Chapter 17, A Diagnostic Approach to Skeletal Dysplasias
The most recent classification has been made by Bonafe et al. Based on the epidemiological and clinical aspects, skeletal dysplasias can be further subdivided in order to simplify the diagnostic approach [ 26 , 27 ]:. To evaluate dysplastic patients, plain films of the entire skeleton should be evaluated Figures 5 — As suggested by Amaka et al. At first, it is important to define the anatomical localization of the abnormalities. Particularly, alteration of appendicular skeleton can involve the epiphysis, metaphysis or diaphysis; depending on the part involved, shortening of appendix is called rhizomelic, if proximal, mesomelic, if in the middle, acromelic, if distal or micromelic, if there is a generalized shortening of the limb.
Finding very small epiphysis due to a delay in ossification or irregularly ossified epiphysis, radiologically suggest an epiphyseal dysplasia. The diagnosis of metaphyseal dysplasia is done if a widened, flared or irregular methapysis is found [ 28 ]. If even the spine is involved, these pathologies can be further differentiated in spondyloepiphyseal, spondylometaphyseal dysplasias [SMDs], or spondyloepimetaphyseal dysplasias [SEMDs] [ 2 ].
Short metacarpals, especially the fourth and fifth; cone-shaped epiphyses. Metaphyseal hooking at the proximal ends of several of the middle phalanges. Perthes-like changes in capital femoral epiphysis. Bones can be described as tall, short, large, broad or hypoplastic. The research of complications is important to have a complete picture of the patient. Fracture due to osteoporosis or osteopetrosis, atlantoaxial subluxation in mucopolysaccharidosis, progressive scoliosis are only few examples of the variety of the clinical scene [ 29 ].
The latest guideline about radiological classification of skeletal dysplasias points out four groups, as follow:. Skeletal dysplasias, as previously explained, affect both the linear growth and the body proportion; particularly, the growth of the legs and arms is often more compromised than the trunk [ 30 ], as well as we can discover in the ACH. In one-fourth of cases of skeletal dysplasias, the short growth is detectable since the prenatal age, while in the three-fourths remaining in the first two-three years of life. The final height is usually below 3 SD; here are presented the ranges of adult height for the most common dysplasis Table 2.
Actually, the growth pattern of these rare pathologies has not been completely understood yet, because of the scarcity of data in the international literature. Therefore, it is difficult to establish whether the child grows under the standard centiles in a linearly way or if there are peculiar moment of important growth decrement.
However, because of many data regarding auxological longitudinal growth in many condition of bone dysplasia is lacking, knowledge on growth pattern is available only for a few skeletal dysplasias. It is interesting to note that different skeletal dysplasias seem to show similar growth pattern, as well as ACH, diastrophic dysplasia and cartilage-hair dysplasia.
Ranges of adult height in the main skeletal dysplasia irrespective of gender. Modified by [ 24 ]. Mean height expressed in SDS for age in Caucasian boys and girls with achondroplasia modified by [24]. Hence, linear growth is fairly normal for the first postnatal months followed by a significative reduction of growth velocity and length to about —5 SD at 2 years of age. Finally, this position is maintained during the prepubertal years with a further loss during puberty Figure The growth hormone GH is a polypeptide made by amino acids, synthesized by somatotrope cells and stored in the anterior pituitary gland.
GH is encoded by GH1 gene situated on the long arm of chromosome 17 at position Mutations or deletions of one of these genes lead to growth hormone deficiency, resulting in short stature. GHRH is a peptide produced in the hypothalamus that activates the production in and release of GH from the pituitary; GHRH binds to specific receptors, a seven transmembrane domain receptor member of the family of G-protein-coupled receptors, and located on the somatotrope cells [ 31 ]. However, STT is peptidic hormone inhibiting the release but not the GH production; STT is present in the hypothalamus but also in other part of central nervous system and in extra-nervous tissues as D-pancreatic cells, gastrointestinal cells and parafollicular thyroid cells.
SST binds to a specific receptors located on the somatotrope cells, but this kind of receptors is tied to inhibitor G protein; so that way when the SST binds its receptors, it will be an inhibition of adenylate cyclase and so a decrease of c-AMP. The final result is an arrest of GH secretion from the cells. Ghrelin, first identified in by Kojima et al.
