American Journal of Medical Genetics 3R451-456 (1990)
“C” Trigonocephaly Syndrome: Clinical Variability and Possibility of Surgical Treatment ~~~
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F. Lalatta, D. Clerici Bagozzi, M.G. Salmoiraghi, P. Tagliabue, C. Tischer, M. Zollino, C. Di ROCCO, G. Neri, and J.M. Opitz Seconda Clinica Pediatrica (F.L.) and Cattedra di Patologia Neonatale (D.C.B.,M.G.S.,C.T.), Universita di Milano Ospedale Nuovo S . Gerardo, Monza (P.T.), and Istituto di Genetica Umana (M.Z.,G.N.) and Istituto di Neurochirurgia (C.D.R.), Facolta di Medicina “A. Gemelli’: U.C.S.C., Roma, Italy; Shodair Children’s Hospital, Helena, Montana (J.M.O.) ~-
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We report on 3 new cases of C trigonocephaly syndrome. In addition to the findings characteristic of this condition, one of the patients also had a large omphalocele. This patient was referred from a suburban hospital with a diagnosis of Down syndrome, stressing the fact that C syndrome is still under-recognized and underdiagnosed. Another patient was diagnosed at birth and immediately submitted to craniosynostectomy. A second operation was performed 7 months later resulting in normal brain growth and close to normal psychomotor development at 3 years, in contrast to the third patient, who was not treated surgically and was severely retarded at 4 years. KEY WORDS: craniosynostosis, craniosynostectomy, mental retardation, omphalocele, recessive inheritance INTRODUCTION The C syndrome, first described by Opitz et al. [19691, is a multiple congenital anomalies/mental retardation (MCA/MR)/dysplasiasyndrome characterized by craniosynostosis resulting in trigonocephaly; facial anomalies with upslanting palpebral fissures, epicanthal folds, hypoplasia of the nasal root, small nose and abnormalities of the external ears; abnormal body proportion with relatively normal trunk and short limbs; joint deformities; polydactyly. Internal malformations, including heart and kidney defects, have also been reported by Opitz et al. [19691 and by Flatz et al. [19841. Mental retardation is usually severe, either as a result of brain
Received for publication October 17,1988;revision received July 7, 1989. Address reprint requests to Faustina Lalatta, M.D. Seconda Clinica Pediatrica Universita di Milano, via Comrnenda 9, 20122 Milano, Italy.
0 1990 Wiley-Liss, Inc.
compression or due to primary abnormality of brain development. In spite of its striking phenotype, the C syndrome is rarely reported. Antley et al. 119811compiled 11cases, 2 were reported by Flatz et al. [19841, and another 5 were described by Sargent et al. [1985]. We describe 3 unrelated patients, the first cases of C syndrome reported in Italy.
CLINICAL REPORTS Patient 1 V.G., a boy, was the second child of healthy, nonrelated parents. Father was 41 and mother 30 years old at the time of his birth. Family history showed several cases of Deta-thalassemia in the mother’s family, but was otherwise unremarkable. The pregnancy was complicated by threatened abortion during the first trimester and by premature delivery at 36 weeks. No prenatal ultrasonography was performed. Birthweight was 3,250 g and length 49 cm (50th and 25th centile, respectively, for a term infant), occipito-frontal head circumference (OFC)35 cm (50th centile). Apgar scores were 4 and 7 a t one and 5 minutes, respectively. A large omphalocele was present and the infant was transferred to the Pediatric Clinic of the University of Milan with a clinical diagnosis of Down syndrome. Physical examination showed trigonocephalic skull due to premature fusion of the metopic suture; sparse scalp hair but hirsute forehead; upslanting palpebral fissures with broad and depressed nasal bridge; small nose with anteverted nostrils; long and flat philtrum, thin vermillion borders, small mouth, and micrognathia (Fig. 1). Ears were apparently low-set, posteriorly angulated, with prominently folded helices. Ophthalmologic examination demonstrated strabismus, microcornea, and normal fundus. The neck was short with loose redundant skin, nipples were widely spaced. There was an omphalocele measuring 5 x 5 cm, containing the liver and the intestinal loops, with partial epithelization (Fig. 2). Testes were undescended and could not be palpated in the inguinal canal. There was a 2/6 systolic murmur a t the mesocardium. Chest radiographs showed cardiomegaly
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Fig. 1. Front (a)and overhead (b)views ofpatient 1,showing trigonocephaly with marked prominence of the metopic suture and bitemporal constrictions.
