Bone fragility, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features: A newly recognized type of osteogenesis imperfecta

doi:10.1016/S0022-3476(87)80292-5

The Journal of Pediatrics

Volume 110, Issue 1, January 1987, Pages 76-80

https://doi.org/10.1016/S0022-3476(87)80292-5 Get rights and content

We report two infants with bone deformities and multiple fractures reminiscent of osteogenesis imperfecta, but also having ocular protosis withorbital craniosynostosis, hydrocephalus, and distinctive facial features. Both infants were normal at birth, but multiple compression fractures of the long bones were noted shortly thereafter, followed by extensive demineralization and culminating in recurrent diaphyseal fractures of the weight-bearing bones before the first birthday. The striking similarity of both the distinctive dysmorphic features and the unique pattern of fractures in two unrelated individuals suggests that this is a previously unrecognized form of osteogenesis imperfecta. Despite the craniosynostosis and hydrocephalus, intellectual performance is unimpaired In both individuals. Bone biopsy in one patient revealed decreased bone volume and increased bone resorption without compensatory new bone formation. Extensive laboratory investigations have not identified a cause, nor have they clarified pathogenesis; further elucidation will require the identification and study of new cases.

References (10)

SmithR et al.
The brittle bone syndrome: osteogenesis imperfecta
SillenceDO et al.
Genetic heterogeneity in osteogenesis imperfecta
J Med Genet
(1979)
SillenceD
Osteogenesis imperfecta: an expanding panorama of variants
Clin Orthoped Rel Res
(1981)
ByersPH et al.
Osteogenesis imperfecta: update and perspective
Am J Med Genet
(1984)
ProckopDJ et al.
Heritable diseases of collagen
N Engl J Med
(1984)

There are more references available in the full text version of this article.

Cited by (56)

