Clinical Genetics 1977: 12: 65-72
An autosomal dominant midline cleft syndrome resembling familial holoprosencephaly ALZCE 0. MARTINI,JANE C. S. PERXIN, w. A. MUIR, E. RUCHAND IRWINA. SCHAFER~
Section of Human Genetics, Department of Obstetrics and Gynecology, Northwestern University Medical School, Chicago, Illinois; Department of Pediatrics, Wayne State University, Detroit, Michigan; Division of Human Genetics, Department of Medicine, Case Western Reserve University School of Medicine; and Genetics Clinic, Cleveland Metropoliian General Hospital, Cleveland, Ohio, U.S.A, We have detected a previously unrecognized autosomal dominant syndrome characterized by: mental retardation, microcephaly; craniofacial anomalies including cleft lip and anterior cleft palate, hypotelorism and antimongoloid slant; skeletal anomalies, notably of the foot and spine; and chronic constipation. Despite similarities to familial holoprosencephaly, this disorder appears to be a distinct entity. Incomplete penetrance and variable expressivity accompany transmission of the abnormal allele through four generations of a large kindred. Three of the four affected males survived past 20 years of age; the fourth is an infant. All three affected females died very early in infancy. Received 22 November 1976, revised I 1 April, accepted for publication 29 April 1977
Five members of a single kindred appear to have a previously unrecognized autosoma1 dominant syndrome, characterized by: mental retardation; microcephaly; craniofacial anomalies including cleft lip and anterior cleft palate, hypotelorism, and antimongoloid slant; skeletal anomalies, notably of the foot and spine; and chronic constipation. Three of the four affected males survived past 20 years of age, and the fourth is an infant. All three affected females died very early in infancy. 1
2
Family History
The pedigree of the family, of Slovak-German ancestry, is shown in Figure 1. None of the matings were consanguineous. The proband (111-18) was initially referred for antenatal diagnosis because several of her relatives were said to have Down syndrome. N o cases of Down syndrome were detected in the family, but an autosomal dominant allele causing a pattern of malformations appeared to be segregating.
Supported in part by PHS Training Grant Gh.100820-13. Supported in part by Medical Service Grant, National Foundation C139.
66
MARTIN, PERRIN, MUIR, RUCH AND SCHAFER
n m N
4FFECTED MALE AFFECTED FEMALE MALE PRESUMED TO CARRY THE G E E FEMALE PRESUMED TOCARRY THE GENE
8
SPONTANEOUS ABORTION DECEASED
0 t
0
Fig. 1. Pedigree.
Affected Males 11-14 (Fig. 2) weighed 2,041 g when born after a 7-month gestation. At birth he was noted to have a right club foot, a cleft lip and a cleft palate. It is not clear from the hospital records whether the clefts were midline or slightly to the left. Both were repaired surgically. 11-14 also had an umbilical hernia, and throughout his life he has had chronic constipation. At 31 years of age, his height was 162.7 cm, his weight 63.5 kg and his head circumference 52 cm (less than 3rd percentile). He was severely retarded, but could follow simple commands. His speech was nasal in quality, and was limited to short phrases. The following anomalies were present: microcephaly, large external ears with smooth protruding lobes, hypotelorism, flat nasal bridge, deviated nasal septum, alveolar notch, dental caries, absence of central and lateral incisors, fissured tongue, highly arched palate, repaired anterior cleft palate with absence of the premaxilla, true hyperplasia of the mandible (prognathism), bilateral descended testes with the right smaller than left, unusually soft palmar skin, normal palmar and phalangeal creases, normal nails, fusion of the second and third cervical vertebrae, mild right meta-
tarsus varus, left calcaneovalgus, and an occasional truncal tremor. His manual dexterity was poor, and he could not walk a narrow base; however, neither ataxia nor spasticity could be elicited. Intravenous and retrograde pyelography revealed bilateral hydronephrosis and a neurogenic bladder with diverticula. His creatinine clearance was 40 96 of normal. Both urine and plasma contained no abnormal amino acids, organic acids or carbohydrates (chromatographic analysis). 111-10 (Fig. 3) attended a school for the
mentally retarded and is currently in a workshop. Like 11-14, he has always had chronic constipation. An examination at 20 years of age revealed antimongoloid slant of the palpebral fissures; highly arched palate; slight prognathism; complete absence of the sacrum and coccyx below S,; spina bifida at Cs, S1 and S2; mild hypoplasia of the posterior portion of the right 0s calcis; lumbar scoliosis; and a right talipes equinovarus. He did not have a cleft lip or a cleft palate. All his teeth had been extracted, and no records are available. 111-23 (Fig. 4) weighed 3,175 g at birth. He was noted to have a cleft lip, cleft pa-
AUTOSOMAL DOMINANT MIDLINE CLEFT SYNDROME
67
Flg. 3. 111-10, a 20-year-old affected male: posterior view showing severe scoliosis.
