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Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
Radiographic features: at birth there is absent (delayed) ossification of the epiphyses of the knees and pubic rami. The long bones are short with squared and sometimes irregular metaphyseal ends. Talipes equinovarus may be present. The thorax is small, short and ‘bell’ shaped and the abdomen appears relatively protuberant. The acetab-ular roofs are horizontal. In the spine there is anisospondyly (a difference in size/shape of the vertebral bodies) with L1 appearing larger than L5. The vertebral bodies appear oval and in the thoracic region there is some posterior constriction giving a pear-shaped appearance. These neonatal appearances are indistinguishable from spondyloepimetaphyseal dysplasia type Strudwick (p. 82). During childhood marked coxa vara develops and there is delayed ossification of the capital femoral epiphyses. In the spine there is platyspondyly. There may be odontoid hypoplasia and deficient ossification of the anterior part of one or more cervical vertebral bodies, resulting in cervical kyphosis which may require stabilisation. There is pectus carinatum.
Fetal Skeletal Dysplasias: Radiologic-Pathologic Classification of 72 Cases
Published in Fetal and Pediatric Pathology, 2022
Distinctive features of type 1 (TD1) and type 2 (TD2) included severe micromelia, anomalies of the extremities (trident hands, short hands and feet) and thoracoabdominal disproportion with narrow thorax and protuberant abdomen (Figure 6). The cloverleaf skull and associated hypertrophy of the temporal lobes with abnormal gyration were diagnostic features of TD1. Radiographic findings included shortened long bones (which were curved in TD1), short ribs, metacarpals and phalanges with cone-shaped epiphyses, severe platyspondyly (H-shaped vertebrae) and small squared iliac wings with trident acetabula. Histologic examination showed significant abnormalities of the growth plate which exhibited short proliferating and hypertrophic zones with no columnar arrangement, lack of chondrocyte hypertrophy, and thick irregularly arranged bone trabeculae.
Chylous Ascites in an Infant with Thanatophoric Dysplasia Type I with FGFR3 Mutation Surviving Five Months
Published in Fetal and Pediatric Pathology, 2018
Jeon Soo-kyeong, Narae Lee, Mi Hye Bae, Young Mi Han, Kyung Hee Park, Shin Yun Byun
Langer et al. classified this disorder into two subtypes (10). TD type I (TD1) is the most common and is distinguished by bowed long bones (especially the femora) and flat vertebral bodies. TD type II (TD2) is characterized by straight femora and taller vertebral bodies, while almost all cases involving severe cloverleaf skulls are TD2 cases. These two types of TD commonly exhibit short limbs, macrocephaly with full forehead, low nasal bridge, narrow thorax with lung hypoplasia, platyspondyly, and a small pelvis.
HDAC6 as a potential therapeutic target for peripheral nerve disorders
Published in Expert Opinion on Therapeutic Targets, 2018
Robert Prior, Lawrence Van Helleputte, Yvonne Eileen Klingl, Ludo Van Den Bosch
As HDAC6 is a key mediator in the pathophysiological processes involved in both hereditary and acquired peripheral neuropathies, this enzyme is emerging as a valuable candidate for new effective and disease-modifying treatments. As discussed in this review, HDAC6 lies at the intersection of multiple key pathways, balancing between neuronal health and neurodegeneration. In several research groups, including our own, HDAC6 activity was shown to be upregulated during pathophysiological process [51,52,55,184]. In rodents, HDAC6-deficient mice are viable, fertile, and appear to have no overall phenotype, and in fact, have been reported to manifest enhanced cognition [185,186]. However, these HDAC6-knockout mice did show signs of an altered immune response and bone mineral densities [185]. Interestingly, using a Drosophila model with a DTS7 mutation, Pandey et al. showed that when the proteasome is inhibited, HDAC6 expression is required for suppressing the neurodegenerative phenotype associated with proteasome impairment [187]. A DST7 mutation causes a temperature sensitive, dominant negative mutant of the β2 subunit of the proteasome. Moreover, this study showed that the catalytic function of HDAC6 is required for suppressing this induced neurodegeneration phenotype [187]. The role of HDAC6’s ZnF-UBP was not investigated in this study. Additionally, in normal flies, knockdown of HDAC6 using RNA interference constructs, they demonstrated that no phenotype was observable in 1 day old flies [187]. Thus, HDAC6 activity may be upregulated during neurodegeneration for autophagy-dependent degradation of accumulating or misfolded proteins. Moreover, sustained elevated levels of HDAC6’s catalytic deacetylating function may also worsen the neurodegeneration over time due to its posttranslational modifications of the microtubules. It would be interesting to investigate how HDAC6-knockout mice respond to stress, or recover from proteasome-induced neurodegeneration. In humans, however, the only known HDAC6 mutations have been identified in the untranslated region of the HDAC6 protein, leading to a dysregulation and causing an overexpression of the HDAC6 protein [188]. Patients with these mutations have been diagnosed with X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia [188]. This form of X-linked dominant chondrodysplasia has a much more severe disease manifestation with body asymmetry and mild mental retardation being reported [188]. However, no mutations that reduce or abolish HDAC6 expression in humans have been reported, therefore, interpreting data from preclinical models can prove to be difficult, as HDAC6 expression may differ in humans compared to the tested preclinical in vivo models. Another point to consider is that HDAC6i could potentially be a lifelong treatment for patients of inherited peripheral neuropathies.