Clinical Genetics 1977: 11: 128-136
X-linked skeletal dysplasia with mental retardation JOE
c. ( h W T I A N , w.DEMYER,E.
A. FRANKEN, J. S. HUFF, S. KHAIRI AND T. REED Indiana University School of Medicine, Indianapolis, Indiana, U.S.A.
A syndrome compatible with an X-linked trait is described, affecting four male cousins in three sibships. The boys had skeletal anomalies, including short stature, ridging of the metopic suture, fusion of cervical vertebrae, thoracic hemivertebrae, scoliosis, sacral hypoplasia and short middle phalanges. In addition, they had moderate developmental retardation, and abducens palsies. Three of the four had glucose intolerance, and one was born with an imperforate anus. Of five female obligate carriers studied, three had fusion of cervical vertebrae, three had some shortening of the middle phalanges and three had glucose intolerance. The syndrome in this family was compared to previously reported syndromes, and the conclusion was reached that it represents a previously unreported X-linked syndrome with minor manifestations in carrier females. Received 30 August, accepted for publication 23 September 1976
Case Reports
Family #901 (Fig. 1) was ascertained through a retarded male who was referred for diagnosis and genetic counseling.
Individual 111-1 (Fig. 2)) born on 8-21-58 after an induced labor lasting 12 hours, weighed 3,320 g, and was kept in an incubator for 24 hours because of respiratory distress. He sucked poorly, sat up at 8 months and walked at 15 months. He spoke single words at 1 year and later had speech therapy because he was difficult to understand. He had plastic surgery for protruding ears and leg braces for tibia1 torsion. When examined at 16 years, his height was 148 cm, weight 41.8 kg (both below the third percentile), and the occipital frontal circumference (OFC) was 55 cm (50th percentile). He had a distinct metopic ridge, antimongoloid palpebral fissures, small
epicanthal folds, and bilateral abducens palsy, but n o corneal, lens or fundus abnormalities. His hearing was intact, and his teeth were normal. He had an asymmetric chest, but n o heart murmur. A pilonidal dimple was present, but no abnormalities of the penis, testes, scrotum or secondary sexual characteristics were noted. His fifth fingers were short and incurved. He had normal muscle strength and reflexes, and a normal sense of smell. Roentgenographic study of the skeleton showed a normal skull and extremities, except for clinodactyly of both fifth fingers. The spine roentgenograms demonstrated occipitalization of the atlas, fusion of C-2 with G 3 (involving the neural arches and bodies), scoliosis secondary to a hemivertebra at T-2, and a normal sacrum. An electroencephalogram revealed diffuse slowing and a spike focus in the right frontal area. A barium enema, done at age
X-LINKED SKELETAL DYSPLASIA WITH MENTAL RETARDATION FAMILY
X
129
901
I
AFFECTED MALES
N
@
OBLIGATE FEMALE CARRIERS
Fig. 1. Pedigree of Family # 901
8 because of constipation, was normal. His urine was normal for protein, ketones, bilirubin, hemoglobin, reducing substances, sulfhydryl groups, keto acids, glycosaminoglycans, methylmalonic acid, auto-oxidation and amino acids. Blood chemistry tests were normal for sodium, potassium, calcium, phosphorus, urea nitrogen, uric acid, cholesterol, triglycerides, total protein, albumin, globulins, bilirubin, alkaline phosphatase, lactic dehydrogenase, glutamic oxaloacetic transaminase and insulin. He had normal hemoglobin, hematocrit and white blood cell values. Following an oral glucose load (1 . 6 g/kg), he spilled glucose in his urine, and his blood glucose rose from 87 mg/100 ml fasting to 250 mg/lOO ml at 1 hour. His Wechsler adult intelligence scale score was in the mildly retarded range (VIQ-68, PIQ-66, FSIQ-6.5). A wide range achievement test revealed similar findings (reading 72, spelling 72 and arithmetic 6.5). Individual 111-3 (Fig. 3) was born on 6-1367, and he weighed 3,750 g. He was slower than his normal sister to develop but faster than his brother (111-1). He sat at 4 months
and walked at 12 months. He has had a continuous problem of tight heel cords, which were treated by physical therapy. Several IQ tests have placed him in the borderline-normal range, but he has been slowest in his verbal abilities. At age 7 he was just below the third percentile for height and weight. H e had metopic ridging, left abducens palsy and fifth finger clinodactyly. His sense of smell, muscle strength and reflexes were normal. On roentgenographic examination the skull and extremities were normal, with the exception of fifth finger clinodactyly. In the cervical spine, the neural arches and possibly the bodies of C-2 and C-3 were fused. There was localized scoliosis with a hemivertebra at T-8, and the sacrum was slightly hypoplastic. The same urine and blood studies were normal as reported for Individual 111-1. He spilled sugar in his urine following a glucose load, and his blood sugar rose from 86 mg/100 ml fasting to 260 mg/100 ml. He scored 83 on a Peabody picture vocabulary test. A developmental test of visual motor integration revealed a standard score of 68.