Fig. 2. Large omphalocele in patient 1.
and EKG demonstrated right ventricular hypertrophy, while echocardiography demonstrated a small subaortic ventral septa1 defect (VSD), a patent ductus arteriosus, and signs of pulmonary hypertension. Chromosomes, assessed by high resolution banding, were normal. Laboratory findings were normal, except for 2 episodes of hypoglycemia and prolonged hyperbilirubinemia. The latter reached a transient peak of 24 mg% and was treated with phototherapy.
Neurological examination showed initially marked hypotonia, which subsequently became hypertonia. At age 1 month the patient had heart failure that was treated pharmacologically. At age 2% months weight was 3,160 g (25th centile), length 58 cm (3rd-25th centile) and psychomotor development appeared delayed. Brain CT scan showed diffuse white matter hypodensity and reduction of the posterior fossa. The patient was seen again at age 6 and 12 months.
C Syndrome Growth was between the 3rd and 25th centile, and psychomotor development was delayed: he was unable to sit or roll and could not follow an object in motion.
Patient 2 M.G., a girl, was born at term by cesarean section after an uneventful pregnancy. Parents were healthy and non-consanguineous. Father was 42 and mother 36 years old at the time of her birth. An older sister is normal. Birthweight was 3,600 g (50th centile) length 47 cm (10th centile), and OFC 37 cm (90th centile). Craniosynostosis and polydactyly were noted immediately and a skeletal survey showed marked dolichocephaly and fusion of the sagittal suture, apparent brevity of humeri and femora, absence of bones in the supernumerary finger of the right hand, hallux varus more marked at left. When examined at age one month, the infant was alert, capable of fixing and focusing. She had an hyperdolochocephalic head, with OFC of 37.6 cm (75th centile), and an anterior dislocation of the occipital hair whorl. There were atrophic scars on the scalp, presumably due to aplasia cutis verticis. There was a bony bulge in place of the anterior fontanelle and prominence of the metopic and anterior half of the sagittal suture, of the glabella and of the root of nose. There was upslanting of the palpebral fissures and marked epicanthal folds, thin upper vermilion border, micrognathia. Ears were posteriorly angulated, anteverted, anteflexed, and soft with open helix and hypoplasia of the lobule (Fig. 3). Thoracic diameter was apparently increased, with a short sternum and slightly anteverted xiphisternum, while the total length of the trunk appeared normal. Upper limbs were short, especially in the rhizomelic segment, and hands were small with relatively short fingers. There were bridged transverse palmar creases bilaterally and on right post-axial hexadactyly. Dermatoglyphics were on right: t, t', hypotenar L", abcd, third IDDL, WWWWL"; and on left: f', abcd, third
453
IDDL, WWWWW. In the hallucal areas there was an open field. Thighs and legs were short, the latter slightly bowed and lymphedematous. Great toes were large, varus (left > right), and separated from the second toe by a wide space. There was a short and soft 316 protosystolic murmur between the second and third intercostal space. Liver was palpable one cm below the costal margin. Genitalia and anus were normal. Chromosome studies, performed with high-resolution R banding and routine laboratory tests were normal. Brain CT scan showed a dolichocephalic skull with fusion of the interparietal suture. The ventricular system and the density of the white matter were normal; the cysterna magna was enlarged. Kidneys were normal by ultrasonography and so was the EEG, in spite of the presence of minimal spontaneous clonus of the 4 limbs. At 1% months a craniosynostectomy was performed and a diamond-shaped bone covering the anterior fontanelle was removed. A second similar operation had to be performed 7 months later to open rapidly re-ossifying sutures. After surgery the patient grew steadily, although below the average for age. At 12 months length was 66.5 cm (
“C” Trigonocephaly Syndrome: Clinical Variability and Possibility of Surgical Treatment ~~~
~
~
~
~