Ghrelin regulation and function are very complexed, in fact it is regulated by a lot of external stimuli, such as the food intake, that decrease its secretion, instead food deprivation, hypoglycaemia and leptin administration increased this hormone [ 33 ]. Ghrelin acts directly on somatotropes cell and indirectly stimulate the release of GHRH. GH secretion is also related to external mechanisms, such as stress, hypoglycaemia, sex hormones secretion, starvation, sleep or exercise, all condition increasing its secretion.
On the contrary, other factors like hyperglycaemia, dopamine or glucocorticoid decrease it. However, many data demonstrate a bipotential action of glucocorticoid on GH secretion. In fact, while physiological level of cortisol is essential to maintain the GH axis, elevated amounts of glucocorticoid seem to increase STT levels, and so reduce GH secretion [ 34 ]. GH makes an auto-feedback that leads a decreased of GHRH secretion, and so that way it reduces itself. During the childhood GH and thyroxine are the most relevant molecules involved in linear growth; so if there is an inadequate GH secretion linear growth slows down, and we can notice a clinical short stature, usually harmonic one.
However, at puberty, the activation of the hypothalamic-gonadal axis leads to a significant increase in h GH, probably because of an interaction between more factors. The result is a physiological and self-limiting hypersomatotropism that it leads to the definitive stature. In this period of life, an important increase of plasma IGF-1 concentrations was observed, leading to the growth velocity peak. Then, during puberty-adult age transition, there is a decrease of GH and IGF-1 plasma concentrations [ 35 ].
Most patients with skeletal dysplasia show severe short stature. Surgical therapy has been attempted to correct bone deformities, but therapy conducted to improve severe short stature has been rarely attempted. However, the optimal management of physiologically and clinically heterogeneous bone disorders requires an understanding of their medical and psychosocial complications. While researchers make progress in understanding the molecular mechanisms behind these disorders and identify possible therapeutic interventions in patients with skeletal dysplasia, it remains to be identified which treatments may allow a better improvement in stature.
For example, for those with achondroplasia and related disorders, fibroblast growth factor receptor 3 FGFR3 has been identified as a critical regulator of endochondral bone growth, and in these patients mutations in the coding sequence of the FGFR3 gene have been identified [ 36 , 37 ]. In these patients, several approaches to reduce FGFR3 signalling by blocking receptor activation or inhibiting downstream signals have been proposed, some promising in preclinical animal models and other in humans [ 38 ]. So, in this section of the chapter, we try to critically evaluate the data available on the endocrine characteristics and response to GH treatment of these patients, considering the great diversity of the studies performed as well as length of observation, the sample size and GH dosage used Table 3.
ACH is characterized by short-limbed dwarfism, macrocephaly with a prominent forehead and midface hypoplasia. In ACH adult, height may be — cm for men and — cm for women [ 79 ], causing considerable inconvenience in daily life and places considerable psychological problems on patients and their families [ 41 ]. In these patients, pathogenesis involves a defective endochondral ossification while periosteal and membranous ossification are normal [ 80 ].
Many data are available about the endocrine features of ACH patients. For example, Yamate et al. However, these data were confirmed by a very large study involving 42 patients with ACH, in which it was shown that some patients presented a blunted response on different GH provocation tests, whereas other patients showed a combination of a blunted response on one provocation test and low GH concentration during sleep [ 41 ]. On the contrary, data suggest that ACH children showed normal thyroid function, TSH response to TRH stimulus, as well as cortisol response to insulin-induced hypoglycaemia.
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In ACH patients, data are available about the treatment with r-hGH, even if with controversial results [ 41 , 81 — 84 ]. Data about trials have shown a variable response to treatment, even if the limited number of patients and the variability in the pubertal stage of the enrolled subjects make it very difficult to draw any final conclusions on the role of GH therapy.
However, a 6-month therapeutical trial carried out in six patients with ACH have showed that the response may to be related on pretreatment growth velocity [ 84 ], with a greater increment of growth velocity in the patients with a lower growth rate before therapy. The authors hypothesized that the variation in response to GH therapy could be related to the different ages and pubertal stages of the enrolled children [ 84 ]. In a large study involving 42 ACH patients, Tanaka et al. However, the responses to GH treatment after the second year were not uniform.
