Colagenopatías tipo 2

Fernando Santos Simarro INGEMM-Instituto de Genética Médica y Molecular

UMDE-Unidad Multidisciplinar de Displasias Esqueléticas Hospital Universitario La Paz-IdiPAZ-CIBERER

Madrid, 27 de Mayo de 2017

Colagenopatías tipo 2

• Causadas por mutaciones en heterocigosis en el gen COL2A1.

• Herencia autosómica dominante.

• Clínicamente heterogéneas (desde formas letales hasta supervivencia normal).

• Talla baja desproporcionada.

• Degeneración articular.

• Manifestaciones extra esqueléticas comunes:

• Hendidura de paladar.

• Afectación ocular (miopía, desprendimiento retina, anomalías vítreo, cataratas,…).

• Pérdida auditiva.

COL2A1 12q13.11 54 coding exons 5071bp 1487aa

Heinegård D and Saxne T. Nature Reviews Rheumatology 2011)

Colagenopatías tipo 2

• Letales:

• Achondrogenesis type 2 / Hypochondrogenesis

• Platyspondylic dysplasia, Torrance type

• No letales con talla baja:

• Spondyloepiphyseal dysplasia congenita (SEDC)

• Kniest dysplasia

• Spondyloepiphyseal dysplasia with marked metaphyseal changes (Strudwick type)

• Spondyloperipheral dysplasia

• Dysspondyloenchondromatosis

• No letales sin talla baja:

• Stickler dysplasia type 1

• SED with metatarsal shortening (Czech dysplasia)

• Dysplasia of the proximal femoral epiphyses

Achondrogenesis type 2 / Hypochondrogenesis

• Missense mutations in the triple helical domain: Gly substitutions.

• Clinical features

• Micromelia

• Short trunk, proportionate abdomen

• Micrognathia; cleft palate

• Hydropic apperance

• Radiological features

• Absent retarded ossification of vertebral bodies

• Very short tubular bones

• Small iliac bones

• Absent/severely retarded ossifications of pubic and ischial bones.

• Differential diagnosis:

• Achondrogeneiss type 1A (TRIP11) / 1B (DTDST).

IMAGEN

Platyspondylic dysplasia Torrance Type

• Missense mutations in the carboxy-propeptide.

• Normally lethal.

• Radiological features

• Severe platyspondyly.

• Broad ischial and pubic bones

Zank et al. AJMG 2005

Type 2 collagenopathies

• Lethal

• Achondrogenesis type 2 / Hypochondrogenesis

• Platyspondylic dysplasia, Torrance type

• Non lethal with short stature

• Spondyloepiphyseal dysplasia congenita (SEDC)

• Kniest dysplasia

• Spondyloepiphyseal dysplasia with marked metaphyseal changes (Strudwick type)

• Spondyloperipheral dysplasia

• Dysspondyloenchondromatosis

• Non-lethal without short stature

• Stickler dysplasia type 1

• SED with metatarsal shortening (formerly Czech dysplasia)

• Dysplasia of the proximal femoral epiphyses

SEDC

• Missense mutations (Gly), splicing mutations or in-frame deletions in the triple helical domain.

• Clinical features

• Short at birth (45cm)

• Flat face, prominente eyes, cleft palate (20%)

• Myopia, retinal detachment (less frequent than Stickler)

• Usually normal hands. Clubfeet

• Scoliosis, odontoid hypoplasia, coxa vara

• Radiological features

• At birth:

• absent ossification of pubic bone and distal femoral epiphysis.

• Absent/retarded ossification of cervical and sacral vertebrae

• Retarded epiphyseal ossification, then dysplastic. Metaphyseal involvment

• Preservation of hands.

• Flattened vertebral bodies.

• Coxa vara.

SEDC

Kniest dysplasia

• Features different from SEDC:

• More involvement of trunk.

• More frequency of cleft palate, hearing loss, myopia.

• Prominent joints.

• Hand involvement

• Large epiphyses.

Spranger et al. AJMG 1997

Spondyloperipheral dysplasia

• Features different from SEDC:

• Short stature less pronounced

• Short hands / feet (metacarpals / metatarsals)

• Missense or frameshift mutations in the C-propeptide.

• Hand involvement

• Large epiphyses.

Zank et al. AJMG 2004

Type 2 collagenopathies

• Lethal

• Achondrogenesis type 2 / Hypochondrogenesis

• Platyspondylic dysplasia, Torrance type

• Non lethal with short stature

• Spondyloepiphyseal dysplasia congenita (SEDC)

• Kniest dysplasia

• Spondyloepiphyseal dysplasia with marked metaphyseal changes (Strudwick type)

• Spondyloperipheral dysplasia

• Dysspondyloenchondromatosis

• Non-lethal without short stature

• Stickler dysplasia type 1

• SED with metatarsal shortening (formerly Czech dysplasia)

• Dysplasia of the proximal femoral epiphyses

Stickler

• Clinical features

• Ocular:

• Myopia (severe)

• Retichal detachment

• Chorioretinal / vitreous degeneration.

• Cataracts / glaucoma.

• Orofacial:

• Cleft palate; submucous / Pierre-Robin

• Flat face, low nasal bridge .

• Auditory:

• Hearing loss (conductive / neursensorial / mixed).

• Osteoarticular:

• Joint pain

• Degenerative joint disease

• Mild hipermobility

• Vertebral abnormalities

IMAGEN

Czech dysplasia

Recomendaciones seguimiento

• Oftalmología: Evaluación al diagnóstico (periodo neonatal) después anual o según precise. Tratamiento precoz.

• Evaluación audición (otoemisiones / potenciales). Hasta desarrollo lenguaje.

• Reparación quirúrgica hendidura paladar. Vigilar alimentación.

• Osteoarticular :

• Unión cráneo-cervical.

• Monitorizar caderas / columna.

• Evitar deportes contacto / obesidad.

• Asesoramiento genético.

• Evaluación multidisciplinar.