Major clinical improvement in a boy with developmental disabilities and a PTPN4 mutation with intensive re-education and an enriched environment in a day care hospital: a case report

Abstract

Background

Protein tyrosine phosphatase, non-receptor type 4 (PTPN4) is a gene involved in glutamate downstream signaling contributing to cerebral maturation. Loss-of-function of this gene has been reported in patients showing various neurodevelopmental disorders, although the PTPN4 gene is not clearly considered a disease-causing gene in the Online Mendelian Inheritance in Man catalogue.

Case presentation

Here, we report the case of a 7-year-old white boy with a homogeneous, heterozygous, 170 kb chromosomal deletion encompassing several exons of the PTPN4 gene. The mutation was transmitted by his father, who had an undiagnosed communication disorder. The patient was referred to a day care unit for complex neurodevelopmental disorders and a suspicion of autism spectrum disorder. He had a severe communication disorder associated with sensory integration issues, anxiety, and elimination disorder. During his 4 years in the day care hospital, he received educational, creative, and academic group activities and specific re-education. Group activities help generalize the newly acquired developmental skills by providing social reinforcers and opportunities for positive peer interactions. In turn, achieving social activities positively influences the patient’s self-esteem, emotional insight, and motivation to make new progress.

Conclusion

Despite a severe communication disorder associated with sensory integration issues, anxiety, and elimination disorder, a diagnosis of autism spectrum disorder was ruled out, and remarkable progress was observed, which allowed our patient to attend same-age mainstream schools with personalized support at discharge. This case illustrates the effect of dimensional interventions to limit developmental impairments in a context of PTPN4 mutation and the benefit of providing an enriched environment in combination with individual re-education to improve developmental outcomes.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13256-026-05892-5.

Background

This case report details the clinical outcome of a 7-year-old white boy, who was followed for 4 years, with complex neurodevelopmental disorders (NDDs), carrying a homogeneous, heterozygous deletion encompassing exons 2–15 (out of a total of 27 exons) of the protein tyrosine phosphatase, non-receptor type 4 (PTPN4) gene, encoding for PTPMEG/PTPN4 [1]. PTPN4 has a very high probability of loss-of-function intolerance in case of genomic sequence variation (pLi = 0.95 in gnomAD version 4.1.0) [2, 3]. It has been identified as 1 of 261 genes likely responsible for human-specific cortical development [4]. PTPN4 interacts with glutamate receptor delta 2 (N-methyl-d-aspartate [NMDA]) and its epsilon subunits during glutamate downstream signaling.

Glutamate transmission, specifically NMDA receptors, plays a key role in memory formation and learning processes [5]. Monoallelic loss-of-function variants of PTPN4 have been implicated in various psychiatric and neurodevelopmental disabilities, including severe-to-moderate intellectual disability, speech and motor developmental delays, attention deficit disorder, motor tics, autism spectrum disorder (ASD), astigmatism, growth abnormalities, seizures, and mildly diminished cerebral white matter volume [6, 7]. In addition, two monozygotic twins with de novo PTPN4 deletion were reported and showed a Rett syndrome-like phenotype with motor and cognitive development, limited speech, seizure, and important growth delay [8].

So far, no report has been published to determine to what extent environmental interventions could moderate the impairments associated with variants of the PTPN4 gene. Here, we report the case of a white boy followed from ages 7 to 11 years with a PTPN4 deletion with a remarkably positive evolution thought to be attributable to intensive and individualized treatment in a day care hospital using an integrative approach.

Case presentation

A 7-year-old white boy was referred to the day care hospital for a severe language disorder, food selectivity, school refusal, intolerance to change, sleep impairments, and suspected ASD. He attended 2nd grade with a dedicated specialized assistant. He failed to learn to read (even to recognize and pronounce letters) and could not perform simple algebraic equations. He had no friends and presented great difficulty participating in group activities.