Fig. 2. Craniofacial anomalies in 11-14, a 31-year-old affected male. a. Anterior view showing deviated nasal septum and flat nasal bridge. b. View of mouth showing missing central and lateral incisors, repaired anterior cleft palate. (111-23 appeared almost identical.)
late, club feet, bilateral inguinal hernias, and a heart murmur not further characterized.
Like 11-10 and 11-14, he has always had chronic constipation. At 8 years of age his I.Q. (Stanford-Binet form L-M) was 53. He received instruction at a special school for the retarded, and now performs simple chores around the house. At 21 years of age, his height was 165.1 cm, his weight 63.5 kg, and his head circumference 53 cm (less than 3rd percentile). His facial appearance was similar to that of 11-14 and 111-10. The following anomalies were noted: microcephaly, large external pinnae, nasal speech, bilateral ptosis of the eyelids, a scar at the site of repair of a cleft lip that appeared to have been midline or slightly to the right, an alveolar notch, fissured tongue, highly
68
MARTIN, PERRIN, MUIR, RUCH AND SCHAFER
Fig. 5. Anterior view of 111-20, an affected female who died at 20 months of age, showing a midline cleft lip, anterior cleft palate, absence of the premaxillary process and protruding eyes. 111-20 resembles individuals reported to have holoprosencephaly. Fig. 4. Craniofacial anomalies in 111-23, a PI-year-old affected male: Anterior view showing ptosis, antimongoloid slant, deviated septum and flat nasal bridge.
arched palate, repaired anterior cleft palate and absence of the premaxilla, patent oral-nasal fistula, true hyperplasia of the mandible (prognathism), absence of lateral and central incisors, webbing of the neck, bilateral herniorrophy scars, large descended testes, unusually soft skin on the hands, bilateral and partially corrected calcaneovalgus of the feet, and a left second toe that overlapped the first. He was unable to walk on either his toes or his heels, and could not walk a narrow base; however, his regular gait appeared unimpeded. He had an occasional truncal tremor, but muscles were well-developed except for the gastrocnemius-soleus group. Chromotographic analysis of urine amino acids was normal. IV-5 was the product of the 23-year-old
proband’s first pregnancy. IV-5 experienced feeding difficulties and chronic constipation as an infant. At 4 weeks of age he developed chronic nasal congestion which has persisted. Examination at 4 months of age showed microcephaly (head circumference 39.5 cm, less than the 3rd percentile), a low-set and posteriorly-rotated left ear, antimongoloid slant of the palpebral fissures, strabismus, hypotelorism, hypoplastic maxilla, highly arched palate, bifid uvula with a possible small submucous cleft, bilaterally inferiorly turned down corners of the mouth, grade I/VI short systolic ejection murmur, right inguinal hernia, umbilical hernia, glanular hypospadias, a 1 cm annular band of fibrous tissue in the rectal ampulla, generalized hypotonia with poor head control, syndactyly of the second and third toes, and developmental retardation. No cleft lip was present. Roentgenographic studies
AUTOSOMAL DOMINANT MIDLINE CLEFT SYNDROME
showed the following additional anomalies: posterior fossa with decreased anteriorposterior diameter and increased superiorinferior diameter, extending to the level of the posterior neural arch of C1; bilateral pes planus with increased talocalcaneal angles; forefeet valgus; partial agenesis of the spine below S1, with fusion and failure of segmentation. Intravenous pyelography electrocardiography, electromyelography, and nerve conduction tests were normal: Affected Females Both 11-8 and 11-9 died at approximately 3 days of age after a full-term gestation. Both had a cleft lip and a cleft palate. Their mother states that the two infants were similar in appearance not only to each other, but also to 111-20 (see below). No additional data are available.
