Wolf-Hirschhorn Syndrome

WHS results from irregularities of the distal short arm of chromosome 4, including deletions of varying size (most common) and microduplications. Several genetic mechanisms have been described (see the image below):

• De novo deletion (50-60% of cases)
• Unbalanced translocation (40-45% of cases) - Either  de novo or inherited from a parent with a balanced translocation
• Other complex rearrangements, leading to a 4p16.3 deletion - Ring 4 chromosome, 4p-mosaicism

Diagnosis is made by confirming a deletion in the WHS critical region (WHSCR) using conventional chromosome analysis, fluorescence in situ hybridization (FISH), or chromosomal microarray. 

Evidence strongly supports the idea that the ‘‘core’’ phenotype (distinctive facial appearance, intellectual disability, growth delay, and seizures or electroencephalographic anomalies) is due to haploinsufficiency of several genes on distal 4p, including WHSC1, WHSC2, TACC3, FGFR3, and LETM1.[7, 8]  Therefore, WHS represents a contiguous gene syndrome with contribution of genes located in the terminal 4p16.3 region, within a 1.5-1.6 Mb region.

The presence of a true genotype-phenotype correlation is controversial, as some studies have indicated that there is not always a correlation between the deletion's size and the severity of the clinical findings[4] . 

Frequency

United States

The frequency of WHS is estimated to be 1 case per 50,000 births to 1 case per 20,000 births.[9, 10]

Mortality/Morbidity

The mortality rate is estimated at 34% in the first 2 years of life. However, because many affected children die before the diagnosis is confirmed or suspected, the mortality rate is underestimated. The usual cause of death is a heart defect, aspiration pneumonia, infection, or seizure.

The prenatal mortality rate of Wolf-Hirschhorn syndrome is not significantly increased because 4p deletions are not reported in spontaneous abortions.

Associated adulthood morbidity includes sequelae from congenital heart defects; marked growth failure; contracture of hands, wrists, and feet; poor development of secondary sexual characteristics; and severe growth and intellectual impairment.

Race

Wolf-Hirschhorn syndrome has no ethnic predilection.

Sex

Wolf-Hirschhorn syndrome is more common in females than in males, with a male-to-female ratio of 1:2.

Age

Usually, the condition is detected in the newborn period because of dysmorphic features.

Wolf-Hirschhorn disease is associated with frequent stillbirths, perinatal deaths, and death within the first year of life. If patients survive beyond infancy, their neurodevelopment progresses slowly but constantly. The clinical spectrum is wider than previously suspected.

Patients with WHS are at risk for the following:

• Seizures
• Failure to thrive
• Cognitive deficits
• Motor deficits
• Deficits in autonomy and sphincter control

Seizures

Seizures are a major concern for patients with WHS and are typically hard to control, especially early on. However, rapid diagnosis and treatment leads to improved control and outcomes. The majority of patients with WHS experience a decrease in the frequency of seizures after age 5 years,[6]  and in approximately 50% of patients, seizures resolve by age 13 years.

Failure to thrive

Growth parameters are typically below the second percentile. Growth charts specific for children with WHS are available.[11]

Cognitive deficits

Severe intellectual disabilities are observed in the majority of patients (65%); however a broad range can be seen, including mild and moderate intellectual disability in 10% and 25% of patients, respectively.[12]

Expressive language is typically limited to guttural or disyllabic sounds. However, a minority of patients (< 10%) are able to communicate using simple sentences. 

Comprehension is typically context specific and limited to simple orders. Intent to communicate is present in most patients. 

Motor deficits

About 45% of patients are able to walk, either independently (25%) or with support (20%). Walking is significantly delayed in these patients, being achieved between ages 2 and 12 years. 

Autonomy and sphincter control

Only about 10% of patients achieve daytime sphincter control (typically between ages 8 and 14 years). Ten percent of patients are able to feed themselves, while about 20% can assist with dressing/undressing. 

