This study aimed to assess the efficacy and safety of 2 Janus kinase (JAK) inhibitors (jakinibs) tofacitinib and ruxolitinib in the treatment of type I interferonopathies patients including STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutières syndrome (AGS), and spondyloenchondrodysplasia with immune dysregulation (SPENCD). A total of 6 patients were considered in this study: 2 patients with SAVI, 1 patient with AGS1, 1 patient with AGS7, and 2 patients with SPENCD. Clinical manifestations, laboratory investigations, radiology examinations, treatment, and outcomes were collected between November 2017 and November 2021 in Peking Union Medical College Hospital. The disease score for patients with SAVI and AGS scale for patients with AGS were documented. The expression of 6 interferon-stimulated genes (ISGs) was assessed by real-time PCR. Three patients (1 patient with SAVI, 2 patients with AGS) were treated with ruxolitinib and 3 patients (1 patient with SAVI, 2 patients with SPENCD) were treated with tofacitinib. The mean duration of the treatment was 2.5 years (1.25-4 years). Upon treatment, cutaneous lesions and febrile attacks subsided in all affected patients. Two patients discontinued the corticoid treatment. Two patients with SAVI showed an improvement in the disease scores (p < 0.05). The erythrocyte sedimentation rate normalized in 2 patients with AGS. The interferon score (IS) was remarkably decreased in 2 patients with SPENCD (p < 0.01). Catch-ups with growth and weight gain were observed in 3 and 2 patients, respectively. Lung lesions improved in 1 patient with SAVI and remained stable in 3 patients. Lymphopenia was found in 3 patients during the treatment without severe infections. The JAK inhibitors baricitinib and tofacitinib are promising therapeutic agents for patients with SAVI, AGS, and SPENCD, especially for the improvement of cutaneous lesions and febrile attacks. However, further cohort studies are needed to assess the efficacy and safety.

Cervical kyphosis is rare in the pediatric population. It may be syndromic or acquired secondary to laminectomy, neoplasia, or trauma. Regardless, this should be avoided to prevent progressive spinal deformity and neurological deficit. Long-term follow-up is needed to evaluate fusion status, spine growth, potential instability, and neurological function. A retrospective review of 27 children (6 months to 16 years) with cervical kyphotic deformity was performed and limited to the MRI era until 2008, to provide a long-term follow-up after which complex instrumentation was available. There were 27 patients, 19 syndromic (average age 5.36 years), and 8 non-syndromic (average age 14 years). Syndromes encountered were spondyloepiphyseal dysplasia (SED) 4, spondylometaphyseal dysplasia 1, unnamed collagen abnormality syndrome 1, osteogenesis imperfecta (OI) 2, Aarskog syndrome 1, Weaver syndrome 1, Larsen syndrome 1, multiple cervical level disconnection syndrome 1, Klippel-Feil 3, congenital absence of C2 pars 4. Non-syndromic cases; 2 with neurofibromatosis (NF1) and prevertebral tumors, fibromatosis 1, spontaneous kyphosis 1, and postlaminectomy 4. Factors considered were age, pathology, flexibility on cervical spine dynamic films, reduction with traction and spinal cord compression. Patients with flexible kyphosis underwent dorsal fixation. Children with non-flexible ventral compression/kyphosis had crown halo traction. Irreducible kyphosis had ventral decompression and fusion as well as dorsal fusion. Eleven of 19 syndromic children with flexible and reducible kyphosis underwent dorsal fixation alone. Four of 8 non-syndromic (2 NF1) needed ventral and dorsal approaches. The preoperative deformity (global and local Cobb angles) as well as neurological status improved. Growth during follow-up was not