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FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome

Synonym: kEDS-FKBP14

, PhD, , MD, PhD, , MD, and , MD.

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Estimated reading time: 17 minutes

Summary

Clinical characteristics.

FKBP14 kyphoscoliotic Ehlers-Danlos syndrome (FKBP14-kEDS) is characterized by congenital muscle hypotonia and weakness (typically improving during childhood), progressive scoliosis, joint hypermobility, hyperelastic skin, gross motor developmental delay, myopathy, and hearing impairment. Most affected children achieve independent walking between ages two and four years. A decline of motor function in adulthood may be seen, but affected individuals are likely to be able to participate in activities of daily living in adulthood and maintain independent walking. Occasional features underlying systemic connective tissue involvement include aortic rupture and arterial dissection, subdural hygroma, insufficiency of cardiac valves, bluish sclerae, bladder diverticula, inguinal or umbilical herniae, and premature rupture of membranes during pregnancy. Rarer findings may include bifid uvula with submucous or frank cleft palate, speech/language delay without true cognitive impairment, and rectal prolapse.

Diagnosis/testing.

Clinical diagnostic criteria rely on the finding of congenital muscular hypotonia AND congenital or early-onset kyphoscoliosis in addition to generalized joint hypermobility or further gene-specific and/or supportive clinical features. The diagnosis of FKBP14-kEDS is established in a proband by the identification of biallelic pathogenic variants in FKBP14 by molecular genetic testing.

Management.

Treatment of manifestations: In those with aortic dilation or vascular dissection, use of beta blockers may be considered; physical and occupational therapy to address age-dependent decline in muscular strength; standard treatment for severe scoliosis, clubbed foot, osteopenia/osteoporosis, refractive error, hearing impairment, and cleft palate.

Surveillance: Blood pressure measurement at each visit; neurodevelopmental assessment at each visit until adolescence; evaluation by an orthopedic physician as clinically indicated but typically at least annually; periodic ophthalmology and hearing evaluations (e.g., every 2-3 years); DEXA scan, echocardiogram with consideration of cardiac MRI, and vascular ultrasonography every 2-5 years.

Agents/circumstances to avoid: Sports that place stress on the joints; contact sports in those with an aortic aneurysm; hypertension.

Pregnancy management: An increased risk for miscarriage, premature rupture of membranes, and rupture of arteries in affected pregnant women should be considered. Delivery in a medical center with a high-risk perinatologist in attendance is recommended.

Genetic counseling.

FKBP14-kEDS is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if both FKBP14 pathogenic variants have been identified in a family.

Diagnosis

Formal clinical diagnostic criteria for FKBP14 Kyphoscoliotic Ehlers-Danlos syndrome (FKBP14-kEDS) were established in the 2017 revised Ehlers-Danlos syndrome (EDS) nosology [Malfait et al 2017]; see Establishing the Diagnosis.

Suggestive Findings

FKBP14 kyphoscoliotic Ehlers-Danlos syndrome (FKBP14-kEDS) should be suspected in individuals with kyphoscoliosis, severe congenital muscle hypotonia, and joint hypermobility

Major and minor clinical features of FKBP14 kyphoscoliotic EDS have been outlined as follows (adapted from Malfait et al [2017] and Giunta et al [2018b]).

Major clinical features

  • Congenital muscular hypotonia
  • Congenital or early onset kyphoscoliosis
  • Generalized joint hypermobility

Gene-specific minor features

  • Early onset sensorineural, conductive or mixed hearing impairment (see Clinical Description)
  • Muscle atrophy
  • Follicular hyperkeratosis
  • Bladder diverticula

Other suggestive findings

  • Marfanoid habitus
  • Pectus deformity
  • Talipes equinovarus
  • Skin hyperextensibility
  • Easily bruisable skin
  • Hernia (umbilical or inguinal)
  • Rupture/aneurysm of a medium-sized artery
  • Blue sclerae
  • Refractive errors (myopia, hypermetropia)
  • Osteopenia/osteoporosis

Supportive laboratory findings

  • Normal or only slightly elevated serum creatine kinase (CK) level
  • Histopathology of muscle biopsies showing nonspecific mild myopathic changes with increased variation in muscle fiber diameter to more pronounced changes with profound fiber atrophy and proliferation of fatty tissue

Note: At the moment, muscle biopsy is not required to make the diagnosis of FKBP14-kEDS.

