Skeletal dysplasia

Skeletal dysplasias also known as osteochondrodysplasias, are a complex heterogeneous group of more than 450 inherited disorders of bone and cartilage, but can also have significant effects on muscle, tendons and ligaments ¹ with extraordinary clinical and molecular heterogeneity ². Skeletal dysplasias are characterized by abnormalities of cartilage and bone growth, resulting in abnormal shape and size of the skeleton and disproportion of the long bones, spine, and head ³. Skeletal dysplasias differ in natural histories, prognoses, inheritance patterns, and etiopathogenetic mechanisms. Typified by short stature (defined as height that is three or more standard deviations below the mean height for age), skeletal dysplasias can be accompanied by involvement of other systems, including the neurologic, respiratory, and cardiac systems.

Fetal skeletal dysplasia affects approximately 2.4–4.5 of 10,000 births ⁴. Although fetal skeletal dysplasia is associated with few chromosomal abnormalities, skeletal dysplasia is mostly associated with mutations in genes that regulate bone formation ⁵.

Skeletal dysplasias frequently present in the newborn period with disproportion, radiographic abnormalities, and occasionally other organ system abnormalities ⁶. For improved clinical care it is important to determine a precise diagnosis to aid in management, familial recurrence and identify those disorders highly associated with mortality. Long-term management of these disorders is predicated on an understanding of the associated skeletal system abnormalities and these children are best served by a team approach to health care surveillance.

Skeletal dysplasia classification changes as scientists learn about their molecular bases. The molecular basis for a large majority of these disorders in now known. Commonly seen skeletal dysplasias include achondroplasia, osteogenesis imperfecta, thanatophoric dysplasia, campomelic dysplasia, and hypochondroplasia.

Over the past decades, substantial advances have been made in understanding the underlying genetic abnormalities responsible for most skeletal dysplasias ⁷. The 2015 revision of Nosology and Classification of Genetic Skeletal Disorders recognizes 436 genetic skeletal diseases, stemming from mutations in 364 genes, with the disorders organized into 42 groups ⁸. Classifications based on the underlying molecular genetic cause are regularly updated ⁹.

Skeletal dysplasias can be inherited as autosomal dominant, autosomal recessive, X-linked, or Y-linked. Examples include the following:

• Autosomal dominant – Fibroblast growth factor 3 ( FGFR3) disorders (achondroplasia, thanatophoric dysplasia, hypochondroplasia) and type II collagen disorders (achondrogenesis II, spondyloepiphyseal dysplasia congenita, Kniest dysplasia)
• Autosomal recessive – Cartilage-hair hypoplasia, Ellis-van Creveld syndrome, hypophosphatasia, osteopetrosis
• X-linked dominant – Chondrodysplasia punctata
• X-linked recessive – Conradi-Hunermann chondrodysplasia punctata

A brief overview of the most common skeletal dysplasias is included below.

Skeletal dysplasia key points

• Children with skeletal dysplasia are ideally care for by a multidisciplinary approach that includes obstetricians (prior to delivery), pediatricians, neonatologists, medical geneticists, endocrinologists, neurosurgeons, otolaryngologists and orthopaedic surgeons.
• Approximately 5% of child with congenital birth defects have skeletal dysplasias
• Lethality usually results from small chest, pulmonary hypoplasia and respiratory compromise
• Diagnosis is made based on clinical and radiographic findings, including molecular diagnosis when possible
• Nonlethal skeletal dysplasias are associated with short stature but overall affected individuals are cognitively normal and have a good quality of life

Skeletal development

The skeletal forms under two distinct processes; endochondral and membraneous ossification ⁶. Endochondral ossification is responsible for the formation of most of the mammalian appendicular skeleton and it involves a sequence of carefully orchestrated developmental processes. These include embryonic limb bud initiation and its outgrowth from lateral plate mesoderm, specification of mesenchymal cells for the future limb elements, mesenchymal condensations triggering cartilage differentiation, ossification of developing bones, and finally, their proper growth and maturation in the postnatal period ¹⁰. Membraneous ossification is the developmental event in which condensing mesenchymal cells progress almost directly to bone cells. The bones of the skull, lateral clavicle and pubis form via mesenchymal ossification. Postnatally, growth continues through the cartilage growth plate in which resting chondrocytes proliferate, undergo hypertrophy, then apoptosis, becoming the growing scaffold of bone ¹¹. Multiple molecular mechanisms (genes) underlie skeleton formation and perturbations to these highly orchestrated processes can lead to skeletal dysplasias ¹².

