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sundry syndromes: Goldenhar, rubinstein-taybi, lenz, and waardenburg

sundry syndromes: Goldenhar, rubinstein-taybi, lenz, and waardenburg

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PART IV  Congenital

son Proteus possessed the ability to transform himself into any shape to avoid being

hounded by mere mortals hoping he would

foretell their future.14

• Probably the most memorable human

affected by Proteus syndrome was Joseph

Merrick, memorialized as “The Elephant


• Music legend Ray Charles, who became

totally blind by age 7, probably had glaucoma with buphthalmos.


1. Hornsby SJ, Adolph S, Gilbert CE, et al: Visual

acuity in children with coloboma, Ophthalmology

107:511–520, 2000.

2. Warburg M: Classification of microphthalmos and coloboma, J Med Genet 30:664–669, 1993.

3. Chang L, Blain D, Bertuzzi S, et al: Uveal coloboma:

clinical and basic science update, Curr Opin Ophthalmol

17:447–450, 2006.

4. Cunliffe HE, McNoe LA, Ward TA, et al: The prevalence

of PAX2 mutations in patients with isolated colobomas or

colobomas associated with urogenital anomalies, J Med

Genet 35:806–812, 1998.

5. Dutton JD: Radiology of the orbit and visual pathways,

Philadelphia, 2010, Elsevier.

6. Quah BL, Hamilton J, Blaser S, et al: Morning glory

disc anomaly, midline cranial defects and abnormal

carotid circulation: an association worth looking for,

Pediatr Radiol 35:525–528, 2005.

7. Murphy BL, Griffing JF: Optic nerve coloboma (morning

glory syndrome): CT findings, Radiology 191:59–61, 1994.

8. Parker BR, Barnes PD: Pediatric radiology: the requisites,

Philadelphia, 2009, Elsevier, p 300.

9. Saglam M, Erdem U, Kocaoglu M, et al: Optic disc

coloboma (the morning glory syndrome) and optic

nerve coloboma associated with transsphenoidal meningoencephalocele, Eur J Radiol Extra 45:71–76, 2003.

10. Kalra VB, Gilbert JW, Levin F, et al: Spectrum of MRI

findings in morning glory syndrome, Neurographics

4:56–60, 2014.

11. Murphy BL, Griffin JF: Optic nerve coloboma (morning

glory syndrome): CT findings, Radiology 191:59–61, 1994.

12. Auber AE, O’Hara M: Morning glory syndrome: MR

imaging, Clin Imaging 23:152–158, 1999.

13. Brodsky MC: Congenital optic disk anomalies. In

Brodsky MC, editor: Pediatric neuro-ophthalmology, ed 2,

New York, 2010, Springer-Verlag.

14. Wiedemann HR, Burgio GR, Aldenhoff P, et al: The

Proteus syndrome, Eur J Pediatrics 140:5–12, 1983.

15. Tibbles JAR, Cohen MM Jr: The proteus

syndrome: the elephant man diagnosed, Br Med J

293:683–685, 1986.

24  Coloboma






FIGURE 24-1  ​n ​Axial (A) T1 and (B) T1 Gd fat suppression images show a large retrobulbar mass arising from and

communicating with the posterior aspect of right globe, clearly arises in the midline and not laterally as with

staphyloma (see Chapter 32: Posterior Ocular Staphyloma). Axial (C) T2 and (D) proton density (PD) images show

a large retrobulbar mass arising from and communicating with the posterior aspect of the right globe, clearly

arising in the midline and not laterally as with staphyloma. Signal follows that in rest of globe (see Chapter 32:

Posterior Ocular Staphyloma).


PART IV  Congenital




Figure 24-2  ​n ​A, B, Axial CECT images shows increased AP dimension to globes bilaterally with a funnel-shaped

excavation of the posterior fundus at the optic disc on the left, emulating the appearance of a morning glory flower.

