American Journal of Medical Genetics 2:275-284 ( 1 978)
The Dubowitz Syndrome R. S. Wilroy, Jr, R. E. Tipton, and R. L. Summitt Departments of Pediatrics and Anatomy, and the Child Development Center, University of Tennessee Center for the Health Sciences, Memphis
The Dubowitz syndrome is an autosomal recessive condition of intrauterine growth retardation, postnatal growth retardation, microcephaly, characteristic facial appearance, high-pitched hoarse voice, and borderline intelligence or mild mental retardation. Cleft palate may occur as well as hypospadias, cryptorchidism in affected males, and mild limb defects. The 13 cases reported in the European literature and eight personally examined patients are reviewed. Key words: Dubowitz syndrome, low birth-weight dwarfism, microcephaly, autosomal recessive inheritance
INTRODUCTION
In 1965 Dubowitz [ I ] described an English infant girl with intrauterine growth retardation (IUGR) and primordial shortness of stature, peculiar face, skin eruptions of the face and flexures of the elbows and knees, microcephaly, and slightly impaired mental development. A sister with similar facial appearance and IUGR died at 3 months of age having never weighed more than 2,041 gm; she had webbing of the toes but n o rash. Dubowitz discussed these siblings as “familial low birth weight dwarfism with an unusual facies and a skin eruption” in the context of the Bloom syndrome; however, when studyinga patient in Madison, Opitz recognized this entity to be different from the Bloom syndrome and called it the Dubowitz syndrome. The Madison case and a follow-up of Dubowitz’s patient, A.R., at 9 years, was published together with one of Gorlin’s patients by Grosse et a1 in the European literature [2] . In 1973 Opitz et al published a follow-up on the original Sheffield and Madison cases, and six new cases from Madison, Miinster (Germany), and Newark, New Jersey, again in the European literature [3]. The only other paper and review of the Dubowitz syndrome was published in 1975 by Majewski et al, again in Europe [4] .
Received for publication January 24, 1978; revision received April 18, 1978. Address reprint requests t o R. S. Wilroy, Jr, MD, Dept of Pediatrics, Univ of Tennessee Center for the Health Sciences, Memphis, TN 38163.
0148-7299/78/0203-0275$02.00 0 1978 Alan R. Liss, Inc
276
Wilroy, Tipton, and Summitt
We have examined eight patients with this syndrome and present a review of the 21 known cases in this report. Historical data from the 21 patients can be found in Table I and the clinical manifestations can be found in Table 11.
CASE REPORTS Case 1
MD230469, a white female, was referred for evaluation of short stature and unusual appearance. She was the first child of nonconsanguinious parents. Her mother was 21 years old at the time of her conception and her father was 24. The 39 week pregnancy was uncomplicated. Maternal consumption of alcohol was denied. Labor and delivery were uneventful. Her birth weight was 2.7 kg and length 46.3 cm. The head circumference (OFC) was not recorded at birth. During the first month of life she did not feed well and was constipated, but did not vomit. Her voice was described as high pitched and cat-cry-like. By 8 months she weighed 4.0 kg, at 22 months she weighed 7.7 kg. She sat without support at 5 months, walked at 11 months, and spoke monosyllable words at 22 months. When examined at age 2 7/12 years her height was 79 cm, weight 8.9 kg, intercanthal distance 3.0 cm, OFC 4 4 cm, and chest circumference 44 cm. Her scalp hair was sparse and straight. The forehead sloped unusually and there were flat supraorbital ridges. Telecanthus was obvious and epicanthal folds were absent. Ptosis of the left upper lid was pronounced. Her ears were normal in architecture and attachment, and her nose was broad and flat, with the bony portion prominent. Twenty deciduous teeth were chalky white and widely spaced, and her palate was narrow and the mandible small. Both fifth fingers were short and clinodactylous, and nine of the 10 digital patterns were ulnar loops. The rest of the examination including neurological tests revealed no abnormalities. Roentgenograms for bone age, IVP, EEG, ECG, hemogram, urinalyses, serum chemistries, and urinary amino acids were normal. Analysis of peripheral lymphocytes revealed an apparently normal 46,XX chromosome constitution. By 3 1/3 years the child weighed 9.7 kg and was 85-cm tall (Fig 1). Successful surgery for her ptosis was performed. An adenoidectomy was done and pressure-equalizing tubes were inserted into her middle ears due to recurrent upper respiratory infections and many episodes of otitis media. She entered the first grade at 6 years, but performed poorly and was very shy. At 6 7/12 years she weighed 14.3 kg and was 101-cm tall. At 7 1/6 years, her bone age was 5 years 9 months. At 7 3/4 years she was 105-cm tall and weighed 1.5.7 kg. She was repeating the first grade with tutorial help, had a short attention span, was very shy, and had normal hearing. Her OFC was 46.5 cm. Intellectual performance has not been evaluated by standard methods. Each measurement recorded for height, weight, and OFC was below the fifth percentile. Case 2
CD021074 is the brother of Case 1. Gestation, labor and birth were uncomplicated. The umbilical cord was "very short". His birth weight was 2.33 kg and his length
BIRTH ORDER
SEX
HYPERACTIVE
SUBNORMAL INTELLECT
WALK (Months1
MATERNAL AGE A T CONCEPTION PATERNAL AGE AT CONCEPTION DURATION: 1 (weeks) GRowHFAILURE+ PRENATAL
I
kz
13
212
+
+ O! + +
+
+
21
43
+
Term
357
+
Term
+
t
21
24
1I 1 20
213
24
Term
111
t
+
12
+
Term
25
27
Table I. Historical Data of 2 1 Patients With the Dubowitr Syndrome
t
Term
25
22
+
o
0
+
?
