BRIEF C L I N I C A L A N D LABORATORY OBSERVATIONS
Articles in this section should require less than three JOURNAL pages: text, less than 1,000 words; 1 or 2 illustrations and/or tables; up to 10 references.
A new syndrome of mental deficiency with craniofacial, limb, and anal abnormalities Margaret A. Keller, M.D.,* Kenneth L. Jones, M.D., William L. Nyhan, M.D., Ph.D., Uta Francke, M.D., and Barbara Dixson, R . N . M . N . , San Diego, Calif.
T H E P U RP O S E o f this c o m m u n i c a t i o n is to d e s c r i b e t h r e e patients with a new syndrome of malformations
in a
p a t t e r n w h i c h to o u r k n o w l e d g e h a s n o t b e e n p r e v i o u s l y r e p o r t e d . T h e p a t i e n t s w e r e siblings, a n d e a c h w a s m a l e . T h e c a r d i n a l clinical f e a t u r e s , s u m m a r i z e d
in T a b l e I,
were m e n t a l r e t a r d a t i o n , s h o r t s t a t u r e , a f r o n t a l u p s w e e p o f t h e hair, lateral d i s p l a c e m e n t o f t h e m e d i a l c a n t h i , a n d a n o m a l i e s o f t h e ears, a n u s , a n d l i m b s . CASE REPORTS Patient J. B. M. was the product of a n o r m a l p r e g n a n c y and delivery; he weighed 2.8 kg at birth. He walked at 28 months. His IQ at 12 years of age was 46. W h e n examined at 29 years , he was 157 cm tall and weighed 56 kg. Head circumference was 55.5 cm. He had an affable, extraordinarily outgoing personality. T h e eyes had a slight antimongoloid slant (Fig. 1). In addition to lateral displacement of the medial canthi, hypertelorism was present (interpupillary distance, 7.0 cm). The skin was delicate, finely
From the Department of Pediatrics, University of California, San Diego, and University of California Medical Center, and San Diego Regional Center for the Developmentally Disabled. Aided by Grants from the National Foundation-March of Dimes No. NFC-89. *Reprint address: Department of Pediatrics, University of California Medical Center, 225 W. Dickinson St., San Diego, Calif. 92103.
T a b l e I. P a t t e r n o f m a l f o r m a t i o n
Performance Mental deficiency Affable personality Craniofacies Frontal hair unsweep Medial eyebrow flare Laterial displacement of medial canthi Small ears with simple structure Limbs Broad great toes Hypoplastic great toe nail Joint contractures Skeletal Short stature Spinal abnormalities Pectus excavatum Other Anal abnormalities Constipation Facial skin wrinkling
Patient JBM
Patient JDM
Patient RGM
+ +
+ +
+ +
+ +
+ + +
+ + +
+
+
+
+ +
+ +
+
+
+
+
+ + +
+ -+
+ + +
+ +
+ + +
+ -
wrinkled, and appeared prematurely aged. There was a slight decrease in mobility of the right ankle and a mild flexion contracture of the left knee. Roentgenographs revealed a mild rotational deformity of the l u m b a r spine and a p r o m i n e n t transverse process of C7. An intravenous pyelogram was normal. Chromosomal analysis revealed a normal 46, XY karyotype. Patient J. D. M. was also the product of a normal pregnancy and delivery. He weighed 3.4 kg at birth. An imperforate anus was corrected at 12 hours of age. The patient also had arrested hydrocephalus. He sat at two years and walked at 6 years of age. His IQ at 5 years was 40. At the time of examination, the patient was 27 years old and 146 cm tall. The head circumference was 55 cm. His extroverted personality and facial features (Fig. 1) were very similar to those of his brother. The lips were thick. The thumbs were broad. Flexion contractures were presen t at the elbows and knees. Examination of the p e r i n e u m revealed an
The Journal of P E D I A T R I C S
589
590
Brief clinical and laboratory observations
The Journal of Pediatrics April 1976
Fig. 1. Three affected male siblings, illustrating the frontal upsweep of the hair, lateral displacement of the medial canthi, and small ears.