Skeletal dysplasia genetics

The skeletal dysplasias are inherited in an autosomal recessive, autosomal dominant, X-linked recessive, X-linked dominant, and Y-linked manner ¹. Appreciation of the mode of inheritance is important because it imparts information to families regarding future recurrences. Family history, including parental and familial heights and growth patterns, should be obtained from the parents of any affected child to determine if there are similarly affected siblings, or other family members, which can lead to a diagnosis or establish the mode of inheritance. There are several X-linked skeletal disorders that recur in male family members and carrier females are either unaffected or only mildly affected (e.g. X-linked Spondyloepiphyseal Tarda) ¹³. Table 1 lists some of these more commonly seen disorders seen in the neonatal period with their respective inheritance pattern. The Nosology and Classification of Genetic Skeletal Disorders ¹ and On-line Inheritance of Man (https://omim.org/) are sources that include information on these disorders and include data on their patterns of inheritance. There are some uncommonly seen patterns of inheritances in the skeletal dysplasias. These include somatic mosaicism, in which one of the parents is mildly affected and their offspring is more severely affected ¹⁴. Evaluation of the parents should be considered if there is any question that one of the parents could have a mild skeletal disorder. Gonadal mosaicism is characterized by familial recurrence of a known dominant disorder resultant from one parent carrying heterozygosity for a mutation in one of the cell lineages that comprise the pool of progenitor germ cells and the parent is clinically unaffected ¹⁵. This is a rare occurrence, but influences counseling of all dominant disorders because if a newborn is diagnosed with an autosomal dominant disorder, counseling should include a less than 1% recurrence risk based on gonadal mosaicism.

Table 1. Skeletal dysplasia types and mode of inheritance and genes

Group/name of disorder	Mode of Inheritance	Gene Symbol
FGFR3 chondrodysplasia group
Thanatophoric dysplasia	AD	FGFR3
Achonodroplasia	AD	FGFR3
Hypochondroplasia	AD	FGFR3
Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN)	AD	FGFR3
Type II collagen disorders
Achondrogenesis II	AD	COL2A1
Hypochondrogenesis	AD	COL2A1
Spondyloepiphyseal dysplasia congenita (SEDC)	AD	COL2A1
Kniest dysplasia	AD	COL2A1
Type X1 collagen disorders
Fibrochondrogenesis	AR	COL11A1
Fibrochondrogenesis	AD	COL11A1, COL11A2
Otospondylomegaepiphyseal dysplasia (OSMED)	AR	COL11A2
Sulfation disorders
Achondrogenesis IB	AR	SLC26A2
Atelosteogenesis II	AR	SLC26A2
Diastrophic dysplasia	AR	SLC26A2
Chondrodysplasia with congenital joint dslocations	AR	CHST3
Perlecan disorders
Dyssegmental dysplasia	AR	PLC
Dyssegmental dysplasia, Silverman-Handmaker type	AR	PLC
Dyssegmental dysplasia, Rolland Desbuquois type	AR	PLC
Filamin Disorders and similar disorders
Otopalatodigital syndrome I and II	XLD	FLNA
Osteodysplasty, Melnick-Needles	XLD	FLNA
Atelosteogenesis types I and III	AD	FLNB
Larsen syndrome	AD	FLNB
Spondylo-carpal-tarsal dysplasia	AR	FLNB
Serpentine fibula-polycystic kidney syndrome	AD	NOTCH2
TRPV4 disorders
Metatopic dysplasia	AD	TRPV4
Short-rib dysplasias (with and without polydactyly)
Chondroectodermal dysplasia (Ellis-van Creveld (EVC)	AR	EVC1, EVC2
Short-rib polydactyly syndrome I, II, III and IV including Asphxiating Thoracic Dystrophy	AR	DYNC2H1
		IFT80
		NEK
		WDR35
		WDR19
		WDR34
Thoracolaryngeal dysplasia	AD	unknown
Metaphyseal dysplasias
Cartilage-hair hypoplasia	AR	RMRP
Metaphyseal dysplasia, Jansen type	AD	PTHR1
Spondylo-epi-(meta)-physeal dysplasia
SEMD, short limb abnormal calcification type	AR	DDR2
Severe spondylodysplastic dysplasias
Achondrogenesis 1A	AR	GMAP210
Schneckenbecken dysplasia	AR	SLC35D1
Opsismodysplasia	AR	INPPL1
Acromesomelic disorders
Acromesomelic dysplasia, type Maroteaux	AR	NPR2
Mesomelic and rhizo-mesomelic dysplasias
Langer type (homozygoud dyschondrosteosis	pseudo-AR/XLD	SHOX
Omodysplasia	AR	GPC6
Robinow syndrome, recessive	AR	ROR2
Robinow syndrome, dominant	AD	WNT5
Bent bone dysplasias
Campomelic dysplasia	AD	SOX9
Stuve-Wiedemann dysplasia	AR	LIFR
Bent bone dysplasia FGFR2 type	AD	FGFR2
Slender bone dysplasias
Microcephalic osteodysplastic primordial dwarfism (MOPD1)	AR	RNU4ATAC
Microcephalic osteodysplastic primordial dwarfism (MOPD2)	AR	PCNT
Osteocraniostenosis		FAM111A
Dysplasias with multiple joint dislocations
Desbuquois dysplasia	AR	CANT1, XYLT1
Pseudodiatrophic dysplasia	AR	unknown
Chondrodysplasia punctata group (CDP)
CDP, X-linked dominant	XLD	EBP
Conradi-Hunermann type (CDPX2)	XLR	ARSE
brachytelephalangic type (CDPX1)	XLD	NSDHL
CHILD syndrome	XLD	EBP
Greenberg dysplasia	AR	LBR
Rhizomelic CDP type 1	AR	PEX7
Rhizomelic CDP type 2	AR	DHPAT
Rhizomelic CDP type 3	AR	AGPS
Neonatal osteosclerotic dysplasias
Bloomstrand dysplasia	AR	PTHR1
Desmosterolosis	AR	DHCR24
Caffey disease (infantile)	AD	COL1A1
Raine dysplasia	AR	FAM20C
Increased bone density group
Osteopetrosis (severe neonatal or infantile forms)	AR	TCIRG1
Osteopetrosis (severe neonatal or infantile forms)	AR	CLCN7
Dysosteosclerosis	AR	SLC29A3
Lenz-Majewski hyperostostic dysplasia	SP	PTDSS1
Osteogenesis imperfecta and decreased bone density group
Osteogenesis imperfecta, moderate, severe and perinatal lethal	AD	COL1A1, COL1A2
		IFITM5
Osteogenesis imperfecta, moderate, severe and perinatal lethal	AR	CRTAP
		P3H1
		PPBI
		FKBP10
		HSP47
		SP7
		WNT1
		TMEM33B
Bruck syndrome		PLOD2
		FKBP10
Osteoporosis-pseudoglioma syndrome	AR	LRP5
Cole-Carpenter dysplasia	SP	unknown
Abnormal mineralization group
Hypophosphatasia, perinatal and infantile forms	AR	ALPL

