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The Genetic Basis for Skeletal Diseases
insight review articles The genetic basis for skeletal diseases Elazar Zelzer & Bjorn R. Olsen Harvard Medical School, Department of Cell Biology, 240 Longwood Avenue, Boston, Massachusetts 02115, USA (e-mail: [email protected]) We walk, run, work and play, paying little attention to our bones, their joints and their muscle connections, because the system works. Evolution has refined robust genetic mechanisms for skeletal development and growth that are able to direct the formation of a complex, yet wonderfully adaptable organ system. How is it done? Recent studies of rare genetic diseases have identified many of the critical transcription factors and signalling pathways specifying the normal development of bones, confirming the wisdom of William Harvey when he said: “nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path”. enetic studies of diseases that affect skeletal differentiation to cartilage cells (chondrocytes) or bone cells development and growth are providing (osteoblasts) within the condensations. Subsequent growth invaluable insights into the roles not only of during the organogenesis phase generates cartilage models individual genes, but also of entire (anlagen) of future bones (as in limb bones) or membranous developmental pathways. Different mutations bones (as in the cranial vault) (Fig. 1). The cartilage anlagen Gin the same gene may result in a range of abnormalities, are replaced by bone and marrow in a process called endo- and disease ‘families’ are frequently caused by mutations in chondral ossification. Finally, a process of growth and components of the same pathway. -
Dwarfism Awareness
LPA Mission Statement LPA is dedicated to improving the quality of life for people with dwarfism throughout their lives, while celebrating with great pride little people’s contribution to social diversity. LPA strives to bring solutions and global For More Information awareness to the prominent issues affecting individuals of Contact LPA short stature and their families. Toll Free…(888) LPA-2001 Direct....(714) 368-3689 Fax…..(707) 721-1896 Dwarfism Check out our website at Awareness www.lpaonline.org A Community Outreach Program 617 Broadway #518 Sponsored by Little People of America Sonoma, CA 95476 LPA is a non-profit tax exempt 501(c)3 organization funded by individual donations. Contact LPA to help. Dwarfism - Facts and Fiction Mythbusters Terminology Bodies come in all shapes and sizes. There are about 400 People with dwarfism are not magical; they do not fly, nor are Preferred terminology is a personal decision, but different types of dwarfism. Each type of dwarfism is they leprechauns, elves, fairies or any other mythological commonly accepted terms are - short stature, different than the other. Many types of dwarfism have creature. They are people - people whose bones happen to dwarfism, little person, dwarf. And we say some medical complications but most people have an grow differently than yours. That is all. "average-height" instead of "normal height". average lifespan, being productive members of society. People with dwarfism do not all know each People with dwarfism are different, yes, but not Eighty percent of people with dwarfism have average- other or look alike, nor are there towns "abnormal". height parents and siblings. -
MECHANISMS in ENDOCRINOLOGY: Novel Genetic Causes of Short Stature
J M Wit and others Genetics of short stature 174:4 R145–R173 Review MECHANISMS IN ENDOCRINOLOGY Novel genetic causes of short stature 1 1 2 2 Jan M Wit , Wilma Oostdijk , Monique Losekoot , Hermine A van Duyvenvoorde , Correspondence Claudia A L Ruivenkamp2 and Sarina G Kant2 should be addressed to J M Wit Departments of 1Paediatrics and 2Clinical Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Email The Netherlands [email protected] Abstract The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFkB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T3/T4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. -
Mutations in C-Natriuretic Peptide (NPPC): a Novel Cause of Autosomal Dominant Short Stature
