Transcript
Page 1: Nasopalpebral Lipoma-Coloboma syndrome: Clinical, radiological, and histopathological description of a novel sporadic case

CLINICAL REPORT

Nasopalpebral Lipoma-Coloboma Syndrome:Clinical, Radiological, and HistopathologicalDescription of a Novel Sporadic CaseOscar F. Chacon-Camacho,1 Monica S. Lopez-Martinez,2 Johanna Vazquez,3

Angel Nava-Castaneda,4 Fernando Martin-Biasotti,5 Raul E. Pina-Aguilar,2

Marisol Iniguez-Soto,4 Job Acosta-Garcıa,5 and Juan C. Zenteno1,6*1Department of Genetics, Institute of Ophthalmology “Conde de Valenciana,”, Mexico City, Mexico2Department of Genetics, Centro Medico Nacional “20 de Noviembre,” ISSSTE, Mexico City, Mexico3Departamento de Estomatologia Pediatrica, Hospital de Especialidades Pediatricas, Tuxtla Gutierrez-Chiapas, Mexico4Department of Oculoplastics, Institute of Ophthalmology “Conde de Valenciana,”, Mexico City, Mexico5Department of Radiology and Imaging, Institute of Ophthalmology “Conde de Valenciana,”, Mexico City, Mexico6Faculty of Medicine, Department of Biochemistry, National Autonomous University of Mexico (UNAM), Mexico City, Mexico

Manuscript Received: 11 December 2012; Manuscript Accepted: 1 February 2013

Nasopalpebral lipoma-coloboma syndrome is an extremely un-

common autosomal dominant condition characterized by con-

genital upper eyelid and nasopalpebral lipomas, colobomata of

upper and lower eyelids, telecanthus, and maxillary hypoplasia.

A few familial and sporadic cases of thismalformation syndrome

have been previously reported. Here, the clinical, radiological,

and histopathological features of a sporadic Mexican patient

with the nasopalpebral lipoma-coloboma syndrome are de-

scribed. To our knowledge, this is the first time that craniofacial

3D computed tomography imaging was used for a detailed

assessment of the facial lipoma. � 2013 Wiley Periodicals, Inc.

Key words: nasopalpebral lipoma-coloboma syndrome; lipoma;

craniofacial syndrome; telechantus; hamartoma

INTRODUCTION

Nasopalpebral lipoma-coloboma syndrome (OMIM%167730) is

an extremely uncommon autosomal dominant disease character-

ized by bilateral congenital nasopalpebral lipomas, bilateral

upper and lower eyelid colobomata, broad forehead, widow’s

peak, flaring of medial eyebrows, telecanthus, and maxillary hypo-

plasia [Penchaszadeh et al., 1982]. Additional features may include

displacedor aplastic lacrimal punctae, persistent epiphora, aberrant

eyelashes, conjunctival hyperemia, corneal and lens opacities, and

divergent strabismus [Penchaszadeh et al., 1982]. This rare syn-

dromewas first described byPenchaszadeh et al. [1982], and to date

only two familial and three sporadic cases have been reported

[Penchaszadeh et al., 1982; Akarsu and Sayli, 1991; Bock-Kunz

et al., 2000;Moreira Gonzalez and Jackson, 2003; Babu et al., 2011].

The etiology is unknown, but it has been hypothesized that a

migration defect of the neural crest cells causes abnormal develop-

ment of the craniofacial anatomy. In this work, the clinical,

radiological, and histopathological features of an additional case

of nasopalpebral lipoma-coloboma syndrome are reported.

CLINICAL REPORT

A 2-month-old Mexican female was referred to our hospital due to

bilateral congenital eyelid malformation. She was the sixth child of

nonconsanguineous and unaffected parents. Hermother was 29 and

How to Cite this Article:Chacon-Camacho OF, Lopez-Martinez MS,

Vazquez J, Nava-Castaneda A, Martin-

Biasotti F, Pina-Aguilar RE, Iniguez-Soto

M, Acosta-Garcıa J, Zenteno JC. 2013.

Nasopalpebral lipoma-coloboma syndrome:

Clinical, radiological, and histopathological

description of a novel sporadic case.

Am J Med Genet Part A 9999:1–5.