Abbreviations: AD = autosomal dominant; AR = autosomal recessive; XLD = X-linked dominant inheritance

[Source ⁶ ]

Skeletal dysplasia types

In the 2010 revision of the Nosology and Classification of Genetic Skeletal Disorders, 456 conditions were classified into 40 groups defined by molecular, biochemical and radiographic criteria ¹⁶. Among these conditions, 316 conditions were associated with mutations in one or more of 226 different genes, providing a basis for the molecular genetic diagnosis of fetal skeletal dysplasia.

Groups of skeletal dysplasia conditions organized according to their molecular bases ²:

1. FGFR3 chondrodysplasia group
2. Type 2 collagen group and similar disorders
3. Type 11 collagen group
4. Sulfation disorders group
5. Perlecan group
6. Aggrecan group
7. Filamin group and related disorders
8. TRPV4 group

Groups of skeletal dysplasia conditions organized according to their clinical presentations:

1. Short-ribs dysplasias (with or without polydactyly) group
2. Short-ribs dysplasias (with or without polydactyly) group
3. Multiple epiphyseal dysplasia and pseudoachondroplasia group
4. Metaphyseal dysplasias
5. Spondylometaphyseal dysplasias
6. Spondylo-epi-(meta)-physeal dysplasias
7. Severe spondylodysplastic dysplasias
8. Acromelic dysplasias (extremities of the limbs)
9. Acromesomelic dysplasias (extremities and middle portion of the limbs)
10. Mesomelic and rhizo-mesomelic dysplasias (proximal and middle portions of the limbs)
11. Bent bones dysplasias
12. Slender bone dysplasia group
13. Dysplasias with multiple joint dislocations
14. Chondrodysplasia punctata group
15. Neonatal osteosclerotic dysplasias
16. Increased bone density group (without modification of bone shape)
17. Increased bone density group with metaphyseal and/or diaphyseal involvement
18. Osteogenesis imperfecta and decreased bone density group
19. Abnormal mineralization group
20. Lysosomal storage diseases with skeletal involvement (dysostosis multiplex group)
21. Osteolysis group
22. Disorganized development of skeletal components group
23. Overgrowth syndromes with skeletal involvement
24. Genetic inflammatory/rheumatoid-like osteoarthropathies
25. Cleidocranial dysplasia and isolated cranial ossification defects group
26. Craniosynostosis syndromes
27. Dysostoses with predominant craniofacial involvement
28. Dysostoses with predominant vertebral with and without costal involvement
29. Patellar dysostoses
30. Brachydactylies (with or without extraskeletal manifestations)
31. Limb hypoplasia—reduction defects group
32. Polydactyly-Syndactyly-Triphalangism group
33. Defects in joint formation and synostoses