impaired, and we did not encounter instability or junctional kyphosis. The only complications were seen in syndromic patients. One patient with SED showed delayed cantilever bending of the ventral fusion mass requiring reoperation, and 1 other OI child had left C5 and C6 nerve root weakness after anterior C4 and C5 decompression which resolved over 1 year. One child with SED developed cervicothoracic junction scoliosis 18 years later after thoracic scoliosis surgery. Syndromic pathology presented early with neurological dysfunction and 24% had rigid kyphosis. An attempt at traction/reduction was successful as in Tables 1 and 2. The majority exhibited long-term improvement in kyphosis and function. A treatment algorithm and literature review is presented. Table 1 Motor function of the modified Japanese Orthopedic Association (JOA) score in children [24, 37] Score Upper extremity •Unable to move hands or feed oneself 0 •Can move hands; unable to eat with spoon 1 •Able to eat with spoon with difficulty 2 •Able to use spoon; clumsy with buttoning 3 •Healthy; no dysfunction 4 Lower extremity •Unable to sit or stand 0 •Unable to walk without cane or walker 1 •Walks independently on level floor but needs support on stairs 2 •Capable to walking, clumsy 3 •No dysfunction 4 Table 2 Pediatric cervical kyphosis-preoperative evaluations Case ID, year presented Age Sex Diagnosis Presentation Imaging Apex Cobb angle degree Reducibility Preop traction Syndromic #1 2003 4 years M SED Progressive quadriparesis Bladder incontinence Severe C2-4 kyphosis with cord compression C3-4 85° No No #2 2001 3 years M SED Progressive quadriparesis C2-3 kyphosis. No dorsal C2. Buckled cord C2-3 25° No No Recurrent weakness after recovery 2 years later Kyphosis at fusion site C2-3 33° No No #3 1997 13 years M SED Neck pain. Hand weakness. Thoracic scoliosis C1-3 kyphosis Os odontoideum C2-3 30° Yes No #4 2006 6 years F SED Tingling in hands Bladder incontinence Deformed C2 body and odontoid C1-2 instability C2-3 27° Yes No #5 1997 4 years M SMD Quadriparesis. Previous C2-3 kyphosis with O-C3 dorsal fusion elsewhere Fixed C1-2 dislocation. C2-3 kyphosis. O-C4 fusion C2 35° Partial Yes 4 days #6 2007 13 years F Syndromic collagen abnormality Neck pain. Leg length discrepancies. T-L scoliosis. Quadriparesis Bilateral C2 and partial C3 spondylolysis C-T levoscoliosis C2-3 35° Partial Yes 4 days #7 2003 14 years F Osteogenesis imperfecta (OI) Only able to use right upper extremity C3-5 kyphosis. Canal diameter 4 mm at C4 C4 25° No No #8 1989 3 years F OI - Bruck's syndrome Quadriparesis age 9 months. Had C1-C3 posterior decompression and fusion elsewhere Progressive kyphosis Worse weakness Bend in fusion C1-2 40° No No #9 1996 11 years M Aarskog syndrome Neck pain with limited neck motion Cervical myelopathy Psychomotor delay C4-5 spondylolysis C5-6 kyphosis C5 30° No Yes 3 days #10 1989 3½ years F Weaver syndrome Quadriparesis age 2 years. Elsewhere C1-C3 dorsal rib fusion and wires Fusion failure C2-3 subluxation Cord compression C2-3 3° Yes Yes 1 day #11 1986 11 years F Larsen syndrome Neck pain in extension Quadriparesis C2-3 kyphosis. Deformed bodies C2-5 Os odontoideum C1-2 instability C2-3 28° Yes Yes 1 day #12 1996 5 years M Multilevel cervical disconnect syndrome Horner pupil on right Small right arm Quadriparesis C4, C5 vertebral bodies behind C5 C5 body in canal Left vertebral artery in C5 body C4-5 35° No No #13 1985 3 years F Klippel-Feil Neck pain. Weak hands Atlas assimilation C3-4 kyphosis No posterior bony arches C3, C4 C3-4 40° Yes No #14 1994 3 years F Klippel-Feil Unable to sit. Floppy. Quadriparesis C2-3 kyphosis No posterior arches C2-3 and L4 C2-3 45° Yes No #15 1993 11 months F Tuberous sclerosis Spondylolysis C2 Salam seizures Quadriparesis No pars C2 C2-3 kyphosis C2-3 30° Yes No #16 