Intellectual Disability-Epilepsy-Endocrine Disorders Syndrome (BFLS)

Intellectual disability-epilepsy-endocrine disorders syndrome (BFLS) is a rare, inherited condition that mainly affects boys and sometimes girls. Children usually have delayed development and learning problems, seizures (epilepsy), and hormone problems such as small testes (hypogonadism), obesity, or growth issues. The condition is caused by changes in a gene called PHF6 on the X chromosome. Doctors manage symptoms one by one: seizure control, hormone replacement if needed, therapy for learning and behavior, and supportive care. There is no single cure yet, but early diagnosis and tailored treatment can improve skills, health, and quality of life. rarediseases.info.nih.gov+3Wiley Online Library+3Wikipedia+3

BFLS is a rare genetic condition that mainly affects brain development, learning, body growth, and hormone balance. It often starts in infancy with low muscle tone and feeding problems, and later shows up as developmental delay, intellectual disability, and sometimes seizures. Many people also develop features related to hormone (endocrine) changes, such as delayed or underactive puberty and fertility problems, and some have increased body weight. Because the responsible gene (PHF6) sits on the X chromosome, the condition is usually stronger in males, but females can be affected—especially with certain mutations or skewed X-inactivation. There is no single “cure,” but symptoms can be treated, and early therapies can improve skills and quality of life. rarediseases.info.nih.gov+1

BFLS is a rare genetic condition that mainly affects brain development, learning, body growth, and hormone balance. It often starts in infancy with low muscle tone and feeding problems, and later shows up as developmental delay, intellectual disability, and sometimes seizures. Many people also develop features related to hormone (endocrine) changes, such as delayed or underactive puberty and fertility problems, and some have increased body weight. Because the responsible gene (PHF6) sits on the X chromosome, the condition is usually stronger in males, but females can be affected—especially with certain mutations or skewed X-inactivation. There is no single “cure,” but symptoms can be treated, and early therapies can improve skills and quality of life. rarediseases.info.nih.gov+1

Another names

• Börjeson–Forssman–Lehmann syndrome (BFLS)

• Intellectual disability-epilepsy-endocrine disorders syndrome (historic/alternative name)

• X-linked intellectual disability syndrome due to PHF6 variants

• BFLS due to PHF6 mutation
  These names refer to the same disorder described across decades as the link between learning challenges, seizures, and endocrine features became clear. PubMed+1

Types

1. Classic BFLS in males – the pattern most often described: intellectual disability, possible seizures, truncal obesity, and hypogonadism (puberty/testicular under-function). Orpha

2. BFLS in females – typically milder but variable; can include learning problems, facial features, and endocrine findings; phenotype partly influenced by X-inactivation. PMC+1

3. De novo variant BFLS – appears in a child without family history due to a new PHF6 change. Nature

4. Truncating/deletion variant BFLS – nonsense/frameshift or multi-exon deletions; often more severe. PMC+1

5. Missense variant BFLS – single-amino-acid changes; severity varies by location/effect on PHF6. PMC

Causes

1. Pathogenic variants in PHF6 – the core cause of BFLS. PMC

2. X-linked inheritance – transmission through the X chromosome explains the male predominance. rarediseases.info.nih.gov

3. De novo mutations – new variants arise in the egg/sperm or early embryo. Nature

4. Truncating variants (nonsense/frameshift) – often disrupt protein function more strongly. PMC

5. Exonic deletions/whole-gene deletions – remove essential parts of PHF6. PLOS

6. Missense variants affecting functional domains – alter protein interactions. ScienceDirect

7. Skewed X-inactivation in females – can unmask or lessen symptoms. Haematologica

8. Mosaicism – variant present in a fraction of cells may modify severity (reported across X-linked disorders). PMC

9. Neuronal migration effects – PHF6 is important for cortical neuron positioning; disruption contributes to neurodevelopmental features. PMC

10. Chromatin/transcription dysregulation – PHF6 participates in chromatin regulation; altered gene expression affects brain and endocrine development. PMC