Supportive imaging findings. MRI of the lower limbs that may demonstrate fatty degeneration of multiple muscle groups, including rectus femoris and soleus

Establishing the Diagnosis

Proposed minimal clinical diagnostic criteria for FKBP14-kEDS include the following [Malfait et al 2017]:

  • Congenital muscular hypotonia AND congenital or early-onset kyphoscoliosis; PLUS
  • Either or both of the following:
    • Generalized joint hypermobility
    • Three minor criteria (from either Gene-specific minor features or Other suggestive findings)

However, the diagnosis of FKBP14-kEDS is established in a proband by identification of biallelic pathogenic variants in FKBP14 by molecular genetic testing (see Table 1).

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of FKBP14-kEDS is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited generalized connective tissue disorders are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic findings suggest the diagnosis of FKBP14-kEDS molecular genetic testing is indicated. Molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of FKBP14 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.
    Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
    Note: A common c.362dupC variant accounts for approximately 70% of disease alleles [Baumann et al 2012, Giunta et al 2018b].
  • A connective tissue disorder multigene panel that includes FKBP14 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited connective tissue disorders, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

Exome array (when clinically available) may be considered if exome sequencing is non-diagnostic.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome

Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method
FKBP14Sequence analysis 324/24 4, 5
Gene-targeted deletion/duplication analysis 6Unknown 7
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

A common pathogenic variant (c.362dupC) has been reported; see Table 6.

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

Clinical Description

FKBP14 kyphoscoliotic Ehlers-Danlos syndrome (FKBP14-kEDS) is characterized by congenital muscle hypotonia and weakness that typically improves during childhood, progressive scoliosis, joint hypermobility, hyperelastic skin, gross motor developmental delay, myopathy, and hearing impairment [Baumann et al 2012, Giunta et al 2018a]. Occasional features underlying systemic connective tissue involvement include aortic rupture and arterial dissection, subdural hygroma (potentially due to subdural bleeding or spontaneous intracranial hypotension), insufficiency of cardiac valves, bluish sclerae, bladder diverticula, inguinal or umbilical herniae, and premature rupture of membranes during pregnancy [Murray et al 2014, Dordoni et al 2016, Giunta et al 2018a].

A range of clinical severity is observed in individuals with FKBP14-kEDS for each of the systems discussed in this section [Baumann et al 2012, Brady et al 2017, Giunta et al 2018a].

Prenatal. Pregnancy involving an affected fetus is often characterized by reduced fetal movements and an increased risk of premature rupture of membranes.

Muscular features. Individuals with FKBP14-kEDS typically present at birth with congenital hypotonia and weakness. They often show feeding problems, and some will need airway management or respiratory support. Most affected infants have poor head control. With rare exceptions, motor developmental delay and reduced motor strength are common features in childhood, although muscle weakness typically improves during childhood [Giunta et al 2018a]. Most children achieve independent walking between ages two and four years. A decline of motor function in adulthood appears to represent an age-dependent feature in the natural course of this condition, but affected individuals are likely to be able to participate in activities of daily living in adulthood and maintain independent walking.

Wider phenotypic variability of the muscular features may exist, as suggested by the presence of early-onset muscle disease with severe involvement of the lower-limb muscles in one recently described affected individual [Castori et al 2019].