anteriorly placed anus. The anal-scrotal distance measured 1.0 cm. Abdominal distension presumably secondary to severe constipation was present. His skin also seemed prematurely aged. Patient R. G. M., the propositus, was the product of a pregnancy complicated by decreased fetal activity. He was delivered from a face presentation; the birth weight was unknown. He developed meningitis at 6 months of age and also had an arrested hydrocephalus. His IQ was 21 at 12 years of age. At 16 years of age, the patient had a height of 155 cm and a weight of 34 kg. His head circumference was 54 cm. He also was very extroverted. The facies was coarse with thick lips (Fig. 1). The patient was confined to a wheelchair. He had limited extension at the elbows and knees, spastic contracture of the left hip, and marked scoliosis. A rectal prolapse presumably secondary to chronic constipation was present. The karyotype was 46, XY. FAMILY
STUDY
The pedigree of this family is shown in Fig. 2. There was no consanguinity. In addition to the three patients studied, there were three sons who died in infancy who were throught to have had a similar pattern of m a l f o r m a tions. Two of these had had an imperforate anus, and each died within the first days of life. A third son had died at 4~A months of age. He had had a high hairline and lowset, small ears. A ventricular septal defect was diagnosed clinically. A small anal opening with clefts on either side
was misplaced anteriorly and connected by a p r o m i n e n t raphe to the scrotum. Barium e n e m a showed a stenotic anus and a megacolon. An intravenous pyelogram was normal. There were also three spontaneous abortions. The first occurred at a maternal age of 31 years and was a male fetus. The sex of subsequent abortions, which occurred when the mother was 42 and 43 years, is unknown. All first degree relatives of the affected siblings have been examined by one of us, and, with exception of the mother, they demonstrated no features o f the disorder. The mother had lateral displacement of the medial canthi (intercanthal distance, 3.6 cm) and hypertelorism (interpupillary distance, 6.7 cm). The anal opening was misplaced anteriorly. She had normal intelligence. Both parents had normal karyotypes. The m o t h e r had four brothers who were unaffected by this disorder. In addition, her three sisters have had ten unaffected children, five of whom were males. DISCUSSION Each of the three male siblings herein described was mentally deficient and had a similar pattern o f m a l f o r m a tions which include anomalies of the craniofacies, limbs, and anus. The frontal upsweep of the hair and the medial flare of the eyebrows suggest a defect in d e v e l o p m e n t of the glabella and'underlying brain prior to 16 weeks of development as proposed by Smith and Gong. ~ Despite
Vohtme 88 Number 4, part 1
Brief clinical and laboratory observations
Fig. 2. Pedigree of the family. their severe mental deficiency, only one of these brothers is institutionalized. Their extremely affable, extroverted personalities have contributed to a very adequate social adjustment. The pedigree is most consistent with an X-linked recessive pattern of inheritance. An older paternal age effect has been demonstrated in maternal grandfathers of fresh mutational cases of certain X-linked recessive disorders. 2 The maternal grandfather of these three patients
The carcinoembryonic antigen assay: Prognostic value in neural crest tumors David B. Frens, M.D.,* Patrick F. Bray, M.D., James T. Wu, Ph.D., and M. Eugene Lahey, M.D., Salt Lake City, Utah
NEURAL CREST TUMORS are common childhood neoplasms whose prognosis depends largely on the age of the child, the clinical stage of the disease, and the From the Division of Pediatric Neurology, Departments of Neurology and Pediatrics, University of Utah College of Medicine and the Primary Children's Medical Center. Supported in part under National Institutes of Health Training Grants Nos. 5TO1-NS 5503 and 5TO1-NS 5309; National Institutes of Health Special Fellowship No. 5Fll-NS 2579 (Dr. Frens); Utah State Health Contract No. 73-1230; Helms Foundation Inc.; Clinical Cancer Training Grant, National Cancer Institute; contributions from the Eleanor Roosevelt Cancer Research Foundation and Hoffmann-LaRoche, Inc. Presented in part to The Society for Pediatric Research, Denver, April, 1975. *Reprint address: Department of Pediatrics, 50 N. Medical Dr., Salt Lake City, Utah 84132
591
was 41-years-old at the time of their mother's birth. The mother, who shares several features of the syndrome with her affected sons, could represent partial expression of an X-linked disorder. However, autosomal recessive inheritance cannot be excluded. Analysis of the XgA blood group, perfQrmed on all patients and their first degree relatives, was not informative. The authors thank Carol Cerrudo for her secretarial assistance.
