Skeletal dysplasias are a large heterogeneous group of disorders consisting of abnormalities of bone or cartilage growth or their structure. Recently, 436 different entities have been described, despite the fact that the total number has gone down compared with the previous revision (by grouping of phenotypically indistinguishable entities).1 Although certain dysplasias individually are quite rare, their overall prevalence as a group has been reported to be 2.3 to 7.6 per 10,000 births in various epidemiologic studies.2–4 Some of them are perinatally lethal and can be diagnosed at birth, whereas some others are nonlethal and compatible with short or long-term survival.4,5 Approximately one-fifth of affected fetuses are stillborn, whereas one-third die during the first week of life.4,5 Lethality in these entities is usually due to thoracic underdevelopment and lung hypoplasia.5 Extensive vertebral and rib anomalies may result in thoracic cage deformity with adverse effects on thoracic growth and function.6 The inability of the thorax to support normal respiration or lung growth leads to thoracic insufficiency.6
Because of the considerable heterogeneity, the diagnosis of a skeletal dysplasia can be difficult.5 Despite advances in molecular genetics, as yet, there is no simple test available to achieve a diagnosis. Family history, and clinical and radiographic assessment all contribute to achieving a diagnosis. Radiographic evaluation is a common primary investigation in many diseases and is part of the skeletal survey for investigation of skeletal dysplasia. The initial identification and the decision to refer a patient for further molecular analysis and expensive genetic tests still frequently relies on clinical and radiological criteria.5–9
In this series, a review of 12 cases of clinico-radiologic diagnosis of skeletal dysplasia, which leads to thoracic insufficiency, is conducted. Thus, we intend to emphasize the examination of the skeletal radiographs based on the analysis of cardinal criteria, from which the most useful information is derived and which make further differentiation possible. Secondly, we would like to emphasize the importance of parental counseling, in accordance with that learned from case studies.
The database of our hospital, which is a maternity and children's hospital, was screened for neonates diagnosed with skeletal dysplasia from January 2011 to December 2014. Twenty-six patients were found. Of them, 15 showed respiratory distress/insufficiency during their hospital course. All hospital records including radiographs of them were reviewed. Two experienced radiologists independently evaluated all available radiographs of the patients. Clinico-radiologic diagnosis of skeletal dysplasia was precisely established in 12 patients. Unfortunately, genetic tests could not be performed due to the retrospective nature of the study. Ethical approval was not required because this is a retrospective case report based on medical records according to the guidelines of the Ministry of Health. Patient consent was not obtained because the study does not include any intervention or private patient information.
Clinico-radiologic diagnosis of skeletal dysplasia in 12 patients were as follows: short-rib polydactyly syndrome (SRPS) type 2 (Majewski syndrome; Figure 1), thanatophoric dysplasia (TD) type I (Figures 2A and B), osteogenesis imperfecta (OI) type IIA (Figure 3A), OI type IIB (Figure 3B), OI type III (Figure 3C), asphyxiating thoracic dystrophy (ATD), Ellis-van Creveld syndrome (EvC; Figure 4), caudal regression syndrome (CRS; Figure 5), congenital scoliosis (CS; Figure 6), spondylocostal dysostosis (SCD; Figure 7), and Klippel–Feil syndrome (KFS; Figures 8A and B). Demographic, clinical, and radiographic features of the cases are provided in Table 1. No case had regular antenatal visits; thus, prenatal diagnosis of abnormality was possible only toward the end of the pregnancies. In case 9, the mother was a diabetic and had a poor obstetric history. The majority of the cases had parental consanguinity (except cases 11 and 12). Nine cases were term, whereas 2 cases (cases 4 and 7) were near term. Case 12 was delivered at 31 weeks of gestational age. Except for cases 6, 7, 8, and 11, the remaining 8 cases required intubation in the delivery room.
Eight cases died within the first week of life due to cardiopulmonary insufficiency. Cases diagnosed with ATD and EvC syndrome were maintained on ventilatory support until their deaths at 4 weeks of life. The patient diagnosed with SCD was discharged with oxygen supplementation. He later required frequent rehospitalizations due to pneumonia and respiratory distress. He is currently waiting for surgery. After primary care and family education, the patient diagnosed with OI type III was discharged with a plan for regular clinical follow-ups of endocrinology, orthopedics, and physical therapy.
Whereas advances in genetic research are clearly important in the diagnosis of skeletal dysplasias and in developing better therapy for those conditions, the role of the pediatrician as the diagnostician has remained unchanged.8–11 Because the widespread use of molecular genetic testing for bone dysplasias is not available in many areas of developing countries, the clinico-radiologic diagnosis is emphasized; distinction among the various bone dysplasias is based largely on clinical and radiographic findings.8,9 The radiologic evaluation begins with a complete skeletal survey, ideally composed of a set of radiographs,8 but because this study was designed retrospectively, the diagnoses of cases were achieved by limited radiography.
