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Background: Dwarfism is associated with skeletal dysplasias and joint deformities that frequently result in osteoarthritis requiring treatment with total knee arthroplasty (TKA). These surgeries can be challenging because of alignment deformities, poor bone stock, and smaller components. This study aims to compare TKA implant survivorship and complications between dwarf and nondwarf patients., Methods: A retrospective case-control study was performed from 1997-2014 evaluating 115 TKAs in patients under the height threshold of 147.32 cm. This cohort was compared with 164 patients of normal height. Medical records were reviewed for demographics, surgical characteristics, and outcomes. All cases had 2-year minimum follow-up., Results: The revision rate was 8.7% in dwarfs compared with 3.7% in controls (P = .08). The 2-, 5-, and 10-year implant survivorship in dwarfs was 96.4%, 92.5%, and 90.2%, respectively; and 96.6%, 95.6%, and 94.8% for controls, respectively (P = .24). Dwarfs underwent significantly more manipulations for arthrofibrosis (P = .002). There was greater femoral (17.4% vs 2.1%, P < .01) and tibial (6.5% vs 2.7%, P < .01) component overhang in dwarfs compared with controls., Conclusion: Despite a 2-fold increase in the revision rate of the dwarf cohort, the midterm survivorship is comparable between the dwarf and nondwarf patients. However, dwarfs were more likely to become stiff and undergo manipulation; the increased propensity for stiffness may be associated with oversized components, as evidenced by greater component overhang. Surgeons should be aware of this increased risk and may consider using smaller or customized implants to account for the morphological differences in this patient population., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Lethal chondrodysplasia (bulldog syndrome) is a well-known congenital syndrome in cattle and occurs sporadically in many breeds. In 2015, it was noticed that about 12% of the offspring of the phenotypically normal Danish Holstein sire VH Cadiz Captivo showed chondrodysplasia resembling previously reported bulldog calves. Pedigree analysis of affected calves did not display obvious inbreeding to a common ancestor, suggesting the causative allele was not a rare recessive. The normal phenotype of the sire suggested a dominant inheritance with incomplete penetrance or a mosaic mutation., Results: Three malformed calves were examined by necropsy, histopathology, radiology, and computed tomography scanning. These calves were morphologically similar and displayed severe disproportionate dwarfism and reduced body weight. The syndrome was characterized by shortening and compression of the body due to reduced length of the spine and the long bones of the limbs. The vicerocranium had severe dysplasia and palatoschisis. The bones had small irregular diaphyses and enlarged epiphyses consisting only of chondroid tissue. The sire and a total of four affected half-sib offspring and their dams were genotyped with the BovineHD SNP array to map the defect in the genome. Significant genetic linkage was obtained for several regions of the bovine genome including chromosome 5 where whole genome sequencing of an affected calf revealed a COL2A1 point mutation (g.32473300 G > A). This private sequence variant was predicted to affect splicing as it altered the conserved splice donor sequence GT at the 5'-end of COL2A1 intron 36, which was changed to AT. All five available cases carried the mutant allele in heterozygous state and all five dams were homozygous wild type. The sire VH Cadiz Captivo was shown to be a gonadal and somatic mosaic as assessed by the presence of the mutant allele at levels of about 5% in peripheral blood and 15% in semen., Conclusions: The phenotypic and genetic findings are comparable to a previously reported COL2A1 missense mutation underlying lethal chondrodysplasia in the offspring of a mosaic French Holstein sire (Igale Masc). The identified independent spontaneous splice site variant in COL2A1 most likely caused chondrodysplasia and must have occurred during the early foetal development of the sire. This study provides a first example of a dominant COL2A1 splice site variant as candidate causal mutation of a severe lethal chondrodysplasia phenotype. Germline mosaicism is a relatively frequent mechanism in the origin of genetic disorders and explains the prevalence of a certain fraction of affected offspring. Paternal dominant de novo mutations are a risk in cattle breeding, especially because the ratio of defective offspring may be very high and be associated with significant animal welfare problems.