Syndromic Hydrocephalus
2022, Neurosurgery Clinics of North America
Citation Excerpt :
Finally, as in other syndromes, concurrent altered brain development may play a role in the development of hydrocephalus. Osteogenesis imperfecta (OI) is a group of disorders of connective tissue that affects bone growth and fragility, caused by defective COL1A1 and COL1A2 genes and is grouped into four types—type II, type III, type IV, and type I—ordered from most to least severe.97,98 OI can be associated with macrocephaly, hydrocephalus, basilar invagination, and cerebral atrophy.99
Characterization of a complex phenotype (fever-dependent recurrent acute liver failure and osteogenesis imperfecta) due to NBAS and P4HB variants
2021, Molecular Genetics and Metabolism
Citation Excerpt :
PDI functions as a redox catalyst and as a chaperone by preventing protein aggregation in the ER or by retaining proteins within the ER where necessary [12,13]. Cole-Carpenter syndrome-1 (CLCRP1; MIM: 112240) is a rare OI-like disorder that was first reported in 1987 in two unrelated patients presenting bone fragility with multiple fractures and normal intelligence [14]. These patients were later diagnosed genetically as carriers of the same heterozygous missense variant in P4HB [15].
We report the clinical, biochemical and genetic findings from a Spanish boy of Caucasian origin who presented with fever-dependent RALF (recurrent acute liver failure) and osteogenesis imperfecta (OI). Whole-exome sequencing (WES) uncovered two compound heterozygous variants in NBAS (c.[1265 T > C];[1549C > T]:p.[(Leu422Pro)];[(Arg517Cys)]), and a heterozygous variant in P4HB (c.[194A > G];[194=]:p.[(Lys65Arg)];[(Lys65=)]) that was transmitted from the clinically unaffected mother who was mosaic carrier of the variant. Variants in NBAS protein have been associated with ILFS2 (infantile liver failure syndrome-2), SOPH syndrome (short stature, optic nerve atrophy, and Pelger-Huët anomaly syndrome), and multisystem diseases. Several patients showed clinical manifestations affecting the skeletal system, such as osteoporosis, pathologic fractures and OI. Experiments in the patient's fibroblasts demonstrated that mutated NBAS protein is overexpressed and thermally unstable, and reduces the expression of MGP, a regulator of bone homeostasis. Variant in PDI (protein encoded by P4HB) has been associated with CLCRP1 (Cole-Carpenter syndrome-1), a type of severe OI. An increase of COL1A2 protein retention was observed in the patient's fibroblasts. In order to study if the variant in P4HB was involved in the alteration in collagen trafficking, overexpression experiments of PDI were carried out. These experiments showed that overexpression of mutated PDI protein produces an increase in COL1A2 retention. In conclusion, these results corroborate that the variants in NBAS are responsible for the liver phenotype, and demonstrate that the variant in P4HB is involved in the bone phenotype, probably in synergy with NBAS variants.
A review of syndromes associated with blue sclera, with inclusion of malformations of the head and neck
2018, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Blue sclera is attributed to a diversity of mechanisms, mostly arising in genetic syndromes and, to a lesser extent, in nongenetic disorders and may occur as a side effect of medication intake. A literature search was conducted to establish a database of blue scleral associations. This article represents the most comprehensive assemblage of etiopathologies coincidental with blue sclera, comprising 66 genetic syndromes, 8 disorders, and 4 pharmacologically induced pigmentations. To increase the knowledge regarding the clinical significance of blue sclera, summaries of the systemic and oral maxillofacial comorbidities are provided. Recognition of the presence of blue sclera is important as it could prompt a timelier and more thorough diagnostic evaluation of possible systemic and dental malformations, potentially improving clinical outcomes.
Cole-carpenter syndrome is caused by a heterozygous missense mutation in P4HB
2015, American Journal of Human Genetics
Citation Excerpt :
Other dominantly and recessively inherited forms of OI are rare and can be caused by mutations in a variety of genes (BMP1 [MIM 112264], CRTAP [MIM 605497], FKBP10 [MIM 607063], IFITM5 [MIM 614757], LEPRE1 [MIM 610339], PPIB [MIM 123841], SERPINF1 [MIM 172860], SERPINH1 [MIM 600943], SP7 [MIM 606633], TMEM38B [MIM 611236], WNT1 [MIM 164820]), which are either involved in the post-translational modification of collagen type I or in the regulation of osteoblast function.8 Collagen type I protein analyses in skin fibroblasts were reportedly normal in the two individuals with CCS where this test was performed.1,3 No further investigations into the molecular cause of CCS have been reported.
Cole-Carpenter syndrome is a severe bone fragility disorder that is characterized by frequent fractures, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features. To identify the cause of Cole-Carpenter syndrome in the two individuals whose clinical results were presented in the original description of this disorder, we performed whole-exome sequencing of genomic DNA samples from both individuals. The two unrelated individuals had the same heterozygous missense mutation in exon 9 of P4HB (NM_000918.3: c.1178A>G [p.Tyr393Cys]), the gene that encodes protein disulfide isomerase (PDI). In one individual, the P4HB mutation had arisen de novo, whereas in the other the mutation was transmitted from the clinically unaffected father who was a mosaic carrier of the variant. The mutation was located in the C-terminal disulfide isomerase domain of PDI, sterically close to the enzymatic center, and affected disulfide isomerase activity in vitro. Skin fibroblasts showed signs of increased endoplasmic reticulum stress, but despite the reported importance of PDI for collagen type I production, the rate of collagen type I secretion appeared normal. In conclusion, Cole-Carpenter syndrome is caused by a specific de novo mutation in P4HB that impairs the disulfide isomerase activity of PDI.
Mutations in SEC24D, encoding a component of the COPII machinery, cause a syndromic form of osteogenesis imperfecta
2015, American Journal of Human Genetics
Citation Excerpt :
We therefore regard the phenotype we report as a clinical entity that can be distinguished from the phenotype of the individuals with CLSD described in the literature, although the symptoms clearly overlap. We reviewed all five published case reports of Cole-Carpenter syndrome12–16 and compared the clinical and radiological findings of the six described individuals in detail with the affected individual from family 1 (Table S5). Information on skull ossification defects—one of the most obvious symptoms in the affected individuals we describe—are incomplete or missing in some of the reports, but overall, the similarities are striking, and consequently, we still consider Cole-Carpenter syndrome to be the best classification for the phenotype.
As a result of a whole-exome sequencing study, we report three mutant alleles in SEC24D, a gene encoding a component of the COPII complex involved in protein export from the ER: the truncating mutation c.613C>T (p.Gln205^∗) and the missense mutations c.3044C>T (p.Ser1015Phe, located in a cargo-binding pocket) and c.2933A>C (p.Gln978Pro, located in the gelsolin-like domain). Three individuals from two families affected by a similar skeletal phenotype were each compound heterozygous for two of these mutant alleles, with c.3044C>T being embedded in a 14 Mb founder haplotype shared by all three. The affected individuals were a 7-year-old boy with a phenotype most closely resembling Cole-Carpenter syndrome and two fetuses initially suspected to have a severe type of osteogenesis imperfecta. All three displayed a severely disturbed ossification of the skull and multiple fractures with prenatal onset. The 7-year-old boy had short stature and craniofacial malformations including macrocephaly, midface hypoplasia, micrognathia, frontal bossing, and down-slanting palpebral fissures. Electron and immunofluorescence microscopy of skin fibroblasts of this individual revealed that ER export of procollagen was inefficient and that ER tubules were dilated, faithfully reproducing the cellular phenotype of individuals with cranio-lentico-sutural dysplasia (CLSD). CLSD is caused by SEC23A mutations and displays a largely overlapping craniofacial phenotype, but it is not characterized by generalized bone fragility and presented with cataracts in the original family described. The cellular and morphological phenotypes we report are in concordance with the phenotypes described for the Sec24d-deficient fish mutants vbi (medaka) and bulldog (zebrafish).
Brittle bone disease (Osteogenesis imperfect; OI) in children - Interdisciplinary management
2013, Pediatria Polska
Brittle bone disease (Osteogenesis imperfect; OI) is a group of disorders related to collagen type 1 defect. Patients suffering from OI experience not only an increased number of fractures due to minor injuries, but also suffer from multiple co-morbidities that require help from different specialists. It is crucial to involve interdisciplinary child care from the moment of the diagnosis. In many countries, guidelines for pediatricians and family physicians help to understand the disease and to provide appropriate management for patients with OI. The aim of this article is to summarize the current knowledge on the pathogenesis, symptoms, diagnostic methods and treatment of brittle bone disease in children.

View all citing articles on Scopus

^*: Supported in part by Grants MOI-RR02172 and AM07072 from the National Institutes of Health.

View full text

Original articleBone fragility, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features: A newly recognized type of osteogenesis imperfecta*

The brittle bone syndrome: osteogenesis imperfecta

Genetic heterogeneity in osteogenesis imperfecta

J Med Genet

Osteogenesis imperfecta: an expanding panorama of variants

Clin Orthoped Rel Res

Osteogenesis imperfecta: update and perspective

Am J Med Genet

Heritable diseases of collagen

N Engl J Med

Original article
Bone fragility, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features: A newly recognized type of osteogenesis imperfecta*