Bathrocephaly and Serpentine Fibula as Underrated Features of Osteogenesis Imperfecta Type I: A Case Report

Abstract

Introduction

Osteogenesis imperfecta (OI) comprises a heterogeneous group of skeletal dysplasias characterized mainly by bone fragility and propensity to fractures. The most common forms include classic types I, II, III, and IV, according to the classification of Sillence, caused by variants in the COL1A1 or COL1A2 genes. This report describes a case series of patients with OI type I confirmed by whole genome sequencing, highlighting the clinical and radiological manifestations of one atypical family.

Case Presentation

Six individuals (1M:5F), aged 8 months to 34 years at their first consultation, were enrolled. All were clinically classified as OI type I due to the presence of osteopenia associated with blue sclerae and bone fractures; four presented with short stature, two with hearing loss, and one with fragile teeth; molecular testing confirmed that all presented with heterozygous pathogenic or likely pathogenic variants in the COL1A1 gene. In one family, an unusual presentation was observed in the patient and her daughter, both of whom presented with severe short stature (Z-score <−6), abnormal skull shape (bathrocephaly), codfish vertebrae, bowing of the long bones in the lower limbs, and serpentine fibulas.

Conclusion

Bathrocephaly and serpentine fibula are rarely reported in classical OI types and are more frequently associated with other skeletal dysplasias, such as Hajdu-Cheney syndrome. This case report highlights the importance of recognizing underrated manifestations in OI and underscores the need for molecular confirmation.

Established Facts

• Osteogenesis imperfecta (OI) comprises a heterogeneous group of skeletal dysplasias, and the most common forms include classic types I, II, III, and IV, according to the classification of Sillence.

• From a clinical point of view, the manifestations ranged from mild forms, with bluish sclera and osteopenia, to more complex conditions with multiple fractures, short stature, and skeletal deformities.

Novel Insights

• An unusual presentation of OI type I was seen in a patient and her daughter, both presenting with severe short stature, bathrocephaly, and bone deformities, including serpentine fibulas, despite a few fractures during their lives.

• Bathrocephaly and serpentine fibula are infrequently reported in the classical OI types, being more often associated with other skeletal dysplasias.

Introduction

Osteogenesis imperfecta (OI) comprises a heterogeneous group of skeletal dysplasias characterized mainly by bone fragility and propensity to fractures. It is classified into distinct phenotypic subtypes based on clinical, radiological, and prognostic findings. The most common forms include classic non-deforming OI with bluish sclera, lethal perinatal OI, progressively deforming OI, and OI with normal sclera, previously denominated types I, II, III, and IV, respectively, according to the classification of Sillence [1, 2]. Clinical suspicion of OI should be considered in individuals who have recurrent fractures not associated with compatible traumas, as well as short stature, progressive bone deformities, bluish or grayish sclera, dentinogenesis imperfecta, progressive hearing loss in adolescence or adulthood, and/or compatible family history [1–7].

The estimated prevalence of OI is 1 in every 15,000–20,000 live births [6]. They are caused by variants in the COL1A1 or COL1A2 genes, which encode the alpha chains of type I collagen, and are confirmed by molecular testing through identification of a heterozygous pathogenic or likely pathogenic variant in the affected individual. In addition to these classic forms of OI, other rarer types have been described, associated with 18 different genes that affect collagen biosynthesis and processing, and, in some cases, follow autosomal recessive and X-linked inheritance, such as CRTAP, P3H1, and SERPINF1 [2, 6].

It is estimated that approximately 60% of mild OI cases result from de novo mutations, and somatic/germline mosaicism can also be found in some families. Thus, the risk of recurrence in future pregnancies depends on the origin of the pathogenic variant identified, and genetic counseling is essential [6].

This report describes a case series of patients with confirmed OI due to COL1A1 variants, highlighting the clinical and radiological manifestations of an atypical family presenting with unusual skeletal features. The CARE guidelines for case reporting were followed [8].

Case Presentation

Six individuals who were seen in the clinical genetics outpatient clinic in a reference service for rare diseases were invited to participate in a research protocol comprising a retrospective descriptive study. Data were obtained from medical records and confirmed by patients and/or relatives, and included sex, age at first hospital assessment, family history, description of clinical and laboratory findings, and molecular results.