FGFR3 chondrodysplasia group

FGFR3 chondrodysplasia group of disorders all result from heterozygosity for activation mutations in the gene that encodes Fibroblast Growth Factor Receptor 3 (FGFR3) ¹⁷. FGFR3 chondrodysplasia group of disorders includes thanatophoric dysplasia, achondroplasia, hypochondroplasia and the very rare severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN). Thanatophoric dysplasia is almost uniformly lethal without aggressive management. Radiographic findings include macrocephaly with narrow skull based, long narrow trunk with handlebar clavicles, flat vertebral bodies, small flared iliac bones with very narrow sacrosciatic notches and generalized micromelia.

Thanatophoric dysplasia

Thanatophoric dysplasia named because it often results in early death, is characterized by micromelia (abnormally small and imperfectly developed extremities) with bowed femurs, short ribs, narrow thorax, macrocephaly, distinctive facial features, brachydactyly, hypotonia. Radiographically, there is rhizomelic shortening of the long bones with irregular metaphyses, platyspondyly, small foramen magnum with brain stem compression, bowed femurs (thanatophoric dysplasia type I) and cloverleaf skull (always in thanatophoric dysplasia type II; sometimes in thanatophoric dysplasia type I). CNS abnormalities include temporal lobe malformations, hydrocephaly, brain stem hypoplasia and neuronal migration abnormalities.

Achondroplasia

This is the most common nonlethal skeletal dysplasia, occurring in 1:26,000-1:28,000 live births and affecting 250,000 individuals worldwide ¹⁸.

Achondroplasia is characterized by small stature with rhizomelia (shortened limbs – arms and legs) and redundant skin folds, limitation of elbow extension and genu varum, short fingers with trident configuration of the hands. Craniocervical junction compression is a major complication which may occur and requires surveillance for early detection and management. There is also thoracolumbar kyphosis, lumbar lordosis, and a large head with frontal bossing with midface hypoplasia. The radiographic findings include short tubular bones with metaphyseal flaring, narrowing of the interpediculate distance of the lumbar spine, rounded ilia and horizontal acetabula, narrow sacrosciatic notch and proximal femoral radiolucency. In hypochondroplasia, there are similar but milder clinical and radiological findings, the head is large but there is no midface hypoplasia.

The molecular mechanism for achondroplasia is a G380R mutation in the FGFR3 transmembrane domain. A gain-of-function mutation, it is present in 99% of affected individuals. Inheritance is autosomal dominant, with 80% of cases involving de novo mutations.

Major characteristics of achondroplasia include the following ¹⁸:

• Disproportionate short stature with rhizomelic (proximal) shortening of the arms and legs and large head with frontal bossing
• Trident hand configuration
• Average final height: 130 cm for men and 125 cm for women
• Normal intelligence and lifespan

Major complications include the following:

• Craniocervical junction compression
• Middle ear infections
• Obstructive apnea
• Spinal stenosis

Hypochondroplasia

Hypochondroplasia is a autosomal dominant disorder characterized by short-limbed dwarfism, lumbar lordosis, short and broad bones, and caudad narrowing of the interpediculate distance of the lumbar spine. It shows some resemblance to achondroplasia, but is much milder and can be distinguished on clinical and radiographic grounds ¹⁹.

Camptodactyly, tall stature, and hearing loss syndrome (CATSHL)

Camptodactyly-tall stature-scoliosis-hearing loss syndrome is characterized by camptodactyly ²⁰, tall stature, scoliosis, and hearing loss (CATSHL). It has been described in around 30 individuals from seven generations of the same family. The CATSHL syndrome is caused by a missense mutation in the FGFR3 gene, leading to a partial loss of function of the encoded protein, which is a negative regulator of bone growth.

Type 2 collagenopathies group

Type 2 collagenopathies are a heterogenous group of disorders that all show some relationship to each other clinically and radiographically ²¹. Type 2 collagenopathies typically result from heterozygosity for mutations in the type II collagen gene, COL2A1. Achondrogenesis II and hychondrogenesis are lethal disorders that present with large skulls, very small and short ribs, almost lack of mineralization of most vertebral bodies. The pelvis has small iliac wings with absent ischia, pubic bones and sacral elements. The extremities show severe rhizomelia and mesomelia with relative sparing of the hands.

