The birth prevalence rates for the skeletal dysplasias.

This study was undertaken to establish the prevalence rates at birth of the skeletal dysplasias that can be recognised in the perinatal period. Using the data base of the Latin-American Collaborative Study of Congenital Malformations (ECLAMC), for the years 1978 to 1983, on 349 470 births (live and stillbirths), a crude prevalence rate of 2.3/10 000 was observed. However, several indications of under-registration suggest that the real value is about twice that observed. The most frequent types of skeletal dysplasia were achondroplasia, with a prevalence rate between 0.5 and 1.5/10 000 births, the thanatophoric dysplasia/achondrogenesis group (0.2 and 0.5/10 000 births), and osteogenesis imperfecta (0.4/10 000 births). The mutation rate for autosomal dominant achondroplasia was estimated at between 1.72 and 5.57 X 10(-5) per gamete per generation.     

Antenatal diagnosis of lethal skeletal dysplasias

Lethal skeletal dysplasias (LSD) are a heterogeneous group of rare but important genetic disorders characterized by abnormal growth and development of bone and cartilage. We describe the diagnosis and outcome of 29 cases of lethal skeletal dysplasias evaluated between January 1989 and December 1996 at the University of Maryland Medical Center and the Ultrasound Institute of Baltimore. Two cases presented at delivery with no prenatal care while the remaining 27 cases were identified by antenatal sonography. Final diagnoses included thanatophoric dysplasia (14), osteogenesis imperfecta, type II (6), achondrogenesis (2), short rib syndromes (3), campomelic syndrome (2), atelosteogenesis (1), and no evidence of a skeletal dysplasia (1). Twenty out of 27 pregnancies were terminated with an average at detection of 21.6 weeks. The other 7 pregnancies that went on to deliver had an average age at detection of 29.2 weeks. Fetal abnormalities in the terminated pregnancies were identified at a significantly earlier gestational age (P = 0.0016) than the pregnancies that continued. While the identification of LSD by sonography was excellent (26/27), only 13/27 (48%) were given an accurate specific antenatal diagnosis. In 8/14 (57%) cases with an inaccurate or nonspecific diagnosis there was a significant or crucial change in the genetic counseling. Thus, while antenatal sonography is an excellent method for discovering LSD, clinical examination, radiographs, and autopsy are mandatory for making a specific diagnosis. Am. J. Med. Genet. 75:518–522, 1998. © 1998 Wiley-Liss, Inc.     

Birth prevalence rates of skeletal dysplasias

This study establishes the prevalence rates at birth of the skeletal dysplasias which can be diagnosed in the perinatal period or during pregnancy. Using a population-based register of congenital anomalies, a prevalence rate of 3.22 0/000 was observed. The most frequent types of skeletal dysplasia were achondroplasia and osteogenesis imperfecta (0.64 0/000, 1/15,000 births), thanatophoric dysplasia and achondrogenesis (0.28 0/000). The mutation rate for achondroplasia was higher in our material than in the other studies: 3.3 x 10(-5) per gamete per generation. Our study demonstrates that prenatal diagnosis by ultrasound is possible in some skeletal dysplasias.     

Morphologic studies in the skeletal dysplasias.

Considerable progress has been made in the delineation of the genetic skeletal dysplasias, a heterogeneous group of disorders, that consist of over 80 distinct conditions. Morphologic studies have added a further dimension to the delineation of these conditions, their diagnosis, and the investigation of their pathogenetic mechanisms. In certain diseases, the morphologic alterations are characteristic and pathognomonic. In others only nonspecific alterations are observed, whereas in still other disorders growth-plate structure is essentially normal. Histologic, histochemical, and electronmicroscopic studies of growth-plate cartilage have provided new insights into the complexity of morphogenetic events in normal growth through the demonstration of morphologic defects in the genetic disorders of skeletal growth. As yet, very little is known of the biochemical abnormalities underlying the morphologic abnormalities. However, the great variety of morphologic findings points to a number of different pathogenetic defects in the synthesis, release, and assembly of connective tissue macromolecules and in the cells involved in growth-plate metabolism.     

