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Borjeson- Forssman- Lehman Syndrome (BFLS) is a rare X-linked recessive intellectual disorder consisting of obesity,hypogonadism, and dysmorphic features. The syndrome is inherited and is caused by a mutation in the PHF6 gene, located on the X chromosome(Xq26-28), which is one of the chromosomes determining sex. As with most X- linked disorders, BFLS affects males more heavily. Men have one X chromosome and one Y chromosome, while women have two X chromosomes. The mutation is typically passed down via a (usually) healthy female carrier who has one normal and one mutated gene. Sons of female carriers of a mutated gene run a 50 percent risk of inheriting the disease and daughters run the same risk of being healthy carriers of a mutated gene. A man with an inherited X-linked recessive disease can pass it on to his sons, but his daughters will be carriers of the mutated genes. In the case of BFLS, it is mainly found in boys, but several mild to moderately symptomatic females have been reported .

X-linked recessive Inheritance

The prevalence for BFLS is unknown, it was first described by M. Borjeson, H. Forssman, and O. Lehmann in 1962 and since approximately 50 patients have been reported from 24 families and other isolated cases where the etiology is unknown. The most helpful clinical diagnostic features of BFLS are the long, fleshy earlobes; shortened, abnormal toes; tapered, malleable fingers, gynaecomastia, moderate obesity in adolescence, and underdeveloped, external genitalia. BFLS is suspected on clinical examination when the characteristic symptoms are present. Another strong indicator of BFLS is a family history showing X-linked recessive inheritance as well as skewed X-chromosome inactivation. X- Chromosome inactivation is the process by which a cell recognizes the presence of two copies of an X-chromosome early in development of XX embryos and chooses one to be active and one to be inactive. X-Chromosome inactivation is thought to explain the rare occurrence of symptomatic females. There is no specific treatment for BFLS. Special education is required from early life and adults require a variable degree of supervision. Symptomatic treatment may be needed for seizures, Perthes disease, and hearing impairment. BFLS is not life threatening but due to the intellectual disability encountered, quality of life is limited.

Signs and Symptoms

BFLS is usually fully expressed in males but females who carry the disease gene may develop some symptoms of the disorder such as moderate intellectual disability and physical manifestation particularly shortened toes, thickened, fleshy ear lobes, pronounced supraorbital ridges, and deep-set eyes. The degree to which BFLS males are affected, both physically and developmentally, differ widely from person to person and even in individuals of the same family. While it is possible to characterize BFLS in males with certain body types and physical characteristics, that in itself should not be the method of identification as to whether or not an individual has BFLS. Molecular testing for a PHF6 mutation can confirm a diagnosis and is strengthened if there are other boys or men in the same family with the syndrome.

Physical

Pregnancy, delivery, and birth weight are normal. Small genitalia and large ears may be evident at birth and many infants have generalized hypotonia and poor feeding which may result in a failure to thrive. Truncal obesity typically emerges in late childhood and gynaecomastia in adolescence. Diabetes has also occurred in some adults with BFLS.

In BFLS, the head circumference is usually normal but macrocephaly and microcephaly may occur in some cases. Distinctive facial features include large ears with fleshy lobes, deep-set eyes, deep ridges above the eyes, and thickened connective tissue of the face, these coarse facial features becomes more pronounced in adulthood. The syndrome is also associated with impaired vision and wandering, jerky eye movements, which can lead to vision problems such as farsightedness and cataracts. The genitalia remain small and most individuals with BFLS have reduced function of the testes or ovaries (hypogonadism). The failure of the testes to produce hormones may cause growth deficiencies resulting in short stature and delay in sexual development. Short stature is typically common among patients with BFLS, but some do reach normal height. In some boys the testicles do not descend into the scrotum, a condition called cryptorchidism. After puberty, some males may develop abnormally enlarged breasts (gynecomastia).

Photographs of affected males with BFLS

The fingers are typically tapered and malleable. The feet are broad with foreshortened, often fixed, toes. In some cases, skeletal abnormalities such as scoliosis or kyphosis have also been observed. Less common findings among patients with BFLS include mild generalized polyneuropathy, epilepsy, Perthes disease, hearing impairment, cleft lip and palate and hypopituitarism.

Cognitive and Developmental

Most male cases of BFLS are characterized by a intellectual disorder of varying severity. As affected children age, they may experience delays in reaching developmental milestones. Motor development is delayed and affected boys usually do not learn to walk until between the ages of four and six.

Intellectual disability can range from mild to severe and is not progressive. These individuals require more time to understand and learn new skills. They may also have difficulties organizing new information, adapting to new situations, and have trouble seeing how things or events relate to each other, thus expressing their will, thoughts, or emotions may take longer than for other children. The development of speech, language, and communication is delayed and may remain under-developed . Patients with BFLS are usually sociable and friendly but some experience anxiety, depression, and challenging or hypersexual behavior.