F. Lalatta, D. Clerici Bagozzi, M.G. Salmoiraghi, P. Tagliabue, C. Tischer, M. Zollino, C. Di ROCCO, G. Neri, and J.M. Opitz Seconda Clinica Pediatrica (F.L.) and Cattedra di Patologia Neonatale (D.C.B.,M.G.S.,C.T.), Universita di Milano Ospedale Nuovo S . Gerardo, Monza (P.T.), and Istituto di Genetica Umana (M.Z.,G.N.) and Istituto di Neurochirurgia (C.D.R.), Facolta di Medicina “A. Gemelli’: U.C.S.C., Roma, Italy; Shodair Children’s Hospital, Helena, Montana (J.M.O.) ~-
~~~
~~
We report on 3 new cases of C trigonocephaly syndrome. In addition to the findings characteristic of this condition, one of the patients also had a large omphalocele. This patient was referred from a suburban hospital with a diagnosis of Down syndrome, stressing the fact that C syndrome is still under-recognized and underdiagnosed. Another patient was diagnosed at birth and immediately submitted to craniosynostectomy. A second operation was performed 7 months later resulting in normal brain growth and close to normal psychomotor development at 3 years, in contrast to the third patient, who was not treated surgically and was severely retarded at 4 years. KEY WORDS: craniosynostosis, craniosynostectomy, mental retardation, omphalocele, recessive inheritance INTRODUCTION The C syndrome, first described by Opitz et al. [19691, is a multiple congenital anomalies/mental retardation (MCA/MR)/dysplasiasyndrome characterized by craniosynostosis resulting in trigonocephaly; facial anomalies with upslanting palpebral fissures, epicanthal folds, hypoplasia of the nasal root, small nose and abnormalities of the external ears; abnormal body proportion with relatively normal trunk and short limbs; joint deformities; polydactyly. Internal malformations, including heart and kidney defects, have also been reported by Opitz et al. [19691 and by Flatz et al. [19841. Mental retardation is usually severe, either as a result of brain
Received for publication October 17,1988;revision received July 7, 1989. Address reprint requests to Faustina Lalatta, M.D. Seconda Clinica Pediatrica Universita di Milano, via Comrnenda 9, 20122 Milano, Italy.
0 1990 Wiley-Liss, Inc.
compression or due to primary abnormality of brain development. In spite of its striking phenotype, the C syndrome is rarely reported. Antley et al. 119811compiled 11cases, 2 were reported by Flatz et al. [19841, and another 5 were described by Sargent et al. [1985]. We describe 3 unrelated patients, the first cases of C syndrome reported in Italy.
CLINICAL REPORTS Patient 1 V.G., a boy, was the second child of healthy, nonrelated parents. Father was 41 and mother 30 years old at the time of his birth. Family history showed several cases of Deta-thalassemia in the mother’s family, but was otherwise unremarkable. The pregnancy was complicated by threatened abortion during the first trimester and by premature delivery at 36 weeks. No prenatal ultrasonography was performed. Birthweight was 3,250 g and length 49 cm (50th and 25th centile, respectively, for a term infant), occipito-frontal head circumference (OFC)35 cm (50th centile). Apgar scores were 4 and 7 a t one and 5 minutes, respectively. A large omphalocele was present and the infant was transferred to the Pediatric Clinic of the University of Milan with a clinical diagnosis of Down syndrome. Physical examination showed trigonocephalic skull due to premature fusion of the metopic suture; sparse scalp hair but hirsute forehead; upslanting palpebral fissures with broad and depressed nasal bridge; small nose with anteverted nostrils; long and flat philtrum, thin vermillion borders, small mouth, and micrognathia (Fig. 1). Ears were apparently low-set, posteriorly angulated, with prominently folded helices. Ophthalmologic examination demonstrated strabismus, microcornea, and normal fundus. The neck was short with loose redundant skin, nipples were widely spaced. There was an omphalocele measuring 5 x 5 cm, containing the liver and the intestinal loops, with partial epithelization (Fig. 2). Testes were undescended and could not be palpated in the inguinal canal. There was a 2/6 systolic murmur a t the mesocardium. Chest radiographs showed cardiomegaly
452
Lalatta et a1.