REFERENCES I. SmithDW, and Gong BT: Scalp hair patterning as a clue to early fetal brain development, 3 PEmATR83:374, 1973. 2. JonesKL, Smith DW, Harvey MAS, Hall BD, and Quan L: Older paternal age and fresh gene mutation; data on additional disorders, J PEDIATR86:84, 1975.
histologic differentiation of the tumor at the time of diagnosis? 3 Unfortunately, the behavior of these tumors is sufficiently variable so that this information, as well as the initial level of urinary catecholamine excretion, is not always completely reliable in predicting outcomer For three years we have measured plasma carcinoembryonic antigen levels in children with neural crest tumors in order to determine the usefulness of this assay in aiding early diagnosis, making accurate prognosis, and assessing tumor activity during treatment. Our results indicate that, although elevated in many cases, the CEA assay contributes very little adjunctive information critical to the early diagnosis of a neural crest tumor. However, a CEA level obtained at the time of diagnosis does appear to be related to outcome, and CEA levels obtained during follow-up accurately reflect tumor activity. Abbreviations used CEA: carcinoembryonic antigen VMA: vanillylmandelic acid
M A T E R I A L S AND M E T H O D S Fourteen children with histologically confirmed neuroblastoma or ganglioneuroblastoma were included in this study (Table I). Their ages ranged from several days to 1 l years, at the time of diagnosis, and their disease was staged according to the criteria of Evans and associates? Treatment included total or partial surgical excision in every case, followed by radiation and chemotherapy in those cases requiring further therapy. Absence of active tumor was suggested by the failure to demonstrate bone
Articles in this section should require less than three JOURNAL pages: text, less than 1,000 words; 1 or 2 illustrations and/or tables; up to 10 references.
A new syndrome of mental deficiency with craniofacial, limb, and anal abnormalities Margaret A. Keller, M.D.,* Kenneth L. Jones, M.D., William L. Nyhan, M.D., Ph.D., Uta Francke, M.D., and Barbara Dixson, R . N . M . N . , San Diego, Calif.
T H E P U RP O S E o f this c o m m u n i c a t i o n is to d e s c r i b e t h r e e patients with a new syndrome of malformations
in a
p a t t e r n w h i c h to o u r k n o w l e d g e h a s n o t b e e n p r e v i o u s l y r e p o r t e d . T h e p a t i e n t s w e r e siblings, a n d e a c h w a s m a l e . T h e c a r d i n a l clinical f e a t u r e s , s u m m a r i z e d
in T a b l e I,
were m e n t a l r e t a r d a t i o n , s h o r t s t a t u r e , a f r o n t a l u p s w e e p o f t h e hair, lateral d i s p l a c e m e n t o f t h e m e d i a l c a n t h i , a n d a n o m a l i e s o f t h e ears, a n u s , a n d l i m b s . CASE REPORTS Patient J. B. M. was the product of a n o r m a l p r e g n a n c y and delivery; he weighed 2.8 kg at birth. He walked at 28 months. His IQ at 12 years of age was 46. W h e n examined at 29 years , he was 157 cm tall and weighed 56 kg. Head circumference was 55.5 cm. He had an affable, extraordinarily outgoing personality. T h e eyes had a slight antimongoloid slant (Fig. 1). In addition to lateral displacement of the medial canthi, hypertelorism was present (interpupillary distance, 7.0 cm). The skin was delicate, finely
From the Department of Pediatrics, University of California, San Diego, and University of California Medical Center, and San Diego Regional Center for the Developmentally Disabled. Aided by Grants from the National Foundation-March of Dimes No. NFC-89. *Reprint address: Department of Pediatrics, University of California Medical Center, 225 W. Dickinson St., San Diego, Calif. 92103.