11
t
Term
21
38 387
19
1/2
26
O
0
?
32
22
20
O
212
t
+
?
387
29
30
+
+
20
0
377
o
t
11
t
39
24
26
111 22
25
212
t
40
28
25
+
0
10
0
347
18
18
111
515
11
0
377
34
29
t
0
14
+
36
27
23
212
+
0
14
t
36
27
23
212
+
0
0
42
27
18
212
111
0
0
10
+
40
20
19
9/21
7121
13.3
16
41 8
256
229
_ . ,I
TOE SYNDACTYLY DELAYED BONE AGE
ECZEMA
+
0
+
t
+
t
+
I
t +
+
+ I
,
I
t
t
+
t
0
o
t
I
I
I
,
t
K.M.
tt
I
I
t
t
+
I
I B.M. 1
I
J.H.
HY POSPAD IAS
I
I
I
I
I
SIBLINGS
CRYPTORCHIDISM
HIGH.PITCHED HOARSE VOIDE
c
r , I,,.",
PALATE
IC
BROAD NOSE
t
t
PHlMOSlS EPICANTHAL FOLDS ABNORMAL
+
A.R.
TELECANTHUS
I
SLOPING FOREHEAD
, 3Vc;I;uv3
1
SIB LINGS
I
I
o
t
t
+
t
A.J.
I
I
I
1
+
0
o
+t
o
t
R.Z.
I
I
1
0
o
o
+
B.Z.
SIBLINGS
Table 11. Phenotypic Data of 21 Patients With the Dubowitz Syndrome
+
I
-* I SIBLINGS
The Dubowitz Syndrome
279
Fig 1. Case 1. Note typical appearance of the Dubowitz syndrome and ptosis of the left eyelid,
was 46.25 cm. Perineoscrotal hypospadias was noted at birth. The infant fed poorly during the first month of life. Profuse diarrhea began on day 3 and persisted with frequent vomiting and rectal prolapse for six months. A persistent rash of the axillae, inguinal areas, and neck responded poorly to topical medications. Examination at 6 months (Fig 2) revealed a weight of 3.4 kg (25th percentile), length of 46 cm (below the fifth percentile), and OFC of 35.5 cm (50th percentile). Facial features closely resembled those of his sister. The infant had sparse scalp hair, flat supraobrital ridges, ptosis and a flat, broad nasal bridge. The abdomen was distended. The penis was 2-cm long and bound ventrally by chordee. The urethral orifice was at the junction of the penis and scrotum. The right testicle was in the scrotum and the left testicle was palpable high in the inguinal canal. Rectal prolapse occurred with crying. At 2 11/12 years he weighed 8.2 kg (below the fifth percentile) and his OFC was 42 cm (below the fifth percentile). He had 20 teeth and his bone age was 1 year. Bilateral ptosis was again noted and the skin was very dry. He spoke monosyllable words. Results of upper gastrointestinal roentgenograms, sweat test, and hemogram were normal. The karyotype of cultured lymphocytes was 46,XY. Case 3
CB100669, a white girl, was referred for genetic evaluation at 6 years, because of short stature and syndactyly of her toes. She is the only child of unrelated parents. Both parents were 18 years old at the time ofher conception. The pregnancy terminated spontaneously “six weeks” before the estimated due date. Following an uncomplicated vaginal birth, the infant weighed 2.5 kg and was 45-cm long. She gained weight poorly during the first year of life. Her developmental progress has been considered normal.