The pathologic process has its epicenter at or near the midline with retro displacement of optic disc. Flattening of

post oculus on right. Bilateral lens replacement surgery for cataracts. B, Keyhole defect of coloboma involving the

iris. C, Fundoscopic view of posterior coloboma with surrounding elevated pigmented rind and radially emanating straightened spokelike vessels. (A, From Simpson MG: Diversity and classification of flowering plants: amborellales,

nymphaeales, austrobaileyales, magnoliids, ceratophyllales, and monocots. In Plant systemics, Philadelphia, 2010, Elsevier.

B, from Tang J, Gokhale PA, Brooks SE, et al: Increased corneal thickness in patients with ocular coloboma. J AAPOS

10:175–177, 2006. C, from Brooks BP: Anophthalmia, microphthalmia, and uveal coloboma. In Rimoin DL, Pyeritz, Korf BR,

editors: Emery and Rimoin’s principles and practice of medical genetics, Philadelphia, 2013, Elsevier.)

24  Coloboma




Figure 24-3  ​n ​A, Axial NECT shows posterior defect near midline on right. B, Axial T2 confirms posterior coloboma

and shows extension along ON.



Figure 24-4  ​n ​A, Axial T1 shows large right retrobulbar intraconal mass with signal similar to vitreous. B, Axial

FLAIR shows large right retrobulbar intraconal mass with signal similar to vitreous. Similar but smaller retrobulbar intraconal mass on left. Bilateral colobomas.


Persistent Hyperplastic

Primary Vitreous


• Definition: Pathologic entity caused

by abnormal hypertrophy of the ocular

hyaloid system.

• Classic clue: Child presenting at or soon

after birth with leukocoria, micropthalmia,

fluid-fluid level, no calcifications, and

persistent Cloquet’s canal is virtually


• In normal embryologic development, the

primary vitreous is replaced by the adult

secondary vitreous and does not normally

hypertrophy or persist to infancy or


• Persistent hyperplastic primary vitreous

(PHPV) is the second most common

cause of leukocoria after retinoblastoma

and is a very important differential.1,2

• Microphthalmia.

• Commonly causes immature cataract

with lens opacity on computed

tomography (CT).

• More than 90% are unilateral.

• Marked vitreal hyperintensity on T1,

proton density, and T2 with conspicuous

fluid-fluid level.


Computed Tomography Features

• Microphthalmia.

• No calcifications (as in retinoblastoma).1,2

• Increased vitreous attenuation.1,2

• Enhancement of abnormal intravitreal tissue (if contrast given).

• Fluid-fluid levels from breakdown of recurrent hemorrhage.

• Lens may be small and irregular.

• Often shallow anterior chamber (type I

anterior PHPV).

• Optic nerve (ON) may be small.


Computed Tomography


• Less preferred, but may be first imaging


• Radiation to orbit undesirable.

• No calcifications (as in retinoblastoma).

Magnetic Resonance Imaging


• Characteristic hyperintense T2 signal differentiates this from retinoblastoma, which

has hypointense T2 signal.3

• Microphthalmia.

• Fluid-fluid level.

• Hypointense to isointense thin triangular

band extending from optic disc to lens.

• Marked hyperintensity of vitreous on T1,

proton density, and T2.





methemoglobin (from hemorrhagic

blood degradation products).

• Avid enhancement of fibrovascular intravitreal mass.

• Retinal detachments frequent:

• Type A detachment from ON.

• Type B detachment from point on wall

eccentric to ON.

• Exact findings depend on type:

• Anterior, posterior, or combined.

MRI Recommendations

• Preferred imaging procedure.

• Better at defining the extent of the abnormality.

• Allows follow up of patient without increasing the cumulative radiation dose.

• Better at demonstrating other findings

(e.g., for those patients who have NF1).


• Three types:

• Type I anterior.

25  Persistent Hyperplastic Primary Vitreous

• Infantile or juvenile onset glaucoma in

anterior type.

• Less frequently described in radiology


• Well described by Castillo, Wallace,

and Mukherji.4

• Type II posterior.

• Well described in radiologic literature.

• Demonstrated in Figure 25-1.

• Type III combined.

• Most common presentation of PHPV.

• Leukocoria, strabismus, and microphthalmia may be present in all three types.

Presentation and Natural History

• Child presenting at or soon after birth with

leukocoria, strabismus, and microphthalmia.

