Introduction to rare skeletal disorders
Major points | Clues examples |
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Clinical work up to determine a clinical pattern | |
Patient’s medical history | |
Prenatal history | |
– Increased nuchal translucency | Skeletal disorders associated with increased nuchal translucency: – Achondrogenesis 2, some type II collagen disorders, ciliopathies, Greenberg dysplasia, every skeletal disorder with cardiac defects |
– Growth parameters – Onset shortness long bones – Thoracic hypoplasia measured by thoracic circumference and by thoracic/abdominal ratio | Onset of shortness of long bones is usually earlier than onset of thoracic hypoplasia – thoracic hypoplasia is a caution signal for putative lethal skeletal disorders – normal thoracic measurements at 20 weeks gestational age do not exclude severe thoracic hypoplasia at birth Skeletal disorder associated with thoracic hypoplasia – Short-rib thoracic dysplasia, thanatophoric dysplasia, achondrogenesis 1A and 1B, some type II collagen disorders |
– Fractures or bowing of bones | Skeletal disorder associated with prenatal fractures of long bones: – Osteogenesis imperfecta types II and III, hypophosphatasia, neurofibromatosis Skeletal disorder associated with prenatal bowing of long bones: – Symmetric: thanatophoric dysplasia, achondrogenesis types IA and IB, atelosteogenesis types I and II and III, campomelic dysplasia, diastrophic dysplasia, short-rib thoracic dysplasia – Asymmetric: osteogenesis imperfecta types II and III, hypophosphatasia |
– Hypomineralization | Skeletal disorder associated with hypomineralization – Osteogenesis imperfecta: hypomineralization of the facial bones and skull with normal mineralization of hands, platyspondyly, fractures, curved long bones – Hypophosphatasia: hypomineralization especially of hands, fractures and chromosome-like long bones – Campomelic dysplasia: hypoplastic fibula and scapula, facial dysmorphism, malformations – Cleidocranial dysplasia: hypo- or aplastic claviculae, hypomineralization of skull, normal long bones – Achondrogenesis IA: hypomineralization of skull and spine, rib fractures, severe micromelia |
– Polyhydramnion | – Risk factor for prematurity; Might be a caution signal for clinical relevant foramen magnum stenosis in achondroplasia |
– Malformations and fetal profile | Characteristic facial features in skeletal disorders: – frontal bossing, midface hypoplasia, nasal flattening Skeletal disorders with cardiac defects especially left side cardiac defects: – e.g., ciliopathies like short-rib thoracic dysplasia, Ellis-van Creveld syndrome, orofaciodigital syndrome Within the group of lethal skeletal disorders – Cloverleaf skull malformation: thanatophoric dysplasia – Microretrognathia, cleft palate: some type II collagen disorders – Polydactyly and cardiac defects: ciliopathies such as short-rib thoracic dysplasia |
– Maternal factors (illness, medication, alcohol, …) | – Fetal warfarin or thalidomide syndrome – Fetal akinesia sequence |
– Prenatal genetic investigations | – Is there a genetic diagnosis? If yes does this diagnosis correlate with the postnatal clinical and radiological pattern? Which disorders have been excluded genetically? |
Growth parameters and percentiles | – From birth to current age – Use disease-specific percentiles whenever available |
Complete medical and developmental history | – Severe illness; pain; progression; – Evidence for extraskeletal manifestation, developmental delay or intellectual disability |
Family history and pedigree analysis | – To establish mode of inheritance: draw at least a 3-generation pedigree and a 5-generation pedigree in case of consanguinity. Similar affected family members? Miscarriages, still born? Known diseases in the family |
Patient’s physical examination | |
Growth parameters | – Height; weight; head circumference; armspan; sitting height; upper/lower segment ratio |
Skeletal disorder-specific physical examination | |
– Stature – Assessment of asymmetry or symmetry | – Stature: short/normal/tall and proportionate/disproportionate – Short limbs: transversal limb defects, rhizomelia, mesomelia, acromelia, micromelia – Type of brachydactyly; narrow chest; scoliosis – Symmetry or asymmetry: Asymmetric involvement with genetic cause: X‑linked dominant chondrodysplasia punctata‑2, Russel Silver syndrome, segmental overgrowth syndromes, neurofibromatosis Asymmetric involvement with exogenic cause: limb defects due to amniotic bands or due to vascular disruption defects |
– Facial dysmorphism | If yes? Characteristic facial features pointing to a specific diagnosis such as – Russel Silver syndrome, 3M syndrome, craniosynostosis syndromes, progeria |
– Fractures | – Hypophosphatasia, osteogenesis imperfecta, osteopetrosis versus adequate trauma |
– Heterotopic ossifications | Skeletal disorders with heterotopic ossifications: – Fibrodysplasia ossificans progressiva, primary osteoma cutis, progressive osseous heteroplasia, pseudohypoparathyroidism, Albright’s hereditary osteodystrophy, pseudopseudohypoparathyroidism |
– Connective tissue involvement/dislocations; contractures/joint limitations | Skeletal disorders with hyperlaxity – several including: collagenopathies, GAG-biosynthesis disorders, cartilage hair hypoplasia, NEPRO-associated skeletal disorder, pseudoachondroplasia |
– Hair, nails and teeth | Skeletal disorders with ectodermal involvement – Sparse hair: cartilage hair hypoplasia, trichorhinophalangeal syndrome, NEPRO-associated skeletal disorder – Nail abnormalities: nail–patella syndrome – Dental anomalies and nail hypoplasia: Weyers acrofacial dysostosis, Ellis-van Creveld – Dentigonesis imperfecta or hypoplasia of enamel: osteogenesis imperfecta, hypophosphatasia – Natal teeth: some progeria syndromes, Ellis-van Creveld, – Supernumerary teeth: cleidocranial dysplasia, Ellis-van Creveld, Weyers acrofacial dysostosis – Hyperpigmentation and café au lait spots: cell cycle defects, neurofibromatosis |
– Malformations and organ dysfunctions | – Cleft palate: type II collagenopathies, GAG-biosynthesis disorders, hyperphosphatasia with mental retardation syndrome – Oral frenulae: ciliopathies such as Ellis-van Creveld – Severe myopia: type II collagenopathies – Infantile glaucoma: type II collagenopathies, GAG-biosynthesis disorders, nail–patella syndrome, filamin A disorders, oculoskeletodental syndrome – Risk for retinopathy, nephropathy and hepatopathy: ciliopathies – Cataracts: X‑linked dominant chondrodysplasia punctata‑2, inborn errors of metabolism with skeletal disorders – Gastrointestinal malformations: cartilage hair hypoplasia, hyperphosphatasia with mental retardation syndrome – Risk for immunodeficiency or hematological involvement: cartilage hair hypoplasia, cell cycle defects, Fanconi anemia syndromes, Shwachman–Diamond syndrome |
– Visual diagnostic clues to rare skeletal disorders | – Congenital malformation of halluces, painful swelling of soft tissue, progressive heterotopic ossification: fibrodysplasia ossificans progressiva – Cystic swelling of the ear: diastrophic dysplasia – Dental and nail abnormalities, mild short stature, polydactyly, ear dysplasia: Weyer acrofacial dysostosis – Absent or hypoplastic patella: nail–patella syndrome – Painful, fleshy papules, progressive contractures and diarrhea: hyaline fibromatosis syndrome – Acanthosis nigricans: thanatophoric dysplasia, achondroplasia, hypochondroplasia |
– Caution signals | – Respiratory insufficiency/failure due to upper airway obstruction or small chest; neurological abnormalities due to foramen magnum stenosis or cervical spine instability; hearing loss; severe infections |
General physical and laboratory examination | – To exclude relevant multisystemic involvement and malformations |
Family investigation | |
Growth parameters Skeletal disorder-specific physical examination Dysmorphic examination | – Height; weight; head circumference; armspan; sitting height; upper/lower segment ratio – Define if other family members are affected and if dysmorphic features in the patient might be familial variants |
Imaging workup to determine an imaging pattern | |
Complete skeletal survey – Spine ap. and lat. – Pelvis with hips ap. – Both hands and feet ap. – Long bones ap. unilateral (bilateral in asymmetric involvement) – Skull lat. – Consider special radiographs dependent on clinical manifestation: radiographs for fractures, flexion and extension of cervical spine | Define a radiological pattern – Which part of long bones: epi-/meta-/diaphyseal – Spine affected? – Which part of the bones are affected/non affected? Don’t miss disease characteristic signs such as – iliac horns in nail–patella syndrome; hypoplastic iliac wings, trident acetabular roofs and sciatic notch spur in ciliopathies; snail-like appearance of the ilia in Schneckenbecken dysplasia; hypoplastic or aplastic claviculae and large fontanells in cleidocranial dysplasia; double-layered patella in multiple epiphyseal dysplasia; Define bone age – Retarded bone age is common in skeletal disorder while accelerated bone age is rare and links to GAG-biosynthesis disorders – Bone age is not suitable to estimate adult height in skeletal disorder Consider age dependent radiological patterning: – For example, chondrodysplasia punctate and accelerated bone age are vanishing with time; in adults: try to obtain pediatric skeletal radiographs |
Consider disease-specific imaging – e.g., MRI, CT, DXA ultrasound, SPECT, HR-pQCT | Don’t miss important complications of skeletal disorders such as – Foramen magnum stenosis in achondroplasia; cervical canal stenosis in heterotopic ossification disorders, chondrodysplasia punctate brachytelephalangic; cervical spine instability for example in SEDC, GAG-biosynthesis disorders, SMED |