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Borjeson-Forssman-Lehmann syndrome(BFLS)

MedGen UID:
78557
Concept ID:
C0265339
Disease or Syndrome
Synonyms: BFLS; Borjeson Syndrome; Mental deficiency, epilepsy and endocrine disorders; MENTAL RETARDATION, EPILEPSY, AND ENDOCRINE DISORDERS; MENTAL RETARDATION, X-LINKED, SYNDROMIC, BORJESON-FORSSMAN-LEHMANN TYPE
SNOMED CT: Borjeson syndrome (21634003); Borjeson-Forssman-Lehmann syndrome (21634003)
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Source: Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
 
Gene (location): PHF6 (Xq26.2)
 
Monarch Initiative: MONDO:0010537
OMIM®: 301900
Orphanet: ORPHA127

Definition

Borjeson-Forssman-Lehmann syndrome (BFLS) is an uncommon X-linked intellectual developmental disorder that evolves with age. Clinical manifestations in males are quite variable, with the most consistent features being initial hypotonia, mild to moderate impaired intellectual development, large fleshy ears, underdeveloped genitalia, gynecomastia, truncal obesity, tapering fingers, and shortening of the fourth and fifth toes. Heterozygous females may have a milder similar clinical phenotype, which can include hypothyroidism; however, many carrier females appear unaffected (summary by Crawford et al., 2006). [from OMIM]

Clinical features

From HPO
Cryptorchidism
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Hypoplasia of the prostate
MedGen UID:
337120
Concept ID:
C1844923
Finding
Micropenis
MedGen UID:
1633603
Concept ID:
C4551492
Congenital Abnormality
Abnormally small penis. At birth, the normal penis is about 3 cm (stretched length from pubic tubercle to tip of penis) with micropenis less than 2.0-2.5 cm.
Tapered finger
MedGen UID:
98098
Concept ID:
C0426886
Finding
The gradual reduction in girth of the finger from proximal to distal.
Short toe
MedGen UID:
322858
Concept ID:
C1836195
Finding
A toe that appears disproportionately short compared to the foot.
Shortening of all middle phalanges of the fingers
MedGen UID:
347331
Concept ID:
C1856912
Finding
Short, hypoplastic middle phalanx of finger, affecting all fingers.
Widely spaced toes
MedGen UID:
369965
Concept ID:
C1969238
Finding
An overall widening of the spaces between the digits.
Shortening of all distal phalanges of the fingers
MedGen UID:
867248
Concept ID:
C4021608
Finding
Hypoplasia of all of the distal phalanx of finger.
Obesity
MedGen UID:
18127
Concept ID:
C0028754
Disease or Syndrome
Accumulation of substantial excess body fat.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Macrotia
MedGen UID:
488785
Concept ID:
C0152421
Congenital Abnormality
Median longitudinal ear length greater than two standard deviations above the mean and median ear width greater than two standard deviations above the mean (objective); or, apparent increase in length and width of the pinna (subjective).
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
Severe mental retardation is defined as an intelligence quotient (IQ) in the range of 20-34.
EEG abnormality
MedGen UID:
56235
Concept ID:
C0151611
Finding
Abnormality observed by electroencephalogram (EEG), which is used to record of the brain's spontaneous electrical activity from multiple electrodes placed on the scalp.
Kyphosis
MedGen UID:
44042
Concept ID:
C0022821
Anatomical Abnormality
Exaggerated anterior convexity of the thoracic vertebral column.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Cervical spinal canal stenosis
MedGen UID:
335056
Concept ID:
C1844925
Finding
An abnormal narrowing of the cervical spinal canal.
Scheuermann-like vertebral changes
MedGen UID:
335057
Concept ID:
C1844926
Finding
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Thickened calvaria
MedGen UID:
346823
Concept ID:
C1858452
Finding
The presence of an abnormally thick calvaria.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Blepharophimosis
MedGen UID:
2670
Concept ID:
C0005744
Anatomical Abnormality
A fixed reduction in the vertical distance between the upper and lower eyelids with short palpebral fissures.
Prominent supraorbital ridges
MedGen UID:
333982
Concept ID:
C1842060
Finding
Greater than average forward and/or lateral protrusion of the supraorbital portion of the frontal bones.
Coarse facial features
MedGen UID:
335284
Concept ID:
C1845847
Finding
Absence of fine and sharp appearance of brows, nose, lips, mouth, and chin, usually because of rounded and heavy features or thickened skin with or without thickening of subcutaneous and bony tissues.
Narrow palpebral fissure
MedGen UID:
382506
Concept ID:
C2675021
Finding
Reduction in the vertical distance between the upper and lower eyelids.
Delayed puberty
MedGen UID:
46203
Concept ID:
C0034012
Pathologic Function
Passing the age when puberty normally occurs with no physical or hormonal signs of the onset of puberty.
Gynecomastia
MedGen UID:
6694
Concept ID:
C0018418
Disease or Syndrome
Abnormal development of large mammary glands in males resulting in breast enlargement.
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Deeply set eye
MedGen UID:
473112
Concept ID:
C0423224
Finding
An eye that is more deeply recessed into the plane of the face than is typical.
Visual impairment
MedGen UID:
777085
Concept ID:
C3665347
Finding
Visual impairment (or vision impairment) is vision loss (of a person) to such a degree as to qualify as an additional support need through a significant limitation of visual capability resulting from either disease, trauma, or congenital or degenerative conditions that cannot be corrected by conventional means, such as refractive correction, medication, or surgery.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVBorjeson-Forssman-Lehmann syndrome
Follow this link to review classifications for Borjeson-Forssman-Lehmann syndrome in Orphanet.