• Type I anterior PHPV not an uncommon

cause of cataract in very young children.

• May sometimes be imaged to rule out

central cause of nystagmus.

• Complications:

• Retinal detachment.

• Chronic retinal hemorrhage.


• Rare condition.

• Associations:

• Any severe ocular malformation:

• Optic dysplasia.

• Trisomy 13.

• Bilaterally suggests congenital syndrome.

• Norrie syndrome.

• PHPV, seizures, deafness, and low IQ.

• Warburg disease.

• The pathogenesis of hypertrophy of any

portion of the primary vitreous is unknown.5

• Usually unilateral.

• Greater than 90%.

• Occasionally bilateral.6

• Less than 10%.

• 6% (if you combine Pollard’s and Haddad’s

series, which range from 2.4% to 11%).7,8

Treatment and Prognosis

• Surgical goals:

• Salvage useful vision.

• Prevent or alleviate glaucoma.

• Correct amblyopia.

• Amblyopia is disorder characterized by

impaired vision in an eye that appears

normal or where visual impairment is

out of proportion to associated structural abnormality.

• Surgical management depends on type:


• Type I anterior PHPV:

• Lensectomy-membranectomy and anterior vitrectomy in pure anterior PHPV.

• Good visual outcome when amblyopia

therapy with contact lens is successful.

• Type II posterior PHPV:

• Vitrectomy in posterior PHPV where

rehabilitation deemed possible.

• Type III combined anterior and posterior


• Lensectomy may be performed when

vision is unsalvageable.


Embryology and Gross Pathology

• Primitive fetal lens and vitreous receive

blood supply from hyaloid system, which

has three sources.

• Hyaloid artery is a branch of ophthalmic

artery and is main vessel of hyaloid system.

• Supplies mainly central primary vitreous.

• Vasa hyaloidea propria.

• Supplies peripheral portion of the primary vitreous.

• Anterior ciliary vessels.

• Supplies iris and lens.

• Anterior portion of this arterial system involutes at 8 months.

• Usually present in premature infants.

• Posterior portion of this arterial system

normally regresses at 7 months.

• Occasionally present in premature infants.

• In the absence of hypertrophy, the hyaloid

system vessels regress completely.

• The anterior and posterior hyaloid vascular

systems may persist independently or together.

• Type II posterior PHPV findings include:

• Vitreous membranes.

• Stalk extending from ON to posterior lens.

• Remnant of Cloquet’s canal, which carries hyaloid artery.

• Optic disc dysplasia.

• Indistinct, possibly pigmented macula.

• Retinal folds.

• Clear lens.

• Type I anterior PHPV findings include:

• Shallow anterior chamber.

• Elongated ciliary process.

• Enlarged iris vessels.

• Cataract.

• Intralenticular hemorrhage.

• Retrolental fibrovascular membrane.

• Persistent hyaloid artery may be present.

• Adult secondary vitreous.

• Begins to form during the third month of



PART IV  Congenital

Differential Diagnosis


1. Retinoblastoma

• PHPV types include involvement of:

• Type I: anterior eye.

• Type II: posterior eye.

• Type III: combination of anterior and

posterior involvement.

• Imaging findings vary depending on the type.

• Very important differential.

• Retinoblastoma (RB) usually has calcifications.1,2

• PHPV has no calcifications.1,2

• RB vitreous: hypointense T2.

• PHPV vitreous: hyperintense T2.

2. Anterior PHPV

• PHPV is classified as anterior, posterior,

and combined.

• Type I anterior PHPV has the following


• Shallow anterior chamber.

• Elongated ciliary processes.

• Enlarged iris vessels.

• Immature cataract.

• Intralenticular hemorrhage.

• Retrolental fibrovascular membrane.

• Lens may be thin and dysplastic.

• Enhancement of ciliary body and lens

secondary to hypervascular tissues.

• Normal vitreous chamber.

• Type II posterior.

• Well described in literature.

• See section on Imaging Recommendations, earlier.

• Type III combined.

• Most frequent type.

• May have a combination of Type I and

Type II findings.9



1. Castillo M: Neuroradiology companion: methods, guidelines, and imaging fundamentals, Philadelphia, 1995, JB

Lippincott, p 327.

