Osteogenesis Imperfecta/Ehlers-Danlos Syndrome Overlap Syndrome

Abstract

Helical mutations near the amino (N)-proteinase cleavage site have been suggested to result in a mixed osteogenesis imperfecta (OI)/Ehlers-Danlos syndrome (EDS) phenotype (Malfait et al. 2013).

Helical mutations near the amino (N)-proteinase cleavage site have been suggested to result in a mixed osteogenesis imperfecta (OI)/Ehlers-Danlos syndrome (EDS) phenotype (Malfait et al. 2013).

Synonyms and Related Disorders

Ehlers-Danlos syndrome; Mixed OI/EDS phenotype; Osteogenesis imperfecta

Genetics/Basic Defects

• 1. Most of the patients studied harbored a COL1A1/COL1A2 mutation residing within the most N-terminal part of the type I collagen helix (Nicholls et al. 1992; Feshchenko et al. 1998; Raff et al. 2000; Cabral et al. 2005) (Malfait et al. 2013).

• 2. These mutations affect the rate of type I collagen N-propeptide cleavage and disturb normal collagen fibrillogenesis.

Clinical Features

• 1. Mainly present as EDS signs (Malfait et al. 2013)

  • 1. Severe joint hyperlaxity

  • 2. Soft and hyperextensible/translucent skin

  • 3. Abnormal wound healing

  • 4. Easy bruising

  • 5. Mild abnormal scarring

  • 6. Sometimes signs of arterial fragility

• 2. Show only subtle signs of OI

  • 1. Blue sclera

  • 2. Osteopenia

  • 3. Fractures

  • 4. Relatively short stature

• 3. Hypotonia

• 4. Clinical overlap with other EDS subtypes, including the classic, hypermobility, vascular, arthrochalasis, and kyphoscoliosis types

Diagnostic Investigations

• 1. Biochemical collagen analysis: a powerful tool necessary to establish the diagnosis because of clinical overlapping with other EDS subtypes

• 2. Molecular sequencing of COL1A1 and COL1A2: allows identification of heterozygous mutations in the triple helical region close to the procollagen type I N-proteinase cleavage site (Malfait et al. 2013)

Genetic Counseling

• 1. Recurrence risk

  • 1. Patient’s sib: if a parent of the proband is affected, the risk to each sib is 50%.

  • 2. Patient’s offspring: a 50% chance of inheriting the mutation and developing the disorder.

• 2. Prenatal diagnosis: has not been accomplished.

• 3. Management: please see the chapters of osteogenesis and Ehlers-Danlos syndrome.

Fig. 1

(a–c) This 3-year-old Caucasian boy was evaluated for collarbone fractures, blue sclera, hypotonia, and hypermobile joints and to rule out osteogenesis imperfecta. He was noted to have hyperextensible fingers/wrists, knees, and ankles and bruise throughout the body. COL1A2 sequencing identified c.432 + 4_432 + 5insAA in one allele of COL1A2, the gene that encodes the pro-alpha 2 (I) chain of type I procollagen. The reference laboratory was able to characterize the outcome of splicing to have resulted in skipping of exon 9 and a mixed osteogenesis imperfecta and Ehlers-Danlos syndrome phenotype with fractures and joint hypermobility.