Last updated:
7/15/2024
Years published: 2024
NORD gratefully acknowledges Kevin McMahon and Gregory Cichon, MD Candidates at Creighton School of Medicine and Dr. Anne Dieux Coeslier, PH, Clinique de Genetique, Hôpital Jeanne de Flandre, France, for the preparation of this report.
Summary
Bent bone dysplasia syndrome (BBDS) is an often-lethal skeletal disorder characterized by poor mineralization of the skull (calvarium), early fusion of skull bones (craniosnostosis), underdevelopment of the pubic bone (pubis), sitting bone (ischium), and clavicles, weak bones (osteopenia), a bell-shaped chest and bent long bones. Facial differences include low-set ears, widely spaced eyes (hypertelorism), a flat midface, prematurely erupted fetal teeth, and a small lower jaw (micrognathia). This condition is caused by a change (disease-causing variant) in the FGFR2 gene that occurs sporadically and is not inherited from either parent.
Introduction
Bent bone dysplasia syndrome was first identified in 2012 and there have been very few children diagnosed since then. These children died shortly after birth. Due to the rarity and newness of this condition, it may be underrecognized by doctors. A similar and even rarer condition known as bent bone dysplasia syndrome-2 (BBDS2) is caused by variants in the LAMA5 gene.
Physical exams and imaging studies of infants with BBDS may identify signs and symptoms in many body systems:
The craniofacial and respiratory abnormalities often lead to feeding and breathing difficulties. Babies often breathe through the nose during feeding and if the nasal passages are blocked, they respond by unlatching or pausing feeds and working harder to breathe (nasal flaring and retractions).
Infants may also suffer from sleep apnea and oral abnormal blockage (malocclusion) due to backward displacement and abnormal growth in the midface (maxilla) and lower jaw (mandible).
The facial differences and protrusion of the eyes may result in inability or difficulty with full closure of the eyelids and retraction of the eyeballs which may result drying and injury of the eyes such as scarring of the cornea.
If the child survives beyond infancy, the combination of hearing impairment, vision impairment, physical limitations and sleep apnea may increase the risk for neurobehavioral and developmental challenges. However, there is little or no information on neurodevelopmental and behavioral features due to the lack of reports describing affected people beyond infancy.
Bent bone dysplasia syndrome (BBDS) is caused by a variant in the FGFR2 gene. These disease-causing variants occur randomly and spontaneously and are not inherited from either parent. Variants disrupt the structure and transportation of the FGFR2 protein produced by this gene leading to low concentrations and function of the protein on the surface of cells and abnormal signaling in cells mostly associated with bone formation. These cells do not multiply correctly and do not properly form the skeleton. The bones of affected infants then have inadequate and abnormal growth.
BBDS is a type of syndromic primary single suture craniosynostosis. This means that the abnormal function of the FGFR2 protein is the direct cause of the early suture closure and is also associated with effects on other parts of the body and this is called a syndrome. It also means that it only affects one specific suture and not the others (single suture). In contrast, when a child has secondary craniosynostosis, the function of cells and tissues is normal but external forces result in early close of the cranial sutures. These external forces include deficient brain growth leading to premature closure of all sutures (small head, normal shape) or abnormal head positioning in the womb or during infancy (often normal head size, abnormal shape).
BBDS follows autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. Children who have been diagnosed with BBDS so far had de novo changes in the FGFR2 gene. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
The relatively recent identification of the disorder and low number of patients means that the population affected by this condition cannot be accurately determined at this time.
A diagnosis of BBDS may be suspected based on a thorough medical and family history, physical exams and imaging studies. Genetic testing for variants in the FGFR2 gene is necessary to confirm the diagnosis.
Prenatal ultrasound may show features that are common to BBDS or other similar conditions including facial differences, premature closure of cranial sutures and abnormalities of the arms/legs and/or hands/feet. Abnormal development of the thorax (ribcage) along with short limbs, curved femurs and skull deformity is strongly suggestive of a diagnosis of BBDS.