Whole genome sequencing was performed on an Illumina platform, and data were processed to detect point mutations, copy numbers, and structural variants as per best practices for the bioinformatics pipeline [9]. Quality metrics were minimum coverage over 20× and at least 90% depth above 15×. The reference genome was GRCh38/hg38. The variants’ nomenclature and classification followed the American College of Medical Genetics and Genomics (ACMG) recommendations [10], with refinements proposed by the standards for constitutional sequence variant classification, adapted to the specific characteristics of the Brazilian population [11].

Five of the six individuals were females, and one was male, aged 8 months to 34 years at the first evaluation. Family history was positive in five probands and negative in patient 3, who was born to consanguineous parents (second-degree cousins). All patients were clinically classified as presenting with OI type I according to the Sillence classification due to the presence of blue sclerae and a low number of fractures limited to infancy and childhood, except for patient 4, who had over 200 fractures even through adulthood until the age of 35 years. Four patients (66%) presented with short stature, two (33%) with hearing loss, and one (16%) with fragile teeth. Complementary evaluation confirmed osteopenia in all six individuals. Most patients presented with a typical manifestation of OI type I, but patient 2 stood out due to an unusual presentation, with uncommon and more severe bone deformities despite the small number of fractures during her life.

Patient 2 was first seen at the age of 34 years with a previous diagnosis of OI. She is the second child of a healthy non-consanguineous couple, the only affected among five children. Pregnancy was uneventful until a maternal fall from standing height 1 week before labor, with diminished fetal movements after that. Delivery was at term and home, and no anthropometric data were recorded, but she was mentioned as a “chubby” baby. Neurological development was normal, and she presented an average health condition, except for four limb fractures with minimal trauma until puberty and early cataract of the right eye in her early 30s. At physical examination (Fig. 1), she presented with a stature of 121.5 cm (−6.39 Z-score) and a weight of 41.5 kg; dysmorphological features included short trunk dwarfism, abnormal skull shape, white sclerae, enlarged thorax, pectus carinatum, thoracolumbar kyphoscoliosis, cubitus valgus, coxa vara, and pes planus. Radiologic findings included generalized osteopenia, bathrocephaly, platyspondyly with flat biconcave (codfish) vertebrae, growth arrest lines on both femurs, bowing of the lower limbs’ long bones, and serpentine fibulas. She has been managed with bisphosphonates weekly (risedronate sodium 35 mg) and calcium carbonate plus vitamin D3 daily since then.

Fig. 1.

Patient 2 at the age of 34 years, presenting with short trunk dwarfism (a), bathrocephaly (b, c), serpentine fibulas (d), and biconcave/codfish vertebrae (e).

Patient 2’s daughter was 8 years old at the first evaluation. Pregnancy was uneventful, and delivery occurred at term; however, no anthropometric data were provided. She had a mild global delay in neurological development and learning difficulties, besides four limb fractures with minimal trauma until that age. At physical examination (Fig. 2), stature was 95.9 cm (−6.32 Z-score) and the weight was 14.1 kg; dysmorphological features were similar to her mother, including short trunk dwarfism, abnormal skull shape, enlarged thorax, pectus carinatum, thoracolumbar kyphoscoliosis, coxa vara, and pes planus, but she also presented low set ears, downslanted palpebral fissures, blue sclerae and bilateral total cutaneous syndactyly of the 3rd and 4th fingers (Fig. 3). Radiologic findings included generalized osteopenia, prominent occiput, platyspondyly with flat biconcave (codfish) vertebrae, bowing of the lower limbs’ long bones, and deformity of the fibulas. She presented progressive hearing loss from the age of 15 years, her final height was 120 cm (−6.59 Z-score), and she had a pregnancy at the age of 20; her daughter presented with three fractures by the age of 2 years. She was also managed with bisphosphonates, but discontinued follow-up in our service at the age of 22 years.

Fig. 2.

Patient 2’s daughter at the age of 8 years, presenting with short trunk dwarfism (a); skeletal survey at the age of 18 years demonstrating bathrocephaly (b, c), bowed fibula more pronounced at left (d), and biconcave/codfish vertebrae (e).

Fig. 3.

Patient 2’s daughter. Note blue sclerae (a) and bilateral total cutaneous syndactyly of the 3rd and 4th fingers (b).

Concerning molecular testing, whole genome sequencing confirmed heterozygous variants in the COL1A1 gene in all six individuals, two were frameshift, two were missense, one was nonsense, and one was intronic on a canonical site; four were classified as pathogenic, and two as likely pathogenic, all previously reported in the literature or the ClinVar database. None of the patients had incidental findings or a second molecular diagnosis. Clinical, radiological, and molecular results are summarized in Table 1.

Table 1.

