RARE DISEASE
Wolf-Hirschhorn syndrome
Wolf-Hirschhorn syndrome
Wolf-Hirschhorn syndrome
Synonyms: 4p- syndrome, Distal deletion 4p, Distal monosomy 4p, Telomeric deletion 4p
Synonyms: 4p- syndrome, Distal deletion 4p, Distal monosomy 4p, Telomeric deletion 4p
Synonyms: 4p- syndrome, Distal deletion 4p, Distal monosomy 4p, Telomeric deletion 4p
Drug discovery
63
papers
On emerging therapies
Overview
Wolf-Hirschhorn Syndrome (WHS) is a rare genetic disorder caused by deletions in the 4p16.3 chromosomal region. Key features include distinctive craniofacial dysmorphism (e.g., "Greek helmet" facies, microcephaly), prenatal/postnatal growth retardation, severe developmental delay, intellectual disability, hypotonia, and treatment-resistant seizures (80–95% prevalence). Associated anomalies include congenital heart defects (50%), skeletal abnormalities, and immune/renal impairments [1][2][13][16].
Therapies
Multidisciplinary care: Antiseizure medications (e.g., valproate, levetiracetam), surgical correction of structural anomalies (cleft palate, cardiac defects), and therapies (PT/OT/speech).
Supportive interventions: Nutritional support, behavioral/educational accommodations, and 24-hour postural/assistive devices [3][6][8][12].
Categories: rare abdominal surgical diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases, rare ophthalmic disorders, rare otorhinolaryngological diseases, rare surgical thoracic diseases
Research Papers
63 drug discovery papers about Wolf-Hirschhorn syndrome. Recent publications:
63 drug discovery papers about Wolf-Hirschhorn syndrome. Recent publications:
categories:
Small molecules
proteins
2025-09-29 | Wolf-Hirschhorn syndrome with growth hormone deficiency: long-term response to RhGH therapy.
To describe the long-term auxological response to recombinant human growth hormone (rhGH) therapy in a patient with genetically confirmed Wolf-Hirschhorn syndrome (WHS) and concurrent growth hormone deficiency (GHD). A male pediatric patient with genetically confirmed Wolf-Hirschhorn syndrome underwent comprehensive endocrine evaluation. Growth hormone stimulation testing revealed partial GHD. He subsequently received rhGH therapy for 11 years, with follow-up every 6 months including auxological measurements, biochemical assessments, and bone age determination. Across 11 years of rhGH, height improved from ~ - 4.2 to ~ - 1.3 SDS with normalized height velocity and a prolonged but uneventful pubertal course. No major adverse effects were observed. Muscle tone improvement was also noted with treatment initiation. To our knowledge, this is the first documented case of a male patient with WHS and confirmed GHD who received long-term rhGH therapy, resulting in marked improvement in growth. These findings underscore the importance of routine endocrine screening for GHD in WHS. Furthermore, rhGH therapy may provide benefits beyond linear growth, potentially improving hypotonia. However, additional studies are needed to substantiate this effect.
2020-12-01 | The first familial NSD2 cases with a novel variant in a Chinese father and daughter with atypical WHS facial features and a 7.5-year follow-up of growth hormone therapy
Abstract Background Wolf-Hirschhorn syndrome is a well-characterized genomic disorder caused by 4p16.3 deletions. Wolf-Hirschhorn syndrome patients exhibit characteristic facial dysmorphism, growth retardation, developmental delay, intellectual disability and seizure disorders. Recently, NSD2 gene located within the 165 kb Wolf-Hirschhorn syndrome critical region was identified as the key causal gene responsible for most if not all phenotypes of Wolf-Hirschhorn syndrome. So far, eight NSD2 loss of function variants have been reported in patients from different parts of the world, all were de novo variants. Methods In our study, we performed whole exome sequencing for two patients from one family. We also reviewed more NSD2 mutation cases in pervious literature. Results A novel loss of function NSD2 variant, c.1577dupG (p.Asn527Lysfs*14), was identified in a Chinese family in the proband and her father both affected with intellectual disability. After reviewing more NSD2 mutation cases in pervious literature, we found none of them had facial features that can be recognized as Wolf-Hirschhorn syndrome. In addition, we have given our proband growth hormone and followed up with this family for 7.5 years. Conclusions Here we reported the first familial NSD2 variant and the long-term effect of growth hormone therapy for patients. Our results suggested NSD2 mutation might cause a distinct intellectual disability and short stature syndrome.
2015-02-28 | Severe short stature and Wolf-Hirschhorn syndrome: response to growth hormone in two cases without growth hormone deficiency
Wolf-Hirschhorn syndrome (WHS) is a rare congenital disorder occurring in approximately 1/50 000 births, with marked pre- and postnatal growth failure. WHS results from the hemizygous deletion encompassing the 4p16.3 region. This report of two children with WHS shows that growth hormone treatment in selected children with WHS and severe short stature may have a substantial effect on long-term growth.
2011-09-16 | C4ORF48, a gene from the Wolf-Hirschhorn syndrome critical region, encodes a putative neuropeptide and is expressed during neocortex and cerebellar development.
In order to identify novel genes involved in mental retardation/intellectual disability, we focused on a microdeletion reported in a patient with a mild form of Wolf-Hirschhorn syndrome. This patient presented with attention-deficit hyperactivity disorder, some learning and fine motor deficits as well as facial abnormalities. The deleted region included three genes. Here, we report the first characterization of one of these genes, C4ORF48. C4ORF48 encodes a short (139 aa) evolutionarily conserved protein with a predicted signal peptide and two potential dibasic convertase cleavage sites. In mice, we demonstrated expression of the corresponding protein exclusively in brain tissue using an anti-mouse C4Orf48 polyclonal antibody. Detailed RNA in situ hybridization experiments revealed expression of C4Orf48 in different zones during cortical and cerebellar development, as well as in almost all cortical and subcortical regions of the adult mouse brain. Based on the present data, we propose that C4Orf48 probably encodes a novel neuropeptide, which, if hemizygously deleted, may be involved in the observed intellectual and fine motor disabilities and thus in the overall neurological aspects of Wolf-Hirschhorn syndrome.