2. Mafee MF, Goldberg MR: Persistent hyperplastic primary

vitreous (PHPV): role of computed tomography and magnetic resonance, Radiol Clin North Am 25(4):683–692, 1987.

3. Runge, VM: Review of neuroradiology, Philadelphia, 1996,

WB Saunders, p 98.

4. Castillo M, Wallace DK, Mukherji S: Persistent hyperplastic primary vitreous involving the anterior eye,

AJNR 18:1526–1528, 1998.

5. Pruett RC: The pleomorphism and complications of

posterior hyperplastic primary vitreous, Am J Ophthalmol

80:625–629, 1975.

6. Sanghvi DA, Sanghvi CA, Purandare NC: Bilateral

persistent hyperplastic primary vitreous, Australasian

Radiol 49:72–74, 2005.

7. Haddad R, Font RL, Reeser F: Persistent hyperplastic

primary vitreous: a clinicopathologic study of 62 cases

and review of the literature, Surv Ophthalmol 23:123–

134, 1978.

8. Pollard ZF: Persistent hyperplastic primary vitreous:

diagnosis, treatment, and results, Trans Am Opthalmol

Soc 95:487–549, 1997.

9. Sun MH, Kao LY: Persistent hyperplastic primary vitreous: magnetic resonance imaging and clinical findings,

Chang Gung Med J 26:269–276, 2003.


FIGURE 25-1  ​n ​A, T1 axial MRI image shows conspicuous micropthalmia OS (left) as compared with OD (right).

There is persistence of Cloquet’s canal extending from the lens posteriorly to optic disc. Posterior chamber fluid

is markedly hyperintense compared with the normal contralateral eye. Fluid-fluid level. B, T1 sagittal MRI image

shows the previously mentioned findings as well. The more hyperintense fluid layers above denser components


25  Persistent Hyperplastic Primary Vitreous




FIGURE 25-2  ​n ​A, Ultrasound shows funnel-shaped echogenic structures corresponding to persistent remnant of

fetal hyaloid vascular system. B, Drawing depicts pertinent ultrasound findings of funnel-shaped echogenic structures from fetal hyaloid vascular system seen on accompanying ultrasound. (From Guthoff RF, Labriola LT, Stachs

O: Diagnostic ophthalmic ultrasound. In Ryan SJ, Hinton DR, Schachat AP, et al, editors: Retina, ed 5, St Louis, 2006,

Mosby, pp 1605–1623.)



FIGURE 25-3  ​n ​Gross (A) and thinner macroscopic (B) cut section through an enucleated canine specimen demonstrates characteristic Type II PHPV appearance involving posterior eye with persistent Cloquet’s canal and

hypertrophied vascular remnants. (From Yanoff M: Congenital anomalies. In Yanoff M, Sassani JW, editors: Ocular

pathology, ed 7, 2015, pp 29–52 e4. [From Yanoff M: Presented at the meeting of the Verhoeff Society, 1989.])


Congenital Orbital Teratoma


• Definition: Congenital orbital teratomas

(COTs) are rare tumors. They are usually

benign, complex masses with cystic and

solid components containing a mixture of

fat, calcium, and bone.

• Synonyms: Orbital teratomas, teratomas.

• Classic clue: Huge orbital mass

containing cystic and solid components,

displacing and deforming the globe in

young children with a complex, bizarre

imaging appearance suggesting multiple

tissue types.

• COTs are characteristically massive,

causing severe proptosis with facial and

eyelid deformity, often enlarging the orbit

two to three times.1

• COTs are usually histologically well

differentiated and benign.2

• Teratomas are encapsulated tumors

with components resembling normal

derivatives of more than one germ layer.

• Although the tissues may be normal

themselves, they may be quite different

from surrounding structures.

• Teratomas have been reported to contain hair,

teeth, bone, and very rarely more complex

structures, such as eyes, limbs, etc.3,4

• Preoperative cross-sectional imaging is


• Displacement of globe and ocular

muscles may impair ocular motility.

• Compression of optic nerve (ON) may

result in visual impairment.

