Wolf-Hirschhorn Syndrome Clinical Presentation

Updated: Feb 15, 2015
  • Author: Harold Chen, MD, MS, FAAP, FACMG; Chief Editor: Luis O Rohena, MD  more...
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Presentation

History

The following may be observed in patients with Wolf-Hirschhorn syndrome:

Pregnancy history

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  • Intrauterine growth retardation
  • Decreased fetal movements
  • Hypotrophic placenta

Developmental history

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  • Delayed psychomotor development
  • Difficulty in ambulation, often with ataxic gait
  • Seizures (50%)

Behavior history

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  • 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
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Physical

Studies of large samples of individuals, including those with submicroscopic deletions and those with a derivative chromosome 4, [8] have led to the recognition of a more complete continuum of the phenotype, pointing out a much wider clinical spectrum than previously thought. [9, 10]

Growth

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  • Prenatal onset growth deficiency followed by postnatal growth retardation ( short stature)

CNS

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  • Developmental delay and mental retardation of varying degree, microcephaly, seizures, congenital hypotonia with muscle hypotrophy particularly of the lower limbs, hypoplasia of cerebellum, cavum or absent septum pellucidum, agenesis of corpus callosum, hypoplasia or absence of olfactory bulbs and tracts, microgyria, migration defects, and hydrocephalus have been reported.
  • A comparison of cognitive-behavioral features of 19 children with Wolf-Hirschhorn syndrome and 26 children with 1 of 3 other subtelomeric deletions. [11] Children with Wolf-Hirschhorn syndrome to be more severely impacted cognitively than children from the other groups. The overall adaptive behavior in children with Wolf-Hirschhorn syndrome is lower compared with children with other subtelomeric deletions. Children with Wolf-Hirschhorn syndrome exhibit strengths in socialization skills comparable to the other groups. The proportion of children with Wolf-Hirschhorn syndrome with autism or autisticlike features is significantly lower than the rates of autism found in the other subtelomeric disorders.

Skull

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  • Frontal bossing
  • High frontal hairline
  • Hemangioma over forehead or glabella
  • Scalp defect with or without underlying bony defect

Face

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  • Characteristic dysmorphic features including prominent glabella
  • Hypertelorism
  • Broad-beaked nose
  • Frontal bossing, collectively described as "Greek warrior helmet" facies (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.

Eyes

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  • 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

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  • Broad or beaked nose
  • Nasolacrimal duct stenosis or atresia

Mouth

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  • Short upper lip
  • Short philtrum
  • Cleft lip or palate
  • Bifid uvula
  • Carplike mouth
  • Micrognathia
  • Retrognathia

Teeth

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  • Hypodontia

Ears

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  • Low-set ears
  • Large, floppy, or misshapen ears
  • Microtia
  • Preauricular dimples
  • Chronic otitis media with effusion
  • Sensorineural hearing loss

Cardiovascular

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Pulmonary

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GI

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  • Diastasis recti
  • Umbilical or inguinal hernias
  • Accessory spleens
  • Absent gallbladder
  • Diaphragmatic hernia

Genitourinary

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  • 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

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  • 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

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  • Infection-prone
  • Immunodeficiency

Dermatoglyphics

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  • Hypoplastic dermal ridges
  • Transverse palmar creases (25%)
  • Excess of digital arches
  • t or t'

Fetal phenotype

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  • 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
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Causes

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  • Wolf-Hirschhorn syndrome 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. [9] The cause in 87% of cases is a de novo interstitial deletion of preferential paternal origin. The remaining 13% are due to unbalanced product of a parental chromosomal rearrangement, usually of a reciprocal translocation. The number of translocations may be higher because fluorescence in situ hybridization (FISH) has demonstrated submicroscopic translocations in cytogenetically normal parents and affected offspring. 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).
  • A new mechanism of familial recurrence of a microdeletion syndrome has been described. Faravelli et al reported a case of familial recurrence of Wolf-Hirschhorn syndrome involving a previously unreported expansion of the deletion during the mother-to-son transmission. [12] The report described a mother with partial Wolf-Hirschhorn syndrome, 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. [13] They also mapped this basic phenotype outside the currently defined Wolf-Hirschhorn syndrome 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 Wolf-Hirschhorn syndrome 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. [14, 15]
  • A patient with developmental delay and several facial characteristics reminiscent of Wolf–Hirschhorn syndrome who carries a terminal 4p16.3 deletion of 1.691 Mb minimally and 1.698 Mb maximally was reported. [16] 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 Wolf–Hirshhorn syndrome in patients with 4p16.3 deletion.
  • A microdeletion proximal to a critical deletion region is associated with mild Wolf-Hirschhorn syndrome. [17]
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