111-20 (Fig. 5) weighed 2,466 g at birth. She had microcephaly; midline cleft lip; anterior cleft palate (soft palate and uvula were intact); absence of the premaxillary process, vomer and nasal cartilages; hypotelorism; protruding eyes; large ears deficient in cartilage; deep sacral dimples; and bilateral talipes equinovarus. At 4 months her height, weight and head circumference (33 cm) were all below the 3rd percentile. She had chronic respiratory infections, chronic constipation, and was developmentally retarded. She died at 20 months of age, at which time her crown-heel length was 65 cm. At autopsy, hypoplasia of the cerebral cortex, asymmetry of the cerebral hemispheres (left smaller than the right), bilateral paraventricular necrosis of cerebral white matter, and thrombosis of many cerebral vessels were noted. Her facies resembled those associated with holoprosencephal y. Other Family Members Because each produced at least one affected
69
child, five family members (1-1 or 1-2, 11-3, 11-5, 11-7, 111-18) are presumed to carry the allele that causes this syndrome. Either I-I or I-2 transmitted the allele to their three affected offspring (11-8, 11-9, and 11-14). 1-2 appears more likely than 1-1 to have had the abnormal allele. This conclusion is based upon reports by family members that several of his nephews, nieces, great-nephews and great-nieces had anomalies similar to those found in the family members we have described. For example, a sister of 1-2 was said to have given birth to two females who had cleft lip and cleft palate and died early in infancy, whereas a brother was said to have had a child with mental retardation and “bone problems.” Anomalies said to be present in other family members include mental retardation, club feet, cleft lip and cleft palate. However, these anecdotal descriptions could not be confirmed and, hence, these individuals may or may not have had the same disorder present in the descendants of 1-1 and 1-2. 1-2 deserted his family after the birth of 11-14, and he cannot be located. No photographs are available, but his family could recall nothing unusual about his appearance or health. 1-1 appeared to be phenotypically normal; however, she would not allow a thorough physical examination. She apparently had no affected relatives other than her descendants described in this report. 11-3 also deserted his family, and, likewise,
no photographs or other data are available. 11-5 was placed in a foot cast early in infancy, apparently because she had varus of the right foot. Her upper lip, philtrum, jaw, tongue and palate, nose and eyes are normal. She appears to be of normal intelligence.
Hernias: Umbilical Inguinal Chronic constipation
Hypotelorism Antimongoloid Slant Eyes Skeletal: Talipes varus Spinal anomalies
Nose Teeth
Highly arched Absence of premaxilla Maxillary hypoplasia Mandibular hyperplasia Ears
Mental retardation Microcephaly Craniofacial anomalies: Cleft lip Palate: Anterior cleft
Features
indicates presence. indicates absence. blank indicates no information,
+
+
+
right scoliosis. spina bifida. absence of sacrum and coccyx
right fusion of CZ and CI
+ -
+
large extracted
-
+
flat, deviated to left no central or lateral incisors
large
possible slight
bilateral sacral dimples
protruding
-
+
large, no cartilage absent septum
+ -
-
+
-
+ + + +
+
+ + + + + + +
II1-20
111-10
11-14
-
Table 1
+
-
+ + + + + +
111-23
+ +
-
bilateral
ptosis
+ +
flat, deviated to right no central or lateral incisors
large, flared
Clinical features of affected individuals shown in Figure 1
+
+
+
(bilateral valgus) sacral agenesis
strabismus
t
+
small pinched appearance
left low set, rotated
+ + -
possible submucous soft palate, bifid uvula
+
+
IV-5
D
I
z
n rn a
D
I
v, 0
0
Is
I
0
C
n
I)
C
-
3
z
-ID
W
rn
0
z
-I
-
n
AUTOSOMAL DOMINANT MIDLINE CLEFT SYNDROME
11-7 would permit neither an examination
nor an interview, and no photographs are available. His relatives state that his appearance and health are normal. 111-18 (the proband) is of normal intelli-
gence and has no overt malformations except for a slight antimongoloid slant of the palpebral fissures. Roentgenograms indicated no skeletal abnormalities. Cytogenetic Studies
G-banded karyotypes derived from lymphocyte cultures of 11-5, 11-14, 111-23 and IV-5 were normal.