In these patients, the ratios of arm span to height and sitting height to overall height were not significantly increased during GH therapy, as well as there was no significant difference in mean height velocity at the end of each year between the patients with normal or subnormal GH secretion, and between the patients treated with 0. During the treatment, the authors did not show significant changes in thyroid function tests or routine laboratory data or in spinal cord compression or narrowing of the foramen magnum [ 41 ]. However, Hertel et al. Besides, Weber et al.
In these patients, oral glucose tolerance test at the beginning and at the end of the therapy were in the normal range [ 86 ]. Therefore, the available data suggested that r-hGH may be useful in some patients with ACH in increasing the height and growth velocity. Waiting for new, more effective and specific treatments in patients with ACH, r-hGH treatment may be beneficial in the treatment of short stature in achondroplasia. About this, it will be helpful to the activation trials evaluating the response to different doses or also evaluate the combination of different, both medical and non-medical treatments.
Hypochondroplasia HCH , a heterogeneous and usually mild form of chondrodystrophy, is a common cause of short stature.
It often goes unrecognized in childhood and is diagnosed in adult life when disproportionate short stature becomes obvious [ 87 ]. Children with severe short stature and disproportion of the body segments usually have the mutation AsnLys [ 87 ]. The available data seem to demonstrate that patients with HCH respond to r-hGH treatment with an increase in spinal length and, coupled with a surgical leg-lengthening procedure, it is possible for some patients to achieve adult heights within the normal range [ 87 ].
However, GH therapy may restore the impairment of growth rate at puberty Figure However, Rothenbuhler et al.
Buy Chapter 17, A Diagnostic Approach to Skeletal Dysplasias: Read Kindle Store Reviews - www.farmersmarketmusic.com A Diagnostic Approach to Skeletal Dysplasias This chapter reviews this sequence of diagnostic steps . due to failure of proper in utero movement [17].
Their mean height SDS increased by 1. These results were confirmed by a meta-analysis involving HCH children, administrated with median 0. In these patients, the therapy progressively improved the height and growth velocity with 12 months catch-up growth, and this improvement resulted constant until 36 months, even if the stature remained subnormal.
While bone age chronologically progressed, no serious adverse events were reported [ 90 ]. Interestingly, using criteria based on the radiographic findings of decreased interpediculate distance between L1 and L5, Mullis et al. In conclusion, patients with HCH seem to show a significative response to r-hGH therapy with an increase in spinal length and stature, and reduced the impaired growth spurt during puberty.
It is important, therefore, to monitor all patients during childhood and give r-hGH treatment to those patients who fail to develop a growth spurt at puberty or showing a severe short stature. Effect of r-hGH therapy the beginning is specified with the black arrow in a female patient with a severe form of hypochondroplasia.
You may notice the significant improvement of their stature in the short and medium term. Pubertal development onset was determined at the time of the last survey reported. X axis corresponds to the age of the patients expressed in years. Effect of r-hGH therapy the beginning is specified with the black arrow in a female patients with type 1 Trichorhinophalangeal syndrome without GH deficiency.
Type 1 trichorhinophalangeal syndrome TRPS1 , first described by Klingmuller in and then named by Giedion in , is a rare genetic condition characterized by typical craniofacial and skeletal abnormalities with short stature [ 92 ]. The patients showed commonly sparse scalp hair and lateral eyebrows, bulbous tip of the nose, long flat philtrum, thin upper vermilion border and protruding ears. Skeletal abnormalities may include cone shaped epiphyses at the phalanges, hip dysplasia and short stature [ 92 ].
The patient shows no response to the GH stimulation tests, thus disclosed a GH deficiency, nevertheless, after r-hGH treatment catch-up growth occurred. However, Naselli et al. Finally, Merjaneh et al. Bone age advanced by 2. He remained prepubertal during treatment. On the contrary, only few cases of GHD were diagnosed: The male patient had also a TSH deficiency [ 99 ]. Treatment with r-hGH was effective in both patients although their growth remained restricted. If the result is subnormal, then GH therapy should be prescribed. Cartilage-hair hypoplasia CHH is an autosomal recessive metaphyseal chondrodysplasia characterized by severe short-limb short stature and hypoplastic hair.