280
Wilroy, Tipton, and Summitt
Fig 2. Case 2. Brother of Case 1 patient with similar face and bilateral ptosis.
At 6 years she weighed 16 kg (fifth percentile) and was 103-cm tall (below the fifth percentile); her OFC was 47 cm (below the fifth percentile). Facial features resembled the two prevjous patients but ptosis was absent, and hcr nasal bridge was prominent, continuous with the forehead, and her nose was “beak-shdped”. Her ears protruded from the skull with small lobules and antitragi. Micrognathia was o h ioiis and the deciduous lateral incisors were fused with the canines. No other abnormalitics were noted except those of the hands and feet. Both fifth fingers were short and clinodactylous. The nail of each fifth toe was absent. Both fourth and fifth toes were syndactplous. Chromosome analysis revealed an apparently normal 46,XX chromosome constitution. Case 4
RH030874, a white boy, was born to nonconsanguinious parents. At the time of his rvnception his mother was 29 years old and his father was 34. The infant was born “three weeks early” but weighed 2.6 kg and was 47.5-cm long. During the first month he cried weakly, was constipated, and could not open his eyes widely. A genetic consultation was requested at 5% months. The patient weighed 5.9 kg (fifth percentile), was 63-cm tall (10th percentile) and his OFC was 29.5 cm (below the fifth percentile). His intercanthal distance was 22 mm, his forehead was high, and his anterior hairline was receeded. Bilateral epicanthal folds were present and the palpebral fissures slanted upward. Severe ptosis of the eyelids was obvious and the ears were large. The chin was normal as was the voice. The chromosome constitution was 46,XY, and urinary amino acids were normal. At 1 year he weighed 7.1 kg (below the fifth percentile), and was 70-cm long (below the fifth percentile); his OFC
The Dubowitz Syndrome
28 1
was 43 cm (below the fifth percentile). By 1 7/12 years he could crawl but not walk, and could say five distinct words. His weight was 7.6 kg, length 78.5 cm, and OFC 44.5 cm (values still below the fifth percentile). Cases 5 and 6
BN131273 and JN131273, twin boys (monozygous based on blood types) were born to a 23 year old mother and a 27 year old father. The parents were unrelated. Labor began spontaneously four weeks before the estimated due date and both infants were delivered vaginally. Case 5 weighed 1.6 kg at birth and was 39.4 cm long. Case 6 weighed 1.7 kg and was 41.3-cm long. Both were noted to have a “cat-like’’ cry shortly after birth. Due to their poor growth they were referred to genetic evaluation at 27 months (Fig 3). Their length, weight, and OFC were more than two standard deviations below the mean for age, but their psychomotor development was considered normal. The voice of each was high pitched and hoarse. Their chromosome constitutions were normal. Case 7
MW260176, a white boy, was initially evaluated at 3 months due to failure to thrive, and multiple congenital anomalies including microcephaly , ptosis, and a cleft palate. The patient’s mother was 18 years old and his father was 27 at the time of his conception. Parental consanguinity was denied. Pregnancy was uncomplicated but fetal distress during labor led to a cesarean section. Resuscitation was required and the infant convulsed on the first day of life. He weighed 3.5 kg at birth. He ate poorly during the
Fig 3. Cases 5 and 6. Monozygous twins with the Dubowitz syndrome.
282
Wilroy, Tipton, and Summitt
first year. He sat alone at 12 months. At 18 months he weighed 6.8 kg, was 65.6-cm tall, and had an OFC of 4 1.8 cm (all values below the fifth percentile). His bone age was 4 months, his serum thyroxine level and the results of his chromosome analysis were normal. Case 8
NW060574, a white girl and only child was referred for genetic evaluation at 1 year because of failure t o thrive. Her mother was 19-years old and her father 20 at the time of her conception, and unrelated. The pregnancy was of normal duration and the labor uncomplicated. Birth weight was 2.0 kg and length 42.5 cm. She developed diarrhea at 3 days and remained in the nursery for one month due to poor weight gain. Her psychomotor development was normal. At 1 year (Fig 4) she weighed 5.5 kg, was 60-cm long, her OFC was 39.5 cm (all values below the fifth percentile), and she had 12 teeth. Results of hemogram and urinalysis were normal. The bone age was 3 months and the IVP was normal. Results of urinary amino acid determination, serum thyroxine, sweat chloride, serum electrolytes, and chromosome analysis were normal.