History

The patient was born full-term via emergency cesarean owing to risk of fetal distress. The pregnancy was marked by tobacco exposure during the first month and intrauterine growth restriction. No neonatal hypotonia was observed. The patient grew up with both parents in the family home in a suburban area. His father works in the construction industry, specializing in interior renovation, and his mother is a spa manager, often working from home. He has a half-brother from his mother’s first marriage who lives with them 1 week out of every 2 and has no medical history. He grew up seeing his maternal grandparents regularly, who reported having no personal psychiatric history. He moved to a house built by his father at the age of 6 years. Food diversification after 4 months of breastfeeding was initially simple. Severe food selectivity suddenly appeared at 18 months, mainly based on sensory characteristics such as texture, color, or smell. The first words appeared around 1.5 years of age, but the first sentences only occurred at 5 years. Daytime and nighttime cleanliness was acquired at 3 years, with secondary encopresis at 5 years in the context of house moving. The patient was described as clumsy, with a walking age of 13 months. Sleep difficulties were always noted. A language examination at age 4 years confirmed a language disorder with severe impairments in phonology and syntax. First-degree relatives had no known history of psychiatric disorders or NDDs.

Clinical and paramedical assessments found mild dysmorphic features, such as hypertelorism, low-lying hair, broad neck, slightly thick ears (not low-lying), non-sparse eyebrows, and bilateral clinodactyly. Weight and size growth were regular at −1 standard deviation (SD), with a sharp decline to −2 SD at 6 years. He had recurrent ear infections. Paramedical assessments showed: growth hormone (GH) peak (27.67 mUI/L) despite low IgF-1 (56 ng/mL, −2.5 SD); negative IgA and IgG anti-transglutaminase and anti-gliadin; normal cerebral magnetic resonance imaging (MRI) centered on the pituitary; normal karyotype (46 XY); and a negative result for the SHOX variant or variants in genes responsible for Noonan syndrome. Chromosomal microarray analysis identified a homogeneous, heterozygous, 170 kb deletion encompassing exons 2–15 of the PTPN4 gene. This copy number variation (CNV) was confirmed by whole-genome sequencing (genomic coordinates chr2(GRCh38):g.(119772338_119942031)del), which did not show any other candidate variant. This deletion was inherited from the father, who presented a very likely oral language disorder (considering a delay in speech acquisition with the first sentences only at 5 years, through no formal assessments were available). Sampling of paternal grandparents is ongoing. This deletion is known to affect several functional domains of the PTPN4 protein: FERM domain C-lobe (found in proteins providing a link between the membrane and cytoskeleton or involved in signal transduction pathways) [9], structural domains (such as band 4.1 and FERM-adjacent domains), which play a regulatory role in assembly and stabilization of plasma-membrane domains [10], as well as other putative phosphoinositide and peptide binding sites (for chemical and polypeptide binding, respectively).

Neurodevelopmental and psychiatric assessment

Psychiatric assessment on admission revealed emotional dysregulation, mental rigidity, inflexible adherence to routines, ritualized patterns, difficulties in maintaining relationships, and persistent negative emotionality (anxiety, depression) frequently related to academic-related stress. Persistent irritability and difficulty tolerating frustration were observed since early childhood and progressively increased with age. Retention encopresis was associated with multiple somatizations. He only ate chicken nuggets and mayonnaise. The diagnosis of ASD was ruled out because the deficits in social interaction and restricted behaviors appeared related to contextual psychopathology. In fact, they disappeared when anxiety was monitored and communication improved. The retained Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnoses were communication disorder (oral language), specific learning disorder (written language acquisition of reading and writing), avoidant/restrictive food intake disorder (ARFID), elimination disorder, and anxiety disorder. Table 1 summarizes multidimensional assessments at ages 7 and 11 years.

Table 1.

