Jordan syndrome due to PPP2R5D gene mutation: a report of two pediatric cases and literature review

Introduction

Jordan syndrome [also known as Houge-Janssens Syndrome 1 (HJS-1), OMIM #601646] is a rare autosomal dominant neurodevelopmental disorder caused by mutations in the PPP2R5D gene. Its clinical characteristics primarily include varying degrees of speech or motor developmental delay, intellectual disability, macrocephaly, hypotonia, seizures, autism spectrum disorder, and other dysmorphic features (1). The syndrome was named after the first identified patient, Jordan (2), and is also referred to as PPP2R5D-related neurodevelopmental disorder or autosomal dominant mental retardation type 35 (MRD35). Since its initial description in 2015 through the Deciphering Developmental Disorders (DDD) study (3), an increasing number of cases have been identified, yet the full phenotypic and genotypic spectrum remains to be elucidated.

To date, approximately 211 cases of Jordan syndrome have been reported worldwide, with 172 having confirmed pathogenic variants and 165 featuring detailed clinical phenotype descriptions (1,3-24). Nearly all pathogenic variants are de novo missense mutations (1,3-24). The PPP2R5D gene (NM_006245.4) is located on chromosome 6p21.1, comprises sixteen exons, and encodes a protein of 602 amino acids with a relative molecular weight of 69,992 (2). It is a member of the B56δ subunit family of protein phosphatase 2A (PP2A) and plays a critical role in regulating PI3K/AKT and GSK3β-mediated growth control and tau phosphorylation, as well as in chromatin remodeling and transcriptional regulation (1). PPP2R5D is highly expressed in the human and murine brain but shows low expression in the heart and skeletal muscle. Mutations in this gene are associated with delayed speech or motor development, intellectual disability, autism, overgrowth, and early-onset Parkinson’s syndrome (1,3,7,11).

This study reports two pediatric patients carrying the same de novo pathogenic variant in exon 5 of PPP2R5D (c.598G>A, p.Glu200Lys). Both cases exhibited classic features of Jordan syndrome, with one patient demonstrating a prolonged febrile episode in infancy—an atypical manifestation not previously reported. This study also presents an updated literature review to expand the known genotype-phenotype correlations and raise clinical awareness for early recognition and diagnosis of this rare disorder. We present this article in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-483/rc).

Case presentation

Case 1

The first patient was a male child born at 38 weeks of gestation via breech cesarean delivery, with a birth weight of 3,200 g. His parents were non-consanguineous (Figure 1). On the day of birth, he presented with seizures, vomiting, and feeding refusal, requiring nasogastric tube feeding. Cranial computed tomography (CT) revealed intracranial hemorrhage, and cranial ultrasound indicated bilateral ventricular enlargement with subependymal and intraventricular hemorrhage. Electroencephalogram (EEG) demonstrated significant epileptiform discharges, and antiepileptic treatment was initiated.

Figure 1 Pedigree and genetic sequencing results of the two families. (A) Family tree of patient 1; (B) family tree of patient 2; (C) Sanger sequencing results of the PPP2R5D gene for both patients (patient 1 on the left) and their parents. Circles represent females, squares represent males, and triangles represent miscarriages.

At 8 months of age, macrocephaly and frontal bossing became apparent, evolving into a dolichocephalic head shape (Figure 2A-2D). At 13 months, he developed persistent, unexplained intermittent fever (peak temperature 38.8 ℃), lasting for 8 months. Comprehensive investigations—including cultures, autoimmune panels, cerebrospinal fluid analysis, and brain imaging—were unremarkable except for a pituitary magnetic resonance imaging (MRI) showing a small Rathke’s cleft cyst and slightly enlarged suprasellar ventricles. Cranial MRI demonstrated subtle lacunar-like changes in the bilateral subcortical regions and mildly enlarged lateral ventricles. Symptoms resolved spontaneously without a clear etiology.

