Europ. J. Pediat. 123, 15--28 (1976) 9 by Springer-Verlag 1976
Original Investigations Studies of Malformation Syndromes of Man XXXIX: A Craniosynostosis-Craniofacial Dysostosis Syndrome with Mental Retardation and Other Malformations: "Craniofacial Dyssynostosis"* Gerhard Neuh/~userl,2, a, E l i s a b e t h G. K a v e g g i a 2,a a n d J o h n M. Opitz~, a 1The Harry A. ~u Center on Mental Retardation and Human Development of the University of Wisconsin, eDepartment of Pediatrics and aWisconsin Clinical Genetics Center of the Department of Medical Genetics of the University of Wisconsin Center for Health Sciences and Medical School, Madison, Wisconsin, USA 53706, and ~Central Wisconsin Colony and Training School, Madison, Wisconsin Received March 4, 1976
Abstract. We report clinical findings in 2 sisters and 5 sporadic cases with a "new" type of craniosynostosis/craniofacial dysostosis and shortness of stature. Premature closure of lambdoid sutures and posterior part of sagittal suture causes a posteriorly narrow, dolichocephalic skull with small, fiat or bulging occiput and protuberance of the forehead; disturbance of the growth of basal skull structures leads to eraniofacial dysostosis and (secondary) anomalies of the face. In one patient the coronal suture was also involved. One of the patients had a congenital heart defect. Four untreated patients had mental retardation; 3 had craniosynostectomy with more or less normal psychomotor development afterwards. Some patients had hydrocephalus and 1 had a brain malformation (agenesis of the corpus callosum with presumed interventricularlipoma). The observation of sisters with the same condition suggests autosomal recessive inheritance. This etiologic hypothesis is supported by the fact that 4 of 7 patients are of Spanish, Mexican, or Puerto Rican ancestry; this population probably has a rather high gene frequency and the trait should be relatively common in areas occupied by this population and their descendants. The condition has been designated craniofacial dyssynostosis. Key words: Craniosynostosis - - Craniofacial dysostosis - - Mental retardation - - Agenesis of corpus eallosum - - Hydrocephalus - - Craniofacial dyssynostosis - - Autosomal recessive inheritance - - Spanish populations. Introduction
W e report the findings in 7 children, 4 of Spanish (i.e. Mexican, P u e r t o Rican, Cuban) ancestry, with a previously a p p a r e n t l y undescribed t y p e of eraniosynostosis a n d eraniofacial dysostosis i n v o l v i n g the l a m b d o i d suture a n d the posterior p a r t of the sagittal s u t u r e as well as structures of the base of the skull, causing a scaphoeephalic head shape with p r o m i n e n t forehead a n d small, n a r r o w oeciput. O b s e r v a t i o n of 2 affected sisters suggests a u t o s o m a l recessive inheritance. * Paper No. 1874 from the University of Wisconsin Genetics Laboratory. Supported, in part, by PI-IS/NIH Grant GM20130 and by a grant from the Brittingham Foundation.
16
G. Neuh~user et al. R e p o r t s of P a t i e n t s
Patient 1 (260273; U W - H o s p . No. 674959) Parents are of Mexican-Italian and Cuban-French ancestry and are healthy, normally developed and of normal intelligence; at the child's birth the father was 33 and the mother 27 years old. The parents are not consanguineous. A sister, born 3 years earlier by caesarian section due to cephalo-pelvic disproportion (birth weight 3500 g, length 46 cm) is developing normally. Between the two pregnancies mother had a spontaneous abortion at 2 mouths. A 1 l/2 year younger sister is patient 2. Pregnancy was normal; birth occurred after a normal 39 week gestation through uncomplicated repeat caesarian section and resulted in a healthy child with a weight of 3000 g, a length of 45 em and an OFC of 30.5 cm. The infant cried spontaneously and no neonatal problems were noted. Early development was normal. When she was admitted at 3 months for abnormal head shape and unusual facial appearance she was found to be a well nourished, relatively small child in good health (length of 53 cm, < 3rd%ile), with a dolichocephalic skull (OFC 37.5 era, at 10th ~ ) ; a bulging, tense 7 X 5 cm anterior foutanel; striking frontal prominence; relative flatness of occiput; normal coronal sutures; osseous ridge over the posterior part of the sagittal suture aud both lambdoid sutures; relatively flat supraorbital ridges; depressed lateral temporal orbital portion of forehead; broad bridge of nose (ICD 24ram, OCD 58 ram); short palpebral fissures with slight antimongoloid slant; slight retraction of upper lids above corneae ("sunset sign") with otherwise uormal eyes; posteriorly angutated auricles of normal shape; compressed ear canals; hypoplastic tip and alae of nose and short septum nasi; mouth-breathing facial deformity with inverted V shape of