The effects of treatment are more evident in patients with more severe growth retardation. However, the effects are temporary without gain in final height. However, serum immunoglobulins did not change during r-hGH treatment. On the contrary, Harada et al. However, Obara-Moszynska et al. In conclusion, the poor data available suggest a possible role of r-hGH in treating the severe short stature in CHH patients. SHOX is the abbreviated designation for the Short stature Homeobox-containing gene and is localized in the pseudoautosomal region of both X and Y chromosomes [ ].
SHOX is one of many genes that regulate longitudinal growth and SHOX deficiency, due to intragenic or regulatory region defects, cause a phenotype ranging from normal stature to mesomelic skeletal dysplasia [ ]. Since discovery of SHOX gene in , r-hGH treatment was potentially reported for growth promotion in these patients [ ]. Because of SHOX deficiency represent the main cause of short stature in TS and the r-hGH acts as an efficient and safe treatment, the same therapy in short children with SHOX mutation at the same dosage of TS displayed an excellent growth spurt, suggesting that growth-promoting therapy with rhGH was effective with regard to height gain in short stature due to SHOX deletions [ ].
In another 2-year prospective open-label randomized study involving two cohorts of SHOX-deficient patients and a cohort of TS patients, the untreated cohort grew with a normal height velocity and unchanged height SDS, whereas the r-hGH-treated cohort grew faster and as fast as the girls with TS [ ]. However, retrospective data showed also that final heights in patients with SHOX deficiency treated for more than 2 years, even if with low r-hGH dose, presented an overall gain in height of 7 cm, not different from the mean gain in height in treated TS girls [ ].
Osteogenesis imperfecta OI or brittle bone disease is a clinically and genetically heterogeneous group of heritable disorders of connective tissue [ ]. The hallmark feature of OI is represented by bone fragility with susceptibility to fracture from minimal trauma. As a consequence, these patients showed bone deformity and growth deficiency [ ]. However, OI patients may show other phenotypic features, as macrocephaly, blue sclerae, dentinogenesis imperfecta, hearing loss, neurological defects and cardiopulmonary complications [ ]. In these patients, genetic counselling and study are essential components of complete care for individuals with OI, as are nonsurgical e.
In general, many data suggest that r-hGH may have a positive effect on bone growth and bone turnover by stimulating osteoblasts, collagen synthesis and longitudinal bone growth [ ]; however, in the first 6 months of r-hGH therapy in GH deficiency GHD patients, bone resorption is usually greater than bone formation, and there are more resorption markers [ ].
Besides these actions on bone GH may show a positive action on collagen metabolism [ , ], stimulating the IGF-1 and IGFBP-3 expression, which in turn regulates the synthesis of type I collagen [ , ]. Besides this aspect, there is scarce data about r-hGH treatment in OI patients [ — ]. Nevertheless, in one of the first attempts to treat OI patients with r-hGH, the treated patients showed, using a bone histomorphometry study, an increase in periosteal new bone formation and intracortical bone resorption, with enhanced osteoblastic activity [ ]. However, the study of GH-somatomedin axis activity in OI showed that IGF-1 serum levels are frequently in the low normal range in the most part of these patients [ , ].
In fact, Marini et al. However, some data suggest that the type IV OI children would benefit from r-hGH treatment in terms of linear growth, bone matrix synthesis and bone histomorphometric parameters [ ].
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In a mouse model of OI, r-hGH injections [ ] increased spine and femur length, produced significant changes in densitometry parameters and ameliorated the biomechanical structural properties of bone. Accordingly, similar results are obtained in human, since r-hGH treatment seems to cause a positive effect on height growth and increase in skeletal volume and BMD, with a possible subsequent reduction in fracture.
However, the combined treatment with r-hGH and neridronate positively increases BMD at the lumbar spine and wrist and significantly increases the rate of linear growth velocity, with no BA advancement; and no influence in the peripheral fracture rate [ 60 ]. EvC is characterized by ectodermal dysplasia affecting mainly the teeth and nails, chondrodysplasia of the long bones, postaxial polydactyly and congenital heart anomalies.
