A Novel Mutation in the TRIP11 Gene: Diagnostic Approach from Relatively Common Skeletal Dysplasias to an Extremely Rare Odontochondrodysplasia

Abstract

Odontochondrodysplasia (ODCD, OMIM #184260) is a quite rare non-lethal skeletal dysplasia characterized by involvement of the spine and metaphyseal regions of the long bones, pulmonary hypoplasia, short stature, joint hypermobility, and dentinogenesis imperfecta. ODCD is inherited in an autosomal recessive fashion with an unknown frequency caused by mutations of the thyroid hormone receptor interactor 11 gene (TRIP11; OMIM *604505). TRIP11 gene encodes the Golgi microtubule-associated protein 210 (GMAP-210), which is an indispensable protein for the function of the Golgi apparatus. Mutations of the TRIP11 gene also cause achondrogenesis type 1A (ACG1A). Null mutations of TRIP11 lead to ACG1A, also known as a lethal skeletal dysplasia, while hypomorphic mutations cause ODCD. Here we report a male child diagnosed as ODCD with a novel compound heterozygote mutation who presented with skeletal changes, short stature, dentinogenesis imperfecta, and facial dysmorphism resembling Achondroplasia (ACH) and Hypochondroplasia (HCH).

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DOI: 10.4274/jcrpe.galenos.2021.2021.0099
Case report
A novel mutation in the TRIP11 gene: Diagnostic approach from relatively common skeletal dysplasias to an
extremely rare Odontochondrodysplasia
Short Title: A novel mutation in the TRIP11 gene with Odontochondrodysplasia
Burcu Yeter1, Ayca Dilruba Aslanger2, Gözde Yesil2, Nursel H. Elcioglu1,3
1Department of Pediatric Genetics, Marmara University Medical School, Istanbul, Turkey
2Department of Medical Genetics, Istanbul University Faculty of Medicine, Istanbul, Turkey
3Eastern Mediterranean University Medical School, Famagusta, Mersin 10, Turkey
What is already known on this topic?
Most patients with odontochondrodysplasia have a compound heterozygous mutation as in our case. Odontochondrodysplasia is a very rare
skeletal dysplasia that is associated with dentinogenesis imperfecta.
What this study adds?
The c.3296_3298delinsTG is a novel pathogenic variant in the TRIP11 gene that leads to odontochondrodysplasia. Joint limitation and
craniocervical stenosis were not observed in patients with odontochondrodysplasia so far. In this respect, our patient is the first case in the
literature.
Abstract
Odontochondrodysplasia (ODCD, OMIM #184260) is a quite rare non-lethal skeletal dysplasia characterized by involvement of the spine and
metaphyseal regions of the long bones, pulmonary hypoplasia, short stature, joint hypermobility, and dentinogenesis imperfecta. ODCD is
inherited in an autosomal recessive fashion with an unknown frequency caused by mutations of the thyroid hormone receptor interactor 11 gene
(TRIP11; OMIM *604505). TRIP11 gene encodes the Golgi microtubule-associated protein 210 (GMAP-210), which is an indispensable protein
for the function of the Golgi apparatus. Mutations of the TRIP11 gene also cause achondrogenesis type 1A (ACG1A). Null mutations of TRIP11
lead to ACG1A, also known as a lethal skeletal dysplasia, while hypomorphic mutations cause ODCD. Here we report a male child diagnosed as
ODCD with a novel compound heterozygote mutation who presented with skeletal changes, short stature, dentinogenesis imperfecta, and facial
dysmorphism resembling Achondroplasia (ACH) and Hypochondroplasia (HCH).