1998 2 years M C2 spondylolysis Quadriparesis, arms worse than legs C2 spondylolysis C2-3 kyphosis C2-3 35° Yes No #17 1998 6 months M C2 spondylolysis Failure to thrive Apneic spells Weak in arms after endoscopy C2-3 kyphosis No C2 lamina Cord compression C3-4 on MRI C2-3 45° Yes No #18 1990 4 years F C2 spondylolysis Developmental delay Quadriparesis C2 spondylolysis C2-3 kyphosis C3 45° Yes No #19 1994 4 years F Klippel-Feil No posterior C2 Torticollis age 6 mo Quadriparesis C2-3 kyphosis No posterior arch C2 Fused C3-4 bodies C2-3 45° Yes No Non-syndromic #20 1996 15 years M NF1. Ventral prevertebral plexiform neurofibroma Neck pain Weak arms Cervical myelopathy C4-5 kyphosis Cord draped over C4-5 Enhanced prevertebral tumor C4-5 60° Partial Yes 4 days #21 1996 6 years M NF1 Age 6 mo had C1-3 laminectomies elsewhere Progressive kyphosis Quadriparesis C3-5 plexiform neurofibromas C2-4 kyphosis C3-4 45° No No #22 1993 11 years M "Fibromatosis" Neck pain Gag ↓ Right hemiparesis C2 body and odontoid curved dorsally C2-3 kyphosis C2 40° No Yes 3 days #23 2007 13 F Mid-cervical kyphosis Neck pain Unable to move neck C3-4 kyphosis C3-4 45° Yes Halo vest elsewhere 6 weeks Repeat traction on referral #24 1998 12 years M Chiari I Syringohydromyelia Difficulty swallowing Quadriparesis Previous posterior fossa and C1-3 decompression Basilar invagination C3-4 kyphosis C3-4 50° Yes Halo traction 3 days #25 1994 16 years M Chiari I. SHM Difficult speech Quadriparesis Previous posterior fossa and C1-4 laminectomies C3-4 kyphosis Basilar invagination C3-4 55° Yes Halo traction 3 days #26 2002 11 years M Chordoma C3-5 Initial quadriparesis improved after posterior decompression then worse Dorsal and lateral tumor C3-4 C3-4 20° Yes Traction 3 days #27 2006 13 years M C4 lamina Aneurysmal bone cyst Neck and shoulder pain C4 laminectomy for tumor resection Worse 4 months later C4-5 kyphosis C3-4 40° Yes No Table 3 Pediatric cervical kyphosis-postoperative evaluations Case ID Diagnosis Treatment-operation Complication PO orthosis F/U time Fusion status Preop Cobb Postop Cobb Preop JOA Postop JOA Comments Syndromic #1 SED Crown halo traction 1. Median mandibular glossotomy. Resection C2-3 bodies with rib graft fusion 2. Dorsal O-C3 rib graft fusion None Halo vest 3 months Soft collar 3 months 8 years Complete anterior and posterior fusion 85° 10° 2 8 Complete neurological recovery #2 SED Crown halo traction 1. Median mandibular glossotomy. C2-4 corpectomies. C2-5 anterior rib graft fusion Recurrent weakness 2 years s later Halo vest 3 months 2 years Fused 25° 20° 4 5 T. scoliosis. Cardiac abnormalities. Walking then quadriparesis Redo ventral resection and C1-4 iliac bone graft Worsening quadriparesis Minerva brace 1 year 18 years Fused 33° 15° 3 5 Much improved in 6 months #3 SED Crown halo traction Dorsal O-C4 fusion with loop and rib graft None Miami J collar 3 months 10 years Fused 30° 13° 4 7 Works in bookstore #4 SED Crown halo traction Dorsal O-C3 fusion with loop and rib graft 4 years later developed C-T scoliosis after T. scoliosis surgery Miami J collar 3 months 14 years Fused 27° 5° 5 7 C-T scoliosis developed after thoracic scoliosis correction #5 SMD Crown halo traction Transoral C2 odontoid resection None Minerva brace 6 months 20 years No from preop status 35° 10° 1 4 In wheelchair. Works as programmer #6 Collagen abnormality Crown halo traction C2-5 ACDF C2-5 plate with C3-4 lag screws Junctional kyphosis 7 years later after scoliosis correction Miami J collar 6 weeks 12 years Fused 36° 5° 4 7 Abnormal vertebral arteries. Thoracic outlet syndrome May-Thurner syndrome #7 OI Crown halo traction C3-5 corpectomies C2-6 Orion plate with iliac crest graft None Soft collar 4 years Fused 25° 30° 1 5 Restrictive lung disease. Multiple fractures Expired #8 OI - Bruck syndrome 1. Redo C1-2 dorsal rib graft fusion No change Molded Minerva brace 4 years Fused 40° 35° 3 4 Increased weakness age 7 2. 