Two missense mutations in the B3GALT6 gene on chromosome 1p36 result in single amino acid substitutions. The changes lead to a deficiency of an enzyme critical for glycosaminoglycan biosynthesis and result in a very rare autosomal recessive disorder.1,2 Defects in this gene result in a phenotype that has features of both skeletal dysplasia and a connective tissue disorder. The many craniofacial, musculoskeletal, and dermatologic abnormalities associated with this disease present unique challenges for an anesthesiologist (Table). We describe the anesthetic management of a child with B3GALT6 mutations and severe phenotypic expression, which includes abnormalities that are atypical for this syndrome and have significant anesthetic ramifications. This case report is published with the written consent of the patient’s mother.
A 5-year-old boy was referred to the Pediatric Anesthesiology Preoperative Clinic before full-mouth dental extractions for recurrent infections and pain. He had a genetic disorder (B3GALT6 mutations), seizures, obstructive sleep apnea with bilevel positive airway pressure (BiPAP) dependence, tracheomalacia, laryngeal cleft, chronic lung disease, recurrent pneumothoraces, dextrocardia, mitral valve prolapse with moderate regurgitation, a moderately dilated aortic valve annulus and aortic root dilation, platelet dysfunction of unknown etiology, severe osteopenia with history of multiple fractures sustained with little or no trauma, connective tissue disease, cervical spine instability, scoliosis, and contractures. The patient was nonverbal and was not able to sit or walk unsupported.
At baseline, the patient required 1 L oxygen via nasal cannula while awake and 3 L oxygen while receiving noninvasive ventilation at night. Although the patient was unable to perform spirometry testing, chronic lung disease and neuromuscular scoliosis contribute to restrictive lung disease. He also had airway obstruction managed with nebulized corticosteroid and bronchodilator therapy. The patient frequently required hospitalization for respiratory tract infections and, 7 weeks prior, he had been admitted for 4 days for treatment including continuous noninvasive ventilatory support. At the time of presentation, he was at his baseline from a respiratory standpoint.
Further review revealed that the patient had presented to the operating room at the age of 6 months, before genetic diagnosis, for tracheostomy for obstructive and restrictive lung disease with chronic respiratory insufficiency. After the patient was positioned, the anterior neck was examined and a large vessel was palpated superior to the thoracic inlet with a palpable thrill. The ultrasound was then used to further evaluate and 2 large vessels were seen tracking across and anterior to the trachea at the position for a tracheostomy. Given risk for erosion and significant vascular trauma, the decision was made to obtain further imaging before proceeding with tracheostomy (Figure 1). Based on results of the imaging, the procedure was aborted. Since that time, the child has been supported with noninvasive ventilation and oxygen therapy.
A history of bruising easily and bleeding excessively with trauma led to hematologic evaluation, which revealed an abnormal platelet function assay (PFA 100). The specific abnormality leading to platelet dysfunction was unknown, but abnormal collagen and fragile vessel walls were thought to be contributors because the patient’s abnormal collagen may not bind von Willebrand factor or platelets well. His bleeding was managed symptomatically with desmopressin as the first-line option and platelet transfusion when treatment with desmopressin was insufficient.
On examination, the child was interactive and in no acute distress, weighing 16 kg. His skin was soft and doughy and arachnodactyly and joint laxity were evident. He had hypotonia and was able to move his extremities against gravity but unable to lift his head. He had significant asymmetric plagiocephaly. No cardiac murmurs were noted. Breathing was unlabored on oxygen by nasal cannula and breath sounds were clear. He had multiple dark bruises on his legs.
In addition to the child’s vascular anomalies in the neck, he was known to have cervical spine abnormalities with severe basilar invagination resulting from the entirety of the C2 vertebral body passing through a widened C1 arch, severe spinal canal narrowing between C2 and the opisthion, and fusion of the posterior elements of C1–C4 (Figure 2). The combination of cervical instability, anticipated difficult airway (it had been difficult to visualize the larynx by direct laryngoscopy when the child presented to the operating room as an infant), and noneligibility for a surgical airway in the setting of vascular abnormalities put the patient at considerable anesthetic risk, which was discussed with his mother at length during their preoperative visit. The child’s mother understood the severity of his disease and ranked his quality of life as her first priority. Because his teeth were causing considerable pain, she elected to proceed with the procedure knowing the risks. She also expressed her desire that, in the setting of a cardiac arrest, chest compressions not be performed due to the fragility of his bones and the low likelihood of a positive outcome. A perioperative plan was formulated by the pediatric anesthesiologist in collaboration with the pediatric dentist, pulmonologist, cardiologist, radiologist, hematologist, otolaryngologist, and intensivist over several weeks.
On the day of surgery, the child was carried to the operating room and positioned on the operating table by his mother. He had a port placed in the past for venous access because peripheral intravenous catheter placement was challenging. His port had been accessed in the preoperative holding area. Pulse oximeter and electrocardiogram leads were placed and his mother was escorted out of the room. A noninvasive blood pressure cuff was not used because previous blood pressure cuff inflation had caused fractures. The patient underwent an inhalation induction with sevoflurane and oxygen supplemented by intravenous lidocaine, fentanyl, and ketamine with 2 anesthesiologists present. He was prepared for fiberoptic nasal intubation with intravenous glycopyrrolate and intranasal oxymetazoline, and spontaneous ventilation was maintained. A small nasopharyngeal airway connected to an endotracheal tube connector was inserted and connected to the anesthesia circuit to administer oxygen and sevoflurane while the patient breathed spontaneously for fiberoptic intubation. Because the purpose of the nasopharyngeal airway was to allow the child to breathe oxygen and sevoflurane and we were concerned about causing bleeding, the size of the nasopharyngeal airway was smaller than that which would be used to bypass obstruction. The fiberoptic scope was introduced nasally and the glottis was visualized, but jaw thrust and external laryngeal manipulation were necessary to move the glottis posteriorly so the scope could be advanced through the vocal cords with maximal flexion of the bronchoscope. The airway was secured with a 4.5 cuffed nasal RAE tube.