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Keywords: Odontochondrodysplasia, TRIP11, skeletal dysplasia, dentinogenesis imperfecta, rare disease
Corresponding Author:
Burcu Yeter, MD
Department of Pediatric Genetics, Marmara University Medical School
Fevzi Çakmak Quarter,
Muhsin Yazıcıoğlu Street, No:10, 34899, Üst Kaynarca/ Pendik
İstanbul, Turkey
90 507 973 08 40
14.04.2021
07.06.2021
Introduction
Odontochondrodysplasia (ODCD, OMIM #184260) is a quite rare non-lethal skeletal dysplasia characterized by involvement of spine and
metaphyseal regions of the long bones, pulmonary hypoplasia, short stature, joint hypermobility, and dentinogenesis imperfecta (1). Spondylo-
metaphyseal dysplasias stand for a group of skeletal dysplasia that includes miscellaneous disorders with vertebra and metaphysis defects. ODCD
is inherited in an autosomal recessive fashion with an unknown frequency caused by mutations of the thyroid hormone receptor interactor 11
gene (TRIP11; OMIM *604505). At first, homozygous mutations of TRIP11 gene were defined for a lethal skeletal dysplasia achondrogenesis
type 1A (ACG1A, OMIM #200600) associated with severe thorax hypoplasia, hypomineralization of several bones, and short extremities (2).
ODCD is a rather mild form compared to ACG1A that leads to a lethal spectrum of TRIP11 gene mutations. Maroteaux et al. reported two cases
with short limbs, and metaphyseal irregularities and dentinogenesis imperfecta and they used the term ODCD for this condition (3). ODCD is
also called Goldblatt syndrome or spondylometaphyseal dysplasia with dentinogenesis imperfecta. Short stature is one of the most common
complaint referrals to genetics clinics. Here we report a male child diagnosed as ODCD with a novel compound heterozygote mutation who
presented with skeletal changes, short stature, dentinogenesis imperfecta, and facial dysmorphism resembling Achondroplasia (ACH) and
Hypochondroplasia (HCH).
Case Report
The patient was the second child of a nonconsanguineous couple of Turkish origin. Maternal history revealed short limbs on second-trimester
ultrasonography (US) that ended with a full-term male baby born through cesarean section due to breech presentation. Fetal mobility and
amniotic fluid were normal. Birth weight was 4035 g (90.p), the length was 47 cm (3-10p) and head circumference was 38 cm (≥97p). After
birth, he was admitted to the neonatal intensive care unit and treated for respiratory distress for 17 days. The mother and father were, 40 and 35
years old, respectively at the time of delivery. The patient has a older healthy sister. There was no particular familial history. The patient was
referred at age 2,5 months for evaluation for possible skeletal dysplasia. On physical examination, the patient's body weight was 4,9 kg (10.p),
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height was 55 cm (10.p) head circumference was 40,5 cm (50-75p). Anterior fontanel was 5*4 cm. Relative macrocephaly, midfacial hypoplasia,
frontal bossing, downslanting palpebral fissures, depressed nasal root, short nose, anteverted nares, short neck, and redundant nuchal skin were
noted as dysmorphic features. Narrow thorax, disproportionately short extremities, redundant skin folds on upper and lower limbs with skin
dimpling over knees, inability to extend elbow/knee fully and brachydactyly were defined. No head control was observed on neurologic
examination. Examination at 15 months of age revealed his body weight was 7,2 kg (-3,2 SDS), height was 67 cm (-3,9 SDS) head circumference
was 46 cm (25-50p). Anterior fontanel was 3*3 cm. 12 months of age, the proband attained his neck control. He could stand with support by 14
months. The first teeth erupted at age 9 months and it was blue-gray and translucent which was confirmed as dentinogenesis imperfecta by
pedodontist. It was learned that he was suffering from insomnia. Intellectual development was normal according to the Denver developmental
screening test. Echocardiogram and abdomen US were normal. Extra cerebrospinal fluid space was at the upper limit of normal on the cranial