11. Pituitary developmental expression of PHF6 – helps explain endocrine involvement. Wikipedia

12. Epigenetic modifiers – background epigenetic differences can shape phenotype (general principle in monogenic NDDs). PMC

13. Other genetic background – co-existing variants may influence seizures or endocrine traits. Cambridge University Press & Assessment

14. Puberty/sex-hormone shifts – hormonal windows can reveal endocrine deficits and affect seizures. Frontiers

15. Nutritional status and obesity – weight and metabolic changes can magnify endocrine problems. Orpha

16. Sleep disturbance – common in neurodevelopmental syndromes; may worsen seizures/behavior. intellectualdisability.info

17. Intercurrent illness/fever – can precipitate seizures in susceptible children. (General epilepsy principle.) intellectualdisability.info

18. Medication interactions – some drugs lower seizure threshold or affect hormones. (General endocrine–neurology interface.) PMC

19. Endocrine abnormalities themselves – thyroid, adrenal, or gonadal problems can influence neurologic symptoms. PMC

20. Age-related changes – features may evolve from infancy to adulthood, shaping the clinical picture over time. National Organization for Rare Disorders

Symptoms

1. Developmental delay – later sitting, crawling, walking, and talking than peers. rarediseases.info.nih.gov

2. Intellectual disability – learning and problem-solving challenges of variable degree. Orpha

3. Seizures (epilepsy) – some have focal or generalized seizures; risk varies. PLOS

4. Low muscle tone (hypotonia) – “floppy” feel in infancy; can delay motor skills. Wikipedia

5. Endocrine issues (hypogonadism/delayed puberty) – under-function of testes/ovaries or delayed sexual development. rarediseases.info.nih.gov

6. Obesity or increased body weight – often truncal; may appear in childhood/adolescence. Orpha

7. Distinctive facial features – described in clinical series; not harmful but help recognition. Orpha

8. Short fingers/toes or tapering digits – minor skeletal differences. monarchinitiative.org

9. Learning/behavioral concerns – attention, anxiety, mood differences can occur. Wikipedia

10. Vision issues – some may develop cataracts, hyperopia, or nystagmus. Wikipedia

11. Peripheral neuropathy (less common) – numbness/weakness in nerves of arms/legs reported in some. Wikipedia

12. Sleep problems – difficulty falling or staying asleep can worsen daytime function. intellectualdisability.info

13. Feeding difficulties in infancy – poor suck/coordination early on. Wikipedia

14. Growth differences – some children have growth-hormone-axis issues. jcrpe.org

15. Variable severity in females – from subtle learning problems to more typical features. PMC

Diagnostic tests

A) Physical exam (bedside assessment)

1. General growth check – chart height/weight/BMI; look for obesity or growth delay. Helps guide nutrition and endocrine work-up. Orpha

2. Puberty staging (Tanner staging) – looks for delayed or incomplete puberty. rarediseases.info.nih.gov

3. Neurologic exam – tone, reflexes, coordination, and signs of neuropathy. Wikipedia

4. Dysmorphology exam – facial features, hands/feet (tapered digits), and other clues. Orpha

5. Developmental/behavioral screening – quick tools to flag delays and plan therapies. (Standard neurodevelopmental practice.) Cambridge University Press & Assessment

B) Manual tests (structured clinical scales)

1. Developmental quotient/cognitive testing (e.g., Bayley, WPPSI, WISC) – estimates current skills; guides special education. (Standard NDD care.) Cambridge University Press & Assessment
2. Adaptive behavior scales (e.g., Vineland) – measures daily-living skills to plan supports. (Standard NDD care.) Cambridge University Press & Assessment
3. Motor function scales (e.g., GMFM) – tracks gross motor progress and therapy needs. (Standard pediatric rehab use.) e-bnr.org
4. Feeding/oral-motor assessments – evaluates coordination and safety in infants with hypotonia. (Standard pediatric practice.) Wikipedia
   10) Sleep questionnaires/diaries – screens for sleep disorders that can worsen seizures/behavior. (Standard epilepsy/ID care.) intellectualdisability.info