Structural changes of collagen fibrils in skeletal dysplasias

Summary The skeletal dysplasias are constitutional, generalized or localized disorders of the skeletal system involving a disturbance of growth and/or bone density; their genetic transmission varies. Pathomorphologically, a combined functional-structural disturbance of the cartilaginous and/or bone tissue is present. Clinically, the result is varying degrees of dwarfism.Within the framework of a systematic examination of skeletal dysplasias, a total of 84 iliac crest specimens/biopsies obtained from stillborn infants and patients varying in age from a few days to 40 years, were investigated in the electron microscope. The sections prepared extended from the perichondrium through the proximal resting zone to the primary mineralization zone. The structure of the collagen fibrils was studied in diastrophic dysplasia, pseudoachondroplasia, the WOLCOTT-RAL-LISON syndrome, osteogenesis imperfecta, and idiopathic juvenile osteoporosis.In diastrophic dysplasia, pseudoachondroplasia and idiopathic osteoporosis, the cartilaginous ground substance contains collagen fibrils that can vary considerably in length, structure and diameter. In one case of WOLCOTT-RALLISON syndrome, the lacunae of the chondrocytes are found to contain very wide amianthoid-like and inadequately aggregated collagen fibrils. In numerous cases, osteogenesis imperfecta reveals very fine and also irregularly structured collagen fibrils with scarcely discernible cross-striation in the region of the osteoid, which is of varying width. In some of the cases, catechin has a favourable effect on the formation of collagen fibrils, resulting in broader and more densely packed fibrils. In addition, the conditions are associated with considerable intracellular changes in the rough endoplasmic reticulum, the Golgi apparatus and the mitochondria.Supported by a grant from the Stiftung Volkswagenwerk Research Project: Skeletal Dysplasias     

Clinical epidemiology of skeletal dysplasias in South America

Currently accepted birth prevalence for osteochondrodysplasias (OCD) of about 2/10,000 is based on few studies from small series of cases. We conducted a study based on more than 1.5 million births. OCD cases were detected from 1,544,496 births occurring and examined in 132 hospitals of ECLAMC (Latin American Collaborative Study of Congenital Malformations) between 2000 and 2007. Cases were detected and registered according to a pre-established protocol, and then ranked in four diagnostic evidence levels (DEL), according to available documentation. For the analysis of risk factors, a healthy control sample born in the same period was used. OCD was diagnosed in 492 newborns, resulting in a prevalence per 10,000 of 3.2 (95% CI: 2.9-3.5). Perinatal lethality (stillbirths plus early neonatal deaths) occurred in 50% of cases. Prenatal ultrasound diagnosis was made in 73% of cases (n = 359). Among 211 cases from the best documented group (DEL-1) and according to international classification, 33% of cases fit into the G-25 (osteogenesis imperfecta), 29% in Group-1 (FGFR3), and 8% in Group-18 (Bent bones). The prevalence of the main OCD types were: OI-0.74 (0.61-0.89); thanatophoric dysplasia-0.47 (0.36-0.59); and achondroplasia-0.44 (0.33-0.55). Paternal age (31.2 ± 8.5), parity (2.6), and parental consanguinity rate (5.4%) were higher in cases than in controls (P < 0.001). In conclusion, the OCD overall prevalence of 3.2 per 10,000 found seems to be more realistic than previous estimates. This study also confirmed the high perinatal mortality, and the association with high paternal age, parity, and parental consanguinity rate.     