Mechanism

BFLS is inherited and is caused by a mutation in the PHF6 gene, located on the X chromosome (Xq26-28). This gene is a member of the plant homeodomain (PHD)- like finger (PHF) family and was first discovered mutated in patients with BFLS. Mutations in the PHF6 gene have since been associated with T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). The PHF6 gene encodes for PHF6, a relatively small protein of 365 amino acids which contain two similar PHD zinc finger domains. Similar PHD fingers are found in proteins involved in regulation of transcription function. Thus, it is believed the PHF6 protein may play a role in gene transcription regulation.

High levels of protein PHF6 is found in the brain, pituitary gland and the face during fetal development. Northern blot and in-situ hybridizationanalyses have revealed that PHF6 is highly expressed during embryonic, fetal, and postnatal stages of brain development and predominately present in the developing embryonic central nervous system. Thus, it appears that PHF6 may play an important role in human brain development. In children and adults, the levels of PHF6 fall, and only low levels of the protein can be identified in certain parts of the brain.

PHF6 is localized in the cell nucleus, more prominently in the nucleolus. It has been shown that PHF6 regulates cell cycle progression by suppressing ribosomal RNA synthesis in the nucleolus. It has also been suggested that PHF6 may function as an X-linked tumor suppressor gene thus believed to play a role in the pathogenesis of hematological malignancies.

Despite the fact PHF6 is implicated to play a role in regulation of transcription, neural development, and tumor suppression, very little is known regarding how PHF6 functions or its role in BFLS pathogenesis. Skewed X-inactivation is thought to explain the rare occurrence of symptomatic females. Meaning the X- chromosome in the obligate carrier which is not mutated becomes randomly inactivated thus such females have been reported with learning disabilities and some females even showed physical manifestations, particularly shortened toes, thickened, fleshy ear lobes, pronounced supraorbital ridges and deep-set eyes. Without knowing the function of PHF6, it is difficult to determine the correlation between the degree of X-inactivation skewing and the type or location of the PHF6 mutation.

Diagnosis

BFLS is suspected on clinical examination when the characteristic symptoms are present and is strongly supported when the patient’s family history is indicative of an X-linked recessive inheritance as well as skewed-X-chromosome inactivation in obligate female carriers. Most commonly, in carrier females, the DNA of their blood leukocytes is tested to determine if skewed X- inactivation is occurring. This test counts the number of leukocytes to determine if X-inactivation skewing is occurring, if for example 93% of the cells have the mutated PHF6 allele, then clearly X-inactivation is happening causing the allele with the normal gene to be inactivated.

For patients with suspected BFLS, sequence analysis is recommended as the first step in mutation identification. Sequence analysis typically consist of amplifying exons in the PHF6 gene of the patient and then using dideoxy sequencing methods to compare patients sequence to a normal reference sequence to determine if the gene is mutated. For patients in whom mutations are not identified by full gene sequencing, deletion/ duplication analysis is performed. In this case most typically a comparative genomic hybridization (CGH) array is used to compare the patients genome against reference genomes to identify genetic imbalances as a result of deletion of a segment of DNA or duplication, or the presence of an extra segment of DNA. A genetic imbalance also confirms a mutation in PHF6 gene.

In order to establish the extent of the syndrome the patient may have a MRI (Magnetic resonance imaging) and EEG (electroencephalography) examination, an eye examination, and an ENeG (electroneuronography) examination to test the functionality of the peripheral nerves. Many boys with an intellectual disorder are obese, but very few have BFLS. The most helpful clinical diagnostic features are the long, fleshy earlobes; shortened, abnormal toes; tapered, malleable fingers, gynaecomastia and moderate obesity in adolescence and underdeveloped, external genitalia. This cluster of signs occurs in 90% or more of those boys where mutations in PHF6 are found.

Differential Diagnosis

The differential diagnosis for BFLS includes Coffin-Lowry syndrome (CFS), Klinefelter syndrome, Prader-Willi syndrome, Bardet-Biedl syndrome, or Wilson-Turner syndrome (WTS). In Coffin-Lowry syndrome (CFS), the characteristic hypertelorism, down slanting eyes, short nose and thick lips are missing in comparison to patients with BFLS. The characteristic large ears of patients with BFLS are not seen in cases with CFS and the intellectual deficit is much more severe with patients with CLS. Patients with Klinefelter syndrome lack the tapered fingers and short toes that are characteristic of patients with BFLS. Also patients with Klinefelter syndrome have an abnormal karyotype, which is caused by an additional X chromosome in males with the syndrome. Prader-Willi syndrome has some resemblances to BFLS but neonatal hypotonia and feeding problems are much more severe, obesity is more extreme, and characteristic finger and toes are lacking. The main differential difference between BFLS and Wilson-Turner syndrome (WTS) are the characteristic facial features of BFLS that are lacking in patients with WTS and the genitals are of normal size in these patients. Female carriers of BFLS with skewed X-inactivation, are often misdiagnosed for CLS or pseudohypoparathyroidism.

