European Journal of Medical Genetics 54 (2011) 76e81

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European Journal of Medical Genetics

journal homepage: http://www.elsevier.com/locate/ejmg

Short report

New ocular ndings in two sisters with YuniseVarn syndrome

and literature review
J. Romn Corona-Rivera a, e, *, Carmen O. Romo-Huerta b, Eloy Lpez-Marure c, Feliciano J. Ramos d,
Sara A. Estrada-Padilla e, Luz Consuelo Zepeda-Romero f
a

Servicio de Gentica, Divisin de Pediatra, Nuevo Hospital Civil de Guadalajara Dr. Juan I. Menchaca, Hospital-Escuela, Guadalajara, Jalisco, Mexico
Servicio de Oftalmologa, Divisin de Pediatra, Nuevo Hospital Civil de Guadalajara Dr. Juan I. Menchaca, Hospital-Escuela, Guadalajara, Jalisco, Mexico
Servicio de Radiologa, Divisin de Pediatra, Nuevo Hospital Civil de Guadalajara Dr. Juan I. Menchaca, Hospital-Escuela, Guadalajara, Jalisco, Mexico
d
Servicio de Pediatra, Hospital Clnico Universitario Lozano Blesa, Facultad de Medicina, Universidad de Zaragoza, Zaragoza, Spain
e
Instituto de Gentica Humana Dr. Enrique Corona-Rivera, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico
f
Servicio de Oftalmologa Peditrica, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
b
c

a r t i c l e i n f o

a b s t r a c t

Article history:
Received 13 May 2010
Accepted 24 September 2010
Available online 14 October 2010

The YuniseVarn syndrome (YVS) represents a rare autosomal recessive syndrome of easy recognition
characterized by cleidocraneal dysplasia, absence of thumbs and halluces, distal aphalangia, ectodermal
anomalies, and poor outcome. Here, we report two sisters with YVS who also had papillo-macular
atrophic chorioretinopathy with salt-and-pepper appearance that could not be attributed to environmental or metabolic causes. Our best hypothesis is that the ocular ndings in our two patients are
part of the phenotypic manifestations of YVS. We suggest that an extensive ophthalmologic examination
should be carried out in all children with YVS in order to dene the frequency and nature of the ocular
ndings in these patients.
2010 Elsevier Masson SAS. All rights reserved.

Keywords:
YuniseVarn syndrome
Cleidocranial dysostosis
Absence of the clavicles
Absent thumbs
Corpus callosum hypoplasia
Pachygyria
Chorioretinopathy

1. Introduction

2. Clinical reports

In 1980 Yunis and Varn [17] reported ve infants from three

Colombian families who had cleidocranial dysplasia, absence of
thumbs and halluces, distal aphalangia, ectodermal anomalies, and
poor outcome. Three years later, Hughes and Partington [9]
conrmed this pattern of anomalies and proposed the eponym of
YuniseVarn syndrome (YVS) for this rare autosomal recessive
syndrome (OMIM #216340). Up to date, 23 patients with YVS from
18 families have been reported [1e6,8e17]. We describe two sisters
with YVS which adds new ocular ndings to the known features of
this syndrome and review all previous reported cases for further
clinical delineation of this entity.

2.1. Patient 1

* Corresponding author at: Clnica de Asesoramiento Gentico, Instituto de

Gentica Humana Dr. Enrique Corona-Rivera, Departamento de Biologa Molecular y Genmica, Centro Universitario de Ciencias de la Salud, Universidad de
Guadalajara, Sierra Mojada 950, Edicio P, Nivel 2, Col. Independencia, 44340
Guadalajara, Jalisco, Mexico. Tel./fax: 52 33 1058 5200x3647.
E-mail address: rocorona@cucs.udg.mx (J.R. Corona-Rivera).
1769-7212/$ e see front matter 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmg.2010.09.013

