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Case Reports
. 2024 Nov 17;11(11):1395.
doi: 10.3390/children11111395.

Broadening the PHIP-Associated Neurodevelopmental Phenotype

Giulia Pascolini  1 , Giovanni Luca Scaglione  2 , Balasubramanian Chandramouli  3 , Daniele Castiglia  4 , Giovanni Di Zenzo  4 , Biagio Didona  5
Affiliations
Case Reports

Broadening the PHIP-Associated Neurodevelopmental Phenotype

Giulia Pascolini et al. Children (Basel). .

Abstract

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.

Keywords: Chung–Jansen syndrome (CHUJANS); PHIP; Pitt–Hopkins syndrome (PTHS)-like phenotype; abnormal skin appendages; neurodevelopment; teeth anomalies.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Face masks of PTHS and CHUJANS (acquired from F2G) and respective causative genes. In this patient, a connection (indicated by the arrow) between the PTHS clinical spectrum, mainly caused by TCF4 perturbations, and PHIP, associated with CHUJANS, is recognizable.
Figure 2
Figure 2
(A,B) Frontal and lateral views of the craniofacial phenotype of this patient at the ages of 4 years and 5 months and 9 years and 9 months, respectively. Note: wide mouth with full lips, wide nasal tip with flared alae nasi, and full and prominent cheeks. (C) Widely spaced teeth. (D,E) Extremities phenotype, consisting of clinodactyly of 5th finger and hands brachydactyly (D), broad halluces with camptodactyly, partial 2nd–3rd toe overriding, bilateral 4th–5th clinodactyly in his feet, and small nails on the 5th toes (E).
Figure 3
Figure 3
Structural model of WD40. The protein is depicted as a ribbon along the vdW surface (in gray).
Figure 4
Figure 4
Overlapping facial regions with PTHS elaborated by F2G for the patient. The D-score for evaluating the degree of craniofacial dysmorphisms in this child is shown.
See this image and copyright information in PMC

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