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Heritable dysmorphic syndrome with normal intelligence
]une, 1967 T h e Journal of P E D I A T R I C S
927
Heritable dysmorpbic syndrome itb normal intelligence A cause of cleft lip and palate, lip pits, genital anomaly, skeletal malformation, nail dysplasia, and webbing of the palpebrae, mouth, perlneum, and popliteal fossae A syndrome of multiple anomalies without mental retardation is analyzed in 2 families. The anomalies include cleft lip and palate, intraoral webbing and lip pits; genital, perineal, and buttock malformations; popIiteal webbing and dysplasia of the extremities. Dermal ridge patterns may extend beyond the soles to the dorsum of the toes and up the heels. Radiologically the acetabular angles appear low and are suggestive of pelvic dysplasia. In both families in this study the disease affected the mother and children, consistent with dominant inheritance.
Frederick Hecht, M.D.ff and Judith M. Jarvinen, M.S. PORTLAND,
ORE.
I N T H E I R BOOK, Syndromes of the head and neck, Gorlin and Pindborg 1 devote a separate chapter to a syndrome of multiple anomalies involving cleft lip and palate, pits of the lower lip, digital and genital anomalies, and popliteal webbing. Uncertain of the cause of the syndrome, they stated: "None of the patients had a parent with similar anomalies, but severaI had siblings with almost identical findings. 24 A1From the Genetics Clinic and Speech and Hearing Clinic, Crippled Children's Division, Department of Pediatrics and Division of Experimental Medicine, University o/Oregon Medical School. Supported in part by grants from the Medical Research Foundation of Oregon, the United States Public Health Service (CA 07941-03), and the Children's Bureau (/or the Genetics Clinic). ~Address, Genetics Clinic, Crippled Children's Division, University of Oregon Medical School, portland, Ore. 97201.
though this syndrome should be investigated for a chromosome anomaly, the evidence at hand would suggest an autosomal recessive trait." In each of the two families reported here a parent was affected, as was the case previously described. 5 The data from these families, therefore, do not support the hypothesis that this syndrome is caused by an autosomal recessive trait, but instead suggest a dominantly inherited mutation. In support o~ the concept of a single gene mutation, chromosomal studies in our patients revealed no abnormalities. F A M I L Y DATA Family 1. This family was originally ascertained because it contained two brothers with cleft lip and palate. An abbreviated version of their family pedigree is shown in Fig. 1. The Vol. 70, No. 6, pp. 927-935
9 2 8 Hecht and Jarvmen
affected mother's family is of Danish-FrenchEnglish-Irish extraction and is not known to be related in any way to Family 2. There is no known consanguinity among her ancestors, or between her and her husband's families. In neither the mother's three siblings nor any other known relative is there a history of any of the malformations included in the present syndrome. Family 2. This family was ascertained because their two children had similar patterns of anomalies. A detailed family history was obtained, part of which is presented in Fig. 1. The affected mother had one sibling, a brother who was reportedly normal. Her father may be mildly affected; he has not yet been examined. There is no known consanguinity among the mother's ancestors, who were Finnish, nor between her and her husband's families. INTRAFAMILIAL
VARIABILITY
T o illustrate the syndrome and its variability of expression, the affected individuals in Family 1 will be described in detail. T h e individuals in Family 2 will be more briefly described, since they manifested similar anomalies and similar variability of expression.
Fornily#1
Fomily#2
Fig. 1. Partial pedigrees of Families 1 and 2. Black squares and circles indicate affected male and female members. Open squares and circles indicate members who were examined and found to be normal.
The Journal of Pediatrics June 1967
Family 1
Mother: mild manifestations. This w o m a n was born with a unilateral (right) complete cleft of the lip and palate and with bilateral pits of the lower lip. There was no oral webbing. H e r clitoris was somewhat enlarged. No webbing of the popliteal fossae could be detected visually or by palpation. H e r hands and feet, likewise, appeared entirely normal without evidence of toe or toenail dysplasia. T h e dermal ridge patterns on the soles did not extend past their usual limits. Older boy: moderate manifestations. This boy was born after a normal full-term pregnancy and weighed 8 pounds, 7 ounces. H e had a slight notch in the right upper lip with a cleft of the hard and soft palate. Bilateral pits of the lower lip were also present (Fig. 2, A ) . T h e IinguaI frenum was attached in an extremely anterior position. No genital anomalies were present. There was mild popliteal webbing. T h e nails on the second toe of the right and the first through third toes of the left foot were hypoplastic and dysplastic (Fig. 3). Dermal ridge patterns were noted to extend over the dorsal surface of the toes with the hypoplastic nails, as well as above the heels, extending 3 cm. above the p r o x i m a l border of the talus. H e is of average height, as are his mother and affected brother. His popliteal webbing is causing progressive tightening of the heel cords. This handicaps him slightly in running. Younger boy: severe manifestations. This boy was the product of an apparently normal pregnancy and delivery; the birth weight was 7 pounds. H e had a unilateral (right) complete cleft lip and palate, bilateral pits of the lower lip, and oral webbing from the tuberosities of the maxillary alveolar ridge to the tuberosities of the mandibular alveolar ridge (Fig. 2, B). T h e lingual frenum was attached in a markedly anterior position, and the uvula was displaced anteriorly approximately two thirds the length of the palate. T h e surgeon commented that it was the most bizarre cleft palate in his experience. There was slight phimosis ; the scrotum was bifid; the left testis
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Heritable dysmorphic syndrome
929
Fig. 2. A, Lip pits in the older affected boy of Family 1. B, Oral webbing in the younger affected boy of Family 1.