The proposita was the product of the third pregnancy of

a healthy 22-year-old mother and a 25-year-old father who were
third cousins and from Mexican origin. The rst born child was
healthy and the second pregnancy was spontaneously aborted.
Pregnancy was uneventful with no exposure to toxic, traumatic,
infectious agents or radiation. Vaginal delivery was at the 36th
week of gestation. Apgar scores were 8 and 9 at 1 and 5 min,
respectively. Birth weight was 2200 g (25th percentile), length
45 cm (25th percentile), and occipitofrontal circumference (OFC)
29 cm (<3rd percentile). Physical examination at 1 month (Fig. 1)
showed general muscular hypotonia, irritability, high pitched cry,
sparse scalp hair, large fontanelles, wide cranial sutures, sparse
eyebrows and eyelashes, hypertelorism, protruding ears, hypoplastic ear lobes with cup-shaped right ear; anteverted nares, thin
upper lip, narrow-arched palate, broad secondary alveolar ridge,
labio-gingival retraction, micrognathia, loose nuchal skin, sloping
shoulders, and heart murmur. The right thumb was virtually absent
and had a hypoplastic nail, and the left was severely hypoplastic.

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77

Fig. 1. Clinical features of patient 1. Typical facial appearance (a), hands and feet malformations (b, c).

Also in the hands, there was bilateral absence of the distal and
middle phalanges of the second ngers, and absence of the
ngernails in the remainder ngers, that were short and pointed.
Halluces were absent bilaterally and toes were short and pointed
with absent nails in the 2nd to 4th toes, and hypoplastic nails in the
5th toes. Palmoplantar hyperkeratosis and transverse palmar
creases were also observed (Fig. 1b). Ophthalmologic evaluation
and uorescein angiography showed papillo-macular atrophic
chorioretinopathy with salt-and-pepper appearance (Fig. 2a), and
visual evoked potential found a reduced response. On X-ray
showed (Fig. 3) reduced ossication of the calvaria, wide cranial
sutures, large fontanelles, hypoplastic clavicles, absent ossication
of inferior sternal segment, anterior concavity on vertebral bodies,
attened acetabuli, and iliac hypoplasia. First metacarpals and
thumbs were absent bilaterally with hypoplasia of proximal
phalanges and bilateral absence of middle and distal phalanges of
the second nger, and hypoplastic middle phalanges with absence
of distal phalanges in the 2nd to 5th ngers in addition to a mild
broadening of the 2nd and 5th metacarpal bones. Halluces showed
rst metatarsal hypoplasia with absent proximal and distal
phalanges, and aplasia of the distal phalanges in the 2nd to 5th toes.
MRI of the brain showed hypoplasia of frontal lobes with pachygyria, corpus callosum hypoplasia, and hypoplasia of the cerebellar

vermis (Fig. 4a, b). Echocardiography showed a ventricular septum

defect. An ultrasonography of the hip and renal ultrasonogram was
normal. Auditory brainstem evoked potentials showed bilateral
profound sensorineural hypoacusia. Results of blood biochemistry,
thyroid function tests, and TORCH serology (toxoplasmosis, syphilis, rubella, cytomegalovirus, and herpes simplex), were normal or
negative. Screening tests for amino acids, lipids, reducing
substances, glycosaminoglycans, and organic acids yielded normal
or negative results in plasma and urine. Cytogenetic analysis with
G-banding at the 550-band level showed a 46,XX karyotype.
Muscle biopsy of the quadriceps analyzed with available histochemical stains e including periodic acid Schiff (PAS), was normal
and failed to detect vacuolization or storage phenomena.
During the rst two months of life she experienced failure to
thrive, feeding difculties, absent swallow reex, and repeated
events of cyanotic spells and aspiration pneumonias. On uoroscopy examination with liquid barium, the oral, pharyngeal, and
esophageal phases of swallowing were abnormal without evidence
of structural anomalies. A Nissen fundoplication and gastrostomy
was performed at 2 months of age with posterior satisfactory
evolution of pulmonary infection events. At the age of 1 year, her
weight was 5.200 g (5.6 SD), height 63 cm (4.8 SD), and OFC
37 cm (6.5 SD), and she showed a severe developmental delay.

Fig. 2. Eye fundus uorescein angiography showed a mottled salt eand-pepper appearance in patient 1 left eye (a), and patient 2 right eye (b).

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J.R. Corona-Rivera et al. / European Journal of Medical Genetics 54 (2011) 76e81

Fig. 3. Skeletal ndings in patient 1. Calvarial disostosis (a), hypoplastic clavicles (b) and preaxial anomalies in hands and feet (c, d).

Fig. 4. Sagittal T1-weighted (b, d) and axial T2-weighted (a, c) magnetic resonance images showing frontal lobe atrophy with pachygyria, corpus callosum hypoplasia and cerebellar
vermis hypoplasia in patient 1 (a, b) and striking similar ndings in patient 2 (c, d).

