Wolf Hirschhorn Syndrome: A case report presented at the College of Optometrists in Vision Development Annual Meeting in Las Vegas 4/2015

1. 3241 South Michigan Avenue, Chicago, Illinois 60616
the fullest extent possible by providing single, clear,
comfortable, binocular and pathology free vision. The
plan for this patient included a prescription for full
time wear of polycarbonate spectacles for astigmatism
and monitoring alternating exotropia. The patient was
to be monitored at a home clinic and scheduled to
return to us in three months. Unfortunately, the patient
did not return for that follow up appointment.
REFERENCES
[1] Stec I, Wright TJ, Van Ommen GJB, De Boer PAJ,Van Haeringen A, Moorman
AFM, Altherr MR, Den Dunnen JT: WHSC1, a 90kb SET domain-containing
gene, expressed in early development and homologous to a Drosophila
dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is
fused to IgH in t(4;14) multiple myeloma. Human Molecular Genetics. 7:1071-
1082
[2] Dickmann A, Parilla R, Salerni A, Savino G, Vasta I, Zollino M, Petroni S,
Zampino G: Ocular manifestations in Wolf-Hirschhorn syndrome. JAAPOS
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[3] Battaglia A; South S, Carey J (2011): Clinical utility gene card for: Wolf-
Hirschhorn (4p-) syndrome. European J Human Gen. Available from http://
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[4] Dugdale III D, Kaneshiro N: Microcephaly available from http://www.nlm.nih.
gov/medlineplus/ency/article/003272.htm
[5] Micrognathia available from http://www.nlm.nih.gov/medlineplus/ency/
article/003306.htm
[6] Van Borelm, J, De Grande S, Buggenhout, G.V, Fryns J: Speech and language
in Wolf-Hirschhorn syndrome: a case-study. J Comm Disorders 2004; 37:21-
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[7] Kerzendorfer C, Hannes F, Colnaghi R, Abramowicz I, Carpenter G,
Vermeesch J, O’Driscoll M: Characterizing the functional consequences of
haploinsufficiency of NELF-A (WHSC2) and SLBP identifies novel cellular
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[8] Venegas-Vega C-A; Fernandez-Ramirez F; Zepeda L-M; Nieto-Martinez K;
Gomez-Laguna L; Garduno-Zarazua L-M; Berumen J; Kofman S; Cervantes
A (2013): Diagnosis of familial Wolf-Hirschhorn syndrome due to a paternal
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[9] American Academy of Pediatrics: Screening Examination of Premature
Infants for Retinopathy of Prematurity available from http://pediatrics.
aappublications.org/content/117/2/572.full
[10] Paradowska-Storlarz AM: Wolf-Hirschhorn syndrome (WHS) –literature
review on the features of the syndrome [Abstract]. Adv Clin Exp Med 2014.
23: 458-489.
[11] Chorioretinal Coloboma available from http://www.atlasrleye.com/index.
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[12] Pagon R, Adam M, Bird T et al (2010): Wolf Hirschhorn Syndrome. Gene
Reviews available from http://www.ncbi.nlm.nih.gov/books/NBK1183/
[13] Wu-Chen WY, Christiansen SP, Berry SA, Engel WK, Fray KJ, Summers CG:
Ophthalmic manifestations of Wolf-Hirschhorn syndrome. JAAPOS 2004; 8:
345-348.