Fig. 3. Toenall abnormaIities in older affected boy of Family 1. Note extension of dermal ridges over dorsum of second and third toes. Discoloration is caused by ink.
was in the scrotum; the right testis was in the inguinal canal along with a hydrocele. T h e legs were severely webbed with genu valgum and flexion contractures; m a x i m u m extension of the knees was 120 degrees on the right and 115 degrees on the left (Fig. 4). At age 3 years the right tibia lacked proximal and distal epiphyses and was 3 inches shorter than the left tibia (Fig. 5). T h e right fibula was 1 inch shorter than the left fibula, and both fibulae were posteriorly dislocated at the knee. There were talipes equinovarus deformities and marked dysplasia of the toes. O n the right the first
and second toes were bifid with syndactyly of the fourth and fifth toes. O n the left foot the first toe was bifid, the second toe absent, the third toe bifid, and the fourth and fifth toes syndactylous. Radiographs revealed Y-shaped fusion of the third and fourth metatarsals on the left. Soft tissue release was attempted surgically in the left popliteal area when the patient was 9 months of age. At this time it was found that the tibial nerve was contained in a dense cicatricial band bowstringing across the popliteal fossa. Skeletal traction was applied to the lower extremities in
9 3 0 Hecht and ]arvinen
The Journal of Pediatrics June 1967
Fig. 4. Center inset shows posterior view of popliteaI webbing in the younger affected boy of Family 1. The radiographs were taken in maximal extension. Note limitation of extension.
alternation with casting, but these measures achieved only slight improvement and at age 2 years bilateral amputations at the knees were performed. He was fitted with lower extremity prostheses, which he has learned to use effectively, so that he walks well. Family 2
Mother: mild manifestations. All of the patient's anomalies, with the exception of a bifid nail on the second toe of the left foot, were: orofacial and consisted of bilateral pits of the lower lip, congenital scars of the upper lip, and complete cleft palate. She was told that oral "adhesions" had to be severed before she could be fed after birth. Girl: moderate manifestations. The birth weight was 6 pounds, 10 ounces. A band between the right lower lip and the right maxillary process was present at birth and had to be severed to permit feeding. There were bilateral pits of the lower lip; these were excised and histologically showed sinus tracts lined with stratified squamous epithe-
lium and accessory salivary glands. There was a complete (right) cleft lip and palate; the palate was unusually short. The right nipple was displaced more toward the anterior axillary line than was the left nipple. The genital and perineal anomalies are shown in Fig. 6. Popliteal webbing could not be seen, but could be easily palpated. The fourth and fifth toes were webbed on both feet. Boy: moderate manifestations. The birth weight was 8 pounds. "Lateral epicanthic folds" were reportedly present at birth and were severed shortly thereafter. There were bilateral pits of the lower lip and a unilateral (right) complete cleft lip and palate. The palate was described as exceptionally short and wide (as in the younger boy in Family 1). Oral webbing extended from the maxillary to the mandibular tuberosity bilaterally. The scrotum was abnormally small, although both testes were contained in it; the penis was normal. The anomalies of the perineum and buttocks and the popliteal webs are shown in Fig. 7. The nails on both
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Fig. 5. Bony anomalies of the lower extremities in the younger affected boy of Family 1.
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931
Fig. 6. Genital abnormality in affected glrl of Family 2. Note aplasia of part of labia majora and lateral displacement of the vulva.
first toes were hypoplastic and bifid. The patient's height and weight have been consistently above the fiftieth percentile for his age. SPECIAL INVESTIGATIONS Evaluation of intelligence. The affected children were tested individually by staff psychologists. The affected children in Family 1 were found to be of average intelligence. The affected boy in Family 2, tested at 2 years and 7 months, scored an I.Q. of 132 on the Stanford-Binet (Form L - M ) . His younger sister, 18 months at the time of testing, had an I.Q. of 111 on the CatteI1 Infant Intelligence Scale. Both affected mothers, on the basis of their functioning during numerous interviews, also appeared to be of normal intelligence. Chromosomal studies. Lymphocytes from peripheral blood were cultured, and cultured chromosomally, from the three affected members of Family 1 and the mother of Family 2; there was no abnormality in chromosome number or morphology.
Fig. 7. Posterior view of affected boy of Family 2. Note asymmetry of buttocks, popliteal webbing, and shortening of the left Achilles tendon.
932
Hecht and ]arvinen
The Journal o/ Pediatrics ]une 1967
Morphology of peripheral blood cells. Peripheral blood smears from the affected individuals were examined for morphological abnormalities6; none was noted. Dermal print studies. Dermal ridge patterns were noted to extend over the dorsal surfaces of several toes and above ttae heels of the older boy in Family 1. Penrose 7 noted that when the nail is congenitally absent ridge patterns will frequently continue dorsally past the usual site of the nailbed, and suggested that dermal ridge patterning is normally prevented from progressing dorsally by the presence of the nail. Since our patient's toes showing dorsal dermal ridge patterns were also those with the smallest, most markedly hypoplastic nails, we are skeptical of the separate significance of this dermatoglyphie finding. The extension of dermal ridge patterns above the heels may indicate that skin normally destined for the sole was dragged up the heel by the webbing. The paImar axial triradius was located more than 15 per cent of the distance along the palm in all six affected persons and more than 40 per cent of the distance in 7 of their 12 palms. Since equally distal palmar axial triradii were present in 2 of the normal individuals in Family 1, the significance of this finding is uncertain. No transverse palmar creases or plantar furrows were present in the affected members of either family. Their digital and hallucal patterns also did not appear to deviate consistently from those of their unaffected relatives. Radiologieal studies. The acetabular and
iliac angles were measured s on roentgenograms of 3 of the 4 affected children. The iliac angles did not deviate significantly from normal values, s-l~ The acetabular angles appeared to be somewhat low (Fig. 8). The measurements are listed in Table I. The bone age of one of the affected boys (the older boy in Family 1) was more than 2 standard deviations below the mean for his chronological age. The bone ages of the other affected chiIdren and those of their normal siblings were between one and two standard deviations below the mean. INCIDENCE
The frequency of this syndrome was estimated among children with cleft lip and
Fig. 8. A b n o r m a l l y flat a c e t a b u l a r angles in girl of F a m i l y 2 at 5 m o n t h s of age.