The entity was mapped at chromosome region 4p16 [ , ] and subsequently the EVC gene was cloned [ ]. A second gene EVC2 located in the same chromosomal region was found to harbour mutations in some EvC patients [ ]. In this syndrome, data on growth patterns are limited, but in general growth is markedly impaired [ 51 ]. In most reports, only one measurement of the patient is mentioned, and few follow-up data are published. For example, Versteegh et al.
In the first, a mutation in the EVC2 gene was reported. Target height was 0. Skeletal age is approximately 1 year behind at the start of r-hGH treatment, at 11 years of age exceeded the chronological age by approximately 2 years. In the second patients, no mutation was detected. GHD was ruled out by an arginine stimulation test, even if, because of a severe decline in growth velocity, treatment with e-hGH was started. Four patients were diagnosed as GHD. All patients except one were treated with GH according to standard protocols. In conclusion, the available data suggest that GHD can play a role in the retarded growth in at least some EvC patients.
Skeletal dysplasias are a wild and complex group of diseases due to several pathogenetic mechanisms. Up to date, even because of their rarity, available knowledge is not so large and most of this is about a very restricted number of dysplasias. Particularly, the specific aspect of the linear growth in these patients has been analysed in a very small number of studies. No specific therapy is available and supportive measures are the only helpful treatment. By the way, data presented in literature allow us to evince that in some cases a pathological GH axis can be associated to the dysplasia.
So we suggest that in this patients could be useful to investigate the function of GH axis and, if defective, to start a replacement therapy with r-hGH.
Growth Hormone Axis in Skeletal Dysplasias
Clearly, GH therapy is not a target treatment for any of these dysplasias and further studies are necessary, but it could have a supportive role in the management of the auxoendocrinological growth in these disorders. We want to thank all the families of children with skeletal dysplasia that with love and dedication follow their children to improve their quality of life. The authors do not have any financial and non-financial competing interests in relation to this manuscript.
Embed this code snippet in the HTML of your website to show this chapter. Help us write another book on this subject and reach those readers. Login to your personal dashboard for more detailed statistics on your publications. Other conditions with craniosynostosis are Carpenter syndrome, hypophosphatasia, acrodysostosis, trimethadione sequence, acrocephalosyndactyly, Antley Bixler syndrome, Apert syndrome and many others.
Acrocephaly or turricephaly is the presence of a pointed head increased craniocaudal diameter caused by premature closure of all sutures. Acrocephaly is typical of Apert syndrome. Brachycephaly is characterized by a reduced occipitofrontal diameter caused by premature closure of the two coronal sutures. Plagiocephaly , which is usually not detected in utero , denotes an asymmetric shape of the skull caused by unilateral premature closure of the coronal and lambdoid sutures. Trigonocephaly indicates a triangular shape of the uppermost part of the skull, and is due to the closure of metopic suture Fig.
However, when the femur length is 5 mm below 2 SD of the mean, a significant skeletal dysplasia is almost certain. To evaluate dysplastic patients, plain films of the entire skeleton should be evaluated Figures 5 — Regional hypomineralization, in some cases. Up to date, even because of their rarity, available knowledge is not so large and most of this is about a very restricted number of dysplasias. However, Rothenbuhler et al.
Frontal bossing is a deformity of the forehead that may not only be associated with achondroplasia and craniosynostosis but also may be due to increased intracranial size with large hydrocephalus. The diagnosis is often suspected in a section of the lips of the fetus the section used to assess the presence of a cleft lip and made or confirmed in a sagittal facial section.
At the same time, a low nasal bridge may be present Fig. A smaller jaw micrognathia should also be sought at this time of the examination. The assessment of the fetal facial profile, performed on. Frontal bossing in sagittal scan in a fetus with achondroplasia Fig. Micrognathia the midsagittal view, is needed to detect micrognathia Fig. While looking at the head, note the distance between the eyes. A decreased distance hypotelorism or increased distance hypertelorism may be present in skeletal dysplasia.
Other associated findings in the face may be cleft palate and cataract. Abnormalities of Thorax Assessment of Spine and Thorax The spine is electively evaluated using the midsagittal view, possibly performed with an anterior spine, in order to assess the vertebral bodies and the cutaneous contour, taking care to reduce the pressure on the transducer to leave some amniotic fluid between the proximal uterine wall and spine, which greatly enhances the acoustic window.