C) Lab and pathological tests

1. Genetic testing for PHF6 – single-gene sequencing or exome/genome confirms BFLS. It is the key diagnostic test. PMC
2. Microarray/Copy-number analysis – detects exon/whole-gene deletions of PHF6. PLOS
3. Hormone panels – LH/FSH, testosterone or estradiol, thyroid function (TSH, free T4), adrenal tests when indicated; documents endocrine involvement. PMC
4. Metabolic screens – basic labs (glucose, lipids, liver, kidney) support obesity/metabolic care. Orpha
5. IGF-1/IGFBP-3 – in growth concerns; low values reported in epileptic cohorts with endocrine issues. seizure-journal.com

D) Electrodiagnostic tests

1. EEG (electroencephalogram) – identifies seizure type and helps select anti-seizure therapy. Wikipedia
2. Nerve conduction studies/EMG – considered if peripheral neuropathy symptoms appear. Wikipedia

E) Imaging tests

1. Brain MRI – maps structural differences related to neurodevelopment; baseline in syndromic epilepsy. PMC
2. Pituitary MRI (when indicated) – evaluates pituitary if labs suggest central endocrine issues. (Standard endocrine-neuro imaging.) PMC
3. Bone age X-ray – helps judge delayed puberty/growth patterns. (Standard pediatric endocrine tool.) PMC

Non-pharmacological treatments

1) Individualized special education
A structured education plan with speech, occupational, and physical therapy helps children build language, motor, and daily living skills. Early intervention improves outcomes in intellectual disability and syndromic epilepsies by matching teaching to the child’s pace and strengths. Family training and assistive technology (visual schedules, communication devices) support learning at home and school. OUP Academic

2) Speech-language therapy
Regular sessions focus on expressive and receptive language, social communication, and feeding/swallowing if hypotonia is present. Better communication can reduce frustration and behavior issues and improve safety. Augmentative and alternative communication (AAC) can be introduced early. OUP Academic

3) Occupational therapy (OT)
OT builds fine-motor skills, self-care (dressing, feeding, toileting), and sensory processing. Sensory-based strategies and environmental adaptations improve attention and participation in school and daily life. OUP Academic

4) Physical therapy (PT)
PT targets hypotonia, balance, coordination, and gait. Strengthening and task-specific practice can improve mobility and reduce falls. Home exercise plans maintain gains between visits. OUP Academic

5) Behavioral therapy (e.g., parent-mediated CBT/ABA techniques)
Structured behavior plans reduce self-injury, aggression, or anxiety using positive reinforcement, predictable routines, and coping skills. Tailoring plans to communication level and sensory needs is essential. OUP Academic

6) Ketogenic or modified Atkins diet (under a specialist team)
High-fat, very low-carb diets can reduce seizures in drug-resistant epilepsy. Benefits must be weighed against side effects (GI upset, kidney stones, dyslipidemia). These diets require careful monitoring, supplements, and trained clinicians. nice.org.uk+3Cochrane Library+3Cochrane+3

7) Sleep hygiene program
Fixed bed/wake times, low evening light, and calming routines help stabilise sleep, which can lower seizure risk and improve daytime behavior. If insomnia persists, clinicians may consider adjuncts like melatonin after weighing evidence and safety. Epilepsy Foundation+1

8) Seizure first-aid training for caregivers
Families learn how to position the person safely, time seizures, and use rescue plans/devices if prescribed. This reduces injury and improves response during prolonged events. Epilepsy Foundation

9) Endocrine lifestyle management
Dietary counselling and activity plans address obesity and insulin resistance associated with BFLS; bone-health guidance (calcium/vitamin D intake, weight-bearing activity) is important when antiseizure medicines affect bone metabolism. Orpha+1

10) Genetic counselling & family planning
Explains X-linked inheritance, recurrence risks, and testing options for relatives. Counselling also supports access to services and registries for rare diseases. rarediseases.info.nih.gov

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Drug treatments

(Always individualize with a pediatric neurologist/endocrinologist. Doses below are label ranges; clinicians adjust by age, weight, indication, and interactions.)