130
CHRISTIAN, DEMYER, FRANKEN, HUFF, KHAlRl AND REED
Fig. 2. Individual 111-1 at 11 and 16 years.
Individual 111-18 (Fig. 4) was born on 5-2760, and weighed 2,640 g. An imperforate anus was treated shortly after birth with surgery and dilatation. Development was slower than that of his siblings. At 6 years of age, trigonocephaly was diagnosed by physical examination and by skull radiographs which showed an abnormally narrow interorbital distance. A pneumoencephalogram revealed moderate dilatation of the lateral and 3rd ventricles; no midline anomalies were noted. An electroencephalogram showed bilateral slowing. H e has
been in special education classes throughout school. When examined at 15 years of age, his height was 60 cm, weight 22.2 kg (below the 3rd percentile), and his OFC was 55 c m (50th percentile). H e had a keel-shaped deformity of his skull, with closely-set eyes, but normal ocular and eyelid movements. His ears showed thick helices. H e walked with a slow gait and inturned feet, but had normal muscle strength and reflexes. Normal secondary sexual characteristics, penis, testes t n d scrotum were present. His sense
X-LINKED SKELETAL DYSPLASIA WITH MENTAL RETARDATION
Fig. 3. years.
of smell was normal. His WISC showed a verbal IQ of 50, performance of 48 and full scale of 44. On roentgenographic study at age 15 years, the long bones were normal, and the skull showed only hypotelorism. There was occipitalization of C-1, a hypoplastic odontoid process, and fusion of the arches and bodies of C-2 and C-3. Localized scoliosis at T-4 was noted, but no hemivertebra or other structural anomaly was identified at this site. The sacrum was slightly hypoplastic. Hand roentgenograms were normal. The same laboratory studies were done as reported for 111-1 and found to be normal. He was also intolerant of an oral glucose load, spilling glucose in his urine, and his fasting glucose of 74 mg/100 ml rose to 161 mg/100 ml at 1 hour.
131
Individual 1 1 1 3 at 3
Individual IV-1 (Fig. 5 ) was born on 8-171 with a birth weight of 3,380 g. He has been somewhat slow in his mental development. He sat at 6 months, walked at 10 months, but was unable to put words together until the age of 2 years. At 19 months of age he had bilateral lateral rectus surgery for bilateral abducens palsy. At 2 years of age he had a single grand ma1 seizure. When examined at 40 months of age, his height was 90 cm and weight 11 kg (both below the 3rd percentile), His OFC was 47.7 cm (20th percentile) and there was slight metopic ridging. The skull was asymmetric. He had flat superior borders of his helices and small epicanthal folds. A normal gait was present and, apart from an impression of slow development, there were
132
CHRISTIAN, DEMYER, FRANKEN, HUFF, KHAlRl AND REED
Fig. 4. Individual 111-18 at 6 years.
Flg. 5. Individual IV-1 months.
at 40
X-LINKED SKELETAL DYSPLASIA WITH MENTAL RETARDATION
133
Table 1 Dermatoglyphic findings in affected males of Family #901 A. Fingers Left
I 111-1 1 1 1 3 111-18 Iv-1
A L" LU A
Right
II
111
IV
v
I
W
W" L" LU Lu
W'
W W*' LU A
Lu LU LU A
w
LU A
' Central pocket
**
w L" L'
111
II
W
L'
IV
W
v LU
w
w
w
w
L" L'
LU L'
L" W'
L" L"
Total ridge count
141 131 155 65
Double loop
B. Palm Left
Right t'(l5%). 0.O.O. 0 .? t'(270/0).0.0.O.L~.Ld t"(41%).W.O.O.O.L~ t'(16°/o).0.0.0.Ld.0
I 11-1 t'(25%).0.L'.O.O.L. I 11-3 t'(30%).0.0.0.Ld.O 111-18 t(80/0).L'.O.O.O.Ld IV-1 t (14%) .O.0.0.O. Ld 111-1 absent c triradius bilaterally C. Sole Left
Right B i g toe
111-1 w.o.w.0 111-3 W.L"O.0 I 11-16 Ate"t.O. Ld.O AP.Ld.O.O IV-1
+I
-
A m-1
METACARPALS
.4 A
L' A
0
Big toe
A A L' A
w.o.w.0 W.O.Ld,O A'@"'.O.O.Ld
Af/Ld.O.O.O
In-18
PROXIMAL
+-
MIDDLE
DISTAL
Flg. 6. Profiles of hand-bone lengths. expressed as standard deviatlons from age- and sex-adjusted means (Poznanski 1974), for the four affected boys i n Family # 901.