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79

Fig. 5. Clinical ndings in patient 2. Typical facial appearance and sloping shoulders (a), thumb and hallux anomalies (b, c).

Genetic counseling for an autosomal recessive inheritance disorders was offered to the parents.
2.2. Patient 2
The propositas youngest sister was born by vaginal delivery at
37.1 weeks of gestation after at uncomplicated pregnancy. We
observed absent thumbs and big toes by prenatal ultrasonography

at 29 weeks of gestation, ndings consistent with the diagnosis of

YVS in the fetus. Birth weight was 2.470 g (25th percentile), height
46 cm (25e50th percentile) and OFC 30 cm (<3rd percentile).
Apgar scores were 9 at 1 and 5 min, respectively. Physical, radiological, and MRI of the brain ndings were similar to patient 1
(Figs. 4c, d, 5, and 6), except for bilateral microtia with absence of
the lower portion of the helix, prominent antihelix, and absent
earlobe on the left ear. Toes were strikingly short and pointed with

Fig. 6. Skeletal ndings in patient 2: calvarial dysostosis (a), absence of clavicles (b) and preaxial anomalies in hands and feet (c, d).

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skin syndactyly and also showed absent nails in all ngers and toes.
Roentgenograms showed absence of the clavicles (Fig. 6b). Hip
dislocation was conrmed by ultrasound. Echocardiogram showed
a patent foramen ovale. At the 7th day of age, ophthalmologic
evaluation and uorescein angiography showed similar results that
in her sister (Fig. 2b). Findings on uoroscopy examination with
liquid barium were also abnormal and a Nissen fundoplication and
gastrostomy was performed at 1 month of age. Initially, outcome
was adequate and the patient was discharged at the age of 45 days.
She died at home of unknown causes at the age of 2 months.
Autopsy was not performed.
3. Discussion
From previous publications [1e6,8e17] and the present reported patients, we have summarized the ndings of the 25 patients
with YVS in Table 1. The true incidence of YVS remains unknown
but meets the denition of rare disease since there are only 25
known affected patients after 30 years of its original description
[17]. Patients have been reported from nearly all ethnic groups and
different countries, suggesting that there are not inter-racial
differences.
External eye anomalies are common in patients with YVS and
include short palpebral ssures [6,8,14,15,17], ocular hypertelorism
[3,10,13,17], protruding eyes [1,3,5,6,8,10,13,14,16,17], epicanthic
folds [1,2], sclerocornea [6], corneal opacity [3], cataracts [6,14,16],
and nystagmus [14]. Reports of patients with fundoscopic examination showed microphthalmia with hypoplasia of the cornea, iris,
pupils, and retina [15], deep optic cups [9], and anomalous take off
of the retinal vessels from the optic disc [1]. Ophthalmoscopic
examination was normal in the patient reported by Dworzak et al.
[5]. The female infant reported by Basel-Vanagaite et al. [2] had
retinal hemorrhages, although they were related with a massive
intracranial bleeding. Thus, the papillo-macular atrophic chorioretinopathy with salt-and-pepper appearance found on fundoscopic examination in our patients adds new ocular ndings to the
known features of the YVS syndrome. However, several congenital
and acquired diseases should be considered in the differential
diagnosis of patients with a salt-and-pepper fundus and/or diffuse
pigmentary lesions in the retina. Among them, the possibility of
a previous systemic infection by TORCH agents, and various
metabolic hereditary disorders and syndromes [7]. In our patients
TORCH serologic titles did not support an infectious etiology for the
retinopathy. A number of syndromes and hereditary diseases as the
Usher syndrome (OMIM #276900), Leber congenital amaurosis
(OMIM #204000), KearnseSayre syndrome (OMIM #530000),
Stargardt disease (OMIM #248200), BardeteBiedl syndrome
(OMIM #209900), neuronal lipoid lipofuscinosis (OMIM #610127),
BasseneKornzweig syndrome (OMIM #200100), or Retinitis Pigmentosa (OMIM #268000), are associated with pigmentary retinopathy, seen at different ages, but all are also associated with
normal eye fundus at birth. This feature makes any of those diagnoses unlikely in our patients. The possibility that the retinal
anomalies are a separate segregating condition from YVS must be
considered as well, although the probability of the co-occurrence of
two independent events in both sisters is very low. The chance of
a contiguous gene deletion cannot be entirely ruled out as well.
Therefore, our best hypothesis is that the ocular ndings in our two
patients are part of the phenotypic manifestations of YVS. Consequently, we propose that an extensive ophthalmologic examination
should be carried out in all patients in whom YVS is suspected. The
identication of further affected patients and/or the genetic basis of
this entity will clarify the validity of our hypothesis.
Consanguinity was found in 6/19 families with YVS (31.5%)
[8,10,13,17, current family], and history of conrmed or suspected