As seen in this small series, some bone dysplasias are lethal.4 A correct diagnosis and typing of the skeletal disorder is essential for the prognosis as is genetic counseling of the family, including the possibility of prenatal diagnosis in subsequent pregnancies.10 A number of these disorders (SRPS, EvC syndrome, ATD) are autosomal recessive inheritance, whereas some (OI type II and III, TD type I, achondroplasia), and most de novo mutations, are autosomal dominant.1,9 The recurrence risk for future pregnancies is close to 25% in autosomal recessive disorders.10 However, it is never 0 for the others, because of de novo mutation. An empiric recurrence risk is estimated as 2% to 3% among siblings resulting from parental mosaicism for the mutation that is lethal in the infant who is heterozygous for the same mutation or due to the rare recessive form.10,12 In this series, the high rate of consanguineous marriages and irregularity of antenatal visits, despite the presence of family history, indicate the lack of competent parental counseling. Additionally, live-born infants affected with perinatally lethal skeletal dysplasias are usually the offspring of families with a low socioeconomic background who have not received prenatal follow-up.
Because sonography has become a routine component of prenatal care, many of these disorders are diagnosed prenatally.6,7 The ability to achieve the correct specific diagnosis by prenatal ultrasound depends on the type of skeletal dysplasia and gestational age at which ultrasound is performed.6,7 Discriminating between lethal and nonlethal forms of skeletal dysplasias is of major clinical importance. Sonographic markers of lethality are mainly based on the assessment of lung biometry, measurements of chest circumference and its relation to the abdominal circumference, femur length, and, finally, assessment of the pulmonary arteries by Doppler ultrasonography.6,7 However, the accuracy of the specific diagnosis is still dependent on the molecular genetic or post mortem examination.5
Short-rib dysplasias (with or without polydactyly) include SRPS (SRPS I–IV), ATD, and EvC syndrome.1 SRPS types 1 through 4 are lethal in the newborn period because of the severe pulmonary hypoplasia and other associated anomalies.13–15 On the other hand, the EvC syndrome and ATD are not uniformly lethal.16,17 Accurate prenatal diagnosis is important to provide adequate counseling.13
Overlap in the clinical and radiological features of SRPS types has led to difficulties in distinguishing between them. Type 1 SRPS (OMIM 613091) differs in shape (long bones with a torpedo-shape appearance) from type 3 SRPS (banana-peel shape), although there is a certain overlap of these features in the 2 disorders. In type 2 (OMIM 263520) and type 4 (OMIM 269860), the pelvis has a more normal appearance and the ends of the tubular bones are smooth. The occurrence of a median cleft lip also identifies type 2 and type 4 SRPS. However, short ovoid tibia are not seen in type 4 SRPS; this is the diagnostic finding of type 2 SRPS.13–15
Ellis-van Creveld syndrome (OMIM 225500) is characterized by progressively acromelic and mesomelic limb shortening, with smooth rounded metaphyses, postaxial polydactyly, small chest, ectodermal dysplasia, and, in many cases, congenital heart defects.16 The ribs are usually shorter in ATD (OMIM 208500), and heart defects and ectodermal dysplasia are not characteristics of ATD.17 The association of a small thorax with short ribs and a small pelvis is also seen in Barnes syndrome (OMIM 187760), which is distinguished from ATD by the presence of laryngeal stenosis and the absence of long bone changes and iliac spurs in infancy.18
Short-rib polydactyly syndrome should also be differentiated from other bone dysplasias presenting with micromelia and narrow thorax, namely achondrogenesis, TD, hypophosphatasia, and OI type II. These disorders are differentiated by their spinal, pelvic, and long bone changes.9,10 However, postaxial polydactyly is present only in SRPS.13
In achondrogenesis (OMIM 200600), there are unossified vertebral bodies, short ribs with splayed ends, hypoplastic ilia, and short, misshapen tubular bones with minimal tubulation.10,19 Infantile hypophosphatasia (OMIM 241500) is associated with severe demineralization and metaphyseal ossification defects reaching far into the diaphyses (the tubular bones are short and bowed with V-shaped ossification defects at their ends reaching deep into the diaphyses).10,20 Metaphyseal cupping and fraying of tubular bones have also been observed in Jansen metaphyseal dysplasia (OMIM 156400), which differs by the presence of splayed rib ends and normal alkaline phosphatase.9,10 In contrast to infantile hypophosphatasia, life expectancy is normal in Jansen metaphyseal dysplasia.10 OI type II (OMIM 166210) differs by the presence of rib and long bone fractures, and the absence of metaphyseal lesions.21 Flat vertebral bodies, squared iliac wings with wide, horizontal inferior margins, and curved femora with radiolucent upper ends in TD (OMIM 187600) rule out other lethal chondrodysplasia.10,22 A radiologically similar disease with favorable outcome is achondroplasia (OMIM 100800). The appearance of the vertebral bodies, pelvis, and tubular bones in achondroplasia is similar but milder than those in TD.10
