with PHF6 mutations. This means that an unaffected carrier female can have an affected carrier female and not only affected males. What is the risk that a female with a PHF6 mutation will be affected cannot yet be precisely determined.
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 a rare disorder that can be fully expressed in males as well as in females. The phenotypic expression in females is highly variable and cannot yet be predicted. 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, but with the identification of singleton affected females we assume it is underascertained. Approximately 40 unrelated families and various isolated cases (males and a growing number of females) have been reported in the medical literature with mutations in the PHF6 gene. However, it is plausible to speculate that the real number of individuals with PHF6 mutation is higher as many, even diagnosed cases are not reported and thus not captured.
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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