Wolf-Hirschhorn syndrome (WHS) is a chromosome 4p deletion syndrome, first described by Cooper and Hirschhorn in 1961, followed by report of Wolf et al. in 1965. The incidence is estimated to be approximately 1 in 50,000 births.
GENETICS/BASIC DEFECTS
1. Caused by the deletion of the distal short arm of chromo- some 4
a. Variable size of the deletion
b. Deletion of the terminal band (4p16.3): essential for full expression of the phenotype
c. Identification of a 165 kb minimal critical region (WHSCR) within 4p16.3
d. Mechanism of deletions
i. De novo deletions (75%): interstitial deletion of preferential paternal origin in 85–90%
ii. Deletions resulting from unusual cytogenetic abnormality (12%) such as ring chromosome 4 iii. Deletions resulting from unbalanced product of a
parental chromosomal rearrangement, usually of a reciprocal translocation (10–15%)
2. Types of chromosome abnormalities
a. Detectable by conventional cytogenetic technique:
large deletions
b. Detectable only by molecular methods i. Terminal microdeletions
ii. Interstitial microdeletions iii. Cryptic translocations 3. Genotype-phenotype correlation
a. Patients with a large 4p16.3 deletion i. Severe mental and growth retardation ii. Major malformations
iii. Seizures
iv. Characteristic facial appearance with wide fore- head, large and protruding eyes, hypertelorism, prominent glabella, down-turned mouth, and micrognathia
b. Patients with a 4p16.3 microdeletion i. Milder phenotype
ii. Lack congenital malformations
c. Using genotype-phenotype correlation analysis in eight informative patients, Zollino (2003) character- ized the following distinctive WHS clinical signs that represent the minimal diagnostic criteria for this con- dition, and mapped this basic phenotype outside the currently defined WHSCR and designated as a new critical region, WHSCR-2.
i. Presence of typical facial appearance ii. Mental retardation
iii. Growth delay iv. Congenital hypotonia
v. Seizures
4. LETM1
a. A gene deleted in WHS, encodes mitochondrial pro- tein
b. Current evidence suggests that at least some (neuro- muscular) features of WHS may be caused by mito- chondrial dysfunction.
CLINICAL FEATURES
1. Maternal gestational history a. Intrauterine growth retardation b. Decreased fetal movements c. Small placenta
2. Developmental history
a. Delayed psychomotor development
b. Difficulty in ambulation, often with ataxic gait c. Seizures (50% of cases)
3. Behavior history a. Stereotypes
i. Holding the hands in front of the face ii. Hand-washing or flapping
iii. Patting self on chest iv. Rocking
v. Head shaking vi. Stretching of legs b. Absence of speech
c. Babbling or guttural sounds, occasionally modulated in a communicative way
d. Comprehension limited to simple orders or to a specific context
e. Affect disorder that improves over time f. Walking with or without support g. Self-feeding
h. Helps in dressing and undressing self
i. Improved abilities and adaptation to new situations j. Communicative abilities and verbal comprehension
with extension of the gesture repertoire and decreased occurrence of withdrawal and anxiety behaviors 4. Growth: severe growth retardation (short stature) 5. CNS
a. Profound mental retardation b. Microcephaly
c. Seizures (50–100%)
d. Congenital hypotonia with muscle hypotrophy partic- ularly of the lower limbs
e. Malformation (33%)
i. Hypoplasia of cerebellum
ii. Cavum or absent septum pellucidum iii. Agenesis of corpus callosum
iv. Hypoplasia or absence of olfactory bulbs and tracts v. Microgyria
vi. Migration defects vii. Hydrocephalus 1047
6. Skull
a. Frontal bossing b. High frontal hairline
