Fkbp14 Kyphoscoliotic Ehlers-Danlos Syndrome
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 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| FKBP14 | Sequence analysis 3 | 24/24 4, 5 |
| Gene-targeted deletion/duplication analysis 6 | Unknown 7 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 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.
Baumann et al [2012], Aldeeri et al [2014], Murray et al [2014], Dordoni et al [2016], Bursztejn et al [2017], Giunta et al [2018a], Castori et al [2019]. Note: The affected individual published by Bursztejn et al [2017] was initially published by Baumann et al [2012].
- 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 individualsType 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 Disorder | Gene(s) | MOI | Clinical Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/FKBP14-kEDS | Distinguishing from FKBP14-kEDS | |||
| PLOD1 kyphoscoliotic EDS | PLOD1 | AR |
|
|
| Musculocontractural EDS (OMIM 601776, 615539) | CHST14 DSE | AR | Joint hypermobility |
|
| Collagen type VI-related disorders | COL6A1 COL6A2 COL6A3 | AD AR |
|
|
| Spondylodysplastic EDS (spEDS) (OMIM 130070, 612350, 615349) | B4GALT7 B3GALT6 SLC39A13 | AR |
|
|
| Myopathic EDS (OMIM 616471) | COL12A1 | AD AR |
|
|
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/Concern | Evaluation | Comment |
|---|---|---|
| Musculoskeletal |
| Referral to orthopedist |
| Physical therapy evaluation | To develop a specific program to be followed by patient | |
| Dual-energy X-ray absorptiometry (DEXA) | In those w/frequent fractures or decreased ambulation | |
| Eyes | Ophthalmologic evaluation | To evaluate for refractive errors |
| Ears | Audiology evaluation | A repeat hearing evaluation is recommended even if patient had normal newborn hearing screen. |
| Cardiovascular | Echocardiography |
|
| Measurement of blood pressure | Maintenance of blood pressure in normal range for age recommended to reduce risk of arterial rupture | |
| Craniofacial | Assessment of the palate for submucous or frank cleft | Referral to craniofacial clinic if palatal anomalies are suspected |
| Miscellaneous/ Other | Developmental assessment | To 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 | Treatment | Considerations/Other |
|---|---|---|
| Severe scoliosis | Standard treatment, ideally in multidisciplinary setting |
|
| Clubbed foot/ Foot deformity | Standard treatment, ideally in multidisciplinary setting | Orthopedic shoe insoles may be beneficial for those w/foot deformity & joint instability |
| Osteopenia/ Osteoporosis | Standard treatment | |
| Age-dependent muscle decline | Physiotherapy program |
|
| Ocular refraction abnormality | Standard treatment(s) as recommended by ophthalmologist | |
| Hearing impairment | Standard treatment, which may include use of hearing aid | See Hereditary Hearing Loss and Deafness Overview. |
| Aortic dilation/ Vascular dissection | Eventually, use of beta blockers in patients with aortic dilation to prevent further expansion |
|
| Cleft palate | Standard treatment |
- 1.
Ong et al [2010]
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/Concern | Evaluation | Frequency |
|---|---|---|
| Musculoskeletal | Evaluations by orthopedic physician & specialist in rehabilitation medicine for managementof kyphoscoliosis, contractures, & foot deformities | As clinically indicated but at least annually |
| DEXA scan | Every 2-5 yrs, or in those w/reduced ambulation | |
| Eyes | Routine ophthalmologic evaluation | Every 2-3 years |
| Ears | Formal hearing evaluation | Every 2-3 years |
| Cardiovascular | Blood pressure measurement 1 | At each visit |
| Every 2-5 yrs starting in early childhood | |
| Neurodevelopment |