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Ehlers-Danlos Syndrome, Kyphoscoliotic Type

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DISEASE CARD

Disease group Connective tissue disorders
DISEASE NAME EHLERS-DANLOS SYNDROME, KYPHOSCOLIOTIC TYPE
Synonymous EDS kyphoscoliotic type, Ehlers-Danlos syndrome oculo-scoliotic type, Ehlers-Danlos Syndrome Type VIA
Estimated prevalence -
OMIM 225400, 614557
Inheritance Autosomal recessive
Gene (s) PLOD 1 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 or lysyl hydroxylase 1) (153454); FKBP14 (614505)

Definition

Kyphoscoliotic EDS (kEDS) is an autosomal recessive connective tissue disorder with the hallmarks of kyphoscoliosis, joint laxity, muscle hypotonia, and, in some individuals, ocular problems. It is caused by mutations in the PLOD1 gene, with deficient activity of the enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1: lysyl hydroxylase 1). An overlapping phenotype is associated with FKBP14 mutations.

 

Clinical Description

The disorder is characterized by neonatal muscle hypotonia and joint hyperlaxity, which may cause delay in gross motor development of varying severity as well as feeding problems. Thoracic kyphoscoliosis is commonly present at birth or may develop within the first year of life. Muscular hypotonia with resulting ligamentous laxity is the suggested cause, as vertebral bodies are inconspicuous. Kyphoscoliosis is usually progressive and adults with severe kyphoscoliosis are at risk for complications from restrictive lung disease and recurrent pneumonia. Other skeletal manifestations include clubfoot, recurrent joint dislocations, a marfanoid habitus and osteoporosis.
Ocular/scleral fragility with rupture of the globe and retinal detachment is present in a minority of affected patients. High myopia however is common, and most individuals have microcornea. Some individuals have glaucoma and/or retinal detachment.
Mitral valve prolapse is common. Moreover patients are at risk for arterial rupture of medium-sized arteries or aorta dilatation and dissection as well as gastrointestinal ruptures. Other features include tissue fragility, skin hyperextensibility, atrophic scarring and easy bruising.1-3

Patients with mutations in FKBP14 display a similar phenotype with kyphoscoliosis (progressive or non‐progressive), severe congenital muscle hypotonia with muscle atrophy, joint hypermobility, and congenital hearing loss (sensorineural, conductive, or mixed) in most patients. The skin is frequently soft, hyperextensible. Follicular hyperkeratosis has been described.1-3

 

Clinical Diagnostic Criteria

Major criteria:

  1. Congenital muscle hypotonia
  2. Congenital or early onset kypho‐scoliosis (progressive or non‐progressive)
  3. Generalized joint hypermobility with dislocations/subluxations (shoulders, hips, and knees in particular)

Minor criteria:

  1. Skin hyperextensibility
  2. Easy bruisable skin
  3. Rupture/aneurysm of a medium‐sized artery
  4. Osteopenia/osteoporosis
  5. Blue sclerae
  6. Hernia (umbilical or inguinal)
  7. Pectus deformity
  8. Marfanoid habitus
  9. Talipes equinovarus
  10. Refractive errors (myopia, hypermetropia)

Gene‐specific minor criteria

  1. PLOD1: Skin fragility (easy bruising, friable skin, poor wound healing), widened atrophic scarring; Scleral and ocular fragility/rupture; Microcornea; Facial dysmorphology
  2. FKBP14: Congenital hearing impairment (sensorineural, conductive, or mixed); Follicular hyperkeratosis; Muscle atrophy; Bladder diverticula

Minimal criteria suggestive for kEDS:

I. and II. plus either III. and/or three minor criteria (either general or gene-specific criteria).

Confirmatory molecular testing is obligatory to reach a final diagnosis.

 

Pathogenesis

Deficiency of the enzyme procollagen-lysine 2-oxoglutarate 5 dioxygenase-1 (lysyl hydroxylase-1, PLOD1), a posttranslational modifying enzyme in collagen biosynthesis, is a cause of kEDS. This enzyme is required for the hydroxylation of specific collagen lysines to produce hydroxylysines that act as precursors for the crosslinking process essential for the strength of collagen. Deficiency of this enzyme causes reduced hydroxylysine-based pyridinoline cross-links in types I and III collagen and consequent mechanical instability of the affected tissues.4

FKBP14 encodes FKBP22, a member of the F506‐binding family of peptidyl‐prolyl cis–trans isomerases expressed in the lumen of the endoplasmic reticulum. FKBP22 preferentially binds to collagen III, IV, VI and X, catalyzes the folding of collagen III and acts as a molecular chaperone for collagen III. Deficiency of FKBP22 was shown to result in an altered assembly of the ECM.5, 6

Diagnosis

The diagnosis of kEDS, kyphoscoliotic form relies upon clinical evaluation.
It can be confirmed by the demonstration of an increased ratio of deoxypyridinoline to pyridinoline crosslinks in urine measured by high-performance liquid chromatography (HPLC), a highly sensitive and specific test. Molecular genetic testing of the PLOD1 gene (or FKBP14 gene if myopathy, hearing loss and normal lysyl hydroxylase enzyme activity is present) is obligatory to reach a final diagnosis.7

 

Treatment

See article "Ehlers-Danlos-Syndrome"

Affected individuals should be referred to an orthopaedic surgeon for management and follow-up of their kyphoscoliosis. Orthopaedic surgery is not contraindicated and should be performed as necessary.
In children with severe muscle hypotonia physical therapy evaluation is necessary in order to develop a plan for ongoing therapy to strengthen large muscle groups and prevent recurrent dislocations.
A baseline echocardiogram with aortic diameter measurement is recommended prior to the age of 10 years with follow-up studies timed according to whether an abnormal measurement is found. Patients with mitral valve prolapse require antibiotic prophylaxis for bacterial endocarditis. Aggressive control of the blood pressure in order to reduce the risk of arterial rupture is mandatory. Routine ophthalmological examination for management of myopia and early detection of glaucoma is necessary.

 

 

References

1. Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):8-26.

2. Brady AF, Demirdas S, Fournel-Gigleux S, Ghali N, Giunta C, Kapferer-Seebacher I, et al. The Ehlers-Danlos syndromes, rare types. Am J Med Genet C Semin Med Genet. 2017;175(1):70-115.

3. Henneton P, Legrand A, Giunta C, Frank M. Arterial fragility in kyphoscoliotic Ehlers-Danlos syndrome. BMJ Case Rep. 2018;2018.

4. Rohrbach M, Vandersteen A, Yiş U, Serdaroglu G, Ataman E, Chopra M, et al. Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation. Orphanet J Rare Dis. 2011;6:46.

5. Ishikawa Y, Mizuno N, Holden P, Lim PJ, Gould DB, Rohrbach M, et al. The novel missense mutation Met48Lys in FKBP22 changes its structure and functions. Sci Rep. 2020;10(1):497.

6. Ishikawa Y, Bächinger HP. A substrate preference for the rough endoplasmic reticulum resident protein FKBP22 during collagen biosynthesis. J Biol Chem. 2014;289(26):18189-18201.

7. Baumann M, Giunta C, Krabichler B, Rüschendorf F, Zoppi N, Colombi M, et al. Mutations in FKBP14 cause a variant of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss. Am J Hum Genet. 2012;90(2):201-216.