2004-02-11 | Mild Wolf–Hirschhorn phenotype and partial gh deficiency in a patient with a 4p terminal deletion
Abstract Wolf–Hirschhorn syndrome (WHS) is caused by a variably‐sized deletion of chromosome 4 involving band 4p16 whose typical craniofacial features are “Greek warrior helmet appearance” of the nose, microcephaly, and prominent glabella. Almost all patients show mental retardation and pre‐ and post‐natal growth delay. Patient was born at term, after a pregnancy characterized by intra‐uterine growth retardation (IUGR). Delivery was uneventful. Developmental delay was evident since the first months of life. At 2 years, he developed generalized tonic‐clonic seizures. Because of short stature, low growth velocity and delayed bone age, at 4 years he underwent growth hormone (GH) evaluation. Peak GH after two provocative tests revealed a partial GH deficiency. Clinical observation at 7 years disclosed a distinctive facial appearance, with microcephaly, prominent eyes, and beaked nose. Brain MRI showed left temporal mesial sclerosis. GTG banded karyotype was normal. Because of mental retardation, subtelomeric fluorescence in situ hybridization (FISH) analysis was performed, disclosing a relatively large deletion involving 4p16.2 → pter (about 4.5 Mb), in the proband, not present in the parents. The smallest deletion detected in a WHS patient thus far includes two candidate genes, WHSC1 and WHSC2 . Interestingly, that patient did not show shortness of stature, and that could be due to the haploinsufficiency of other genes localized in the flanking regions. Contribution of GH alterations and possible GH therapy should be further considered in WHS patients. © 2004 Wiley‐Liss, Inc.
small molecules
2026-07-27 | NSD2 Coordinates the Neurogenic-to-Gliogenic Transition via H3K36me2-Dependent Activation of the EGFR-ERK Pathway.
Haploinsufficiency of the histone methyltransferase NSD2 is a major cause of Wolf-Hirschhorn syndrome (WHS) and the related Rauch-Steindl syndrome (RAUST), both of which exhibit microcephaly and intellectual disability. However, the precise role of NSD2 in brain development remains unclear. Here, we identify NSD2 as a pivotal epigenetic regulator orchestrating the transition from neurogenesis to gliogenesis in the developing mouse neocortex. Conditional knockout of Nsd2 severely impairs astrocyte production in late embryogenesis, while its overexpression promotes astrocytic fate. Integrated epigenomic and transcriptomic analyses reveal that NSD2 deposits the activating histone mark H3K36me2 directly at the Egfr promoter, sustaining EGFR expression and downstream ERK signaling-a pathway essential for gliogenesis. Pharmacological activation of ERK phosphorylation rescues the astrogliogenesis defects both in vitro and in vivo. Notably, Nsd2-deficient mice exhibit significant deficits in learning and memory. Our findings define an NSD2-H3K36me2-EGFR-ERK axis that drives cortical gliogenesis and provide mechanistic insights into the potential contribution of NSD2 deficiency to neurodevelopmental abnormalities.
2025-11-27 | Epilepsy in Wolf-Hirschhorn Syndrome: Clinical Insights from a Pediatric Cohort and a Review of the Literature.
Background: Wolf-Hirschhorn syndrome (WHS) is a rare contiguous gene deletion disorder associated with a high incidence of early-onset epilepsy. Despite the clinical relevance of seizures in this population, few large-scale studies have provided detailed data on epilepsy phenotypes and treatment outcomes. Methods: We analyzed a cohort of 140 individuals with WHS from Spain and Latin America. Using validated caregiver-reported questionnaires, we collected detailed information on seizure types, antiseizure medications (ASM) use, and associated comorbidities. Statistical comparisons were made to identify correlations between epilepsy severity, deletion size, and functional outcomes. Results: Epilepsy was observed in 92% of patients, typically beginning before 12 months of age. Multiple seizure types were common, particularly generalized tonic-clonic and atypical absence seizures. Status epilepticus occurred in 58% of cases, with a high proportion requiring multiple ASMs. Valproic acid and levetiracetam were the most commonly used treatments. Patients with more severe epilepsy tended to have larger deletions (>9 Mb) and poorer developmental outcomes. ASM discontinuation was significantly associated with older age at evaluation, supporting improved seizure control over time. Conclusions: Epilepsy in WHS is frequent, often severe in early childhood, and associated with neurodevelopmental impairment and increased treatment burden. While some patients show improvement with age, early aggressive management using appropriate ASMs may be critical to improve neurological prognosis. Advances in diagnosis, early intervention, and targeted therapies offer hope for improved long-term outcomes in this vulnerable population.
2025-08-26 | Elevated levels of Letm1 drives mitochondrial dysfunction and cardiomyocyte stress-mediated apoptosis in cultured cardiomyocytes.