• Rupture may incite a severe inflammatory



Computed Tomography Features

• Not preferred, but may be the first imaging


• Orbit exposure to radiation is undesirable.

• Irregular, heterogeneous masses with solid

and multiloculated cystic components.


• Cystic areas may contain fat-fluid levels.

• Calcifications common and may represent

bone and teeth.

• Bony orbit is typically enlarged.

• Lesion may extend intracranially or into


• Moderate contrast enhancement of solid


Magnetic Resonance Imaging


• Preferred imaging procedure is magnetic

resonance imaging (MRI) with Gd and fat


• Better at defining disease extent.

• Allows sequential follow-up of a patient without increasing the cumulative radiation dose.

• Fat saturation imaging is often quite helpful.

• Orbital mass with a heterogeneous signal

from cystic and solid elements.

• Areas with inflammation may be hyperintense on T2 and T1 1 Gd images.

• T1 shows hyperintense fatty components.

• May have fat-fluid levels.

• Upper lipid level brighter T1 and lower

T2 signal compared to lower waterkeratin layer.

• T1 1 Gd.

• Moderate rim and solid component enhancement.

• No enhancement of cyst cavities.

• Calcifications and ossifications less conspicuous than on CT have a low MRI signal

similar to cortical bone.

• May show a chemical shift artifact.

• Not specific to teratoma.

• Can be present with lipoma, dermoid,

and teratoma, etc.



• If the abnormality is not noted on prenatal

ultrasound (US), Most COTs present at, or

soon after, birth.

• COTs present with severe, rapidly progressing unilateral proptosis and prominent

craniofacial deformity.

26  Congenital Orbital Teratoma

• There is considerable eyelid stretching with

chemosis and keratopathy.

Natural History

• COTs are rare tumors derived from all

three germ cell layers.

• Intrauterine diagnosis may be made by


• Intrauterine rupture of these lesions has

been reported as a cause of fetal death.6


• Congenital and present at birth.

• Small COTs are often not discovered until

later in life.

• Usually grow larger after birth. Slower

growth has been reported in adults.7

• Do not erode bone.7

• Extension of benign teratomas into periorbital sinuses and cranial fossa has been reported.7

• Teratomas occur as a developmental anomaly with embryonic elements trapped in the

closing neural tube between the fifth and

sixth gestational weeks.

• The main systems for categorizing the

spectrum of epidermoids, dermoids, and

teratomas depend on the embryonic layers


• Epidermoid cysts contain only desquamated squamous epithelium.

• Dermoids have only dermal and epidermal


• Teratomas contain tissue from the mesoderm and endoderm.


• Prompt resection is suggested for cosmetic purposes and is a safeguard against

inadvertent rupture or malignant transformation.7

• Left unresected, rapid growth risks necrosis, hemorrhage, and globe rupture.

• Even though the globe is normal, it is

frequently not possible to preserve the eye

during surgery because of ON atrophy or

complications of exophthalmos.8

• COT is typically treated by surgical resection, usually by orbital exenteration.9

•The surgical goal is to allow normal orbitofacial development and achieve an

acceptable cosmetic conclusion.9

• In massive lesions, decompressing the tumor before resection may increase the likelihood of saving the eye.10


• Approximately 15 patients have been reported to have had visual acuity preserved

by surgery.11

• Teratomas are well encapsulated and noninvasive into adjacent tissues, although

they may extend into adjacent spaces,

such as periorbital sinuses or the intracranial cavity.

• In rare instances, for surgically inaccessible

or probably malignant cases, chemotherapy

could be considered as a first treatment.



• Teratoma means monstrous growth in Greek.12

•Congenital orbital teratomas are rare encapsulated tumors containing normal-

appearing cells derived from different

tissue types, none of which is native to

the orbit.

• Although the tissues may appear normal,

they are quite different from the surrounding structures.

• The first orbital teratoma was reported by

Holmes in 1862.7

• Holmes’ case was actually a teratoid tumor

(consisting of two germ layers).

• Teratomas may contain hair, teeth, bone,

and very rarely more complex structures,

such as eyes and limbs, etc.3,4

• Teratomas may contain one or more fluidfilled cyst(s).

