Wolf-Hirschhorn Syndrome (WHS, OMIM 194190) is a rare congenital malformation syndrome caused by a partial deletion of the short arm (p) of chromosome 4. It is characterized by “Greek warrior helmet” facies, central nervous system disorders including seizures and structural defects, and intrauterine growth restriction, among numerous other systemic anomalies.  Ophthalmic and orbital developmental abnormalities have been described in up to 40% of WHS patients, including orbital and eyelid malformations, nystagmus, microphthalmos, microcornea, peripheral corneal scleralization, Peter's anomaly, foveal hypoplasia, glaucoma, and colobomas of the eyelid, choroid, retina, or iris [1,2].

The ophthalmologist may be called to the neonatal intensive care unit (NICU) for evaluation of a variety of ocular conditions seen with WHS. Here, we detail the ocular findings that initially were suspicious for congenital glaucomatous optic nerves and describe the associated systemic features of WHS.

The subject was female, born by spontaneous vaginal delivery at gestational age 37 weeks and 1 day, with a birth weight of 2,045 grams, birth height of 46 centimeters (cm), and birth head circumference of 30 cm with APGAR scores of 9 and 9 at 1 and 5 minutes, respectively.

The pregnancy was complicated by intrauterine growth restriction with incomplete formation of the corpus callosum with colpocephaly on the fetal MRI scan. The infant at birth was described as small for gestational age with a small head, a broad nasal bridge, canthal folds, small palpebral fissures, posteriorly rotated and pointed helices, and hypertonic muscle tone, with wide set and hypoplastic nipples, a left club foot, and small toe nails. Small kidneys (right kidney measured 3.1 cm, left kidney measured 2.7 cm) that were otherwise structurally normal were revealed on the renal ultrasound. An echocardiogram demonstrated newborn pulmonary hypertension, moderate secundum atrial septal defect with left to right flow, small to moderate patent ductus arteriosus with left to right flow, mild pulmonary valve stenosis, and moderate right ventricular hypertrophy (follow up echocardiogram demonstrated resolution of the patent ductus arteriosus at 1 week). Head ultrasound demonstrated a grade 1 intraventricular hemorrhage on the left. Profound sensorineural hearing loss at 2000-4000 Hertz in the right ear and normal hearing in the left ear were measured.

Chromosomes and microarray testing resulted on the subject’s 7^th day of life, revealing a deletion of 4p15.3, consistent with WHS.

Ophthalmic examination had been initiated when the subject was 4 days old before the diagnosis of WHS. External exam was significant for hypertelorism with normal eyelids and eyelashes without colobomas in either eye or a normal anterior segment examination.  Dilated fundus exam revealed incomplete retinal vasculature to anterior zone 3. The optic nerves looked abnormal with large cup to disc ratios, 0.9 right and 0.8 left eye, with intact rims with anomalous structure.  There were no colobomas in either eye. The average intra-ocular pressures (IOPs) measured with Tonopen in millimeters of mercury (mm Hg) was 13.7 right eye and 15.3 left eye.

The increased cup to disc ratio was suspicious for glaucoma, but the intraocular pressures were not elevated. Corneas were clear and the diameters were 11 mm vertically and 11 mm horizontally bilaterally. The constellation of findings was labeled as ‘glaucoma suspect’ and managed with serial biweekly exams with IOPs in the normal range in the low teens. Once the diagnosis of WHS was established by the pediatric geneticist, the suspicious glaucomatous optic nerves were found to be consistent with the ‘congenital cavitary disc anomaly’ associated with the syndrome (Figures 1 and 2).

The deletion of 4p15.3 in our subject was consistent with WHS, which is caused by a variety of changes to the short arm of chromosome 4. It is reported that 55-75% of cases of WHS are due to de novo terminal deletions, 13-40% due to unbalanced translocations, and 5-12% due to other cytogenetic abnormalities [3]. There was no known family history of genetic disease in our patient, so we suspect a de novo mutation in this case.

WHS is estimated to occur in 1/50,000 – 1/20,000 births with a male to female incidence ratio of 1:2 [4]. In a study of 87 patients with WHS in the US and Italy, 93% of patients had seizure disorder, 80% had intrauterine growth restriction, 80% had structural abnormalities in the central nervous system, 60% had skeletal anomalies, 50% had heart lesions, 50% had abnormal tooth development, and 40% had hearing loss [4]. Almost all patients demonstrated developmental delay and hypotonia, with 50% able to walk alone or with support. It was also found that the size of the deletion was proportional the severity of the facial phenotypic malformations. Our patient had intrauterine growth restriction, incomplete formation of the corpus callosum with colpocephaly, left club foot, structural heart defects, and sensorineural hearing loss all consistent with the diagnosis of WHS.

Ophthalmic and orbital developmental abnormalities have been described in up to 40% of WHS patients, including hypertelorism, downslanting palpebral fissures, upper lid colobomas, epicanthal folds, shallow orbits, nasolacrimal drainage system obstruction, ptosis, eyelid hypoplasia, nystagmus, exotropia, microphthalmos, microcornea, peripheral corneal scleralization, Peter's anomaly, foveal hypoplasia, glaucoma, refractive errors (hyperopia greater than 2.5 diopters, myopia greater than one diopter, astigmatism greater than one diopter, and anisometropia greater than two diopters), and colobomas of the eyelid, choroid, retina, optic nerve, or iris [1,2]. Our subject was only found to have bilateral congenital optic disc anomalies, hypertelorism, and exotropia.

Dickmann et al. described that patients with WHS have a higher incidence of divergent strabismus than would be expected in the general population of patients with strabismus, where esodeviations are much more common [2].Our subject was found to have an exodeviation, consistent with this finding.

Patients with WHS and glaucoma have been hypothesized to have large deletions in chromosome 4p that include a gene or genes that may be responsible for a dominant form of congenital glaucoma [5]. The diagnosis of congenital glaucoma in a patient with WHS must be suspected early on, with serial corneal examinations and diameter and IOP measurements [5].

Descriptions of the optic nerve in patients with WHS have varied in the published literature, including: megalopapilla, optic nerve coloboma, morning glory disc anomaly, dysplastic, glaucomatous, and congenital cavitary optic disc anomaly [1]. Ali et al. published an overview of the different descriptions and decide that ‘congenital cavitary optic disc anomaly’ is the best descriptor of this optic nerve appearance [1]. Our subject had physiologic IOPs and corneal diameters with no corneal clouding, but is being monitored carefully with serial examinations.