US. Skeletal survey by at the age of 2,5 months showed short long bones with irregular flaring of metaphyses, small thoracic cage, small
sacroiliac notch, flat acetabular roof, enlargement of iliac wings, and short tibia in relation to fibula. Additionally, when he was 15 months old,
platyspondyly, coronal clefts at lower thoracal vertebrae, broad-cupped metacarpals, short phalanges, cone-shaped epiphyses, and mildly delayed
carpal ossification were detected on roentgenogram. His radiologic examination was otherwise unchanged from the previous visit. Photographs
and X-rays of the patient, who was 2,5 and 15 months old, are shown in Figures 1 and 2. Although there was no neurological finding, the patient
was consulted to neurosurgery in terms of craniocervical involvement when he was about 2 years old. His magnetic resonance imaging (MRI)
was detected craniocervical stenosis and he was operated by neurosurgeon. Metabolic screening (calcium, phosphorus, alkaline phosphatase,
parathyroid hormone, 25-hydroxy vitamin D, and thyroid hormone) was normal. After obtaining written informed consent, genetic analysis was
performed on blood samples from the proband and his parents. Karyotyping was normal 46, XY in standard resolution in the proband. No
mutation was detected in FGFR3 gene in the patient. Afterward, whole-exome sequencing was performed. Heterozygous variants c.1225G>T
(p.Asp409Tyr) and c.3296_3298delinsTG (p.Lys1099Metfs*6) were determined in the TRIP11 (NM_001321851.1) gene. The c.1225G>T
variant is located in the first base of exon 9 and has previously been reported to cause missplice, resulting in ODCD (4). It is also found in the
ClinVar database and submitted as a likely pathogenic variant. DANN, EIGEN, FATHMM-MKL, M-CAP, MutationAssessor, MutationTaster,
and SIFT computational algorithms predicted the variant as deleterious. The novel c.3296_3298delinsTG variant causes frameshift and leads to a
premature stop codon after 6 residues. Both variants were not found in the gnomAD exomes and genomes. Finally, both variants were considered
as pathogenic according to American College of Medical Genetics guideline (5). Also, the c.1225G>T variant in the mother and the
c.3296_3298delinsTG variant in the father were detected as heterozygous, thus confirming the compound heterozygosity in the patient. Images of
variants in the Integrative Genomics Viewer are shown in Figure 3. His sister had no relevant variants mentioned above in this gene. As a result,
our patient was diagnosed with ODCD with all these clinical, radiological, and molecular findings.
Discussion
ODCD was first described by Goldblatt et al. in a 3,5-year-old male patient based upon spondylometaphyseal dysplasia, joint hypermobility, and
dentinogenesis imperfecta in 1991(6). Until Wehrle et al. found TRIP11 gene mutations leading to ODCD in 2019, the diagnosis of ODCD was
made with clinical and radiologic features. TRIP11 gene is located at 14q32.12 containing 21 exons. TRIP11 gene encodes the Golgi
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microtubule-associated protein 210 (GMAP-210), which is an indispensable protein for the function of the Golgi apparatus (7). In 2010, Smith et
al. revealed in his study about lethal skeletal dysplasia that the GMAP-210 protein is essential for glycosylation and cellular transport of proteins
(8). In the absence of GMAP210 protein, endochondral and intramembranous ossification is dramatically decreased (9). TRIP11 is the only
known gene associated with ODCD. Mutations of TRIP11 gene also causes ACG1A. Null mutations of TRIP11 lead to ACG1A, also known as a
lethal skeletal dysplasia, while hypomorphic mutations cause ODCD (4). Loss of function mutations in the TRIP11 gene lead to ACG1A which
is characterized by short limbs, small thorax, domed skulls, lacked several bone ossifications, decreased alveolar formation in the lungs in mice
and humans (8). ODCD is classified in group 12 Spondylometaphyseal dysplasias (SMD) because of involvement vertebrae and affecting
metaphyses of all tubular long bones at Nosology and classification of genetic skeletal disorders in the last revision published in 2019 (10).
