Work Up Diagnosis

• Fenotype diagnosis : Osteogenesis Imperfecta

• Genotype diagnossis : heterozygous mutation in the COL1A1 gene (
120150) or the COL1A2 gene (120160) in 17q21.33

https://www.omim.org/entry/166200?search=osteogenesis%20imperfecta&highlight=imperfecta%20osteogenesi
 Osteogenesis Imperfecta
• A hereditary condition resulting from a decrease in the amount of
normal Type I collagen
• 1 case for every 20,000 live births; equally common in males and females
• Type I collagen is the most important structural protein of bone, skin,
tendon, dentin, sclera
• Triple helix structure
• two alpha-1 chains coded by genes COL1A1 gene on chromosome 17 encodes the
pro-alpha1 chain
• one alpha-2 chain coded by gene COL1A2 gene on chromosome 2 encodes the pro-
alpha2 chain
Triple helix structure is possible because of glycine at every 3rd amino acid residue

Genetic mutations alter triple helix by substitution of glycine with another amino acid
https://www.orthobullets.com/pediatrics/4102/osteogenesis-imperfecta
 •90% have an identifiable genetic mutation (COL 1A1 and COL 1A2)
•causes abnormal collagen cross-linking via a glycine substitution in the procollagen molecule
•autosomal dominant and autosomal recessive forms
•milder autosomal dominant forms (Types I and IV) -> 90%
•severe autosomal recessive forms (Types II and III) 
•CRTAP and LEPRE1 genes associated with severe, lethal forms of OI not associated with primary
structural defect of type I collagen

https://www.orthobullets.com/pediatrics/4102/osteogenesis-imperfecta
• The gene sequence coding for the triple-helix domain has a repeating motif of (Gly-X-Y)(n)
X : hydroxyproline
Y : hydroxylysine.
Glycine plays an important role in the superhelix formation
• In 85-90% of cases, the gene mutation occurs in the region where the exon and intron splice sites are
sequenced, in the Human Type 1 Collagen Mutation Database.
• In OI due to quantitative defects of type 1 collagen, mutations of COL1A gene -> production of a premature
stop codon or a microsense frame shift -> mutant messenger RNA (mRNA) in the nucleus. Cytoplasm
contains normal alpha1 Mrna -> reduced amounts of structurally normal collagen are produced.
• In OI due to qualitative defects of type 1 collagen, autosomal dominant mutations are found on either the
COL1A or the COL1B gene -> production of a mixture of normal and mutant collagen chains. Substitution of a
larger amino acid (eg, cysteine or alanine) for glycine results in abnormal helix formation, but these chains
can combine with normal chains to produce type 1 collagen. The type 1 collagen thus formed is functionally
impaired because of the mutant chain
https://www.orthobullets.com/pediatrics/4102/osteogenesis-imperfecta
 Case 1 – Osteogenesis Imperfecta

In this case, the patient has recurrent fracture and history of the
same fracture in the mother and his sister.
The patient also shows blue sclera and bowing of tibia and fibula.
From the pedigree, patient’s mother and his sister are affected
that show autosomal dominant mode of inheritance.

https://www.orthobullets.com/pediatrics/4102/osteogenesis-imperfecta