134
CHRISTIAN, DEMYER, FRANKEN, HUFF, KHAlRl AND REED
no neurological abnormalities. No developmental testing was done. A glucose tolerance test revealed a fasting level of 61 mg/ 100 ml, which rose only to 110, and he spilled no glucose in his urine. Roentgenographic examination of the skull showed slight flattening of the base and high supraorbital ridges, but was otherwise normal. The neural arches but not the bodies of (3-2 and C-3 were fused. Scoliosis and a T-11 hemivertebra were noted. The sacrum was normal. Clinodactyly of both fifth digits was noted. Chromosome studies, including G-banding (trypsin), were done on individuals 111-1, 111-3, and 11-2, and were normal. The dermatoglyphic findings of the four affected males are shown in Table 1, after the method of Cummins & Midlo (1961). It is difficult to discern a diagnostic pattern; however, there appears to be an excess of arches in hallucal, big toe or digital patterns, when compared with other family members. In addition, two of the boys (III1, 3) have bilateral simian creases, and one (111-1) has bilateral single flexion creases of the little fingers. Bone anomalies. Three of the four affected boys had clinodactyly of the fifth digits indicative of Type A3 brachydactyly (Temtamy & McKusick 1969). Radiographic anthropometry of the affected boys’ hands was done to determine if a pattern of bone anomalies could be ascertained. In Figure 6, the mean lengths of each individual’s right and left metacarpals and phalanges are plotted as standard scores (Poznanski 1974). The boys have similar patterns with all of their bones being generally short, which is compatible with their stature. There is a tendency to more marked shortening from the second through the fifth middle and distal phalanges, but the first
distal phalanges are shorter than 2-5. The short fifth middle phalanges were associated with clinically evident clinodactyly in three of the four affected boys. In contrast to the middle and distal phalanges, the second and third metacarpals tended to be the shortest.
Discussion The familial relationship, developmental retardation, glucose intolerance, and similar skeletal findings, including the metopic ridging, cervical vertebral fusion and similar bone-length profiles of the hands leave little doubt that these four boys share an inherited syndrome (Table 2). The most likely mode of transmission is an X-linked recessive trait, although a sex-limited autosoma1 dominant trait is possible. These boys do not appear to fit any previously described syndrome. They do, however, share in addition to developmental retardation, physical findings with several probably X-linked syndromes. Opitz et al.
Table 2
Summary of findings in the affected males of Family #901 Findings 1. Developmental 2. 3. 4. 5. 6.
7. 8.
9. 10. 11. 12.
retardation Short stature Metopic suture ridging Cervical vertebral fusion Scoliosis Short fifth middle phalanges Abducens palsy Clinodactyly of 5th finger Thoracic hemivertebra Glucose intolerance Hypoplastic sacrum Imperforate anus
111-1
111-3
111-18
IV-1
+ +
+ +
+
+ +
+
+ +
+
+
+
+
+
+ +
+ + + + + -
+
+
+
+
+
+
-
+
+ + +
+
+ + + + -
+ -
-
t
X-LINKED SKELETAL DYSPLASIA WITH MENTAL RETARDATION
(1969) described four brothers with what they termed the G syndrome. All had ear anomalies and one had an imperforate anus. The Coffin syndrome (Coffin et al. 1966, Procopia & Turner 1972) has skeletal anomalies, including cervical fusion, in common with our cases. Opitz & Kaveggia (1974) reported the FG syndrome in which affected males had imperforate anus, fifth finger clinodactyly and vertebral anomalies. The hypertelorism-hypospadias syndrome (Opitz et al. 1969, Christian et al. 1969), which may be X-linked, has skull abnormalities and imperforate anus. The otopalatal-digital syndrome is also a syndrome of developmental retardation and skeletal dysplasia with metopic prominence (Dudding et al. 1967). In addition, there are several dysmorphic syndromes which are probably X-linked and in which, although developmental retardation is not a prominent feature, physical findings are shared with the present family. The Aarskog syndrome (Aarskog 1970) has