DISCUSS 10N
In 1965 Dubowitz [ 11 stated that “the family recorded here suggests that the syndrome is inherited in a recessive manner”. Grosse et al [2] also suggested that the Dubowitz syndrome is recessively inherited. Opitz et al [3] confirmed this in 1973 on the basis of sibling occurrence with normal parents and parental consanguinity in one case.
Fig 4. Case 8. See text for details.
The Dubowitz Syndrome
283
All 21 known patients are Caucasian. Siblings were affected six times, including one set of monozygous twins. The sex ratio is 1 (1 1 F, 10 M). The approximate average age of the mothers at conception of the probands was 22.9 years, and of the fathers, 25.6 years. The average duration of the pregnancies was 41.8 weeks based on estimated dates alone. Of the 21 patients, 16 had intrauterine growth retardation (IUGRless than the 25th percentile) [5] . The average birth weight was 2.27 kg and the average birth length was about 45 cm. Thirteen ate poorly during infancy; 7 had diarrhea during the first 6 months, and 6 vomited frequently. Subnormal intellect was definite in 7, and 9 patients were described as hyperactive. Postnatal growth retardation is usually characteristic of the syndrome although one of the patients reported by Opitz et al [3] apparently grew well after birth although she had typical dysmorphic facial features. Figures 7-10 of Majewski et al [4] summarize prenatal growth patterns, postnatal length/height, weight, and OFC growth, respectively, in 12 Dubowitz-syndrome patients. Microcephaly is a consistent finding. Dysmorphic facial features include sparse hair, sloping forehead, flat supraorbital ridges with the bridge of the broad nose continuous with the forehead, telecanthus, ptosis and/or blepharophimosis (frequently asymmetrical), epicanthal folds, and micrognathia. The voice may be high-pitched and hoarse. Cleft palate has been found in four patients. Internal abnormalities have not been reported. Hypospadias and/or cryptorchism may be encountered in affected males. Eight have had syndactyly of their toes. The ultimate intellectual performance of children with the Dubowitz syndrome has yet to be determined. Their microcephaly is of such a degree that severe mental retardation might be anticipated. However, this has not been the case since the patients usually appear to be mentally normal or at worst, mildly retarded. They are often shy, hyperactive and have brief attention spans. The Dubowitz syndrome should not be confused with the Seckel syndrome [6] , or the fetal alcohol syndrome [ 7 , 8 ] , two conditions of prenatal and postnatal growth retardation. The mental retardation in the Seckel syndrome may be more severe and the facial appearance is distinctly different. Historical data as well as characteristic appearance and congenital cardiac defects and abnormal digits, should aid in making the diagnosis of the fetal alcohol syndrome. The Dubowitz syndrome is a bona fide clinical entity, inherited in an autosomal recessive manner. No biochemical or chromosome defect has been found. The ultimate intellectual function and height of these children is unknown and requires further study.
ACKNOWLEDGMENTS
This work was supported by Special Project 900, Division of Health Services, MCHS, HSMHA, DHEW, and by a grant from the National Foundation-March of Dimes. We thank Tricia Davis who helped gather this information and typed this manuscript.
REFERENCES 1. Dubowitz V: Familial low birth weight dwarfism with an unusual facies and a skin eruption, J Med Genet 2:12-17, 1965.
284
Wilroy, T i p t o n , and S u m m i t t
2. Grosse R, Gorlin J, Opitz JM: The Dubowitz syndrome. Z Kinderheilk 110:175-187, 1971. 3. Opitz JM, Pfeiffer RA, Hermann JPR, Kushnick T: Studies of malformation syndromes of man X X N B : the Dubowitz syndrome. Further observations. Z Kinderheilk 116:l-12, 1973. 4. Majewski F, Michaelis R, Moosmann K, Bierich JR: A rare type of low birth weight dwarfism: the Dubowitz syndrome. Z Kinderheilk 120:283-292,1975. 5 . Lubchenco LO, Hansman C, Boyd E: Intrauterine growth in length and head circumference as estimated from live births at gestational ages from 26 to 42 weeks. Pediatrics 37:403-408, 1966. 6. Seckel HPG: “Bird-headed Dwarfs. Studies in Developmental Anthropology including Human Proportions.” Springfield: Thomas, 1960. 7 . Lemoine P, Harousseau H, Borteyru JP, Menuet JC: Les enfants de parents alco8liques; anomalies observe‘es propos d e 127 cas. Ouest Med 25:476-482,1968. 8. Jones KL, Smith DW, Ullelan CN, Streissguth AP: Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1:1267, 1973.