1) Levetiracetam (Keppra / XR / Spritam) — antiseizure
Class: SV2A modulator. Typical dose/time: Titrated; commonly 20–60 mg/kg/day in children divided BID; XR daily in older patients. Purpose: Reduce focal and generalized seizures. Mechanism: Modulates synaptic vesicle protein 2A, dampening hyper-synchronous firing. Side effects: Somnolence, irritability, dizziness; rare behavior change. Label variations for IV and oral forms exist. FDA Access Data+2FDA Access Data+2

2) Lamotrigine (Lamictal / XR) — antiseizure
Class: Sodium-channel blocker with glutamate modulation. Dose/time: Slow titration; pediatric doses vary; risk-minimizing schedules especially with valproate. Purpose: Focal/generalized seizures; mood benefits in some. Mechanism: Stabilizes neuronal membranes. Side effects: Boxed warning for serious rash (SJS/TEN), higher risk with valproate; dizziness, ataxia. FDA Access Data+1

3) Valproate/valproic acid (Depakene/Depacon/Stavzor) — antiseizure
Class: Broad-spectrum AED (multiple mechanisms incl. GABA). Dose/time: Weight-based; IV or oral forms. Purpose: Generalized and focal epilepsies. Mechanism: Increases GABA levels and modulates sodium/calcium channels. Side effects: Boxed warnings for hepatotoxicity, pancreatitis, teratogenicity; hyperammonemia (consider carnitine in select cases). Avoid in pregnancy if possible. FDA Access Data+2FDA Access Data+2

4) Topiramate (Topamax) — antiseizure
Class: Broad-spectrum AED (Na+ channel, GABA-A modulation, AMPA/kainate inhibition, carbonic anhydrase inhibition). Dose/time: Slow titration to effect; sprinkle capsules useful. Purpose: Focal/generalized seizures; migraine prevention. Side effects: Cognitive slowing, paresthesia, weight loss, nephrolithiasis; metabolic acidosis risk. FDA Access Data

5) Clobazam (Onfi / Sympazan) — antiseizure (LGS & adjunct)
Class: 1,5-benzodiazepine. Dose/time: Weight- and response-based; oral suspension/film options. Purpose: Adjunct for refractory seizures (e.g., Lennox-Gastaut). Side effects: Sedation, tolerance, dependence; opioid interaction warning. FDA Access Data+2FDA Access Data+2

6) Rescue benzodiazepines (e.g., diazepam nasal/rectal; midazolam nasal)
Class: Benzodiazepines. Use: Intermittent rescue for seizure clusters or prolonged seizures per plan. Mechanism: GABA-A positive modulation. Side effects: Sedation, respiratory depression if misused; follow labelled device instructions. (Label selection depends on product brand; your team chooses a specific device.) Epilepsy Foundation

7) Levothyroxine (Synthroid / others) — hormone replacement
Class: Thyroid hormone (T4). Dose/time: Daily; weight- and TSH-guided. Purpose: Treat hypothyroidism sometimes seen in related neuro-endocrine syndromes, improving energy, growth, and cognition. Side effects: Over-/under-replacement (tachycardia, bone loss vs. fatigue, weight gain). Not for weight loss. FDA Access Data+1

8) Testosterone gel (e.g., AndroGel) — hypogonadism in eligible males
Class: Androgen. Dose/time: Daily topical with strict skin-transfer precautions. Purpose: Pubertal development, bone/muscle support, sexual health when true hypogonadism is confirmed. Side effects: Secondary exposure risk (boxed warnings), acne, erythrocytosis; 2025 FDA labeling updates address CV/blood-pressure data and warnings. Use only for confirmed hypogonadism. FDA Access Data+2FDA Access Data+2

9) Somatropin (Genotropin) — growth hormone deficiency
Class: Recombinant human growth hormone. Dose/time: SC injections; dosing varies by age/indication. Purpose: Treat proven GH deficiency or syndromic short stature per label. Side effects: Edema, arthralgia, glucose intolerance; special cautions (e.g., PWS). FDA Access Data+1

10) Weight-management where indicated (Topiramate component of Qsymia)
Class: Phentermine/topiramate ER for chronic weight management in selected adolescents/adults; not a pediatric first-line in BFLS—listed here for context in severe obesity with specialist oversight. Risks: Teratogenicity, mood effects, tachycardia; strict REMS-style precautions. Use only when benefits outweigh risks. FDA Access Data

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Dietary molecular supplements

(Use only under clinician guidance; supplements can interact with ASMs.)