[14] Curtin et al: Clinical characterization and proposed mechanism of juvenile
glaucoma--a patient with a chromosome 4p deletion Wolf-Hirschhorn
Syndrome. Ophthal Genet.2010. 31:135
[15] Martinez-Quintana, E, Rodriguez-Gonzalez, F: Clinical features in adult
patient with Wolf-Hirschhorn Syndrome. Morphologie 2014. 98:86-89
[16] Hanley-Lopez Jean, Estabrooks L, Stiehm, R: Antibody Deficiency in Wolf-
Hirschhorn syndrome. J Pediat. 1998. 133:141-143
DISCUSSION/
CONCLUSION
Wolf et al. and Hirschhorn et al individually described
Wolf-Hirschhorn syndrome as occurring because
of a contiguous gene syndrome with differing
phenotypes.10
The most common ophthalmic finding
is exogtropia, with bilateral nasolacrimal obstruction
being the second most frequently encountered
anomaly in patients with WHS.3
There are several other
frequently encountered features many of which were
not noted in our patient.2,11
This particular patient had
a limited ability to communicate and cooperate during
the assessment.6
However, there are instances where
speech and language skills have developed.6
The more common ophthalmic presentation with Wolf
Hirschhorn syndrome are strabismus (exodeviations),
nasolacrimal obstruction, shallow orbits, epicanthal
folds, foveal hypoplasia and nystagmus. We provided
an appropriate refractive correction and am
monitoring the other areas of concern (glaucoma
suspect). The challenges of patients with WHS will
require the optometrist to work within a multi-
disciplinary environment so that management of
these patients can best increase their quality of life to
ABSTRACT
BACKGROUND: Wolf Hirschhorn Syndrome
(WHS) describes a series of malformations caused
by a deletion of one copy of the distal short arm of
chromosome 4p (called 4p-). WHS is characterized by
anomalies that occur in the first trimester that result in
intellectual disability, delayed development, seizures,
and a characteristic face appearance referred to as
the “Greek Warrior Helmet Face.” The extent of the 4p
deletion determines the occurrence of microcephaly,
midline defects, cardiac and renal anomalies. To
provide appropriate ophthalmic and medical care
to children with Wolf Hirschhorn syndrome, it is
important to understand this rare genetic abnormality.
A case study of a nine year and seven month old
Caucasian male with WHS is presented.
CASE REPORT: A 9 year 7 month old Caucasian
male child with Wolf-Hirschhorn syndrome presented
with a large angle exotropia, possible glaucoma
and high astigmatism. He also has hypertelorism,
developmental delays and a history of occupational
and physical therapy.
CONCLUSION: Wolf-Hirschhorn syndrome
diagnosis is determined by phenotypical expressions,
such as classic facial abnormalities and confirmed
by detection of a deletion of the Wolf Hirschhorn
critical region (WHCR) (chromosome 4P16.3). The
developmental problems vary based on the size of
the deletion while the pathogenesis is determined
by chromosome abnormalities, extent of seizures,
and systemic deviations. WHS patients can benefit
from genetic counseling, systemic treatment, ocular,
and management of psychosocial issues. This will
help the patient and families to deal with common
problems like limited speech and comprehension. Any
and all oculo-visual problems should be monitored,
diagnosed and treated as is appropriate.
KEYWORDS: Partial deletion 4p-, microcephaly,
Greek warrior helmet face, hypertelorism, wolf-
hirschhorn syndrome, seizures
Dominick M. Maino, OD, MEd, FAAO, FCOVD-A a
, Utang Ekpo b
Professor, Illinois College of Optometry a
, 4th year student, Illinois College of Optometry b
Wolf-Hirschhorn Syndrome: A Case Report
CONTACT INFORMATION
Dominick M. Maino, OD, MEd, FAAO, FCOVD-A
Illinois College of Optometry
3241 S. Michigan Ave. Chicago, Il 60616
dmaino@ico.edu
INTRODUCTION
The etiology of Wolf Hirschhorn syndrome (WHS) is
partial deletion of the short arm of chromosome 4p
(4p16.3). The WHS critical region is the smallest region
of overlap with WHS patients and is limited to 165kb.
A 25 exon 90kb gene called WHSC1 has been mapped
to the WHS critical region. It is expressed in early
development and encodes a 136kDa protein that has
four domains that are found in other development
proteins. WHSC1 is expressed with a preference for
fast growing embryonic tissues in a method that
corresponds to affected organs in patients with WHS.1
There is an estimated 30% percent of WHS patients
with anomalous ophthalmic manifestations.2
The
estimated prevalence of the disease is 1:50,000 births
with a 2:1 female/male ratio.3
WHS appearance in
patients has been described as the ‘Greek Warrior
Helmet Face” because of the broad nasal bridge
accompanying ocular hypertelorism.2
Also, this Greek
warrior face describes an enlarged glabella, high
arched eyebrow, wide nasal bridge, proptosis with a
downturned mouth, epicanthal folds and bilateral cleft
lip or palate (especially in infancy).2
Microcephaly and
micrognathia (smaller lower jaw that often interferes
with normal tooth development) are frequently noted
as well.4, 5, 6
Other anomalies include hypotonia, intra-
uterine and postnatal growth retardation, intellectual
disability and cardiac problems.6,7,8
CASE REPORT
The 9 year 7 month old child with WHS has a
noteworthy medical history. He was born full-term
after 38 weeks of gestation, birth weight of 907 grams
and reported oxygen therapy for 2-3 months in NICU
after birth. Despite being at risk for retinopathy of
prematurity based on the screening criteria reported
by the American Academy of Ophthalmologists (birth
weight of less than or equal to 1500 grams, gestational
age of 30 weeks or less or birth weight between 1500
and 2000grams or gestational age of more than 32
weeks with an unstable clinical course), no retinopathy
of prematurity was noted in this patient.9
His family
history was unremarkable with no alcohol, tobacco or
illicit drug use.