• Teratomas are usually benign.

• Several types of malignant teratoma exist

and some of these are common.

• Mature teratomas are typically benign, and

more commonly found in women.

• Immature teratomas are typically malignant

and more commonly found in men.

Gross Pathology

• Mature cystic teratomas are encapsulated

tumors with mature cell types.

•Teratomas are composed of well-

differentiated lines of at least two of the

three germ layers.

• Teratomas are classified as choristomas

rather than true neoplasms.12

• Choristomas consist of normal tissues located

in abnormal sites.12

• The first orbital teratoma reported by

Holmes in 1862.7

• Holmes’ case was actually a teratoid

tumor (consisting of two germ layers).


PART IV  Congenital

• Teratomas may contain hair, teeth, bone,

and very rarely more complex structures,

such as eyes, extremities, etc.3,4

• Teratomas contain one or more fluid-filled cyst.

• Teratomas are usually benign.

• Several types of malignant teratoma exist

and are common to teratomas.

• Mature teratomas are typically benign, and

more commonly found in women.

• Immature teratomas are typically malignant and more commonly found in men.

Microscopic Pathology

• Definitive diagnosis is based on microscopic appearance.

• Teratomas belong to class of tumors

called nonseminomatous germ cell tumors


• Abnormal development of pluripotent

germ cells and embryonic cells.

• Commonly classified using the GonzalezCrussi grading system13:

• Grade 0: mature or benign.

• Grade 1: immature, probably benign.

• Grade 2: immature, possibly malignant.

• Grade 3: frankly malignant.

• Teratomas with malignant transformation:

• May metastasize.

• May contain somatic non–germ cell elements, such as carcinoma, sarcoma, or


• Mixed germ cell tumors have elements of

other germ cell tumors.

• In infants and young children they may

develop endodermal sinus tumors and


Germ Cell Types

• Ectoderm: predominant germ cell type

with hair follicles, sweat glands, and neuroglial cells.

• Mesoderm: next most frequent cell type

with fat, muscles, and bone cartilage.

•Endoderm: least common type with gastrointestinal tissues or cysts lined by

respiratory epithelium.


1. Orbital Dermoids

• Orbital dermoids (OD) are usually unilocular with single fat-fluid level; COTs

are usually multilocular with multiple fatfluid levels.

• Orbital dermoids have a mildly heterogeneous internal pattern; COTs have a

conspicuous collection of cystic and solid


• Orbital dermoids also have a capsule and

typically exhibit a thin enhancing rim.

• A chemical shift artifact may be seen in lipoma, dermoid, and teratoma.

2. Orbital Lipoma

• Orbital lipomas are extremely rare, accounting for less than 1% of orbital tumors.

• Orbital lipomas may have thin septations.

Orbital teratomas have a conspicuous collection of cystic and solid components.

• True primary orbital lipomas are as uncommon as lipomas elsewhere are common.

• Orbital lipomas are heterogeneous lowdensity masses with Hounsfield attenuation

values similar to fat.

• Orbital lipomas have high MRI T1 similar

to orbital fat. Low T1 MRI signal with fat


• T2 signal in orbital lipoma may be indistinguishable from adjacent orbital hemorrhage.

• Enhancement pattern varies with histology;

for example, angiolipomas, etc.

• Dermoids, orbital lipomas, and COTs are


3. Epidermoid Inclusions

• On CT, epidermoid inclusion cysts are usually similar in appearance to water or cerebral spinal fluid.9 This is probably because

of their proteinaceous content.

4. Lymphangiomas

• Multilocular.

• Do not contain fat or calcifications.9

5. Cephaloceles

• Contain cerebrospinal fluid.

• Generally have adjacent osseous abnormalities.

• Unlike dermoids and teratomas, do not

contain lipid.9

6. Microphthalmos with cystic eye

• Small cystic eye is in clinician’s differential

diagnosis of COT.7

• Lacks the myriad of pathologic findings on

imaging studies found on COTs and is not

a problem for the radiologist.

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sundry syndromes: Goldenhar, rubinstein-taybi, lenz, and waardenburg

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