Table. I. Acetabular angles
Family No.
Subject
1
Y o u n g e r boy
Age when -~ examined I (too.)
Acetabular angles (degrees) Right Le[t A v e r a g e Normal
19 12 15 i3.5 27 16 17 t6.5 2 Boy 89 8 14 11 89 I1 13 12 2 Girl 5 11 7 9 5 14 12 13 18 13 8 11.5 ~Meart acetabular angles from normal children of same age and sex based on references 8 to I0.
mean* 20 17 26 26 23 23 21
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Heritable cIysmorphic syndrome
palate born in the state of Oregon from 1954 to 1963. The records of the Crippled Children's Division of the state of Oregon were reviewed for cases with cleft lip or palate, as were birth certificates filed with the Health Department and the records of surgeons engaged in correcting cleft lip or palate in Oregon. A total of 594 cases were ascertained and complete medical records were obtained in all cases as part of a larger study? ~ Individuals presenting one or more additional malformations suggestive of the present syndrome were then investigated. Aside from the two propositi in Family 1, who had been previously ascertained, no further cases with this syndrome were found. This suggests that this syndrome is a relatively rare cause of cleft lip and palate. CLINICAL MANIFESTATIONS OF S Y N D R O M E
As with most syndromes, this syndrome was initially detected mainly in individuals with dramatic manifestations. ~-~, ~, ~ This bias in ascertainment has led to the idea, for example, that all individuals with the syndrome have popliteal webs a and cleft lip or palate. Since neither of the mothers in our families had popliteal webbing and a further patient has been described ~ without a cleft lip or palate, the search for an in-
.4
CLEFT LIP-PALATE
933
variable anomaly in this syndrome appears likely to be illusory. Knowledge of the general pattern of anomalies in this syndrome (Fig. 9) and examination of other family members should, however, help in diagnosis. Orofacial anomalies. Cleft lip and palate and lip pits without other abnormalities may be transmitted as an autosomal dominant disorder?~, ~s The mother in Family 1 could easily have been accorded this diagnosis. Is the syndrome observed in her children a more severe expression of this same gene? The answer to this question might come from more complete evaluation of families a'~ with lip pits and cleft lip and palate, looking specifically for the toenail anomalies, the webbing, the shallow acetabular angles, and other associated defects. Oral webbing is found in the oral-facialdigital syndrome, ~s but this should not occasion difficulties in differential diagnosis because of the numerous differences between that syndrome, which rarely if ever occurs in male subjects, as and the present syndrome, which involves the 3 boys described above. Abnormalities of the extremities. Popliteal webbing, when present, may vary in severity (as in Family 1) and in symmetry, sometimes affecting only one leg. s Bony malformations of the legs have been
V.~.......%~.~.....~.......~..~...V.~....~...~.~.V.~.~...~.......'.~.~.......~...~.~.~;~.~.~..~.~.~.'
LIP PITS !iiiii!i!i!i!i!i!iiiiiii!!i;!!;!!;!!!!i!!!!!iii!!!i!iii!i!i!!!iii!i!i!i!i!iiiiiiiiiii!iiiiiiii!!i!i!iii! ORAL WEBBING iiSi iiiiiii;ii;iiiii i ;iiiiiiiiiiiiiiiiiiit FUSED EYELIDS. SYNDACTYLY OF FINGERS POPLITEAL WEBBING BONY MALFORMATION OF LEGS .
CLUB FEET SYNDACTYLY OF TOES TOENAIL DYSPLASIA
GENITAL/PERINEAL ANOMALIES NORMAL INTELLIGENCE
Fig. 9. Pattern of findings in this syndrome based on the six individuals from the two families in this report and two individuals from a similar two-generatlon family previously reported, s
9 3 4 Hecht and ]arvinen
previously observed in this syndrome. ~ The younger boy in Family 1 had the most severe involvement yet encountered in thi~ syndrome. Although the bony malformations in our cases were confined to the pelvis and lower extremities, other patients with the syndrome 2, ~, ~, la have been found with malformations of the upper extremities such as syndactyly of the fingers, fusion of the distal interphalangeal joints, and fingernail anomalies. Genital and perineal anomalies. Genital anomalies may range from a somewhat enlarged clitoris or a bifid scrotum, as in Family 1, to frankly ambiguous external genitalia2 Perineal anomalies have not been previously described, but two of the children reported here with genital anomalies had unilateral hypoplasia of the perineum, inconspicuous gluteal folds, and malformed buttocks (Figs. 6 and 7). Other anomalies. Scalp hair was abnormal in several previously reported cases, 2, a but was unexceptional in our patients. Vertebral anomalies have also been described in this syndrome, 2, 4 but none was noted in our patients. Intelligence. Our 6 patients were all of normal intelligence, as have been those previously reported patients in whom intelligence was mentioned. 2' 5, za Therefore, intellectual retardation does not appear to be a part of this syndrome. This speaks against the possibility that the syndrome could be caused by an undetected autosomaI chromosomal abnormality, since autosomal chromosomal abnormalities responsible for multiple congenital anomalies appear also to impair intelligence. ETIOLOGY On the basis of our family studies, as welI as two reports in the literature, 3, ~ it appears that this syndrome may be inherited as a dominant trait. Autosomal dominance is most probable, but X-linkage has yet to be excluded by the demonstration of male-tomale transmission. The fact that in our families the syndrome was transmitted as a d o m -
The ]ournal o[ Pediatrics June 1967
inant disorder does not eliminate the possibility that in other families a presently indistinguishable syndrome may be due to a recessive mode of inheritance or to nongenetic causes. The expression of this dominant gene has been noted to vary. Some individuals with the gene, such as the mother in Family 1, have relatively few anomalies. A logical extension is the idea that some individuals with the gene may be phenotypically normal. One family a provides some evidence'for this, as the grandfather had a cleft lip, and his daughter, who appeared unaffected, had two children affected with the syndrome.