Skeletal/joint features

  • Kyphoscoliosis is a hallmark of FKBP14-kEDS and is usually severe and progressive. Two thirds of affected individuals manifest kyphoscoliosis before age one year (range: birth–7 years in 15 affected individuals described by Giunta et al [2018a]). Progressive kyphoscoliosis may respond to bracing, but often surgery is needed. Severe kyphoscoliosis may lead to restrictive lung disease without need for assisted ventilation.
  • Pronounced joint hypermobility (mean value of Beighton score 8/9) is seen in 23/23 affected individuals [Giunta et al 2018a] for the small joints and 21/23 for the large joints. Joint hypermobility usually decreases with age.
    • Hypermobility may result in recurrent joint dislocations/sprains or chronic pain (5/23 affected individuals reported).
    • Foot deformities that include congenital or postural talipes and pes planus / planovalgus have been found in 23/23 of affected individuals.
  • Despite significant joint hypermobility, congenital contractures are present in up to one third of affected individuals and may impact the fingers, wrist, elbows, or knees (7/23). Congenital hip dislocation is present in 4/17 of affected individuals.
  • Fractures probably due to osteopenia/osteoporosis from immobility occurred in 3/23.
  • Atlantoaxial subluxation/instability has been reported in three individuals [Dordoni et al 2016, Giunta et al 2018a, Castori et al 2019].

Eyes. Refractive errors, myopia, and hypermetropia are moderately frequent, present in about two thirds of affected individuals. Blue sclerae are present in about one third of affected individuals.

Ears. Hearing impairment can manifest at birth, in early infancy, or even later in life [Giunta et al 2018a]. Sensorineural hearing impairment is the most frequent, present in about half of affected individuals; conductive hearing loss is present in up to one quarter. Hearing impairment (either conductive or sensorineural) may manifest later in life or remain subclinical, thus necessitating periodic investigations (see Management).

Cardiovascular. Vascular complications in adulthood and their possible occurrence in childhood suggests that cardiovascular investigations in the routine assessment and follow up of affected individuals is indicated (see Management). Cardiovascular complications can be congenital (septal defects in a minority) or acquired (usually mild mitral or pulmonary valve insufficiency or dilatation of the ascending aorta).

Additionally, artery dissections occurred in two adult individuals (internal carotid artery and celiac artery) [Murray et al 2014, Giunta et al 2018a] and a pseudoaneurysm rupture occurred in one child (hypogastric artery) [Dordoni et al 2016].

Skin and integument. All individuals described to date have had a subjective finding of soft skin texture. Hyperextensibility was found in 17/23. Atrophic and hypertrophic scarring are seen in fewer than half of affected individuals, as is easy bruising. Additional findings may include follicular hyperkeratosis and crisscross palms/soles.

Other findings

  • Inguinal and/or umbilical hernia in about half of affected individuals (11/23), sometimes with redundant umbilical skin.
  • Bifid uvula with submucous cleft palate or frank cleft palate (7/23)
  • Speech or language delay (7/20); true intellectual disability is rare and may be unrelated in children of consanguineous relationships.
  • Visceral complications, including large bladder diverticula (3/19) and (rarely) rectal prolapse.

Prognosis. It is unknown if life span in individuals with FKBP14-kEDS is reduced. One reported individual is alive at age 53 years [Giunta et al 2018a], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

Genotype-phenotype correlations that predict risk for specific complications or clinical severity have not been reported to date.

Pathophysiology

The pathomechanism of FKBP14-kEDS is only partially understood [Baumann et al 2012]. Pathology findings include the following:

  • Normal collagen biosynthesis and secretion of collagen types I, III, and V
  • Disarray of the main components of the extracellular matrix (i.e., collagen type I, III, and VI; fibronectin; tenascins; thrombospondin) by indirect immunofluorescence on skin fibroblast from affected individuals
    Type V collagen is organized in an extracellular network that is similar to control fibroblasts.
  • Loss of the main receptors of collagens and fibronectin, α2β1 and α5β1 integrins.
  • Marked enlargement of the ER cisterns with accumulation of flocculent material in skin cells of affected individuals by transmission electron microscopy

See also Molecular Pathogenesis.

Nomenclature

FKBP14-kEDS was initially referred to as a variant of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss. Since the development of the 2017 EDS Nosology [Malfait et al 2017], it is known as kEDS-FKBP14, FKBP14-kEDS, and FKBP14-related kEDS.

