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Diminisbed stature-defective palate syndrome: A dominantly inherited disorder
470
Brief clinical and laboratory observations
symptoms of cholecystadenomyoma. Rapid injection of cholecystokinin in doses as high as 1 ivy unit per kilogram into normal subjects produces contraction of the gallbladder without p a i n ? ~ 1~ T h e response of this patient to cholecystokinin administration was most impressive. She complained of abdominal pain identical to that which p r o m p t e d her admission to the hospital. T h e rarity of a d e n o m y o m a has not permitted us to further evaluate the use of cholecystokinin. However, because of the uncertainty of the relationship of symptoms to the presence of adenomyoma, it seems reasonable to try and distinguish a population that will benefit from surgical removal of the gallbladder. We believe this test should be done with suitable placebo administration as described in this study. REFERENCES
i. Jutras, J. A., and Levesque, H. P.: Adenomyoma and adenomyomatosis of the gallbladder, Radiol. Clin. N. Amer. 4: 483, 1966.
Diminished staturedefective palate syndrome: A dominantly inherited disorder
The ]ournal of Pediatrics September 1971
2. Fotopoulos, J. P., and Crompton, A. R.: Adenomyomatosis of the gallbladder, Med. Clin. N. Amer. 48: 9, 1964. 3. Seller, I.: Gallbladder disease in children, Amer. J. Dis. ChiId. 99: 662, 1960. 4. Shepard, V. D., Watters, W., and Doekerty, M. B.: Benign neoplasms of the gallbladder, Arch. Surg. 45: I, 1942. 5. Kirbey, J. A., Jr., and Holcomb, G. W.: Surgical management of diseases of the gallbladder and common duct in children and adolescents, Amer. J. Surg. 111: 39, 1966. 6. Hawkins, P. E., Graham, F. B., and Holliday, P.: Gallbladder disease in children, Amer. J. Surg. 111: 741, 1966. 7. King, E. S. J.: Cholecystitis glandularis and diverticula of the gallbladder, Brit. J. Surg. 41: 156, 1953. 8. King, E. S. J., and MacCallum, P.: Cholecystitis glandularis proliferans (cystica), Brit. J. Surg. 19: 310, 1931. 9. Glenn, F., and Mannix, H., Jr.: The aealculous gallbladder, Ann. Surg. 144: 620, 1956. 10. Broden, B.: Experiments with cholecystokinin in cholecystography, Acta Radiol. 49: 25, 1958. 11. Edholm, P.: Gallbladder evacuation in the normal man induced by cholecystokinin, Acta Radiol. 53: 257, 1960.
T H E P U R P O S E of this paper is to describe a newly recognized dominantly inherited growth disorder in which short stature is a consistent feature and defects in palatal closure are a variable finding. T h e affected individuals are otherwise healthy and of normal intelligence. FAMILY
F r a n k J. Gareis, M.D., and David W. Smith, M.D. * SEATTLE, W A S H .
REPORT
(FIGS.
1 TO
3)
T h e propositus will be described in some detail in a case report; the findings in the remaining members of this family are presented in summary form. CASE R E P O R T
From the Department of Pediatrics, Dysmorphology Unit, University of Washington School of Medicine. Supported by a grant from the Children's Bureau. ~Reprlne address: Department o] Pediatrics, Dymorphology Unit, University o] Washington School oJ Medicine, Seattle, Wash. 98105.
We were prompted to study the family of a 14-year-old boy who was initially seen by us because of growth deficiency. He was the product of a full-term pregnancy; at birth he weighed 6 pounds 6 ounces and was 17 inches long. In early infancy a submucous cleft palate and bifid uvula were discovered. These defects have given rise to no particular problems except imparting
Volume 79 Number 3
Brie[ clinical and laboratory observations
471
" 4'6"
,']I 1 2
3
4
5
6
7
9 Examined Short stature
8
9
10 11 12-14 15 16-17 18-20 21
22
~ Submucouscleft [ ] Cleft palate
Fig. 1. Family pedigree, proband indicated by arrow.
