What is Wolf-Hirschhorn syndrome?

Wolf-Hirschhorn Syndrome

Wolf-Hirschhorn syndrome (WHS) is a rare chromosomal disorder caused by deletion of the distal short arm of chromosome 4 (4p16.3), characterized by profound growth retardation, intellectual disability, distinctive facial dysmorphism resembling a "Greek warrior helmet," and seizures. 1, 2

Genetic Basis

• WHS results from hemizygous deletion of chromosome 4p16.3, with the NSD2 gene (also called WHSC1) being deleted in every case and considered essential for pathogenesis 3, 4
• The severity and spectrum of features depend on the size and extent of the deletion, functioning as a contiguous gene syndrome where multiple genes contribute to the full phenotype 3, 4
• Most cases arise from de novo deletions, though the mechanism can vary 1, 2
• NSD2 haploinsufficiency alone produces a milder phenotype with intellectual disability and facial features but typically without seizures, representing an atypical or partial WHS presentation 3

Core Clinical Features (Present in >75% of Cases)

Growth and Development

• Intrauterine growth retardation occurs in many but not all cases 1, 5
• Postnatal growth failure is a constant feature, with profound growth retardation persisting throughout life 1, 2
• Psychomotor delay and intellectual disability affect 95% of patients, ranging from severe mental deficiency to milder developmental delay depending on deletion size 1, 2, 5

Neurological Manifestations

• Seizures are a hallmark feature of classic WHS, typically beginning in the neonatal or early infantile period 1, 2, 5
• Congenital hypotonia is nearly universal, present in approximately 80% of cases 1, 5
• Microcephaly occurs in one-third of affected individuals 5

Distinctive Facial Dysmorphism ("Greek Warrior Helmet" Appearance)

• High frontal hairline with prominent forehead and bitemporal narrowness 1, 5
• Hypertelorism (widely spaced eyes) with upslanting palpebral fissures 3, 5
• Prominent glabella creating the characteristic "Greek warrior helmet" appearance 2, 5
• Broad or beaked nose 1
• Micrognathia and full lips 3, 5

Variable Associated Features

Midline Fusion Defects

• Cleft lip and/or cleft palate occur with variable frequency 2, 5
• Cardiac septal defects (ventricular or atrial) are common but not universal 1, 3, 5

Skeletal Abnormalities

• Clinodactyly and syndactyly may be present 3
• Hypoplastic cervical vertebrae have been reported 5
• Classic WHS displays more severe skeletal abnormalities compared to isolated NSD2 deletions 3

Other Organ System Involvement

• Renal anomalies including dysplastic kidneys, renal cysts, or structural defects should be actively sought as they represent rare but important manifestations 1, 5
• Structural brain abnormalities including partial or complete agenesis of corpus callosum occur in some cases 1, 5
• Coloboma of the iris has been described 5
• Immunodeficiencies represent rare manifestations that warrant evaluation 1
• Cryptorchidism and genital abnormalities may occur 3

Diagnostic Approach

Clinical Recognition

• Suspect WHS in any infant with the combination of growth retardation, characteristic facial dysmorphism, hypotonia, and seizures 1, 2, 5
• The absence of seizures should prompt consideration of NSD2 haploinsufficiency rather than classic WHS, particularly if skeletal abnormalities are mild 3

Genetic Confirmation

• Chromosomal microarray analysis (CMA) is the current standard diagnostic test for detecting 4p deletions 1
• Multiplex ligation-dependent probe amplification (MLPA) serves as a reliable and cost-effective screening method, with positive cases requiring confirmation by CMA or karyotype 1
• Standard karyotype analysis can detect larger deletions but may miss smaller, cryptic deletions 1, 2
• Whole genome or exome sequencing identifies point mutations in NSD2 in cases with atypical presentations 3

Essential Evaluations Once Diagnosis Suspected

• Echocardiography to detect cardiac septal defects or other structural heart disease 1, 3, 5
• Renal ultrasound to identify dysplastic kidneys, cysts, or structural anomalies 1, 5
• Brain MRI to evaluate for corpus callosum abnormalities and other structural defects 1, 5
• Ophthalmologic examination for coloboma and other eye abnormalities 5
• Immunologic evaluation given the risk of immunodeficiency 1

Prognostic Considerations

• Phenotypic severity correlates with deletion size, with larger deletions producing more severe manifestations 1, 4
• Patients with isolated NSD2 mutations display milder intellectual disability, absence of seizures, and less severe skeletal involvement compared to classic WHS 3
• The presence of seizures, cardiac defects, and renal anomalies significantly impacts long-term morbidity 1, 5

Genetic Counseling Implications

• Medical genetics evaluation is essential to discuss clinical manifestations, natural history, and recurrence risks for parents and family members 1, 5
• Most cases are de novo, but parental chromosomal analysis may be warranted to exclude balanced translocations 5
• Prenatal diagnosis is important given the broad spectrum of morphologic abnormalities and inevitable intellectual disability 5