This sagittal view allows display of neural tube defects as well as possible fusions of vertebral bodies. It also allows the suspicion of scoliosis to be raised, if the axis of the spine cannot be displayed from head to breech on a single plane; if this is suspected, a coronal view of the spine allows one to evaluate the degree of scoliosis 24 Fig. Hemivertebra have also been diagnosed in utero.
Also, the midsagittal view of the spine allows one to identify possible focal or general mineralization defects of the vertebrae. Parasagittal views at the level of the outer thoracic walls are used to display, on 2D ultrasound, gross mineralization or developmental anomalies of the ribs, as well as fractures Fig. To exclude thoracic hypoplasia, the dimensions of the thorax should be assessed on the 4-chamber and on the midsagittal view Fig.
At the level of the chest, look for abnormal rib size resulting in a chest that is too marrow Fig. Thoracic dimensions can be assessed by measuring the thoracic circumference at the level of four chamber view of the heart. It is ideal to refer to charts showing relationship between gestational age and thoracic circumference Fig.
These conditions are not lethal because the bones are abnormal, but the ribs are too short and, thus prevent the normal growth of the lungs. The resulting pulmonary hypoplasia is lethal. Differential Diagnosis of Short Ribs Achondrogenesis Asphyxiating thoracic dysplasia Jeune syndrome Atelosteogenesis Camptomelic dysplasia Chondroectodermal dysplasia Ellis-van Creveld syndrome Cleidocranial dysostosis syndrome Fibrochondrogensis Hypophosphatasia Jarcho-Levin syndrome Kniest dysplasia Melnick-Needles syndrome osteodysplasty.
Fractured fetal ribs with beaded appearance seen in a case of osteogenesis imperfecta type 2 Fig. Ossification and segmentation defects of spine seen at 14 weeks of gestation Fig. Showing narrow thorax suggestive of impending lethality due to pulmonary hypoplasia Metatropic dysplasia Osteogenesis imperfecta type II Otopalatodigital syndrome type II Pena-Shokeir syndrome Short-rib polydactyly syndrome type I and II Thanatophoric dysplasia. Figure showing short ribs leading to a narrow thorax Fig.
Comparison of chest circumference with abdominal circumference in a case of thanatophoric dysplasia Abnormalities of Spine The most common spinal abnormality seen in skeletal dysplasias is platyspondyly, which consists of flattening of the vertebrae Fig. This sign is typical of thanatophoric dysplasia. Achondroplasia shows absence of normal widening of the lumbar spine. Achondrogenesis type I is characterized radio graphically by poor ossification of the spine Fig. Spondyloepiphyseal dysplasia shows multiple vertebral anomalies. Longitudinal scan of the spine in a fetus with thanatophoric dysplasia and platyspondyly.
The intervertebral discs white arrows are greater in height than the vertebra black arrows which are flat Fig. Fetal spine showing scoliosis Obstetric Management Owing to the fact that most of the skeletal dysplasias diagnosed in the fetus are lethal, and if diagnosed within the legal time limit for termination of pregnancy where this is allowed , most will result in termination.
Furthermore, karyotyping should be performed only in the few cases in which a differential diagnosis with aneuploidies need be carried out, as in the case of diffuse joint contractures, which may be associated with trisomies 18 and 13 and neuroarthrogryposes. The perinatal management is also rather limited due to the fact that the non-lethal forms will need some respiratory assistance and physiokinesiotherapy in long-term.
After the Delivery Despite all efforts to establish an accurate prenatal diagnosis, a careful study of the newborn is required in all instances. The evaluation should include a detailed physical examination performed by a geneticist or an individual with experience in the field of skeletal dysplasia and radiograms of the skeleton. The latter should include a-. Examination of the skeletal radiographs permits precise diagnoses in the overwhelming majority of cases, since the classification of skeletal dysplasias is largely based on radiographic findings.