Discussion
Five members of a single kindred (Fig. 1) have a pattern of developmental anomalies (Table 1). These include mental retardation; microcephaly; large external ears; craniofacial anomalies including cleft lip, anterior cleft palate, absence of central and lateral incisors, absence of the premaxilla, hypotelorism, and antimongoloid slant; skeletal anomalies, notably talipes varus and spinal anomalies; and chronic constipation. Individuals in this family share some features with individuals who have certain other disorders, particularly familial holoprosencephaly (Dallaire et al. 1971). However, the pattern of anomalies in the family we have described appears to represent a separate entity. The syndrome we have reported appears to be inherited as an autosomal dominnnt with incomplete penetrance. (From the pedigree shown in Figure 1, penetrance can be estimated as 7/12 = 0.58; based only upon generation 11, penetrance is 3/6 = 0.50.) Four of the five individuals who transmitted the abnormal allele (1-1 or 1-2, 11-3, 11-7, and 111-1 8) apparently failed to
71
express it. 11-5 had congenital varus of the right foot. As discussed by Edwards (1960, 1969), there is often great difficulty in the differentiation between single factor (Mendelian) and multifactorial models of inheritance. The difficulty is especially marked if: 1. incomplete penetrance is invoked for single factor models; 2. familial correlations are high for factors underlying the discontinuity for which a multifactorial threshold model (Falconer 1965) has been invoked; 3. the condition being analyzed is relatively common. Because of the rarity of this syndrome and its appearance in successive generations with no evidence of familial environmental factors or of nonrandom introduction of genes into the pedigree, its inheritence most likely results from the segregation of a single allele. Variation in developmental sequences controlled either by genetic or non-genetic factors could certainly be responsible for the incomplete penetrance. As is often the case with autosomal dominant syndromes, variable espressivity was present. For example, 111-20 had a midline cleft lip and an anterior cleft palate; 11-14 and 111-23 each had a cleft lip, anterior cleft palate, and highly arched palate; IV-5 had a highly arched palate, bifid uvula, and a possible small submucous cleft; 111-10 had only a highly arched palate. In this syndrome, affected females apparently die in early infancy; males survive to adulthood. Females also appear to be more severely malformed than males. This cannot be satisfactorily explained by a simple genetic hypothesis. The probability that among seven affected, the three who died were female and the four who lived were male is 2.9 % (Fisher exact probability test, one-tailed), assuming lethality is independent of the sex of the affected.
72
MARTIN, PERRIN, MUIR, RUCH AND SCHAFER
References
Dallaire, L., F. C. Fraser & F. W. Wiglesworth (1971). Familial holoprosencephaly. Birth Defects: Original Article Series, Vol. VII, No. 7, pp. 136-142. Edwards, J. H. (1960). The simulation of Mendelism. Acta genet. (Basel) 10, 63-70. Edwards, J. H. (1969). Familial predisposition in man. Brit. med. Bull. 25, 58-64. Falconer, D. S. (1965). The inheritance of liability to certain diseases, estimated from
the incidence among relatives. Ann. hum. Genet. 29, 51-76. Address: Alice 0. Martin, Ph.D. Section of Human Genetics Department of Obstetrics and Gynecology Northwestern University School of Medicine 333 East Superior Street Chicago, Illinois 6061 I U.S.A.
