Wolf-Hirschhorn Syndrome Clinical Presentation

Updated: Jan 19, 2021
  • Author: Santina A Zanelli, MD; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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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 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]


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]


See the list below:

  • Frontal bossing

  • High frontal hairline

  • Hemangioma over forehead or glabella

  • Scalp defect with or without underlying bony defect


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


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


See the list below:

  • Broad or beaked nose

  • Nasolacrimal duct stenosis or atresia


See the list below:

  • Short upper lip

  • Short philtrum

  • Cleft lip or palate

  • Bifid uvula

  • Carplike mouth

  • Micrognathia

  • Retrognathia


See the list below:

  • Hypodontia

  • Delayed dentition

  • Taurodontism in the primary dentition

  • Peg-shaped teeth


See the list below:

  • Low-set ears

  • Large, floppy, or misshapen ears

  • Microtia

  • Preauricular dimples

  • Chronic otitis media with effusion

  • Sensorineural hearing loss


See the list below:


See the list below:


See the list below:

  • Diastasis recti

  • Umbilical or inguinal hernias

  • Accessory spleens

  • Absent gallbladder

  • Diaphragmatic hernia


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


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


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.
The result of a fluorescence in situ hybridization The result of a fluorescence in situ hybridization (FISH) study of a patient with Wolf-Hirschhorn syndrome. FISH photograph shows deletion of a locus-specific probe for the Wolf-Hirschhorn critical region (absence of a probe signal at 4p16.3).

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]