c. Hemangioma over forehead or glabella
d. Scalp defect with or without underlying bony defect 7. Face: characteristic dysmorphic features collectively
described as “Greek warrior helmet” facies (prominent glabella, hypertelorism, broad beaked nose, and frontal bossing)
8. Eyes
a. Hypertelorism
b. Down-slanting palpebral fissures c. Epicanthal folds
d. Strabismus e. Coloboma
f. Proptosis due to hypoplasia of orbital ridges g. Ectopic pupils
h. Esotropia i. Ptosis
j. Microphthalmia k. Megalocornea
l. Sclerocornea m. Cataracts
n. Hypoplastic anterior chamber and ciliary body of iris o. Persistence of lenticular membrane
p. Hypoplastic retina with formation of rosettes q. Cup-shaped optic discs
r. Congenital nystagmus s. Early onset glaucoma
t. Rieger anomaly 9. Nose
a. Broad or beaked nose
b. Nasolacrimal duct stenosis or atresia 10. Mouth
a. Short upper lip b. Short philtrum c. Cleft lip or palate d. Bifid uvula e. Carplike mouth
f. Micrognathia g. Retrognathia 11. Ears
a. Low-set ears
b. Large, floppy, or misshapen ears c. Microtia
d. Preauricular dimples
e. Chronic otitis media with effusion f. Sensorineural hearing loss 12. Cardiovascular
a. Atrial septal defect b. Ventricular septal defect
c. Persistent left superior vena cava d. Valve abnormalities
e. Complex cardiac defects 13. Pulmonary
a. Bilateral bilobed or trilobed lungs
b. Lung hypoplasia secondary to diaphragmatic hernia 14. GI anomalies
a. Diastasis recti
b. Umbilical or inguinal hernias
c. Accessory spleens d. Absent gallbladder e. Diaphragmatic hernia
f. Intestinal malrotation 15. Genitourinary anomalies (25%)
a. Hypoplastic kidneys b. Cystic dysplastic kidneys c. Unilateral renal agenesis d. Hydronephrosis
e. Exstrophy of the bladder f. Hypoplastic external genitalia
g. Cryptorchidism and hypospadias in males
h. Hypoplastic müllerian derivatives (i.e., agenesis of vagina, cervix or uterus; hypoplastic uterus; ovarian streaks) in females
16. Skeletal anomalies (60–70%)
a. Long slender fingers with additional flexion creases b. Long narrow chest
c. Hypoplastic widely spaced nipples
d. Hypoplasia or duplication of thumbs and great toes e. Talipes equinovarus
f. Hypoplasia of pubic bones g. Vertebral and rib anomalies h. Defective calvarium ossification
i. Scoliosis j. Kyphosis k. Osteoporosis
l. Delayed bone maturation m. Sacral dimple
17. Infection-prone, immunodeficiency 18. Malignant hematological disorders
a. Myelodysplastic syndrome b. Leukemia
19. Dermatoglyphics
a. Hypoplastic dermal ridges b. Transverse palmar creases (25%) c. Excess of digital arches
d. t or t’
20. Pitt-Rogers-Danks syndrome (PRDS) a. Phenotypic overlap with WHS
i. Prenatal and postnatal growth retardation ii. Microcephaly
iii. Seizures
iv. Developmental delay v. Facial features
a) A wide mouth b) Short upper lip c) Flat philtrum d) Beaked nose e) Prominent eyes
f) Maxillary hypoplasia
b. Microdeletion of 4p16.3 detected in most cases c. Current evidence suggests that PRDS is not a separate
clinical entity but may represent the milder end of the WHS spectrum.
21. Fetal phenotype a. Major anomalies
i. Intrauterine growth retardation ii. Microcephaly
iii. Cleft palate
iv. Corpus callosum agenesis v. Ventricular septal defect vi. Diaphragmatic hernia vii. Renal hypoplasia b. Minor anomalies
i. Scalp defect
ii. Hypertelorism usually with a prominent glabella iii. Pulmonary isomerism
iv. Common mesentery v. Hypospadias vi. Sacral dimple 22. Prognosis
a. Crude infant mortality rate: 17%
b. Mortality rate in the first two years: 21%
c. Cases with large de novo deletions are more likely to die than those with smaller deletions.