At the time of diagnosis, genetic counseling is available to explain X-linkage to families and identify female carriers. Very few patients with BFLS reproduce, but asymptomatic female carriers can pass on the mutation to their children. When a PHF6 mutation is known to exist in a parent, antenatal diagnosis is possible.

Treatment and Prognosis

There is no current cure for BFLS. The treatment is therefore directed at managing the symptoms and compensating for functional limitations. Special education is required from early life and followed throughout adolescence and adulthood. Adults require variable degree of supervision which may include institutionalization in severe cases.

Epilepsy is treated with antiepileptic drugs to prevent seizures. In some cases, bilateral mastectomy and/ or testosterone replacement therapy may be considered for the treatment of gynecomastia. In boys whose testicles have not descended into the scrotum, would require early surgical intervention.

Boys should have their vision, and their need for vision aids, assessed by an ophthalmologist at an early stage. Individuals with impaired vision, with the help of a specialist, should learn to make full use of their vision and learn techniques to help compensate for visual impairments. As hearing may be impaired, these children should be evaluated by an otologist. It is important to work with the child’s speech, language, and communication as well as offering other forms of support including augmentative and alternative communication (AAC), a term for forms of communication not based on speech.

Symptomatic treatment of Perthes disease typically requires periods of immobilization or limitations of usual activities. Since a cleft lip can cause feeding problems, a thorough examination of the palate and palatal function should be carried out at an early stage. Clefting would require surgical repair. Parents of children who have problems sucking and eating require early contact with a dietitian to establish good feeding routines.

A social network is important for patients with BFLS, as these patients benefit from strong social relationships. A neuropsychiatric examination should be carried out to assess behavioral abnormalities. A neurological examination is included in this investigation and is important for estimating levels of intellectual disability. Early developmental intervention is important in ensuring that affected children with BFLS reach their potential. BFLS is not life threatening but due to the intellectual disability encountered, quality of life is limited and lifelong supervision is often required.

Recent Studies

Researchers from a recent study published in the Journal of Pediatrics wanted to determine if distinct behavioral phenotypes exist among patients with BFLS in comparison to other syndromes. The study compared BFLS behavioral features with other age-matched men through the use of standardized questionnaires: the Child Behavior Checklist, the Vineland Adaptive Behavior Scale, and Reiss Personality profile. Participants included 10 patients with BFLS, 10 with Prader- Willi syndrome, and 23 with Klinefelter syndrome variants. The study showed men with BFLS had higher daily living and social skills but lower communicative skills. Despite the weakness with communicative skills, men with BFLS had many positive attributes in their personality style, as seen in their desire to help and interact with others, a trait not noted among men with Prader-Willi syndrome or Klinefelter syndrome variants. Also in comparison to the other men, men with BFLS showed low risk of delinquency or aggressive behaviors. Although the sample size in this study was a limitation, using behavioral phenotypes may help in the future with differential diagnosis.

The PHF6 gene is mutated in BFLS and adult acute myeloid and T-cell acute lymphoblastic leukemias. There are no clinical trials for possible treatments at this time for patients with BFLS. There has been more recent attention on determining the function of the PHF6 gene to provide clinical relevance in prevention of the diseases associated with the mutation of PHF6. In a 2013 study published in Neuron, Chi Zhang et al. knocked down the expression of the PHF6 gene in mice and determined that the loss of PHF6 impaired neuronal migration in the mouse cerebral cortex, which lead to the formation of white matter heterotopia accompanied by unusual neuronal activity patterns of hyperexcitability. They also found that PHF6 physically associates with the PAF-1 transcription elongation complex, and that this PAF-1 complex is required for neural migration. Regulation of transcriptional elongation is a fundamental aspect of gene expression control, thus their findings suggest that the control of transcriptional elongation may represent a critical point of regulation in neuronal migration, with relevance to intellectual disability and epilepsy.

In a more recent study, another group of researchers, Krunze et al. showed in vitro using formalin-fixed, paraffin-embedded (FFPE) bone marrow biopsy (BMB) tissue that a mutation in the gene, JAK3 and a microdeletion in the Xq26.3 gene caused the loss of PHF6. Interesting enough, it has also been shown that PHF6 may function as an X-linked tumor suppressor gene. Researchers continue to search for a mechanism of how PHF6 functions as a tumor suppressor. A recent study by Wang et al. showed that the knocked down of PHF6 leads to increased DNA damage at the ribosomal DNA (rDNA) locus. DNA damage in PHF6 deficient cells could eventually result in genomic instability and contribute to tumorigenesis.