COUNSELING The need for appropriate counseling regarding the risk of recurrence may be emphasized by mention of the incorrect counsel received by our families. The mother in Family 1 was advised by several physicians prior to marriage that she had no chance of having affected children. She was consequently surprised and distressed when her older boy was affected and doubly distressed when her younger boy was born even more severely affected. Furthermore, when the younger boy was in infancy his parents were told that he would, in all probability, be mentally retarded. Multiple physical anomalies are so frequently associated with retardation that, unless the physician recognizes the syndrome as one not affecting intelligence, the family may be burdened with needless concern and the care of the child may be influenced. The affected mother in Family 2 grew up in a small town in midwestern United States where she fell in love with a distant cousin. She was advised by her doctor not to marry the cousin because such a union might lead to children with the same anomalies. She married another man and had two children, both of whom are affected. She is understandably a bitter woman.
SUMMARY Two families are described with a syndrome of multiple congenital anomalies in-
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cluding cleft lip and palate, lip pits, genital anomalies, popliteal webbing, and malformations of the extremities. I n each family the mother and two of the children were affected. T h e syndrome was widely variable in expression within each family. This syndrome may therefore be inherited as a dominant trait. T h e responsible gene is probably autosomal, but X-linkage has not yet been excluded by the demonstration of male-to-male transmission. T h e frequency of this syndrome was determined in a large cleft lip and palate population, and no other persons with the syndrome were found, suggesting that this m u t a n t gene is a relatively rare cause of cleft lip and palate. T h e intelligence of the affected individuals was within the normal range. O t h e r features which have not been emphasized include: (1) low acetabular angles; (2) malformations of the perineum and buttocks; and (3) dermal ridge patterns which may extend over the dorsal surface of the toes as well as above the heels. We thank Dr. Richard L. Sleeter and Mrs. Susan Underwood for making their unpublished data available; Drs. Pierre Ferrier, Ellen Magenis, Havelock Thompson, Rodney K. Beals, Robert C. Burns, Robert Boyd, John Gullikson, Robert Weis, Bhim Savara, William Tracy, Mr. Milton Case, and the Children's Orthopedic Hospital, Seattle, Washington, and the Shriners Hospital for Crippled Children, Portland, Oregon, for their assistance. REFERENCES
1. Gorlin, R. J., and Pindborg, J. J.: Syndromes of the head and neck, New York, 1964, McGraw-Hill Book Co., Inc., p. 122. 2. Marquardt, W.: Die angeborene Flughautbildung und ihre konservative Behandlung, Ztschr. f. Orthop. 67: 379, 1937. 3. Champion, R., and Cregan, J.: Congenital popliteal webbing in siblings: A report of two cases, J. Bone & Joint Surg. 41-B: 355, 1959. 4. Rosselli, D., and Gulienetti, R.: Ectodermal dysplasia, Brit. J. Plast. Surg. 14: 190, 1961.
Heritable dysmorphic syndrome
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5. Klein, D.: Un curieux syndrome h6r6ditaire: ch61io-palatoschizis avec fistules de la l~vre inf6rieure associ6 ~. une syndactylie, une onychodysplasie particuli~re, un pt6rygion poplit6 unilat6ral et des pieds varus 4quins, J. G6n4t. Hum. 11: 65, 1962. 6. Lutzner, M. A., and Hecht, F.: Nuclear anomalies of the neutrophil in a chromosomal triplication: The DI (13-15) trisomy syndrome, Lab. Invest. 15: 597, 1966. 7. Penrose, L. S.: Dermatoglyphic topology, Nature 205" 544, 1965. 8. Caffey, J., and Ross, S.: Mongolism (mongoloid deficiency) during early infancy-some newly recognized diagnostic changes in the pelvic bones, Pediatrics 17: 642, 1956. 9. Ryder, C. T., Mellin, G. W., and Caffey, J.: The infant's hip--normal or dysplastic ? Clin. Orthop. 22: 7, 1962. 10. Heublein, G. W., Bernstein, L., and Hubenet, B. J.: Hip lesions of infants and children seen at the Newington Home and Hospital for Crippled Children, I~adiology 51: 611, 1948.
11. Sleeter, R., and Underwood, S. : Cleft lip and palate, and index to congenital malformations. In progress. i2. Schramm, G.: Ober die angeborene Flughautbildung, Ztschr. f. Orthop. 70: 189, 19391940. 13. SchiSnenberg, H.: Ober die Kombination von Lippen-Kiefer-Gaumen-Spalten mit Extremit~tenmissbildungen, Ztschr. Kinderh. 76: 79, 1955. 14. Test, A. R., and Falls, H. F.: Dominant inheritance of cleft lip and palate in five generations, J. Oral Surg. 5: 292, 1947. 15. Van der Woude, A.: Fistula labii inferioris congenita and its association with cleft lip and palate, Am. J. Human Genet. 6: 244, 1954. 16. Doege, T. C., Thuline, It. C., Priest, J. H., Norby, D. E., and Bryant, J. S.: Studies of a family with the oral-facial-digital syndrome, New England J. Med. 271" 1073, 1964. ADDENDUM
A report of an additional family with this syndrome is genetically informative. The family studied by E. Lewis (Proc. Roy. Soc. Med. 41: 864, 1948) contained a sister and brother with cleft palate and popliteal webbing (the sister also had "bilateral incomplete harelip"); their father had cleft lip and palate. The father-to-son transmission rules out X-linkage and establishes this syndrome as an autosomal dominant phenotype.