© American College of Medical Genetics and Genomics ORIGINAL RESEARCH ARTICLE Mutations in C-natriuretic peptide (NPPC): a novel cause of autosomal dominant short stature Alfonso Hisado-Oliva, PhD1,2,3, Alba Ruzafa-Martin, MSc1, Lucia Sentchordi, MD, MSc1,3,4, Mariana F.A. Funari, MSc5, Carolina Bezanilla-López, MD6, Marta Alonso-Bernáldez, MSc1, Jimena Barraza-García, MD, MSc1,2,3, Maria Rodriguez-Zabala, MSc1, Antonio M. Lerario, MD, PhD7,8, Sara Benito-Sanz, PhD1,2,3, Miriam Aza-Carmona, PhD1,2,3, Angel Campos-Barros, PhD1,2, Alexander A.L. Jorge, MD, PhD5,7 and Karen E. Heath, PhD1,2,3 Purpose: C-type natriuretic peptide (CNP) and its principal receptor, reductions in cyclic guanosine monophosphate synthesis, confirming natriuretic peptide receptor B (NPR-B), have been shown to be their pathogenicity. Interestingly,onehasbeenpreviouslylinkedto important in skeletal development. CNP and NPR-B are encoded by skeletal abnormalities in the spontaneous Nppc mouse long-bone natriuretic peptide precursor-C (NPPC) and natriuretic peptide receptor abnormality (lbab)mutant. NPR2 NPR2 2( ) genes, respectively. While mutations have been Conclusions: Our results demonstrate, for the first time, that NPPC describedinpatientswithskeletaldysplasias and idiopathic short stature mutations cause autosomal dominant short stature in humans. The (ISS), and several Npr2 and Nppc skeletal dysplasia mouse models exist, NPPC NPPC mutations cosegregated with a short stature and small hands no mutations in have been described in patients to date. phenotype. A CNP analog, which is currently in clinical trials for the Methods: NPPC was screened in 668 patients (357 with dispro- treatment of achondroplasia, seems a promising therapeutic approach, portionate short stature and 311 with autosomal dominant ISS) and 29 since it directly replaces the defective protein. -
Laron Syndrome
Laron syndrome Description Laron syndrome is a rare form of short stature that results from the body's inability to use growth hormone, a substance produced by the brain's pituitary gland that helps promote growth. Affected individuals are close to normal size at birth, but they experience slow growth from early childhood that results in very short stature. If the condition is not treated, adult males typically reach a maximum height of about 4.5 feet; adult females may be just over 4 feet tall. Other features of untreated Laron syndrome include reduced muscle strength and endurance, low blood sugar levels (hypoglycemia) in infancy, small genitals and delayed puberty, hair that is thin and fragile, and dental abnormalities. Many affected individuals have a distinctive facial appearance, including a protruding forehead, a sunken bridge of the nose (saddle nose), and a blue tint to the whites of the eyes (blue sclerae). Affected individuals have short limbs compared to the size of their torso, as well as small hands and feet. Adults with this condition tend to develop obesity. However, the signs and symptoms of Laron syndrome vary, even among affected members of the same family. Studies suggest that people with Laron syndrome have a significantly reduced risk of cancer and type 2 diabetes. Affected individuals appear to develop these common diseases much less frequently than their unaffected relatives, despite having obesity (a risk factor for both cancer and type 2 diabetes). However, people with Laron syndrome do not seem to have an increased lifespan compared with their unaffected relatives. Frequency Laron syndrome is a rare disorder. -
Fibrochondrogenesis
Fibrochondrogenesis Description Fibrochondrogenesis is a very severe disorder of bone growth. Affected infants have a very narrow chest, which prevents the lungs from developing normally. Most infants with this condition are stillborn or die shortly after birth from respiratory failure. However, some affected individuals have lived into childhood. Fibrochondrogenesis is characterized by short stature (dwarfism) and other skeletal abnormalities. Affected individuals have shortened long bones in the arms and legs that are unusually wide at the ends (described as dumbbell-shaped). People with this condition also have a narrow chest with short, wide ribs and a round and prominent abdomen. The bones of the spine (vertebrae) are flattened (platyspondyly) and have a characteristic pinched or pear shape that is noticeable on x-rays. Other skeletal abnormalities associated with fibrochondrogenesis include abnormal curvature of the spine and underdeveloped hip (pelvic) bones. People with fibrochondrogenesis also have distinctive facial features. These include prominent eyes, low-set ears, a small mouth with a long upper lip, and a small chin ( micrognathia). Affected individuals have a relatively flat-appearing midface, particularly a small nose with a flat nasal bridge and nostrils that open to the front rather than downward (anteverted nares). Vision problems, including severe nearsightedness (high myopia) and clouding of the lens of the eye (cataract), are common in those who survive infancy. Most affected individuals also have sensorineural hearing loss, which is caused by abnormalities of the inner ear. Frequency Fibrochondrogenesis appears to be a rare disorder. About 20 affected individuals have been described in the medical literature. Causes Fibrochondrogenesis can result from mutations in the COL11A1 or COL11A2 gene. -
Subbarao K Skeletal Dysplasia (Non - Sclerosing Dysplasias – Part II)
REVIEW ARTICLE Skeletal Dysplasia (Non - Sclerosing dysplasias – Part II) Subbarao K Padmasri Awardee Prof. Dr. Kakarla Subbarao, Hyderabad, India Introduction Out of 70 dwarfism syndromes, the most In continuation with Sclerosing Dysplasias common form of dwarfism is (Part I), non sclerosing dysplasias constitute achondroplasia. It is a proportionate a major group of skeletal lesions including dwarfism and is rhizomelic in 70% of the dwarfism syndromes. The following list patients. It is autosomal dominant. There is includes most of the common dysplasias rhizomelic type of short limbs with increased either involving epiphysis, metaphysis, spinal curvature. Skull abnormalities are also diaphysis or epimetaphysis. These include noted. The radiographic features are multiple epiphyseal dysplasia, spondylo- mentioned in Table I. epiphyseal dysplasia, metaphyseal dysplasia, spondylometaphyseal dysplasia and Table I: Achondroplasia- Radiographic epimetaphyseal dysplasia (Hindigodu features Syndrome). These are included in dwarfism Large skull with prominent frontal syndromes. bones and a narrow base. The interpedicular distance decreases Dwarfism indicates a short person in stature caudally in lumbar region but with due to genetic or acquired causes. It is normal vertebral height. defined as an adult height of less than Posterior scalloping 147 cm (4 feet 10 inches). The pelvis is square with small sciatic notches and the inlet The average height of Indians is men- 5ft 3 configuration with classical ½ inches and women–5 ft 0 inches much less champagne glass appearance than average American or Chinese people. Trident hands Delayed appearance of carpal bones Dwarfism syndromes consist of 200 distinct Dumb bell shaped limb bones medical entities. In Proportionate Dwarfism, the body appears normally proportioned, but is unusually small. -
Fibrochondrogenesis, an Antenatal and Postnatal Correlation
Editor-in-Chief: Vikram S. Dogra, MD OPEN ACCESS Department of Imaging Sciences, University of Rochester Medical Center, Rochester, USA HTML format Journal of Clinical Imaging Science For entire Editorial Board visit : www.clinicalimagingscience.org/editorialboard.asp www.clinicalimagingscience.org CASE REPORT Fibrochondrogenesis, an Antenatal and Postnatal Correlation Nischal G. Kundaragi, Kishor Taori, Chetan Jathar, Amit Disawal Department of Radiodiagnosis, Government Medical College, Nagpur, India Address for correspondence: Dr. Nischal G. Kundaragi, ABSTRACT Consultant, Government Medical College, Nagpur and SRM University Fibrochondrogenesis is a rare, neonatally lethal osteochondrodysplasia, with autosomal Medical College, Kanchipurum, recessive inheritance. It differs from other lethal dwarfisms in that it leads to broad, Tamil Nadu, India. long-bone metaphyses (dumb-bell shaped) and pear-shaped vertebral bodies. E-mail: [email protected] We report a case of fibrochondrogenesis with severe pear-shaped platyspondyly, suspected antenatally, and give a comprehensive pictorial review of the antenatal