Fig. 1. Front (a)and overhead (b)views ofpatient 1,showing trigonocephaly with marked prominence of the metopic suture and bitemporal constrictions.
Fig. 2. Large omphalocele in patient 1.
and EKG demonstrated right ventricular hypertrophy, while echocardiography demonstrated a small subaortic ventral septa1 defect (VSD), a patent ductus arteriosus, and signs of pulmonary hypertension. Chromosomes, assessed by high resolution banding, were normal. Laboratory findings were normal, except for 2 episodes of hypoglycemia and prolonged hyperbilirubinemia. The latter reached a transient peak of 24 mg% and was treated with phototherapy.
Neurological examination showed initially marked hypotonia, which subsequently became hypertonia. At age 1 month the patient had heart failure that was treated pharmacologically. At age 2% months weight was 3,160 g (25th centile), length 58 cm (3rd-25th centile) and psychomotor development appeared delayed. Brain CT scan showed diffuse white matter hypodensity and reduction of the posterior fossa. The patient was seen again at age 6 and 12 months.
C Syndrome Growth was between the 3rd and 25th centile, and psychomotor development was delayed: he was unable to sit or roll and could not follow an object in motion.
Patient 2 M.G., a girl, was born at term by cesarean section after an uneventful pregnancy. Parents were healthy and non-consanguineous. Father was 42 and mother 36 years old at the time of her birth. An older sister is normal. Birthweight was 3,600 g (50th centile) length 47 cm (10th centile), and OFC 37 cm (90th centile). Craniosynostosis and polydactyly were noted immediately and a skeletal survey showed marked dolichocephaly and fusion of the sagittal suture, apparent brevity of humeri and femora, absence of bones in the supernumerary finger of the right hand, hallux varus more marked at left. When examined at age one month, the infant was alert, capable of fixing and focusing. She had an hyperdolochocephalic head, with OFC of 37.6 cm (75th centile), and an anterior dislocation of the occipital hair whorl. There were atrophic scars on the scalp, presumably due to aplasia cutis verticis. There was a bony bulge in place of the anterior fontanelle and prominence of the metopic and anterior half of the sagittal suture, of the glabella and of the root of nose. There was upslanting of the palpebral fissures and marked epicanthal folds, thin upper vermilion border, micrognathia. Ears were posteriorly angulated, anteverted, anteflexed, and soft with open helix and hypoplasia of the lobule (Fig. 3). Thoracic diameter was apparently increased, with a short sternum and slightly anteverted xiphisternum, while the total length of the trunk appeared normal. Upper limbs were short, especially in the rhizomelic segment, and hands were small with relatively short fingers. There were bridged transverse palmar creases bilaterally and on right post-axial hexadactyly. Dermatoglyphics were on right: t, t', hypotenar L", abcd, third IDDL, WWWWL"; and on left: f', abcd, third
453
IDDL, WWWWW. In the hallucal areas there was an open field. Thighs and legs were short, the latter slightly bowed and lymphedematous. Great toes were large, varus (left > right), and separated from the second toe by a wide space. There was a short and soft 316 protosystolic murmur between the second and third intercostal space. Liver was palpable one cm below the costal margin. Genitalia and anus were normal. Chromosome studies, performed with high-resolution R banding and routine laboratory tests were normal. Brain CT scan showed a dolichocephalic skull with fusion of the interparietal suture. The ventricular system and the density of the white matter were normal; the cysterna magna was enlarged. Kidneys were normal by ultrasonography and so was the EEG, in spite of the presence of minimal spontaneous clonus of the 4 limbs. At 1% months a craniosynostectomy was performed and a diamond-shaped bone covering the anterior fontanelle was removed. A second similar operation had to be performed 7 months later to open rapidly re-ossifying sutures. After surgery the patient grew steadily, although below the average for age. At 12 months length was 66.5 cm (