Cardiac ischemia, a predominant cause of heart failure, is marked by profound mitochondrial dysfunction, dysregulated ion homeostasis, and maladaptive cellular remodeling, all of which compromise cardiac performance. The mitochondrial inner membrane protein Leucine zipper-EF-hand containing Transmembrane Protein 1 (Letm1), implicated in Wolf-Hirschhorn Syndrome, is essential for mitochondrial function. Although genetic alterations in Letm1 are linked to cardiomyopathies, its specific contributions to cardiac pathophysiology, particularly in the context of ischemic heart disease, remain poorly defined. This study aims to elucidate the role of Letm1 in ischemic cardiac pathology and its mechanistic impact on cardiomyocyte function. Letm1 expression was assessed in human and murine models of heart failure due to ischemic cardiomyopathy (ICM) and cardiac hypertrophy. Letm1 was overexpressed in neonatal rat ventricular cardiomyocytes, adult mouse cardiomyocytes, and human induced pluripotent stem cell (iPSC)-derived cardiomyocytes to study mitochondrial function (Seahorse assays), structural and molecular remodeling (fluorescence microscopy, transmission electron microscopy (TEM), qPCR, immunoblotting), transcriptomic/proteomic profiles, calcium handling and electrophysiology (patch-clamp), autophagic flux (Bafilomycin A1, LC3-RFP-GFP), and cell survival. Letm1 was markedly upregulated in ICM in both human and murine hearts, but unchanged in hypertrophic heart failure. Overexpression of Letm1 in cardiomyocytes resulted in profound mitochondrial dysfunction, including downregulation of oxidative phosphorylation (OXPHOS) genes, impaired membrane potential, reduced ATP output, increased proton leak, and elevated ROS levels. A metabolic shift toward glycolysis was observed, accompanied by reduced fatty acid oxidation. Electron microscopy revealed mitochondrial fragmentation, mitophagic vesicles, and sarcomeric disarray. Transcriptomic and proteomic analyses highlighted dysregulation of genes linked to mitochondrial organization, ion transport, and autophagy. Electrophysiologically, Letm1 reduced L-type Ca2+ current density and significantly shortened action potential duration, leading to impaired contractility. Letm1 overexpression activated upstream autophagy regulators (AMPK, ULK1) and enhanced LC3-II and p62 accumulation, but autophagic flux was impaired, as confirmed by LC3-RFP-GFP reporter and exacerbated by Bafilomycin A1 treatment. This dysregulated autophagy was coupled with mitochondrial stress, increased apoptosis (cleaved caspases), and reduced cardiomyocyte viability. This study indicates that Letm1 upregulation drives mitochondrial dysfunction, electrophysiology alterations, and activation of autophagy and apoptosis, culminating in cardiomyocyte injury in ischemic cardiomyopathy. By disrupting OXPHOS, calcium handling, and cell survival pathways, Letm1 contributes to ischemic remodeling and cardiac dysfunction. Targeting Letm1 presents a promising therapeutic strategy to alleviate ischemic damage and preserve cardiac function.
2025-05-20 | VALPROIC ACID AS AN EFFECTIVE TREATMENT FOR SELF-INJURIOUS BEHAVIOR IN A PATIENT WITH WOLF-HIRSCHHORN SYNDROME: A CASE REPORT
Wolf-Hirschhorn Syndrome (WHS) is a neurodevelopmental disorder (NDD) characterized by a microdeletion, often accompanied by maladaptive behaviors. First-line medical treatment involves antipsychotics; however, when antipsychotics prove insufficient, treatment options become limited. In this case, it was aimed to demonstrate that valproic acid as monotherapy could eliminate maladaptive behaviors in a patient diagnosed with WHS accompanied by self-injurious behavior. A 10-year 4-month-old female patient with WHS exhibited intense self-injurious behaviors. When her demands were not met, she would bang her head against the wall with significant force, risking severe traumatic injury, and bite her hand. She had previously received sufficient dosage and durations of aripiprazole and risperidone treatments without benefit. Valproic acid was initiated at a dose of 400 mg/day in divided doses. After the first month of treatment, the patient ceased the behavior of banging her head. Additionally, the behavior of biting her hand significantly decreased. The Aberrant Behavior Checklist (ABC) score, initially assessed at 51 points, decreased to 28 points after the first month of treatment. The decrease in the ABC score was particularly marked in the subscales of irritability and social withdrawal. This outcome suggests that in patients diagnosed with neurodevelopmental disorders (NDD) where antipsychotics have failed, valproic acid as a mood stabilizer may be beneficial as monotherapy in reducing self-injurious behavior.
2025-03-25 | Effectiveness and Safety of High-Dose Oral Phenobarbital in Children With Recurrent and Treatment-Refractory Seizures.
In this study, we applied high-dose oral phenobarbital (PB) to children with recurrent and treatment-refractory seizures or recurrent status epilepticus and evaluated the effectiveness and safety of this treatment. We retrospectively reviewed patients' medical records who received oral high-dose PB treatment between January 2019 and July 2024. In this study, recurrent and treatment-refractory seizures was defined as the persistence of daily epileptic seizures or recurrent attacks of status epilepticus despite treatment with oral antiepileptic drugs or continuous intravenous midazolam therapy. High-dose oral PB therapy was performed on 11 patients (7 females and 4 males). The median age at the onset of epilepsy was 2 months (range: 0.06-132 months). The underlying disorders or comorbidity were genetic disorders (1q14 del, compound heterozygous for the PNKP gene, Wolf-Hirschhorn syndrome, ring chromosome 14 syndrome) in 4 patients, cerebral palsy in 2 patients, metabolic disorders (Zellweger syndrome, pyridoxine-dependent epilepsy) in 2 patients, traumatic brain injury and hypoxia, hemimegalencephaly, and ataxia and intellectual disability in 1 patient. The median age at initiation of high-dose PB therapy was 11 months (range: 2-203 months). The maximal dose of PB ranged from 6 to 14.7 mg/kg/d (median: 10 mg/kg/day). The maximal serum PB levels ranged from 33 to 56 µg/mL (median: 44 µg/mL). We evaluated the effectiveness of this treatment as follows: "effective" represented more than 50% seizure reduction, "ineffective" represented less than 50% seizure reduction, and "exacerbation" represented an increase in seizure frequency. In 7 of the 11 patients (63.6%), oral high-dose PB therapy was effective and was transiently effective in the other 4 patients. Adverse effects were noted in 6 patients (54.5%) during high-dose oral PB therapy: drowsiness in 5 patients and mild elevations in transaminases in 2 patients.
gene therapies
2025-11-04 | Proximal 4p deletion syndrome in a woman with intellectual disability: a case report and literature review.