97 70 t
GIRLS
BOYS
97
60-
50to
~409 Affected o Unaffected
30-
20 I
0
l
l
J
l
l
l
5
l
J
l
l
l
l
J
l
10 Age (years)
"J
15 0
I
I
E
I
5
I
~
I
I
[
I
10 Age (years)
I
I
I
I
I
I
I
I
15
Fig. 2. Stature in the children of affected individuals as compared to normal percentile standards. Regarding the 13-year-old girls at the third percentile, the affected girl (III-9) is fully pubertal and close to her final height attainment, while her unaffected first cousin (III-7) is in early puberty with good potential for further growth. a mild nasal quality to his speech. Short stature has been present from birth, and, although puberty began at age 11, there has been a noticeable lack of the usual pubertal growth spurt. According to his parents, he has grown only 4 to 5 inches in the past 4 years. Physical examination at 14.5 years disclosed a short but well-developed boy whose height was 52.5 inches (height age, 8.5 years) and whose weight was 84 pounds. Sitting height was 30 inches, corresponding to the fiftieth percentile for
11.5 years, and his arm span measured 51 inches, both measurements indicating relative shortness of limbs. He had an underdeveloped mandible and a submucous cleft palate with a bifid uvula. Pubertal development was well advanced. Laboratory data included normal values for serum electrolytes, calcium, phosphorous, urea nitrogen, and serum protein-bound iodine. Roentgenograms of the skull and long bones revealed no boney abnormalities, and osseous maturation was at a level of 13.5 years.
472
Brief clirdcal a~M Iaborato~y observatio~s
The Journal of Pediatrics September 1971
DISCUSSION
Fig. 3. From left to right, Cases Ili-6, III-5, IlI-1, (the proband), II-1 (their mother). FAMILY
STUDY
This patient's family history is remarkable in that among his siblings and maternal relatives a total of 10 other individuals have short stature, and a majority of these also have defects in palatal closure. These findings are set fourth in the pedigree chart in Fig. 1 and are smnmarized as follows : The degree of short stature of the children within this pedigree is depicted in Fig. 2. Prenatal onset of diminished stature is denoted by relatively low birth length for weight; affected individuals had an average birth length of 18.1 inches and an average birth weight of 7 pounds 10 ounces. The affected children appear to grow at a rate that is about two thirds that of normal; the final height attaimnent in the 5 affected adults is indicated in Fig. 1. Defects in palatal development varied from submucous clefts in 4 individuals to cleft palate in another zb persons; one of the latter (III-6) had the Pierre Robin syndrome. Additional features found in the above patients included relative shortness of limbs in all of the affected individuals, and underdevelopment of the mandible in 5 of 11 affected ones. Beyond problems associated with defective palatal development, affected family members have had no special health problems and are of normal intelligence.
This is a previously undescribed don> inantly inherited disorder with shortness of stature and relatively short limbs as a consistent feature and defects of p a l a t a l closure a n d small m a n d i b l e as less consistent features. T h e m a j o r adverse effect of the presumably altered gene a p p e a r e d to be on mesenchymal tissues resulting in diminished skeletal growth a n d incomplete palatal c!osure. Prenatal onset was indicated by the failure of closure of the p a l a t i n e shelves which normally occurs by 8 to 9 weeks of fetal life; in this disorder this m a y simply represent deficiency of growth within these structures. Relatively diminished length for weight at birth provided additional evidence for p r e n a t a l onset. T h e r e was n o indication of faulty organization of tissue resulting in skeletal dysplasia; roentgenograms disclosed normal bone morphology. A d o m i n a n t mode of inheritance m a y be inferred by the occurrence of this disorder in 50 per cent of 18 persons at risk in generations I I and I I I , excluding the propositus. T h e r e was no indication of lack of penetrance, since no unaffected person h a d an affected child. T h e p r o b a n d ' s m a t e r n a l g r a n d m o t h e r m a y represent a fresh m u t a t i o n since we were unable to clearly discern any affected individuals a m o n g her siblings or forebears. All affected individuals were relatively short, with childhood growth rate being about two thirds of n o r m a l a n d final height a t t a i n m e n t averaging 4 feet 9 inches in the 4 adult w o m e n and 5 feet in the only a d u l t man. Seventy-three per cent of affected individuals h a d defects in p a l a t a l closure, comprising all 4 affected m e n a n d 4 of the 7 affected women. T h e most p r o b a b l e mode of inheritance appears to be autosomal dominant. However, X-linked d o m i n a n t inheritance has not been excluded; there has been no known o p p o r t u n i t y to test m a l e - t o - m a l e transmission. The authors wish to express their appreciation to Mrs. Lyle Harrah, medical research librarian, for her assistance in reviewing the literature and to Mrs. Mary Pearlman, secretary.