In lethal skeletal dysplasias, histologic examination of the chondroosseous tissue should be included, as this information may help reach a specific diagnosis. Chromosomal studies should be included, as there is a specific group of constitutional bone disorders associated with cytogenetic abnormalities. Biochemical studies are helpful in rare instances. DNA restrictions and enzymatic activity assays should be considered in those cases in which the phenotype suggests a metabolic disorder such a mucopolysaccharidosis. Two subtypes of thanatophoric dysplasia have been identified: This unusual aspect, also evident on ultrasound, has been noted as resembling the shape of a French telephone receiver.
The ribs are very short and, on the midsagittal low-magnification view of the fetal trunk, a dip typical of severe thoracic hypoplasia can be seen at the level of thoracoabdominal junction. The head is large with frontal bossing and a low nasal bridge, no major synostoses are present in type I thanatophoric dysplasia. On the contrary, in type II, there is a classic cloverleaf skull, recognizable on a coronal view of the fetal head, which is due to synostosis of the lambdoid, coronal and sagittal sutures responsible for the temporal b- Fig.
Telephone femur with redundant soft tissue in a case of thanatophoric dwarfism. The femurs are short, although less so than in type I, and, above all, they tend to be straighter. Severe polyhydramnios is constantly associated. In particular, all cases showing a LysGlu substitution are type II and show straight femurs and cloverleaf skull.
All other types of mutations found in the same gene have bowed femurs and no cloverleaf skull type I. Therefore, the recurrence risk is very low. Differential Diagnosis This includes the other skeletal dysplasias characterized by micromelia and severe thoracic hypoplasia namely achondrogenesis, hypophosphatasia and osteogenesis imperfecta type II.
With regard to type II thanatophoric dysplasia, the cloverleaf skull can also be present in very rare syndromes, such as Pfeiffer syndrome different skeletal anomalies and Crouzon syndrome no limb shortening. Ultrasound Diagnosis Type II: Ubiquitous and diffuse fractures Figs 26 and 27 thoracic hypoplasia, hypomineralization of the calvarium. Late onset bowing of long bones and fractures. Types I and IV are not diagnosable in the fetus. Motor disability of various forms in type III. Recently, therapy with bisphosphonates and stem cell transplantation has given good results in the non-lethal forms.
Inheritance pattern and recurrence risk: Autosomal dominant inheritance pattern. Ultrasound images show bone fractures and deformities. Postmortem histopathology of the affected bone in a case of osteogenesis imperfecta Differential Diagnosis OI type II should be differentiated from other lethal skeletal dysplasias presenting with micromelia and calvarial hypomineralization, namely, achondrogenesis, and hypophosphatasia.
In general, hypomineralization with clavicle sparing is a typical of hypophosphatasia. Micrognathia, present in achondrogenesis, is absent in hypophosphatasia while fractures are characteristic of OI type II. OI type III shows motor disability of variable severity kyphosis and fractures and worsening with age due to the extreme fragility of the bones. By adulthood, hearing loss otosclerosis , a need for walking aids and dentition problems are extremely frequent.
Types I and IV, which cannot be detected in the fetus, are associated with a better prognosis. De novo mutations with autosomal dominant inheritance. Subtypes of Achondrogenesis Two main subtypes have been recognized differing in inheritance pattern autosomal recessive for type I and autosomal dominant for type II and in a few sonographic aspects. In type I, or Parenti-Fraccaro type, the ribs tend to be thin often with multiple fractures, and the cranium is disproportionately large due to marked edema of soft tissues.
In fact, hydrops is frequently associated. Ultrasound Diagnosis The ultrasound diagnosis is based on the recognition of micromelia and thoracic hypoplasia, hypomineralization and micrognathia. In particular, the long bones appear barely visible and curved and the thorax extremely hyperplasic due to the underdeveloped ribs. The hypomineralization involves predominantly the spine, pelvis and calvarium. Severe micrognathia is also regularly associated. If the condition is recognized at 12 to 14 weeks of gestation, which is likely, hydrops and diffuse subcutaneous edema 'spaceman's suit' may also be seen.
The constant occurrence of fractures in osteogenesis imperfecta type II, the lack of micrognathia in hypophosphatasia, and the only mild hypomineralization in thanatophoric dysplasia, which often also shows curved femurs, are the selective ultrasound findings that should contribute to reaching the correct final diagnosis. In some cases, cardiac defects too. Regional hypomineralization, in some cases. Inheritance Pattern and Recurrence Risk Autosomal recessive: All are characterized by micromelia, thoracic hypoplasia with short ribs, and postaxial polydactyly.