11 years age anterior C3-7 decompression and plate C3-7 Worsening left deltoid and biceps function Molded Minerva brace 30 years Fused 52° 34° 3 5 Lives alone. Wheelchair. Computer technologist Uses hands well #9 Aarskog syndrome Crown halo traction C2-6 anterior cervical fusion with iliac crest graft None Molded Minerva brace 20 years Fused 30° 14° 4 7 Works on a farm. No myelopathy. Syndrome in family #10 Weaver syndrome Crown halo traction Redo C1-4 dorsal rib graft fusion None Miami J collar 2 years Fused 3° 10° 2 5 Neuroblastoma age 3 months. Chemotherapy Stable #11 Larsen syndrome Crown halo traction O-C5 dorsal fusion None Halo vest 6 weeks Miami J 3 months 6 years Fused 28° 10° 3 7 Doing well #12 Multilevel cervical disconnect syndrome Crown halo traction C5 corpectomy C4-6 iliac bone fusion anteriorly Dorsal C4-6 fusion None Halo vest 3 months 5 years Fused 35° 5° 3 7 Persistent Horner pupil #13 Klippel-Feil Crown halo traction C2-6 posterior rib graft fusion None Halo vest 3 months 19 years Fused 40° 12° 3 7 Hearing loss Genitourinary abnormalities Sprengel's deformity #14 Klippel-Feil Crown halo C2-5 dorsal rib graft fusion None Halo vest 3 months 35 years Fused 45° 10° 1 6 Hearing loss Genitourinary abnormalities #15 Tuberous sclerosis Spondylolysis C2 C1-4 dorsal interlaminar rib fusion None Halo vest 3 months 6 years Fused 30° 5° 1 6 Psychomotor delay #16 C2 spondylolysis C1-4 dorsal interlaminar fusion None Halo vest 3 months 4 years Fused 35° 10° 2 6 Recovered full function in one year #17 C2 spondylolysis Tracheostomy Molded cervicothoracic brace None Mold brace 4 years 6 years Formed C2 posterior arches 45° 20° 1 3 Reformed C2 at 4 years on CT Parents did not wish surgery #18 C2 spondylolysis Intraoperative traction C1-3 dorsal rib graft fusion None Neck brace 4 months 8 years Fused 45° 12° 2 5 Developed C2 posterior elements #19 Klippel-Feil Intraoperative traction O-C4 fusion with rib graft None Molded brace 6 months 1 years Fused O-C2 dorsally 45° 16° 1 4 Able to sit and use hands Non-syndromic #20 NF1 Resection of ventral tumor C3-6 C4-5 corpectomies; C4-5 iliac graft; C3-7 Orion plate None Halo vest 6 weeks 14 years Fused 60° 15° 3 7 Recovered in 6 weeks. Works on a farm #21 NF1 Intraoperative traction Resect prevertebral tumor C2-5 kyphectomies; C2-6 anterior fusion iliac crest None Halo vest 3 months 2 years Fused 45° 20° 3 5 Initial C1-3 decompression done elsewhere #22 Fibromatosis 1. Transoral C2 decompression 2. Dorsal O-C3 fusion with loop None Brace 3 months 12 years Fused 40° 12° 4 6 Age 2 years had neck mass resected. Diagnosis "fibromatosis" #23 Mid-cervical kyphosis Traction C2-5 lateral mass fusion with screws, rods and rib grafts Worse after removal of initial traction Brace 3 months 8 years Fused 45° 15° 7 8 Doing well #24 Chiari I SHM Intraoperative traction O-C5 rib graft fusion None Halo vest 3 months 21 years Fused 50° 7° 2 6 Facets atrophied C2, C3 at surgery #25 Chiari I SHM Intraoperative traction O-C5 dorsal fusion with loop and rib None Miami J brace 4 months 22 years Fused 55° 10° 3 6 Facets atrophied C2-4 at surgery #26 Chordoma C3-4 1. Dorsal lateral C3-6 fusion 2. C2-5 anterior fusion with iliac bone None Miami J brace 6 months 18 years Fused 20° 12° 5 8 Weak in hands after initial surgery elsewhere #27 ABC tumor C4 Anterior C3-5 fusion with plate and bone None Miami J brace 4 weeks 12 years Fused 40° 15° 5 8 No recurrence SED spondyloepiphyseal dysplasia, SMD spondylometaphyseal dysplasia, JOA Japanese Orthopedic Association, MRI magnetic resonance imaging, SHM syringohydromyelia, NF1 neurofibromatosis type 1, f/u follow up, OI osteogenesis imperfecta, CT computed tomography, JK junctional kyphosis.