unusual facies, metopic ridging, abnormal ears, vertebral anomalies and hypoplastic middle phalanges. McKusick (1975) reviewed an X-linked syndrome with cleft palate and metopic ridging, as well as an X-linked form of imperforate anus. We have, therefore, concluded that a previously undescribed X-linked syndrome is segregating in Family #901. The availability of five obligate carriers in Family #901 (Fig. 1) led to efforts to discover physical and metabolic abnormalities in these women. There was no evidence for developmental retardation or abducens palsy in any of the obligate carriers. None of the carriers had metopic ridging, all had normal skull roentgenograms, and n o distinctive pattern of dermatoglyphic findings was detected. However, cervical spine roentgenograms revealed bony fusion of G 2 and G 3 in two of the five women (11-2, 1-2). In addition, 11-10 had narrowing and limi-
135
tation of movement between C 2 and CL3. Cervical spine films of 11-6 and 111-10 were apparently normal. Sacral roentgenograms were taken of 1-2, 11-2 and 11-10, and found to be within normal limits. Radiologic anthropometry (Poznanski 1974) revealed three of the five carriers to have a pattern of increasing shortening of the middle phalanges from 2-5, but only one carrier had a fifth middle phalanx greater than 2 standard deviations below the population mean. Two of the five carriers are being treated for diabetes mellitus (1-2 and 11-10), In addition, Individual 11-2 was found to be intolerant of a 100 g oral glucose load, as blood glucose rose from 105 mg/100 ml fasting to 210 accompanied by glucosuria. Some female carriers, therefore, appear to have minor manifestations in common with the more severely affected boys, although it is impossible at this time to determine if some of these associations are due to chance (e.g. diabetes mellitus). Acknowledgments
We thank Drs. R. J . Gorlin, J. Herrmann and J. M. Opitz for reviewing the clinical material. This is publication #76-08 from the Department of Medical Genetics and was supported in part by the Indiana University Human Genetics Center, PHS G M 21054, PHS RR-00750, PHS T22 G M 8 and PHS TO1 GM 1056.
References
Aarskog, D. (1970). A familial syndrome of short stature associated with facial dysplasia and genital anomalies. J . Pediat. 77, 856-87 1.
Christian, J. C., D. Bider, S. C. Blythe .& A. D. Merritt (1969). Familial telecanthus with associated congenital anomalies. Birth Defects: Original Article Series V o l . V NO. 2, 82-85.
136
CHRISTIAN, DEMYER, FRANKEN, HUFF, KHAlRl AND REED
Coffin, G. S., E. Siris & L. C. Wegienk (1966). Mental retardation with osteocartilaginous anomalies. Amer. J . Dis. Child. 112, 205213. Cummins, H. & C. Midlo (1961). Fingerprints, Palms and Soles, 2nd Ed. New York, Dover Publications. Dudding, B. A., R. J. Gorlin C L. 0. Langer (1967). The oto-palatal-digital syndrome: A new symptom-complex consisting of deafness, dwarfism, cleft palate, characteristic facies and a generalized bone dyspIasia. Amer. J . Dis. Child. 113, 214-221. McKusick, V. A. (1975). Mendelian Inheritance in Man, 4th Ed. Baltimore, The Johns Hopkins Press. Opitz, J. M., J. L. Frias, J. E. Gutenberger C J . R. Pellett (1969). The G syndrome of multiple congenital anomalies. Birth Defects: Original Arricle Series Vol. V No. 2, 95-100. Opitz, J. M. & E. G. Kaveggia (1974). Studies of malformation syndromes of man XXXIII: The FG syndrome. Z . Kinderheilk. 117, 1-18. Opitz, J. M., R. L. Summit & D. W. Smith
(1969). The BBB syndrome. Familial tels canthus with associated congenital anomalies. Birth Defects: Original Article Series Vol. v NO. 2, 86-94. Poznanski, A. D. (1974). The Hand in Radio. logic Diagnosis. Philadelphia, W. B. Saunders
co. Procopia, P. G. C B. Turner (1972). Mental retardation, abnormal fingers and skeletal anomalies: Coffin’s syndrome. Amer. J . Dis. Child. 124, 258-261. Temtamy, S. A. & V. A. McKusick (1969). Synopsis of hand malformations with particular emphasis on genetic factors. Birth Defects: Original Article Series Vol. V , No. 3, 125-184. Address: Joe C . Christian, Ph.D., M . D . Indiana University School of Medicine Indianapolis Indiana 46202 U.S.A.
