Clinical Challenge: Blue Sclera in a Patient With Skeletal Fractures

Osteogenesis imperfecta refers to a heterogeneous group of disorders affecting bone formation. It is characterized by low bone mass and increased susceptibility to fractures. Most cases are due to defects in the synthesis of type I collagen. Cutaneous manifestations are...

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Osteogenesis imperfecta refers to a heterogeneous group of disorders affecting bone formation. It is characterized by low bone mass and increased susceptibility to fractures. Most cases are due to defects in the synthesis of type I collagen. Cutaneous manifestations are largely the result of weak dermal collagen, and dermatological management is predominantly preventative.

Osteogenesis imperfecta affects approximately 5 to10 in every 10,000 individuals. Most cases (~90%) are due to autosomal dominant mutations in either of the two genes coding for type I collagen, COL1A1 and COL1A2. Milder forms of the disease display a quantitative defect in type I collagen, whereas more severe forms display a qualitative defect. The remaining 10% of cases are due to recessive mutations in eight genes involved in collagen synthesis.

Osteogenesis imperfecta affects the bones, joints, eyes, ears, teeth and skin. The most prominent feature is that of brittle bones. Fractures are common, and most often occur before puberty and after middle age. Some fractures may occur in-utero.

Patients may present with skeletal deformations (kyphoscoliosis, bowing of the arms and legs) and short stature. There is often laxity of the joints, which may lead to dislocation. The sclera may be blue — although this can be a clue to the diagnosis, it is of little functional significance.

Affected individuals may develop hearing loss, which often occurs in the second decade of life and is indistinguishable from otosclerosis. Abnormal development of dentin may lead to translucent brown teeth, termed dentinogenesis imperfecta.

Cutaneous manifestations are largely the result of structural defects in the dermal connective tissue and vasculature, and include thin and translucent skin, easy bruising and atrophic scarring. Some patients may experience hyperhidrosis.

Osteogenesis imperfecta has been associated with elastosis perforans serpiginosa (EPS).  EPS presents as skin-colored or erythematous keratotic papules with a serpiginous configuration on the face, neck and arms. Onset is usually during adolescence and lesions may last for many years. 

Osteogenesis imperfecta is largely categorized into four types (types I-IV) based on severity. Recent histologic examination of bone architecture has reclassified some of type IV to types V-VII.

Type I is the mildest and most common form. Individuals are often of normal height, have blue sclerae and develop fractures after ambulation.

Type II is most severe and results in perinatal death from multiple intrauterine fractures and cardiorespiratory compromise.

Type III is characterized by severe skeletal deformity and dentinogenesis imperfecta. Individuals suffer multiple fractures in utero, but survive past infancy. They are often confined to a wheelchair and suffer from lifelong cardiorespiratory problems.

Type IV is of moderate severity. Individuals are of short stature, have dentinogenesis imperfecta, and display mild-moderate skeletal deformities. The sclerae are typically not blue.

Individuals with types V-VII are of short stature and have moderate skeletal deformities without blue sclera or dentinogenesis imperfecta.

The diagnosis can be established through DNA testing or skin biopsy. DNA analysis of the peripheral blood or saliva can be used to look for gene mutation known to be involved in osteogenesis imperfecta. Skin biopsy will show either reduced or abnormal expression of type I procollagen when cultured on dermal fibroblasts.

Other answer choices:

Marfan syndrome is due to an autosomal dominant mutation of FBN1, which codes for fibrillin-1. Skeletal abnormalities include disproportionately long limbs and arachnodactyly.

Affected individuals may present with ectopia lentis and are at risk for dilation and possible dissection of the ascending aorta. Cutaneous manifestations include striae and a lack of peripheral subcutaneous fat. It is associated with elastosis perforans serpinginosa.

Ehlers-Danlos syndromes are a group of seven genetically distinct disorders of connective tissue affecting collagen synthesis. The most prominent clinical manifestation is hyper-flexible joints, especially fingers, toes and knees.

Cutaneous manifestations include fragile and hyperextensible skin, easy bruising, atrophic scarring and calcification of the skin. Affected individuals may fracture easily and display skeletal deformities (kyphoscoliosis), but skeletal manifestations are less prominent than in ontogenesis imperfecta. Ehlers-Danlos syndromes are also associated with elastosis perforans serpinginosa.

Tuberous sclerosis is a disease characterized by ectodermal and mesodermal hyperplasia. It is due to autosomal dominant mutations in the tumor suppressor genes, TSCS1 and TSCS2.

Cutaneous manifestations include hypomelanotic macules (“ash-leaf spots” and “confetti” macules), angiofibromas, connective tissue nevi (shagreen patch) and ungual fibromas (Koenen tumors). Other manifestations are central nervous system tumors, gray or yellow retinal plaques, cardiac rhabdomyomas and mixed cell type hamartomas. Affected individuals may be mentally retarded and may suffer from recurrent seizures.

Treatment & Prognosis

Treatment of osteogenesis imperfecta is multidisciplinary and includes orthopedists, physical medicine specialists, endocrinologists and dermatologists. Surgical intervention is often required for fractures. Bisphosphonates are used to increase bone mineral density.

Dermatologic management mainly focuses on prevention. Patients should be advised to avoid harsh skin products and be conscious of avoiding trauma and resultant scarring.

Sun protection is especially important, as ultraviolet radiation will accelerate already dysfunctional dermal collagen. Patients should use broad-spectrum sunscreens, wear protective clothing and avoid sun exposure from 10 am to 4 pm. Most patients benefit from oral vitamin D supplementation.

Treatment for elastosis perforans serpinginosa can be very difficult. Success has been reported with imiquimod cream, oral isotretinoin and tazarotene gel, as well as with cryotherapy, carbon dioxide laser resurfacing and stripping the keratinous surface with cellophane tape.  

Andrew S. Fischer, BA, and Christopher B. Rizk, BA, are medical students at Baylor College of Medicine.

Adam Rees, MD, is a graduate of the University of California Los Angeles School of Medicine and a resident in the Department of Dermatology at Baylor College of Medicine also in Houston.