Synopsis of the patients’ clinical, radiological, and molecular findings

Finding	Patient						Frequency
	1	2	3	4	5	6
Sex	F	F	F	F	F	M	1:5 (M:F)
Family history	+	+	−	+	+	+	5/6 (83%)
Age of first symptoms	4 yr 6 mo	1 yr	2 yr	1 yr 3 mo	1 yr 10 mo	4 yr	$\overline{\mathrm{x}}$ = 29.2 mo
Age at first evaluation	34 y	34 y	3 y	8 m	6 m	12 y	$\overline{\mathrm{x}}$ = 14.03 y
Short stature	+ (−2.04 ZS)	+ (−6.39 ZS)	− (−1.43 ZS)	+ (−3.57 ZS)	− (−0.60 ZS)	+ (−2.18 ZS)	4/6 (66%)
Number of fractures	5	4	5	>200	4	2	$\overline{\mathrm{x}}$ = 37
Bone deformities	−	+	−	−	−	−	1/6 (16%)
Blue sclera	+	−	+	+	+	+	5/6 (83%)
Dentinogenesis imperfecta	+	−	−	−	−	−	1/6 (16%)
Hearing loss	+	−	−	+	−	−	2/6 (33%)
Osteopenia/osteoporosis	+	+	+	+	+	+	6/6 (100%)
DXA lumbar spine	−3.1 ZS	−2.9 ZS	nd	−2.2 ZS	nd	nd	​
DXA femoral head	nd	−3.9 ZS	nd	−4.0 ZS	nd	−2.4 ZS	​
Other radiological findings	−	+	−	−	−	−	1/6 (16%)
Sillence classification	Type I	Type I	Type I	Type I	Type I	Type I	Type I (100%)
Variant
Codon	c.2450dup	c.859G>A	c.1243C>T	c.769G>A	c.2452-1G>A	c.432dup	​
Protein	Gly818Trpfs*3	Gly287Ser	Arg415*	Gly257Arg	p.?	Gly145Argfs*24	​
Type	Frameshift	Missense	Nonsense	Missense	Intronic	Frameshift	​
ClinVar ID	rs193922149	rs72645340	rs72648326	rs72645321	rs72651667	rs72667016	​
Classification	P	LP	P	P	LP	P	​
ACM criteria	PVS1_versus, PS4_sup, PM2_sup	PS4_sup, PM1_s, PP3_sup, PP4_sup, PM2_sup	PVS1_versus, PS4_mod, PP4_sup, PM2_sup	PS3_sup, PP3_sup, PM2_sup, PM1_s, PS4_s	PVS1_s, PS4_sup, PP4_sup, PM2_sup	PVS1_versus, PS4_sup, PM2_sup	​

All variants in the COL1A1 gene (NM_000088.4) were found to be in a heterozygous state. −, absent; +, present; ?, unknown; DXA, bone density scanning; F, female; LP, likely pathogenic; M, male; mo, month(s); nd, no data; P, pathogenic; $\overline{\mathrm{x}}$, mean; yr, year(s); ZS, Z-score.

Discussion

OI has a broad phenotypic spectrum, ranging from lethal forms in the perinatal period to asymptomatic conditions, with preserved stature and minimal functional impact. The cases presented here (Table 1) show the significant phenotypic variability associated with the different variants of the COL1A1 gene, even among individuals with the same clinical subtype of the disease, and reinforce the importance of detailed family history and genotype-phenotype correlation for the proper diagnosis and management of OI [1–7].

From a clinical point of view, the manifestations ranged from mild forms, with bluish sclera and osteopenia, to more complex conditions with multiple fractures, short stature, and skeletal deformities. The presence of dentinogenesis imperfecta and hypoacusis was also relevant, being auxiliary markers in the clinical suspicion of OI. It is worth noting that findings such as Wormian bones and the presence of codfish vertebrae on imaging studies contributed to diagnostic confirmation, especially in adult patients with a history of childhood fractures [3, 4].

The molecular characterization of the six cases described in this study revealed heterogeneity in COL1A1 variants, reflecting the phenotypic diversity observed in the patients. Among the cases analyzed, missense, frameshift, splicing, and nonsense variants types were identified, all classified as pathogenic or likely pathogenic, according to the ACMG criteria [10, 11]. Missense-like variants involving glycine residues in the collagen triple helix, such as Gly257Arg and Gly287Ser, are often associated with moderate to severe forms of OI, given their impact on collagen helix stability. On the other hand, variants of the nonsense or frameshift type, which generate null alleles, tend to cause milder forms of the disease, such as OI type I, resulting in reduced but structurally normal production of type I collagen. This variability aligns with recent studies demonstrating that missense variants, particularly those that replace glycine in the Gly-X-Y repeat, are often associated with the most severe forms of OI due to their direct impact on the formation of the triple helix of type I collagen [12, 13]. This was observed in patient 4 of the present sample, with the Gly257Arg variant, who presented over 200 fractures during her lifetime, and patient 2, with the Gly287Ser variant, despite the low number of fractures, exhibits severe short stature and significant skeletal deformities, corroborating this genotype-phenotype correlation.