X-linked skeletal dysplasia with mental retardation JOE
c. ( h W T I A N , w.DEMYER,E.
A. FRANKEN, J. S. HUFF, S. KHAIRI AND T. REED Indiana University School of Medicine, Indianapolis, Indiana, U.S.A.
A syndrome compatible with an X-linked trait is described, affecting four male cousins in three sibships. The boys had skeletal anomalies, including short stature, ridging of the metopic suture, fusion of cervical vertebrae, thoracic hemivertebrae, scoliosis, sacral hypoplasia and short middle phalanges. In addition, they had moderate developmental retardation, and abducens palsies. Three of the four had glucose intolerance, and one was born with an imperforate anus. Of five female obligate carriers studied, three had fusion of cervical vertebrae, three had some shortening of the middle phalanges and three had glucose intolerance. The syndrome in this family was compared to previously reported syndromes, and the conclusion was reached that it represents a previously unreported X-linked syndrome with minor manifestations in carrier females. Received 30 August, accepted for publication 23 September 1976
Case Reports
Family #901 (Fig. 1) was ascertained through a retarded male who was referred for diagnosis and genetic counseling.
Individual 111-1 (Fig. 2)) born on 8-21-58 after an induced labor lasting 12 hours, weighed 3,320 g, and was kept in an incubator for 24 hours because of respiratory distress. He sucked poorly, sat up at 8 months and walked at 15 months. He spoke single words at 1 year and later had speech therapy because he was difficult to understand. He had plastic surgery for protruding ears and leg braces for tibia1 torsion. When examined at 16 years, his height was 148 cm, weight 41.8 kg (both below the third percentile), and the occipital frontal circumference (OFC) was 55 cm (50th percentile). He had a distinct metopic ridge, antimongoloid palpebral fissures, small
epicanthal folds, and bilateral abducens palsy, but n o corneal, lens or fundus abnormalities. His hearing was intact, and his teeth were normal. He had an asymmetric chest, but n o heart murmur. A pilonidal dimple was present, but no abnormalities of the penis, testes, scrotum or secondary sexual characteristics were noted. His fifth fingers were short and incurved. He had normal muscle strength and reflexes, and a normal sense of smell. Roentgenographic study of the skeleton showed a normal skull and extremities, except for clinodactyly of both fifth fingers. The spine roentgenograms demonstrated occipitalization of the atlas, fusion of C-2 with G 3 (involving the neural arches and bodies), scoliosis secondary to a hemivertebra at T-2, and a normal sacrum. An electroencephalogram revealed diffuse slowing and a spike focus in the right frontal area. A barium enema, done at age
X-LINKED SKELETAL DYSPLASIA WITH MENTAL RETARDATION FAMILY
X
129
901
I
AFFECTED MALES
N
@
OBLIGATE FEMALE CARRIERS
Fig. 1. Pedigree of Family # 901
8 because of constipation, was normal. His urine was normal for protein, ketones, bilirubin, hemoglobin, reducing substances, sulfhydryl groups, keto acids, glycosaminoglycans, methylmalonic acid, auto-oxidation and amino acids. Blood chemistry tests were normal for sodium, potassium, calcium, phosphorus, urea nitrogen, uric acid, cholesterol, triglycerides, total protein, albumin, globulins, bilirubin, alkaline phosphatase, lactic dehydrogenase, glutamic oxaloacetic transaminase and insulin. He had normal hemoglobin, hematocrit and white blood cell values. Following an oral glucose load (1 . 6 g/kg), he spilled glucose in his urine, and his blood glucose rose from 87 mg/100 ml fasting to 250 mg/lOO ml at 1 hour. His Wechsler adult intelligence scale score was in the mildly retarded range (VIQ-68, PIQ-66, FSIQ-6.5). A wide range achievement test revealed similar findings (reading 72, spelling 72 and arithmetic 6.5). Individual 111-3 (Fig. 3) was born on 6-1367, and he weighed 3,750 g. He was slower than his normal sister to develop but faster than his brother (111-1). He sat at 4 months
and walked at 12 months. He has had a continuous problem of tight heel cords, which were treated by physical therapy. Several IQ tests have placed him in the borderline-normal range, but he has been slowest in his verbal abilities. At age 7 he was just below the third percentile for height and weight. H e had metopic ridging, left abducens palsy and fifth finger clinodactyly. His sense of smell, muscle strength and reflexes were normal. On roentgenographic examination the skull and extremities were normal, with the exception of fifth finger clinodactyly. In the cervical spine, the neural arches and possibly the bodies of C-2 and C-3 were fused. There was localized scoliosis with a hemivertebra at T-8, and the sacrum was slightly hypoplastic. The same urine and blood studies were normal as reported for Individual 111-1. He spilled sugar in his urine following a glucose load, and his blood sugar rose from 86 mg/100 ml fasting to 260 mg/100 ml. He scored 83 on a Peabody picture vocabulary test. A developmental test of visual motor integration revealed a standard score of 68.