Deletions in chromosome 4p can lead to two distinct phenotypes, Wolf-Hirschhorn syndrome (WHS) and proximal 4p deletion syndrome. While WHS, associated with distal deletions, has well-characterized phenotypic features, proximal 4p deletion syndrome, involving the 4p14-p 16.1 region, shows moderate manifestations, and its causative gene remains unknown with fewer reported cases. Here we report a Chinese case: a 21-year-old female with a peripheral blood chromosomal karyotype of 46,XX, del(4)(p15.3-p16). NGS-CNVA further revealed an 11.7 Mb deletion in the 4p16.2-p15.32 region and a 1.25 Mb microduplication in 16p13.13. She had ovarian dysfunction, and moderate Intellectual Disability(ID) without typical proximal 4p deletion phenotypes. Through analysis of Genecards and OMIM databases, we identified two neurodevelopmental genes DRD5 and WFS1, and four ovarian dysfunction-related genes WFS1, CC2D2A, PROM1, and QDPR, suggesting their roles in the patient's manifestations. Additionally, a review of 37 published cases of proximal 4p deletion syndrome revealed 17 cases with an overlap in the deleted region with our case. This report not only enhances the recognition of this rare syndrome among clinicians but also provides a basis for further exploration of the potential causative genes, contributing to a better understanding of the genotype-phenotype correlations in proximal 4p deletion syndrome.
2025-10-02 | Congenital cataract as a component of a rare hereditary chromosomal pathology
The article presents a description of clinical cases of a rare hereditary pathology with eye damage - Wolf–Hirschhorn and Conradi–Hünermann syndromes (chondrodysplasia punctata). The diagnoses are confirmed by genetic studies. Congenital cataract in a patient with chondrodysplasia punctata was accompanied by skeletal changes and skin manifestations of the type of congenital ichthyosis in the neonatal period. In a patient with Wolf–Hirschhorn syndrome, lens opacification was accompanied by hypertelorism, divergent strabismus, pupil dislocation, congenital coloboma of the iris, optic nerve atrophy, as well as paresis of the upper and lower extremities, mental retardation, epilepsy, and congenital heart disease. Surgical treatment of hereditary cataracts is complicated by both concomitant changes in the anterior segment of the eye and the presence of various somatic pathologies. Key words: congenital cataract, hereditary cataract, Wolf–Hirschhorn syndrome, punctate chondrodysplasia.
2025-03-31 | Deletion Disorders
Cri-du-chat, Wolf-Hirschhorn, 22q11.2, Prader-Willi, and Smith-Magenis are neurogenetic disorders caused by a deletion of genetic material on one chromosome. Each condition is associated with a relatively well-defined developmental, physical health, and mental health phenotype. This chapter reviews the current state of knowledge regarding these deletion disorders with a focus on general and syndrome-specific assessment and intervention considerations.
2025-02-06 | A Unique Derivative Chromosome 4 with a Predominant 4p16.3 Microduplication Phenotype and a Literature Review.
Constitutional structural abnormalities affecting chromosome 4 result in variable distinct phenotypic traits including duplication 4p syndrome, deletion 4p or Wolf-Hirschhorn syndrome (WHS), deletion 4q and duplication 4q syndromes. Complex rearrangements involving both chromosome 4 arms are very rarely reported with different break points occurring within regions of 4p13-p16 and 4q32-35. They most commonly occur in familial cases due to parental pericentric inversion resulting in a recombinant chromosome 4 "rec(4)." The clinical picture is dependent on the size and type of copy number imbalance and the genes involved. We report on a female patient with delayed developmental milestones and lower limb anomalies, who carried a de novo unique type of complex rearrangement affecting both chromosome 4 arms, diagnosed by karyotype and fluorescence in situ hybridization analysis and chromosomal microarray (CMA). The chromosome 4 rearrangement involved three copy number alterations, consisting of a terminal 1.17 Mb 4p16.3 deletion with a contiguous proximal 1.8 Mb 4p16.3 duplication, including the Wolf-Hirschhorn critical (WHSC) region, and an inverted 27 Mb terminal 4q32-35.2 duplication attached to terminal 4p. The patient's predominant phenotype was consistent with 4p16.3 microduplication syndrome. The rearrangement occurred as a de novo abnormality, and thus it was designated as a derivative chromosome 4. To the best of our knowledge, this complex type of chromosome 4 rearrangement has not been reported so far. The present report adds to the scarce 4p16.3 microduplication syndrome reports and emphasizes the role of WHSC region in the syndromic phenotype. It also reveals the importance of CMA in detecting subtle copy number variations (CNVs) that could be dominantly reflected on the phenotype, which is very important in patients' management and family counselling.
2013-05-28 | Letm1, the mitochondrial Ca2+/H+ antiporter, is essential for normal glucose metabolism and alters brain function in Wolf-Hirschhorn syndrome.