Prevalence

FKBP14-kEDS is rare; the exact prevalence is unknown. From its first description in 2012, 30 individuals are known to the Authors at the time of review (2019). A disease incidence of approximately 1:100,000 live births is a reasonable estimate. Prevalence does not vary by race or ethnicity.

Differential Diagnosis

Table 2.

Disorders to Consider in the Differential Diagnosis of FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome

Differential Diagnosis DisorderGene(s)MOIClinical Features of Differential Diagnosis Disorder
Overlapping w/FKBP14-kEDSDistinguishing from FKBP14-kEDS
PLOD1 kyphoscoliotic EDSPLOD1AR
  • Congenital muscular hypotonia
  • Congenital/early onset kyphoscoliosis
  • Generalized joint hypermobility
  • Absence of hearing impairment
  • ↑ ratio of urinary pyridinolines
Musculocontractural EDS
(OMIM 601776, 615539)
CHST14
DSE
ARJoint hypermobility
  • Characteristic craniofacial features
  • Peculiar fingers (tapering, slender, cylindric)
Collagen type VI-related disordersCOL6A1
COL6A2
COL6A3
AD
AR
  • Congenital muscular hypotonia
  • Progressive kyphoscoliosis
  • Joint hypermobility
  • Follicular hyperkeratosis
  • Myopathy on muscle biopsy 1
  • Respiratory muscle failure
  • Absence of skin hyperelasticity & easy bruising
  • Absence of hearing impairment & cardiovascular problems
Spondylodysplastic EDS (spEDS)
(OMIM 130070, 612350, 615349)
B4GALT7
B3GALT6
SLC39A13
AR
  • Congenital muscular hypotonia
  • Kyphoscoliosis (B3GALT6-spEDS)
  • Joint hypermobility
  • Pectus deformities
  • Progressive short stature
  • Primary skeletal involvement
  • Dysplastic teeth
Myopathic EDS
(OMIM 616471)
COL12A1AD
AR
  • Congenital muscular hypotonia
  • Motor developmental delay
  • Soft, doughy skin
  • Muscular atrophy
  • Myopathy on muscle biopsy 1
  • Severe progressive scoliosis

AD = autosomal dominant; AR = autosomal recessive; EDS = Ehlers-Danlos syndrome; MOI = mode of inheritance

1.

In Bethlem myopathy, muscle biopsies reveal myopathic or dystrophic changes. Collagen VI immunolabeling is often normal or shows only subtle alterations. Conversely, in Ulrich congenital muscular dystrophy muscle biopsies more commonly show dystrophic features with degeneration and regeneration and replacement of muscle with fat and fibrous connective tissue. Collagen VI immunolabeling from the endomysium and basal lamina ranges from absent to moderately or markedly reduced, but may be normal around the capillaries (see Collagen Type VI-Related Disorders).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with FKBP14 kyphoscoliotic Ehlers-Danlos syndrome (FKBP14-kEDS), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with FKBP14-kEDS

System/ConcernEvaluationComment
Musculoskeletal
  • Clinical & radiologic documentation of kyphoscoliosis & measurement of curvature
  • Evaluation for joint contractures & other skeletal features 1
Referral to orthopedist
Physical therapy evaluationTo develop a specific program to be followed by patient
Dual-energy X-ray absorptiometry (DEXA)In those w/frequent fractures or decreased ambulation
EyesOphthalmologic evaluationTo evaluate for refractive errors
EarsAudiology evaluationA repeat hearing evaluation is recommended even if patient had normal newborn hearing screen.
CardiovascularEchocardiography
  • To include measurement of aortic root size and assessment of heart valves
  • Cardiac & abdominal ultrasound /MRI may also be considered to monitor for aortic dilatation.
Measurement of blood pressureMaintenance of blood pressure in normal range for age recommended to reduce risk of arterial rupture
CraniofacialAssessment of the palate for submucous or frank cleftReferral to craniofacial clinic if palatal anomalies are suspected
Miscellaneous/
Other
Developmental assessmentTo include motor, speech/language evaluation, general cognitive, & vocational skills
Consultation w/clinical geneticist &/or genetic counselor
1.