Analysis of skeletal dysplasias in the Utah population

The Utah Birth Defect Network (UBDN) collects population-based data for Utah on births from all resident women. The prevalence of skeletal dysplasias and epidemiologic characteristics/outcomes were evaluated. Cases categorized as a skeletal dysplasia from all live births, stillbirths, and pregnancy terminations (TAB) between 1999 and 2008 were reviewed by three clinical geneticists. After case review, 153 were included for analysis (88% live births, 3% stillborn, 9% TAB), and categorized by groupings defined by molecular, biochemical, and/or radiographic criteria as outlined in the 2010 Nosology and Classification of Genetic Skeletal Disorders. The overall prevalence for skeletal dysplasias was 3.0 per 10,000 births, and 20.0 per 10,000 stillbirths. The most common diagnostic groups were osteogenesis imperfecta (OI; n = 40; 0.79 per 10,000), thanatophoric dysplasia (n = 22; 0.43 per 10,000), achondroplasia (n = 18; 0.35 per 10,000), and cleidocranial dysplasia (n = 6; 0.12 per 10,000). The most common groups based on the 2010 Nosology and Classification of Genetic Skeletal Disorders were the FGFR3 chondrodysplasia group (n = 41; 0.81 per 10,000), the OI/decreased bone density group (n = 40; 0.79 per 10,000), and the type 2 collagen group (n = 10; 0.2 per 10,000). Median age of postnatal diagnosis was 30 days (range 1-2,162). Of those deceased, 88% were prenatally suspected; of those alive 29% prenatally suspected. Median age of death for live born individuals was 1 day (range 1-1,450 days). Previously reported prevalence rates vary, but our data provide a population-based approach not limited to the perinatal/neonatal period. Understanding the range for survival within each group/diagnosis is beneficial for health care providers when counseling families.     

Blood pressure in adults with short stature skeletal dysplasias

Hypertension, compounded by obesity, contributes to cardiovascular disease and mortality. Data describing hypertension prevalence in adults with short stature skeletal dysplasias are lacking, perhaps due to poor fit of typical adult blood pressure cuffs on rhizomelic or contracted upper extremities. Through health screening research, blood pressure was measured in short stature adults attending support group meetings and skeletal dysplasia clinics. Blood pressure was measured with a commercially available, narrower adult cuff on the upper and/or lower segment of the arm. Height, weight, age, gender, diagnosis, exercise, and medications were collected. Subjects were classified as normotensive, prehypertensive, or hypertensive for group analysis; no individual clinical diagnoses were made. In 403 short stature adults, 42% were hypertensive (systolic >140, diastolic >90 OR taking antihypertensive medications). For every BMI unit and 1 kg weight increase in males, there was a 9% and an 8% increase, respectively, in the odds of hypertension versus normotension. In females, the increase was 10% and 6%, respectively. In those with achondroplasia, the most common short stature dysplasia, males (n = 106) had 10% greater odds of hypertension versus normotension for every BMI unit and kilogram increase. In females with achondroplasia (n = 128), the odds of hypertension versus normotension was 8% greater for each BMI unit and 7% for each additional kilogram. These data suggest a high population prevalence of hypertension among short stature adults. Blood pressure must be monitored as part of routine medical care, and measuring at the forearm may be the only viable clinical option in rhizomelic short stature adults with elbow contractures.     

Guidelines for the prenatal diagnosis of fetal skeletal dysplasias

The osteochondrodysplasias, or skeletal dysplasias are a genetically heterogeneous group of over 350 distinct disorders, and many of them can present in the prenatal period as demonstrated by ultrasound. Differentiating these disorders in the prenatal period can be challenging because they are rare and many of the ultrasound findings are not necessarily pathognomic for a specific disorder. However, differentiating known lethal disorders from nonlethal disorders, providing differential diagnoses before delivery, determining postdelivery management plans and ultimately determining accurate recurrences risks to the at-risk couples improves patient care. These guidelines provide an approach to a fetus suspected of manifesting a skeletal dysplasia.     

The long and the short of it: developmental genetics of the skeletal dysplasias

The skeletal dysplasias are a large heterogeneous group of genetic conditions characterized by abnormal shape, growth, or integrity of bones. Often, there may be prominent features associated with other organ systems as part of a more encompassing skeletal malformation syndrome. Tremendous advances have been made in the clinical and molecular delineation of these conditions over the past 20–30 years. We have progressed from initial broad clinical classifications of these conditions in the first two-thirds of this century, to extensive delineation based on radiographic features in the 1970s and 1980s, to the present reconsideration and grouping of these conditions according to their molecular pathogenesis. This has in part been spurred on by advances in the understanding of the developmental pathways which govern skeletal development, as well as by the human genome sequencing effort, which has provided a plethora of positional candidate genes for many of these conditions. The pathogenetic correlations derived from such studies are often based on parallels between the human phenotype and mouse models of the human condition, and have sometimes revealed novel developmental functions.     

