Explore the vast range of titles available.

Background: Monoallelic damaging variants in PHIP (MIM*612870), encoding the Pleckstrin Homology Domain Interacting Protein, have been associated with a novel neurodevelopmental disorder, also termed Chung–Jansen syndrome (CHUJANS, MIM#617991). Most of the described individuals show developmental delay (DD)/intellectual disability (ID), obesity/overweight, and variable congenital anomalies, so the condition can be considered as an ID–overweight syndrome. Case Description: We evaluated a child presenting with DD/ID and a craniofacial phenotype reminiscent of a Pitt–Hopkins syndrome (PTHS)-like condition. We performed a clinical exome analysis on his biological sample, as well as an in silico prediction of the obtained data. At the same time, we interrogated the DeepGestalt technology powered by Face2Gene (F2G), using a frontal image of the proband, and clinically reviewed the earlier CHUJANS patients. In this child, we found a novel PHIP pathogenetic variant, which we corroborated through a protein modeling approach. The F2G platform supported the initial clinical hypothesis of a PTHS-like condition, while the clinical review highlighted the lack of the main frequent CHUJANS clinical features in this child. Conclusions: The unusual clinical presentation of this novel patient resembles a PTHS-like condition. However, a novel variant in PHIP has been unexpectedly detected, expanding the phenotypic spectrum of CHUJANS. Notably, PTHS (MIM#610954), which is a different ID syndrome caused by heterozygous variants in TCF4 (MIM*610954), is not classically considered in the differential diagnosis of CHUJANS nor has been cited in the previous studies. This could support other complex diagnoses and invite further patients’ descriptions.

In 2016 and 2018, Chung, Jansen and others described a new syndrome caused by haploinsufficiency of PHIP (pleckstrin homology domain interacting protein, OMIM *612,870) and mainly characterized by developmental delay (DD), learning difficulties/intellectual disability (ID), behavioral abnormalities, facial dysmorphism and obesity (CHUJANS, OMIM #617991). So far, PHIP alterations appear to be a rare cause of DD/ID. “Omics” technologies such as exome sequencing or array analyses have led to the identification of distinct types of alterations of PHIP , including, truncating variants, missense substitutions, splice variants and large deletions encompassing portions of the gene or the entire gene as well as adjacent genomic regions. We collected clinical and genetic data of 23 individuals with PHIP -associated Chung-Jansen syndrome (CHUJANS) from all over Europe. Follow-up investigations (e.g. Sanger sequencing, qPCR or Fluorescence-in-situ-Hybridization) and segregation analysis showed either de novo occurrence or inheritance from an also (mildly) affected parent. In accordance with previously described patients, almost all individuals reported here show developmental delay (22/23), learning disability or ID (22/23), behavioral abnormalities (20/23), weight problems (13/23) and characteristic craniofacial features (i.e. large ears/earlobes, prominent eyebrows, anteverted nares and long philtrum (23/23)). To further investigate the facial gestalt of individuals with CHUJANS, we performed facial analysis using the GestaltMatcher approach. By this, we could establish that PHIP patients are indistinguishable based on the type of PHIP alteration (e.g. missense, loss-of-function, splice site) but show a significant difference to the average face of healthy individuals as well as to individuals with Prader-Willi syndrome (PWS, OMIM #176270) or with a CUL4B -alteration (Intellectual developmental disorder, X-linked, syndromic, Cabezas type, OMIM #300354). Our findings expand the mutational and clinical spectrum of CHUJANS. We discuss the molecular and clinical features in comparison to the published individuals. The fact that some variants were inherited from a mildly affected parent further illustrates the variability of the associated phenotype and outlines the importance of a thorough clinical evaluation combined with genetic analyses for accurate diagnosis and counselling.

Chung‐Jansen Syndrome (CJS) is a rare autosomal dominant neurodevelopmental disorder caused by heterozygous mutations in the PHIP gene (6q14.1). It is characterized by developmental delay, intellectual disability, behavioral disturbances including autism spectrum disorder and attention deficit hyperactivity disorder, obesity, and distinct facial dysmorphism such as synophrys and an upturned nose. Although clinical presentations vary, behavioral problems and delayed motor and speech milestones are common. We report a 7‐year‐old male with delayed motor and speech development, synophrys, and an upturned nose—features that are rarely documented in CJS. The patient exhibited significant resistance to multiple psychotropic treatments and presented with severe psychological and neurological symptoms. Whole Exome Sequencing revealed pathogenic mutations in both the PHIP and CLCN4 genes. The PHIP mutation was associated with core neuropsychiatric symptoms, including anxiety and depression, whereas the CLCN4 mutation contributed to severe brain atrophy observed in neuroimaging, further exacerbating cognitive and behavioral deficits. Additional copy number variations (CNVs) were detected, indicating a complex genetic background. The interplay between PHIP and CLCN4 mutations appeared to disrupt neuronal growth and synaptic function, thereby intensifying the clinical phenotype. The constellation of symptoms, including resistance to standard therapies, highlights how genetic overlap can aggravate neurodevelopmental and psychiatric manifestations in CJS. This case underscores the necessity of comprehensive genetic testing, including whole exome sequencing and CNV analysis, in patients with atypical or severe presentations of CJS. The findings emphasize that genetic interactions can amplify clinical severity and advocate for further research into the molecular mechanisms underlying such complex syndromes to improve diagnostic precision and inform targeted therapeutic strategies. Key Clinical Message Clinicians should consider dual genetic diagnoses in rare syndromes presenting with complex psychiatric features such as ADHD, as overlapping mutations can intensify neurodevelopmental symptoms and necessitate early, multidisciplinary evaluation and management.