927
Heritable dysmorpbic syndrome itb normal intelligence A cause of cleft lip and palate, lip pits, genital anomaly, skeletal malformation, nail dysplasia, and webbing of the palpebrae, mouth, perlneum, and popliteal fossae A syndrome of multiple anomalies without mental retardation is analyzed in 2 families. The anomalies include cleft lip and palate, intraoral webbing and lip pits; genital, perineal, and buttock malformations; popIiteal webbing and dysplasia of the extremities. Dermal ridge patterns may extend beyond the soles to the dorsum of the toes and up the heels. Radiologically the acetabular angles appear low and are suggestive of pelvic dysplasia. In both families in this study the disease affected the mother and children, consistent with dominant inheritance.
Frederick Hecht, M.D.ff and Judith M. Jarvinen, M.S. PORTLAND,
ORE.
I N T H E I R BOOK, Syndromes of the head and neck, Gorlin and Pindborg 1 devote a separate chapter to a syndrome of multiple anomalies involving cleft lip and palate, pits of the lower lip, digital and genital anomalies, and popliteal webbing. Uncertain of the cause of the syndrome, they stated: "None of the patients had a parent with similar anomalies, but severaI had siblings with almost identical findings. 24 A1From the Genetics Clinic and Speech and Hearing Clinic, Crippled Children's Division, Department of Pediatrics and Division of Experimental Medicine, University o/Oregon Medical School. Supported in part by grants from the Medical Research Foundation of Oregon, the United States Public Health Service (CA 07941-03), and the Children's Bureau (/or the Genetics Clinic). ~Address, Genetics Clinic, Crippled Children's Division, University of Oregon Medical School, portland, Ore. 97201.
though this syndrome should be investigated for a chromosome anomaly, the evidence at hand would suggest an autosomal recessive trait." In each of the two families reported here a parent was affected, as was the case previously described. 5 The data from these families, therefore, do not support the hypothesis that this syndrome is caused by an autosomal recessive trait, but instead suggest a dominantly inherited mutation. In support o~ the concept of a single gene mutation, chromosomal studies in our patients revealed no abnormalities. F A M I L Y DATA Family 1. This family was originally ascertained because it contained two brothers with cleft lip and palate. An abbreviated version of their family pedigree is shown in Fig. 1. The Vol. 70, No. 6, pp. 927-935
9 2 8 Hecht and Jarvmen
affected mother's family is of Danish-FrenchEnglish-Irish extraction and is not known to be related in any way to Family 2. There is no known consanguinity among her ancestors, or between her and her husband's families. In neither the mother's three siblings nor any other known relative is there a history of any of the malformations included in the present syndrome. Family 2. This family was ascertained because their two children had similar patterns of anomalies. A detailed family history was obtained, part of which is presented in Fig. 1. The affected mother had one sibling, a brother who was reportedly normal. Her father may be mildly affected; he has not yet been examined. There is no known consanguinity among the mother's ancestors, who were Finnish, nor between her and her husband's families. INTRAFAMILIAL
VARIABILITY
T o illustrate the syndrome and its variability of expression, the affected individuals in Family 1 will be described in detail. T h e individuals in Family 2 will be more briefly described, since they manifested similar anomalies and similar variability of expression.
Fornily#1
Fomily#2
Fig. 1. Partial pedigrees of Families 1 and 2. Black squares and circles indicate affected male and female members. Open squares and circles indicate members who were examined and found to be normal.
The Journal of Pediatrics June 1967
Family 1
Mother: mild manifestations. This w o m a n was born with a unilateral (right) complete cleft of the lip and palate and with bilateral pits of the lower lip. There was no oral webbing. H e r clitoris was somewhat enlarged. No webbing of the popliteal fossae could be detected visually or by palpation. H e r hands and feet, likewise, appeared entirely normal without evidence of toe or toenail dysplasia. T h e dermal ridge patterns on the soles did not extend past their usual limits. Older boy: moderate manifestations. This boy was born after a normal full-term pregnancy and weighed 8 pounds, 7 ounces. H e had a slight notch in the right upper lip with a cleft of the hard and soft palate. Bilateral pits of the lower lip were also present (Fig. 2, A ) . T h e IinguaI frenum was attached in an extremely anterior position. No genital anomalies were present. There was mild popliteal webbing. T h e nails on the second toe of the right and the first through third toes of the left foot were hypoplastic and dysplastic (Fig. 3). Dermal ridge patterns were noted to extend over the dorsal surface of the toes with the hypoplastic nails, as well as above the heels, extending 3 cm. above the p r o x i m a l border of the talus. H e is of average height, as are his mother and affected brother. His popliteal webbing is causing progressive tightening of the heel cords. This handicaps him slightly in running. Younger boy: severe manifestations. This boy was the product of an apparently normal pregnancy and delivery; the birth weight was 7 pounds. H e had a unilateral (right) complete cleft lip and palate, bilateral pits of the lower lip, and oral webbing from the tuberosities of the maxillary alveolar ridge to the tuberosities of the mandibular alveolar ridge (Fig. 2, B). T h e lingual frenum was attached in a markedly anterior position, and the uvula was displaced anteriorly approximately two thirds the length of the palate. T h e surgeon commented that it was the most bizarre cleft palate in his experience. There was slight phimosis ; the scrotum was bifid; the left testis
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Heritable dysmorphic syndrome
929
Fig. 2. A, Lip pits in the older affected boy of Family 1. B, Oral webbing in the younger affected boy of Family 1.
