First descriptions . . .
In 1965, Dr. Victor Dubowitz of the University of Sheffield, England
published a paper [31] describing a young girl with pre- and postnatal
growth retardation, microcephaly, unusual facial features, and a history
of eczema occurring on her face and insides of her knees and elbows.
The patient's birth weight was 5 lb. 6 oz. At 9 months, she weighed
only 9 lbs. 9 oz., and her head circumference measured 37.8 cm (average
size of a 5-week-old infant). Although quite small, she was normally
proportioned. The child's voice and cry were soft and high-pitched.
Her motor and mental development progressed steadily--she sat unsupported
and took an interest in her surroundings by 9 months. At 10 months, she
crawled and pulled herself to a stand. At 13 months, weighing only 12 lb.,
she drank from a cup, said two words with meaning, and successfully stacked
two cubes. At 16 months, weighing 13 lb. 3oz., the child began to walk without
support and to use a spoon. At 18 months of age, she weighed 14 lb., and
although her motor skills had continued to advance, her language ability had
not. Overall, the child was thought to have some degree of mental retardation
(an opinion later to be revised). Her biochemical and chromosomal studies had
produced consistently normal results.
Dr. Dubowitz noted that an older female sibling of the child, who had
exhibited a similar facial appearance, had died at 3 months of age.
The sister's birth weight had been only 4 lb., and although she had shown
no eczema, she did have some webbing between her toes. Based on the
similar features of the two siblings, Dr. Dubowitz suggested their condition
may represent a distinct and recognizable autosomal recessive syndrome.
He went on to compare his patient to a number of other patients described
in previous literature, and questioned whether the new condition might
represent a variation of a previously described syndrome.
In 1971, Dr. John Opitz and Dr. Frank Gross of the University of Wisconsin
Medical School, in collaboration with Dr. Robert Gorlin of the University
of Minnesota School of Dentistry, published a paper [53] elaborating on
the condition described by Dr. Dubowitz through the presentation of
three additional patients. Following intensive study, Dr. Opitz concluded
that the condition was a distinct and unique genetic syndrome, and
proposed the designation of Dubowitz syndrome.
The authors defined the syndrome as a constellation of features--
intrauterine and postnatal growth retardation, microcephaly, mild
cognitive impairment, and a characteristic facial appearance.
Characteristics cited as contributing to the facial appearance
were sparse hair, fleeting forehead, relatively flat ridges over the
eyes, nasal bridge in line with forehead, increased distance between
the eyes, blepharophimosis (narrowing of the distance between the
eyelids), short palpebral fissures (eye openings) which may be slightly
slanted upward or downward, ptosis (drooping of the eyelids) which
may be asymmetric, hypoplasia (underdevelopment) of the lateral portions
of the eyebrows, and rather severe micrognathia (underdevelopment
of the lower jaw with receding chin). Hyperactivity, stubbornness, and
shyness were noted to be the outstanding behavioral features of the
syndrome.
Two of the three new patients were brother and sister. The sister had
been born 5 weeks prematurely weighing slightly over 4 lb. She suffered
from eczema and frequent upper respiratory infections, and had experienced
chronic diarrhea from ages 3 to 5 months. Developmentally, she sat at 8
months, used words at 12 months, stood at 16 months, and walked at 21
months; however, by 16 months her speech development was considerably
delayed. At age 4, her height, weight, and head circumference were below
the 3rd percentile. In addition to the characteristic facial appearance,
she had a high-arched palate and submucous cleft palate (a separation
of the bone was beneath the skin or mucous membrane). Her voice was
high-pitched, and she displayed hyperactive behavior to a degree that
was disruptive to her examination, as noted in the article: "The child
was extremely uncooperative and further examinations could not be
performed."
Her brother had been born at term weighing about 4.5 lb., with a
head circumference of just over 44 cm. He had also experienced
persistent diarrhea from 3 to 5 months of age. His skin was dry,
but eczema was not present. His height, weight, and head circumference
were all below the 3rd percentile at 5 months of age, and his facial
appearance was similar to that of his sister. It was noted that
neither parent exhibited any feature of Dubowitz syndrome.
The third patient was a little girl who had been born weighing less
than 5 lb. following a 41-week gestation. She had been hospitalized
for a time after birth due to poor weight gain, and later failed to
gain weight despite adequate feeding. Her cry was inaudible as a
young infant, but subsequently became high-pitched. She exhibited
a characteristic facial appearance and in addition the right side of
her face was slightly smaller than the left. In infancy she developed
eczema that responded poorly to treatment, along with chronic
nasal discharge and inflammation of the tear duct. By 18 months her
eczema had become so severe that large areas of her face, scalp and
extremities were raw and sometimes infected. She was miserable
from the intense itching, and unfortunately her eczema did not improve
until after age 3 despite various treatments. She experienced chronic
ear infections and required several myringotomy procedures. At age
6, an X-ray disclosed an abnormality of her spine described as "narrowing
of the T12-L1 interspace and spina bifida of L5 and the upper part of the
sacrum which showed an unusual posterior angulation at S5" (spina
bifida is defined as a defective closure of the bones encasing the
spinal cord).
The authors remark that the appearance of the four known patients with
the Dubowitz syndrome was "so strikingly similar that we would feel reasonably
confident in making this diagnosis in a case with this appearance, intrauterine
growth retardation and microcephaly, even without the presence of eczema
or the other above mentioned anomalies."
Dr. Dubowitz contributed follow-up information on his patient for the
article, and included the interesting fact that, although the girl had
initially been considered to have mild mental retardation, re-examination
at age 6 indicated her intelligence was rather probably low-normal.
(The earlier impression of mental retardation was thought to be partly
due to her extreme shyness and unwillingness to talk to strangers.)
In 1973, Dr. Opitz and Dr. R. Pheiffer, along with Dr. J. Hermann of
the University of Munster, Germany, and Dr. T. Kushnick of the New
Jersey Medical School, published a paper [52] on Dubowitz syndrome
which describes six additional patients--three from the U.S. and three
others from Germany. The group included two brother-and-sister
pairs. Two of the mothers had reportedly experienced severe morning
sickness during pregnancy. In one case the parents were biologically
related as first cousins.
While one of the new patients was said to have no history of behavioral
problems, another was described as having hyperactivity that was "barely
manageable" along with "considerable resistance to an educational setting,
shyness, easy fatigueability, [and] reluctance to cooperate." A third
patient, an infant, was said to be "hyper-reactive to light, touch, and
auditory stimuli." The article included an update provided by Dr. Dubowitz
indicating that his patient, like Dr. Opitz's, had a high-pitched voice,
absence of the outer half of the eyebrows, and had recently been
discovered to have a submucous clef palate. Study of the new patients
revealed that eczema could be absent in Dubowitz syndrome--six of
the known patients had nonexistent or minimal eczema. The authors
also note that "the abnormal voice and remarkable behavioral
phenotype are emerging as prominent characteristics of the syndrome."
