American Journal of Medical Genetics 72:18–23 (1997)
Microphthalmia, Marked Short Stature, Hearing
Loss, and Developmental Delay: Extension of the
Phenotype of GOMBO Syndrome?
S.A. Farrell*
Division of Genetics, The Credit Valley Hospital, Mississauga, Ontario, Canada
An adult male with microphthalmia, severe
developmental delay, conductive hearing
loss, marked short stature of prenatal onset,
and radiographic skeletal changes is de-
scribed. A review of the literature, focusing
on his major findings, suggests that his
manifestations might be an extension of the
phenotype of GOMBO (growth retardation,
ocular abnormalities, microcephaly,
brachydactyly, oligophrenia) syndrome.
Am. J. Med. Genet. 72:18–23, 1997.
© 1997 Wiley-Liss, Inc.
KEY WORDS: microphthalmia; short stat-
ure; conductive hearing
loss; developmental delay;
GOMBO; Myhre syndrome
INTRODUCTION
The patient of this report has severe developmental
disabilities, extremely short stature, abnormal radio-
graphs, ectodermal defects, hearing loss, and microph-
thalmia. Since microphthalmia is a relatively uncom-
mon problem, the differential diagnosis was considered
with microphthalmia as a major component. His pat-
tern of manifestations could be an extension of the phe-
notype of GOMBO (growth retardation, ocular abnor-
malities, microcephaly, brachydactyly, oligophrenia)
syndrome, first described by Verloes et al. [1989].
CLINICAL REPORT
This 23-year-old white man was evaluated because
his sibs wondered about their chances of having chil-
dren with similar disabilities. He was born to a young,
nonconsanguineous couple. His brother and sister are
well. No one else in the family has similar problems.
The pregnancy was normal until maternal hyperten-
*Correspondence to: S.A. Farrell, Division of Genetics, The
Credit Valley Hospital, 2200 Eglinton Ave., West, Mississauga,
Ontario, Canada, L5M 2N1.
Received 22 May 1996; Accepted 25 December 1996
© 1997 Wiley-Liss, Inc.
sion developed, requiring hospitalization at 32 weeks.
Labor was induced at 37 weeks because of hyperten-
sion and polyhydramnios. Delivery was vaginal and
vertex. Apgar scores were 5 and 7 at 1 and 5 min. Birth
weight was 1.56 kg, length 43 cm, and head circumfer-
ence (OFC) 28.5 cm. All measurements were below the
3rd centile. A blue cyst covered the right orbit. The
right lower lid was elevated and the area transillumi-
nated. An extremely small eye was seen within the
orbit. The cyst was thought to represent an underde-
veloped cystic eye. The blue color and the swelling had
regressed by age 3 months. He also had severe left
microphthalmia.
Results of neonatal investigations, including amino
acid and organic acid screens, titers for rubella and
toxoplasmosis, urine culture for cytomegalovirus, and
skull, limb, and chest radiographs, were normal. He
was reinvestigated at age 4. Urine amino acid screen-
ing, sweat chlorides, thyroid studies, and immunoglob-
ulin levels were normal. The banded karyotype was
normal. An IVP was normal except for unexplained
splenic calcifications. Hemoglobin electrophoresis was
normal. This was done because of several unexplained
episodes of mild jaundice. During one episode, anisocy-
tosis was noted. Later, the smear was unremarkable.
Liver function tests were normal. Skull radiographs at
age 4 documented a tower-shaped skull and raised the
question of premature fusion of the lambdoid sutures.
The original radiographs are missing. Bone age was
2 5
significantly delayed. At age 412 years, bone age was 312
years. His short stature, with no catch-up growth fol-
lowing the history of intrauterine growth retardation,
led to investigations of growth hormone. None was
measurable while fasting, and responses to stimulation
were abnormally low. The EEG done at age 11 was
abnormal, with high-voltage spike waves, complex par-
oxysmal slowing, and diffuse, poorly organized pat-
terns and rhythms. Clinical seizure activity has not
been observed.
Psychomotor development was significantly delayed.
Initial feeding was by gavage. Around age 1 month,
feeding was achieved by spooning milk thickened with
infant cereal. He smiled at 1 year, and sat around 3
years. Independent walking has not developed, al-
though he took a few steps at 8 years. Use of a rollator
to facilitate upright mobility allowed him to move up to

50 feet by his late teens. At 23 years, signing by touch
is used for communication, as he is blind and has hear-
ing impairment. He recognizes 50 signs and uses 20.