Fig. 3. Toenall abnormaIities in older affected boy of Family 1. Note extension of dermal ridges over dorsum of second and third toes. Discoloration is caused by ink.
was in the scrotum; the right testis was in the inguinal canal along with a hydrocele. T h e legs were severely webbed with genu valgum and flexion contractures; m a x i m u m extension of the knees was 120 degrees on the right and 115 degrees on the left (Fig. 4). At age 3 years the right tibia lacked proximal and distal epiphyses and was 3 inches shorter than the left tibia (Fig. 5). T h e right fibula was 1 inch shorter than the left fibula, and both fibulae were posteriorly dislocated at the knee. There were talipes equinovarus deformities and marked dysplasia of the toes. O n the right the first
and second toes were bifid with syndactyly of the fourth and fifth toes. O n the left foot the first toe was bifid, the second toe absent, the third toe bifid, and the fourth and fifth toes syndactylous. Radiographs revealed Y-shaped fusion of the third and fourth metatarsals on the left. Soft tissue release was attempted surgically in the left popliteal area when the patient was 9 months of age. At this time it was found that the tibial nerve was contained in a dense cicatricial band bowstringing across the popliteal fossa. Skeletal traction was applied to the lower extremities in
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The Journal of Pediatrics June 1967
Fig. 4. Center inset shows posterior view of popliteaI webbing in the younger affected boy of Family 1. The radiographs were taken in maximal extension. Note limitation of extension.
alternation with casting, but these measures achieved only slight improvement and at age 2 years bilateral amputations at the knees were performed. He was fitted with lower extremity prostheses, which he has learned to use effectively, so that he walks well. Family 2
Mother: mild manifestations. All of the patient's anomalies, with the exception of a bifid nail on the second toe of the left foot, were: orofacial and consisted of bilateral pits of the lower lip, congenital scars of the upper lip, and complete cleft palate. She was told that oral "adhesions" had to be severed before she could be fed after birth. Girl: moderate manifestations. The birth weight was 6 pounds, 10 ounces. A band between the right lower lip and the right maxillary process was present at birth and had to be severed to permit feeding. There were bilateral pits of the lower lip; these were excised and histologically showed sinus tracts lined with stratified squamous epithe-
lium and accessory salivary glands. There was a complete (right) cleft lip and palate; the palate was unusually short. The right nipple was displaced more toward the anterior axillary line than was the left nipple. The genital and perineal anomalies are shown in Fig. 6. Popliteal webbing could not be seen, but could be easily palpated. The fourth and fifth toes were webbed on both feet. Boy: moderate manifestations. The birth weight was 8 pounds. "Lateral epicanthic folds" were reportedly present at birth and were severed shortly thereafter. There were bilateral pits of the lower lip and a unilateral (right) complete cleft lip and palate. The palate was described as exceptionally short and wide (as in the younger boy in Family 1). Oral webbing extended from the maxillary to the mandibular tuberosity bilaterally. The scrotum was abnormally small, although both testes were contained in it; the penis was normal. The anomalies of the perineum and buttocks and the popliteal webs are shown in Fig. 7. The nails on both
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Fig. 5. Bony anomalies of the lower extremities in the younger affected boy of Family 1.
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Fig. 6. Genital abnormality in affected glrl of Family 2. Note aplasia of part of labia majora and lateral displacement of the vulva.
first toes were hypoplastic and bifid. The patient's height and weight have been consistently above the fiftieth percentile for his age. SPECIAL INVESTIGATIONS Evaluation of intelligence. The affected children were tested individually by staff psychologists. The affected children in Family 1 were found to be of average intelligence. The affected boy in Family 2, tested at 2 years and 7 months, scored an I.Q. of 132 on the Stanford-Binet (Form L - M ) . His younger sister, 18 months at the time of testing, had an I.Q. of 111 on the CatteI1 Infant Intelligence Scale. Both affected mothers, on the basis of their functioning during numerous interviews, also appeared to be of normal intelligence. Chromosomal studies. Lymphocytes from peripheral blood were cultured, and cultured chromosomally, from the three affected members of Family 1 and the mother of Family 2; there was no abnormality in chromosome number or morphology.
Fig. 7. Posterior view of affected boy of Family 2. Note asymmetry of buttocks, popliteal webbing, and shortening of the left Achilles tendon.
932
Hecht and ]arvinen
The Journal o/ Pediatrics ]une 1967
Morphology of peripheral blood cells. Peripheral blood smears from the affected individuals were examined for morphological abnormalities6; none was noted. Dermal print studies. Dermal ridge patterns were noted to extend over the dorsal surfaces of several toes and above ttae heels of the older boy in Family 1. Penrose 7 noted that when the nail is congenitally absent ridge patterns will frequently continue dorsally past the usual site of the nailbed, and suggested that dermal ridge patterning is normally prevented from progressing dorsally by the presence of the nail. Since our patient's toes showing dorsal dermal ridge patterns were also those with the smallest, most markedly hypoplastic nails, we are skeptical of the separate significance of this dermatoglyphie finding. The extension of dermal ridge patterns above the heels may indicate that skin normally destined for the sole was dragged up the heel by the webbing. The paImar axial triradius was located more than 15 per cent of the distance along the palm in all six affected persons and more than 40 per cent of the distance in 7 of their 12 palms. Since equally distal palmar axial triradii were present in 2 of the normal individuals in Family 1, the significance of this finding is uncertain. No transverse palmar creases or plantar furrows were present in the affected members of either family. Their digital and hallucal patterns also did not appear to deviate consistently from those of their unaffected relatives. Radiologieal studies. The acetabular and
iliac angles were measured s on roentgenograms of 3 of the 4 affected children. The iliac angles did not deviate significantly from normal values, s-l~ The acetabular angles appeared to be somewhat low (Fig. 8). The measurements are listed in Table I. The bone age of one of the affected boys (the older boy in Family 1) was more than 2 standard deviations below the mean for his chronological age. The bone ages of the other affected chiIdren and those of their normal siblings were between one and two standard deviations below the mean. INCIDENCE
The frequency of this syndrome was estimated among children with cleft lip and
Fig. 8. A b n o r m a l l y flat a c e t a b u l a r angles in girl of F a m i l y 2 at 5 m o n t h s of age.