The Gly287Ser variant in the COL1A1 gene has been reported twice in the ClinVar database in individuals with OI; however, no clinical details are available, hindering phenotypic comparison. Patient 2 and her daughter had an atypical clinical and radiological presentation, in contrast to the other individuals in this study, including bathrocephaly and fibular deformity, although the latter is milder in the child than in the mother; this could be explained by the variable expressivity of the disease or by an age-dependent manifestation.

Bathrocephaly is a deformity of the occipital bone, resulting in a prominent occiput that angles sharply inward toward the neck but without frontal bossing, biparietal narrowing, or sagittal ridging, caused by failure of fusion of the mendosal suture. It is most commonly a benign, isolated finding not associated with any underlying skull or brain disorder, although it is occasionally present in other forms of craniosynostosis [14, 15]. Bathrocephaly is not listed as a frequent manifestation of OI or in the HPO databank under entry HP: 0034974 [16–18]. However, it has been previously reported in a pediatric patient with OI, bathrocephaly, and scoliosis [19].

Serpentine fibula is characterized by thin, elongated, and S-curved fibulas, which is an uncommon finding limited to a few bone dysplasias, such as Hajdu-Cheney syndrome [20, 21], Frank-Ter Haar syndrome [22], or neurofibromatosis type 1 [23]. It has been described in severe autosomal recessive OI due to variants in the BMP1 gene [24] but is not reported in the classical OI types [16–18]. It should not be confused with the serpentine deformity or skewfoot, an adductus deformity of the forefoot combined with a valgus heel and abductus of the navicular on the talus, which was reported in classical OI [25].

The association of bathrocephaly, growth retardation, bowed limbs, and serpentine fibula was part of the Serpentine fibula-polycystic kidney syndrome (formerly OMIM 600330), which is now part of the Hajdu-Cheney syndrome (OMIM 102500) [20, 21], an autosomal dominant condition caused by variants in the NOTCH2 gene. Due to their discrepant clinical presentation regarding the remaining patients, the diagnosis of OI type I in patients 2 and 2-daughter was briefly questioned until the opportunity to perform genetic testing. This reinforces the importance of knowing uncommon manifestations in conditions with atypical features and the need for molecular confirmation in such cases.

Acknowledgment

The authors would like to thank the patients for their cooperation and authorization to use the images.

Statement of Ethics

This study was conducted following the Declaration of Helsinki and was reviewed and approved by the Institutional Ethics Committee Board under protocol number CEP/FCM/Unicamp 29567220.4.2005.5404. All patients were informed before the data collection and signed a written informed consent form. Written informed consent was obtained from the parents or legal guardians of the patients for the publication of details of their medical cases and any accompanying images.

Conflict of Interest Statement

The authors declare that they have no conflicts of interest.

Funding Sources

This research was also made possible through access to the data and findings generated by the Brazilian Rare Genomes Project, an initiative of Hospital Israelita Albert Einstein in partnership with the Programa de Apoio ao Desenvolvimento Institucional do Sistema Único de Saúde from the Brazilian Ministry of Health (PROADI-SUS 25000.083098/2019-71).

Author Contributions

F.F.N., R.P.O.S., and C.E.S. collected and analyzed clinical data. T.F.A. and the BRGPC (Brazilian Rare Genomes Project Consortium) performed molecular studies. F.F.N. and C.E.S. reviewed molecular data. C.E.S. guided the conception and oversight of manuscript development. All authors reviewed the text for academic content and approved the final manuscript as submitted.

Funding Statement

This research was also made possible through access to the data and findings generated by the Brazilian Rare Genomes Project, an initiative of Hospital Israelita Albert Einstein in partnership with the Programa de Apoio ao Desenvolvimento Institucional do Sistema Único de Saúde from the Brazilian Ministry of Health (PROADI-SUS 25000.083098/2019-71).

Data Availability Statement

The data supporting this study’s findings are available from the corresponding author upon reasonable request.