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 2009. 13: 264-67.

[3] Battaglia A; South S, Carey J (2011): Clinical utility gene card for: Wolf-Hirschhorn (4p-) syndrome. European J Human Gen. Available from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060313/

[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; 37:21-33.

[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 phenotypes in Wolf-Hirschhorn syndrome. Human Mole Genet 2012. 21: 2181-2193.

[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 cryptic chromosomal rearrangement by conventional and molecular cytogenetic techniques Biomed Res Int. 2013. 204-209. Epub 2013 Feb 3. http//dx/doi.org/10.1155/2013/209204.

[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.php/en/atlas/disease/68-chorioretinal-coloboma].

[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 INFORMATIONDominick M. Maino, OD, MEd, FAAO, FCOVD-AIllinois College of Optometry 3241 S. Michigan Ave. Chicago, Il 60616dmaino@ico.edu

INTRODUCTIONThe 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 REPORTThe 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

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

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