Edited b y John M. O p i t z
The Dubowitz Syndrome R. S. Wilroy, Jr, R. E. Tipton, and R. L. Summitt Departments of Pediatrics and Anatomy, and the Child Development Center, University of Tennessee Center for the Health Sciences, Memphis
The Dubowitz syndrome is an autosomal recessive condition of intrauterine growth retardation, postnatal growth retardation, microcephaly, characteristic facial appearance, high-pitched hoarse voice, and borderline intelligence or mild mental retardation. Cleft palate may occur as well as hypospadias, cryptorchidism in affected males, and mild limb defects. The 13 cases reported in the European literature and eight personally examined patients are reviewed. Key words: Dubowitz syndrome, low birth-weight dwarfism, microcephaly, autosomal recessive inheritance
INTRODUCTION
In 1965 Dubowitz [ I ] described an English infant girl with intrauterine growth retardation (IUGR) and primordial shortness of stature, peculiar face, skin eruptions of the face and flexures of the elbows and knees, microcephaly, and slightly impaired mental development. A sister with similar facial appearance and IUGR died at 3 months of age having never weighed more than 2,041 gm; she had webbing of the toes but n o rash. Dubowitz discussed these siblings as “familial low birth weight dwarfism with an unusual facies and a skin eruption” in the context of the Bloom syndrome; however, when studyinga patient in Madison, Opitz recognized this entity to be different from the Bloom syndrome and called it the Dubowitz syndrome. The Madison case and a follow-up of Dubowitz’s patient, A.R., at 9 years, was published together with one of Gorlin’s patients by Grosse et a1 in the European literature [2] . In 1973 Opitz et al published a follow-up on the original Sheffield and Madison cases, and six new cases from Madison, Miinster (Germany), and Newark, New Jersey, again in the European literature [3]. The only other paper and review of the Dubowitz syndrome was published in 1975 by Majewski et al, again in Europe [4] .
Received for publication January 24, 1978; revision received April 18, 1978. Address reprint requests t o R. S. Wilroy, Jr, MD, Dept of Pediatrics, Univ of Tennessee Center for the Health Sciences, Memphis, TN 38163.
0148-7299/78/0203-0275$02.00 0 1978 Alan R. Liss, Inc
276
Wilroy, Tipton, and Summitt
We have examined eight patients with this syndrome and present a review of the 21 known cases in this report. Historical data from the 21 patients can be found in Table I and the clinical manifestations can be found in Table 11.
CASE REPORTS Case 1
MD230469, a white female, was referred for evaluation of short stature and unusual appearance. She was the first child of nonconsanguinious parents. Her mother was 21 years old at the time of her conception and her father was 24. The 39 week pregnancy was uncomplicated. Maternal consumption of alcohol was denied. Labor and delivery were uneventful. Her birth weight was 2.7 kg and length 46.3 cm. The head circumference (OFC) was not recorded at birth. During the first month of life she did not feed well and was constipated, but did not vomit. Her voice was described as high pitched and cat-cry-like. By 8 months she weighed 4.0 kg, at 22 months she weighed 7.7 kg. She sat without support at 5 months, walked at 11 months, and spoke monosyllable words at 22 months. When examined at age 2 7/12 years her height was 79 cm, weight 8.9 kg, intercanthal distance 3.0 cm, OFC 4 4 cm, and chest circumference 44 cm. Her scalp hair was sparse and straight. The forehead sloped unusually and there were flat supraorbital ridges. Telecanthus was obvious and epicanthal folds were absent. Ptosis of the left upper lid was pronounced. Her ears were normal in architecture and attachment, and her nose was broad and flat, with the bony portion prominent. Twenty deciduous teeth were chalky white and widely spaced, and her palate was narrow and the mandible small. Both fifth fingers were short and clinodactylous, and nine of the 10 digital patterns were ulnar loops. The rest of the examination including neurological tests revealed no abnormalities. Roentgenograms for bone age, IVP, EEG, ECG, hemogram, urinalyses, serum chemistries, and urinary amino acids were normal. Analysis of peripheral lymphocytes revealed an apparently normal 46,XX chromosome constitution. By 3 1/3 years the child weighed 9.7 kg and was 85-cm tall (Fig 1). Successful surgery for her ptosis was performed. An adenoidectomy was done and pressure-equalizing tubes were inserted into her middle ears due to recurrent upper respiratory infections and many episodes of otitis media. She entered the first grade at 6 years, but performed poorly and was very shy. At 6 7/12 years she weighed 14.3 kg and was 101-cm tall. At 7 1/6 years, her bone age was 5 years 9 months. At 7 3/4 years she was 105-cm tall and weighed 1.5.7 kg. She was repeating the first grade with tutorial help, had a short attention span, was very shy, and had normal hearing. Her OFC was 46.5 cm. Intellectual performance has not been evaluated by standard methods. Each measurement recorded for height, weight, and OFC was below the fifth percentile. Case 2
CD021074 is the brother of Case 1. Gestation, labor and birth were uncomplicated. The umbilical cord was "very short". His birth weight was 2.33 kg and his length
BIRTH ORDER
SEX
HYPERACTIVE
SUBNORMAL INTELLECT
WALK (Months1
MATERNAL AGE A T CONCEPTION PATERNAL AGE AT CONCEPTION DURATION: 1 (weeks) GRowHFAILURE+ PRENATAL
I
kz
13
212
+
+ O! + +
+
+
21
43
+
Term
357
+
Term
+
t
21
24
1I 1 20
213
24
Term
111
t
+
12
+
Term
25
27
Table I. Historical Data of 2 1 Patients With the Dubowitr Syndrome
t
Term
25
22
+
o
0
+
?