Oscar F. Chacon-Camacho and Monica S. Lopez-Martinez contributed

equally to the conduct of this research and are to be considered first

authors.�Correspondence to:

Dr. Juan C. Zenteno, Research Unit, Institute of Ophthalmology,

“Conde de Valenciana,” Chimalpopoca 14, Col. Obrera, Mexico City,

CP 06800, Mexico. E-mail: [email protected]

Article first published online in Wiley Online Library

(wileyonlinelibrary.com): 00 Month 2013

DOI 10.1002/ajmg.a.35916

� 2013 Wiley Periodicals, Inc. 1

Page 2: Nasopalpebral Lipoma-Coloboma syndrome: Clinical, radiological, and histopathological description of a novel sporadic case

her father 30 years old when she was born. Her family history was

uneventful and all siblings were healthy. The proband’s mother

received regular prenatal care and denied exposure to potentially

teratogenic agents. The patient was born via spontaneous vaginal

delivery andherbirth lengthwas51 cm(75thcentile),weight 3,050 g

(50th centile), andhad anApgar score of 9/9; noothermeasurements

were documented. Several facial abnormalities were apparent at

birth. Physical examination was performed at 2 months of age

(Fig. 1A), when she was 52 cm long (3rd centile), weighed 3,800 g

(3rd centile) and had a head circumference of 37 cm (25th

centile). At seven months (Fig. 1B), her length was 59 cm (below

3rd centile), weight 5,800 g (below 3rd centile) andOFC 41 cm (3rd

centile). Delayed physical development may have been related to

chronic malnutrition and recurrent respiratory tract infections.

Examination disclosed bilateral symmetrical accumulation of sub-

cutaneous tissue in the nasopalpebral region, extending to the

forehead and upper lip (Fig. 1A,B). This tumor was round, soft,

and displaced the inner canthi laterally causing marked telecanthus

(Fig. 1A,B). Symmetrical colobomataofupper and lower lids, located

at the junction of the inner andmiddle thirds of lids (Fig. 1C), as well

asabsenceordisplacementofupperand lower lacrimalpunctae,were

seen.Absenceof themedial eyelashes (Fig. 1C) andbilateral epiphora

were evident. In addition, she had dolicocephaly, broad forehead,

widow’speak, sparseandmaldirectedeyebrows,broadanddepressed

nasalbridge, and low-set, cuppedanddysplastic ears (Fig. 1D).Atage

7months the forehead and nasopalpebral tumors weremore promi-

nent, circumscribed to the same anatomic regions, and covering the

medial segment of the irises (Fig. 1B). Physical examination identi-

fied bilateral clinodactyly of fifth finger, but no other systemic

anomalies.

Karyotype analysis using GTG-banding was normal female (46,

XX in 30 cells). Eye ultrasound was performed at 7 months of age

demonstrating a short anteroposterior length: 18.3 mm in right

eye and 18.7 mm in left, classified as bilateral nanophthalmos

FIG. 1. Facial appearance of the patient at 2 (A) and 7 (B) months of age. A,B: Frontal view demonstrating a nasopalpebral tumor expanding

to the frontal and upper lip regions. Bilateral symmetrical upper and lower eyelid colobomata, broad forehead widow’s peak, flaring of medial

eyebrows, telecanthus were also observed. C: Bilateral symmetrical upper and lower colobomata at the junction of the inner and middle thirds,

absence of eyelashes lateral to the eyelid cleft, and telecanthus are evident on the right side. D: Right ear dysplasia with overturned helix,

crumpled ear and prominent helical root (“railroad track” ear).

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(average axial length for age: 20.1 mm) [Frazier and Green, 2002].

Computed axial and coronal tomography (CT) demonstrated no

brain malformation and confirmed the hypodense subcutaneous

tumor involving the forehead and nasal bridge, suggestive of

lipomatous tissue (Fig. 2A–C). CT with three-dimensional recon-

struction of facial bones and soft tissues showed lipomatous tissue

covering the forehead and nasopalpebral regions (Fig. 2D,E) as

well as maxillary hypoplasia and normal interorbital distance

(15 mm; Fig. 2F). A biopsy of forehead skin and subcutaneous

tissue was compatible with hamartoma of smooth muscle, mixed

with lipomatous tissue (Fig. 3A,B). Clinical findings in our patient

were compared with those in previously reported cases (Table I).

FIG. 2. Image studies. A: Computed axial tomographic scan of patient showing a hypodense lesion (white arrow) between the nasal bones

and the maxillar edge, and the globes. B: Computed axial tomographic axial scan showing well-defined hypodense tissue (white arrow) on

the superficial frontal region. C: Computed coronal tomographic image demonstrates increased tumor tissue (white arrow) on the lateral

superficial edge of the nasal region. D,E: Frontal and lateral views of computed tomography with three-dimensional reconstruction of facial

soft tissues showing abnormal lipomatous tissue on the fronto-nasal region. F: Computed tomography with three-dimensional reconstruction

of facial bones showing normal interorbital distance (15 mm) and maxillar hypoplasia.