After birth, these findings on exams and additional imaging tests help support the diagnosis. A detailed evaluation may show findings like a bulging soft spot (fontanelle) on the head, whether the eyelids fully cover the eyes (due to eye bulging), nasal flaring and chest wall retractions or inability to place a feeding tube through the nose. Early identification of these features help identify acute complications of the disorder and alert physicians to the need for quick treatment.
X-rays and other imaging may show underdevelopment of the collar bones (clavicles) and pubis (front of the pelvis), shortening of the limbs with bowing of the upper legs (femurs) and general under-mineralization of the calvarium (top of the skull). There may also be thin under mineralized bones (osteopenia), irregular surfaces on the bones (most pronounced in fingers/toes) and coronal craniosynostosis (early closure of the suture running from temple to temple).
A definitive diagnosis of BBDS can only be confirmed with genetic testing that identifies a disease-causing variant in the FGFR2 gene. Different types of genetic testing can be done and are determined by the medical and family history as well as findings on imaging and the physical exam. If findings are characteristic of BBDS, single gene testing may be conducted. However, if findings are more uncertain, a multigene panel or genome sequencing may be done to look for disease-causing variants in multiple genes associated with multiple disorders. Genetic testing may also be recommended for parents of an affected child.
An accurate diagnosis can help families make decisions about treatment and planning for future children.
Treatment
If BBDS or another FGFR craniosynostosis syndrome is suspected before birth based on ultrasound findings, the pregnancy should be monitored for features that may be life threatening or lead to severe disability after birth. Pregnant mothers should be encouraged to deliver at a hospital with access to pediatric physicians specializing in plastic surgery, neurosurgery, otolaryngology and pulmonary medicine in case intubation, resuscitation and acute intervention are needed at delivery. This is due to the high rate of complications such as respiratory obstruction.
Despite the poor prognosis for infants with BBDS, these children may benefit from a multidisciplinary team consisting of various clinicians and physicians, therapists, social workers and geneticists with a strong emphasis on palliative care medicine (reducing discomfort). These professionals may help to treat the numerous challenges of this disorder which can include increased intracranial pressure (hydrocephalus), cervical spine instability, respiratory distress and airway obstruction (upper airway abnormalities), feeding difficulties, facial and skeletal deformities, ear/hearing problems, dental problems, eye/vision problems, obstructive sleep apnea, gut malrotation, genitourinary problems and heart defects.
Genetic counseling is recommended for parents of an affected child.
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JOURNAL ARTICLES
Nishimura G, Handa A, Miyazaki O, et al. Prenatal diagnosis of bone dysplasias. Br J Radiol. 2023;96(1147):20221025. doi:10.1259/bjr.20221025
Barad M, Csukasi F, Bosakova M, et al. Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia. EBioMedicine. 2020;62:103075. doi:10.1016/j.ebiom.2020.103075
Stichelbout M, Dieux-Coeslier A, Clouqueur E, Collet C, Petit F. A new case of bent bone dysplasia–FGFR2 type and review of the literature. Am J Med Genet A. 2016;170(3):785-789. doi:10.1002/ajmg.a.37473
Merrill AE, Sarukhanov A, Krejci P, et al. Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling. Am J Hum Genet. 2012;90(3):550-557. doi:10.1016/j.ajhg.2012.02.005
Mornet E. Hypophosphatasia. Orphanet J Rare Dis. 2007;2:40. Published 2007 Oct 4. doi:10.1186/1750-1172-2-40
INTERNET
Wenger T, Miller D, Evans K. FGFR Craniosynostosis Syndromes Overview. 1998 Oct 20 [Updated 2020 Apr 30]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1455/ Accessed May 20, 2024.
Machol K, Mendoza-Londono R, Lee B. Cleidocranial Dysplasia Spectrum Disorder. 2006 Jan 3 [Updated 2023 Apr 13]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1513/ Accessed May 20, 2024.
FGFR2-related bent bone dysplasia. Orphanet. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=313855 Accessed May 20, 2024.
BENT BONE DYSPLASIA SYNDROME 1; BBDS1. Online Mendelian Inheritance in Man (OMIM). Updated5/15/2024. https://www.omim.org/entry/614592 Accessed May 20, 2024.
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