An autosomal dominant midline cleft syndrome resembling familial holoprosencephaly ALZCE 0. MARTINI,JANE C. S. PERXIN, w. A. MUIR, E. RUCHAND IRWINA. SCHAFER~
Section of Human Genetics, Department of Obstetrics and Gynecology, Northwestern University Medical School, Chicago, Illinois; Department of Pediatrics, Wayne State University, Detroit, Michigan; Division of Human Genetics, Department of Medicine, Case Western Reserve University School of Medicine; and Genetics Clinic, Cleveland Metropoliian General Hospital, Cleveland, Ohio, U.S.A, We have detected a previously unrecognized autosomal dominant syndrome characterized by: mental retardation, microcephaly; craniofacial anomalies including cleft lip and anterior cleft palate, hypotelorism and antimongoloid slant; skeletal anomalies, notably of the foot and spine; and chronic constipation. Despite similarities to familial holoprosencephaly, this disorder appears to be a distinct entity. Incomplete penetrance and variable expressivity accompany transmission of the abnormal allele through four generations of a large kindred. Three of the four affected males survived past 20 years of age; the fourth is an infant. All three affected females died very early in infancy. Received 22 November 1976, revised I 1 April, accepted for publication 29 April 1977
Five members of a single kindred appear to have a previously unrecognized autosoma1 dominant syndrome, characterized by: mental retardation; microcephaly; craniofacial anomalies including cleft lip and anterior cleft palate, hypotelorism, and antimongoloid slant; skeletal anomalies, notably of the foot and spine; and chronic constipation. Three of the four affected males survived past 20 years of age, and the fourth is an infant. All three affected females died very early in infancy. 1
2
Family History
The pedigree of the family, of Slovak-German ancestry, is shown in Figure 1. None of the matings were consanguineous. The proband (111-18) was initially referred for antenatal diagnosis because several of her relatives were said to have Down syndrome. N o cases of Down syndrome were detected in the family, but an autosomal dominant allele causing a pattern of malformations appeared to be segregating.
Supported in part by PHS Training Grant Gh.100820-13. Supported in part by Medical Service Grant, National Foundation C139.
66
MARTIN, PERRIN, MUIR, RUCH AND SCHAFER
n m N
4FFECTED MALE AFFECTED FEMALE MALE PRESUMED TO CARRY THE G E E FEMALE PRESUMED TOCARRY THE GENE
8
SPONTANEOUS ABORTION DECEASED
0 t
0
Fig. 1. Pedigree.
Affected Males 11-14 (Fig. 2) weighed 2,041 g when born after a 7-month gestation. At birth he was noted to have a right club foot, a cleft lip and a cleft palate. It is not clear from the hospital records whether the clefts were midline or slightly to the left. Both were repaired surgically. 11-14 also had an umbilical hernia, and throughout his life he has had chronic constipation. At 31 years of age, his height was 162.7 cm, his weight 63.5 kg and his head circumference 52 cm (less than 3rd percentile). He was severely retarded, but could follow simple commands. His speech was nasal in quality, and was limited to short phrases. The following anomalies were present: microcephaly, large external ears with smooth protruding lobes, hypotelorism, flat nasal bridge, deviated nasal septum, alveolar notch, dental caries, absence of central and lateral incisors, fissured tongue, highly arched palate, repaired anterior cleft palate with absence of the premaxilla, true hyperplasia of the mandible (prognathism), bilateral descended testes with the right smaller than left, unusually soft palmar skin, normal palmar and phalangeal creases, normal nails, fusion of the second and third cervical vertebrae, mild right meta-
tarsus varus, left calcaneovalgus, and an occasional truncal tremor. His manual dexterity was poor, and he could not walk a narrow base; however, neither ataxia nor spasticity could be elicited. Intravenous and retrograde pyelography revealed bilateral hydronephrosis and a neurogenic bladder with diverticula. His creatinine clearance was 40 96 of normal. Both urine and plasma contained no abnormal amino acids, organic acids or carbohydrates (chromatographic analysis). 111-10 (Fig. 3) attended a school for the
mentally retarded and is currently in a workshop. Like 11-14, he has always had chronic constipation. An examination at 20 years of age revealed antimongoloid slant of the palpebral fissures; highly arched palate; slight prognathism; complete absence of the sacrum and coccyx below S,; spina bifida at Cs, S1 and S2; mild hypoplasia of the posterior portion of the right 0s calcis; lumbar scoliosis; and a right talipes equinovarus. He did not have a cleft lip or a cleft palate. All his teeth had been extracted, and no records are available. 111-23 (Fig. 4) weighed 3,175 g at birth. He was noted to have a cleft lip, cleft pa-
AUTOSOMAL DOMINANT MIDLINE CLEFT SYNDROME
67
Flg. 3. 111-10, a 20-year-old affected male: posterior view showing severe scoliosis.