Mitochondrial metabolism, respiration, and ATP production necessitate ion transport across the inner mitochondrial membrane. Leucine zipper-EF-hand containing transmembrane protein 1 (Letm1), one of the genes deleted in Wolf-Hirschhorn syndrome, encodes a putative mitochondrial Ca(2+)/H(+) antiporter. Cellular Letm1 knockdown reduced Ca(2+)mito uptake, H(+)mito extrusion and impaired mitochondrial ATP generation capacity. Homozygous deletion of Letm1 in mice resulted in embryonic lethality before day 6.5 of embryogenesis and ~50% of the heterozygotes died before day 13.5 of embryogenesis. The surviving heterozygous mice exhibited altered glucose metabolism, impaired control of brain ATP levels, and increased seizure activity. We conclude that loss of Letm1 contributes to the pathology of Wolf-Hirschhorn syndrome in humans and may contribute to seizure phenotypes by reducing glucose oxidation and other specific metabolic alterations.
proteins
2025-09-29 | Wolf-Hirschhorn syndrome with growth hormone deficiency: long-term response to RhGH therapy.
To describe the long-term auxological response to recombinant human growth hormone (rhGH) therapy in a patient with genetically confirmed Wolf-Hirschhorn syndrome (WHS) and concurrent growth hormone deficiency (GHD). A male pediatric patient with genetically confirmed Wolf-Hirschhorn syndrome underwent comprehensive endocrine evaluation. Growth hormone stimulation testing revealed partial GHD. He subsequently received rhGH therapy for 11 years, with follow-up every 6 months including auxological measurements, biochemical assessments, and bone age determination. Across 11 years of rhGH, height improved from ~ - 4.2 to ~ - 1.3 SDS with normalized height velocity and a prolonged but uneventful pubertal course. No major adverse effects were observed. Muscle tone improvement was also noted with treatment initiation. To our knowledge, this is the first documented case of a male patient with WHS and confirmed GHD who received long-term rhGH therapy, resulting in marked improvement in growth. These findings underscore the importance of routine endocrine screening for GHD in WHS. Furthermore, rhGH therapy may provide benefits beyond linear growth, potentially improving hypotonia. However, additional studies are needed to substantiate this effect.
2020-12-01 | The first familial NSD2 cases with a novel variant in a Chinese father and daughter with atypical WHS facial features and a 7.5-year follow-up of growth hormone therapy
Abstract Background Wolf-Hirschhorn syndrome is a well-characterized genomic disorder caused by 4p16.3 deletions. Wolf-Hirschhorn syndrome patients exhibit characteristic facial dysmorphism, growth retardation, developmental delay, intellectual disability and seizure disorders. Recently, NSD2 gene located within the 165 kb Wolf-Hirschhorn syndrome critical region was identified as the key causal gene responsible for most if not all phenotypes of Wolf-Hirschhorn syndrome. So far, eight NSD2 loss of function variants have been reported in patients from different parts of the world, all were de novo variants. Methods In our study, we performed whole exome sequencing for two patients from one family. We also reviewed more NSD2 mutation cases in pervious literature. Results A novel loss of function NSD2 variant, c.1577dupG (p.Asn527Lysfs*14), was identified in a Chinese family in the proband and her father both affected with intellectual disability. After reviewing more NSD2 mutation cases in pervious literature, we found none of them had facial features that can be recognized as Wolf-Hirschhorn syndrome. In addition, we have given our proband growth hormone and followed up with this family for 7.5 years. Conclusions Here we reported the first familial NSD2 variant and the long-term effect of growth hormone therapy for patients. Our results suggested NSD2 mutation might cause a distinct intellectual disability and short stature syndrome.
2015-02-28 | Severe short stature and Wolf-Hirschhorn syndrome: response to growth hormone in two cases without growth hormone deficiency
Wolf-Hirschhorn syndrome (WHS) is a rare congenital disorder occurring in approximately 1/50 000 births, with marked pre- and postnatal growth failure. WHS results from the hemizygous deletion encompassing the 4p16.3 region. This report of two children with WHS shows that growth hormone treatment in selected children with WHS and severe short stature may have a substantial effect on long-term growth.
2011-09-16 | C4ORF48, a gene from the Wolf-Hirschhorn syndrome critical region, encodes a putative neuropeptide and is expressed during neocortex and cerebellar development.
In order to identify novel genes involved in mental retardation/intellectual disability, we focused on a microdeletion reported in a patient with a mild form of Wolf-Hirschhorn syndrome. This patient presented with attention-deficit hyperactivity disorder, some learning and fine motor deficits as well as facial abnormalities. The deleted region included three genes. Here, we report the first characterization of one of these genes, C4ORF48. C4ORF48 encodes a short (139 aa) evolutionarily conserved protein with a predicted signal peptide and two potential dibasic convertase cleavage sites. In mice, we demonstrated expression of the corresponding protein exclusively in brain tissue using an anti-mouse C4Orf48 polyclonal antibody. Detailed RNA in situ hybridization experiments revealed expression of C4Orf48 in different zones during cortical and cerebellar development, as well as in almost all cortical and subcortical regions of the adult mouse brain. Based on the present data, we propose that C4Orf48 probably encodes a novel neuropeptide, which, if hemizygously deleted, may be involved in the observed intellectual and fine motor disabilities and thus in the overall neurological aspects of Wolf-Hirschhorn syndrome.