Figure 2 Facial features of the two patients and EEG of patient 1. (A) Patient 1 at 8 months, presenting with frontal prominence and macrocephaly. (B) Patient 1 at 5 years, showing frontal prominence and macrocephaly. (C) Patient 1 at 7 years, demonstrating a long head shape and wide interpupillary distance. (D) Patient 1 at 12 years, showing a long head shape and wide interpupillary distance. (E,F) Abnormal EEG of patient 1 at 7 years: abundant 200–300 µV sharp waves, spikes, and 1.5–3 Hz spike-slow wave complexes intermittently superimposed on background activity during both awake and sleep states. The discharges were generalized, with prominent activity in the occipital region, and asymmetric with greater prominence on the right side, particularly during sleep. The abnormal discharge index during NREM was approximately 60–70%, indicating the presence of ESES. (G) Patient 2 at 1 year, presenting with macrocephaly, wide interpupillary distance, broad nasal bridge, and short neck. (H) Patient 2 at 4 years, showing frontal prominence, wide interpupillary distance, and broad nasal bridge. These images are published with the legal guardians of patients’ consent. EEG, electroencephalogram; ESES, electrical status epilepticus in sleep; NREM, non-rapid eye movement.

The child exhibited global developmental delay. He achieved unsupported walking at approximately 5–6 years of age and could only speak simple words by age 7 years. At that age, physical examination revealed a long head shape, macrocephaly (head circumference: 52 cm), and short stature [height: 113.6 cm, <−2 standard deviation (SD)]. He was unable to communicate effectively, had an unsteady gait with frequent falls, and showed hypotonia and poor motor coordination. He could not climb stairs or perform basic self-care.

Serial EEG recordings showed persistent high-amplitude generalized sharp and spike-wave discharges, most prominent during sleep (Figure 2E,2F). Although no clinical seizures recurred after infancy, EEG abnormalities remained despite long-term antiepileptic treatment. The latest EEG continued to show frequent paroxysmal activity, with increased amplitude over the left frontal and temporal regions. Rehabilitation therapy yielded limited developmental gains.

Case 2

The second patient was a male infant (G3P2) born at term (40 weeks) by spontaneous vaginal delivery, with a birth weight of 3,490 g, length of 50 cm, and head circumference of 36.5 cm. The pregnancy was complicated by gestational diabetes managed with insulin. The parents were non-consanguineous and had one healthy daughter. After birth, the child developed jaundice and feeding difficulties, and cranial MRI revealed small punctate lesions in the periventricular white matter near the posterior horns of the lateral ventricles. Echocardiography showed a small atrial septal defect (0.28 cm), and gastrointestinal imaging suggested mild esophageal reflux. Supportive treatments—including phototherapy, feeding therapy, and neurotrophic agents—resulted in partial clinical improvement.

At 7 months, due to persistent developmental delay, repeat cranial MRI showed an open cavum septum pellucidum. At 1 year, follow-up imaging revealed possible gliosis in the left frontal and temporal lobes and widened perivascular spaces in the frontal and parietal lobes. At 4 years and 11 months, cranial MRI confirmed multiple rounded cystic lesions near the posterior horns of the lateral ventricles and an enlarged cavum septum pellucidum.

Dysmorphic facial features included macrocephaly, frontal bossing, wide-set eyes, and a broad nasal bridge (Figure 2G,2H). Gross motor and language development were significantly delayed: the child could walk independently by age 2 years and spoke his first word (“mama”) at 4 years. Language assessments indicated expressive language at approximately 12 months and receptive language at 16 months. Griffiths neurodevelopmental evaluation at 3 years and 7 months showed global delays in gross motor skills, language, and hand-eye coordination.

Molecular genetic findings

Whole exome sequencing (WES) was performed for both patients and their parents using the Exome V6 capture kit (Agilent Technologies, Santa Clara, CA, USA) followed by sequencing on the Illumina platform (Illumina, San Diego, CA, USA). Bioinformatic analysis and variant annotation were conducted using NextGENe^® and Ingenuity variant interpretation tools. Sanger sequencing validated the findings.