Table 1
Clinical and radiological features reported in 25 patients with YuniseVarn
syndrome.
Features

Previous cases of
YuniseVarn
syndrome (n 23)

Present report

Frequency (%)

Patient 1

Patient 2

Gender (male:female)

11:12

Birth
Mean birth weight (g  SD)
Mean birth length (cm  SD)
Mean OFC (cm  SD)

2451  313
46  2.4
31.9  2.8

2100
46
28

2470
46
30

Head and neck

Sparse scalp hair
Wide fontanelle/sutures
Protruding eyes
Anteverted nostrils
Short philtrum
Short upper lip
Labial-gingival retraction
High arched palate
Micrognathia
Low set/dysplastic ears
Loose skin in neck

20/20
19/20
13/16
16/17
9/9
16/16
9/13
11/13
18/18
22/23
8/10

(100)
(95)
(81.2)
(94.1)
(100)
(100)
(69.2)
(84.6)
(100)
(95.6)
(80)




5/19 (26.3)
4/14 (28.5)

(95.2)
(94.4)
(95)
(94.7)
(88.8)
(80)

9/16 (56.2)
8/8 (100)

(95)
(90.9)
(71.4)
(88.8)
(92.3)
(72.7)
(94.4)
(94.4)

14/15 (93.3)

16/19 (84.2)

18/18 (100)

18/18 (100)

Thorax
Congenital heart defect
Absent/hypoplastic nipples
Limbs
Absent/hypoplastic thumbs
Short pointed ngers
Absent/hypoplastic halluces
Short pointed toes
Absent/hypoplastic nails
Single palmar crease
Central nervous system
Structural brain anomalies
Hypotonia
Radiological
Calvarial dysostosis
Craniofacial disproportion
Absent/hypoplastic clavicles
Absent sternal ossication center
Pelvic dysplasia
Hip dislocation
Thumb aplasia/hypoplasia
Agenesia/hypoplasia of distal
phalanges of the ngers
Agenesia/hypoplasia of middle
phalanges of the ngers
Agenesia/hypoplasia of the
rst metatarsal
Agenesia/hypoplasia of the
hallucal phalanges
Agenesia/hypoplasia of the
distal phalanges of the toes

20/21
17/18
19/20
18/19
16/18
8/10

19/20
10/11
15/21
8/9
12/13
8/11
17/18
17/18

similar affectation in sibs and/or recurrent spontaneous abortions

was reported in 11/19 families (57.8%) [3,6,10,15e17, current
report], and parents were reported as normal in all published cases.
Therefore, autosomal recessive inheritance (with early lethality)
was the most likely for this entity (OMIM #216340). Genetic
counseling should include a 25% recurrence risk for future sibs. A
possible metabolic defect was suggested based on the nding of an
abnormal urinary excretion of an unidentied oligosaccharide and
vacuolar degeneration changes with intracellular deposits [5,16].
However, such hypothesis remains unconrmed because the ndings were not found in another eight patients in whom a complete
autopsy study were performed [3,6,14,17], nor in several patients
with biochemical or biopsy studies for metabolic imbalances
[1,2,13,15,17, our patient 1]. Chromosomal studies performed in 17

J.R. Corona-Rivera et al. / European Journal of Medical Genetics 54 (2011) 76e81

patients with YVS were normal and no candidate gene, locus or

molecular basis for YVS have been identied to date. Consequently,
further reports are needed to elucidate whether YVS is in fact an
inborn error of metabolism or just an inborn error of development.
Besides, new molecular technologies, such as the next generation
sequencing, should allow detection of the faulty gene.
Acknowledgments
We are grateful to the anonymous reviewers of this manuscript
for their analytical support and helpful discussion.
Appendix. Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.ejmg.2010.09.013.
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