There are some vocalizations but no words. He can dis-
tinguish between caregivers.
When examined at age 23, he was strikingly abnor-
mal and short of stature (Fig. 1). Height was 107 cm
(50th centile for 5 years). Contractures of both knees
were present, and this made assessment of proportion-
ality of the upper and lower segments impossible to
determine (contractures were first noted in early child-
hood). OFC of 48.7 cm was <3rd centile, and propor-
tionate to his height. The inner canthal distance of 3.0
cm was on the 50th centile for 9 years, and the nasal
root was broad. Outer canthal distance was 8.0 cm
(50th centile for 7 years). He had prominent eyebrow
ridges and prominences of the parietal regions. The
forehead was tall. Head shape was brachycephalic. The
hair whorl was diffuse and displaced to above the right
occiput. The hair was sparse and was described as slow
to grow, requiring a haircut much less often than oth-
ers in the family (he sweats normally and the nails
require cutting with normal frequency). The frontal
area had an upswept hair pattern. Over the vertex was
a 1-cm round area of alopecia, resembling cutis aplasia.
The ears were normally positioned, but the helices
Fig. 1. Frontal facial view, age 23 years.
Microphthalmia and Short Stature 19
were broad and the antihelices were unusually shaped
(Fig. 2). The ear canals were tiny, and the drums were
not seen. Ear length was 4.4 cm (<3rd centile). The
palpebral fissures were horizontal. The eye sockets
were small and shallow. The eyebrows and lashes were
sparse. The nasal tip was broad and almost bifid in
appearance. His mouth looked small, and the alveolar
ridges were thick. Chest, abdomen, and cardiovascular
systems were normal. The fingers were tapered and
short distally, with mild soft-tissue syndactyly between
each (Figs. 3, 4). The hand length of 9.9 cm was at the
50th centile for 18 months, while the middle finger
length of 3.5 cm was at the 50th centile for a 9-month
infant. The nails were hypoplastic. There were bilat-
eral single distal transverse creases and mild fifth-
finger clinodactyly. The skin of the palms was
wrinkled. On the left foot, the second toe was much
shorter than the first or third toes. This was less so on
the right foot. A well-developed sixth toe was located
postaxially on the left foot. The heels were prominent
and the soles were flat. Tone was difficult to assess
since he had reacted unfavorably to the presence of a
stranger. Assessments by others suggested moderate
hypotonia. Deep-tendon reflexes were symmetric and
brisk. Both testes were descended. Pubertal develop-
ment was early Tanner stage II. There was no body or
facial hair.
He was reinvestigated at age 23. The karyotype was
normal at a level of resolution of 550 bands. He was
blind, although he reacted to bright lights. There was
bilateral conductive hearing loss, moderately severe on
the right and profound on the left. Brain-stem audi-
tory-evoked potentials showed no response in the right
ear until 95 dB. In the left ear, a wave 5 response was
noted at 80 dB, with a possible response at 60 dB. With
a left-ear hearing aid, the responses improved slightly.
Skull radiographs showed a large pituitary fossa. CT
scan of the brain showed mild prominence of the lateral
ventricles, more so on the right. Both eyes were present
but were small. In the left eye there was a central cal-
cified mass, thought perhaps to be a calcified dislocated
lens. There was a small fleck of calcification at the
region of the optic nerve head, perhaps representing a
Fig. 2. Left external ear.
20 Farrell
Fig. 3. Palmar view of hands.
small drusen. The optic nerves appeared to be normal.
At 23 years, bone age was between 13–14 years. This is
significantly more delayed than the result at age 4.
There was generalized osteopenia. The vertebrae
showed central depression of the superior and inferior
end plates. The epiphyseal-metaphyseal junction of the
lower end of the radius and ulna were V-shaped (Fig.
5). The metacarpophalangeal pattern profile is shown
in Figure 6. Despite wide consultation, a specific radio-
logic diagnosis of the bony abnormalities was not
achieved. FSH was elevated at 13.2 IU/l (normal range
for age 1–12). Growth hormone was normal. This was
in contrast to the deficiency documented at age 4. Den-
tition was unusual, with retention of many primary
teeth and absence of secondary teeth. Dental develop-
ment was estimated to be age 6.5–7.5 years. Tooth
shape was normal.