Brief clinical and laboratory observations
symptoms of cholecystadenomyoma. Rapid injection of cholecystokinin in doses as high as 1 ivy unit per kilogram into normal subjects produces contraction of the gallbladder without p a i n ? ~ 1~ T h e response of this patient to cholecystokinin administration was most impressive. She complained of abdominal pain identical to that which p r o m p t e d her admission to the hospital. T h e rarity of a d e n o m y o m a has not permitted us to further evaluate the use of cholecystokinin. However, because of the uncertainty of the relationship of symptoms to the presence of adenomyoma, it seems reasonable to try and distinguish a population that will benefit from surgical removal of the gallbladder. We believe this test should be done with suitable placebo administration as described in this study. REFERENCES
i. Jutras, J. A., and Levesque, H. P.: Adenomyoma and adenomyomatosis of the gallbladder, Radiol. Clin. N. Amer. 4: 483, 1966.
Diminished staturedefective palate syndrome: A dominantly inherited disorder
The ]ournal of Pediatrics September 1971
2. Fotopoulos, J. P., and Crompton, A. R.: Adenomyomatosis of the gallbladder, Med. Clin. N. Amer. 48: 9, 1964. 3. Seller, I.: Gallbladder disease in children, Amer. J. Dis. ChiId. 99: 662, 1960. 4. Shepard, V. D., Watters, W., and Doekerty, M. B.: Benign neoplasms of the gallbladder, Arch. Surg. 45: I, 1942. 5. Kirbey, J. A., Jr., and Holcomb, G. W.: Surgical management of diseases of the gallbladder and common duct in children and adolescents, Amer. J. Surg. 111: 39, 1966. 6. Hawkins, P. E., Graham, F. B., and Holliday, P.: Gallbladder disease in children, Amer. J. Surg. 111: 741, 1966. 7. King, E. S. J.: Cholecystitis glandularis and diverticula of the gallbladder, Brit. J. Surg. 41: 156, 1953. 8. King, E. S. J., and MacCallum, P.: Cholecystitis glandularis proliferans (cystica), Brit. J. Surg. 19: 310, 1931. 9. Glenn, F., and Mannix, H., Jr.: The aealculous gallbladder, Ann. Surg. 144: 620, 1956. 10. Broden, B.: Experiments with cholecystokinin in cholecystography, Acta Radiol. 49: 25, 1958. 11. Edholm, P.: Gallbladder evacuation in the normal man induced by cholecystokinin, Acta Radiol. 53: 257, 1960.
T H E P U R P O S E of this paper is to describe a newly recognized dominantly inherited growth disorder in which short stature is a consistent feature and defects in palatal closure are a variable finding. T h e affected individuals are otherwise healthy and of normal intelligence. FAMILY
F r a n k J. Gareis, M.D., and David W. Smith, M.D. * SEATTLE, W A S H .
REPORT
(FIGS.
1 TO
3)
T h e propositus will be described in some detail in a case report; the findings in the remaining members of this family are presented in summary form. CASE R E P O R T
From the Department of Pediatrics, Dysmorphology Unit, University of Washington School of Medicine. Supported by a grant from the Children's Bureau. ~Reprlne address: Department o] Pediatrics, Dymorphology Unit, University o] Washington School oJ Medicine, Seattle, Wash. 98105.
We were prompted to study the family of a 14-year-old boy who was initially seen by us because of growth deficiency. He was the product of a full-term pregnancy; at birth he weighed 6 pounds 6 ounces and was 17 inches long. In early infancy a submucous cleft palate and bifid uvula were discovered. These defects have given rise to no particular problems except imparting
Volume 79 Number 3
Brie[ clinical and laboratory observations
471
" 4'6"
,']I 1 2
3
4
5
6
7
9 Examined Short stature
8
9
10 11 12-14 15 16-17 18-20 21
22
~ Submucouscleft [ ] Cleft palate
Fig. 1. Family pedigree, proband indicated by arrow.