The other rare skeletal dysplasias associated with narrow thorax and micromelia include campomelic dysplasia (OMIM 114290; bowed femora and tibia, normal bone density, hypoplastic scapula and vertebrae, and eleven pairs of ribs), Schneckenbecken dysplasia (OMIM 269250; short ribs with splayed ends, small ilia with medial projection from the inner margins, shortened, dumbbell-shaped tubular bones), fibrochondrogenesis (OMIM 228520; radiologically similar to Schneckenbecken dysplasia, small ilia with spurs extending caudally from the acetabular roof), metatropic dysplasia (OMIM 156530; mushrooming of the long tubular bones), and lethal metaphyseal chondrodysplasia (OMIM 250220; short ribs with splayed posterior ends and cupped anterior ribs ends, mildly shortened tubular bones with metaphyseal cupping and irregularity).9,10
Osteogenesis imperfecta type II is characterized by early prenatal onset of severe bone shortening and bowing of the long bones due to multiple fractures, poor demineralization of the skull, and a narrow and bell-shaped chest caused by fractures of the ribs.21,23 OI type II has been divided into OI types II-A, II-B, and II-C on the base of radiological characteristics.21 OI type II differs in the shortened, crumpled long bones, especially compressed (“telescoped” or “accordion-like”) femurs and/or humeri, and continuous beaded and broad ribs from OI type III (OMIM 259420), which has thin ribs with rare fractures and markedly angulated long bones, with wide metaphyses and thinner diaphyses.10,21 Although OI type III is not uniformly lethal in early infancy, as seen in this study, due to continuing fractures after birth, the appearance of the long bones can change in the course of time to the thick tubular bones seen in newborns with type II bone changes.10,21 In OI type III, thoracic insufficiency is also evident in later periods.21
Congenital scoliosis is a skeletal disorder in which lateral curvature of the skeletal spine results from asymmetric biomechanical forces, and can occur with many conditions including abnormal vertebral segmentation, neuromuscular disorders, and rare congenital syndromes.24 Therefore, it may be described as a clinical finding rather than a precise diagnosis. Severe CS may produce a progressive loss of torso mobility, resulting in fixed postural asymmetry, reduction in chest wall movement, and a consequent pulmonary hypoplasia and thoracic insufficiency.24
Caudal regression syndrome (OMIM 600145) is a rare and often sporadic congenital malformation of the lower vertebral column, characterized by partial or complete absence of sacrum and lumbar vertebrae.25 Associations most often reported with CRS include genitourinary, anorectal, vertebral, and cardiopulmonary anomalies, and may also include VACTERL association (OMIM 192350; abnormality of vertebrae, anus, cardiovascular system, trachea, esophagus, renal system, and limb buds), and sirenomelia (fusion of the lower limbs).25,26 Respiratory problems may arise from abnormal chest shape and size.25
Spondylocostal dysostosis is one of the 2 forms of Jarcho–Levin syndrome (OMIM 277300), which is characterized by distinctive malformations of bones of the spinal column (vertebrae) and the ribs, respiratory insufficiency, and/or other abnormalities.27 It is important to distinguish between SCD and spondylothoracic dysplasia (STD), because survival may be possible in the former, but the latter is usually fatal.27 SCD is differentiated by vertebral malformations, frequent dramatic rib malformations, and the absence of fan-like or crab-like thoracic configuration, whereas STD is characterized by vertebral body malformations and ribs that flare in a fan-like pattern, but that are not significantly malformed.27 The differential diagnosis of a patient with vertebral and rib anomalies includes KFS (OMIM 118100; cervical vertebral fusion, Sprengel deformity of the shoulder),28 dyssegmental dysplasia (OMIM 224400; micromelia with reduced mobility, bowing of the long bone with dumbbell-shaped metaphyses), CS, VATER/VACTERL, and COVESDEM (OMIM 268310; costovertebral segmentation defects with mesomelia) associations.
The clinical findings and examination of the skeletal radiographs permit precise diagnoses in the majority of cases with skeletal dysplasias, since the classification of skeletal dysplasias is largely based on clinico-radiographic findings. Knowledge of the main findings allows us to make the differential diagnosis. The high rate of consanguineous marriages and the irregularity of antenatal visits, plus the presence of a family history of skeletal dysplasias, emphasize the importance of both detailed and persistent parental counseling.
The authors acknowledge the support of Nilufer Okur, MD, for her help in data collection and of Ercan Donmez, Radiologist, for his help in the evaluation of radiographs.
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