Introduction: Skeletal dysplasia are a heterogenous group of disorders which affect the natural development of skeletal system and manifest as abnormalities of limbs, chest, skull or spine. These are genetic diseases which result in abnormal formation of chondro-osseous tissues. Their prevalence varies from 1:5000 to 1:3000 births with such wide variation primarily because of incomplete evaluation of still births and early neonatal deaths in several studies (1). These disorders contribute to a significant proportion of still births and early neonatal deaths, however several of them have better prognosis with survival well into adulthood. They have a varied clinical presentation and can be diagnosed at various ages due to this variable presentation (2). A comprehensive knowledge of these disorders is required for timely suspicion, complete examination, appropriate testing and diagnosis. Early and correct diagnosis is essential as most of these cases are lethal and a diagnosis helps in subsequent pregnancies.

Clinical presentation: Skeletal dysplasias may present in either of the following four presentations: (I) Still birth with antenatal suspicion (growth retardation, short bones, vertebral and facial anomalies) with/without antenatal diagnosis (II) still birth undiagnosed with postnatal findings of shorening, limb, chest or facial anomalies (III) neonate with shortening of trunk and/or limbs, facial anomalies, respiratory insufficiency, fractures (IV) infancy to adulthood with short stature and limb or spine deformities, fractures, eye/ear/dental abnormalities.

Clinical evaluation of a case of suspected skeletal dysplasia: Skeletel dysplasia is a very broad group involving host of disorders. The ones which present during neonatal period are listed in table 1 along with their features. A complete head to toe examination is required to find out all the abnormalities which can help in diagnosis. Skull should be examined for shape (barchycephaly, clover leaf, craniosynostosis), facial abnormal features like hypo/hypertelorism, cleft lip/palate, dentition anomalies, thorax should be examined for size, signs of respiratory insufficiency, spine should examined for kyphoscoliosis, limbs examined for shortening and contractures, site of shortening like proximal (rhizomelia), middle (mesomelia), distal (acromelia). Femur length-foot length ration less than 1 suggests skeletal dysplasia. Table 2 illustrates these clinical features along with their associated causes.

Radiological evaluation of a case of suspected skeletal dysplasia: A comprehensive and detailed skeletal survey is essential in aiding in diagnoses (3,4). Survey must include AP & lateral views of skull and thoracolumbar spine, AP views of chest, pelvis, one upper and lower limb, left hand (for bone age). The axial and appendicular skeleton must be properly examined for abnormalities like workman bones, thick skull, degree of ossification, platyspondyly (flat vertebral body), coronal clefts (radiolucent band running through at least one vertebral body), abnormal vertebral bodies like central beaking in Morquio’s disease and posterior hump shaped in SEDT. In appendicular skeleton, the site of affection (epiphyses, metaphases or diaphyses), type of limb shortening (rhizomelia, mesomelia, acromelia). The aetiologies associated with these findings are elaborated in table 2.

Postnatal management: After the delivery of a case of suspected skeletal dysplasia, initial stabilisation is very crucial which is to be followed by multi-disciplinary approach to diagnosis and ongoing care. Table 3 depicts the summarised care of such a baby. It is very essential to obtain samples for genetic tests for diagnosis as many of these disorders have poor prognosis and antenatal diagnosis in future pregnancies is crucial.

Conclusion: Skeletal dysplasia is a group of disorders with varied presentation and a strong clinical suspicion is necessary for timely diagnosis as outcomes are not very good. A multidisciplinary team approach is necessary to ensure a proper quality of life to survivors. Appropriate timely antenatal diagnosis at this point is primarily the mode of management. Future research on gene therapy and other treatments are required for ensuring better survival and quality of life to these individuals.

Table 1: Skeletal dysplasia which present during neonatal period. Abbreviations: AD autosomal dominant, AR autosomal recessive.