Table. I. Acetabular angles
Family No.
Subject
1
Y o u n g e r boy
Age when -~ examined I (too.)
Acetabular angles (degrees) Right Le[t A v e r a g e Normal
19 12 15 i3.5 27 16 17 t6.5 2 Boy 89 8 14 11 89 I1 13 12 2 Girl 5 11 7 9 5 14 12 13 18 13 8 11.5 ~Meart acetabular angles from normal children of same age and sex based on references 8 to I0.
mean* 20 17 26 26 23 23 21
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Heritable cIysmorphic syndrome
palate born in the state of Oregon from 1954 to 1963. The records of the Crippled Children's Division of the state of Oregon were reviewed for cases with cleft lip or palate, as were birth certificates filed with the Health Department and the records of surgeons engaged in correcting cleft lip or palate in Oregon. A total of 594 cases were ascertained and complete medical records were obtained in all cases as part of a larger study? ~ Individuals presenting one or more additional malformations suggestive of the present syndrome were then investigated. Aside from the two propositi in Family 1, who had been previously ascertained, no further cases with this syndrome were found. This suggests that this syndrome is a relatively rare cause of cleft lip and palate. CLINICAL MANIFESTATIONS OF S Y N D R O M E
As with most syndromes, this syndrome was initially detected mainly in individuals with dramatic manifestations. ~-~, ~, ~ This bias in ascertainment has led to the idea, for example, that all individuals with the syndrome have popliteal webs a and cleft lip or palate. Since neither of the mothers in our families had popliteal webbing and a further patient has been described ~ without a cleft lip or palate, the search for an in-
.4
CLEFT LIP-PALATE
933
variable anomaly in this syndrome appears likely to be illusory. Knowledge of the general pattern of anomalies in this syndrome (Fig. 9) and examination of other family members should, however, help in diagnosis. Orofacial anomalies. Cleft lip and palate and lip pits without other abnormalities may be transmitted as an autosomal dominant disorder?~, ~s The mother in Family 1 could easily have been accorded this diagnosis. Is the syndrome observed in her children a more severe expression of this same gene? The answer to this question might come from more complete evaluation of families a'~ with lip pits and cleft lip and palate, looking specifically for the toenail anomalies, the webbing, the shallow acetabular angles, and other associated defects. Oral webbing is found in the oral-facialdigital syndrome, ~s but this should not occasion difficulties in differential diagnosis because of the numerous differences between that syndrome, which rarely if ever occurs in male subjects, as and the present syndrome, which involves the 3 boys described above. Abnormalities of the extremities. Popliteal webbing, when present, may vary in severity (as in Family 1) and in symmetry, sometimes affecting only one leg. s Bony malformations of the legs have been
V.~.......%~.~.....~.......~..~...V.~....~...~.~.V.~.~...~.......'.~.~.......~...~.~.~;~.~.~..~.~.~.'
LIP PITS !iiiii!i!i!i!i!i!iiiiiii!!i;!!;!!;!!!!i!!!!!iii!!!i!iii!i!i!!!iii!i!i!i!i!iiiiiiiiiii!iiiiiiii!!i!i!iii! ORAL WEBBING iiSi iiiiiii;ii;iiiii i ;iiiiiiiiiiiiiiiiiiit FUSED EYELIDS. SYNDACTYLY OF FINGERS POPLITEAL WEBBING BONY MALFORMATION OF LEGS .
CLUB FEET SYNDACTYLY OF TOES TOENAIL DYSPLASIA
GENITAL/PERINEAL ANOMALIES NORMAL INTELLIGENCE
Fig. 9. Pattern of findings in this syndrome based on the six individuals from the two families in this report and two individuals from a similar two-generatlon family previously reported, s
9 3 4 Hecht and ]arvinen
previously observed in this syndrome. ~ The younger boy in Family 1 had the most severe involvement yet encountered in thi~ syndrome. Although the bony malformations in our cases were confined to the pelvis and lower extremities, other patients with the syndrome 2, ~, ~, la have been found with malformations of the upper extremities such as syndactyly of the fingers, fusion of the distal interphalangeal joints, and fingernail anomalies. Genital and perineal anomalies. Genital anomalies may range from a somewhat enlarged clitoris or a bifid scrotum, as in Family 1, to frankly ambiguous external genitalia2 Perineal anomalies have not been previously described, but two of the children reported here with genital anomalies had unilateral hypoplasia of the perineum, inconspicuous gluteal folds, and malformed buttocks (Figs. 6 and 7). Other anomalies. Scalp hair was abnormal in several previously reported cases, 2, a but was unexceptional in our patients. Vertebral anomalies have also been described in this syndrome, 2, 4 but none was noted in our patients. Intelligence. Our 6 patients were all of normal intelligence, as have been those previously reported patients in whom intelligence was mentioned. 2' 5, za Therefore, intellectual retardation does not appear to be a part of this syndrome. This speaks against the possibility that the syndrome could be caused by an undetected autosomaI chromosomal abnormality, since autosomal chromosomal abnormalities responsible for multiple congenital anomalies appear also to impair intelligence. ETIOLOGY On the basis of our family studies, as welI as two reports in the literature, 3, ~ it appears that this syndrome may be inherited as a dominant trait. Autosomal dominance is most probable, but X-linkage has yet to be excluded by the demonstration of male-tomale transmission. The fact that in our families the syndrome was transmitted as a d o m -
The ]ournal o[ Pediatrics June 1967
inant disorder does not eliminate the possibility that in other families a presently indistinguishable syndrome may be due to a recessive mode of inheritance or to nongenetic causes. The expression of this dominant gene has been noted to vary. Some individuals with the gene, such as the mother in Family 1, have relatively few anomalies. A logical extension is the idea that some individuals with the gene may be phenotypically normal. One family a provides some evidence'for this, as the grandfather had a cleft lip, and his daughter, who appeared unaffected, had two children affected with the syndrome.