DISCUSSION
This young adult has a very unusual pattern of mani-
festations, including severe developmental disabilities
out of proportion to his visual and auditory impair-
ments, remarkable bony changes in association with
extremely short stature, sparse hair, cutis aplasia, oli-
Fig. 4. Dorsal view of hands.
godontia, and microphthalmia. Since microphthalmia
is a relatively uncommon finding, his differential diag-
nosis was considered with this in mind. Microphthal-
mia is a component of a number of disorders of varying
causes, both genetic and nongenetic [Warburg, 1981a,
1993; Gorlin et al., 1990; Temple et al., 1990]. Microph-
thalmia and anophthalmia are considered to be a spec-
trum of eye anomalies, since either can occur within
the same single-gene disorder [Warburg, 1981a]. Al-
though anophthalmia or microphthalmia can be iso-
lated, frequently there are anomalies outside of the
ocular system. Anophthalmia/microphthalmia can be
primary, due to failure of development of the optic pit,
or secondary to a developmental anomaly of the fore-
brain. A secondary defect often is associated with other
cerebral anomalies. Microphthalmia can be degenera-
tive, with involution of the optic vesicle [Marcus et al.,
1990]. Failure of invagination of the optic vesicle re-
sults in congenital cystic eye. Warburg [1993] classes
cystic eye as a form of microphthalmia. Thus, the blue
orbital cyst of this patient might represent a congenital
cystic eye. Warburg [1981b] suggests that there is an
increased incidence of microphthalmia in association
with developmental disabilities. Since the optic vesicle
is derived from an outgrowth of the forebrain, the as-
sociation is not surprising. In the patient of this report,
the association of microphthalmia and severe develop-
mental disabilities also was found.
Endocrine anomalies have been noted in association
with microphthalmia. Perhaps these endocrine
changes are part of the spectrum of cerebral anomalies
which occur with secondary microphthalmia. Keepen
et al. [1990] described hypogonadotropic hypogonadism
in 5 of 13 developmentally delayed adults with mi-
crophthalmia or anophthalmia. Panhypopituitarism
was reported in an infant with anophthalmia, bilateral
cleft lip and palate, cerebral anomalies, diabetes insipi-
dus, and cutis aplasia [Leichtman et al., 1994]. The
patient in this report had documented deficiency of
growth hormone response to stimulation in childhood,
although the baseline level at age 23 was considered
normal for that age. However, at 23 years his height
was at the 50th centile for a 5-year-old. The relative
contributions to his short stature from growth hormone
deficiency and from the bony changes noted on skeletal
radiographs are unclear.
The differential diagnosis was considered using
POSSUM, version 4.51 (1996) (Computer Power Pty,
Ltd, & the Murdoch Institute for Research into Birth
Defects). The condition with the greatest number of
matching manifestations was GOMBO syndrome. This
was described in 2 sibs and an unrelated case by Ver-
loes et al. [1989]. They had similar ophthalmologic
findings, short stature, brachycephaly, sparse hair, ab-
normal dentition, brachydactyly, unusual wrinkling of
the skin of the hands, abnormal external ears, and de-
velopmental delay. However, there are some differ-
ences including cutis aplasia, polydactyly, and contrac-
tures present in the patient of this report, but not noted
in GOMBO syndrome. There are radiographic differ-
ences, including the metacarpophalangeal pattern pro-
file. The facial appearances do not match.

Fig. 5. a: Lateral radiograph of spine. b: Anterior posterior view of spine. Spinal views show central depression of end plates. c: Radiograph of hand
and distal forearm, showing V-shape of epiphyseal-metaphyseal junction and brachydactyly.
Recently, Bottani and Verloes [1995] speculated that
GOMBO syndrome might be an extension of the phe-
notype of Myhre syndrome. Since very few cases of ei-
ther GOMBO syndrome or of Myhre syndrome have
been reported, the authors suggested that further ex-
amples are needed to determine if they are separate
entities. Myhre syndrome comprises short stature,
small size at birth, blepharophimosis, prognathism,
muscle hypertrophy with decreased joint mobility, sen-
sorineural deafness, developmental delay, and bony
changes, including platyspondyly, large vertebrae with
large pedicles, broad ribs, thick calvaria, hypoplastic
iliac wings, and short tubular bones [Garcia-Cruz et
al., 1993]. The short stature and delayed puberty are
reminiscent of the patient here. However, the patient
of this report has conductive hearing loss, while those
with Myhre syndrome have sensorineural loss. The de-
scriptions of the bony changes differ. Joint stiffness,
not contractures, has been noted in Myhre syndrome.