The long and the short of it: developmental genetics of the skeletal dysplasias

The skeletal dysplasias are a large heterogeneous group of genetic conditions characterized by abnormal shape, growth, or integrity of bones. Often, there may be prominent features associated with other organ systems as part of a more encompassing skeletal malformation syndrome. Tremendous advances have been made in the clinical and molecular delineation of these conditions over the past 20–30 years. We have progressed from initial broad clinical classifications of these conditions in the first two-thirds of this century, to extensive delineation based on radiographic features in the 1970s and 1980s, to the present reconsideration and grouping of these conditions according to their molecular pathogenesis. This has in part been spurred on by advances in the understanding of the developmental pathways which govern skeletal development, as well as by the human genome sequencing effort, which has provided a plethora of positional candidate genes for many of these conditions. The pathogenetic correlations derived from such studies are often based on parallels between the human phenotype and mouse models of the human condition, and have sometimes revealed novel developmental functions.     

Skeletal dysplasias reveal genes of importance in skeletal development and structure

Naturally occurring and induced genetic anomalies of skeletal development offer a unique opportunity to identify all the genes that are relevant to the development, maintenance, and repair of the skeleton. Such studies also should provide new insights into the regulation of gene expression, the order of gene expression, interactions of the gene products, and the role of environmental factors in normal and abnormal skeletogenesis.     

COL2A1-related skeletal dysplasias with predominant metaphyseal involvement

Skeletal dysplasias induced by mutations in the collagen 2 gene (the so-called "type 2 collagenopathies") form a wide spectrum in severity and are distinguished by subtle clinical and radiographic differential signs. The unifying features are predominant involvement of the vertebral bodies and the epiphyses of the long bones ("spondylo-epiphyseal" pattern). A mild degree of metaphyseal dysplasia can be seen in the so-called Strudwick variant of spondyloepimetaphyseal dysplasia and is generally mild or absent in other forms.We report here on four individuals with COL2A1 mutations associated with marked metaphyseal involvement with only mild epiphyseal and spondylar changes. One patient who carried a Gly283Arg substitution had a pattern of metaphyseal dysplasia that corresponded precisely to what was termed "Murdoch type metaphyseal dysplasia" in 1960s and was renamed Strudwick type SEMD in 1980s; the second patient carried a Gly181Arg substitution and had severe metaphyseal dysplasia with fractures at the metaphyses reminiscent of the "corner fractures" or Sutcliffe type spondylometaphyseal dysplasia. The third patient also had major metaphyseal involvement but more epiphyseal changes than the others in this study and had a Gly922Arg mutation in COL2A1. The final patient had a small in-frame deletion and unusually ballooned and distorted metaphyses.While it remains true that most individuals with COL2A1 mutations have chondrodysplasia with a spondylo-epiphyseal pattern, metaphyseal involvement is not incompatible with a COL2A1 dysplasia and mutation analysis can be indicated. The observation of these individuals with metaphyseal dysplasia indicates that the phenotypic spectrum associated with mutations in type 2 collagen, the main cartilage protein, is even wider than hitherto assumed.     

Skeletal dysplasias caused by a disruption of skeletal patterning and endochondral ossification

Identification of a number of the genes that cause skeletal dysplasias has helped clinicians to provide accurate diagnoses, genetic counseling, and pre-natal diagnosis for this complex group of disorders. This review considers how some of the recent advances in human and murine genetics have led to an increased understanding of normal bone development and, in particular, the processes of skeletal patterning and endochondral ossification.     

Neurologic abnormalities in the skeletal dysplasias: A clinical and radiological perspective

The neurologic manifestations of the skeletal dysplasias are reviewed. Three important major groups are identified: Achondroplasia (cranio-cervical junction problems in infancy, spinal stenosis and neurogenic claudication in the adult). Type II collagenopathies (upper cervical spine anatomic and functional problems), and craniotubular and sclerosing bone dysplasias (osseous overgrowth with foraminal obstruction problems). The remainder of the well-identified 150 or so bone dysplasias are also evaluated in depth for their diverse neurologic abnormalities. The findings discussed are important both for the diagnosis and management of these patients. Am. J. Med. Genet. 69:33–43, 1997. © 1997 Wiley-Liss, Inc.