2004-02-11 | Mild Wolf–Hirschhorn phenotype and partial gh deficiency in a patient with a 4p terminal deletion
Abstract Wolf–Hirschhorn syndrome (WHS) is caused by a variably‐sized deletion of chromosome 4 involving band 4p16 whose typical craniofacial features are “Greek warrior helmet appearance” of the nose, microcephaly, and prominent glabella. Almost all patients show mental retardation and pre‐ and post‐natal growth delay. Patient was born at term, after a pregnancy characterized by intra‐uterine growth retardation (IUGR). Delivery was uneventful. Developmental delay was evident since the first months of life. At 2 years, he developed generalized tonic‐clonic seizures. Because of short stature, low growth velocity and delayed bone age, at 4 years he underwent growth hormone (GH) evaluation. Peak GH after two provocative tests revealed a partial GH deficiency. Clinical observation at 7 years disclosed a distinctive facial appearance, with microcephaly, prominent eyes, and beaked nose. Brain MRI showed left temporal mesial sclerosis. GTG banded karyotype was normal. Because of mental retardation, subtelomeric fluorescence in situ hybridization (FISH) analysis was performed, disclosing a relatively large deletion involving 4p16.2 → pter (about 4.5 Mb), in the proband, not present in the parents. The smallest deletion detected in a WHS patient thus far includes two candidate genes, WHSC1 and WHSC2 . Interestingly, that patient did not show shortness of stature, and that could be due to the haploinsufficiency of other genes localized in the flanking regions. Contribution of GH alterations and possible GH therapy should be further considered in WHS patients. © 2004 Wiley‐Liss, Inc.
small molecules
2026-07-27 | NSD2 Coordinates the Neurogenic-to-Gliogenic Transition via H3K36me2-Dependent Activation of the EGFR-ERK Pathway.
Haploinsufficiency of the histone methyltransferase NSD2 is a major cause of Wolf-Hirschhorn syndrome (WHS) and the related Rauch-Steindl syndrome (RAUST), both of which exhibit microcephaly and intellectual disability. However, the precise role of NSD2 in brain development remains unclear. Here, we identify NSD2 as a pivotal epigenetic regulator orchestrating the transition from neurogenesis to gliogenesis in the developing mouse neocortex. Conditional knockout of Nsd2 severely impairs astrocyte production in late embryogenesis, while its overexpression promotes astrocytic fate. Integrated epigenomic and transcriptomic analyses reveal that NSD2 deposits the activating histone mark H3K36me2 directly at the Egfr promoter, sustaining EGFR expression and downstream ERK signaling-a pathway essential for gliogenesis. Pharmacological activation of ERK phosphorylation rescues the astrogliogenesis defects both in vitro and in vivo. Notably, Nsd2-deficient mice exhibit significant deficits in learning and memory. Our findings define an NSD2-H3K36me2-EGFR-ERK axis that drives cortical gliogenesis and provide mechanistic insights into the potential contribution of NSD2 deficiency to neurodevelopmental abnormalities.
2025-11-27 | Epilepsy in Wolf-Hirschhorn Syndrome: Clinical Insights from a Pediatric Cohort and a Review of the Literature.
Background: Wolf-Hirschhorn syndrome (WHS) is a rare contiguous gene deletion disorder associated with a high incidence of early-onset epilepsy. Despite the clinical relevance of seizures in this population, few large-scale studies have provided detailed data on epilepsy phenotypes and treatment outcomes. Methods: We analyzed a cohort of 140 individuals with WHS from Spain and Latin America. Using validated caregiver-reported questionnaires, we collected detailed information on seizure types, antiseizure medications (ASM) use, and associated comorbidities. Statistical comparisons were made to identify correlations between epilepsy severity, deletion size, and functional outcomes. Results: Epilepsy was observed in 92% of patients, typically beginning before 12 months of age. Multiple seizure types were common, particularly generalized tonic-clonic and atypical absence seizures. Status epilepticus occurred in 58% of cases, with a high proportion requiring multiple ASMs. Valproic acid and levetiracetam were the most commonly used treatments. Patients with more severe epilepsy tended to have larger deletions (>9 Mb) and poorer developmental outcomes. ASM discontinuation was significantly associated with older age at evaluation, supporting improved seizure control over time. Conclusions: Epilepsy in WHS is frequent, often severe in early childhood, and associated with neurodevelopmental impairment and increased treatment burden. While some patients show improvement with age, early aggressive management using appropriate ASMs may be critical to improve neurological prognosis. Advances in diagnosis, early intervention, and targeted therapies offer hope for improved long-term outcomes in this vulnerable population.
2025-08-26 | Elevated levels of Letm1 drives mitochondrial dysfunction and cardiomyocyte stress-mediated apoptosis in cultured cardiomyocytes.