Adult health risks

In adulthood, patients with WHS are at risk for the following:

• Chronic kidney disease
• Malignancies - Specifically liver adenomas

 

The following websites contain updated information for patients and their families:

• https://ghr.nlm.nih.gov/condition/wolf-hirschhorn-syndrome
• https://rarediseases.info.nih.gov/diseases/7896/wolf-hirschhorn-syndrome
• https://rarediseases.org/rare-diseases/wolf-hirschhorn-syndrome/

The following may be observed in patients with WHS.

Pregnancy history

See the list below:

• Intrauterine growth retardation

• Decreased fetal movements

• Hypotrophic placenta

Developmental history

See the list below:

• Delayed psychomotor development

• Difficulty in ambulation, often with ataxic gait

• Seizures (50%)

Behavior history

See the list below:

• Stereotypes (holding the hands in front of the face, hand-washing or flapping, patting self on chest, rocking, head-shaking, stretching of legs)

• Absence of speech

• Babbling or guttural sounds, occasionally modulated in a communicative way

• Comprehension limited to simple orders or to a specific context

• Affect disorder that improves over time

• Walking with or without support

• Self-feeding

• Helps in dressing and undressing self

• Improved abilities and adaptation to new situations

• Communicative abilities and verbal comprehension with extension of the gesture repertoire and decreased occurrence of withdrawal and anxiety behaviors

Studies of large samples of individuals, including those with submicroscopic deletions and those with a derivative chromosome 4,[12] have led to the recognition of a more complete continuum of the phenotype in WHS, pointing out a much wider clinical spectrum than previously thought.[13, 14, 6]

Growth

Growth deficiency of prenatal onset followed by postnatal growth retardation is seen in 80% of patients with WHS. Short stature and slow weight gain is common postnatally.

Central nervous system

Neurologic concerns are common and include the following.

Structural brain deficits

Structural brain defects are common (80% of cases). The most commonly reported defects include, in order of frequency: corpus callosum hypoplasia, enlargement of the lateral ventricles, cortical and subcortical atrophy, delayed myelination, and cerebellar anomalies.

High risk of epilepsy

Seizures occur in 90% of patients and typically present in early childhood, with a peak incidence around ages 6-12 months.[5] . Of note, electroencephalographic abnormalities are present in 90% of patients.[15]

Hypotonia

Generalized hypotonia with muscle hypotrophy, particularly of the lower limbs, occurs. About 45% of patients can walk, either independently or with support.

Global developmental delay and cognitive disabilities of varying degree

Patients experience expressive language delays. Moreover, a study that compared cognitive-behavioral features of 19 children with WHS and 26 children with one of three other subtelomeric deletions found that the cognitive impact of WHS was more severe than it was in the other groups. The overall adaptive behavior in children with WHS was lower compared with children with the other subtelomeric deletions. However, children with WHS displayed strengths in socialization skills similar to that of the other groups. In addition, compared with the rates of autism found in the other subtelomeric disorders, a significantly lower proportion of children with WHS had autism or autisticlike features.[16]

Skull

See the list below:

• Frontal bossing

• High frontal hairline

• Hemangioma over forehead or glabella

• Scalp defect with or without underlying bony defect

Face

Characteristic dysmorphic features include the following (collectively described as "Greek warrior helmet" facies):

• Prominent glabella

• Hypertelorism

• Broad-beaked nose

• Frontal bossing (See the images below.)

  A child with Wolf-Hirschhorn syndrome. Note the characteristic dysmorphic facial features, including prominent glabella, hypertelorism, beaked nose, and frontal bossing, collectively described as "Greek warrior helmet" facies.

  A fetus with Wolf-Hirschhorn syndrome. Note the presence of "Greek warrior helmet" facies.

Eyes

See the list below:

• Hypertelorism

• Down-slanting palpebral fissures

• Epicanthal folds

• Strabismus

• Coloboma

• Proptosis due to hypoplasia of orbital ridges

• Ectopic pupils

• Exotropia

• Ptosis

• Microphthalmia

• Megalocornea

• Sclerocornea

• Cataracts

• Hypoplastic anterior chamber and ciliary body of iris

• Persistence of lenticular membrane

• Hypoplastic retina with formation of rosettes

• Cup-shaped optic discs

• Congenital nystagmus

• Rieger anomaly

Nose

See the list below:

• Broad or beaked nose

• Nasolacrimal duct stenosis or atresia

Mouth

See the list below:

• Short upper lip

• Short philtrum

• Cleft lip or palate

• Bifid uvula

• Carplike mouth

• Micrognathia

• Retrognathia

Teeth

See the list below:

• Hypodontia

• Delayed dentition

• Taurodontism in the primary dentition

• Peg-shaped teeth

Ears

See the list below:

• Low-set ears

• Large, floppy, or misshapen ears

• Microtia

• Preauricular dimples

• Chronic otitis media with effusion

• Sensorineural hearing loss

Cardiovascular

See the list below:

• Atrial septal defect

• Ventricular septal defect

• Persistent left superior vena cava

• Valve abnormalities

• Complex cardiac defects

Pulmonary

See the list below:

• Bilateral bilobed or trilobed lungs

• Lung hypoplasia secondary to diaphragmatic hernia

Gastrointestinal

See the list below:

• Diastasis recti

• Umbilical or inguinal hernias

• Accessory spleens

• Absent gallbladder

• Diaphragmatic hernia

• Intestinal malrotation

Genitourinary

See the list below:

• Hypoplastic kidneys

• Cystic dysplastic kidneys

• Unilateral renal agenesis

• Hydronephrosis

• Exstrophy of bladder

• Hypoplastic external genitalia

• Cryptorchidism and hypospadias in males

• Hypoplastic müllerian derivatives (ie, agenesis of vagina, cervix, or uterus; hypoplastic uterus; ovarian streaks) in females

Skeletal

See the list below:

• Long slender fingers with additional flexion creases

• Long narrow chest

• Hypoplastic widely spaced nipples

• Hypoplasia or duplication of thumbs and great toes

• Talipes equinovarus

• Hypoplasia of pubic bones

• Vertebral and rib anomalies

• Defective calvaria ossification

• Scoliosis

• Kyphosis

• Osteoporosis

• Delayed bone maturation

• Sacral dimple

• Split hand/foot malformation

Immune system

See the list below:

• Infection-prone

• Immunodeficiency

Dermatoglyphics

See the list below:

• Hypoplastic dermal ridges

• Transverse palmar creases (25%)

• Excess of digital arches

• t or t'

Fetal phenotype

See the list below:

• Minor anomalies - Scalp defect, hypertelorism usually with a prominent glabella, pulmonary isomerism, common mesentery, hypospadias, sacral dimple

• Major anomalies - Intrauterine growth retardation, microcephaly, cleft palate, corpus callosum agenesis, ventricular septal defect, diaphragmatic hernia, renal hypoplasia

Frequency of clinical findings in WHS

Present in greater than 75% of patients[4, 5] :

• Typical facial appearance - "Greek warrior helmet" appearance of the nose (wide nasal bridge continuing to the forehead), high-arched eyebrows, hypertelorism, epicanthus, high anterior hairline, short philtrum, downturned corner of the mouth
• Microcephaly
• Low-set ears with pits or tags
• Intrauterine growth restriction (IUGR)/postnatal growth deficiency
• Hypotonia with decreased muscle bulk

Present in 50-75% of patients[4, 5] :

• Skeletal anomalies - Kyphosis and scoliosis with malformed vertebral bodies, accessory or fused ribs, clubfeet, split hand
• Skin - Hemangiomas, marble and/or dry skin
• Craniofacial asymmetry
• Dental anomalies - Delayed dentition, taurodontism in the primary dentition, peg-shaped teeth, dental agenesis
• Ptosis

Present in 25-50% of patients[4, 5] :

• Heart murmur secondary to congenital heart defect, most commonly atrial septal defects; pulmonary stenosis, ventricular septal defects, patent ductus arteriosus, aortic insufficiency, and tetralogy of Fallot are also seen
• Ophthalmologic anomalies - Exodeviation, nasolacrimal obstruction, eye or optic nerve coloboma
• Unilateral or bilateral cleft lip/palate
• Stereotypies - Hand washing/flapping, rocking

WHS is caused by a deletion in the terminal band of the short arm of chromosome 4 (band 4p16.3) and is considered a contiguous gene syndrome with contribution from several genes (WHSC1, WHSC2, LEMT1, TACC3, FGFR3) located in a 1.5-1.6 Mb region on the distal 4p16.3.[13] The genetic mechanisms involved are as follows:

• De novo deletion (50-60% of cases)
• Unbalanced translocation (40-45% of cases) - Either  de novo or inherited from a parent with a balanced translocation; the most commonly observed translocation involves a rearrangement of distal 4p and 8p
• Other complex rearrangements leading to a 4p16.3 deletion - Ring 4 chromosome, 4p-mosaicism
• See the image below.