Summary of test results

	7 years	11 years	Comments
General intelligence
	WISC-V	WISC-V
Verbal comprehension	NC	81	An assessment of verbal comprehension abilities could not be performed on admission. However, with improvement, they reached a normal range by 11 years, despite a below-average vocabulary
Similarities	Impossible	8
Vocabulary	Impossible	5
Visual-spatial	NC	114	Similarly, improvement in behavior allowed for proper assessment of visual-spatial abilities, which were in the normal range at the age of 11 years
Block design	11	13
Visual puzzles	Impossible	12
Fluid reasoning	103	not assessed	Fluid reasoning was around the average level, with heterogeneity of indices at age 11 years
Matrix reasoning	11	9
Figure weights	10	13
Working memory	NC	79	Working memory performance was not calculated owing to difficulties in understanding the instructions during the initial test. At 11 years, performance was at the limit for his age group
Digit span	3	7
Picture span	4	6
Processing speed	92	72	At 11 years, performance worsened to the level of weakness. We hypothesized a lack of ease in visual scanning and graphomotor gestures
Coding	8	5
Symbol search	9	5
Motor skills
Total coordinationM−ABC 2	37%	Not assessed as previously normal	Global coordination at age 7 years was in the normal range
Manual dexterityM−ABC 2	50%
Aiming and catchingM−ABC 2	25%
BalanceM−ABC 2	50%
Hand imitation of gestures coordinationEMG	5.5/10 (−4.23 SD)		Hand imitation and coordination showed deficits when drawing the human body at age 7 years. Human body drawing improved at age 11 years
Finger imitation of gesturesEMG	10/16 (−0.66 SD)
Human body drawingGood enough	25% (5 years 9 months)	50% (10 years 6 months)
Left/right knowledgePiaget head	Acquired	Acquired
Basic space–time conceptsPiaget head	Partially acquired	Acquired	The integration of time concepts related to social activities remained difficult at age 11 years
Reproduction of rhythmic structuresStambak	Impossible
Qualitative writing testBHK−F	Impossible	+0.5 SD	Initially, writing in cursive was impossible, spontaneously mixing script and block capitals At 10 years of age, he wrote 23 words per minute, results similar to 5th-grade level, but quality was impaired
Speed writing testBHK−F	Impossible	−2.3 SD
Food selectivity
Food selectivity score	70/156 (45%)	153/156 (98%)	A score based on textures, temperatures, flavors, and oral–lingual–facial praxis. Higher score indicates willingness to eat
Visual-spatial skills
Visual-perception total scoreFrostig, DTPV−2	102 (50%)	105 (63%)	Visual-spatial abilities seemed okay, but visual-motor precision was slow and cognitively costly. Together with processing speed scores, this suggested a sluggish cognitive tempo
Visual-motor integrationDTPV−2		93 (32%)
Cubes testNEPSY−II		11 (+0.3 SD)
Comprehension of instructionNEPSY−II		5 (−1.7 SD)
Tapping testNEPSY−II		10 (0 SD)
Visual-motor precision testNEPSY−II		std score=10 (0 SD) Errors: 26–50% Pencil lift: > 75%
Oral language1
Word repetitionELO	7/32 (−6.2 SD)	19/32 (−2.7 SD)	Severe phonological disorder: presence of interdental sigmatism; assimilations (for example, Tr → Cr, Dr → Gr); substitutions (for example, vowels: o/on/an, k/g, ch/j, p/b, s/z); and errors in syllabic structuring processes such as simplifications of consonant clusters, omission of letters in cases of double consonants, omission of final consonants (for example, car → ca), regular omission of /r/
Repetition of monosyllabic words AN−EEL	−3.5 SD	Not performed
Repetition of monosyllabic words BN−EEL	6/28 (−8.5 SD)	22/28 (−1.3 SD)
Plurisyllabic words repetitionN−EEL	20/50 (−7.2 SD)	48/50 (+0.3 SD)
Receptive lexiconELO	11/20 (−2.0 SD)	14/20 (−0.6 SD)	The lexical stock in reception and production was deficient
Productive lexiconELO	16/30 (−4.5 SD)	30/42 (+0.2 SD)
Immediate understanding of statementsELO	4/21 (−1.0 SD)	17/21 (+1.3 SD)	Deficient syntactic comprehension and syntactic encoding. The plural forms of nouns and adjectives had not been acquired, nor had the plural forms of verbs. The gender of nouns and adjectives was also challenging as determiners were confused. Difficulties in understanding and expressing the future, past, negation, and passive voice. Understanding instructions was very challenging. Sentence structure was not yet established
General understanding of statementsELO	10/21 (−5.4 SD)	20/21 (+0.5 SD)
Statement productionELO	3/16 (−3.3 SD)	8/16 (−2 SD)
ReadingFiche de Bicêtre
Grapheme	Impossible	20/26 (−0.3 SD)	Reading remains very challenging. Given the difficulty, he was assessed at 11 years with very basic tests that we usually use for first grade
Simple syllables		22/24 (+0.9 SD)
Complex syllables		5/10 (NC)
Digraphs in isolation		9/10 (NC)