Both patients harbored a heterozygous de novo missense variant in PPP2R5D (c.598G>A, p.Glu200Lys) (Table 1), which was not found in either parent, confirming a de novo origin (Figure 1). This variant is absent from the gnomAD (https://gnomad.broadinstitute.org/) population database and has been previously reported in association with Jordan syndrome (25). Bioinformatic analyses using PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) and AlphaFold (https://alphafold.ebi.ac.uk/) predicted the mutation to be deleterious (Figure 3). According to the American College of Medical Genetics and Genomics (ACMG) variant classification guidelines, this mutation can be classified as “pathogenic”.

Figure 3 Predictions from PolyPhen-2 and AlphaFold software. (A) PolyPhen-2 software predicted the pathogenicity of the PPP2R5D E200K mutation as “probably damaging”, with a score of 0.984 (sensitivity: 0.74; specificity: 0.96). (B) AlphaFold software predicted the PPP2R5D E200K mutation to be “pathogenic”, with a score of 0.998. (C) AlphaFold software prediction of the PPP2R5D protein structure.

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the ethics committee of the Shanghai Children’s Medical Center (No. SCMCIRB-TKJB2023002). Written informed consent was obtained from the legal guardians of both patients for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

This study describes two unrelated pediatric patients harboring the same heterozygous de novo missense mutation in the PPP2R5D gene (c.598G>A, p.Glu200Lys), expanding the clinical and neuroimaging spectrum of Jordan syndrome. Both children exhibited global developmental delays, macrocephaly, and characteristic dysmorphic features, with additional findings including persistent EEG abnormalities, nonspecific brain MRI changes, and, notably, unexplained fever in one case—an atypical feature not previously reported in the literature.

In case 1, the patient presented with neonatal seizures, persistent epileptiform EEG activity, and developmental stagnation despite long-term antiepileptic treatment. Although overt seizures were not observed after infancy, repeated EEGs demonstrated persistent spike-and-wave discharges, particularly during sleep. The patient also experienced recurrent, unexplained fever for over 8 months during early infancy. No infectious, autoimmune, or metabolic etiology was identified, raising the possibility of a novel systemic or neuroimmune manifestation related to PPP2R5D dysfunction.

Case 2 exhibited a milder phenotype without epilepsy but had multiple abnormal findings on brain MRI, including open cavum septum pellucidum, widened perivascular spaces, and gliotic changes. Despite intensive rehabilitation, both children showed limited improvement over 5 years of follow-up, underscoring the persistent and refractory nature of the disorder.

The PPP2R5D gene encodes the regulatory B56δ subunit of the PP2A holoenzyme, which is a serine/threonine phosphatase involved in regulating numerous intracellular pathways, including PI3K/AKT and GSK3β signaling, tau phosphorylation, and chromatin remodeling (26,27). The PP2A holoenzyme comprises A (scaffold), B (regulatory), and C (catalytic) subunits. The B56δ isoform, encoded by PPP2R5D, is highly expressed in the developing brain and contributes to substrate specificity and neuronal signaling fidelity (1,28).

De novo missense mutations in PPP2R5D are associated with neurodevelopmental disorders and macrocephaly. Clinical features primarily include varying degrees of speech or motor developmental delay, intellectual disability, macrocephaly, hypotonia, autism spectrum disorder, and epilepsy. Brain MRI findings may include megacephaly and other nonspecific abnormalities such as mild to moderate ventriculomegaly, cavum septum pellucidum, white matter abnormalities, and hydrocephalus (2,3,25). Individuals with these clinical and MRI features should be considered for neurodevelopmental abnormalities associated with PPP2R5D (2). Among affected individuals, the severity of clinical manifestations varies, partly due to differences in PPP2R5D genotypes.

Literature review

We conducted a search in the PubMed, Web of Science, and SinoMed databases for articles published prior to July 2025. The inclusion criteria were as follows: (I) case reports or cohort studies of Jordan’s syndrome caused by PPP2R5D variants; (II) individuals with confirmed genetic variants; and (III) articles published in English or Chinese. The search strategy for PubMed was: (PPP2R5D protein, human[Supplementary Concept]) OR ((PPP2R5D[Title]) OR ((Jordan’s syndrome[Title]) AND (PP2A))); for Web of Science, the search strategy was: PPP2R5D (Title) OR Jordan’s syndrome (Abstract); and for SinoMed, the search strategy was: “PPP2R5D”[Common Field: intelligent] OR “Jordan’s syndrome”[Abstract: intelligent] OR “Autosomal dominant intellectual disability”[Abstract: intelligent] AND “35”[Abstract: intelligent] AND “Type (MRD35)”[Abstract: intelligent].