Care providers should be made aware of the possibility of atlantoaxial instability; however, proactive assessment for this finding is not typically done.

Treatment of Manifestations

Table 4.

Treatment of Manifestations in Individuals with FKBP14-kEDS

Manifestation/
Concern
TreatmentConsiderations/Other
Severe scoliosisStandard treatment, ideally in multidisciplinary setting
  • Surgery may be indicated for severe scoliosis.
  • At surgery caution should be taken due to risk for vascular complications, atlantoaxial instability, & primary muscle disease.
Clubbed foot/
Foot deformity
Standard treatment, ideally in multidisciplinary settingOrthopedic shoe insoles may be beneficial for those w/foot deformity & joint instability
Osteopenia/
Osteoporosis
Standard treatment
Age-dependent muscle declinePhysiotherapy program
  • Orthopedists, rehabilitation medicine, & physical & occupational therapists can assist in recommending appropriate devices to improve joint stability.
  • Walker or wheelchair may be necessary for mobility.
Ocular refraction abnormalityStandard treatment(s) as recommended by ophthalmologist
Hearing impairmentStandard treatment, which may include use of hearing aidSee Hereditary Hearing Loss and Deafness Overview.
Aortic dilation/
Vascular dissection
Eventually, use of beta blockers in patients with aortic dilation to prevent further expansion
  • Use of beta blockers (e.g., celiprolol) may be considered based on their efficiency in vascular EDS. 1
  • Vascular surgery is extremely risky because of vascular fragility in EDS.
Cleft palateStandard treatment

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility.
  • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended for individuals who have difficulty feeding due to poor oral motor control.

Surveillance

Standardized medical surveillance guidelines for individuals with FKBP14-kEDS have not been published.

Table 5.

Recommended Surveillance for Individuals with FKBP14-kEDS

System/ConcernEvaluationFrequency
MusculoskeletalEvaluations by orthopedic physician & specialist in rehabilitation medicine for managementof kyphoscoliosis, contractures, & foot deformitiesAs clinically indicated but at least annually
DEXA scanEvery 2-5 yrs, or in those w/reduced ambulation
EyesRoutine ophthalmologic evaluationEvery 2-3 years
EarsFormal hearing evaluationEvery 2-3 years
CardiovascularBlood pressure measurement 1At each visit
  • Echocardiography w/consideration of cardiac MRI
  • Vascular ultrasonography to evaluate abdominal &peripheral arteries & veins
Every 2-5 yrs starting in early childhood
NeurodevelopmentAssessment of developmental progressAt each visit until adolescence
1.

Maintenance of blood pressure in the normal range for age is recommended to reduce the risk of arterial rupture.

Agents/Circumstances to Avoid

Avoid the following:

  • For children with severe joint hypermobility, sports that place stress on the joints
  • High blood pressure
  • For individuals with aortic aneurysm, contact sports

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and surveillance measures. Molecular genetic testing can be used if the pathogenic variants in the family are known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

No pregnancies in women with FKBP14-kEDS have been reported to date. An increased risk for miscarriage, premature rupture of membranes, and rupture of arteries in affected pregnant women should be considered. Delivery in a medical center with a high-risk perinatologist in attendance is recommended.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

FKBP14 kyphoscoliotic Ehlers-Danlos syndrome (FKBP14-kEDS) is inherited in an autosomal recessive manner.