FIG. 3. Histopathological analysis of forehead tumor biopsy showing smooth muscle tissue (white arrow) combined with lipomatous tissue

(black arrow). A: H&E 10�; B: H&E 40�.

CHACON-CAMACHO ET AL. 3

� 2013 Wiley Periodicals, Inc. 3

Page 4: Nasopalpebral Lipoma-Coloboma syndrome: Clinical, radiological, and histopathological description of a novel sporadic case

DISCUSSION

Nasopalpebral lipoma-coloboma syndrome is an extremely un-

common cranio-facial disorder reported in a few familial and

sporadic cases [Penchaszadeh et al., 1982; Akarsu and Sayli,

1991; Bock-Kunz et al., 2000; Moreira Gonzalez and Jackson,

2003; Babu et al., 2011]. The first description was by Penchaszadeh

et al. [1982], who studied a Venezuelan family with eight affected

individuals. In this pedigree, vertical and male-to-male transmis-

sion suggested autosomal dominant inheritance. Complete

penetrance was observed, although mild clinical variability in

malformations of the lacrimal punctae, corneal opacities and

strabismus occurred [Penchaszadeh et al., 1982] (Table I). Akarsu

and Sayli [1991] reported a family with seven affected individuals

over three generations. Interestingly, the propositus also showed

variability in his anomalies, such as lacrimal punctae malforma-

tions (the upper being displaced, whereas the lower were normal),

corneal opacities and conjunctival hyperemia (Table I). Midfacial

hypoplasia, listed as a cardinal feature by Penchaszadeh [1982], was

absent in the proband and his affected mother [Akarsu and Sayli,

1991]. To date, only three sporadic cases have been reported (Table

I). Bock-Kunz et al. [2000] described a young affected male who

presented all major clinical features but normal intraorbital bony

distance; mild maxillary hypoplasia, and lipomatous tissue on the

forehead and nasal bridge were demonstrated by CT. In the patient

reported here, CT scan demonstrated that the hypodense lesion in

the nasopalpebral and forehead region is composed of lipomatous

tissue. Moreover, a normal interorbital distance and presence of

lipomatous tissue were confirmed on three-dimensional CT recon-

struction of facial bones and soft tissues. To our knowledge, this

imaging technique has not been applied previously to patients with

nasopalpebral lipoma-coloboma syndrome. In 2003, Moreira et al.

reported a Russian boy with all major signs of the syndrome, but

withnormal bony anatomyandnormal intercanthal distance inCT.

Magnetic resonance imaging showed lateral displacement of the

globes due to the midline lipomatous accumulation in the naso-

palpebral area [Moreira et al., 2003]. Recently, Babu et al. [2011]

described a 16-year-old female with features of the syndrome, but

affecting only the right side of the face. This patient also had right

limbal dermoid and right iris coloboma.

TABLE 1. Clinical Characteristics in the Present Patient and Previously Familial and Sporadic Reported Subjects With NasopalpebralLipoma-Coloboma Syndrome

Features

Familial cases (FC)

Findings

frequency (%)

FC1 FC2 Sporadic cases (SC)

IV-1 III-2 II-2 III-8 III-9 III-10 Probanda 1 2 3 4

Age at diagnosis 15 m 32 y 71 y 10 y 6½ y 3½ y 5 y 2 m 1 d 16 m 16 y �Sex Ma Ma Ma Fe Fe Fe Ma Fe Ma Ma Fe �Bilateral symmetrical

nasopalpebral lipomas

þ þ þ þ þ þ þ þ þ þ þ, c 100

Bilateral symmetrical upper and

lower lid colobomas

þ þ þ þ þ þ þ þ þ þ þ, c 100

Broad forehead þ þ þ þ þ þ þ þ NR þ NR 82

Widow’s peak þ þ þ þ þ þ NR þ NR þ NR 73

Outflaring of medial eyebrow þ þ þ þ þ þ NR þ NR þ NR 73

Telecanthus þ þ þ þ þ þ þ þ þ þ NR 91

Maxillary hypoplasia þ þ þ þ þ þ NR þ þ þ NR 82

Malposition of lacrimal punctae þ, L þ, U þ, U þ, U þ, U þ, U þ, U þ, L � NR NR 73