d. Causes of death i. Birth anoxia
ii. Withdrawal of treatment after premature delivery iii. Lower respiratory tract infections
iv. Sudden unexplained death
v. Congenital anomalies, such as congenital heart disease, dysplastic kidneys, renal hypoplasia, diaphragmatic hernia, and pulmonary hypoplasia
DIAGNOSTIC INVESTIGATIONS
1. Conventional cytogenetic studies: most common method to detect chromosome arm 4p deletions (60–70% of deletions)
2. High resolution cytogenetic studies: to detect smaller deletions of chromosome band 4p16.3
3. Fluorescence in situ hybridization (FISH) using Wolf- Hirschhorn critical region probe: detecting >95% of dele- tions. 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 the paternal allele for the marker is indicative of monosomy for that chromosomal region.
4. Immune workup
a. Common variable immunodeficiency
b. Immunoglobulin A (IgA) and immunoglobulin G2 (IgG2) subclass deficiency
c. IgA deficiency
d. Impaired polysaccharide responsiveness e. Normal T-cell immunity
5. Radiography
a. Delayed bone maturation b. Microcephaly
c. Hypertelorism d. Micrognathia
e. Anterior fusion of vertebrae f. Fused ribs
g. Dislocated hips
h. Proximal radioulnar synostosis i. Clubfeet
6. Echocardiography to detect heart defects 7. Renal ultrasound to detect renal anomalies
8. MRI and CT scans to demonstrate underlying brain pathology including agenesis of corpus callosum and ventriculomegaly
9. EEG for seizure monitoring
10. Swallowing study for feeding difficulty
11. Comprehensive audiologic and otologic evaluation to rule out possible hearing impairment
12. Ophthalmologic examination 13. Developmental testing
a. Speech and motor evaluation b. Appropriate psychometric evaluation
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. De novo deletion cases: no significant increased risk
ii. Deletion resulting from a parental chromosomal rearrangement: increased risk for unbalanced product in offspring
b. Patient’s offspring: reproduction unlikely due to men- tal retardation
2. Prenatal diagnosis available to families in which one par- ent is known to be a carrier of a chromosome rearrange- ment by amniocentesis, CVS, or PUBS
a. Ultrasonography to detect in utero manifestation of distinct phenotype
i. Severe intrauterine growth retardation ii. Microcephaly
iii. Hypertelorism, usually with prominent glabella iv. Micrognathia
v. Cleft lip and palate vi. Diaphragmatic hernia b. Chromosome analysis
i. Conventional karyotyping ii. FISH
iii. Whole chromosome painting 3. Management
a. Multidisciplinary team approach
i. Early intervention program to improve motor development, cognition, communication, and social skills
ii. Speech, physical, and occupational therapies iii. Appropriate school placement
b. Manage feeding difficulties and failure to thrive i. Gavage feeding
ii. Gastrostomy
iii. Occasional gastroesophageal fundoplication c. Anticonvulsants for seizure control
d. Orthopedic care for skeletal abnormalities i. Clubfoot
ii. Scoliosis iii. Kyphosis
e. Care for possible immunodeficiency
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Fig. 1. A patient with Wolf-Hirschhorn syndrome at different ages showing characteristic facial features consisting of prominent glabel- la, hypertelorism, beaked nose, and frontal bossing, collectively described as “Greek warrior helmet” facies.
Fig. 2. A girl with WHS showing characteristic face and deletion of WHS locus (FISH).
Fig. 3. Two children with WHS showing characteristic facial features of the syndrome.
Fig. 5. Karyotype of the sister showing deletion of 4p, derived from the mother with balanced translocation (4p;8p) (partial karyotypes).
Fig. 4. Two siblings with WHS showing characteristic features of the syndrome.
Fig. 7. A fetus with WHS showing broad triangular-shaped nasal root and the flat facial profile resembling “Greek warrior helmet.” The radiographs show hypoplasia of the cervical vertebral bodies.
Fig. 6. Karyotype and FISH of another patient with Wolf-Hirschhorn syndrome.