T a b l e I. P a t t e r n o f m a l f o r m a t i o n
Performance Mental deficiency Affable personality Craniofacies Frontal hair unsweep Medial eyebrow flare Laterial displacement of medial canthi Small ears with simple structure Limbs Broad great toes Hypoplastic great toe nail Joint contractures Skeletal Short stature Spinal abnormalities Pectus excavatum Other Anal abnormalities Constipation Facial skin wrinkling
Patient JBM
Patient JDM
Patient RGM
+ +
+ +
+ +
+ +
+ + +
+ + +
+
+
+
+ +
+ +
+
+
+
+
+ + +
+ -+
+ + +
+ +
+ + +
+ -
wrinkled, and appeared prematurely aged. There was a slight decrease in mobility of the right ankle and a mild flexion contracture of the left knee. Roentgenographs revealed a mild rotational deformity of the l u m b a r spine and a p r o m i n e n t transverse process of C7. An intravenous pyelogram was normal. Chromosomal analysis revealed a normal 46, XY karyotype. Patient J. D. M. was also the product of a normal pregnancy and delivery. He weighed 3.4 kg at birth. An imperforate anus was corrected at 12 hours of age. The patient also had arrested hydrocephalus. He sat at two years and walked at 6 years of age. His IQ at 5 years was 40. At the time of examination, the patient was 27 years old and 146 cm tall. The head circumference was 55 cm. His extroverted personality and facial features (Fig. 1) were very similar to those of his brother. The lips were thick. The thumbs were broad. Flexion contractures were presen t at the elbows and knees. Examination of the p e r i n e u m revealed an
The Journal of P E D I A T R I C S
589
590
Brief clinical and laboratory observations
The Journal of Pediatrics April 1976
Fig. 1. Three affected male siblings, illustrating the frontal upsweep of the hair, lateral displacement of the medial canthi, and small ears.
anteriorly placed anus. The anal-scrotal distance measured 1.0 cm. Abdominal distension presumably secondary to severe constipation was present. His skin also seemed prematurely aged. Patient R. G. M., the propositus, was the product of a pregnancy complicated by decreased fetal activity. He was delivered from a face presentation; the birth weight was unknown. He developed meningitis at 6 months of age and also had an arrested hydrocephalus. His IQ was 21 at 12 years of age. At 16 years of age, the patient had a height of 155 cm and a weight of 34 kg. His head circumference was 54 cm. He also was very extroverted. The facies was coarse with thick lips (Fig. 1). The patient was confined to a wheelchair. He had limited extension at the elbows and knees, spastic contracture of the left hip, and marked scoliosis. A rectal prolapse presumably secondary to chronic constipation was present. The karyotype was 46, XY. FAMILY
STUDY
The pedigree of this family is shown in Fig. 2. There was no consanguinity. In addition to the three patients studied, there were three sons who died in infancy who were throught to have had a similar pattern of m a l f o r m a tions. Two of these had had an imperforate anus, and each died within the first days of life. A third son had died at 4~A months of age. He had had a high hairline and lowset, small ears. A ventricular septal defect was diagnosed clinically. A small anal opening with clefts on either side
was misplaced anteriorly and connected by a p r o m i n e n t raphe to the scrotum. Barium e n e m a showed a stenotic anus and a megacolon. An intravenous pyelogram was normal. There were also three spontaneous abortions. The first occurred at a maternal age of 31 years and was a male fetus. The sex of subsequent abortions, which occurred when the mother was 42 and 43 years, is unknown. All first degree relatives of the affected siblings have been examined by one of us, and, with exception of the mother, they demonstrated no features o f the disorder. The mother had lateral displacement of the medial canthi (intercanthal distance, 3.6 cm) and hypertelorism (interpupillary distance, 6.7 cm). The anal opening was misplaced anteriorly. She had normal intelligence. Both parents had normal karyotypes. The m o t h e r had four brothers who were unaffected by this disorder. In addition, her three sisters have had ten unaffected children, five of whom were males. DISCUSSION Each of the three male siblings herein described was mentally deficient and had a similar pattern o f m a l f o r m a tions which include anomalies of the craniofacies, limbs, and anus. The frontal upsweep of the hair and the medial flare of the eyebrows suggest a defect in d e v e l o p m e n t of the glabella and'underlying brain prior to 16 weeks of development as proposed by Smith and Gong. ~ Despite
