Coexistent ankylosing spondylitis and intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures

Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease mainly affecting the axial skeleton, with chronic back pain and spinal stiffness as primary presenting symptoms.1 AS is heritable and exhibits familial aggregation.2 The disease course is frequently complicated with other immune diseases, cardiovascular disease, and depression.3 Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures (IDDBCS) (Online Mendelian Inheritance in Man [OMIM]: 618725) is an autosomal dominant inherited multisystem involvement syndrome caused by mutation in the PHD finger protein 21A (PHF21A) gene (OMIM: 608325). IDDBCS is characterized by intellectual developmental disorder or varying degrees of intellectual disability accompanied by motor skills impairment and language delay; macrocephaly, obesity, and overgrowth are also common manifestations. Neurobehavioral disorders, including autism, are common, and approximately half of the patients have seizures.4, 5 In 2019, Hamanaka et al..5 first reported heterozygous mutations in the PHF21A gene in patients with IDDBCS The PHF21A gene is located on chromosome 11p11.2 and encodes BHC80, a component of the BRAF35-histone deacetylase complex (BHC), which is involved in transcriptional repression of neuron-specific genes and expressed highly in brain and skeletal muscle.5, 6 PHF21A haploinsufficiency is associated with intellectual disability and craniofacial anomalies.7 To date, 15 cases have been reported involving microdeletion frameshift or nonsense variants in the PHF21A gene.4, 5, 8-13 This report describes AS coexisting with a PHF21A-related disorder. The patient was a 16-year-old Chinese boy who was the first child of unrelated parents. He was born full-term after an uneventful pregnancy and vaginal delivery with a birth weight of 8 kg. Signs of developmental delay and intellectual disabilities appeared early in life. He learned to crawl at 12 months and to walk at 18 months and experienced poor balance and motor coordination. Speech delay was also present. He learned to say short sentences at 2.5 years of age. At 1 year of age, he underwent surgery to correct an atrioventricular septal defect. The patient visited the Rheumatology Clinic of Shandong Provincial Hospital at 14 years old with a complaint of 1.5 years of low back pain, which had developed gradually. He experienced morning stiffness that improved with exercise but not with rest. At presentation, he weighed 93 kg (97th percentile), and his height was 178 cm (97th percentile). He showed the unique features of a broad forehead, low and flat nasal bridge, sparse teeth, and externally rotated ears. Physical examination revealed restricted spinal movement in both the sagittal and frontal planes and percussion tenderness over the T12–L2 spine; neurological examination findings were within normal limits. Laboratory testing demonstrated a positive human leukocyte antigen B27 (HLA-B27) result, prolonged erythrocyte sedimentation rate (43 mm/h; reference range: 0–15 mm/h), and elevated C-reactive protein (15.60 mg/L; reference range: 0–5 mg/L) and interleukin 6 (15.41 pg/mL; reference range: 0–7 pg/mL) concentrations. Other routine laboratory examination results, such as blood counts, liver function, and blood biochemistry, were normal. Autoantibodies, including antinuclear antibodies, antidouble-stranded DNA antibodies, anticyclic citrullinated peptide antibodies, and antineutrophil cytoplasmic antibodies, were absent. Tuberculosis screening tests, namely tuberculosis antibody, T-SPOT, and purified protein derivative tests, were negative; the result of rheumatoid factor testing was also negative. Lumbar and sacroiliac joint magnetic resonance imaging (MRI) showed a normal physiological curve, narrowed intervertebral spaces, and a coarse margin of L1/2. MRI also showed inflammatory lesions, Hummer's nodules in L1 and L2, herniated intervertebral disks at L4/5 and L5/S1, and abnormal patchy high T1 signal intensity in bilateral sacroiliac joints, indicating sacroiliitis. Upon biopsy of the L2 vertebra, a slimy substance was detected, and pathological analysis revealed neutrophil proliferation and mild edema of the bone trabecula. No granulomatous inflammation, such as that seen with tuberculosis, was observed. Immunohistochemical studies showed that immunoglobulin G4, Congo red staining, and cluster of differentiation (CD)68 and CD117 evaluations were negative while CD235a was positive. As the patient was under 45 years of age and presented with more than one clinical criterion of AS, namely inflammatory low back pain for more than 3 months, limited lumbar spinal motion in both the sagittal and frontal planes and signs of bilateral sacroiliitis on MRI, the radiological criteria met the modified New York criteria for diagnosis of AS.14 The clinical features and test results did not support a diagnosis of diseases with similar manifestations, such as psoriasis; Reiter syndrome; synovitis, acne, pustulosis, and osteitis syndrome; diffuse idiopathic skeletal hyperostosis; enteropathic arthritis; and spinal tuberculosis. The patient had also visited the endocrinology department previously because of overgrowth and underwent relevant examinations, including hormone levels for the different pituitary axes, and pituitary MRI. As a result, endocrine and metabolic diseases such as acromegaly were ruled out because the hormone profile did not reveal abnormal