We studied 20 cases with fibrochondrogenesis (FCG) diagnosed prenatally. Four cases were diagnosed at our fetal unit, and 16 cases were identified through a review of literature (in English). The prenatal diagnosis of FCG was made in 4/20 (20%). Six (30%) patients opted for termination of pregnancy (TOP). A total of 13 cases delivered at term. Four (30.8%) had a caesarean section. Four neonates (30.7%) were stillborn and seven (53.8%) neonates died within 3 months. Two infants survived beyond 3 years of age, but both had severe global developmental delay. A molecular study of the surviving children revealed two null homozygous mutations in COL11A1 [c.4084C > T (p.R1362X) and c.3708 + c.437T > G]. We concluded that the prenatal diagnosis of fibrochondrogenesis is feasible. Fibrochondrogenesis is usually a fatal disease and survivors suffer from severe physical and neurological impairment.

Kenny-Caffey syndrome (KCS) and the similar but more severe osteocraniostenosis (OCS) are genetic conditions characterized by impaired skeletal development with small and dense bones, short stature, and primary hypoparathyroidism with hypocalcemia. We studied five individuals with KCS and five with OCS and found that all of them had heterozygous mutations in FAM111A. One mutation was identified in four unrelated individuals with KCS, and another one was identified in two unrelated individuals with OCS; all occurred de novo. Thus, OCS and KCS are allelic disorders of different severity. FAM111A codes for a 611 amino acid protein with homology to trypsin-like peptidases. Although FAM111A has been found to bind to the large T-antigen of SV40 and restrict viral replication, its native function is unknown. Molecular modeling of FAM111A shows that residues affected by KCS and OCS mutations do not map close to the active site but are clustered on a segment of the protein and are at, or close to, its outer surface, suggesting that the pathogenesis involves the interaction with as yet unidentified partner proteins rather than impaired catalysis. FAM111A appears to be crucial to a pathway that governs parathyroid hormone production, calcium homeostasis, and skeletal development and growth., (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive multisystemic disorder caused by mutations of the SMARCAL 1 gene (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1)., Clinical Features: Main clinical features are: disproportional growth deficiency due to spondyloepiphyseal dysplasia, nephrotic syndrome with focal and segmental glomerulosclerosis, and defective cellular immunity. Patients with severe SIOD have life-limiting complications like cerebral ischemia due to vaso-occlusive processes. Only a few patients reached adulthood., Case Reports: The clinical course of four adult SIOD patients is presented., Conclusion: Even patients with severe SIOD can reach adulthood. Therefore, doctors working in the field of internal medicine and family doctors should be familiar with the clinical picture of SIOD.

Longitudinal bone growth is determined by endochondral ossification that occurs as chondrocytes in the cartilaginous growth plate undergo proliferation, hypertrophy, cell death, and osteoblastic replacement. The natriuretic peptide family consists of three structurally related endogenous ligands, atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP), and is thought to be involved in a variety of homeostatic processes. To investigate the physiological significance of CNP in vivo, we generated mice with targeted disruption of CNP (Nppc(-/-) mice). The Nppc(-/-) mice show severe dwarfism as a result of impaired endochondral ossification. They are all viable perinatally, but less than half can survive during postnatal development. The skeletal phenotypes are histologically similar to those seen in patients with achondroplasia, the most common genetic form of human dwarfism. Targeted expression of CNP in the growth plate chondrocytes can rescue the skeletal defect of Nppc(-/-) mice and allow their prolonged survival. This study demonstrates that CNP acts locally as a positive regulator of endochondral ossification in vivo and suggests its pathophysiological and therapeutic implication in some forms of skeletal dysplasia.