Vohtme 88 Number 4, part 1
Brief clinical and laboratory observations
Fig. 2. Pedigree of the family. their severe mental deficiency, only one of these brothers is institutionalized. Their extremely affable, extroverted personalities have contributed to a very adequate social adjustment. The pedigree is most consistent with an X-linked recessive pattern of inheritance. An older paternal age effect has been demonstrated in maternal grandfathers of fresh mutational cases of certain X-linked recessive disorders. 2 The maternal grandfather of these three patients
The carcinoembryonic antigen assay: Prognostic value in neural crest tumors David B. Frens, M.D.,* Patrick F. Bray, M.D., James T. Wu, Ph.D., and M. Eugene Lahey, M.D., Salt Lake City, Utah
NEURAL CREST TUMORS are common childhood neoplasms whose prognosis depends largely on the age of the child, the clinical stage of the disease, and the From the Division of Pediatric Neurology, Departments of Neurology and Pediatrics, University of Utah College of Medicine and the Primary Children's Medical Center. Supported in part under National Institutes of Health Training Grants Nos. 5TO1-NS 5503 and 5TO1-NS 5309; National Institutes of Health Special Fellowship No. 5Fll-NS 2579 (Dr. Frens); Utah State Health Contract No. 73-1230; Helms Foundation Inc.; Clinical Cancer Training Grant, National Cancer Institute; contributions from the Eleanor Roosevelt Cancer Research Foundation and Hoffmann-LaRoche, Inc. Presented in part to The Society for Pediatric Research, Denver, April, 1975. *Reprint address: Department of Pediatrics, 50 N. Medical Dr., Salt Lake City, Utah 84132
591
was 41-years-old at the time of their mother's birth. The mother, who shares several features of the syndrome with her affected sons, could represent partial expression of an X-linked disorder. However, autosomal recessive inheritance cannot be excluded. Analysis of the XgA blood group, perfQrmed on all patients and their first degree relatives, was not informative. The authors thank Carol Cerrudo for her secretarial assistance.
REFERENCES I. SmithDW, and Gong BT: Scalp hair patterning as a clue to early fetal brain development, 3 PEmATR83:374, 1973. 2. JonesKL, Smith DW, Harvey MAS, Hall BD, and Quan L: Older paternal age and fresh gene mutation; data on additional disorders, J PEDIATR86:84, 1975.
histologic differentiation of the tumor at the time of diagnosis? 3 Unfortunately, the behavior of these tumors is sufficiently variable so that this information, as well as the initial level of urinary catecholamine excretion, is not always completely reliable in predicting outcomer For three years we have measured plasma carcinoembryonic antigen levels in children with neural crest tumors in order to determine the usefulness of this assay in aiding early diagnosis, making accurate prognosis, and assessing tumor activity during treatment. Our results indicate that, although elevated in many cases, the CEA assay contributes very little adjunctive information critical to the early diagnosis of a neural crest tumor. However, a CEA level obtained at the time of diagnosis does appear to be related to outcome, and CEA levels obtained during follow-up accurately reflect tumor activity. Abbreviations used CEA: carcinoembryonic antigen VMA: vanillylmandelic acid
M A T E R I A L S AND M E T H O D S Fourteen children with histologically confirmed neuroblastoma or ganglioneuroblastoma were included in this study (Table I). Their ages ranged from several days to 1 l years, at the time of diagnosis, and their disease was staged according to the criteria of Evans and associates? Treatment included total or partial surgical excision in every case, followed by radiation and chemotherapy in those cases requiring further therapy. Absence of active tumor was suggested by the failure to demonstrate bone