We report a further case of spondylometaphyseal dysplasia - corner fracture type due to the fibronectin-1 gene (SMD-FN1) in a child originally thought to have metaphyseal chondrodysplasia-Brussels type (MCD Brussels). We highlight phenotypic differences with the SMD-FN1 published reports. This case is unique in terms of the method of molecular confirmation. Findings from the 100 000 Genomes Project were originally negative (in both tier 1 and 2); however, subsequent reanalysis, initiated by an automated search for new gene-disease associations in PanelApp, highlighted a candidate diagnostic variant. Our child had short stature, facial dysmorphism, spondylometaphyseal dysplasia and corner fractures and a heterozygous de novo missense variant in FN1 (c.675C>G p.(Cys225Trp), which was likely pathogenic. The variant matched the clinical and radiological features and a diagnosis of SMD-FN1 was confirmed. We explore the diagnostic journey of this patient, compare her findings with the previous 15 patients reported with SMD-FN1 and discuss the diagnostic utility of automated reanalysis. We consider differences and similarities between MCD Brussels and SMD-FN1, by reviewing literature on both conditions and assess whether they are in fact the same disorder.

Recent evidence has implicated EFL1 in a phenotype overlapping Shwachman-Diamond syndrome (SDS), with the functional interplay between EFL1 and the previously known causative gene SBDS accounting for the similarity in clinical features. Relatively little is known about the phenotypes associated with pathogenic variants in the EFL1 gene, but the initial indication was that phenotypes may be more severe, when compared with SDS. We report a pediatric patient who presented with a metaphyseal dysplasia and was found to have biallelic variants in EFL1 on reanalysis of trio whole-exome sequencing data. The variant had not been initially reported because of the research laboratory's focus on de novo variants. Subsequent phenotyping revealed variability in her manifestations. Although her metaphyseal abnormalities were more severe than in the original reported cohort with EFL1 variants, the bone marrow abnormalities were generally mild, and there was equivocal evidence for pancreatic insufficiency. Despite the limited number of reported patients, variants in EFL1 appear to cause a broader spectrum of symptoms that overlap with those seen in SDS. Our report adds to the evidence of EFL1 being associated with an SDS-like phenotype and provides information adding to our understanding of the phenotypic variability of this disorder. Our report also highlights the value of exome data reanalysis when a diagnosis is not initially apparent.

We previously reported exome sequencing in a short-rib thoracic dystrophy (SRTD) cohort, in whom recessive mutations were identified in SRTD-associated genes in 10 of 11 cases. A heterozygous stop mutation in the known SRTD gene WDR60 was identified in the remaining case; no novel candidate gene/s were suggested by homozygous/compound heterozygous analysis. This case was thus considered unsolved. Re-analysis following an analysis pipeline update identified a homozygous mutation in C21orf2 (c.218G > C; p.Arg73Pro). This homozygous variant was previously removed at the quality control stage by the default GATK parameter "in-breeding co-efficient." C21orf2 was recently associated with both Jeune asphyxiating thoracic dystrophy (JATD) and axial spondylometaphyseal dysplasia (axial SMD); this particular mutation was reported in homozygous and compound heterozygous state in both conditions. Our case has phenotypic features of both JATD and axial SMD; and the extent of thoracic involvement appears more severe than in other C21orf2-positive cases. Identification of a homozygous C21orf2 mutation in this case emphasizes the value of exome sequencing for simultaneously screening known genes and identifying novel genes. Additionally, it highlights the importance of re-interrogating data both as novel gene associations are identified and as analysis pipelines are refined. Finally, the severity of thoracic restriction in this case adds to the phenotypic spectrum attributable to C21orf2 mutations.