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one FKBP14 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with FKBP14-kEDS are obligate heterozygotes (carriers) for a pathogenic variant in FKBP14.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of a FKBP14 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the FKBP14 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the FKBP14 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association Francaise des Syndrome d'Ehlers Danlos (AFSED)
    67, rue Jules Lecesne
    Le Havre 76600
    France
    Phone: 0820 20 37 33
    Email: contact@afsed.com
  • Ehlers-Danlos Society - Europe
    35-37 Ludgate Hill
    Office 7
    London EC4M 7JN
    United Kingdom
    Phone: +44 203 887 6132
  • Ehlers-Danlos Society Headquarters
    P.O. Box 87463
    Montgomery Village MD 20886
    Phone: 410-670-7577
    Email: info@ehlers-danlos.com
  • Ehlers-Danlos Support Group
    PO Box 337
    Aldershot Surrey GU12 6WZ
    United Kingdom
    Phone: 01252 690940
    Email: director@ehlers-danlos.org
  • Ehlers-Danlos Support UK
    PO Box 748
    Borehamwood WD6 9HU
    United Kingdom
    Phone: 0208 736 5604; 0800 9078518
  • Medline Plus
  • National Library of Medicine Genetics Home Reference
  • Ehlers-Danlos Society EDS & Related Disorders Global Registry

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome (View All in OMIM)

614505FK506-BINDING PROTEIN 14; FKBP14
614557EHLERS-DANLOS SYNDROME, KYPHOSCOLIOTIC TYPE, 2; EDSKSCL2

Molecular Pathogenesis

FKBP14 (transcript variant 1) encodes a 211-amino acid FKBP22 (alias FKBP14) protein, which contains a signal peptide of 18 residues and forms a dimer of identical subunits [Boudko et al 2014]. The protein consists of three domains:

  • The PPIase catalytic domain (aa 45-135)
  • The first EF-hand1 domain (aa 135-170)
  • The second EF-hand2 domain (aa 179-211)

FKBP22 is an ER resident protein that belongs to the FK506-binding protein (FKBP) class of immunophilins, which have been implicated in catalyzing cis-trans-isomerization of peptidyl-prolyl peptide bonds and are supposed to accelerate protein folding. FKBP22 catalyzes the folding of type III collagen and interacts with type III collagen, type VI collagen, and type X collagen, but not with type I collagen, type II collagen, or type V collagen [Ishikawa & Bächinger 2014]. Remarkably, pathogenic variants in type III and type VI collagens cause the vascular type of EDS (vEDS) and COL6-related muscular dystrophies, respectively. Therefore, the clinical features of vascular abnormalities and myopathy documented in the affected individuals clearly correlates with the interaction of FKBP14 with type III and VI collagens [Giunta et al 2018a] (see also Pathophysiology).

Mechanism of disease causation. The majority of FKBP14 pathogenic variants are loss-of-function variants [Baumann et al 2012, Giunta et al 2018a]. The common c.362dupC frameshift, which is found with a frequency of approximately 70%, is the most common pathogenic variant [Baumann et al 2012, Giunta et al 2018a] and has been linked to the same haplotype in all individuals tested [Murray et al 2014].

A missense variant, p.Met48Lys [Giunta et al 2018a], and an in-frame deletion, p.Glu191del [Dordoni et al 2016], have also been reported. Mapping of the missense variant p.Met48Lys onto the protein crystal structure near the potential PPIase active site of FKBP22 supports complete or partial loss of function of FKBP14 as a further disease mechanism in addition to loss of protein [Giunta et al 2018a].

Western blot analysis using a FKBP14 mouse polyclonal antibody showed deficiency of FKBP14 in two individuals with FKBP14-kEDS [Baumann et al 2012].

FKBP14-specific laboratory technical considerations. FKBP14 consists of three small exons, a rather large fourth exon, which includes the 3' UTR, and three rather large introns. Transcript variants 2 and 3 are noncoding.

Table 6.

Notable FKBP14 Pathogenic Variants

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_017946​.3
NP_060416​.1
c.573_575delp.Glu191delOnly in-frame variant reported [Dordoni et al 2016]
c.362dupCp.Glu122ArgfsTer7Common pathogenic variant [Baumann et al 2012, Dordoni et al 2016, Giunta et al 2018a, Castori et al 2019]
c.143T>Ap.Met48LysMissense change reported near PPIase active site [Giunta et al 2018a]

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

References

Literature Cited

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Chapter Notes

Revision History

  • 23 May 2019 (ma) Review posted live
  • 5 October 2018 (cg) Original submission
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