Fig. 2. Craniofacial anomalies in 11-14, a 31-year-old affected male. a. Anterior view showing deviated nasal septum and flat nasal bridge. b. View of mouth showing missing central and lateral incisors, repaired anterior cleft palate. (111-23 appeared almost identical.)
late, club feet, bilateral inguinal hernias, and a heart murmur not further characterized.
Like 11-10 and 11-14, he has always had chronic constipation. At 8 years of age his I.Q. (Stanford-Binet form L-M) was 53. He received instruction at a special school for the retarded, and now performs simple chores around the house. At 21 years of age, his height was 165.1 cm, his weight 63.5 kg, and his head circumference 53 cm (less than 3rd percentile). His facial appearance was similar to that of 11-14 and 111-10. The following anomalies were noted: microcephaly, large external pinnae, nasal speech, bilateral ptosis of the eyelids, a scar at the site of repair of a cleft lip that appeared to have been midline or slightly to the right, an alveolar notch, fissured tongue, highly
68
MARTIN, PERRIN, MUIR, RUCH AND SCHAFER
Fig. 5. Anterior view of 111-20, an affected female who died at 20 months of age, showing a midline cleft lip, anterior cleft palate, absence of the premaxillary process and protruding eyes. 111-20 resembles individuals reported to have holoprosencephaly. Fig. 4. Craniofacial anomalies in 111-23, a PI-year-old affected male: Anterior view showing ptosis, antimongoloid slant, deviated septum and flat nasal bridge.
arched palate, repaired anterior cleft palate and absence of the premaxilla, patent oral-nasal fistula, true hyperplasia of the mandible (prognathism), absence of lateral and central incisors, webbing of the neck, bilateral herniorrophy scars, large descended testes, unusually soft skin on the hands, bilateral and partially corrected calcaneovalgus of the feet, and a left second toe that overlapped the first. He was unable to walk on either his toes or his heels, and could not walk a narrow base; however, his regular gait appeared unimpeded. He had an occasional truncal tremor, but muscles were well-developed except for the gastrocnemius-soleus group. Chromotographic analysis of urine amino acids was normal. IV-5 was the product of the 23-year-old
proband’s first pregnancy. IV-5 experienced feeding difficulties and chronic constipation as an infant. At 4 weeks of age he developed chronic nasal congestion which has persisted. Examination at 4 months of age showed microcephaly (head circumference 39.5 cm, less than the 3rd percentile), a low-set and posteriorly-rotated left ear, antimongoloid slant of the palpebral fissures, strabismus, hypotelorism, hypoplastic maxilla, highly arched palate, bifid uvula with a possible small submucous cleft, bilaterally inferiorly turned down corners of the mouth, grade I/VI short systolic ejection murmur, right inguinal hernia, umbilical hernia, glanular hypospadias, a 1 cm annular band of fibrous tissue in the rectal ampulla, generalized hypotonia with poor head control, syndactyly of the second and third toes, and developmental retardation. No cleft lip was present. Roentgenographic studies
AUTOSOMAL DOMINANT MIDLINE CLEFT SYNDROME
showed the following additional anomalies: posterior fossa with decreased anteriorposterior diameter and increased superiorinferior diameter, extending to the level of the posterior neural arch of C1; bilateral pes planus with increased talocalcaneal angles; forefeet valgus; partial agenesis of the spine below S1, with fusion and failure of segmentation. Intravenous pyelography electrocardiography, electromyelography, and nerve conduction tests were normal: Affected Females Both 11-8 and 11-9 died at approximately 3 days of age after a full-term gestation. Both had a cleft lip and a cleft palate. Their mother states that the two infants were similar in appearance not only to each other, but also to 111-20 (see below). No additional data are available.