97 70 t
GIRLS
BOYS
97
60-
50to
~409 Affected o Unaffected
30-
20 I
0
l
l
J
l
l
l
5
l
J
l
l
l
l
J
l
10 Age (years)
"J
15 0
I
I
E
I
5
I
~
I
I
[
I
10 Age (years)
I
I
I
I
I
I
I
I
15
Fig. 2. Stature in the children of affected individuals as compared to normal percentile standards. Regarding the 13-year-old girls at the third percentile, the affected girl (III-9) is fully pubertal and close to her final height attainment, while her unaffected first cousin (III-7) is in early puberty with good potential for further growth. a mild nasal quality to his speech. Short stature has been present from birth, and, although puberty began at age 11, there has been a noticeable lack of the usual pubertal growth spurt. According to his parents, he has grown only 4 to 5 inches in the past 4 years. Physical examination at 14.5 years disclosed a short but well-developed boy whose height was 52.5 inches (height age, 8.5 years) and whose weight was 84 pounds. Sitting height was 30 inches, corresponding to the fiftieth percentile for
11.5 years, and his arm span measured 51 inches, both measurements indicating relative shortness of limbs. He had an underdeveloped mandible and a submucous cleft palate with a bifid uvula. Pubertal development was well advanced. Laboratory data included normal values for serum electrolytes, calcium, phosphorous, urea nitrogen, and serum protein-bound iodine. Roentgenograms of the skull and long bones revealed no boney abnormalities, and osseous maturation was at a level of 13.5 years.
472
Brief clirdcal a~M Iaborato~y observatio~s
The Journal of Pediatrics September 1971
DISCUSSION
Fig. 3. From left to right, Cases Ili-6, III-5, IlI-1, (the proband), II-1 (their mother). FAMILY
STUDY
This patient's family history is remarkable in that among his siblings and maternal relatives a total of 10 other individuals have short stature, and a majority of these also have defects in palatal closure. These findings are set fourth in the pedigree chart in Fig. 1 and are smnmarized as follows : The degree of short stature of the children within this pedigree is depicted in Fig. 2. Prenatal onset of diminished stature is denoted by relatively low birth length for weight; affected individuals had an average birth length of 18.1 inches and an average birth weight of 7 pounds 10 ounces. The affected children appear to grow at a rate that is about two thirds that of normal; the final height attaimnent in the 5 affected adults is indicated in Fig. 1. Defects in palatal development varied from submucous clefts in 4 individuals to cleft palate in another zb persons; one of the latter (III-6) had the Pierre Robin syndrome. Additional features found in the above patients included relative shortness of limbs in all of the affected individuals, and underdevelopment of the mandible in 5 of 11 affected ones. Beyond problems associated with defective palatal development, affected family members have had no special health problems and are of normal intelligence.
This is a previously undescribed don> inantly inherited disorder with shortness of stature and relatively short limbs as a consistent feature and defects of p a l a t a l closure a n d small m a n d i b l e as less consistent features. T h e m a j o r adverse effect of the presumably altered gene a p p e a r e d to be on mesenchymal tissues resulting in diminished skeletal growth a n d incomplete palatal c!osure. Prenatal onset was indicated by the failure of closure of the p a l a t i n e shelves which normally occurs by 8 to 9 weeks of fetal life; in this disorder this m a y simply represent deficiency of growth within these structures. Relatively diminished length for weight at birth provided additional evidence for p r e n a t a l onset. T h e r e was n o indication of faulty organization of tissue resulting in skeletal dysplasia; roentgenograms disclosed normal bone morphology. A d o m i n a n t mode of inheritance m a y be inferred by the occurrence of this disorder in 50 per cent of 18 persons at risk in generations I I and I I I , excluding the propositus. T h e r e was no indication of lack of penetrance, since no unaffected person h a d an affected child. T h e p r o b a n d ' s m a t e r n a l g r a n d m o t h e r m a y represent a fresh m u t a t i o n since we were unable to clearly discern any affected individuals a m o n g her siblings or forebears. All affected individuals were relatively short, with childhood growth rate being about two thirds of n o r m a l a n d final height a t t a i n m e n t averaging 4 feet 9 inches in the 4 adult w o m e n and 5 feet in the only a d u l t man. Seventy-three per cent of affected individuals h a d defects in p a l a t a l closure, comprising all 4 affected m e n a n d 4 of the 7 affected women. T h e most p r o b a b l e mode of inheritance appears to be autosomal dominant. However, X-linked d o m i n a n t inheritance has not been excluded; there has been no known o p p o r t u n i t y to test m a l e - t o - m a l e transmission. The authors wish to express their appreciation to Mrs. Lyle Harrah, medical research librarian, for her assistance in reviewing the literature and to Mrs. Mary Pearlman, secretary.