Only one patient in the literature had a consanguineous marriage who had a homozygous mutation as expected (11). In 2019, Wehrle et al.
suggested an autosomal recessive pattern in this disorder (4). Almost all patients diagnosed with ODCD have had a compound heterozygous
mutation. The compound heterozygote appearance of this mutation in our patient stood in agreement with the autosomal recessive trait of ODCD,
too. The mutations of ODCD can be listed in order of frequency: missense, small deletion, and splice-site mutations but for that, there were no
hotspot regions in TRIP11 gene related to ODCD (4). Unger et al. published a case series which consist of 6 patients that were diagnosed with
clinical and radiographic findings in 2008 (1). In that article, mesomelic limb shortening (6/6 cases), narrow chest (5/6 cases), dentinogenesis
imperfecta (5/6 cases) (1 patient could not be evaluated because he died at the age of 4 months), and scoliosis (2/6 cases) were been ascertained.
Wehrle et al. confirmed this skeletal dysplasia by studying the molecular diagnosis of these patients (4). The comparison between common
abnormalities of our, Unger et al and Medina et al's patients are summarized in Table I.
Cystic renal disease, pulmonary dysplasia, and non-obstructive hydrocephaly were seen in few cases with ODCD (4). While generalized joint
hypermobility is observed in ODCD, in our patient had limitation of extension at joints. Joint limitations in our case is not a typical finding
observed in ODCD patients. In this respect, it was the first case in the literature. There was no joint hypermobility or limitation in one of the six
patients in the publication of Unger et al. Short limbs on the prenatal US, large head with protruding forehead, midface hypoplasia,
brachydactyly, and short tubular bones with metaphyseal flare are also observed in HCH and ACH like ODCD. In this respect, ODCD can be
confused with these genetic skeletal disorders. Nevertheless, lumbar lordosis, progressive narrowing, or unchanged interpedicular distance in
lumbar vertebrae, short iliac bones, short femoral neck, and bowing of legs are expected in HCH and ACH (12). However, the skeletal anomalies
of HCH are milder and can be detected in late childhood. Characteristic facial features are more pronounced in ACH compared with ODCD and
HCH. Dentinogenesis imperfecta is only seen in ODCD among them. Even though his phenotype overlapped significantly with achondroplasia
and hypochondroplasia, as we expected, the known causal gene for these was not found in the patient. Our patient had suffered from respiratory
distress in the newborn period due to pulmonary hypoplasia. Thoracic hypoplasia is observed in skeletal ciliopathies notably in Jeune
asphyxiating thoracic dysplasia (JATD). A small thoracic cage is more severe in JATD and that accompanied by short extremities with
brachydactyly like ODCD. Whereas short stature is less conspicuous than ODCD and, skull and spine are unaffected in JATD. Poly-syndactyly
is another distinctive feature seen in JATD and the other ciliopathies. Renal involvement, which is a typical feature of ciliopathies, is rarely seen
in ODCD. In this respect, it has a common feature with ciliopathies besides lung hypoplasia.
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Dentinogenesis imperfecta is one of the most characteristic features of ODCD. Nearly all patients with ODCD have dentinogenesis imperfecta
although there is no dentinogenesis imperfecta in most genetic skeletal diseases. Dentinogenesis imperfecta is a genetic disorder caused by
impaired dentin development that results in discolored and fragile teeth. Dentin is formed by odontoblasts that secrets an extracellular matrix
after mineralization and this matrix is comprised of 90% of type I collagen and 10% of non-collagenous proteins and lipids (13). This entity
influences both deciduous and permanent teeth. The incidence is estimated to be 1 in 7000 in the USA according to the last published study in
1975 (14). The coexistence of dentinogenesis imperfecta and skeletal dysplasia is rare except for osteogenesis imperfecta. However, osteogenesis
imperfecta has rather different clinical and radiological features than patients with ODCD such as blue sclera, hearing loss, and increased
frequency of fracture.