130
CHRISTIAN, DEMYER, FRANKEN, HUFF, KHAlRl AND REED
Fig. 2. Individual 111-1 at 11 and 16 years.
Individual 111-18 (Fig. 4) was born on 5-2760, and weighed 2,640 g. An imperforate anus was treated shortly after birth with surgery and dilatation. Development was slower than that of his siblings. At 6 years of age, trigonocephaly was diagnosed by physical examination and by skull radiographs which showed an abnormally narrow interorbital distance. A pneumoencephalogram revealed moderate dilatation of the lateral and 3rd ventricles; no midline anomalies were noted. An electroencephalogram showed bilateral slowing. H e has
been in special education classes throughout school. When examined at 15 years of age, his height was 60 cm, weight 22.2 kg (below the 3rd percentile), and his OFC was 55 c m (50th percentile). H e had a keel-shaped deformity of his skull, with closely-set eyes, but normal ocular and eyelid movements. His ears showed thick helices. H e walked with a slow gait and inturned feet, but had normal muscle strength and reflexes. Normal secondary sexual characteristics, penis, testes t n d scrotum were present. His sense
X-LINKED SKELETAL DYSPLASIA WITH MENTAL RETARDATION
Fig. 3. years.
of smell was normal. His WISC showed a verbal IQ of 50, performance of 48 and full scale of 44. On roentgenographic study at age 15 years, the long bones were normal, and the skull showed only hypotelorism. There was occipitalization of C-1, a hypoplastic odontoid process, and fusion of the arches and bodies of C-2 and C-3. Localized scoliosis at T-4 was noted, but no hemivertebra or other structural anomaly was identified at this site. The sacrum was slightly hypoplastic. Hand roentgenograms were normal. The same laboratory studies were done as reported for 111-1 and found to be normal. He was also intolerant of an oral glucose load, spilling glucose in his urine, and his fasting glucose of 74 mg/100 ml rose to 161 mg/100 ml at 1 hour.
131
Individual 1 1 1 3 at 3
Individual IV-1 (Fig. 5 ) was born on 8-171 with a birth weight of 3,380 g. He has been somewhat slow in his mental development. He sat at 6 months, walked at 10 months, but was unable to put words together until the age of 2 years. At 19 months of age he had bilateral lateral rectus surgery for bilateral abducens palsy. At 2 years of age he had a single grand ma1 seizure. When examined at 40 months of age, his height was 90 cm and weight 11 kg (both below the 3rd percentile), His OFC was 47.7 cm (20th percentile) and there was slight metopic ridging. The skull was asymmetric. He had flat superior borders of his helices and small epicanthal folds. A normal gait was present and, apart from an impression of slow development, there were
132
CHRISTIAN, DEMYER, FRANKEN, HUFF, KHAlRl AND REED
Fig. 4. Individual 111-18 at 6 years.
Flg. 5. Individual IV-1 months.
at 40
X-LINKED SKELETAL DYSPLASIA WITH MENTAL RETARDATION
133
Table 1 Dermatoglyphic findings in affected males of Family #901 A. Fingers Left
I 111-1 1 1 1 3 111-18 Iv-1
A L" LU A
Right
II
111
IV
v
I
W
W" L" LU Lu
W'
W W*' LU A
Lu LU LU A
w
LU A
' Central pocket
**
w L" L'
111
II
W
L'
IV
W
v LU
w
w
w
w
L" L'
LU L'
L" W'
L" L"
Total ridge count
141 131 155 65
Double loop
B. Palm Left
Right t'(l5%). 0.O.O. 0 .? t'(270/0).0.0.O.L~.Ld t"(41%).W.O.O.O.L~ t'(16°/o).0.0.0.Ld.0
I 11-1 t'(25%).0.L'.O.O.L. I 11-3 t'(30%).0.0.0.Ld.O 111-18 t(80/0).L'.O.O.O.Ld IV-1 t (14%) .O.0.0.O. Ld 111-1 absent c triradius bilaterally C. Sole Left
Right B i g toe
111-1 w.o.w.0 111-3 W.L"O.0 I 11-16 Ate"t.O. Ld.O AP.Ld.O.O IV-1
+I
-
A m-1
METACARPALS
.4 A
L' A
0
Big toe
A A L' A
w.o.w.0 W.O.Ld,O A'@"'.O.O.Ld
Af/Ld.O.O.O
In-18
PROXIMAL
+-
MIDDLE
DISTAL
Flg. 6. Profiles of hand-bone lengths. expressed as standard deviatlons from age- and sex-adjusted means (Poznanski 1974), for the four affected boys i n Family # 901.