Recent clinical studies

Etiology

Miyake N, Tsurusaki Y, Matsumoto N
Am J Med Genet C Semin Med Genet 2014 Sep;166C(3):257-61. Epub 2014 Jul 31 doi: 10.1002/ajmg.c.31406. PMID: 25081545
de Winter CF, van Dijk F, Stolker JJ, Hennekam RC
J Intellect Disabil Res 2009 Apr;53(4):319-28. Epub 2009 Feb 2 doi: 10.1111/j.1365-2788.2009.01156.x. PMID: 19187102
Visootsak J, Rosner B, Dykens E, Schwartz C, Hahn K, White SM, Szeftel R, Graham JM
J Pediatr 2004 Dec;145(6):819-25. doi: 10.1016/j.jpeds.2004.07.041. PMID: 15580208
Ardinger HH, Hanson JW, Zellweger HU
Am J Med Genet 1984 Dec;19(4):653-64. doi: 10.1002/ajmg.1320190405. PMID: 6517094
Veall RM, Brett EM, Rivinus TM, Stephens R
J Ment Defic Res 1979 Dec;23(4):231-42. doi: 10.1111/j.1365-2788.1979.tb00858.x. PMID: 537034

Diagnosis

Vos N, Haghshenas S, van der Laan L, Russel PKM, Rooney K, Levy MA, Relator R, Kerkhof J, McConkey H, Maas SM, Vissers LELM, de Vries BBA, Pfundt R, Elting MW, van Hagen JM, Verbeek NE, Jongmans MCJ, Lakeman P, Rumping L, Bosch DGM, Vitobello A, Thauvin-Robinet C, Faivre L, Nambot S, Garde A, Willems M, Genevieve D, Nicolas G, Busa T, Toutain A, Gérard M, Bizaoui V, Isidor B, Merla G, Accadia M, Schwartz CE, Ounap K, Hoffer MJV, Nezarati MM, van den Boogaard MH, Tedder ML, Rogers C, Brusco A, Ferrero GB, Spodenkiewicz M, Sidlow R, Mussa A, Trajkova S, McCann E, Mroczkowski HJ, Jansen S, Donker-Kaat L, Duijkers FAM, Stuurman KE, Mannens MMAM, Alders M, Henneman P, White SM, Sadikovic B, van Haelst MM
Hum Genet 2024 Jun;143(6):761-773. Epub 2024 May 24 doi: 10.1007/s00439-024-02679-w. PMID: 38787418Free PMC Article
Jain V, Foo SH, Chooi S, Moss C, Goodwin R, Berland S, Clarke AJ, Davies SJ, Corrin S, Murch O, Doyle S, Graham GE, Greenhalgh L, Holder SE, Johnson D, Kumar A, Ladda RL, Sell S, Begtrup A, Lynch SA, McCann E, Østern R, Pottinger C, Splitt M, Fry AE
Eur J Hum Genet 2023 Dec;31(12):1421-1429. Epub 2023 Sep 14 doi: 10.1038/s41431-023-01447-0. PMID: 37704779Free PMC Article
Bellad A, Bandari AK, Pandey A, Girimaji SC, Muthusamy B
J Mol Neurosci 2020 Sep;70(9):1403-1409. Epub 2020 May 12 doi: 10.1007/s12031-020-01560-5. PMID: 32399860
de Winter CF, van Dijk F, Stolker JJ, Hennekam RC
J Intellect Disabil Res 2009 Apr;53(4):319-28. Epub 2009 Feb 2 doi: 10.1111/j.1365-2788.2009.01156.x. PMID: 19187102
Veall RM, Brett EM, Rivinus TM, Stephens R
J Ment Defic Res 1979 Dec;23(4):231-42. doi: 10.1111/j.1365-2788.1979.tb00858.x. PMID: 537034