Multiple genetic mechanisms are described in the literature.

An alternative mechanism of familial recurrence of a microdeletion syndrome was described by Faravelli et al, who reported a case of familial recurrence of WHS involving a previously unreported expansion of the deletion during the mother-to-son transmission.[17] The report described a mother with partial WHS, facial "gestalt,” borderline mental delay, a few episodes of seizures as a child, normal weight and head circumference, height at the lower limit of the reference range, and a smaller 4p deletion that spanned the 1.5-Mb region from locus D4S96 to the telomere.

Molecular analysis of various patients localized the critical region to the approximate 450-700 kb between D4S168/FGFR3 and D4S166/D4S43. The chromosome band 4p16.3 region also contains a gene called DFNA6, which encodes for autosomal dominant nonsyndromic hereditary hearing loss.

Using genotype-phenotype correlation analysis in 8 informative patients, Zollino et al (2003) characterized the following minimal diagnostic criteria for this condition: presence of typical facial appearance, mental retardation, growth delay, congenital hypotonia, and seizures.[18] They also mapped this basic phenotype outside the currently defined WHS critical region (WHSCR) and designated a new critical region, WHSCR-2.

LETM1 has been proposed as a candidate gene for the neuromuscular aspects of the WHS phenotype. Its position immediately distal to the critical region means that it is deleted in almost all affected individuals. In yeast, it has been shown to be involved in mitochondrial potassium homeostasis.[19, 20]

A patient with developmental delay and several facial characteristics reminiscent of WHS who carries a terminal 4p16.3 deletion of 1.691 Mb minimally and 1.698 Mb maximally was reported.[21] This deletion contains the FGFRL1 gene but does not include the WHSC1 gene. Given its expression pattern and its involvement in bone and cartilage formation during embryonic development, the FGFRL1 gene represents a plausible candidate gene for part of the facial characteristics of WHS in patients with 4p16.3 deletion.

A microdeletion proximal to a critical deletion region is associated with mild WHS.[22]

A study by Corrêa et al suggested that the varied phenotypes of WHS and their associated symptoms can be linked to particular cell signaling pathways, including dopamine receptor, fibroblast grow factor–activated receptor activity, and nicotinamide adenine dinucleotide (NAD+) nucleosidase activity pathways.[23]

A study by Gofin et al on a female fetus that had a 4p16.3 deletion and a male infant with compound heterozygous missense variants in FGFRL1 indicated that an association exists between deleterious FGFRL1 variants and the development of congenital diaphragmatic hernias. The investigators found evidence that in WHS, the critical region for congenital diaphragmatic hernia can be narrowed to a region stretching approximately 1.9 Mb in which FGFRL1 is located.[24]

Genetic testing

Diagnosis of WHS is confirmed by the detection of a deletion in the WHSCR.

Chromosomal microarray

This leads to diagnosis in greater than 95% of probands.

Cytogenetic analysis (routine and high resolution) 

This detects 50-60% of WHS.

Fluorescence in situ hybridization (FISH)

FISH using a WHCR probe detects more than 95% of deletions in WHS. Molecular cytogenetic studies using FISH allow the diagnosis to be made in patients with very small deletions or cryptic translocations.

FISH uses genetic markers that have been precisely localized to the area of interest. The absence of signal from either the maternal or paternal allele for the marker indicates monosomy for that chromosomal region.

Commercially, D4S96 or D4Z1 chromosome band 4p16.3–specific probe (Wolf-Hirschhorn region, Vysis, Inc) is available for FISH study.

Immune workup

Patients should be assessed for common variable immunodeficiency, immunoglobulin A (IgA) and immunoglobulin G2 (IgG2) subclass deficiency, IgA deficiency, impaired polysaccharide responsiveness, and normal T-cell immunity.