11
t
Term
21
38 387
19
1/2
26
O
0
?
32
22
20
O
212
t
+
?
387
29
30
+
+
20
0
377
o
t
11
t
39
24
26
111 22
25
212
t
40
28
25
+
0
10
0
347
18
18
111
515
11
0
377
34
29
t
0
14
+
36
27
23
212
+
0
14
t
36
27
23
212
+
0
0
42
27
18
212
111
0
0
10
+
40
20
19
9/21
7121
13.3
16
41 8
256
229
_ . ,I
TOE SYNDACTYLY DELAYED BONE AGE
ECZEMA
+
0
+
t
+
t
+
I
t +
+
+ I
,
I
t
t
+
t
0
o
t
I
I
I
,
t
K.M.
tt
I
I
t
t
+
I
I B.M. 1
I
J.H.
HY POSPAD IAS
I
I
I
I
I
SIBLINGS
CRYPTORCHIDISM
HIGH.PITCHED HOARSE VOIDE
c
r , I,,.",
PALATE
IC
BROAD NOSE
t
t
PHlMOSlS EPICANTHAL FOLDS ABNORMAL
+
A.R.
TELECANTHUS
I
SLOPING FOREHEAD
, 3Vc;I;uv3
1
SIB LINGS
I
I
o
t
t
+
t
A.J.
I
I
I
1
+
0
o
+t
o
t
R.Z.
I
I
1
0
o
o
+
B.Z.
SIBLINGS
Table 11. Phenotypic Data of 21 Patients With the Dubowitz Syndrome
+
I
-* I SIBLINGS
The Dubowitz Syndrome
279
Fig 1. Case 1. Note typical appearance of the Dubowitz syndrome and ptosis of the left eyelid,
was 46.25 cm. Perineoscrotal hypospadias was noted at birth. The infant fed poorly during the first month of life. Profuse diarrhea began on day 3 and persisted with frequent vomiting and rectal prolapse for six months. A persistent rash of the axillae, inguinal areas, and neck responded poorly to topical medications. Examination at 6 months (Fig 2) revealed a weight of 3.4 kg (25th percentile), length of 46 cm (below the fifth percentile), and OFC of 35.5 cm (50th percentile). Facial features closely resembled those of his sister. The infant had sparse scalp hair, flat supraobrital ridges, ptosis and a flat, broad nasal bridge. The abdomen was distended. The penis was 2-cm long and bound ventrally by chordee. The urethral orifice was at the junction of the penis and scrotum. The right testicle was in the scrotum and the left testicle was palpable high in the inguinal canal. Rectal prolapse occurred with crying. At 2 11/12 years he weighed 8.2 kg (below the fifth percentile) and his OFC was 42 cm (below the fifth percentile). He had 20 teeth and his bone age was 1 year. Bilateral ptosis was again noted and the skin was very dry. He spoke monosyllable words. Results of upper gastrointestinal roentgenograms, sweat test, and hemogram were normal. The karyotype of cultured lymphocytes was 46,XY. Case 3
CB100669, a white girl, was referred for genetic evaluation at 6 years, because of short stature and syndactyly of her toes. She is the only child of unrelated parents. Both parents were 18 years old at the time ofher conception. The pregnancy terminated spontaneously “six weeks” before the estimated due date. Following an uncomplicated vaginal birth, the infant weighed 2.5 kg and was 45-cm long. She gained weight poorly during the first year of life. Her developmental progress has been considered normal.