The patient was referred from another clinic for a
refractive assessment and a possible strabismus
of the right eye. The last eye examination was 2
months prior as described in the table below. Visual
acuity was not recorded at that visit, perhaps due to
limited cooperation, receptive/express speech and/
or comprehension. The mother of the patient had
not noticed the eye-turn prior to the referral but had
noticed frequent voluntary bulging of eyes. His mother
also denied seeing any squinting or other visually/
ocular induced anomalous behaviors. The patient
participated in occupational and physical therapy at
the time of this visit.
Table 1: Case Summary
Table 2: Characteristic Anomalies Associated
with Wolf Hirschhorn Syndrome and those
characteristics noted in our patient
Macula Clear
OD: Large C/D, cupping
OS: Large C/D, cupping, PPA
0.7 A/V ratio
Periphery Limited periphery secondary to poor
fixation
Additional Testing Hirschberg~60 prism diopters Alternating
Exotropia (XT) OD fixation preference
Kappa Central, steady OD, OS
Krimsky: 50 prism diopters
MEM: Attempted, poor fixation
7
Table 1: Case Summary
Chief complaint/Hx
Wolf-Hirschhorn Syndrome,
School for special needs, occupation
and physical therapy
History of Present Illness
Ocular History
Systemic History
Medications
Referred for strabismus and refractive
care, no squinting or other anomalies
noted
Glaucoma Suspect
Low kidney function
Seizure disorder
Enapril Maleate and Phenobarbital
Latanoprost qhs OU
Pediatric History Gestational age: 38 weeks, premature
delivery, Birth weight: 2 lbs, No ROP
Oxygen required: 2-3months duration in
NICU
Entrance Test Findings Abnormal mood, Oriented x3
Pinpoint pupils, dark = light OD, OS
CVF unable to test: poor fixation
Motility: poor fixation, torsional nystagmus
Anterior Segment Unremarkable
Penlight shadow test: Angles open
Posterior Segment Vitreous Clear
10
Table 3: Ophthalmic Manifestations noted in literature for Wolf Hirschhorn
Syndrome13
Ophthalmic Presentations with WHS Patient description
Out of 10 patients aged 4 months to
11 years with ophthalmic
presentations studied 13
8 patients with 4p- showed
interruptions that ranged from
band 4p14 to 4p16.3
Exodeviation 9 patients
Nasolacrimal obstruction 6 patients
Shallow Orbits 3 patients
Epicanthal folds 3 patients
Foveal hypoplasia 3 patients
Upper lid coloboma 2 patients
Optic Disc Anomalies 2 patients
Down-slanting Palpebral fissures 2 patients
Hypertelorism 1 patient
Nystagmus 1 patients
8
Macula Clear
OD: Large C/D, cupping
OS: Large C/D, cupping, PPA
0.7 A/V ratio
Periphery Limited periphery secondary to poor
fixation
Additional Testing Hirschberg~60 prism diopters Alternating
Exotropia (XT) OD fixation preference
Kappa Central, steady OD, OS
Krimsky: 50 prism diopters
MEM: Attempted, poor fixation
Table 2: Characteristic Anomalies Associated with Wolf Hirschhorn
Syndrome and those characteristics noted in our patient
Anomalies associated with WHS Anomalies present in our patient
Exodeviation Large angle Exotropia
Nystagmus Torsional Nystagmus
Seizures Seizure Disorder
Growth delays and
Developmental disability
Intellectual delay/Developmental
Delay
9
Congenital and juvenile
glaucoma
Glaucoma suspect-low risk
Facial Abnormalities:
Epicanthal folds
Hypertelorism
Proptosis
Microcephaly
Wide nasal bridge
Microagnathia
Enlarged glabella
Hypertelorism
Ocular Abnormalities
Shallow orbits
Anterior segment anomalies,
Optic disc abnormalities
Nasolacrimal obstruction
Chorioretinal colobomas
Foveal hypoplasia
Down slanting palpebral
fissures
Microcornea
Large C/D optic nerves
Table 3: Ophthalmic Manifestations noted in
literature for Wolf Hirschhorn Syndrome13