There are no reports of cutis aplasia nor of polydactyly
in Myhre syndrome. The face, particularly the nasal
and chin areas, is not similar to that of the patient of
this report.
The differential diagnosis was extended by linking
selected major anomalies with microphthalmia. Syn-
dromes with anophthlamia/microphthalmia, and cere-
bral and cutaneous anomalies, were considered. Delle-
man (oculocerebrocutaneous) syndrome is character-
ized by orbital cysts, microphthalmia, aplastic/
hypoplastic skin lesions, and unusual skin appendages.
There are intracranial cysts or agenesis of the corpus
callosum plus other cerebral anomalies, often in asso-
ciation with significant developmental delay [Al-Gazali
Microphthalmia and Short Stature 21
et al., 1988]. Other than minor skull defects and rib
anomalies, the skeleton seems to be normal in Delle-
man syndrome. Although the ocular findings and the
cutis aplasia are similar, the patient of this report
lacked the skin appendages and intracranial cysts
characteristic of Delleman syndrome, and had signifi-
cant skeletal anomalies, which are not part of Delle-
man syndrome.
Leichtman et al. [1994] described a patient with a
more complex pattern of midline defects than is usually
found in Delleman syndrome, but with some overlap-
ping features including cutis aplasia, anophthalmia,
orbital cyst, and cerebral anomalies. Differences from
Delleman syndrome included multiple facial anomalies
including micrognathia, a Tessier III unilateral cleft
lip, and cleft palate, with small tongue. Other than
fifth-finger clinodactyly, the skeleton was normal.
Their patient had panhypopituitarism with diabetes
insipidus. The authors indicated that their case could
represent a more complex form of Delleman syndrome,
but more likely was a new syndrome. Although there is
overlap in some of the physical characteristics, the fa-
cial features of the patient of Leichtman et al. [1994]
are not those of the patient of this report.
Bierich et al. [1991] suggested that the combination
of microphthalmia/anophthalmia, cerebral anomalies,
and cutis aplasia could be a midline developmental
field defect. The presence of these features in Delleman
syndrome, in the case of Leichtman et al. [1994], and in
this case, lends support to the possibility of an embryo-
logic link between these anomalies.
The combination of anophthalmia/microphthalmia
and skeletal and dental anomalies was considered in
22 Farrell
Fig. 6. Metacarpophalangeal pattern profile.
the differential diagnosis. Oculodentodigital dysplasia
[Judisch et al., 1979; Gorlin et al., 1990] is character-
ized by a thin nose with hypoplastic alae and narrow
nostrils, microcornea, and microdontia with enamel hy-
poplasia. Stature and developmental status usually are
normal in oculodentodigital dysplasia. The face, bony
changes, and developmental status differ from the pa-
tient of this report. Gorlin-Chaudhry-Moss syndrome
(GCM) [Ippel et al., 1992] includes short stature, small
palpebral fissures, oligodontia, hypodontia, unusual fa-
cial shape, conductive hearing loss, hypertrichosis, and
distal digital hypoplasia. Psychomotor development is
normal. Radiologic anomalies include craniosynostosis
and maxillary underdevelopment. Although there are
some signs in common, the major disparities between
GCM and this patient (skeleton, developmental status,
and facies) argue against this possibility.
In summary, the many unusual anomalies of the in-
dex case, including short stature with radiographic
anomalies, hearing loss, severe developmental disabili-
ties, ectodermal changes, polydactyly, and microph-
thalmia, are similar but not identical to those of
GOMBO syndrome. It is possible that his manifesta-
tions represent a more severe phenotype than noted in
previous cases. More reports would be helpful in better
delineating the phenotypic variability of this combina-
tion of anomalies.
ACKNOWLEDGMENTS
I thank Dr. A. Verloes for a helpful review of the
clinical information, Dr. J. Lawrence for the metacar-
pophalangeal profile and for reviewing the CT scan, Dr.
A. Hunter for facilitating the review of the radiographs,
Dr. D. Chadwick for helpful discussions and for review-
ing the manuscript, and A. Visco for secretarial assis-
tance.
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