Stickler syndrome

Stickler syndrome is characterized by ocular findings of myopia, cataract, and retinal detachment, sensorineural and conductive hearing loss, flat mala and cleft palate (alone or as part of the Robin sequence), mild spondyloepiphyseal dysplasia and early-onset arthritis ²².

Spondyloepiphyseal dysplasia congenita

Spondyloepiphyseal dysplasia congenita presents with disproportionate short stature (short trunk), abnormal epiphyses, and flattened vertebral bodies. Spondyloepiphyseal dysplasia is usually nonlethal and clinical presentation includes severely short trunked, short-limbed infant with normal appearing hands, feet and skull. There may be micrognathia and a Pierre Robin sequence and attention should be paid to the upper cervical spine, which can be hypomineralized. Radiographic findings in the newborn period include short thorax with short ribs, pear shaped or oval vertebral bodies, absent pubic ossification, short long bones and unossified talus and calcaneus (which are typically ossified by about 24 weeks of gestation) ²³. Pediatricians should be aware that these children can have some respiratory issues based on small rib cage, feeding difficulties due to micrognathia and flat mid face and are at risk for recurrent ear infections. Families should be counseled that serial evaluation of the cervical spine by a team of specialists who can management odontoid hypoplasia in childhood as part of long-term care for these children.

Osteogenesis imperfecta

Osteogenesis imperfecta also known as brittle bone disease, is a heterogenous group of heritable connective tissue disorders, is another common skeletal dysplasia, with a prevalence of 1:15,000-1:20,000 births. Severe forms may present in the newborn period with fractures sustained in-utero. Osteogenesis imperfecta has been classified in numerous forms, mild, moderate, severe and perinatal forms. These classifications are used by clinicians to manage the complications and predict some of the natural history associated with the disorder, and are somewhat arbitrary ²⁴. In the last decade there has been enormous progress in unwinding the molecular genetics associated with osteogenesis imperfecta ²⁵. About 90% of the cases result from mutations in the genes that encode type I collagen, COL1A1 and COL1A2. Most of the remaining cases result from gene mutations that are recessively inherited ²⁵. These recessively inherited cases usually present with severe forms of osteogenesis imperfecta, some of them perinatal lethal ²⁶. They are extremely rare, and unless there is a family history consistent with autosomal recessive inheritance (previously affected sibling or consanguinity), most osteogenesis imperfecta cases result from dominantly or sporadically inherited mutations.

Newborns with osteogenesis imperfecta present with relative macrocephaly, flat facies, short limbs, narrow thorax, deformed and fractured extremities, with normal appearing hands and feet. Radiographs show poor ossification of the skull, fractured ribs, under-mineralized bone with fractures and in very severe cases, femurs that are accordion in appearance, diffuse osteopenia including the vertebrae, flattened acetabulae and relatively normal appearing hands and feet. Similarly to the aforementioned skeletal dysplasias, there is a broad phenotypic spectrum in osteogenesis imperfecta. The perinatal lethal form usually presents with a very small chest and deformed extremities. Care should be taken if a newborn with osteogenesis imperfecta and in-utero occurring fractured ribs requires ventilator assistance. There is probable underlying pulmonary insufficiency due to a small chest and ventilation may cause ongoing fractures in a probable lethal condition; thus the degree and period of active intervention should be discussed with the family.

For those newborns who are stable, but present with fractures, orthopaedic surgeons should evaluate the patient. In many instances, the treatment modality depends on the site of the fracture and degree of angulation at the site. Many of these fractures are managed by immobilization using strapping (e.g. femoral fractures in the subtrochanteric region are managed by strapping of the thigh to abdomen) while fractures of the shaft of bones may be managed by casting ²⁷. In nonlethal but severe cases, consultation should be obtained from medical genetics or pediatric endocrinology for consideration of treatment with intravenous bisphosphonates while in the nursery. Studies have shown that early treatment with bisphosphonates decreases the number of subsequent fractures ²⁸. Individuals with osteogenesis imperfecta also have fragile skin and blood vessels because type I collagen is an important component of connective tissue. Care in handling of these children should be discussed with staff.

Inheritance in osteogenesis imperfecta is as follows:

• Types I-IV (Sillence classification, 85% of cases): Autosomal dominant
• Types V-XII: Autosomal recessive, except for type V (autosomal dominant)

Major characteristics of the most common forms of osteogenesis imperfecta are as follows.

All types

All forms are characterized by bone fragility and susceptibility to fracture from minimal trauma.

