OSTEOGENESIS IMPERFECTA

Disease definition

Osteogenesis imperfecta (OI) comprises a heterogeneous group of genetic disorders characterized by increased bone fragility, low bone mass, and susceptibility to bone fractures with variable severity.

Synonyms

Brittle bone disease, Glass bone disease, Lobstein disease, OI, Osteopsathyrosis

Epidemiology

Prevalence is estimated at between 1/10,000 and 1/20,000.

Clinical description

Age at diagnosis depends on the severity of the disease. Five clinically distinct types of OI have been identified. The most clinically relevant characteristic of all types of OI is bone fragility, which manifests as multiple spontaneous fractures. Osteogenesis imperfecta type II is lethal, type III is severe, types IV and V are moderate, and type I is mild (see these terms). Type I is nondeforming with normal height or mild short stature, blue sclera, and no dentinogenesis imperfecta (DI; see this term). Patients with type II present multiple rib and long bone fractures at birth, marked deformities, broad long bones, low density on skull X-rays, and dark sclera. The main signs of type III include very short stature, a triangular face, severe scoliosis, grayish sclera, and DI. Patients with type IV have moderately short stature, mild to moderate scoliosis, grayish or white sclera, and DI. Type V is characterized by mild to moderate short stature, dislocation of the radial head, mineralized interosseous membranes, hyperplastic callus, white sclera, and no DI. Other genetically different types have been observed (types VI to IX) but they are not clinically different from types II-IV.

Etiology

In 95% of cases, OI is caused by mutations in the COL1A1 and COL1A2 genes (17q21.33 and 7q21.3) encoding the alpha1 and alpha2 chains of type 1collagen. These mutations can cause all five clinical types of OI. Transmission is autosomal dominant. Autosomal recessive forms of OI are also observed and are caused by mutations in the LEPRE1, CRTAP, and PPIB genes (1p34.1, 3p22 and 15q21-q22). Autosomal recessive forms are always severe forms with severe hypotonia.

Diagnostic methods

Diagnosis is based on skeletal and extra-skeletal clinical findings. Radiological studies reveal osteoporosis and the presence of wormian-like bones. Bone densitometry confirms the low bone mass.

Differential diagnosis

Differential diagnoses include in utero diagnosis of chondrodysplasia, idiopathic juvenile osteoporosis, osteoporosis-pseudoglioma syndrome, Cole-Carpenter and Bruck syndromes, hyper or hypophosphatasia, panostotic form of polyostotic fibrous dysplasia (see these terms), non-accidental injury (multiple fractures without osteoporosis), and osteoporosis due to medication, nutritional deficiency, metabolic disease, or leukemia. The presence of several fractures should not lead to the assumption of child abuse.

Antenatal diagnosis

Antenatal diagnosis may be suspected through ultrasonography and/or confirmed through molecular analysis of amniocytes or chorionic villus cells if the causative mutation in the family has been identified.

Management and treatment

Management should be multidisciplinary involving experienced medical, orthopedic, physiotherapy and rehabilitation specialists. Bisphosphonates with potent antiresorptive properties are now considered as the standard of care for severe forms but do not constitute a cure. Prevention of vitamin D and calcium deficiency is essential throughout life. Surgical management is essential for the correction of bone and spinal deformities and the prevention of long bone fractures (centro-medullary osteosynthesis). Early physiotherapy improves autonomy by helping to evaluate any motor deficits, reducing the risk of falls and encouraging patients to take up a sporting activity.

Prognosis

Functional prognosis depends on the severity of the disease and on the quality of management. Vital prognosis depends on the severity of any respiratory complications associated with spinal deformities.

Expert reviewer(s):  Dr Véronique FORIN – Last update: March 2010

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ACHONDROPLASIA

Disease definition

Achondroplasia is the most common form of chondrodysplasia, characterized by rhizomelia, exaggerated lumbar lordosis, brachydactyly, and macrocephaly with frontal bossing and midface hypoplasia.

Epidemiology

Estimated incidence is at about 1/25,000 live births worldwide.

Clinical description

Characteristic clinical features (short limbs with rhizomelia, long and narrow trunk and macrocephaly with frontal bossing and midfacial hypoplasia with depressed nasal bridge) are visible at birth. Achievement of gross motor skills is slower than typical due to short limbs, short neck, and large head, in addition to hypotonia. Midface hypoplasia in combination with adenoid and tonsil hypertrophy can lead to obstructive sleep apnea. Chronic otitis media can lead to hearing problems. Dental crowding is common. Thoracolumbar kyphosis is very common in infancy. Most joints can be hyperextensible and hands are broad, short and trident shaped. Cord compression at the level of the foramen magnum can be encountered in infancy and early childhood causing central apnea, developmental delay, and long-track signs. Genu varum often occurs in childhood. There is also a small risk of hydrocephalus, with raised intracranial venous pressure. Lower lumbar spinal stenosis with accompanying neurological deficits, has an increased frequency in adulthood, as does cardiovascular disease. Obesity is a common issue. Adults reach a height of 131±5.6 cm (men) and 124±5.9 cm (women). Affected women must deliver by caesarian section due to small pelvis size.

Etiology

Achondroplasia is due to mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, encoding a transmembrane receptor that is important in regulating linear bone growth, among other functions.

Diagnostic methods

Diagnosis is based on the presence of characteristic clinical and radiological findings. Skeletal X-rays demonstrate rhizomelia, generalized metaphyseal irregularities, narrowing of the interpediculate distance of the lower lumbar vertebrae and an abnormal pelvis with small square iliac wings and narrow sacrosciatic notch. Molecular genetic testing can confirm a diagnosis by the presence of a FGFR3 mutation.

Differential diagnosis

Differential diagnoses include hypochondroplasia, thanatophoric dwarfism (types I and II), and SADDAN (see these terms).

Antenatal diagnosis

Prenatal diagnosis can occur incidentally during routine prenatal ultrasound examination in the 3rd trimester. In high risk pregnancies, or in those where achondroplasia is suspected after an ultrasound, fetal DNA can be tested for the FGFR3 mutation to confirm diagnosis. Pre-implantation genetic diagnosis is possible in specialized laboratories.

Genetic counseling

Inheritance is autosomal dominant so genetic counseling is warranted. If one parent has achondroplasia there is a 50% chance of passing it on to offspring. In 80% of cases, it is due to a de novo mutation in children with parents of average stature. Homozygous achondroplasia is a lethal condition.

Management and treatment

Management is multidisciplinary and anticipatory care is essential. Infants may require surgical decompression of the foramen magnum, and/or shunting for hydrocephalus. Some may choose controversial limb lengthening procedures. Treatment of ear infections and serous otitis media, along with assessment of any hearing problems is needed. Speech therapy can be offered if concerns arise. Treatment of obstructed sleep apnea may include adenotonsillectomy, weight loss, and/or continuous positive airway pressure. Surgical correction can re-align bowing of legs. Adult patients may require a lumbar laminectomy to treat spinal stenosis. Weight gain should be monitored in childhood to avoid later complications. Activities which lead to a risk of injury to the craniocervical junction should be avoided. Social and psychological support should be offered.

Prognosis

There is only a slight decrease in life expectancy compared to the general population, potentially due to cardiovascular disease.

Expert reviewer

 Dr Michael BOBER – Angela DUKER – Last update: April 2013

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HYPOPHOSPHATASIA

Disease definition

Hypophosphatasia (HPP) is a rare heritable metabolic disorder characterized by defective mineralization of bone and/or teeth in the presence of reduced activity of unfractionated serum alkaline phosphatase (ALP). The clinical spectrum is extremely wide, from stillbirth at one end to fractures of the lower extremities in adulthood, at the other, or even no bone manifestations (odontohypophosphatasia).

Epidemiology

Exact prevalence and incidence data for hypophosphatasia are not available. The prevalence ofsevere forms of the disease has been estimated to be 1/300,000 births in Europe.

Clinical description

Six different clinical forms of HPP have been described. Prenatal benign hypophosphatasia involves prenatal skeletal manifestations that slowly resolve to become the milder childhood or adult form. Perinatal lethal hypophosphatasia involves significant hypomineralization and leads to hypercalcemia and respiratory insufficiency. Infantile hypophosphatasia is characterized by rickets developing between birth and six months of age. Childhood-onset hypophosphatasia ranges from low bone mineral density with unexplained fractures to rickets. Adult hypophosphatasia involves early loss of adult dentition and stress fractures of the lower extremities in middle age. Lastly, odontohypophosphatasia includes premature exfoliation of primary teeth and/or severe dental caries. Rare cases of infantile hypophosphatasia that have normal serum alkaline phosphatase activity are known as ”pseudohypophosphatasia”.

Etiology

More than 250 different mutations in the ALPL gene (1p36.12) are known to cause hypophosphatasia. The gene encodes alkaline phosphatase, tissue-nonspecific isozyme (TNSALP) involved in skeletal mineralization.

Diagnostic methods

The diagnosis is based on laboratory testing and molecular genetic testing of the ALPL gene to detect causative mutations. Serum alkaline phosphatase (AP) activity is markedly reduced while urinary phosphoethanolamine (PEA) is increased but these abnormalities are not pathognomonic. Ultrasound is used in prenatal and perinatal forms. Clinical examinations and radiographs help to establish the diagnosis in infantile, childhood and adult forms.

Differential diagnosis

The differential diagnosis includes osteogenesis imperfecta and campomelic dysplasia in early diagnosis, and hypophosphatemic rickets and achondrogenesis in later diagnosis (see these terms).

Antenatal diagnosis

Prenatal diagnosis can be performed through mutation analysis following chorionic villus sampling.

Genetic counseling

Perinatal and severe infantile HPP are inherited as autosomal recessive traits. Prenatal benign, moderate infantile, childhood HPP, adult HPP and odontohypophosphatasia can be inherited in an autosomal recessive or autosomal dominant manner, depending on the specific effect the gene mutation has on TNSALP activity. The less severe the disease, the more likely it is dominantly inherited. The range of inheritance patterns partially explains the clinical heterogeneity. In autosomal recessive hypophosphatasia, rare de novo mutations have been reported. In autosomal dominant hypophosphatasia, affected patients may have an affected parent but penetrance appears to be low and de novo mutations have not been reported. HPP displays highly variable expressivity. Genetic counseling is complicated by these factors but should be offered to affected families.

Management and treatment

Supportive symptomatic treatment in childhood and adult forms includes non-steroidal anti-inflammatory drugs (children), teriparatide (adults) and orthopedic management. Dental monitoring and care are essential. Enzyme replacement therapy also plays a role. Bisphosphonates are generally contraindicated in hypophosphatasia.

Prognosis

The perinatal form is almost always fatal within days or weeks. Respiratory complications lead to high mortality rates in the infantile form. Life expectancy is not thought to be affected in the adult form or in odontohypophosphatasia.

Expert reviewer

Pr Etienne MORNET – Last update: April 2015

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MULTIPLE OSTEOCHONDROMAS

Disease definition

Multiple osteochondromas (MO) is characterised by development of two or more cartilage capped bony outgrowths (osteochondromas) of the long bones.

Synonym

Bessel-Hagen disease, Multiple cartilaginous exostoses

Epidemiology

The prevalence is estimated at 1:50,000, and seems to be higher in males (male-to-female ratio 1.5:1).

Clinical description

Osteochondromas develop and increase in size in the first decade of life, ceasing to grow when the growth plates close at puberty. They are pedunculated or sessile (broad base) and can vary widely in size. The number of osteochondromas may vary significantly within and between families, the mean number of locations is 15-18. The majority are asymptomatic and located in bones that develop from cartilage, especially the long bones of the extremities, predominantly around the knee. The facial bones are not affected. Osteochondromas may cause pain, functional problems and deformities (especially of the forearm), which may provide reason for surgical removal. The most important complication is malignant transformation of osteochondroma towards secondary peripheral chondrosarcoma, which is estimated to occur in 0.5-5% of cases.

Etiology

Germline mutations in the tumour suppressor genes, EXT1 or EXT2, are found in almost 90% of MO patients. The EXT genes encode glycosyltransferases, catalyzing heparan sulphate polymerization.

Diagnostic methods

The diagnosis is based on radiological and clinical documentation, supplemented with, if available, histological evaluation of the osteochondromas.

Differential diagnosis

MO should be distinguished from metachondromatosis, dysplasia epiphysealis hemimelica and Ollier disease (see these terms).

Antenatal diagnosis

If the exact mutation is known antenatal diagnosis is technically possible.

Genetic counseling

MO is an autosomal dominant disorder and is genetically heterogeneous.

Management and treatment

Management includes removal of osteochondromas when they are the cause of complaints. Removed osteochondromas should be examined for malignant transformation towards secondary peripheral chondrosarcoma. Patients should be well instructed and regular follow-up for early detection of malignancy seems justified. For secondary peripheral chondrosarcoma, en-bloc resection of the lesion and its pseudocapsule with tumour-free margins should be performed, preferably in a bone tumour referral centre.

Prognosis

Osteochondromas are benign lesions and do not affect life expectancy.

Expert reviewer

 Pr J.V.M.G. [Judith] BOVÉE – Last update: February 2008

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