Table 2: Clinical features in case of skeletal dysplasia. Abbreviations: OI osteogenesis imperfecta, TD thanatropic dysplasia, JLS Jarcho-Levin syndrome, CDP chondrodysplasia punctata, CD campomelic dysplasia, CCD cleidocranial dysplasia, CDP chondrodysplasia punctata, DD diastrophic dysplasia, SEDC spondyloepiphyseal dysplasia congenita, SRPS short rib polydactyly syndrome, EVS Ellis van Creveld syndrome, HC Hypochondroplasia, FHUFS femoral hypoplasia-unusual face syndrome, MD metatrophic dysplasia, KD Kniest dysplasia, CFD craniofacial fibrous dysplasia, PD pyknodysostosis

Table 3: Postnatal management in case of suspected skeletal dysplasia. Abbreviations: BP blood pressure, CFT capillary refill time, PPHN persistent pulmonary hypertension, OI osteogenesis imperfecta, CKD chronic kidney disease.

References:

1. Andreas Zankl.Genetics of Bone Biology and Skeletal Disease (Second Edition), 2018
2. Seth J Langston, Deborah Krakow, Alison Chu. Revisiting Skeletal Dysplasias in the Newborn. Neoreviews 2021 Apr;22(4):e216-e229.
3. G R Mortier. The diagnosis of skeletal dysplasias: a multidisciplinary approach. Eur J Radiol 2001 Dec;40(3):161-7.
4. D Krakow. Skeletal Dysplasias. Clin Perinatol. 2015 June ; 42(2): 301–319.

What is the ideal time to look for the skeletal dysplasia?
The long bones, vertebrae and calvarium begin ossifying by 12 weeks, so the presence of certain skeletal dysplasias especially the lethal ones can be suggested as early as the first trimester.

When should we suspect for skeletal dysplasia?
Any fetus showing femoral length (FL) or humerus length (HL) measurements less than 5th centile or −2 SD from the mean at all gestations should be evaluated.

Table 1: Checklist to approach to the skeletal dysplasias.

Table 2:Important ratios to evaluate skeletal dysplasia.

• The femur length is more than >5 mm below 2 standard deviations (equivalent to greater than 4 standard deviations below the mean), the sonologist can be certain he or she is dealing with a significant skeletal dysplasia (Fig. 1a) (8). Femur length normalized chart is in Table
• The femur/foot length ratio (FL: foot) nomogram appears to be a useful parameter to help differentiate fetuses that have dysplastic limb reduction from those whose limbs are short because of constitutional factors or IUGR, significant correlation was demonstrated (r = 0.98; P less than .0001) (Fig. 1b)(9).
• 3D US calculated lung volumes compared to normal fetuses (
• Femur length to abdominal circumference ratio (FL:AC), (Sensitivity 92–96%) whencombined with the presenceof polyhydramnios, the ability to predict lethality has been reported tobe as high as 100% (11) (Fig. 1c).
• Chest circumference to abdominal circumference ratio (CC:AC), chest circumference to abdominal circumference ratio had the highest diagnostic accuracy for antenatal diagnosis of pulmonary hypoplasia (sensitivity: 93.5% and specificity: 90.3%) independent of gestational age (Fig. 1d) (12).

Lethality occurs in most skeletal dysplasia’s as a result of a small chest circumference and resultant pulmonary hypoplasia(13).Flowchart 1.Systematic approach to evaluate

Table 3: Ultrasound findings in Major skeletal dysplasias’s:

What is the role of 3D USG?

The overall accuracy for the diagnosis of the specific type of skeletal dysplasia using routine USG approaches only 40%-60%,which can be enhanced by the use of other imaging modalities. 3dimentional USG is helpful in differentiating the fetal facial abnormalities and in the evaluation of fetal limbs better, for example: severe flattening of the nasal bridge and craniosynostoses in thanatophoric dysplasia. Fetal MRI has been reserved for cases with suspected spinal abnormalities in the form of scoliosis or diastemetomylia. (14)

Is there any role for MRI in the diagnosis of skeletal dysplasia?

MRI has superior soft tissue contrast, better resolution, ability to examine both sides of the fetus simultaneously and also provide information about the stages of maturation of gray and white matter. Similar to USG it does not expose the fetus to ionizing radiation and has no teratogenic effect during pregnancy. (15) Echoplanar MRI may also be valuable in determining the presence or absence of ossification. Skeletal dysplasias such as osteogenesis imperfecta and hypophosphatasia, present with a generalized decrease in osseous density, which is demonstrated as lack of hypointense signal (indicative of normal ossification) on echoplanar imaging sequences. (16)

Prenatal use of CT scan in the diagnosis?

