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Postnatal evaluation and management of a case of suspected skeletal dysplasia

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.

Category Disease name Clinical and radiologic features Genes involved, inheritance and prognosis
FGFR3 group Thanatropic dysplasia
  • Narrow thorax with pulmonary hypoplasia
  • Short extremeties, normal trunk length
  • Cloverleaf skull, telephone receiver femurs
  • 4p16
  • AD
  • Lethal
Achondroplasia
  • Short extremeties, rhizomelia, normal trunk lengt
  • Macrocephaly, hydrocephalus
  • Trident hand, Hypotonia
  • Foramen magnum stenosis
  • Recurrent otitis media
  • Normal intelligence
  • 4p16
  • AD
  • Excellent
Hypochondroplasia Similar to achondroplasia, milder severity, later onset in second decade
  • 4p16, AD
  • Excellent
Type II collagen group Achondrogenesis type II
  • Hydrops, short trunk, prominent abdomen
  • Severe limb shortening
  • Severely retarded bone ossification
  • 12q 13 (COL 2A1)
  • AD, Lethal
Hypochondrogenesis
  • Similar to achondrogenesis but milder shortening and better ossification
  • Most die within first 3 months from respiratory insufficiency
  • 12q 13 (COL 2A1)
  • AD, poor
Kniest dysplasia
  • Thoracic kyphoscoliosis, lumbar lordosis
  • Platyspondyly, anterior vertebral wedging, coronal clefts
  • Flat mid face, depressed nasal bridge, cleft palate
  • Joint contractures, delayed ossification and deformation of epiphyses
  • Myopia, retinal detachement
  • Chronic otitis media, hearing loss
  • 12q 13 (COL 2A1)
  • AD
  • Fair to good
Spondyloepiphyseal dysplasia congenita
  • Similar to Kniest dysplasia but milder
  • Normal long bones
  • Coronal clefts absent
  • 12q 13 (COL 2A1), AD
  • Fair to good
Stickler syndrome
  • Midface hypoplasia, small upturned nose, cleft palate, Pierre Robin sequence
  • Joint hyper mobility
  • Vertebral coronal clefts, widened epiphyses
  • Myopia, cataracts, hearing loss
  • 12q 13 (COL 2A1),
  • AD
  • Good
Short rib dysplasia group Ellis van Crevald syndrome
  • Narrow thorax, dental anomalies
  • Polydactyly, rhizomelia, hypoplastic nails
  • Congenital heart disease
  • 4p 16 (EVC1&2), AR
  • Fair to good
Asphyxiating thoracic dysplasia (Jeune)
  • Narrow thorax with respiratory insufficiency
  • Polydactyly, short hands and feet
  • Metaphysical irregularities, short middle & distal phalanges
  • Chronic kidney disease, pancreatic and hepatic fibrosis
  • Hirschsprung disease, multiple gingival frenulae, hydrocephalus
  • 3q 24-26 (IFT80), 15q 13
  • AR
  • Fair
Decreased bone density group Osteogenesis imperfecta type I-IX
  • Type II and III evident at birth, others variable age group presentation frm infancy to adulthood
  • Type II most severe with multiple fractures and high lethality, others with variable fracture rates and short stature severity
  • Blue sclera in types I to III, hearing loss in types I and III
  • I, IV,V: AD
  • II & III: AD or AR
  • VI-IX: AR
  • I to IV: COL1A1 or 2
Defective mineralization group Hypophosphatasia

  • Perinatal lethal
  • Infantile
  • Severe shortening, respiratory failure, seizures
  • Undermineralization, rachicitic metaphases, craniosynostosis
  • Short stature, premature loss of deciduous teeth, symptomatic hypercalcemia
  • 1p36 (TNAP), AR, lethal
  • 1p36 (TNAP), AR, variable

 

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

 

Part of body Clinical or radiological feature Possible ethology
SKULL Macrocephaly/ Microcephaly TD, achondroplasia, JLS/ CDP
Irregular skull shape TD (cloverleaf), CDP, JLS
Hydrocephalus CD, Oi type 2, osteoporosis
Normal size