280
Wilroy, Tipton, and Summitt
Fig 2. Case 2. Brother of Case 1 patient with similar face and bilateral ptosis.
At 6 years she weighed 16 kg (fifth percentile) and was 103-cm tall (below the fifth percentile); her OFC was 47 cm (below the fifth percentile). Facial features resembled the two prevjous patients but ptosis was absent, and hcr nasal bridge was prominent, continuous with the forehead, and her nose was “beak-shdped”. Her ears protruded from the skull with small lobules and antitragi. Micrognathia was o h ioiis and the deciduous lateral incisors were fused with the canines. No other abnormalitics were noted except those of the hands and feet. Both fifth fingers were short and clinodactylous. The nail of each fifth toe was absent. Both fourth and fifth toes were syndactplous. Chromosome analysis revealed an apparently normal 46,XX chromosome constitution. Case 4
RH030874, a white boy, was born to nonconsanguinious parents. At the time of his rvnception his mother was 29 years old and his father was 34. The infant was born “three weeks early” but weighed 2.6 kg and was 47.5-cm long. During the first month he cried weakly, was constipated, and could not open his eyes widely. A genetic consultation was requested at 5% months. The patient weighed 5.9 kg (fifth percentile), was 63-cm tall (10th percentile) and his OFC was 29.5 cm (below the fifth percentile). His intercanthal distance was 22 mm, his forehead was high, and his anterior hairline was receeded. Bilateral epicanthal folds were present and the palpebral fissures slanted upward. Severe ptosis of the eyelids was obvious and the ears were large. The chin was normal as was the voice. The chromosome constitution was 46,XY, and urinary amino acids were normal. At 1 year he weighed 7.1 kg (below the fifth percentile), and was 70-cm long (below the fifth percentile); his OFC
The Dubowitz Syndrome
28 1
was 43 cm (below the fifth percentile). By 1 7/12 years he could crawl but not walk, and could say five distinct words. His weight was 7.6 kg, length 78.5 cm, and OFC 44.5 cm (values still below the fifth percentile). Cases 5 and 6
BN131273 and JN131273, twin boys (monozygous based on blood types) were born to a 23 year old mother and a 27 year old father. The parents were unrelated. Labor began spontaneously four weeks before the estimated due date and both infants were delivered vaginally. Case 5 weighed 1.6 kg at birth and was 39.4 cm long. Case 6 weighed 1.7 kg and was 41.3-cm long. Both were noted to have a “cat-like’’ cry shortly after birth. Due to their poor growth they were referred to genetic evaluation at 27 months (Fig 3). Their length, weight, and OFC were more than two standard deviations below the mean for age, but their psychomotor development was considered normal. The voice of each was high pitched and hoarse. Their chromosome constitutions were normal. Case 7
MW260176, a white boy, was initially evaluated at 3 months due to failure to thrive, and multiple congenital anomalies including microcephaly , ptosis, and a cleft palate. The patient’s mother was 18 years old and his father was 27 at the time of his conception. Parental consanguinity was denied. Pregnancy was uncomplicated but fetal distress during labor led to a cesarean section. Resuscitation was required and the infant convulsed on the first day of life. He weighed 3.5 kg at birth. He ate poorly during the
Fig 3. Cases 5 and 6. Monozygous twins with the Dubowitz syndrome.
282
Wilroy, Tipton, and Summitt
first year. He sat alone at 12 months. At 18 months he weighed 6.8 kg, was 65.6-cm tall, and had an OFC of 4 1.8 cm (all values below the fifth percentile). His bone age was 4 months, his serum thyroxine level and the results of his chromosome analysis were normal. Case 8
NW060574, a white girl and only child was referred for genetic evaluation at 1 year because of failure t o thrive. Her mother was 19-years old and her father 20 at the time of her conception, and unrelated. The pregnancy was of normal duration and the labor uncomplicated. Birth weight was 2.0 kg and length 42.5 cm. She developed diarrhea at 3 days and remained in the nursery for one month due to poor weight gain. Her psychomotor development was normal. At 1 year (Fig 4) she weighed 5.5 kg, was 60-cm long, her OFC was 39.5 cm (all values below the fifth percentile), and she had 12 teeth. Results of hemogram and urinalysis were normal. The bone age was 3 months and the IVP was normal. Results of urinary amino acid determination, serum thyroxine, sweat chloride, serum electrolytes, and chromosome analysis were normal.