¹At the age of 11 years, speech impairment scores were assessed using the same test as during intake to ensure intra-individual comparability. Therefore, the normative age-group comparison does not correspond to the child’s current age. BHK-F Batterie d’évaluation de l’écriture chez l’enfant – version francophone, DTVP-2 Developmental Test of Visual Perception – 2nd Edition, ELO Évaluation du Langage Oral, EMG Évaluation de la Motricité Gnosopraxique distale, Frostig Test de Développement de la Perception Visuelle de Frostig, M-ABC 2 Movement Assessment Battery for Children – Second Edition, WIC-V Wechsler Intelligence Scale for Children – Fifth Edition, NC Not Calculable, N-EEL Nouvelle Épreuve pour l’Examen du Langage, SD Standard Deviation

Treatment plan

During the day care hospital, the patient received three types of intervention: (i) individualized re-education targeting several developmental domains, (ii) group creative, recreational, or academic activities, and (iii) psychotherapeutic and medical interventions.

Individual intensive speech therapy was provided during three sessions per week, focusing during the first year on phonological awareness and then written language acquisition. Individual motor therapy was provided, focusing on fine-motor competence and then participation in group motor therapy. An oral sensory-based program to address food aversion based on sensory habituation was planned every week.

During the day, educators organized several group recreational activities. These activities aim to promote the patient’s symbolic expression through age-adapted creative activities (for example, the co-writing of an illustrated story with a professional illustrator or constructing a space shuttle model). Progressively specialized teaching was provided in the hospital-related school.

The principles of dimensional interventions were explained to the parents (based on psychoeducation, parental guidance, and reward system) to target sleep and elimination difficulties. Dietary consultations were planned with a prescription of a calcium supplement (500 mg) and vitamin D (Fig. 1).

Fig. 1.

Timeline of the patient’s symptom course and care provided

Evolution

The patient’s high functional impairments in family, school, and relational domains progressively decreased. While food selectivity was initially severe, he was positively reinforced for trying new foods at home after reintroduction during the oral sensory-based program. All meals in the day care hospital were an opportunity to continue the habituation process initiated in the program. In addition, improved emotional communication was concomitant with expressing his sadness and frustrations related to his communication difficulties, especially in forming close relationships. A decline in behavioral problems was progressively observed, with improvement in self-affirmation. Relations with peers were more reciprocal, with less rigid or coercive behaviors. He developed new noninvasive age-appropriate interests (for example, Harry Potter) to share with peers. He was progressively more open to social interaction (for example, managing to make new friends at the park).

The reluctance to attend re-education or school activities progressively declined with improved oral language skills. He accepted school adaptations such as a computer with vocal dictation, which appeared key in providing him a sense of autonomy. Parental guidance and educational video games, such as Dynamilis [11], were also offered to continue the rehabilitation work at home after the day care hospital’s activities. Dynamilis provides a series of serious games designed to train different writing features: static features, kinematic features, pressure features, and tilt features. Static features include the purely geometric characteristics of a written text, kinematic features designate the dynamics of the handwriting path, pressure features designate characteristics of the pressure recorded between the pen tip and the tablet surface, and tilt features include the characteristics of the pen tilt [11, 12].

Creative artistic activities were well invested in and provided an excellent opportunity to consolidate the re-education. For example, he enjoyed pottery workshops and was congratulated for his creativity and newly acquired skills. For example, co-creating a comic with a professional artist was key to significant improvements in self-esteem and speech progress (from sentences to story construction).

The parents observed an improvement in the patient’s level of understanding and autonomy. He started to sleep in his own bed. For encopresis, guidance was provided on a behavioral routine for elimination (going to the toilet for 15 minutes several times a day, even if he does not feel the need initially). Improvement of these symptoms coincided with the child’s acceptance of orientation to a new school. Regressive and anxiety-related behaviors were sometimes reported, but remained limited in frequency, and environmental stressors were also identified by the patient and his parents. Food intake also improved at home, with increased quantities and diversity, with no need for specific meals when he left the structure. A food selectivity score was used to track the change in food competence. The score includes items from forms, textures, temperatures, oral praxis, and flavors. A score of 0 indicates refusal, 1 indicates almost acquired, and 2 indicates fully acquired. The total score changed from 70 (out of 156) at 8 years to 153 at 11 years.