Due to the risk of fractures with noninvasive blood pressure measurements, a femoral arterial line was placed under ultrasound guidance for blood pressure monitoring after intubation. General anesthesia was maintained with 2.5% sevoflurane in oxygen and air, 0.5 µg/kg/h dexmedetomidine, and intermittent fentanyl boluses totaling 3 µg/kg over the 3.5-hour intraoperative course. The child’s history of easy bruising and bleeding due to platelet dysfunction was discussed with his hematologist preoperatively, and desmopressin was recommended as first-line therapy in the event of intraoperative bleeding. As the teeth were removed, there was significant bleeding and desmopressin was given intravenously. In accordance with the preoperative plan, the patient was transferred to the pediatric intensive care unit intubated and sedated in preparation for extubation to BiPAP when he had recovered from anesthesia due to concerns about the impact of anesthesia on his compromised pulmonary status.
The patient remained intubated and sedated with a dexmedetomidine infusion and intermittent boluses of fentanyl and midazolam overnight. We were consulted to evaluate readiness for extubation on postoperative day (POD) 1. The patient had done well from a pulmonary standpoint but significant bleeding from the oral mucosa precluded extubation. At the recommendation of the hematologists, platelets were administered in addition to a second dose of desmopressin and bleeding improved. He was extubated on POD 2 to his home BiPAP with his intraoperative anesthesiologist at the bedside. He went home on POD 2 at his baseline medically with his very appreciative mother.
Individuals with the enzyme deficiency caused by mutations in the B3GALT6 gene have been categorized with a clinical diagnosis of spondyloepimetaphyseal dysplasia with joint laxity, or with Ehlers-Danlos syndrome progeroid type (EDS progeroid type 2). The association between these overlapping phenotypes and genetic defects in B3GALT6 was first described by 2 groups in 2013,1,2 in a series of patients who demonstrated specific craniofacial dysmorphisms including proptosis, blue sclera, micrognathia, and cleft palate. Musculoskeletal findings included kyphoscoliosis, large and small joint laxity, hand contractures, hip dislocation, clubfeet and muscular hypotonia, with a number of radiological features (most common being platyspondyly, anterior beak of vertebral body, short ilia, metaphyseal flaring, and elbow malalignment). The skin was notable for very soft and doughy texture, cutis laxa, and sparse hair. There is no known association between abnormal bleeding or platelet dysfunction and B3GALT6 mutations.
Reports of patients with this clinical diagnosis are rare and, as such, estimates of prevalence cannot be made. In the cases reported to date, there is no apparent dominance of sex, and the life expectancy is not known; however, individuals surviving up to 30 years of age have been reported. Because the disorder is autosomal recessive with presumed low carrier frequency of mutations in the population, most cases are isolated unless they are members of a consanguineous family with a B3GALT6 mutation, in which case, more than 1 individual has been identified in a family.3 Most cases have confirmed carrier status of parents.
Our patient underwent extensive, targeted genetic testing for recessive forms of osteogenesis imperfecta and various types of EDS and ultimately was diagnosed at the age of 4 by exome-sequencing which revealed that he was compound heterozygous for mutations in the B3GALT6 gene (different missense mutations on each allele of the gene), consistent with the diagnosis of SEDM-JL and EDS progeroid type 2. Genetic testing was performed in his parents confirming that each mutation was inherited from a respective parent. His clinical and radiographic features are consistent with other patients reported in the literature, with a notably severe phenotype likely related to a more severe deficiency of the enzyme. The degree of residual enzyme activity correlates with severity of disease in limited studies of other patients.1
Beyond the patient’s findings consistent with those reported in other patients with the disease, he had vascular anomalies that have not previously been associated with his genetic diagnosis. Similar vascular anomalies in patients without B3GALT6 mutations have resulted in a fatal outcome during percutaneous dilatational tracheostomy4 and a near miss during open tracheostomy.5
We describe a patient with an extremely rare condition that, to our knowledge, is without published anesthetic considerations or recommendations. B3GALT6 mutations result in multisystemic pathology with variable anesthetic implications depending on the severity. In our case, skeletal and vascular abnormalities led to an anticipated difficult and unstable airway in which tracheostomy was not a feasible rescue. Without knowledge of his airway anatomy, we would have considered him a candidate for emergent cricothyrotomy or tracheostomy, a potentially fatal error. Thorough preoperative assessment and planning with a pulmonologist, cardiologist, radiologist, hematologist, otolaryngologist, and intensivist as well as thoughtful communication with the child’s mother were essential to the success of the child’s perioperative care. This case illustrates the anesthetic challenges associated with severe phenotypic expression in a child with B3GALT6 mutations and the successful multispecialty approach to their condition in the perioperative period.
Name: Megan Brockel, MD.
Contribution: This author helped write, edit, and revise the manuscript.
Name: Kathryn Chatfield, MD.
Contribution: This author helped write the manuscript.
Name: David Mirsky, MD.
Contribution: This author helped write the manuscript.
Name: Christopher D. Baker, MD.
Contribution: This author helped write the revised manuscript.
Name: Norah Janosy, MD.
Contribution: This author helped write, edit, and revise the manuscript.
This manuscript was handled by: Mark C. Phillips, MD.