We report two unrelated infants with cephaloskeletal dysplasia or Taybi-Linder syndrome, also referred to as osteodysplastic primordial dwarfism Type III. They presented with peculiar facial features, microcephaly and skeletal and cerebral abnormalities documented radiographically and with cranial MRI and/or CT. Some dissimilarities were observed in the skeletal findings between the two patients, most likely reflecting phenotypic variability within the same disorder. Some radiographic features were shown to evolve with time in both patients. Also of interest is the unusually long survival of these patients, more than 4 years in the first and of over 6 years in the second.

MT1-MMP is a membrane-bound matrix metalloproteinase (MT-MMP) capable of mediating pericellular proteolysis of extracellular matrix components. MT1-MMP is therefore thought to be an important molecular tool for cellular remodeling of the surrounding matrix. To establish the biological role of this membrane proteinase we generated MT1-MMP-deficient mice by gene targeting. MT1-MMP deficiency causes craniofacial dysmorphism, arthritis, osteopenia, dwarfism, and fibrosis of soft tissues due to ablation of a collagenolytic activity that is essential for modeling of skeletal and extraskeletal connective tissues. Our findings demonstrate the pivotal function of MT1-MMP in connective tissue metabolism, and illustrate that modeling of the soft connective tissue matrix by resident cells is essential for the development and maintenance of the hard tissues of the skeleton.

We report on a male infant born with clinical and radiographic evidence of a lethal form of dyssegmental dysplasia not comparable to Silverman-Handmaker type, who had a prolonged survival of more than eight months. He had ocular and central nervous system abnormalities which have not been previously described. His course included significant feeding and respiratory difficulties, severe physical and psychomotor retardation, and recurrent fever of unknown etiology believed to be of central origin. The relatively long survival of this infant enabled us to focus on the natural history of this rare syndrome. The infant was born to first cousin parents of Druze Lebanese origin supporting an autosomal recessive mode of inheritance for the condition. This is the first documentation of dyssegmental dysplasia Silverman-Handmaker type in a family of Druze Lebanese ethnicity.

Four cases of thanatophoric dwarfism which appeared between 1974 and 1977 are described. Thanatophoric dwarfism was firstly described in 1967. In the mean-time there are reports about 44 cases. The frequency of thanatophoric dwarfism is considered to be 1 to 6393 newborns. There is no clear evidence about the occurrence of thanatophoric dwarfism, chromosone patterns have been always normal. This type of dwarfism is differentiated from other similar syndromes.

A new case of atipic chondrodystrophies classified as tanatophoric dwarfism, with pathologic studies is presented. At the same time a revision of the most important works of literature is made. Genetic, clinic and pathologic aspects of the picture have being studied, presenting the differential diagnosis with other osteochondrodysplasias of the newborn.

Report on a thanatophoric dwarfism, which is a variety of achondroplasia. New born children with this failure are not able to survive the first few days after birth. This early death is due to a cardiorespiratory deficiency as a consequence of the extremely short ribs but also of the abnormal cartilaginous growth in the wall of bronchi and bronchioles. In this present case of the thanatophoric dwarfism the question is discussed in how far the disorder of the bronchial cartilage is the basis of the respiratory distress.

Thanatophoric dwarfism is a severe form of short-limbed dwarfism in which cardiorespiratory failure uniformly results in death in the neonatal period. Its radiographic features include markedly flattened vertebral bodies with a typical U-shaped deformity, a flat squat pelvis, and short, bowed extremities with flaring and irregularity of the metaphyses. These characteristic features distinguish this entity from the two other most commonly confused congenital short-limbed forms of dwarism--achondroplasia and achondrogenesis. The distinctions are discussed in the text.

A clinical study was performed on 14 patients with diastrophic dysplasia (DD), including three pairs of sibs. Six of these patients, including two pairs of sibs, died shortly after birth of respiratory and circulatory insufficiency. We consider these six patients to represent a special lethal variant of DD. In all infants with the lethal variant of DD the birth weight was lower than in those with the non-lethal variant. There were also roentgenological differences between these two groups. Overlapping in joints and dislocation of the cervical spine were seen in all the lethal cases. In addition, four of the six patients with lethal DD cases had a congenital heart defect, and none in the non-lethal group.