Clinical report
Dual diagnosis of osteogenesis imperfecta (OI) and short stature and advanced bone age with or without early-onset osteoarthritis and/or osteochondritis dissecans (SSOAOD) reveals a cumulative effect on stature caused by mutations in COL1A1 and ACAN genes

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Abstract

Short stature is a feature when a person's height is more than 2 SDS below the corresponding mean height for a given age, gender and population. It can be influenced by many factors essential to growth plate. Here we report a three-generation family with 13 patients affected by osteogenesis imperfecta (OI) type I, short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans (SSOAOD) or both. Panel sequencing of the proband revealed mutations in two extracellular matrix related genes: COL1A1 and ACAN. When comparing the quantitative trait, height within the family of different mutation carrier groups, we found an interesting cumulative effect, the ones with both mutations manifest shortest stature. Dual diagnoses of the family also suggest the necessity of a comprehensive molecular diagnosis method, such as panel/exome sequencing, especially encountering patients with novel phenotype or extreme trait.

Introduction

Short stature is a feature when a person's height is more than 2 SDS below the corresponding mean height for a given age, gender and population (Wit et al., 2008). There are multiple factors contributing to human growth, such as genetics, hormones, nutrition and environmental factors (Argente, 2016). It is estimated that genetic factors are accountable for approximately 80% of height variations within a given population. Extremely shortness is more likely due to pathogenic variations in genes critical for growth plate (GP) activity regulation, these genes involved in hormone signaling, intracellular signal pathways, paracrine factors, cartilage extracellular matrix (ECM) molecules and other regulatory factors (Baron et al., 2015; Dauber et al., 2014). ECM is secreted by chondrocytes. The major components: collagens, proteoglycan (including aggrecan) play important roles in the normal function of growth plate. The defect in single ECM component coding gene is sufficient to affect skeletal function and height. Here we present a three-generation family affected by mutations in ACAN and COL1A1 genes (both encode ECM components), and their stature showed cumulative effect caused by the two mutations.

The proband (III-11, Fig. 1A) was first referred to the clinic due to short stature at the age of five years and eight months. He was proportionally short with a height of 95.3 cm (−4.5 SDS). Physical examination revealed dentinogenesis imperfecta, short neck and blue sclera. The X-ray image showed femoral bowing. No finger dysplasia, platyspondyly or irregularity of the spinal bones were observed. Bone age was evaluated based on Greulich and Pyle Atlas (GP) bone age determination system, 2nd edition (same hereinafter). At the age of five years and eleven months, his bone age was between six and seven years (Fig. 1B). The bone mineral density (BMD) was measured using Hologic Discovery Dual Energy X-ray Absorptiometry (DXA) scanner. At the age of six, his BMD was 0.466 g/cm2, which was −1 SDS lower than the value of age-matched boys (Ref: mean ± SD: 0.531 ± 0.046 g/cm2) (Liu et al., 2017). He experienced a hairline fracture in the scapula at the age of three. His father (II-5) also fractured several times during his childhood and had mild osteopenia according to X-ray results. His elder sister (III-9) was 138 cm (−3.7 SDS) at fourteen years old, and she had menarche at the age of 12 years and exhibited growth cessation. She fractured twice in her childhood, once in the elbow and once in the toe. These features lead to the clinical diagnosis of osteogenesis imperfecta (OI) in the core family. After the molecular diagnosis was drawn for the proband, we further collected the family history and identified a three-generation family. I-2, II-1, II-5 and III-1 had multiple fractures when they were young. Several family members were short in various degrees. They denied arthritis or back pain. Detailed features of the three-generation family are summarized in Table 1.

III-11 was treated with alendronate since he was six years old. The dosage was 5 mg per day. After treatment for one year and eleven months, his BMD reached 0.622 g/cm2, which was above the mean value of age-matched boys (Ref mean ± SD reported at the age of eight 0.610 ± 0.051 g/cm2) at the age of seven years and ten month (Liu et al., 2017). However, he was still extremely short with the height of 105 cm (−4.5 SDS). And the bone age was between eight and nine years, which kept slightly advanced (Fig. 1B).

Section snippets

Panel sequencing

Library preparation and data analysis were performed as described previously (Sun et al., 2017). In brief, genomic DNA was purified from peripheral blood and the inherited disease panel (Agilent Technologies, CA, USA) was implemented for the target fragments capture. The captured fragments were subsequently sequenced on Illumina Hiseq 4000 platform in pair end mode. Variants were called following GATK best practice (version 3) from pass filtered reads. The output vcf files were annotated by

Results

The variants detected in III-11 were listed in Supplementary Material S2 in vcf format. Panel sequencing revealed a “likely pathogenic” heterozygous mutation (NM_000088.3:c.1354-12G > A) in COL1A1 gene, encoding pro-alpha1(I) chain of type I collagen, the major component of type I collagen precursor. Heterozygous mutations in COL1A1 gene cause several types of OI. This mutation has been reported in several sporadic cases with OI, type I (OMIM 166200) (Schleit et al., 2015; Swinnen et al., 2011

Discussion

Dual diagnosis of OI type I and SSOAOD was drawn for the proband and his elder sister by identifying mutations in COL1A1 and ACAN gene. Both genes encode components in ECM. Height is a quantitative trait influenced by many factors including ECM. When comparing height within the family, we found an interesting cumulative effect of the two mutations (Fig. 1C). In most cases, patients with OI type I have normal or near normal stature (Lund et al., 1999). Meanwhile height of the ones who only carry

CRediT authorship contribution statement

Xiantao Ye: Investigation, Writing - original draft. Di Fang: Visualization. Yunjuan He: Validation. Hui Yan: Investigation. Wenjuan Qiu: Resources, Writing - review & editing. Yu Sun: Conceptualization, Writing - review & editing.

Acknowledgements

We would like to thank the patients and their family members for their participation. This work was funded by Precision Medical Research of National Key Research and Development Program (2016YFC0905100, 2018YFC1002400), National Natural Science Foundation of China (81873724), Shanghai Municipal Commission of Health and Family Planning Foundation (2017YQ020).

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These authors contribute equally to this work.

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