As presented in Table 1, all dimensional assessments improved. Most Wechsler Intelligence Scale for Children^®, Fifth Edition (WISC-V) subscores were in the normal ranges. The patient frequently asks with curiosity what the words he does not know mean, while exhibiting a fragile capacity for verbal conceptualization, a lack of words, and imprecise language. Improvements in motor acquisitions, such as integration of body schema and writing, are shown in Fig. 2.

Fig. 2.

Body scheme (a) and cursive writing (b) at 7 and 11 years old. 1a illustrates the delayed integration of body schema at 7 years, which normalizes at 11 years. In 1b, the BHK test is impossible to complete at age 7 years. It improves dramatically at age 11 years (translation of the sentences he copied: “It is sunny”; “I am fine”; “I see water but I do not know where it goes”)

At discharge, when the patient was 11 years old, he could attend mainstream school without any age difference, with personalized support in an adapted educational facility. Although he still needs teacher guidance, speech therapy, and occupational therapy, he shows a desire to progress, follow a conventional diet, and demonstrate the ability to manage subtle social interactions. He still maintains his clinical and functional improvement 1 year after hospital discharge. The latest information provided by the family at age 12 years indicates that the patient is continuing to make progress at school, with increasing periods of inclusion in mainstream classes.

Discussion and conclusion

Comparing the current case with previous cases

PTPN4 encodes a protein tyrosine phosphatase, which interacts with glutamate receptor delta 2 and its epsilon subunits for tyrosine dephosphorylation during glutamate downstream signaling. The role of glutamate is well established in synaptic transmission, plasticity, and overall development. Furthermore, consistent data across species (such as fish, birds, monkeys, and humans) show that NMDA receptors are crucial in memory formation and the learning process [5]. PTPN4 pathogenic variants have been reported in human cases showing ADHD, autism-like features, speech and motor impairment, among other abnormalities (Table 2). This is consistent with animal studies that showed that the loss of expression of PTPN4 resulted in defective neuronal development in brain regions involved in olfactory learning, memory, sensory integration, motor coordination [13–15], and motor learning [16]. Growth anomalies were previously reported in patients with PTPN4 variants [6] and were observed in this case. It may be explained by the implication of the phosphatase activity of PTPN4 in the regulation of cytoskeletal events [17]. PTPN4 also dephosphorylates the NMDA receptor subunit GRIN2A [18], variants of which may cause epilepsy and intellectual disability [19]. Among patients with PTPN4 pathogenic variants, epilepsy and cognitive and developmental delays were common; however, one reported case of a patient, similar to ours, had borderline intelligence (with an intelligence quotient [IQ] of 71) [6]. Such variants have also been identified as possible candidates for ASD [6, 20]. Our patient was initially referred to us with a suspicion of ASD. This diagnosis was eventually ruled out, but the suspicion may be due to complex NDDs. Indeed, youths with co-occurring NDDs generally also exhibit persistent emotional dysregulation with a significant impact on social skills and sometimes pseudo-autistic presentations [21, 22].

Table 2.

Review of published cases with PTPN4 mutation (adapted and completed from [6])