1) L-carnitine
In children taking valproate who develop low carnitine or high ammonia, L-carnitine may help restore mitochondrial fatty-acid transport and reduce hyperammonemia. Typical adjunct doses reported ~50 mg/kg/day (clinical judgement needed). Benefits are greatest when deficiency or VPA-related toxicity is present. PMC+2BPS Publications+2

2) Vitamin D
Long-term antiseizure therapy can lower vitamin D and harm bone health. Supplementation (e.g., 400–1000 IU/day in some pediatric studies) helps maintain sufficiency; whether it reduces seizures is uncertain, but bone protection is important. Dosing is individualized to labs and age. PMC+2PubMed+2

3) Melatonin (for sleep problems)
Adjunct melatonin improved sleep latency and night awakenings in randomized pediatric epilepsy trials, with mixed effects on seizures; doses vary (often 1–5 mg at night). Only use after sleep-hygiene steps and medical review. PubMed+1

4) Omega-3 fatty acids (EPA/DHA)
Small RCTs and recent analyses suggest possible seizure-frequency benefits at lower doses in some patients, though evidence is inconsistent. Omega-3s also support cardiometabolic health in obesity. Use standardized products and monitor for bleeding risk. PubMed+2epilepsybehavior.com+2

5) Multivitamin/mineral support on ketogenic regimens
Keto/modified Atkins often require supplements (multivitamin, selenium, magnesium, calcium) to prevent deficiencies while maintaining ketosis for seizure control. Supplement set-up belongs in a specialist keto clinic. Cochrane Library+1

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Immune-booster / regenerative / stem-cell drugs

There are no disease-modifying immune or stem-cell drugs approved specifically for BFLS. Management is symptomatic. Below are contexts where such agents appear, with careful specialist oversight:

1) Recombinant growth factors (somatropin)
When true GH deficiency is present, somatropin supports growth and body composition; this is replacement, not “boosting immunity.” Doses and monitoring follow label and endocrine norms. FDA Access Data

2) Nutritional immune support (vitamin D, omega-3)
Both have general immune and anti-inflammatory roles; in epilepsy the primary rationale is bone health and possible seizure modulation rather than direct “immune boosting.” Use is lab- and safety-guided. PMC+1

3) Investigational avenues
Gene-targeted or cell-based therapies for X-linked neurodevelopmental disorders are experimental; none are approved for PHF6/BFLS today. Families may follow registries and natural-history efforts for future trials. rarediseases.info.nih.gov

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Surgeries/procedures

1) Vagus nerve stimulation (VNS)
An implanted stimulator delivers programmed impulses to reduce seizure frequency in refractory epilepsy when drugs and diets are insufficient. It can improve alertness and recovery time after seizures for some patients. Risks include hoarseness and cough. Epilepsy Foundation

2) Corpus callosotomy
Neurosurgeons cut part of the corpus callosum to reduce drop attacks or generalized seizures that cause frequent injuries when focal resection is not an option. It’s palliative—not a cure—and selection requires epilepsy-surgery evaluation. Epilepsy Foundation

3) Cryptorchidism repair / cleft palate repair (when present)
Some individuals with BFLS need standard pediatric surgeries such as orchiopexy or palate repair to improve fertility potential, speech, feeding, and ear health. Timing and techniques follow pediatric surgical guidelines. Wikipedia

(I can add two more surgical options—e.g., focal resection/laser ablation when a resectable focus exists; deep brain stimulation of the anterior thalamus in eligible older patients—if you’d like.)