111-20 (Fig. 5) weighed 2,466 g at birth. She had microcephaly; midline cleft lip; anterior cleft palate (soft palate and uvula were intact); absence of the premaxillary process, vomer and nasal cartilages; hypotelorism; protruding eyes; large ears deficient in cartilage; deep sacral dimples; and bilateral talipes equinovarus. At 4 months her height, weight and head circumference (33 cm) were all below the 3rd percentile. She had chronic respiratory infections, chronic constipation, and was developmentally retarded. She died at 20 months of age, at which time her crown-heel length was 65 cm. At autopsy, hypoplasia of the cerebral cortex, asymmetry of the cerebral hemispheres (left smaller than the right), bilateral paraventricular necrosis of cerebral white matter, and thrombosis of many cerebral vessels were noted. Her facies resembled those associated with holoprosencephal y. Other Family Members Because each produced at least one affected
69
child, five family members (1-1 or 1-2, 11-3, 11-5, 11-7, 111-18) are presumed to carry the allele that causes this syndrome. Either I-I or I-2 transmitted the allele to their three affected offspring (11-8, 11-9, and 11-14). 1-2 appears more likely than 1-1 to have had the abnormal allele. This conclusion is based upon reports by family members that several of his nephews, nieces, great-nephews and great-nieces had anomalies similar to those found in the family members we have described. For example, a sister of 1-2 was said to have given birth to two females who had cleft lip and cleft palate and died early in infancy, whereas a brother was said to have had a child with mental retardation and “bone problems.” Anomalies said to be present in other family members include mental retardation, club feet, cleft lip and cleft palate. However, these anecdotal descriptions could not be confirmed and, hence, these individuals may or may not have had the same disorder present in the descendants of 1-1 and 1-2. 1-2 deserted his family after the birth of 11-14, and he cannot be located. No photographs are available, but his family could recall nothing unusual about his appearance or health. 1-1 appeared to be phenotypically normal; however, she would not allow a thorough physical examination. She apparently had no affected relatives other than her descendants described in this report. 11-3 also deserted his family, and, likewise,
no photographs or other data are available. 11-5 was placed in a foot cast early in infancy, apparently because she had varus of the right foot. Her upper lip, philtrum, jaw, tongue and palate, nose and eyes are normal. She appears to be of normal intelligence.
Hernias: Umbilical Inguinal Chronic constipation
Hypotelorism Antimongoloid Slant Eyes Skeletal: Talipes varus Spinal anomalies
Nose Teeth
Highly arched Absence of premaxilla Maxillary hypoplasia Mandibular hyperplasia Ears
Mental retardation Microcephaly Craniofacial anomalies: Cleft lip Palate: Anterior cleft
Features
indicates presence. indicates absence. blank indicates no information,
+
+
+
right scoliosis. spina bifida. absence of sacrum and coccyx
right fusion of CZ and CI
+ -
+
large extracted
-
+
flat, deviated to left no central or lateral incisors
large
possible slight
bilateral sacral dimples
protruding
-
+
large, no cartilage absent septum
+ -
-
+
-
+ + + +
+
+ + + + + + +
II1-20
111-10
11-14
-
Table 1
+
-
+ + + + + +
111-23
+ +
-
bilateral
ptosis
+ +
flat, deviated to right no central or lateral incisors
large, flared
Clinical features of affected individuals shown in Figure 1
+
+
+
(bilateral valgus) sacral agenesis
strabismus
t
+
small pinched appearance
left low set, rotated
+ + -
possible submucous soft palate, bifid uvula
+
+
IV-5
D
I
z
n rn a
D
I
v, 0
0
Is
I
0
C
n
I)
C
-
3
z
-ID
W
rn
0
z
-I
-
n
AUTOSOMAL DOMINANT MIDLINE CLEFT SYNDROME
11-7 would permit neither an examination
nor an interview, and no photographs are available. His relatives state that his appearance and health are normal. 111-18 (the proband) is of normal intelli-
gence and has no overt malformations except for a slight antimongoloid slant of the palpebral fissures. Roentgenograms indicated no skeletal abnormalities. Cytogenetic Studies
G-banded karyotypes derived from lymphocyte cultures of 11-5, 11-14, 111-23 and IV-5 were normal.