Imaging studies in WHS include the following:

• Radiography - May reveal delayed bone maturation, microcephaly, hypertelorism, micrognathia, anterior fusion of vertebrae, fused ribs, dislocated hips, proximal radioulnar synostosis, clubfeet, and split hand/foot abnormality
• Echocardiography - Should be obtained in all patients to evaluate for heart defects
• Renal ultrasonography - Used to detect renal anomalies
• Magnetic resonance imaging (MRI) and computed tomography (CT) scanning - May reveal underlying brain pathology, including agenesis of the corpus callosum and ventriculomegaly

In a study of 10 prenatal cases of Wolf-Hirschhorn syndrome (WHS), Xing et al found that the most common prenatally detected ultrasonographic features of the condition were intrauterine growth retardation (97.7%) and typical facial appearance (82.9%). Other phenotypic characteristics found ultrasonographically included renal hypoplasia (36.2%), cardiac malformation (29.8%), cleft lip and palate (25.5%), cerebral abnormalities (25.5%), skeletal anomalies (21.3%), and increased nuchal translucency/nuchal fold thickness (19%).[25]

These include the following:

• Electroencephalogram-video monitoring - To evaluate for atypical or subtle seizures in children (aged 1-6 years)
• Swallowing study - For feeding difficulty
• Comprehensive audiologic and otologic evaluation - To rule out possible hearing impairment
• Ophthalmologic examination
• Developmental testing and referral to early intervention and appropriate school placement
• Specific growth charts - Should be used to monitor growth parameters in patients with WHS between birth and age 4 years ^[11]

Gastrostomy may be necessary in infancy to protect the airway of patients with major feeding difficulty.

Medical care is supportive in patients with Wolf-Hirschhorn syndrome. The underlying disorder has no known treatment.

• Gavage feeding and/or gastrostomy - This is indicated for feeding difficulties

• Seizure control - Sodium bromide is a helpful drug for many patients with WHS, particularly to prevent status epilepticus;[6] valproic acid is used for atypical absence seizures, and benzodiazepines are also indicated in status epilepticus

• Multidisciplinary team approach, including speech and communication therapy and sign language

• Standard care for skeletal anomalies, ophthalmologic abnormalities, congenital heart defects, and hearing loss

• Genetic counseling

  • Recurrence risk is negligible unless a parent is a translocation carrier.

  • Reassessing patients with abnormal phenotypes previously reported as cytogenetically normal is imperative because the precise diagnosis in the propositus has important reproductive implications.

  • Fluorescence in situ hybridization (FISH) can demonstrate submicroscopic translocations in cytogenetically normal parents and affected offspring.

  • Prenatal diagnosis is clinically available to families in which one parent is known to be a carrier of a chromosome rearrangement. Guidelines for prenatal genetic screening have been established.[26]

See the list below:

• Nissen-Hill fundoplication procedure is indicated for severe gastroesophageal reflux.

• Standard orthopedic surgery is recommended for foot deformities at an early age.

See the list below:

• Clinical geneticist

• Developmental pediatrician

• Neurologist

• Cardiologist

• Ophthalmologist

• Orthopedist

• Physical therapist

• Occupational therapist

• Speech language pathologist

• Audiologist

• Dentist

• Nephrologist

See the list below:

• No special diet is required.

See the list below:

• Activities are limited because of profound mental retardation and physical limitations.

Medical care is supportive in patients with WHS.

 

 

Up-to-date information about the syndrome should be made available to the families through the following organizations:

• The 4P-Support Group, Inc

  • 131 Green Cook Road

  • Sunbury, OH 43074

  • Phone: (740) 936-5095

  • E-mail: amanda@4p-supportgroup.org

• National Organization for Rare Disorders, Inc (NORD)

  • 55 Kenosia Avenue

  • Danbury, CT 06810

  • Phone: (203) 744-0100

  • Fax: (203) 798-2291

• Chromosome Deletion Outreach, Inc.

  • PO Box 724

  • Boca Raton, FL 33429-0724

  • Phone: (561) 395-4252

  • E-mail: info@chromodisorder.org