134
CHRISTIAN, DEMYER, FRANKEN, HUFF, KHAlRl AND REED
no neurological abnormalities. No developmental testing was done. A glucose tolerance test revealed a fasting level of 61 mg/ 100 ml, which rose only to 110, and he spilled no glucose in his urine. Roentgenographic examination of the skull showed slight flattening of the base and high supraorbital ridges, but was otherwise normal. The neural arches but not the bodies of (3-2 and C-3 were fused. Scoliosis and a T-11 hemivertebra were noted. The sacrum was normal. Clinodactyly of both fifth digits was noted. Chromosome studies, including G-banding (trypsin), were done on individuals 111-1, 111-3, and 11-2, and were normal. The dermatoglyphic findings of the four affected males are shown in Table 1, after the method of Cummins & Midlo (1961). It is difficult to discern a diagnostic pattern; however, there appears to be an excess of arches in hallucal, big toe or digital patterns, when compared with other family members. In addition, two of the boys (III1, 3) have bilateral simian creases, and one (111-1) has bilateral single flexion creases of the little fingers. Bone anomalies. Three of the four affected boys had clinodactyly of the fifth digits indicative of Type A3 brachydactyly (Temtamy & McKusick 1969). Radiographic anthropometry of the affected boys’ hands was done to determine if a pattern of bone anomalies could be ascertained. In Figure 6, the mean lengths of each individual’s right and left metacarpals and phalanges are plotted as standard scores (Poznanski 1974). The boys have similar patterns with all of their bones being generally short, which is compatible with their stature. There is a tendency to more marked shortening from the second through the fifth middle and distal phalanges, but the first
distal phalanges are shorter than 2-5. The short fifth middle phalanges were associated with clinically evident clinodactyly in three of the four affected boys. In contrast to the middle and distal phalanges, the second and third metacarpals tended to be the shortest.
Discussion The familial relationship, developmental retardation, glucose intolerance, and similar skeletal findings, including the metopic ridging, cervical vertebral fusion and similar bone-length profiles of the hands leave little doubt that these four boys share an inherited syndrome (Table 2). The most likely mode of transmission is an X-linked recessive trait, although a sex-limited autosoma1 dominant trait is possible. These boys do not appear to fit any previously described syndrome. They do, however, share in addition to developmental retardation, physical findings with several probably X-linked syndromes. Opitz et al.
Table 2
Summary of findings in the affected males of Family #901 Findings 1. Developmental 2. 3. 4. 5. 6.
7. 8.
9. 10. 11. 12.
retardation Short stature Metopic suture ridging Cervical vertebral fusion Scoliosis Short fifth middle phalanges Abducens palsy Clinodactyly of 5th finger Thoracic hemivertebra Glucose intolerance Hypoplastic sacrum Imperforate anus
111-1
111-3
111-18
IV-1
+ +
+ +
+
+ +
+
+ +
+
+
+
+
+
+ +
+ + + + + -
+
+
+
+
+
+
-
+
+ + +
+
+ + + + -
+ -
-
t
X-LINKED SKELETAL DYSPLASIA WITH MENTAL RETARDATION
(1969) described four brothers with what they termed the G syndrome. All had ear anomalies and one had an imperforate anus. The Coffin syndrome (Coffin et al. 1966, Procopia & Turner 1972) has skeletal anomalies, including cervical fusion, in common with our cases. Opitz & Kaveggia (1974) reported the FG syndrome in which affected males had imperforate anus, fifth finger clinodactyly and vertebral anomalies. The hypertelorism-hypospadias syndrome (Opitz et al. 1969, Christian et al. 1969), which may be X-linked, has skull abnormalities and imperforate anus. The otopalatal-digital syndrome is also a syndrome of developmental retardation and skeletal dysplasia with metopic prominence (Dudding et al. 1967). In addition, there are several dysmorphic syndromes which are probably X-linked and in which, although developmental retardation is not a prominent feature, physical findings are shared with the present family. The Aarskog syndrome (Aarskog 1970) has