Subject	1	2	3	4	5	6	7	8	9	10	CR
Age, years	11 years	23 months	20 months	19 years	15 years	17 years	Birth	5 years	17 years	17 years	11 years
Sex	M	M	M	M	F	M	F	M	F	F	M
Mutation type	Substitution								Deletion
Transmission	De novo				N/A	Maternal6H	De novo				Paternal
Height Weight OPC	> 99th > 99th > 99th	5% 2% 79%	< 1% 2% 20%	65% 71% > 99%	61% 30% 7%	> 99th 2% 98%	2% < 1% < 1%	50% 50% 25%	50% > 10% 50%	> 10% 50% > 10%	< 3% < 3% > 99%
Growth	Overgrowth		OFC > 99% at 16 months	Homogeneous				At 3 years old: height > 75%, weight 25%, OFC 50%	Delay
Development	DD Averbal	DD	DD	Moderate ID	BIF	Mild ID	N/A	ID	ID	ID	NormalLB1
Behavioral	ADHD Autism	None	None	ADHD Autism	ADHD	ADHD	N/A	Rigidity, ritualized behaviors	Stereotypic behaviors	Rett syndrome-like	ADHD Rigidity and ritualized behaviors
Speech impairment	Yes	Yes	Not reported					Yes	Yes	Yes	Yes
Neurological signs	Tight hamstrings	Hypotonia; distal extremity tremor	Congenital torticollis	Normal tone, motor delays	Tic disorder	None	Increased tone in all extremities	Sensory deficit	None		Motor delays
Musculoskeletal	None		Radial deficiency and vertebral anomalies3M	Joint laxity, pes planus	Butterfly vertebrae	None
Other	Tapering fingers, crouch gait, café-au-lait macules	Tapering fingers, café-au-lait macules, other anomalies2O	Meets criteria for VACTERL association	Tapering fingers, joint laxity, motor unsteadiness, astigmatism, hyperacusis	Visual processing deficit	None	Hypoplastic left heart syndrome	None			Hypertelorism, low-lying hair, broad neck, slightly thick ear (not low-lying), non-sparse eyebrows
Seizures and EEG	No seizures N/A	No seizures Negative	No seizures N/A	No seizures N/A	Absences seizures Abortive generalized spike wave discharges	Abnormal	No seizures Not performed	No seizures, N/A	Seizures; spike-and-wave generalized paroxysmal discharges	Generalized seizures	No seizures Negative
MRI	Normal non-contrast MRI	Large perivascular space/neuroglial cyst	Diminished white matter volume3I	Diminished white matter volume and other anomalies4I	Normal non-contrast MRI	Normal	Anatomical anomalies7I	Normal non-contrast MRI	N/A	N/A	Normal non-contrast MRI
Reference	Chmielewska et al.							Szczałuba et al.	Christodolou et al.		This study

N/A  not available, ADHD attention deficit hyperactivity disorder, DD developmental delay, ID intellectual disability, BIF borderline intellectual function, LB1 normal intelligence with discrepancy between indexes, 2O wide distal phalanges, strawberry hemangioma × 1, wide-based gait, 6H from mosaic mother, 3 M radial deficiency with oligodactyly talipes equinovarus and vertebral anomalies (thoracic region block vertebrae with rib fusions and lumbosacral hemivertebra) 3I mildly diminished cerebral white matter volume, prominence of the ventricles and supratentorial extra-axial spaces may reflect white matter loss and or impaired cerebrospinal fluid resorption, 4I large cavum septum pellucidum, slight reduction in white matter around posterior horns, thin corpus callosum, 7I semilobar holoprosencephaly and microcephaly, small 3rd ventricle, formed but thin splenium of corpus callosum, partial thalamic fusion, complete basal ganglia fusion, dorsal interhemispheric fissural cyst

However, some of the variations previously reported as likely or possibly pathogenic in Chmielewska et al. have been added to the Genome Aggregation Database (gnomAD version 4.1.0) [23] of control individuals. Therefore, the pathogenicity of the PTPN4 gene variation can be questioned and must not be taken for granted. In the current case, the CNV has not been reported yet and is also present in the father, who had oral language impairments. Therefore, the pathogenicity of the CNV reported here was categorized as of unknown significance. Taken together, these data do not provide sufficient evidence to support a clear causal link between the PTPN4 gene and the clinical phenotype observed in this family. Consequently, the association between the CNV and the symptoms reported is unclear and should not be taken for granted. While the whole-genome sequencing performed here did not find another candidate variant, further in-depth explorations would be required to provide evidence for PTPN4 pathogenicity.

Dimensionally tailored intervention and evolution

The pathophysiology of NDDs remains unclear and is probably linked to a complex interaction between genetic and environmental vulnerability factors. Environmental enrichment is the fundamental rationale of early/tailored developmental interventions, which aim to strengthen the environment to mitigate developmental deficits [24]. By fostering a more stimulating and adapted environment and offering all interventions in a single setting, the day care hospital can help to restart interaction and reinforcement loops, maximizing the chances of progress and social adaptation [25]. It also favors the interplay between acquisitions in different development areas. This interdependence explains why improvement in a specific skill can often have positive repercussions on other areas of development. For example, progress in motor skills can promote social interaction by enabling better imitation of peers [26]. Improvement in language skills can contribute to better emotional regulation, notably by supporting more adaptive regulation strategies [27].