In a study conducted by Miyoko et al 3D-CT was more accurate than was 2D ultrasound in visualizing vertebral anomalies (abnormal shape of the vertebral bodies, abnormal interpedicular distance), pelvic bone malformations (delayed ossification of the pubic bones, abnormal acetabular shape) and enlarged metaphysis or synostoses in long bones. Both imaging techniques are useful in the management of fetal dysplasia; 2D ultrasound is a useful screening test and 3D-CT is a valuable complementary diagnostic tool (14). Because of the associated radiation dose, which may be similar to that of conventional fetal radiography, the use and potential impact of CT is limited. (17). There are ongoing newer studies on low dose 3D CT, where the dose is below 100mGy, reducing the overall exposure risk to mother and fetus.

What investigations are recommended in women who opt to discontinue the pregnancy?

Cases of suspected lethal skeletal dysplasia where the couple opt to discontinue the pregnancy or where there has been an antepartum stillbirth ,in order to reach a specific diagnosis a minimum post-delivery work up should include(a)external examination with photographs anterior and posterior of the appendicular and axial skeleton including hands and feet(b)post whole body radiographs/infantogram anteroposterior and lateral views (c)skin or tissue biopsy specimens for chromosome analysis or preservation of fibroblasts/DNA storage (d)if possible a complete autopsy should be performed. (18)

How to counsel the couple?

In cases where there is a previous molecular diagnosis of a childaffected by skeletal dysplasia, there is a role of prenatal diagnosis in the form of chorionic villous sampling or amniocentesis.In situations where either of the parent has a clinically identifiable skeletal dysplasia, they should be encouraged to get a molecular diagnosis before planning pregnancy.Role of Non-invasive testing in the diagnosis of Skeletal Dysplasia
There are several studies about the different techniques used for the non-invasive prenatal testing (NIPT) of achondroplasia like conventional PCR with restriction enzymes, matrix assisted laser desorption/ionization(MALDI) time of flight mass spectrometry, real time quantitative PCR, digital PCR and next generation sequencing (19-23).In 2019 Vivanti etal (24) reported the results of a novel simple non-invasive molecular analysis technique using high-resolution melting (HRM) analysis for the prenatal diagnosis of achondroplasia in a prospective multicentre cohort study. They also suggested thatcell free DNA can be advised in the first trimester in cases where there is history of an affected child with FGFR3 related skeletal dysplasia or where the father is affected but for technical reasons it cannot be applied to pregnant women who are affected by the disease, as their plasma contains a background of mutated DNA. NIPT can also be offered where neither of the parent is affected but FGFR3 related skeletal dysplasia is suspected in the fetus on the basis of USG.

How do we manage the pregnancy and labour?

The aim of antepartum care is to reach a final diagnosis as to the type of skeletal dysplasia the baby has, as that is one of the main indicators of the final outcome. The delivery should be planned in a tertiary care centre with a multidisciplinary team consisting ofan obstetrician,neonatologist, paediatric orthopedician and emergency medicine specialist. If possible, instrumentation during delivery should be avoided when fetal skeletal dysplasia is suspected due to the increased risk of intracranial and cervical spine complications.(25)Caesarean section is usually performed for obstetric indications or in cases where the biparietal diameter (BPD)>40cm.The role of elective caesarean section in women carrying a baby with suspected Osteogenesis imperfecta is controversial with newer guidelines indicating that an elective caesarean section vs a vaginal delivery does not reduce the risk of fractures(26). Postnatal genetic evaluation should be performed in order to confirm the diagnosis and also to assess the recurrence risk in future pregnancies.

References:

• Barbosa-Buck CO, Orioli IM, da Graça Dutra M, Lopez-Camelo J, Castilla EE,Cavalcanti DP. Clinical epidemiology of skeletal dysplasias in South America. AmJ Med Genet A 2012.
• Geert R. Mortier,Daniel H. Cohn,et al, Nosology and classification of genetic skeletal disorders: 2019 revision, Am J Med Genet. 2019.
• Parilla BV, Leeth EA, KambichMP et al (2003) Antenatal detection of skeletal dysplasias. J Ultrasound Med.
• Gaffney G,Manning N, Boyd PA et al (1998) Prenatal sonographic diagnosis of skeletal dysplasias–a report of the diagnostic and prognostic accuracy in 35 cases. Prenat Diagn.