A total of 23 studies have reported 211 cases of Jordan’s syndrome globally (1,3-24), and with the inclusion of the 2 cases presented in this study, the total reaches 213 cases. Among these, 167 patients are summarized according to their primary clinical features in Table 2. Based on the patients’ medical histories, hypotonia (74.3%) and speech delay (71.9%) were the most common characteristics. A significant number of individuals also presented with macrocephaly (65.3%), intellectual disability/developmental delay (53.9%), epilepsy (40.7%), and ocular abnormalities (36.5%) (Table 2). Due to the lack of brain MRI data in many patients and the exclusion of megacephaly anomalies, only 35 cases (21.0%) showed abnormal brain MRI findings. For example, in Oyama et al.’s (24) study, 15 out of 72 patients underwent brain MRI, and apart from the most common megacephaly, nine cases exhibited nonspecific findings, including focal cortical abnormalities, cavum septum pellucidum and its eversion, temporal lobe sclerosis, plagiocephaly, white matter abnormalities, and mild ventriculomegaly.

Among the 68 patients with epilepsy, excluding the study by Sudnawa et al. (9) that did not report the correlation between epilepsy and genotype, the most common mutation site was p.Glu198Lys (27/48, 56.3%) (1,4,7,10,14,19,21,24). The most common types of seizures were tonic-clonic and myoclonic seizures, with some patients presenting with simple partial, complex partial, or status epilepticus seizures (9,21). There was significant variability in the frequency of seizures between patients, ranging from one seizure per year to more than 100 seizures per day in severe cases (24). Walking abnormalities mainly included delays in independent walking, ataxia, or unsteady gait, with considerable individual variation in the age of independent walking. For instance, in Houge et al.’s (7) study, the age range for independent walking was 1.5 to 9 years. Language delay primarily manifested as nonverbal communication (completely relying on gestures, facial expressions, or other non-verbal methods for communication) or the ability to say only single words. The Vineland assessment conducted by Oyama et al. (24) on 48 patients indicated that the average score for expressive communication was the lowest, while the average score for receptive communication was the highest. Ocular abnormalities included downward slanting palpebral fissures, wide-set eyes, nystagmus, strabismus, and astigmatism (1,7). Dysmorphic facial features were nonspecific and varied among individuals, including deformities, prominent forehead, triangular face, low-set ears, facial asymmetry, torticollis, scoliosis, and pectus carinatum. Furthermore, research by Shang et al. (1) indicated that some patients exhibited abnormal habits or behavioral problems, such as stereotyped behaviors, aggression, and impulse control issues. Further studies by Oyama et al. (24) demonstrated that individuals with the p.Glu200Lys mutation showed an increase in oppositional behaviors with age.