DISCUSS 10N
In 1965 Dubowitz [ 11 stated that “the family recorded here suggests that the syndrome is inherited in a recessive manner”. Grosse et al [2] also suggested that the Dubowitz syndrome is recessively inherited. Opitz et al [3] confirmed this in 1973 on the basis of sibling occurrence with normal parents and parental consanguinity in one case.
Fig 4. Case 8. See text for details.
The Dubowitz Syndrome
283
All 21 known patients are Caucasian. Siblings were affected six times, including one set of monozygous twins. The sex ratio is 1 (1 1 F, 10 M). The approximate average age of the mothers at conception of the probands was 22.9 years, and of the fathers, 25.6 years. The average duration of the pregnancies was 41.8 weeks based on estimated dates alone. Of the 21 patients, 16 had intrauterine growth retardation (IUGRless than the 25th percentile) [5] . The average birth weight was 2.27 kg and the average birth length was about 45 cm. Thirteen ate poorly during infancy; 7 had diarrhea during the first 6 months, and 6 vomited frequently. Subnormal intellect was definite in 7, and 9 patients were described as hyperactive. Postnatal growth retardation is usually characteristic of the syndrome although one of the patients reported by Opitz et al [3] apparently grew well after birth although she had typical dysmorphic facial features. Figures 7-10 of Majewski et al [4] summarize prenatal growth patterns, postnatal length/height, weight, and OFC growth, respectively, in 12 Dubowitz-syndrome patients. Microcephaly is a consistent finding. Dysmorphic facial features include sparse hair, sloping forehead, flat supraorbital ridges with the bridge of the broad nose continuous with the forehead, telecanthus, ptosis and/or blepharophimosis (frequently asymmetrical), epicanthal folds, and micrognathia. The voice may be high-pitched and hoarse. Cleft palate has been found in four patients. Internal abnormalities have not been reported. Hypospadias and/or cryptorchism may be encountered in affected males. Eight have had syndactyly of their toes. The ultimate intellectual performance of children with the Dubowitz syndrome has yet to be determined. Their microcephaly is of such a degree that severe mental retardation might be anticipated. However, this has not been the case since the patients usually appear to be mentally normal or at worst, mildly retarded. They are often shy, hyperactive and have brief attention spans. The Dubowitz syndrome should not be confused with the Seckel syndrome [6] , or the fetal alcohol syndrome [ 7 , 8 ] , two conditions of prenatal and postnatal growth retardation. The mental retardation in the Seckel syndrome may be more severe and the facial appearance is distinctly different. Historical data as well as characteristic appearance and congenital cardiac defects and abnormal digits, should aid in making the diagnosis of the fetal alcohol syndrome. The Dubowitz syndrome is a bona fide clinical entity, inherited in an autosomal recessive manner. No biochemical or chromosome defect has been found. The ultimate intellectual function and height of these children is unknown and requires further study.
ACKNOWLEDGMENTS
This work was supported by Special Project 900, Division of Health Services, MCHS, HSMHA, DHEW, and by a grant from the National Foundation-March of Dimes. We thank Tricia Davis who helped gather this information and typed this manuscript.
REFERENCES 1. Dubowitz V: Familial low birth weight dwarfism with an unusual facies and a skin eruption, J Med Genet 2:12-17, 1965.
284
Wilroy, T i p t o n , and S u m m i t t
2. Grosse R, Gorlin J, Opitz JM: The Dubowitz syndrome. Z Kinderheilk 110:175-187, 1971. 3. Opitz JM, Pfeiffer RA, Hermann JPR, Kushnick T: Studies of malformation syndromes of man X X N B : the Dubowitz syndrome. Further observations. Z Kinderheilk 116:l-12, 1973. 4. Majewski F, Michaelis R, Moosmann K, Bierich JR: A rare type of low birth weight dwarfism: the Dubowitz syndrome. Z Kinderheilk 120:283-292,1975. 5 . Lubchenco LO, Hansman C, Boyd E: Intrauterine growth in length and head circumference as estimated from live births at gestational ages from 26 to 42 weeks. Pediatrics 37:403-408, 1966. 6. Seckel HPG: “Bird-headed Dwarfs. Studies in Developmental Anthropology including Human Proportions.” Springfield: Thomas, 1960. 7 . Lemoine P, Harousseau H, Borteyru JP, Menuet JC: Les enfants de parents alco8liques; anomalies observe‘es propos d e 127 cas. Ouest Med 25:476-482,1968. 8. Jones KL, Smith DW, Ullelan CN, Streissguth AP: Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1:1267, 1973.
Edited b y John M. O p i t z