COUNSELING The need for appropriate counseling regarding the risk of recurrence may be emphasized by mention of the incorrect counsel received by our families. The mother in Family 1 was advised by several physicians prior to marriage that she had no chance of having affected children. She was consequently surprised and distressed when her older boy was affected and doubly distressed when her younger boy was born even more severely affected. Furthermore, when the younger boy was in infancy his parents were told that he would, in all probability, be mentally retarded. Multiple physical anomalies are so frequently associated with retardation that, unless the physician recognizes the syndrome as one not affecting intelligence, the family may be burdened with needless concern and the care of the child may be influenced. The affected mother in Family 2 grew up in a small town in midwestern United States where she fell in love with a distant cousin. She was advised by her doctor not to marry the cousin because such a union might lead to children with the same anomalies. She married another man and had two children, both of whom are affected. She is understandably a bitter woman.
SUMMARY Two families are described with a syndrome of multiple congenital anomalies in-
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cluding cleft lip and palate, lip pits, genital anomalies, popliteal webbing, and malformations of the extremities. I n each family the mother and two of the children were affected. T h e syndrome was widely variable in expression within each family. This syndrome may therefore be inherited as a dominant trait. T h e responsible gene is probably autosomal, but X-linkage has not yet been excluded by the demonstration of male-to-male transmission. T h e frequency of this syndrome was determined in a large cleft lip and palate population, and no other persons with the syndrome were found, suggesting that this m u t a n t gene is a relatively rare cause of cleft lip and palate. T h e intelligence of the affected individuals was within the normal range. O t h e r features which have not been emphasized include: (1) low acetabular angles; (2) malformations of the perineum and buttocks; and (3) dermal ridge patterns which may extend over the dorsal surface of the toes as well as above the heels. We thank Dr. Richard L. Sleeter and Mrs. Susan Underwood for making their unpublished data available; Drs. Pierre Ferrier, Ellen Magenis, Havelock Thompson, Rodney K. Beals, Robert C. Burns, Robert Boyd, John Gullikson, Robert Weis, Bhim Savara, William Tracy, Mr. Milton Case, and the Children's Orthopedic Hospital, Seattle, Washington, and the Shriners Hospital for Crippled Children, Portland, Oregon, for their assistance. REFERENCES
1. Gorlin, R. J., and Pindborg, J. J.: Syndromes of the head and neck, New York, 1964, McGraw-Hill Book Co., Inc., p. 122. 2. Marquardt, W.: Die angeborene Flughautbildung und ihre konservative Behandlung, Ztschr. f. Orthop. 67: 379, 1937. 3. Champion, R., and Cregan, J.: Congenital popliteal webbing in siblings: A report of two cases, J. Bone & Joint Surg. 41-B: 355, 1959. 4. Rosselli, D., and Gulienetti, R.: Ectodermal dysplasia, Brit. J. Plast. Surg. 14: 190, 1961.
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5. Klein, D.: Un curieux syndrome h6r6ditaire: ch61io-palatoschizis avec fistules de la l~vre inf6rieure associ6 ~. une syndactylie, une onychodysplasie particuli~re, un pt6rygion poplit6 unilat6ral et des pieds varus 4quins, J. G6n4t. Hum. 11: 65, 1962. 6. Lutzner, M. A., and Hecht, F.: Nuclear anomalies of the neutrophil in a chromosomal triplication: The DI (13-15) trisomy syndrome, Lab. Invest. 15: 597, 1966. 7. Penrose, L. S.: Dermatoglyphic topology, Nature 205" 544, 1965. 8. Caffey, J., and Ross, S.: Mongolism (mongoloid deficiency) during early infancy-some newly recognized diagnostic changes in the pelvic bones, Pediatrics 17: 642, 1956. 9. Ryder, C. T., Mellin, G. W., and Caffey, J.: The infant's hip--normal or dysplastic ? Clin. Orthop. 22: 7, 1962. 10. Heublein, G. W., Bernstein, L., and Hubenet, B. J.: Hip lesions of infants and children seen at the Newington Home and Hospital for Crippled Children, I~adiology 51: 611, 1948.
11. Sleeter, R., and Underwood, S. : Cleft lip and palate, and index to congenital malformations. In progress. i2. Schramm, G.: Ober die angeborene Flughautbildung, Ztschr. f. Orthop. 70: 189, 19391940. 13. SchiSnenberg, H.: Ober die Kombination von Lippen-Kiefer-Gaumen-Spalten mit Extremit~tenmissbildungen, Ztschr. Kinderh. 76: 79, 1955. 14. Test, A. R., and Falls, H. F.: Dominant inheritance of cleft lip and palate in five generations, J. Oral Surg. 5: 292, 1947. 15. Van der Woude, A.: Fistula labii inferioris congenita and its association with cleft lip and palate, Am. J. Human Genet. 6: 244, 1954. 16. Doege, T. C., Thuline, It. C., Priest, J. H., Norby, D. E., and Bryant, J. S.: Studies of a family with the oral-facial-digital syndrome, New England J. Med. 271" 1073, 1964. ADDENDUM
A report of an additional family with this syndrome is genetically informative. The family studied by E. Lewis (Proc. Roy. Soc. Med. 41: 864, 1948) contained a sister and brother with cleft palate and popliteal webbing (the sister also had "bilateral incomplete harelip"); their father had cleft lip and palate. The father-to-son transmission rules out X-linkage and establishes this syndrome as an autosomal dominant phenotype.