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First entry - generic for Geneticiens de l'Ouest - Berder 12
Martine Le Merrer
Affecting only the cervical vertebrae : Klippel-Feil with or without Sprengel, eg. probably genetically heterogeneous, assoc with translocation 8q22.2-q22.3 Lots of overlap with Wildervranck (not dominant linked to X but predominantly female) and Goldenhar syndromes.
Concerns the whole A-P axis, like a craniorachischisis. Mutations in MESP2 and DLL3. The vertebrae are in “galet” shape – flat, smoothened. Can be associated with neural tube defects (NTDs), anal imperforation and heart malformations. Not dysmorphic. Get hemi-vertebrae and short thorax, head in the shoulders. Mostly sporadic. Autosomal dominant (AD) forms are more moderate. DLL# is on 19q31; heterozygous mutations given the same phenotype as hmz Remember that hairy/enhancer-of-split genes repress achaete-scute-like MASH/HASH gene transcription. MESP1 leads to Notch transcription or activation? Which Notch? These mutations are gain-of-function.
Fewer segments, hernias, fused ribs and caudal something. 2q32.1 locus in 2001. May or may not be the same as Jarcho-Levin syndrome. Martine might be doing more with this one.
Associated with sacral anomalies, AR eg translocation (6;9)(p12;q12)
Futions of dorsal vertebrae at cervical/lumbar levels, with campodactyly – mutations of Filamin B (autosomal dominant)
Eye anterior chamber, vertebrae “aile de papillon”, few biliary canals. Pulmonary stenosis and vasculopathy. Jagged-1.
Short fingers, young face. Del9q or AD or AR – [ROR2 gene. (Isn’t this an orphan receptor? no, it's a co-receptor in the Wnt pathway)] in the AR form the vertebral phenotype is very severe; associated with short distal phalanges.
SOX9 – small iliacs? Lower cervicals/upper thoracics – more localized.
Also associated with maternal diabetes
“Vertebral puzzle” – torticolli and scoliosis. Can get reduced ossification in hypophosphatasia – hydramnios, AR. Variable phenotype. ALPL gene. FGFR3 mutations, thanatophore. H-shaped vertebral bodies – flat and big intervertebral disks. * Fibrochrondrogenesis is very rare with dumbbell shaped metaphyses. Similar vertebral bodies to Schenckenbecken syndrome – SCL35D1. After birth, H-shaped vertebrae also very wide metaphyses in the long bones as well as short diaphyses.
Leads to scoliosis, wide intervertebral disks. I wonder if this is a problem of later notochord differentiation? Why does it disappear in the vertebrae and get larger in the intervertebral disks?
Pseudoachondroplasia is a “regressive” rather than a “progressive” form, the joint problems get worse but the vertebrae get better (alarming X-rays at birth improve).
Small occipital hole can manifest as apnea or congenital torticolli, must get X-ray. Any sort of instability affecting the cervical area is worrisome – floppiness can lead to compression. Also applies to Larsen or other dysplasias as well as Morquio. All mucopolysaccharidoses lead to stenosis of occipital foramen. Get lipid/GAG accumulation in meninges and/or in the dura mater. Lead to neurosurgery where rods are placed in neck but that has its own risks – a few anecdotes of successful operations with vascular accidents during recovery leading to the very tetraplegia that they were looking to avoid. Even death. GAG overload leads to cuneiform deformations. Can get compression lower down with a small vertebral canal as in FGFR3 or SHOX mutations.
Lots of causes, also LRP5 gene which leads to an ocular anomaly.
Condensations of vertebral bodies, chloride channel 7. OC116 In newborn normally see a cleft during the first year that closes called Hann cleft. Can get coronal clefts in Kniest or boys associated with other problems cf. no gene yet known for cerebro-osseous-digital syndrome with icthyosis; cf article Am J Med Genet 2002.
COL2A1 is type 2, DTDST is type 1B and type 1A not sure yet. Type 2 is less severe with punctiform vertebral bodies in AD. If a htz mutation can also get incomplete ossification. Also known as (?) spondyloepiphyseal dysplasia).
Can have aspects of ossification defects.
Proteus syndrome cf the pedicules. Also cf. DTDST sulfate transporter evolutive scoliosis without vertebral body malformations. Problems of “statique” vertebrals (what the heck does that mean? I’m retranscribing my own notes). Also cf. Zn++ transporter SLC39A13 which interacts with the PLOD genes in Ehlers Danlos (cf AM J Hum Genet June 2008).
100% X-inactivation (instead of 50/50) otherwise in the rest of the females in the family maybe that’s not the case for all tissues. No EBP, cholesterol metab ok. Linkage to pericentric region of 25Mb and Didier is sequencing these. They published the clinical report together in 2004.