unusual facies, metopic ridging, abnormal ears, vertebral anomalies and hypoplastic middle phalanges. McKusick (1975) reviewed an X-linked syndrome with cleft palate and metopic ridging, as well as an X-linked form of imperforate anus. We have, therefore, concluded that a previously undescribed X-linked syndrome is segregating in Family #901. The availability of five obligate carriers in Family #901 (Fig. 1) led to efforts to discover physical and metabolic abnormalities in these women. There was no evidence for developmental retardation or abducens palsy in any of the obligate carriers. None of the carriers had metopic ridging, all had normal skull roentgenograms, and n o distinctive pattern of dermatoglyphic findings was detected. However, cervical spine roentgenograms revealed bony fusion of G 2 and G 3 in two of the five women (11-2, 1-2). In addition, 11-10 had narrowing and limi-
135
tation of movement between C 2 and CL3. Cervical spine films of 11-6 and 111-10 were apparently normal. Sacral roentgenograms were taken of 1-2, 11-2 and 11-10, and found to be within normal limits. Radiologic anthropometry (Poznanski 1974) revealed three of the five carriers to have a pattern of increasing shortening of the middle phalanges from 2-5, but only one carrier had a fifth middle phalanx greater than 2 standard deviations below the population mean. Two of the five carriers are being treated for diabetes mellitus (1-2 and 11-10), In addition, Individual 11-2 was found to be intolerant of a 100 g oral glucose load, as blood glucose rose from 105 mg/100 ml fasting to 210 accompanied by glucosuria. Some female carriers, therefore, appear to have minor manifestations in common with the more severely affected boys, although it is impossible at this time to determine if some of these associations are due to chance (e.g. diabetes mellitus). Acknowledgments
We thank Drs. R. J . Gorlin, J. Herrmann and J. M. Opitz for reviewing the clinical material. This is publication #76-08 from the Department of Medical Genetics and was supported in part by the Indiana University Human Genetics Center, PHS G M 21054, PHS RR-00750, PHS T22 G M 8 and PHS TO1 GM 1056.
References
Aarskog, D. (1970). A familial syndrome of short stature associated with facial dysplasia and genital anomalies. J . Pediat. 77, 856-87 1.
Christian, J. C., D. Bider, S. C. Blythe .& A. D. Merritt (1969). Familial telecanthus with associated congenital anomalies. Birth Defects: Original Article Series V o l . V NO. 2, 82-85.
136
CHRISTIAN, DEMYER, FRANKEN, HUFF, KHAlRl AND REED
Coffin, G. S., E. Siris & L. C. Wegienk (1966). Mental retardation with osteocartilaginous anomalies. Amer. J . Dis. Child. 112, 205213. Cummins, H. & C. Midlo (1961). Fingerprints, Palms and Soles, 2nd Ed. New York, Dover Publications. Dudding, B. A., R. J. Gorlin C L. 0. Langer (1967). The oto-palatal-digital syndrome: A new symptom-complex consisting of deafness, dwarfism, cleft palate, characteristic facies and a generalized bone dyspIasia. Amer. J . Dis. Child. 113, 214-221. McKusick, V. A. (1975). Mendelian Inheritance in Man, 4th Ed. Baltimore, The Johns Hopkins Press. Opitz, J. M., J. L. Frias, J. E. Gutenberger C J . R. Pellett (1969). The G syndrome of multiple congenital anomalies. Birth Defects: Original Arricle Series Vol. V No. 2, 95-100. Opitz, J. M. & E. G. Kaveggia (1974). Studies of malformation syndromes of man XXXIII: The FG syndrome. Z . Kinderheilk. 117, 1-18. Opitz, J. M., R. L. Summit & D. W. Smith
(1969). The BBB syndrome. Familial tels canthus with associated congenital anomalies. Birth Defects: Original Article Series Vol. v NO. 2, 86-94. Poznanski, A. D. (1974). The Hand in Radio. logic Diagnosis. Philadelphia, W. B. Saunders
co. Procopia, P. G. C B. Turner (1972). Mental retardation, abnormal fingers and skeletal anomalies: Coffin’s syndrome. Amer. J . Dis. Child. 124, 258-261. Temtamy, S. A. & V. A. McKusick (1969). Synopsis of hand malformations with particular emphasis on genetic factors. Birth Defects: Original Article Series Vol. V , No. 3, 125-184. Address: Joe C . Christian, Ph.D., M . D . Indiana University School of Medicine Indianapolis Indiana 46202 U.S.A.