Jordan syndrome is extremely rare in the general population, with an estimated incidence of 2.32 to 2.87 per 100,000 (29). To date, 172 reported cases of Jordan syndrome with described genotypes have identified 25 distinct mutations, including 17 different pathogenic/likely pathogenic variants, the majority of which are missense mutations that result in a single amino acid substitution. The frequencies of these mutations are shown in Figure 4 (1,3-7,9-22,24). Additionally, two deletion-insertion mutations have been identified: p.Glu200_Pro201delinsArgHis (24) and a novel deletion mutation in the PPP2R5D gene involving 21 nucleotides (NM_006245.4; c.581_601del, p.Phe194_Pro201delinsSer) (30). Most cases are due to missense mutations that replace a single amino acid, affecting three distinct regions within the B56δ protein: (I) a conserved acidic loop facing the C subunit (193-EFPEEDEPTLEAAWPHLQ-211); (II) a conserved region facing the C subunit (246-LFDSEDPRERD-256); and (III) a conserved helix downstream of the protein (415-HFQVAERALYYWN-427) (24). The PP2A B56δ regulatory subunit has a long disordered arm with a short linear motif (SLiM) resembling that of its substrates, which is involved in the regulation of complex cellular processes and signaling pathways (31). Most pathogenic variants described in the literature occur within the conserved acidic loop, where one of six amino acids (Glu197, Glu198, Glu200, Pro201, Trp207, and Gln211) is replaced by a positively charged lysine or arginine residue (1,7,17,24). The p.Glu198Lys variant has a similar allosteric pathway as the fully phosphorylated enzyme, with a higher baseline level of substrate SLiM binding (31), which may correlate with a more severe clinical phenotype (1,7,24,31). The two cases reported herein both carry the relatively common p.Glu200Lys pathogenic variant (32), which disrupts the interaction between the A and C subunits of PP2A or impairs substrate binding, thus compromising its dephosphorylation activity (7,30,33). Previous reports suggest a milder degree of impairment associated with this mutation (7,24).

Figure 4 Frequency of PPP2R5D variants among 174 individuals with PPP2R5D mutations.

Currently, prenatal diagnosis of Jordan syndrome is not feasible, and diagnosis is mainly made through molecular genetic testing. WES of patients exhibiting the main clinical features and brain MRI abnormalities can improve diagnostic rates. Jordan syndrome does not have a specific treatment, and management is symptomatic based on the presenting symptoms. Levine et al. (32) recommend age-appropriate and clinically driven care to improve the quality of life, such as speech therapy (including sign language and alternative communication devices), social interaction to address speech delays in infancy, and attention-deficit hyperactivity disorder (ADHD) medications to manage attention-deficit disorders in preschool children. Recent cellular-level research has shown that rapamycin and RPS6 kinase inhibitors can suppress the abnormal RPS6 hyperphosphorylation caused by PPP2R5D mutations (E198K and E420K) (34,35), suggesting potential therapeutic strategies for patients.

In summary, Jordan syndrome caused by novel missense mutations in the PPP2R5D gene is associated with a range of neurodevelopmental disorders, including macrocephaly, language and motor delays, and other neurological features such as feeding difficulties, epilepsy, and pervasive neurobehavioral issues. The phenotype of Jordan syndrome exhibits heterogeneity depending on the mutation site. The two cases reported in this study present with typical motor and language developmental delays, and clinical features such as epilepsy, macrocephaly, wide-set eyes, and prominent forehead, which have been previously described in the literature (1,24). One child also experienced an 8-month episode of unexplained fever in infancy, which has not been reported in the literature, and its causal relationship with the PPP2R5D gene mutation remains unclear. For families with a history of Jordan syndrome, genetic counseling and prenatal testing are recommended for those planning subsequent pregnancies.

Conclusions

This study presents two pediatric patients with Jordan syndrome caused by the recurrent PPP2R5D c.598G>A (p.Glu200Lys) mutation, both exhibiting hallmark features including macrocephaly, developmental delay, and dysmorphic facial characteristics. One patient also presented with persistent EEG abnormalities and an unusual phenotype of prolonged unexplained fever in infancy, a finding not previously described in the literature. These cases expand the known clinical spectrum of the p.Glu200Lys variant and reinforce the heterogeneity of PPP2R5D-related neurodevelopmental disorders.

Given the lack of curative treatments, early diagnosis through genetic testing and multidisciplinary intervention remains essential. Future research should focus on elucidating the underlying molecular mechanisms of phenotypic variation among different PPP2R5D mutations and exploring targeted therapeutic strategies.

Acknowledgments

We thank the patients and their parents for their participation in the study.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-483/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-483/prf

Funding: This study was supported by the 2024 National Key Clinical Specialty Construction Project for the Improvement of Medical Services and Security Capabilities (No. 10000015Z155080000004) and the Fundamental Research Funds for the Central Universities (No. YG2023QNA35).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-483/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the ethics committee of the Shanghai Children’s Medical Center (No. SCMCIRB-TKJB2023002). Written informed consent was obtained from the legal guardians of both patients for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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