Blue Sclerae FREE

A 60-year-old man with a history of multiple fractures after minor trauma presents for evaluation of anemia with a hemoglobin level of approximately 9 g/dL. Other medical problems include chronic hypertension and worsening chronic kidney disease (CKD). His family history is remarkable for short stature and dental problems. Physical examination reveals a short male with blue sclerae (Figure). Iron levels are normal and ferritin is elevated. A kidney biopsy performed for renal dysfunction progressing more rapidly than expected reveals glomerulosclerosis compatible with hypertensive nephropathy. A bone marrow biopsy is negative for malignancy and shows elevated iron levels.

Osteogenesis imperfecta

C. Offer genetic counseling, including evaluation of family members.

The key clinical feature in this case is to recognize that blue sclerae in a patient with multiple fractures points toward a collagen abnormality.¹ Obtaining a detailed history is of utmost importance when evaluating a predisposition to bone fractures, including mechanism of injury, chronic medical conditions, treatment with glucocorticoids, long-term parenteral nutrition, and family history.

Osteogenesis imperfecta (OI) is a genetically and phenotypically heterogeneous condition with variable modes of inheritance and penetrance. Osteogenesis imperfecta is associated with many mutations in type I collagen genes and other genes involved in bone integrity. These genetic aberrations result in reduced production of normal collagen, leading to bone fragility and thinning of the sclerae, which permits visualization of the underlying bluish choroid.¹ Patients can present in infancy or later in life with single or multiple fractures.

Many tests could be performed, although they are not required for confirming a diagnosis of osteogenesis imperfecta. Laboratory tests used to assess the possibility of a metabolic bone disease include measurements of serum calcium, alkaline phosphatase, 25-hydroxyvitamin D, phosphorus, and parathyroid hormone. A skeletal survey could be considered to identify occult fractures, whereas a bone scan, typically obtained during the evaluation of metastatic disease to the bone, would not be part of the usual workup for osteogenesis imperfecta.

Osteogenesis imperfecta types I through V are inherited in an autosomal dominant manner; however, the mode of inheritance of types VI through XII appears to be autosomal recessive. Approximately 60% of individuals with mild osteogenesis imperfecta have de novo mutations.² Each child of an individual with a dominantly inherited form of osteogenesis imperfecta has a 50% chance of inheriting the mutation and developing some manifestations; hence, genetic counseling should be offered. Bone biopsy is not required for the diagnosis but may be an adjunct to the diagnosis of osteogenesis imperfecta types V and VI.

Approximately 90% of patients with osteogenesis imperfecta types I, II, III, and IV have an identifiable mutation in either COL1A1 or COL1A2,² whereas no individuals with osteogenesis imperfecta types V, VI, and VII have had an identifiable mutation in either COL1A1 or COL1A2. Thus, the lack of such mutations does not rule out a diagnosis of osteogenesis imperfecta. Testing for COL1A1 and COL1A2 mutations is expensive and the results usually will not alter clinical management. Multiple other mutations have been identified.³

Genetic counseling, including evaluation of family members who may have less severe forms of the disease, is paramount when evaluating diseases characterized by abnormal collagen. Prenatal testing for at-risk pregnancies should be considered. Analysis of type I collagen and sequence analysis of COL1A1 and COL1A2 should be discussed in individual cases.

Blue sclerae are not pathognomonic for osteogenesis imperfecta. The differential diagnosis includes alkaptonuric ochronosis, Ehlers-Danlos syndrome, Loeys-Dietz syndrome, De Barsy syndrome, and Marshall-Smith syndrome.^4- 8 Bisphosphonates, the cornerstone of preventing and treating fragility fractures, appear to be a promising supportive therapy in this population of patients.

In this patient, the physical finding of blue sclerae combined with a history of multiple bone fractures should suggest the diagnosis of osteogenesis imperfecta. Anemia was believed to be secondary to CKD, which was, in turn, due to chronic uncontrolled hypertension and unrelated to the main diagnosis of osteogenesis imperfecta. Further testing is not required for this patient because the diagnosis is clinical. Although treatment with bisphosphonates was considered, the patient's CKD prevents use of these drugs. The patient was treated supportively with pain medications for his multiple fractures and vitamin supplementation, and he was encouraged to avoid situations that may predispose to further fractures.