Some feature other anomalies, including median cleft lip, congenital heart disease transposition of the great arteries and renal dysplasia. Etiology and Pathogenesis The real incidence of these syndromes is not known, but they are very rare disorders. The genetic defect responsible for the SRPS is still unknown. Ultrasound Diagnosis The ultrasound diagnosis is based on the detection of severe micromelia, severe thoracic hypoplasia with short ribs, and postaxial polydactyly other anomalies that may be detected by ultrasound in the various types include: Differential Diagnosis SRPS should be differentiated from the other lethal skeletal dysplasias presenting with micromelia and thoracic hypoplasia namely achondrogenesis, thanatophoric dysplasia, hypophosphatasia, and osteogenesis imperfecta type II.
Hydrops and subcutaneous edema if detected at 12 to 14 weeks. Outcome The forms detectable in utero are always lethal. Ultrasound Diagnosis Rhizomelia, mild late-onset macrocrania, and low nasal bridge. No risk of mental retardation. Orthopedic and pulmonary long-term sequelae due to the relatively small thorax.
Inheritance Pattern and Recurrence Risk Heterozygotic: Definition There are two types of achondroplasia defined according to their inheritance pattern: The former type, which is almost invariably lethal severe pulmonary hypoplasia , is by far the rarer variant due to the fact that it occurs only if both parents are affected.
The heterozygotic variant is the commoner one usually detected at birth and in some cases, in utero. Achondroplasia should short or borderline femur length and a tendency to macrocrania be detected in the 2nd trimester. However, in pregnancies at risk for achondroplasia, such as those in which one of the parents is affected, this search may be done on the chorionic villi, so that the diagnosis of achondroplasia can be confirmed or excluded.
Differential Diagnosis The differential diagnosis should include the other conditions that are possibly characterized by a borderline or short femur. The first and th-. In addition, the same cells may be used to extract the DNA needed for the diagnosis of achondroplasia. The other most important condition to rule out is early-onset a typical fetal growth restriction FGR , the onset of which may rarely be characterized by selective underdevelopment of the long bones.
The other skeletal dysplasias that may enter in the differential diagnosis, due to the presence of moderate rhizomelia at least in the 2nd trimester , are campomelic dysplasia, which is often characterized by micrognathia, and always by bowed bones, chondroectodermal dysplasia Ellis-Van Creveld Syndrome , which is associated with significant thoracic hypoplasia, polydactyly, and cardiac defects.
Ultrasound Diagnosis The ultrasound diagnosis is difficult, since the rhizomelia is of late-onset becoming evident only at 26 to 28 weeks of gestation. The femur and humerus are slightly-moderately shorter than normal showing biometry in the 1st to 5th centile range addition.
The morphology of the affected long bones is normal, which makes the diagnosis even more difficult. In some cases, the involvement of the humerus is more severe than that of the femur. Additional criteria that, if present, may support the ultrasound diagnosis of achondroplasia are a tendency to macrocrania and a low nasal bridge.
Ninety-seven percent of achodroplasic individuals show the same mutation, namely a guanine-to-adenine transition at nucleotide of the complementary DNA. This mutation prevents binding of FGF to its receptor, which in turn impairs bone growth. The birth prevalence ratios for the skeletal dysplasias. J Med Genet ;23 4: Camera G, Mastroiacovo P. Birth prevalence of skeletal dysplasias in the Italian multicentric monitoring system for birth defects.
Prog Clin Biol Res ; Mutations in the transmember domain of FGFR3 causes the most common genetic form of dwarfism, achondroplasia. Textbook of fetal and perinatal pathology. Charts of fetal size: Br J Obstet Gynecol ; Fetal femur length as a predictor of menstrual age: Fetal size charts for the Italian population.
Normative curves of head, abdomen and long bones. Usefulness of a short femur in the in utero detection of skeletal dysplasia. In utero analysis of heterozygous achondroplasia: Variable time of onset as detected by femur length measurements. J Ultrasound Med ;5 3: