Common variable moderate Osteogenesis Imperfecta with normal sclerae (OI type IV) is a moderate form of OI (see also OI type I). It is characterized by increased bone fragility, low bone mass (DEXA z-scores in the range of –3 to –5 SD), and susceptibility to bone fractures. Most fractures occur either prior to puberty or beyond middle age.

(OMIM phenotype number #166220)

Common variable moderate Osteogenesis Imperfecta with normal sclerae (OI type IV) is a moderate form of OI (see also OI type I). It is characterized by increased bone fragility, low bone mass (DEXA z-scores in the range of –3 to –5 SD), and susceptibility to bone fractures. Most fractures occur either prior to puberty or beyond middle age. Vertebral compressions in childhood and laxity of paraspinal muscles may lead to significant scoliosis. Patients with OI type IV show also moderately short stature, grayish or white sclera, and dentinogenesis imperfecta. Body proportions approach normal, although the legs are still short for the trunk and the cranium is relatively macrocephalic. With medical intervention these individuals have an essentially normal life span.

Gene

• COL1A1 gene, 17q21.33 (OMIM gene/locus number #120150).
• COL1A2 gene, 7q21.3 (OMIM gene/locus number #120160).
• WNT1 gene, 12q13.12 (OMIM gene/locus number #164820).
• CRTAP gene, 3p22.3 (OMIM gene/locus number #605497).
• PPIB gene, 15q22.31 (OMIM gene/locus number #123841).
• SP7 gene, 12q13.13 (OMIM gene/locus number #606633).
• PLS3 gene, Xq23 (OMIM gene/locus number #300131).

Phenotype

Moderate form of OI, some cases indistinguishable from type III, adult hearing loss, variable phenotype, osteoporosis, bone fractures, short stature, vertebral deformity and scoliosis, triangular face, normal sclerae, hypermobility of the joints, and mild dentinogenesis imperfecta in some cases.

Images

Fig. X-rays of a patient affected by OI type IV. (A) Radiograph shows the neonatal skeletal survey. Note the gracile and poorly mineralized ribs and short femurs with bilateral midshaft fractures and flared metaphyses. (B) Radiograph of the lower extremities before rod placement at about 4 years of age. There are marked osteoporosis, thin cortices, and a healing fracture of the left femur. The long bones have undergone notable remodeling and are of a more normal overall configuration as compared to (A).

This research was originally published in J Biol Chem. Marini JC, Grange DK, Gottesman GS, et al. Osteogenesis imperfecta type IV. Detection of a point mutation in one alpha 1(I) collagen allele (COL1A1) by RNA/RNA hybrid analysis. J Biol Chem. 1989;264:11893-900. © The American Society for Biochemistry and Molecular Biology.

Other resources:

• http://www.oif.org/
• http://www.oife.org/
• http://www.oife.org/index.php/EN/other-oi-organisations
• http://www.brittlebone.org/

Familial exudative vitroretinopathy (FEVR) is an inherited disorder, caused by mutation in the LRP5 gene. FEVR is characterized by an abnormal development of the retinal vessels, particularly in the temporal retinal periphery, resulting to several variable manifestations, ranging from asymptomatic to complete blindness. 

(OMIM phenotype number #601813)

Familial exudative vitroretinopathy (FEVR) is an inherited disorder, caused by mutation in the LRP5 gene. FEVR is characterized by an abnormal development of the retinal vessels, particularly in the temporal retinal periphery, resulting to several variable manifestations, ranging from asymptomatic to complete blindness. Visual problems are caused by this progressive vascular anomalies and by various complications such as retinal neovascularization, exudates, fibrovascular proliferation, retinal folds, optic disc dragging, and retinal detachment. FZD4, LRP5, and TSPAN12 genes mutations, have been described as responsible for autosomal dominant form of FEVR, LRP5 gene mutation for autosomal recessive form, and NDP gene mutation for X-linked form. The encoded proteins of these four genes are involved in the wingless (Wnt) signaling pathway, which monitor retinal vascular development. Recessive LRP5 mutations are known to be responsible of osteoporosis pseudoglioma syndrome (OPPG) (see also OPPG), characterized by low bone mass and congenital or infancy onset blindness. Similarly, low bone mass has been described also in the heterozygous mutation carriers in OPPG families and in FEVR patients with dominant LRP5 mutations.

Gene

LRP5 gene, 11q13.1 (OMIM gene/locus number #603506). LRP5 gene, encoding low-density lipoprotein receptor-related protein 5.

Phenotype

Decreased visual acuity, blindness, falciform retinal folds, tractional retinal detachment, macular ectopia, retinal exudates, vitreous detachment, subcapsular opacities peripheral retinal avascularization, neovascularization, vitreous hemorrhage, horizontal pendular nystagmus, and decreased bone mineral density.

Images

Fig. Clinical pictures of family members showing classic features of FEVR. (A) Fundus photograph of the proband’s left eye taken at age 17. White glial tisssue is visible at the disc with the suggestion of a hyaloid artery remnant running forward into the vitreous. (B, C) Fundus photographs of an other patient taken at age 12. In the right eye (B) a strand within the vitreous associated with glial tissue appears to obscure the posterior pole. In the left eye (C) there is slight straightening of the temporal arcades. (D) Fundus photograph of the right eye of an other patien taken at age 10. Extensive vitreoretinal traction is seen distorting the retinal vessels emerging from the disc and producing a ‘‘dragged disc’’ appearance.

Reproduced from Br J Ophthalmol,Paul SA, Simon SS, Karthik AK, et al., volume 90, pages 1163-7, copyright notice 2006 with permission from BMJ Publishing Group Ltd.

Other resources:

• http://www.fevr.net/

The inherited osteolysis syndromes are a heterogeneous group of diseases characterized by bone destruction and resorption. There are several forms of osteolysis described under a variety of designations with often overlapping clinical findings, and their classification is still a matter of debate. Torg syndrome, Winchester syndrome and Nodulosis Arthropathy Osteolysis syndrome (NAO) are three autosomal recessive inheritance osteolysis syndromes with multicentric involvement.

• Winchester syndrome (OMIM phenotype number #277950)
• Torg syndrome, Nodulosis-Arthropathy-Osteolysis Syndrome (OMIM phenotype number #259600)

The inherited osteolysis syndromes are a heterogeneous group of diseases characterized by bone destruction and resorption. There are several forms of osteolysis described under a variety of designations with often overlapping clinical findings, and their classification is still a matter of debate. Torg syndrome, Winchester syndrome and Nodulosis Arthropathy Osteolysis syndrome (NAO) are three autosomal recessive inheritance osteolysis syndromes with multicentric involvement. Recently, it has been hypothesized that these three syndromes may be allelic disorders of a continuous clinical spectrum. Indeed, mutations in the MMP2 (matrix metalloproteinase 2) gene have been identified in affected individuals with a clinical diagnosis of NAO and Winchester syndrome. Mutations in the MMP2 gene has been identified also in a patient with Torg syndrome with a complete loss of MMP2 activity. MMP2 is a key enzyme involved in connective tissue turnover, degrading type IV collagen, the major component of basement membranes, and denaturing collagen (gelatin). Winchester syndrome is also caused by homozygous mutation in the MMP14 gene. It has a similar phenotype to NOA, but the subcutaneous nodules are absent.

Gene

MMP2 gene, 16q12.2 (OMIM gene/locus number #120360).

Phenotype

Torg syndrome (includes NAO syndrome): multiple, painless, subcutaneous nodules (interphalangeal joints, knees, feet, elbows, pretibial), mild to moderate osteoporosis and osteolysis usually limited to the hands and feet, widening of the metacarpal and metatarsal bones. Winchester syndrome: subcutaneous nodules are characteristically absent, severe osteolysis in the hands and feet, and various additional features including coarse face, corneal opacities, gum hypertrophy, and EKG coarse face

Main biochemical alterations

High ANA, high IL-6, and high IL-1β.