Osteogenesis imperfecta type I – mild form with diagnosis in early childhood

This is characterized by the following:

• Sclera may be blue
• Dentinogenesis imperfecta (subtype IB)
• Normal stature reached
• Hearing loss in 50% of patients

Osteogenesis imperfecta type II – perinatal lethal form

The condition is characterized as follows:

• Patients may survive the neonatal period
• Later mortality can occur secondary to pneumonia and respiratory insufficiency

Osteogenesis imperfecta type III – progressive deforming form

This form is characterized as follows:

• Moderate deformity at birth
• Development of chest wall deformities
• Most patients are wheelchair dependent
• Very short stature
• Variable sclera
• Dentinogenesis imperfecta and hearing loss are common.

Osteogenesis imperfecta type IV – moderately severe form

Characteristics include the following:

• Mild to moderate bone deformity
• Variable short stature
• Hearing loss occurs in some families
• Variable sclera

Major complications

• These include bone fractures, bone deformity, and growth deficiency.

Skeletal dysplasia diagnosis

Diagnosis of skeletal dysplasias requires a multidisciplinary approach and includes radiologic and genetic evaluations. This approach is required for accurate diagnosis and the determination of the best treatment options, as well as for accurate counseling on outcomes and risk of recurrence. The approach to the initial evaluation of newborn with a suspected skeletal dysplasia is outlined in Figure 1 below.

If the diagnosis has been determined in the prenatal period or based on family history, then laboratory testing or radiographs should be obtained to confirm the clinical or molecular diagnosis. If the skeletal dysplasia is undiagnosed or unexpected then a similar approach should be taken. Once the newborn is stable, a thorough physical exam should be undertaken. Key measurements include head circumference (HC), birth weight (BW), birth length (BL), chest circumference if it appears small, and palm and middle finger lengths. Carefully delineation of any dysmorphic facial features should be performed and include evaluation of the fontanels, nasal bridge, midface, philtrum, mandible, palate and ears. Frequently, the neck will appear short and if the chest is small the nipples may appear widely spaced. In many disorders the hands will appear small, and the fingers will appear to have wide spaces between them because they are short. Attention should be paid to the proportion of the upper and mid sections of the arm. In most newborns they appear subjectively one to one, and in skeletal disorders, there is frequently subjective disproportion. Rhizomelia is common in achondroplasia and spondyloepiphyseal dysplasia congenita, two of the commonly seen nonlethal disorders. Very significant mesomelia relative to the rhizomelic segment suggests a group of specific disorders, the mesomelic dysplasias. Frequently, when there is rhizomelia and mesomelia, there are increased skin creases and skin folds due to the abnormal underlying bone length. A significantly curved long bone may appear substantially much shorter externally than by radiographs.

After clinical evaluation, it is critical to obtain conventional radiographic examination of the dysplastic skeleton. The skeletal survey should include the skull (anteroposterior [AP], lateral views), chest (AP), spine (AP and lateral views, including dedicated lateral view of the cervical spine), pelvis (AP), tubular bones (AP), and/or hands and feet (AP) ²⁹. Radiographic evaluation should start with overall assessment of epiphyseal ossification to determine if they are delayed or irregular for age, then there should be consideration for an epiphyseal dysplasia. If the metaphyses are widened, flared or irregular then the diagnosis of a metaphyseal chondrodysplasia should be entertained. If diaphyseal abnormalities are present, such as widening and/or cortical thickening, or marrow space expansion then a diaphyseal dysplasia is implied. Combination of the aforementioned abnormalities helps categorize the disorder, e.g. epimetaphyseal disorder. If the vertebral bodies are affected then there is a spondylo-component present, further categorizing the disorder. Once the extent of radiographic abnormalities are determined and placed with a category, e.g. spondylometaphyseal dysplasia, radiographic textbooks can aid in refining the diagnosis.

Organ system abnormalities beyond the skeleton are occasionally seen and can be clues to diagnosis. Congenital heart defects are commonly seen in the skeletal ciliopathies (chondroectodermal dysplasia, asphyxiating thoracic dysplasia, short rib polydactyly syndromes), abnormal formed genitalia in the skeletal ciliopathies, campomelic dysplasia, omodysplasia, Robinow dysplasia, Antley-Bixler and severe disorders of cholesterol metabolism ³⁰. Immune deficiency and Hirschprung disease are seen in metaphyseal chondrodysplasia, McKusick type (Cartilage hair hypoplasia) ³¹.

In addition, genetic testing plays a critical role in the diagnosis and management of skeletal dysplasias. Molecular diagnostic techniques have led to the identification of the underlying gene disorders in about two thirds of known skeletal dysplasias.

Prenatal diagnosis

Rapid advances of in both imaging modalities and molecular diagnostics has improved doctors abilities to recognize osteochondrodysplasias in the prenatal period ³². For those families with a parent affected by an autosomal dominant disorder, either molecular diagnostics via invasive techniques or by ultrasound imaging, can aid in predicting whether the fetus will be similarly affected (Figure 1). For at-risk families based on a previously affected child with an autosomal recessive disorder, the same above-mentioned approach can be utilized. However, affected neonates with skeletal dysplasias are often the first affected children in their respective families.

Many pregnant women are offered an array of noninvasive tests to determine if their fetuses are at risk for genetic disorders ³³. These molecular screening panels are for autosomal recessive and X-linked disorders including skeletal dysplasias such as diastrophic dysplasia; however it is important to note that many genes and mutations that can cause skeletal dysplasias are presently not included in these panels. Usually if one parent screens positive for a disorder, then the other parent is screened, determining a baseline risk for a disorder. First trimester ultrasound analysis, usually used to identify aneuploidy, is also affective in identifying severe, usually lethal skeletal dysplasias including osteogenesis imperfecta, thanatophoric dysplasia, and the short-rib polydactyly syndromes, as some examples ³⁴. If a neonate with a skeletal disorder was noted to have abnormal ultrasound findings in the first trimester including a small crown-rump length for gestational age and increased nuchal fold thickness, the likelihood is that the fetus has a severe, probable lethal skeletal dysplasia.

Many prenatal skeletal dysplasias are diagnosed in the late second trimester when many pregnant women are screened by ultrasound for congenital anomalies ³⁵. The advantages to early detection (with and without a precise diagnosis) allows for preparation prior to delivery. This includes discussion of active resuscitation, proper assembly of consultants, collection of appropriate material for molecular diagnosis from cord blood, and smoother transition for the fetus from the prenatal to neonatal period. This is particularly important if the neonate is predicted to have a severe, but non-lethal skeletal disorder.

Experience has informed us that many skeletal disorders are not diagnosed in the late second trimester, but either in the third trimester or at birth. These disorders tend to be milder, with a less profound effect on the skeletal, including the thorax, thus severe respiratory compromise is not usually encountered. Achondroplasia, Spondyloepiphyseal Dysplasia Congenita and nonlethal forms of Osteogenesis Imperfecta are frequency first encountered in the newborn period. Many parents are distraught if the suggestion of a skeletal dysplasia is made at birth, and question if “something” was missed at second trimester ultrasound evaluation. It is helpful to explain that for the milder skeletal disorders, long bone measurements are frequently on the normal growth curves at 20 weeks, and fall off occurs in the third trimester since in most of these disorders the defect is in endochondral ossification (not condensation or other earlier-occurring processes) which is a process that is most active in the third trimester ³⁶.

Beyond ultrasound and enhanced carrier screening panels, noninvasive prenatal testing from maternal blood for Mendelian disorders may soon be a clinical reality. Screening for cell free fetal DNA in maternal blood during the first trimester of gestation is employed for the detection of aneuploidy, including disorders of copy number variations ³⁷. Reports of de novo FGFR3 mutations (thanatophoric dysplasia) from the fetal cell free DNA fraction in maternal blood illustrates that this technology has the future potential to diagnose de novo autosomal dominant skeletal disorders ³⁸.

Figure 1. Scheme of management in newborns with a skeletal dysplasia

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://www.abgc.net/about-genetic-counseling/find-a-certified-counselor/) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx) has a searchable database of medical genetics clinic services in the United States.

Skeletal dysplasia management

Treatment is supportive. Medical care for individuals with skeletal dysplasia should be directed at preventing neurologic and orthopedic complications due to spinal cord compression, joint instability, and long bone deformity.

Surgical intervention depends on the signs and symptoms of skeletal dysplasia. For example, progressive kyphosis, which may lead to spinal cord compression and spastic paraparesis, is best treated by anterior and posterior fusion. Lumbar lordosis with spinal stenosis responds to extensive lumbar laminectomy. Surgical decompression is required to relieve edema of the cervicomedullary cord secondary to bony compression.

Defining Lethality

If a newborn has been diagnosed with a known lethal disorder in the fetal period, then treating physicians should offer comfort care for the newborn, but not aggressive management. Defining lethality in the prenatal period can be accomplished by two means; molecular diagnosis of a known lethal disorder, precise diagnosis by ultrasound or chest size abnormalities seen by ultrasound that correlate with lethality. If the chest to abdominal circumference ratio is less than 0.7, the heart to chest circumference is >50 percent or the abdomen to femur length ratio is < 0.16, these objective measures are highly correlated with lethality. However, these measurements can be gestational age dependent and may not apply to the infant ³² with significant prematurity and a skeletal dysplasia; the presenting disorder may be a known lethal disorder, but the aforementioned criteria may not quite have been reached, or conversely a severely affected child may survive for a prolonged period of time. When lethality is suspected based only on prenatal ultrasound measurements, it is important to counsel parents that while a lethal condition is suspected that only at birth will a true assessment of lethality be possible.

Postnatally, similar criteria can apply to management of a newborn. If clinical and radiographic findings and/or molecular findings indicate a known lethal diagnosis, then supportive care is indicated. Some of the more difficult clinical management scenarios result from the clinical spectrum of disease that is associated individual gene defects. This is particularly true for the disorders listed in the categories in Table 1. For example, in type II collagen disorders, hypochonodrogenesis diagnosed by radiographic criteria is often associated with lethality due to a small chest and respiratory compromise, yet some of these infants survive the neonatal period and then are categorized as severe spondyloepiphyseal dysplasia congenita ²¹. Thus for each group of skeletal dysplasias, clinical judgment must be used to determine the severity of the skeletal disorder and whether aggressive management is indicated. If highly aggressive ventilation is necessary because of severe respiratory insufficiency particularly due to a small chest, respiratory failure and lethality commonly occurs ³⁹. For all newborns that die of complications from skeletal disorders, radiographs and a source of DNA should be obtained, and families should be offered autopsy. Collection of postmortem material aids in final diagnosis, which helps to provide parents emotional closure and determine recurrence risk for families through clinical molecular diagnosis or research participation.

If the newborn is known to have a uniformly lethal disorder, then supportive care is indicated. Similarly, if the diagnosis is known prior to delivery then management is predicated on the knowledge regarding the natural history of the disorder. Newborns with recognized skeletal disorders present in the newborn period with disproportion. Dependent on the skeletal disorder, there are some common findings; this includes relative macrocephaly, narrow chest appearance relative to the abdomen, rhizomelia (short upper portion extremity), mesomelia (short mid-portion extremity), and frequently brachydactyly (short hands, including phalanges). Frequently the face is normal but there are numerous disorders associated with a flat nasal bridge, frontal bossing and midface hypoplasia and include many of the lethal skeletal disorders, achondroplasia, campomelic dysplasia, chondrodysplasia punctate (all forms), type II collagen disorders, Larsen syndrome, and the mucopolysaccharidoses (most forms). Disorders with micrognathia include some of the following disorders: type II collagen disorders, acrofacial dysostoses, Robinow syndrome and again, many of the lethal skeletal dysplasias. Attention must be paid to the Robin-Pierre Robin sequence (small mandible and posterior cleft palate) associated with these disorders. Few of these newborns are delivered by EXIT procedures because of the mandibular abnormality and safety of the airway ⁴⁰, but some of these children require post delivery intubation and subsequent tracheostomies until definitive surgery for jaw retraction or time, awaiting facial growth. If the newborn has Pierre-Robin sequence, timing of the repair of the cleft palate should be deferred to the craniofacial surgery team or plastic surgeons ⁴¹.

Care should be taken regarding the trachea in the skeletal dysplasias. The trachea is composed of fifteen to twenty incomplete C-shaped tracheal rings that contain cartilage that reinforces the front and sides of the trachea to protect and maintain the airway ⁴². Pediatricians, neonatologists and anesthesiologists should be informed that many skeletal disorders have been associated with tracheal anatomic changes complicating respiratory status, intubation and any manipulations. The abnormalities include tracheal agenesis, congenital stenosis, premature cartilage calcifications, short trachea and tracheomalacia, as well as disorders associated with tracheoesphageal fistulas ⁴³. Caretakers should be aware of this when caring for newborns with skeletal abnormalities, and can affect prognosis in many of the nonlethal skeletal disorders.

Long-term follow-up

Children with skeletal dysplasia are best managed by a multidisciplinary approach that includes obstetricians (prior to delivery), pediatricians, neonatologists, medical geneticists, endocrinologists, neurosurgeons, otolaryngologists and orthopaedic surgeons. Sub-speciality care should be directed toward the individual presenting issue. Families should be prepared for ongoing visits to supervise health management. For most children with nonlethal skeletal dysplasias, their quality of life is good. Families should be encourage to seek out support from organizations dedicated to the well being of individuals with forms of dwarfism that include Little People of America (https://www.lpaonline.org/) and the Osteogenesis Imperfecta Foundation (http://www.oif.org/site/PageServer). Pediatricians should be aware that these children with normal immune systems should receive standard doses of vaccines on routine schedules, as well as recognizing the potential for increased ear infections in disorders associated with midface hypoplasia, hearing loss due to increased infection and abnormalities of the stapes, as well as hydrocephalous in disorders associated with foramen magnum stenosis (achondroplasia, hypochondroplasia, diastrophic dysplasia and metatropic dysplasia).

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