The most characteristic radiologic features of ODCD include small thorax, platyspondyly with coronal clefts, broadened iliac wings with
horizontal acetabulum and, cupping of metaphyses, and shortening of all long bones (1). All of these radiologic findings were found in our
patient. With advancing ages, metaphyseal alterations in metacarpals deteriorate which mimic enchondroma, and mesomelic shortening occurs
more apparent (1). The most characteristic clinical features are macrocephaly, short stature, pulmonary hypoplasia, dentinogenesis imperfecta.
Likewise, our patient had all of these findings. There is no intellectual disability, hearing loss, and ophthalmologic involvement in this skeletal
dysplasia (1).
The diagnosis of ODCD is suspected on clinical and radiologic keystones of prenatal onset of short stature, pulmonary hypoplasia with a narrow
thorax, short long bones, and dentinogenesis imperfecta and confirmed by molecular analysis. Wehrle et al. proposed significantly clinical
variability within the same families in this skeletal dysplasia owing to mild and severe phenotypes (for example infant death) in the same family
(4).
Conclusion
In summary, ODCD is a very rare skeletal dysplasia. We described a male affected with ODCD who had facial dysmorphism, dentinogenesis
imperfecta, short stature, joint hypermobility, due to a novel compound heterozygote mutation in TRIP11 gene. Novel mutations are crucial to
extend the molecular spectrum of ODCD and to understand clearly the genotype-phenotype correlation in larger patient populations. In skeletal
dysplasias accompanied by dentinogenesis imperfecta, ODCD should be included in the differential diagnosis, except osteogenesis imperfecta.
We also highlighted that the presence of dentinogenesis imperfecta may make the diagnosis easier. It is predicted that this mutation has a
pathogenic and damaging influence on TRIP11 protein. More than 20 parients have been reported to date. To our knowledge, this is the third
published Turkish case with a clinical, radiographic, and molecular diagnosis of ODCD.
Statement of Ethics
All experimental procedures were conducted in accordance with the principles of the Declaration of Helsinki, and written informed consent was
obtained from the patient’s parents.
Conflict of Interest Statement
The authors have no conflict of interest to declare.
Authorship Contributions
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Ayça Dilruba Aslanger and Gözde Yeşil performed WES analysis of the patient and parents’. Nursel H. Elçioğlu reviewed the manuscript.
Additionally, this case report was evaluated and approved by all of the authors.
Financial Disclosure
There was no funding relevant to this study.
References
1) Unger S, Antoniazzi F, Brugnara M, Alanay Y, Caglayan A, et al. Clinical and radiographic delineation of odontochondrodysplasia. American
Journal of Medical Genetics, 146A 2008;(6):770–778.
2) Vanegas S, Sua LF, Lopez-Tenorio J, Ramirez-Montano D, Pachajoa H. Achondrogenesis type 1A: clinical, histologic, molecular, and
prenatal ultrasound diagnosis. Appl Clin Genet. 2018;11:69-73.
3) Maroteaux P, Briscioli V, Lalatta F, Bonaventure J. L’odontochondrodysplasie. Arch Pediatr. 1996;3:549–554.
4) Wehrle A, Witkos TM, Unger S, Schneider J, Follit JA, et al. Hypomorphic mutations of TRIP11 cause odontochondrodysplasia. JCI Insight
2019;4:124701.
5) Richards S, Aziz N, Bale S, Bick D, Das S, et al. ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the
interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the
Association for Molecular Pathology. Genet Med. 2015;17(5):405-24.
6) Goldblatt J, Carman P, Sprague P. Unique dwarfing, spondylometaphyseal skeletal dysplasia, with joint laxity and dentinogenesis imperfecta.
Am J Med Genet. 1991;39:170–172.
7) Follit JA, San Agustin JT, Xu F, Jonassen JA, Samtani R, et al. The Golgin GMAP210/TRIP11 anchors IFT20 to the Golgi complex. PLoS
Genetics 2008;4(12), e1000315.