ultrasound and postnatal radiographic findings. Only few cases of fibrochondrogenesis are diagnosed before the termination of pregnancy. Received : 03-01-2012 Accepted : 28-01-2012 Key words: Antenatal diagnosis, fibrochorogenesis, platyspondyly, ultrasonography Published : 18-02-2012 INTRODUCTION (dumbbell shaped) and shortened ribs with pear-shaped vertebral bodies. We report a case of fibrochondrogenesis Fibrochondrogenesis is a genetically inherited form of with severe pear-shaped platyspondyly (flattened spine), osteochondrodysplasia that occurs in neonate. This lethal suspected on antenatal ultrasound examination. Only few variant results from the inheritance of an autosomal recessive cases of fibrochondrogenesis are diagnosed before the gene and causes abnormal development of cartilage and termination of pregnancy.[1] This case gives a comprehensive fibrous connective tissues. -
Anesthesia for a Patient with Osteogenesis Imperfecta, Achondroplastic Dwarfism and History of Malignant Hyperthermia
anesthesia for a Patient with osteogenesis imPerfecta, achondroPlastic dwarfism and history of malignant hyPerthermia Jaclyn Harvey SRNA AbstrAct A primary goal for anesthesia providers is to maintain patient safety. This is an even greater concern when taking care of a patient with a complicated medical history. This case report, discusses the care of a 47 year-old female patient who presented to a tertiary care center for an orthopedic procedure. Her medical history included osteogenesis imperfecta (OI), achondro- plastic dwarfism and suspicion of malignant hyperthermia (MH). There were multiple anesthetic implications to ensure safety for this patient during the perioperative period. OI concerns include bone fragility and potential for multiple fractures even after inoffensive trauma. Achondroplastic dwarfism concerns include abnormalities of the upper airway and difficulty with visual- izing the glottic opening during direct laryngoscopy.1 Malignant Hyperthermia is a life threatening disorder, which places the patient at risk for a hypermetabolic reaction if exposed to select anesthetic agents. IntroductIon: Patients with osteogenesis imperfect (OI) are placed at high risk during anesthesia for both physiological and anatomical reasons. Complications include osteoporosis, joint laxity, and tendon weakness.2 Pulmonary compromise may also occur if the patient displays thoracic distortion. These patients have an elevated basal metabolic rate that causes an increase in core body temper- ature and can mistaken to be MH. No consistent evidence has shown that OI is always associated with MH.2 Achondroplastic dwarfism is the most common form of dwarfism occurring at the rate of 1:30,000 live births. Airway abnormalities such as macroglossia, micrognathia, small oral opening and temporo- mandibular joint immobility can make mask ventilation and intubation challenging for anesthesia providers. -
Current Understanding on the Molecular Basis of Chondrogenesis
Clin Pediatr Endocrinol 2014; 23(1), 1–8 Copyright© 2014 by The Japanese Society for Pediatric Endocrinology Review Article Current Understanding on the Molecular Basis of Chondrogenesis Toshimi Michigami1 1 Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan Abstract. Endochondral bone formation involves multiple steps, consisting of the condensation of undifferentiated mesenchymal cells, proliferation and hypertrophic differentiation of chondrocytes, and then mineralization. To date, various factors including transcription factors, soluble mediators, extracellular matrices (ECMs), and cell-cell and cell-matrix interactions have been identified to regulate this sequential, complex process. Moreover, recent studies have revealed that epigenetic and microRNA-mediated mechanisms also play roles in chondrogenesis. Defects in the regulators for the development of growth plate cartilage often cause skeletal dysplasias and growth failure. In this review article, I will describe the current understanding concerning the regulatory mechanisms underlying chondrogenesis. Key words: chondrocyte, transcription factors, growth factors, extracellular matrix, differentiation Introduction plates, and are characterized by the