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Preventions

1. Genetic counselling before future pregnancies to explain X-linked inheritance and testing options. rarediseases.info.nih.gov

2. Early seizure control plans (regular follow-up, medication adherence, rescue protocol) to reduce status epilepticus and injuries. Epilepsy Foundation

3. Bone health precautions during long-term ASM use (optimize vitamin D/calcium, weight-bearing exercise, monitor levels). PMC

4. Weight and metabolic risk management (nutrition, activity) to counter obesity common in BFLS. Orpha

5. Sleep and illness management (good sleep hygiene, prompt treatment of fevers) to minimize seizure triggers. Epilepsy Foundation

6. Safety adaptations (helmets for drop attacks, bathroom and bed safeguards) to prevent injuries. Epilepsy Foundation

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When to see a doctor

See a clinician urgently for seizures lasting >5 minutes, clusters without recovery, new breathing problems, new weakness, sudden behavior regression, or confusion after starting a new medicine. Arrange routine visits at least every 3–6 months with neurology and endocrinology to check growth/puberty, bone health, weight, thyroid or gonadal function, and seizure control. Seek genetic counselling when planning pregnancy. Epilepsy Foundation+1

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What to eat and what to avoid

• If on ketogenic/modified Atkins: follow the clinic’s exact ratios and do not alter fat/carbs without approval; take prescribed supplements. Cochrane Library

• Everyday pattern (not on keto): balanced diet emphasizing whole foods, vegetables, fruits, lean proteins, and high-fiber carbs to support weight and energy. PMC

• Hydration: steady fluids help prevent kidney stones, especially on topiramate or keto. FDA Access Data

• Calcium/vitamin D intake: meet age-based targets to support bones (supplement if the team advises). PMC

• Limit excess caffeine/energy drinks that may worsen sleep/anxiety. Epilepsy Foundation

• Avoid alcohol in adolescents/adults; it can interact with ASMs and provoke seizures. Epilepsy Foundation

• Watch added sugars/ultra-processed foods to aid weight control. Orpha

• Consider omega-3-rich foods (fish) after checking for interactions. PubMed

• Food triggers are uncommon, but track any individual triggers with a diary. Epilepsy Foundation

• Follow all diet changes with your epilepsy/endocrine team, especially if growth or thyroid issues exist. PMC

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FAQs

1) Is there a cure for BFLS?
No single cure exists. Care focuses on seizures, hormones, learning/behavior, and general health. Research is growing, but no gene or cell therapy is approved yet. rarediseases.info.nih.gov

2) Will seizures get better with age?
Some children improve with the right combination of medicines, diet, and (sometimes) devices or surgery, but others have persistent epilepsy. Regular reviews optimize therapy. Epilepsy Foundation

3) What causes BFLS?
Pathogenic variants in PHF6 on the X chromosome. Inheritance is usually X-linked, so males are more affected; females can be affected due to skewed X-inactivation. Wikipedia+1

4) Are the endocrine problems treatable?
Yes. Endocrinologists can treat hypothyroidism with levothyroxine, hypogonadism with carefully supervised testosterone in eligible males, and growth failure with GH when indicated. FDA Access Data+2FDA Access Data+2

5) Are ketogenic diets safe?
They can work for drug-resistant epilepsy but require expert clinics, labs, supplements, and side-effect monitoring. They are not general weight-loss diets. Cochrane Library+1

6) Which antiseizure drug is “best”?
There is no single “best.” Choice depends on seizure type, age, comorbidities, side-effect profiles, and interactions. Common first-line options include levetiracetam, lamotrigine, valproate, and topiramate. FDA Access Data+3FDA Access Data+3FDA Access Data+3

7) Do ASMs affect hormones or bones?
Some ASMs interact with vitamin D and bone metabolism; long-term plans should include bone-health monitoring and supplementation when indicated. PMC+1

8) Where can families learn more or join a registry?
Rare-disease portals (NORD, Orphanet) provide overviews and links to support groups and research updates. rarediseases.info.nih.gov+1

Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical  history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.

The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members

Last Updated: October 30, 2025.