Cardiac ischemia, a predominant cause of heart failure, is marked by profound mitochondrial dysfunction, dysregulated ion homeostasis, and maladaptive cellular remodeling, all of which compromise cardiac performance. The mitochondrial inner membrane protein Leucine zipper-EF-hand containing Transmembrane Protein 1 (Letm1), implicated in Wolf-Hirschhorn Syndrome, is essential for mitochondrial function. Although genetic alterations in Letm1 are linked to cardiomyopathies, its specific contributions to cardiac pathophysiology, particularly in the context of ischemic heart disease, remain poorly defined. This study aims to elucidate the role of Letm1 in ischemic cardiac pathology and its mechanistic impact on cardiomyocyte function. Letm1 expression was assessed in human and murine models of heart failure due to ischemic cardiomyopathy (ICM) and cardiac hypertrophy. Letm1 was overexpressed in neonatal rat ventricular cardiomyocytes, adult mouse cardiomyocytes, and human induced pluripotent stem cell (iPSC)-derived cardiomyocytes to study mitochondrial function (Seahorse assays), structural and molecular remodeling (fluorescence microscopy, transmission electron microscopy (TEM), qPCR, immunoblotting), transcriptomic/proteomic profiles, calcium handling and electrophysiology (patch-clamp), autophagic flux (Bafilomycin A1, LC3-RFP-GFP), and cell survival. Letm1 was markedly upregulated in ICM in both human and murine hearts, but unchanged in hypertrophic heart failure. Overexpression of Letm1 in cardiomyocytes resulted in profound mitochondrial dysfunction, including downregulation of oxidative phosphorylation (OXPHOS) genes, impaired membrane potential, reduced ATP output, increased proton leak, and elevated ROS levels. A metabolic shift toward glycolysis was observed, accompanied by reduced fatty acid oxidation. Electron microscopy revealed mitochondrial fragmentation, mitophagic vesicles, and sarcomeric disarray. Transcriptomic and proteomic analyses highlighted dysregulation of genes linked to mitochondrial organization, ion transport, and autophagy. Electrophysiologically, Letm1 reduced L-type Ca2+ current density and significantly shortened action potential duration, leading to impaired contractility. Letm1 overexpression activated upstream autophagy regulators (AMPK, ULK1) and enhanced LC3-II and p62 accumulation, but autophagic flux was impaired, as confirmed by LC3-RFP-GFP reporter and exacerbated by Bafilomycin A1 treatment. This dysregulated autophagy was coupled with mitochondrial stress, increased apoptosis (cleaved caspases), and reduced cardiomyocyte viability. This study indicates that Letm1 upregulation drives mitochondrial dysfunction, electrophysiology alterations, and activation of autophagy and apoptosis, culminating in cardiomyocyte injury in ischemic cardiomyopathy. By disrupting OXPHOS, calcium handling, and cell survival pathways, Letm1 contributes to ischemic remodeling and cardiac dysfunction. Targeting Letm1 presents a promising therapeutic strategy to alleviate ischemic damage and preserve cardiac function.
2025-05-20 | VALPROIC ACID AS AN EFFECTIVE TREATMENT FOR SELF-INJURIOUS BEHAVIOR IN A PATIENT WITH WOLF-HIRSCHHORN SYNDROME: A CASE REPORT
Wolf-Hirschhorn Syndrome (WHS) is a neurodevelopmental disorder (NDD) characterized by a microdeletion, often accompanied by maladaptive behaviors. First-line medical treatment involves antipsychotics; however, when antipsychotics prove insufficient, treatment options become limited. In this case, it was aimed to demonstrate that valproic acid as monotherapy could eliminate maladaptive behaviors in a patient diagnosed with WHS accompanied by self-injurious behavior. A 10-year 4-month-old female patient with WHS exhibited intense self-injurious behaviors. When her demands were not met, she would bang her head against the wall with significant force, risking severe traumatic injury, and bite her hand. She had previously received sufficient dosage and durations of aripiprazole and risperidone treatments without benefit. Valproic acid was initiated at a dose of 400 mg/day in divided doses. After the first month of treatment, the patient ceased the behavior of banging her head. Additionally, the behavior of biting her hand significantly decreased. The Aberrant Behavior Checklist (ABC) score, initially assessed at 51 points, decreased to 28 points after the first month of treatment. The decrease in the ABC score was particularly marked in the subscales of irritability and social withdrawal. This outcome suggests that in patients diagnosed with neurodevelopmental disorders (NDD) where antipsychotics have failed, valproic acid as a mood stabilizer may be beneficial as monotherapy in reducing self-injurious behavior.
2025-03-25 | Effectiveness and Safety of High-Dose Oral Phenobarbital in Children With Recurrent and Treatment-Refractory Seizures.
In this study, we applied high-dose oral phenobarbital (PB) to children with recurrent and treatment-refractory seizures or recurrent status epilepticus and evaluated the effectiveness and safety of this treatment. We retrospectively reviewed patients' medical records who received oral high-dose PB treatment between January 2019 and July 2024. In this study, recurrent and treatment-refractory seizures was defined as the persistence of daily epileptic seizures or recurrent attacks of status epilepticus despite treatment with oral antiepileptic drugs or continuous intravenous midazolam therapy. High-dose oral PB therapy was performed on 11 patients (7 females and 4 males). The median age at the onset of epilepsy was 2 months (range: 0.06-132 months). The underlying disorders or comorbidity were genetic disorders (1q14 del, compound heterozygous for the PNKP gene, Wolf-Hirschhorn syndrome, ring chromosome 14 syndrome) in 4 patients, cerebral palsy in 2 patients, metabolic disorders (Zellweger syndrome, pyridoxine-dependent epilepsy) in 2 patients, traumatic brain injury and hypoxia, hemimegalencephaly, and ataxia and intellectual disability in 1 patient. The median age at initiation of high-dose PB therapy was 11 months (range: 2-203 months). The maximal dose of PB ranged from 6 to 14.7 mg/kg/d (median: 10 mg/kg/day). The maximal serum PB levels ranged from 33 to 56 µg/mL (median: 44 µg/mL). We evaluated the effectiveness of this treatment as follows: "effective" represented more than 50% seizure reduction, "ineffective" represented less than 50% seizure reduction, and "exacerbation" represented an increase in seizure frequency. In 7 of the 11 patients (63.6%), oral high-dose PB therapy was effective and was transiently effective in the other 4 patients. Adverse effects were noted in 6 patients (54.5%) during high-dose oral PB therapy: drowsiness in 5 patients and mild elevations in transaminases in 2 patients.
gene therapies
2025-11-04 | Proximal 4p deletion syndrome in a woman with intellectual disability: a case report and literature review.