expression of type II, IX, and XI collagen (Col II, IX and In mammals, most of the skeleton including XI) and proteoglycans such as aggrecan. the long bones of the limbs and the vertebral When chondrocytes differentiate, they become columns is formed through endochondral bone hypertrophic and begin to produce a high level formation, which consists of the mesenchymal of alkaline phosphatase and type X collagen (Col condensation of undifferentiated cells, X). Eventually, the terminally differentiated proliferation of chondrocytes and differentiation chondrocytes undergo apoptosis, and the into hypertrophic chondrocytes, followed by cartilaginous matrix is mineralized and replaced mineralization (1–3). -
Discover Dysplasias Gene Panel
Discover Dysplasias Gene Panel Discover Dysplasias tests 109 genes associated with skeletal dysplasias. This list is gathered from various sources, is not designed to be comprehensive, and is provided for reference only. This list is not medical advice and should not be used to make any diagnosis. Refer to lab reports in connection with potential diagnoses. Some genes below may also be associated with non-skeletal dysplasia disorders; those non-skeletal dysplasia disorders are not included on this list. Skeletal Disorders Tested Gene Condition(s) Inheritance ACP5 Spondyloenchondrodysplasia with immune dysregulation (SED) AR ADAMTS10 Weill-Marchesani syndrome (WMS) AR AGPS Rhizomelic chondrodysplasia punctata type 3 (RCDP) AR ALPL Hypophosphatasia AD/AR ANKH Craniometaphyseal dysplasia (CMD) AD Mucopolysaccharidosis type VI (MPS VI), also known as Maroteaux-Lamy ARSB syndrome AR ARSE Chondrodysplasia punctata XLR Spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1) B3GALT6 Ehlers-Danlos syndrome progeroid type 2 (EDSP2) AR Multiple joint dislocations, short stature and craniofacial dysmorphism with B3GAT3 or without congenital heart defects (JDSCD) AR Spondyloepimetaphyseal dysplasia (SEMD) Thoracic aortic aneurysm and dissection (TADD), with or without additional BGN features, also known as Meester-Loeys syndrome XL Short stature, facial dysmorphism, and skeletal anomalies with or without BMP2 cardiac anomalies AD Acromesomelic dysplasia AR Brachydactyly type A2 AD BMPR1B Brachydactyly type A1 AD Desbuquois dysplasia CANT1 Multiple epiphyseal dysplasia (MED) AR CDC45 Meier-Gorlin syndrome AR This list is gathered from various sources, is not designed to be comprehensive, and is provided for reference only. This list is not medical advice and should not be used to make any diagnosis. -
Pituitary Dwarfism
Pituitary Dwarfism Other names for this condition: juvenile panhypopituitarism, hypopituitarism, growth hormone deficiency, hyposomatotropism. Disease description Pituitary dwarfism is a congenital abnormality of the pituitary gland that results in reduced growth and development. It can be caused by an isolated growth hormone (GH) deficiency, but sometimes it is part of a combined pituitary hormone deficiency syndrome whereby other hormones (e.g., thyroid, reproductive, etc.) are also deficient.1-3 Pituitary dwarfism is seen most often in the German shepherd dog, but is also seen in the Karelian Bear Dog, Saarloos Wolfhound, Czechoslovakian Wolfdog, Miniature pinscher, American Eskimo Dog (Spitz), and Weimaraner. Symptoms While not all pituitary dwarfs display the same symptoms, most have marked growth Two 7 weeks old German shepherd litter mates. retardation (usually noted by 2-5 months of age) and retention of their “puppy coat,” resulting in an abnormally soft and woolly hair. The fur is easily removed, resulting in baldness that begins at points of wear, such as the collar area on the neck and on the tail. Eventually, much or the hair on the body and rear end is lost. Fur often remains on the head and legs/feet. The skin becomes progressively blackened and scaly, often with secondary bacterial infections.1 There are delays in bone growth, and premature closure of the growth plates resulting in small stature. The teeth erupt later than usual and external genitalia remain infantile. Some affected patients also have congenital Most pups in the litter averaged 13-14 pounds (left) except for one that weighed less than 4 pounds (right).