  • Partial absent bones
  • Total absent bones
  • Hypoechogenic bones
CCD, OI type 1 & 2CCDCCD, OI type 2, achondrogenesis
Wormian bones/ Thick skull CCD, PD, OI, hypophosphatasia, Osteopetrosis, CFD
FACE Facial anomalies (micrognathia, hypo/hypertelorism, frontal bossing CDP, achondroplasia, CD, cleidocranial dysplasia, DD, OI type 1, SEDC
Cleft lip or palate/ Gingival frenulae SRPS, CD/EVS
Eye abnormalities:

  • Orbit anomaly/Ctataract
CCD/CDP
Teeth

  • Natal teeth
  • Supernumerary teeth
  • Dentinogenesis imperfecta
  • Hypoplasia of dental cementum
EVSCCDOIHypophosphatasia
THORAX Narrow

  • Short horizontal ribs
  • Short ribs, 1 or more absent
  • Hypoechogenic ribs with fractures
  • Hypoechogenic ribs without fractures
Osteopetrosis, CCD, EVSTD, CCD, JLSOI type 1&3TD, achondrogenesis, OI type 3
Short barrel shaped JLS, SEDC
LIMBS Normal limb echogenecity with severe shortening

  • Rhizomelia with bowing
  • Rhizomelia with straight bones
  • Mesomelia with bowing
  • Mesomelia with straight bones
  • Rhizomesomelia with bowing
  • Rhizomesomelia with straight bones
Amelia, osteoporosis, SRPS, CCD, EVS
TD, CCD, JLS
OI type 1&3
TD, achondrogenesis 1A & 1B, OI type 3
HC, JLS, OI type 3, SRPS, SEDC
DD, FHUFS
Normal limb echogenecity with mild to moderate shortening

  • Rhizomelia
  • Mesomelia
  • Rhizomesomelia
EVSMesomelic dysplasia, SEDCOI type 1, SRPS, SEDC
Decreased limb bone echogeenicity

  • Short limbs
  • Normal length limbs
Achondrogenesis, OI type 1 & 2
OI type 2
Hypoplastic nails EVS, CDP
SPINE Platyspondyly MD, Morquio syndrome, OI, TD, KD
Coronal cleft CDP, MD, KD

 

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.

 

Arm of treatment Components
Initial stabilisation Airway and breathing:

  • Respiratory insufficiency requiring invasive or non invasive ventilation
  • Xray to assess pulmonary hypoplasia and thorax dimensions

Circulation:

  • Monitor BP, CFT, echo to assess cardiac disease and PPHN
  • Shock management, management of pulmonary hypertension

Neurological:

Seizures management with AED

  • Apnea: mechanical ventilation

Others:

Handling: if suspicion of OI then gentle handling and supportive care to prevent fractures

  • Skeletal survey: all necessary X-rays as stated above radiological evaluation section
  • Nutrition managenet: pareneteral nutrition if sick and unable to take enterally
  • Fluid and electrolyte balance: as these babies are IUGR, may have associated PPHN, shock, renal disease
Multidisciplinary approach to diagnosis
  • Intensivist: to manage the components of survival as stated above in initial stabilisation
  • Radiologist: interpretation of skeletal survey and aiding in diagnosis
  • Medical geneticist: to aid in understanding the mode of inheritance (family tree), required genetic tests, aiding in diagnosis and counselling
  • Cardiologist: to aid in diagnosis of any cardiac disease and management of shock and/or PPHN
  • Pulmonologist: management of respiratory insufficiency and management of chronic lung disease
  • Nephrologist: management of CKD in select cases
  • Neurologist: management of seizures, neurodevelopment assessment
  • Orthopedics: management of fractures, correction of deformities
  • Physiotherapist and Occupation therapist
  • Ophthalmologist and ENT: eye and ear problems as discussed
  • Nutritionist: to ensure adequate growth
  • Psychologist: to provide support to family
  • Dentist: to manage dentition associated problems
  • Neurogsurgeon: problems like cord compression, hydrocephalus
Specific therapies
  • OI – bisphosphonates, growth hormone, teriparatide
  • Hypophosphatasia – asfotase alfa
Postmortem analysis Include the following:

  • Photographs
  • Skeletal survey
  • Skin and tissue biopsies

 

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.
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