Deletions in chromosome 4p can lead to two distinct phenotypes, Wolf-Hirschhorn syndrome (WHS) and proximal 4p deletion syndrome. While WHS, associated with distal deletions, has well-characterized phenotypic features, proximal 4p deletion syndrome, involving the 4p14-p 16.1 region, shows moderate manifestations, and its causative gene remains unknown with fewer reported cases. Here we report a Chinese case: a 21-year-old female with a peripheral blood chromosomal karyotype of 46,XX, del(4)(p15.3-p16). NGS-CNVA further revealed an 11.7 Mb deletion in the 4p16.2-p15.32 region and a 1.25 Mb microduplication in 16p13.13. She had ovarian dysfunction, and moderate Intellectual Disability(ID) without typical proximal 4p deletion phenotypes. Through analysis of Genecards and OMIM databases, we identified two neurodevelopmental genes DRD5 and WFS1, and four ovarian dysfunction-related genes WFS1, CC2D2A, PROM1, and QDPR, suggesting their roles in the patient's manifestations. Additionally, a review of 37 published cases of proximal 4p deletion syndrome revealed 17 cases with an overlap in the deleted region with our case. This report not only enhances the recognition of this rare syndrome among clinicians but also provides a basis for further exploration of the potential causative genes, contributing to a better understanding of the genotype-phenotype correlations in proximal 4p deletion syndrome.
2025-10-02 | Congenital cataract as a component of a rare hereditary chromosomal pathology
The article presents a description of clinical cases of a rare hereditary pathology with eye damage - Wolf–Hirschhorn and Conradi–Hünermann syndromes (chondrodysplasia punctata). The diagnoses are confirmed by genetic studies. Congenital cataract in a patient with chondrodysplasia punctata was accompanied by skeletal changes and skin manifestations of the type of congenital ichthyosis in the neonatal period. In a patient with Wolf–Hirschhorn syndrome, lens opacification was accompanied by hypertelorism, divergent strabismus, pupil dislocation, congenital coloboma of the iris, optic nerve atrophy, as well as paresis of the upper and lower extremities, mental retardation, epilepsy, and congenital heart disease. Surgical treatment of hereditary cataracts is complicated by both concomitant changes in the anterior segment of the eye and the presence of various somatic pathologies. Key words: congenital cataract, hereditary cataract, Wolf–Hirschhorn syndrome, punctate chondrodysplasia.
2025-03-31 | Deletion Disorders
Cri-du-chat, Wolf-Hirschhorn, 22q11.2, Prader-Willi, and Smith-Magenis are neurogenetic disorders caused by a deletion of genetic material on one chromosome. Each condition is associated with a relatively well-defined developmental, physical health, and mental health phenotype. This chapter reviews the current state of knowledge regarding these deletion disorders with a focus on general and syndrome-specific assessment and intervention considerations.
2025-02-06 | A Unique Derivative Chromosome 4 with a Predominant 4p16.3 Microduplication Phenotype and a Literature Review.
Constitutional structural abnormalities affecting chromosome 4 result in variable distinct phenotypic traits including duplication 4p syndrome, deletion 4p or Wolf-Hirschhorn syndrome (WHS), deletion 4q and duplication 4q syndromes. Complex rearrangements involving both chromosome 4 arms are very rarely reported with different break points occurring within regions of 4p13-p16 and 4q32-35. They most commonly occur in familial cases due to parental pericentric inversion resulting in a recombinant chromosome 4 "rec(4)." The clinical picture is dependent on the size and type of copy number imbalance and the genes involved. We report on a female patient with delayed developmental milestones and lower limb anomalies, who carried a de novo unique type of complex rearrangement affecting both chromosome 4 arms, diagnosed by karyotype and fluorescence in situ hybridization analysis and chromosomal microarray (CMA). The chromosome 4 rearrangement involved three copy number alterations, consisting of a terminal 1.17 Mb 4p16.3 deletion with a contiguous proximal 1.8 Mb 4p16.3 duplication, including the Wolf-Hirschhorn critical (WHSC) region, and an inverted 27 Mb terminal 4q32-35.2 duplication attached to terminal 4p. The patient's predominant phenotype was consistent with 4p16.3 microduplication syndrome. The rearrangement occurred as a de novo abnormality, and thus it was designated as a derivative chromosome 4. To the best of our knowledge, this complex type of chromosome 4 rearrangement has not been reported so far. The present report adds to the scarce 4p16.3 microduplication syndrome reports and emphasizes the role of WHSC region in the syndromic phenotype. It also reveals the importance of CMA in detecting subtle copy number variations (CNVs) that could be dominantly reflected on the phenotype, which is very important in patients' management and family counselling.
2013-05-28 | Letm1, the mitochondrial Ca2+/H+ antiporter, is essential for normal glucose metabolism and alters brain function in Wolf-Hirschhorn syndrome.
Mitochondrial metabolism, respiration, and ATP production necessitate ion transport across the inner mitochondrial membrane. Leucine zipper-EF-hand containing transmembrane protein 1 (Letm1), one of the genes deleted in Wolf-Hirschhorn syndrome, encodes a putative mitochondrial Ca(2+)/H(+) antiporter. Cellular Letm1 knockdown reduced Ca(2+)mito uptake, H(+)mito extrusion and impaired mitochondrial ATP generation capacity. Homozygous deletion of Letm1 in mice resulted in embryonic lethality before day 6.5 of embryogenesis and ~50% of the heterozygotes died before day 13.5 of embryogenesis. The surviving heterozygous mice exhibited altered glucose metabolism, impaired control of brain ATP levels, and increased seizure activity. We conclude that loss of Letm1 contributes to the pathology of Wolf-Hirschhorn syndrome in humans and may contribute to seizure phenotypes by reducing glucose oxidation and other specific metabolic alterations.
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