Discussion
Five members of a single kindred (Fig. 1) have a pattern of developmental anomalies (Table 1). These include mental retardation; microcephaly; large external ears; craniofacial anomalies including cleft lip, anterior cleft palate, absence of central and lateral incisors, absence of the premaxilla, hypotelorism, and antimongoloid slant; skeletal anomalies, notably talipes varus and spinal anomalies; and chronic constipation. Individuals in this family share some features with individuals who have certain other disorders, particularly familial holoprosencephaly (Dallaire et al. 1971). However, the pattern of anomalies in the family we have described appears to represent a separate entity. The syndrome we have reported appears to be inherited as an autosomal dominnnt with incomplete penetrance. (From the pedigree shown in Figure 1, penetrance can be estimated as 7/12 = 0.58; based only upon generation 11, penetrance is 3/6 = 0.50.) Four of the five individuals who transmitted the abnormal allele (1-1 or 1-2, 11-3, 11-7, and 111-1 8) apparently failed to
71
express it. 11-5 had congenital varus of the right foot. As discussed by Edwards (1960, 1969), there is often great difficulty in the differentiation between single factor (Mendelian) and multifactorial models of inheritance. The difficulty is especially marked if: 1. incomplete penetrance is invoked for single factor models; 2. familial correlations are high for factors underlying the discontinuity for which a multifactorial threshold model (Falconer 1965) has been invoked; 3. the condition being analyzed is relatively common. Because of the rarity of this syndrome and its appearance in successive generations with no evidence of familial environmental factors or of nonrandom introduction of genes into the pedigree, its inheritence most likely results from the segregation of a single allele. Variation in developmental sequences controlled either by genetic or non-genetic factors could certainly be responsible for the incomplete penetrance. As is often the case with autosomal dominant syndromes, variable espressivity was present. For example, 111-20 had a midline cleft lip and an anterior cleft palate; 11-14 and 111-23 each had a cleft lip, anterior cleft palate, and highly arched palate; IV-5 had a highly arched palate, bifid uvula, and a possible small submucous cleft; 111-10 had only a highly arched palate. In this syndrome, affected females apparently die in early infancy; males survive to adulthood. Females also appear to be more severely malformed than males. This cannot be satisfactorily explained by a simple genetic hypothesis. The probability that among seven affected, the three who died were female and the four who lived were male is 2.9 % (Fisher exact probability test, one-tailed), assuming lethality is independent of the sex of the affected.
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MARTIN, PERRIN, MUIR, RUCH AND SCHAFER
References
Dallaire, L., F. C. Fraser & F. W. Wiglesworth (1971). Familial holoprosencephaly. Birth Defects: Original Article Series, Vol. VII, No. 7, pp. 136-142. Edwards, J. H. (1960). The simulation of Mendelism. Acta genet. (Basel) 10, 63-70. Edwards, J. H. (1969). Familial predisposition in man. Brit. med. Bull. 25, 58-64. Falconer, D. S. (1965). The inheritance of liability to certain diseases, estimated from
the incidence among relatives. Ann. hum. Genet. 29, 51-76. Address: Alice 0. Martin, Ph.D. Section of Human Genetics Department of Obstetrics and Gynecology Northwestern University School of Medicine 333 East Superior Street Chicago, Illinois 6061 I U.S.A.