Therapy

Zhang X, Fan Y, Liu X, Zhu MA, Sun Y, Yan H, He Y, Ye X, Gu X, Yu Y
J Clin Res Pediatr Endocrinol 2019 Nov 22;11(4):419-425. Epub 2019 Jan 11 doi: 10.4274/jcrpe.galenos.2019.2018.0220. PMID: 30630810Free PMC Article
Xiang J, Wang G, Xia T, Chen Z
Biomed Pharmacother 2019 Jan;109:2210-2217. Epub 2018 Nov 28 doi: 10.1016/j.biopha.2018.11.083. PMID: 30551478

Prognosis

Gerber CB, Fliedner A, Bartsch O, Berland S, Dewenter M, Haug M, Hayes I, Marin-Reina P, Mark PR, Martinez-Castellano F, Maystadt I, Karadurmus D, Steindl K, Wiesener A, Zweier M, Sticht H, Zweier C
Clin Genet 2022 Sep;102(3):182-190. Epub 2022 Jun 14 doi: 10.1111/cge.14173. PMID: 35662002Free PMC Article
Bao Y, Liu Z, Zhang J, Wu J, Shi Y
Biomol NMR Assign 2016 Apr;10(1):1-4. Epub 2015 Aug 19 doi: 10.1007/s12104-015-9627-x. PMID: 26286319
Voss AK, Gamble R, Collin C, Shoubridge C, Corbett M, Gécz J, Thomas T
Gene Expr Patterns 2007 Oct;7(8):858-71. Epub 2007 Jul 6 doi: 10.1016/j.modgep.2007.06.007. PMID: 17698420
Veall RM, Brett EM, Rivinus TM, Stephens R
J Ment Defic Res 1979 Dec;23(4):231-42. doi: 10.1111/j.1365-2788.1979.tb00858.x. PMID: 537034

Clinical prediction guides

Vos N, Haghshenas S, van der Laan L, Russel PKM, Rooney K, Levy MA, Relator R, Kerkhof J, McConkey H, Maas SM, Vissers LELM, de Vries BBA, Pfundt R, Elting MW, van Hagen JM, Verbeek NE, Jongmans MCJ, Lakeman P, Rumping L, Bosch DGM, Vitobello A, Thauvin-Robinet C, Faivre L, Nambot S, Garde A, Willems M, Genevieve D, Nicolas G, Busa T, Toutain A, Gérard M, Bizaoui V, Isidor B, Merla G, Accadia M, Schwartz CE, Ounap K, Hoffer MJV, Nezarati MM, van den Boogaard MH, Tedder ML, Rogers C, Brusco A, Ferrero GB, Spodenkiewicz M, Sidlow R, Mussa A, Trajkova S, McCann E, Mroczkowski HJ, Jansen S, Donker-Kaat L, Duijkers FAM, Stuurman KE, Mannens MMAM, Alders M, Henneman P, White SM, Sadikovic B, van Haelst MM
Hum Genet 2024 Jun;143(6):761-773. Epub 2024 May 24 doi: 10.1007/s00439-024-02679-w. PMID: 38787418Free PMC Article
Jain V, Foo SH, Chooi S, Moss C, Goodwin R, Berland S, Clarke AJ, Davies SJ, Corrin S, Murch O, Doyle S, Graham GE, Greenhalgh L, Holder SE, Johnson D, Kumar A, Ladda RL, Sell S, Begtrup A, Lynch SA, McCann E, Østern R, Pottinger C, Splitt M, Fry AE
Eur J Hum Genet 2023 Dec;31(12):1421-1429. Epub 2023 Sep 14 doi: 10.1038/s41431-023-01447-0. PMID: 37704779Free PMC Article
Gerber CB, Fliedner A, Bartsch O, Berland S, Dewenter M, Haug M, Hayes I, Marin-Reina P, Mark PR, Martinez-Castellano F, Maystadt I, Karadurmus D, Steindl K, Wiesener A, Zweier M, Sticht H, Zweier C
Clin Genet 2022 Sep;102(3):182-190. Epub 2022 Jun 14 doi: 10.1111/cge.14173. PMID: 35662002Free PMC Article
Mathews KD, Ardinger HH, Nishimura DY, Buetow KH, Murray JC, Bartley JA
Am J Med Genet 1989 Dec;34(4):470-4. doi: 10.1002/ajmg.1320340403. PMID: 2624254
Turner G, Gedeon A, Mulley J, Sutherland G, Rae J, Power K, Arthur I
Am J Med Genet 1989 Dec;34(4):463-9. doi: 10.1002/ajmg.1320340402. PMID: 2624253

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