results. Hence, we initiated therapy with oral nonsteroidal anti-inflammatory drugs (loxoprofen sodium 60 mg three times daily, which was subsequently changed to celecoxib 0.2 g twice daily) and injections of etanercept (25 mg twice weekly). However, the patient experienced no significant pain relief after 3 months of treatment. Therefore, we initiated 150 mg secukinumab therapy for the next 3 months instead. Adalimumab (40 mg biweekly) was given subcutaneously thereafter. However, the patient complained of persistent lower back pain at the most recent follow-up visit. The patient's father had proximal junctional kyphosis with a 10-year history of low back pain, and he suffered from intellectual disability. HLA-B27 testing revealed a positive result, and he had been diagnosed as having AS 1 year after his son was diagnosed. Other known family members were unaffected (Figure 1A). Whole exome sequencing was performed on a high throughput sequencing platform for the patient and his parents. Sequencing results were compared with reference genome hg19, and the pathogenicity of detected variants was evaluated in accordance with the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines.15 The heterogeneous variant, PHF21A (NM_00110802.1) c.840del (p.S280Sfs*14), was identified and confirmed to be of paternal origin by Sanger sequencing (Figure 1B). In accordance with the 2015 ACMG guidelines, the c.840del (p.S280Sfs*14) variant was defined as the pathogenic variant on the basis of the following evidence: this was a known loss-of-function variant recorded in the Human Gene Mutation Database; the deletion of the 840th nucleobase of the PHF21A gene caused frameshift and premature termination of protein synthesis (p.S280Sfs*14) (PVS1); and this variant was absent from the population databases in the Genome Aggregation Database (PM2). IDDBCS is caused by a heterozygous mutation in the PHF21A gene. The PHF21A gene encodes BHC80, a subunit of BHC, and mediates negative regulation of neuron-specific gene expression. This occurs by recruitment at the cis-regulatory element (repressor element 1 or neuron-restrictive silencer element sites) by repressor element 1 silencing transcription factor. BCH80 acts as a chromatin modifier by regulating histone demethylation and deacetylation.16, 17 Histone methylation dysregulation is a major driver of neurodevelopmental disorders, including intellectual disabilities and autism spectrum disorder (ASD).18 Orthologous suppression of PHF21A in a zebrafish model caused neuronal apoptosis and abnormal development of the head, face, and jaw,7 supporting the etiological role of PHF21A in neural and craniofacial abnormalities. The high transcription levels of PHF21A in the brain and skeletal muscle further support its relationship with neurological and hypotonia phenotypes.4 Although the phenotypic spectrum of intellectual disabilities, developmental delays, facial anomalies, overgrowth, and obesity in our case was generally consistent with that of previously reported cases, the pathogenic variant carried by our patient differed from those in previous reports.4, 5, 12, 13 This finding reinforces that PHF21A haploinsufficiency could contribute to intellectual developmental disorders and facial dysmorphism. Compared with previous cases, our patient showed no obvious cranial anomalies, finger anomalies, epilepsy, hypotonia, or diagnosis of ASD or attention-deficit hyperactivity disorder. Different nucleotide changes between previous cases and our case may account for the discrepancy mentioned above, with mutations possibly located in different exons. Satterstrom et al.10 identified a female patient who carried the same frameshift mutation in exon 9 as that in our patient. However, the clinical features in the report were not provided except for the presence of ASD. Thus, there was insufficient evidence to confirm a clear relationship between the phenotypic spectrum and specific nucleotide changes. Several possible reasons may explain the limited response to nonsteroidal anti-inflammatory drugs and biological agents in our patient. One is that the low back pain had mechanical features that resulted from spinal overload caused by obesity and/or an excessive vertebral growth rate. Another was that the drug dosages were insufficient owing to the patient's overweight. It is also possible that IDDBCS itself could have resulted in poor therapeutic effects; however, the underlying mechanism is unclear. We report the coexistence of AS and IDDBCS in a patient with a genetic familial history, and the paternally-inherited frameshift variant c.840del (p.S280Sfs*14) was detected in the PHF21A gene. PHF21A gene haploinsufficiency has been reconfirmed as a cause of neurobehavioral disorders and craniofacial dysmorphism. Our findings provide additional insight into phenotypes and genotypes of PHF21A-related disorders. However, an association between PHF21A gene disruption and the pathogenesis of AS was not confirmed and requires further research. Weizhen Xiang and Min Fu collected data and wrote the manuscript. Zhenzhen Ma and Qingrui Yang designed, supervised, and edited the manuscript. We are grateful for the constructive comments provided by anonymous reviewers. No funding was received to carry out the work described in this article. The authors declare no conflict of interest. Informed consent was obtained from the subjects included. The data used in this article shall be available with the corresponding author upon reasonable request.