In this case, persistent emotional dysregulation observed could have been underpinned by difficulties with mentalization and inner language. The inability to formulate accurate hypotheses about the mental states of others to adapt to their intentions and emotions can lead to conflict, oppositional behavior, or social avoidance. Mentalization relies on essential prerequisites for self-construction, such as a sense of agency and representational and symbolic skills. These skills are closely linked to motor, language, and sensory–motor skills [27]. Progress in self-regulation and mentalization could have contributed to the patient’s enhanced sense of autonomy, facilitating the expression of feelings in distressing situations.

The case for early integrated dimensional care

Here, we made the case for complex severe NDDs where integrative day care hospitals can provide dimensional comprehensive assessments of patients, tailored treatment recommendations, and school re-adaptations (Figs. 1 and 3). Multidisciplinarity helps to improve, extend, and consolidate the gains made during remediation by recruiting newly acquired abilities in a more natural and ecological setting, facilitating their transfer to everyday life. Furthermore, individual remediations are continued and optimized by participation in group sessions, reinforcing newly acquired skills and social integration. Achieving positive interaction with peers boosts the patient’s self-esteem, which in turn leads to a more positive attitude toward care and learning activities. This approach aligns with recent guidelines for intervention for children with ASD [25]. Furthermore, a recent meta-analysis showed no increased effect with increasing the amount of intervention, suggesting that quality is more important than quantity in child care [28].

Fig. 3.

Principle of integrative care provided for the patient in the day care hospital. The scheme, create by the authors, illustrates hypothetical links between neurodevelopmental impairments (“Dev impairments” in red stars) and difficulties of emerging socio-emotional domains in childhood. The yellow box on the right summarizes the main interventions provided in the day care hospital, with numbers for the priority levels. Black arrows between each “module” express the interdependences of developmental and cognitive competencies and how, during the care, we hoped to ultimately improve high-order cognitive ability (such as emotional regulation)

This is the first report of a longitudinal follow-up of a patient with PTPN4 mutation. The case reported here showed a positive evolution, with an almost normalized IQ test and improved speech impairment and significantly reduced socio-emotional difficulties. This allowed the patient to attend mainstream school with personalized support in an adapted educational facility on discharge. The fact that school-adapted and creative group activities played a crucial role in the patient’s evolution supports the importance of an integrative and multidimensional approach in the management of complex NDDs.

Abbreviations

ADHD

Attention-deficit/hyperactivity disorder

ASD

Autism spectrum disorder

CNV

Copy number variation

EEG

Electroencephalogram

MRI

Magnetic resonance imaging

NDDs

Neurodevelopmental disorders

NMDA

N-methyl-d-aspartate

PTPN4

Protein tyrosine phosphatase, non-receptor type 4

SD

Standard deviation

WISC-V

Wechsler Intelligence Scale for Children^®, Fifth Edition

Author contributions

CT, DC, and XB conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript. CT, AO, CG, SO, IZ, OG, and JM followed the patient and contributed to data acquisition. CM analyzed and interpreted genetic data and critically reviewed the manuscript. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.

Funding

No specific grant supports this research.

Availability of data and materials

Data sharing does not apply to this article as no datasets were generated during the current study. Genomic databases were used to analyze the case reported. Perez, G. et al. The UCSC Genome Browser database: 2025 update. Nucleic Acids Res. 53, D1243–D1249 (2025). 10.1093/nar/gkae974. Firth, H.V. et al. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am. J. Hum. Genet. 84, 524–533 (2009). 10.1016/j.ajhg.2009.03.010

Declarations

Ethics approval and consent to participate

Written informed consent was obtained from the patient to publish any potentially identifiable images or data in this article. This manuscript follows the CARE guideline for publishing case reports, with the completed CARE 2013 checklist provided in the Supplementary Materials. Ethical committees/internal review boards: not applicable.

Consent for publication

Written informed consent was obtained from the patient’s legal guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.