Absence of lacrimal punctae þ, U � þ, L � � � � þ, U þ, U NR NR 37

Persistent epiphora þ þ þ þ þ þ � þ þ þ NR 82

Conjuntival hyperemia þ þ þ þ þ þ � þ NR þ NR 73

Corneal opacities � B B Le Le B � � � � NR 46

Lens opacities � R � � Le � NR � � � NR 18

Divergent strabismus þ þ þ þ þ þ NR � þ � NR 64

Ear dysplasia � � � � � � � þ � � � 9

Clinodactyly � � � � � � � þ � � � 9

Nanophthalmos

(ocular echography finding)

� � � � � � � þ � � � 9

Combined hamartoma

(histopathological finding)

� � � � � � � þ � � � 9

Characteristic:þ, present;�, absent;c, right unilateral lesions; B, bilateral anomaly; d, days; Fe, female; L, lower lids; Le, left anomaly; Ma,male; m,months; NR, not reported; R, right anomaly; U, upper lids;y, years.FC1, Penchaszadeh’s et al. family; FC2, Akarsu and Sayli’s propositus; SC1, Present case; SC2, Bock-Kunz’s et al. patient; SC3,Moreira and Jackson’s patient; SC4, Babu’s et al. patient (this patient had limbaldermoid and iris coloboma in right eye).a<No other affected relatives were described in the original article.

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Page 5: Nasopalpebral Lipoma-Coloboma syndrome: Clinical, radiological, and histopathological description of a novel sporadic case

In the patient described here, two novel clinical findings were

identified. First, ocular echography performed at age 7 months

revealed shorteningof the antero-posterior axial length, leading to a

diagnosis of bilateral nanophthalmos. Second, histopathological

examination of the nasopalpebral mass revealed a hamartoma of

smoothmusclemixedwith lipomatous tissue.Hamartomaspresent

as disorganized but benign mass, composed of cells indigenous to

the particular site [Kumar et al., 2010].

The primary defect leading to the development of the nasopal-

pebral lipoma-coloboma syndrome is unknown. No cytogenetic

abnormality has been demonstrated in these patients and other

genetic studies havenot beenperformed.Penchaszadeh et al. [1982]

proposed a pathogenic mechanism where tumor, coloboma and

other malformations might be due to local morphogenetic inter-

ference from lipomatous hamartomata. They suggested that a

mutant gene in the early phase of embryonic development could

be responsible for the production of the hamartoma of smooth

muscle in this particular region. Hence, a somatic mutation could

interfere with normal facial morphogenesis. Alterations in the

formation, migration, and subsequent development of ectomesen-

chymal neural crest cells have also been postulated as an alternative

pathogenic cause [Penchaszadeh et al., 1982].

Several conditions such as frontonasal dysplasia [Sedano and

Gorlin, 1988], MOTA syndrome [Marles et al., 1992], and fronto-

nasal encephalocele [Jackson et al., 1983] can show overlap with

nasopalpebral lipoma-coloboma syndrome. Characteristics of

these conditions include orbital hypertelorism, cranium bifidum

occultum, bifid nose, and medial cleft lip/palate (frontonasal

dysplasia) and orbital hypertelorism, oculopalpebral synechia,

microphthalmia–anophthalmia, nasal tip groove, anal stenosis

and aberrant anterolateral scalp hairline (MOTA syndrome).

Our patient did not have features suggestive of these disorders.

Considering that the syndrome is associated with facial alter-

ations alone, cosmetic surgery is relevant for the management.

Previously, surgical corrections had satisfactory results in some

patients [Sevin et al., 1991; Moreira Gonzalez and Jackson, 2003].

In conclusion, this is the sixth report of the nasopalpebral

lipoma-coloboma syndrome. Nanophthalmos and hamartoma

of smooth muscle are new features that expand the clinical spec-

trum of the disorder. The application of technologies such as whole

exome or genomic sequencing may shed light to the origin of this

unusual autosomal dominant syndrome.

ACKNOWLEDGMENTS

The authors thank Biol. Concepcion Yerena and Biol. Roberto

Guevara for chromosome analysis.

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Bock-Kunz AL, Lyon DB, Singhal VK, Grin TR. 2000. Nasopalpebrallipoma-coloboma. Arch Ophthalmol 118:1699–1701.

Frazier S, Green RL. 2002. Ultrasound of the eye and orbit. Saint Louis,USA: Mosby Co. 245 p.

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