8) Smits P, Bolton AD, Funari V, Hong M, Boyden ED, et al. Lethal skeletal dysplasia in mice and humans lacking the golgin GMAP-210. New
England Journal of Medicine 2010;362(3): 206–216.
9) Bird IM, Kim SH, Schweppe DK, Caetano-Lopes J, Robling AG, et al. The skeletal phenotype of achondrogenesis type 1A is caused
exclusively by cartilage defects. Development 2018;145(1):dev156588.
10) Mortier GR, Cohn DH, Cormier-Daire VC, Hall C, Krakow D, et al. Nosology and classification of genetic skeletal disorders: 2019 revision.
Am J Med Genet Part A 2019;1–27.
11) Medina CTN, Sandoval R, Oliveira G, da Costa Silveira K, Cavalcanti DP, et al. Pathogenic variants in the TRIP11 gene cause a skeletal
dysplasia spectrum from odontochondrodysplasia to achondrogenesis 1A. Am J Med Genet Part A 2010;1–8.
12) Yao G, Wang G, Wang D, Su G. Identification of a novel mutation of FGFR3 gene in a large Chinese pedigree with hypochondroplasia by
next-generation sequencing: A case report and brief literature review. Medicine (Baltimore) 2019;98(4):e14157.
13) Molla MD, Fournier BP, and Berdal A. Isolated dentinogenesis imperfecta and dentin dysplasia: revision of the classification. European
Journal of Human Genetics 2015;23(4):445-451.
14) Witkop Jr CJ. Hereditary defects of dentin. Dent Clin North Am. 1975;19:25–45.
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Figure 1. Clinical and radiologic findings of the proband at the age of 2,5 months. a. Narrow thorax, short extremities, and redundant skin folds
on upper and lower limbs with skin dimpling over knees. b, c, d. Short long bones with irregular flaring of metaphyses, small thoracic cage,
small sacroiliac notch, flat acetabular roof, enlargement of iliac wings, and short tibia in relation to the fibula
a b d
c
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Figure 2. Radiologic findings of the proband at the age of 15 months. a. Platyspondyly and coronal clefts at lower thoracal vertebrae. b.
Cupping of the metaphyses of the radius and ulna, broad-cupped metacarpals, short phalanges, cone-shaped epiphyses, and mildly delayed carpal
ossification.
a b
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Figure 3. The Integrative Genomics Viewer visualization of the c.1225G> T and c.3296_3298delinsTG variants
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Table1: Clinical and Genetic outcomes of Odontochondrodysplasia
Case 1
(Sibling 1)
Unger et. al
Case 2
(Sibling 2)
Unger et. al
Case 3
Unger et. al
Case 4
Unger
et. al
Case 5
Unger et. al
Case 6
Unger et.
al
Case 7
Medina
et. al
Case 8
Our patient
Sex Male Female Female Female Female Male Female Male
Relationsh
ip
- - - - - - + -
Relative
macroceph
aly
- - - - - - + +
Short
extremities
+ + + + + + + +
Joint
laxity
? + + + - + + -
Restriction
of joints
- - - - - - - +
Redundan
t skin folds
- - + - - + - +
Skin
dimpling
over limbs
- - - - - - - +
Dentinoge
nesis
imperfecta
? + + + + + + +
Neuromot
or
developme
nt delay
? + ? + ? + - +
Molecular c.(1314+5G>A); c.(1314+5G>A); c.(1228G>T); c.(586C c.(1228G>T); c.(1622de c.1314+5 c.1225G>T;
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analysis (chr14:g.(?_92.47
4.069)_
(92.597.431_?)del
(chr14:g.(?_92.47
4.069)_
(92.597.431_?)del
(4815_4818delA
GAG)
>T);
(4534C>
T)
(2128_2129d
elAT)
lA);
(5416A>
G)
G>A c.3296_3298del
insTG
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