upper lip, normal palate without submucous cleft and slight micrognathia. Heart and lungs were normal; liver and spleen were not enlarged but a small umbilical hernia, diastasis recti, normal genitalia and extremities, slight clinodactyly and overriding of fifth over fourth fingers and an unusually wide diastasis between first and second toe were noted. Dermatoglyphics are cited in Table 1. Psychomotor development was normal; except fbr the tense and bulging anterior fontauel no other signs of increase intraoranial pressure could be found. Roentgenograms of skull (Fig. 1 a) showed brachycephaly with frontal bossing and synostosis of both lambdoid sutures and the posterior part of the sagittal suture; the anterior fentanel was more posteriorly located than usual; the mandible was small, foramcn magnum and orbits were of normal size and shape. Lumbar pneumoeneephalography showed an unremarkable fourth ventricle, aqueduct and third ventricle; the left temporal horn was slightly larger than the right; the lateral ventricles were mildly dilated. Minimal eor~ical atrophy (?) aud a eavum veli interpositi was noted. No farther abnormalities could be seen on a skeletal survey; chest films were normal as was an intravenous pyelogram. E E G was normal for age; special tests showed no impairment of hearing abilities, l~esults of CBC and urinalysis and the B U N levels were normal; serologic reactions (Sabin dye test, cytomegalovirus and rubella tests) were negative. The spinal fluid was normal. An eye examination showed limitation of upward gaze, but was otherwise normal. Following a successful craniosynostectomy of both lambdoid sutures at 3 months the child developed normally and head circumference increases followed the 10th percentile. At 18 months roentgenograms showed open metopic, coronal and squamous sutures and open lambdoid synostectomy, but an ahnost completely closed sagittal suture (Fig. l b), marked frontal bossing, widening of the diploie space of the frontal bones and hypertelorism. A successful craniosynostectomy of the sagittal suture was performed primarily for cosmetic reasons. Her psychomotor and mental development is normal to date (Fig. 2a and b).
Patient 2 (201174; U W - H o s p . No. 715208; sister o f p ~ t i e n t 1) This infant was delivered by repeat caesarian section after a normal, 40 week gestation; birth weight was 3000 g, length 49 cm. An abnormally shaped skull was noted at birth, otherwise the child was reported to be in good condition. There were no feeding difficulties but she had pneumonia and diarrhea at 6 weeks. She smiled sometimes but did not follow with
(a)
Fig. 1. (a) Left: Lateral view of the skull of patient 1 at 3 months: bulging forehead, relatively steep and fiat oeciput. (b) Right: Lateral view of skull of patienl~ I at 18 months after synostectomy of lambdoid sutures. Note dolichocephaly and increased thickness of frontal bone
(b)
5"
18
G. Neuhiiuser et al.
(a)
(b) Fig. 2 a a n d b. P a t i e n t 1 a t age 2 years following craniosynosteetomy
(a)
(b) Fig. 3a and b. P a t i e n t 2 a t 3 m o n t h s
her eyes; she h a d no seizures, b u t i n t e r m i t t e n t opisthotonie arching was noted when lying supine or when pulled up for sitting. She was a d m i t t e d to the hospital a t 3 m o n t h s beeause of vomiting a n d was found to have a length of 54 cm ( < 3rd %ile), brachyturrieephalic skull (OFC 34.4 era, < 3rd ~ with abnormal occipital hair pattern, one occipital hairwhorl to the right of the midline, and a frontal hairwhorl; flat, hypoplastie oeciput and inion; a p r o m i n e n t ridge over b o t h lambdoid sutures, the posterior p a r t of the sagittal suture and lower p a r t of the right coronal suture; closed posterior fontanel, b u t widely open and tense anterior fontanel, the anterior edge of which was located more anteriorly and to the right side of the midline; open metopie suture; prominent, somewhat bulging forehead and flat supraorbital ridges. There was a scattered
Craniofaeial Dyssynostosis
19
Table 1. Dermatoglyphics of cases 1---6 Case
Hand
Trirad. Thenar Hypoth. Interdig.
1
l
R
t
--
--
4 DL
L P~ L R L
t t t t' t'
------
------
4 DL 3 DL 3 DL ---
I~
t'
--
--
L
t
--
5
R
V
--
6
L I~ L
V t t
----
------
2a 3 4
2
3
4
5
gallueal
U
W U
U
U
U U U W W
At A A A A
Up U U U U
U U U U U A UpU U U
DL W DL DL ?OF ?OF
3DL v
W
W
F~pW U
---3DL v 3+4DL v
U W U U U
WU U U U U UPU W U
WU U U U U W W W W
TL
TL DL DL DLp DLP
Low TBC.
capillary hemangioma over glabella and nose, marked asymmetry of face and ealvarium with a facial seoliosis concave to the right side; the right side of face was smaller than the left, the right eye was located somewhat lower t h a n the left, and the right temporal region was markedly bulging (Fig. 3a and b). Except for divergent strabismus the eyes were normal. The child had a broad bridge of nose (ICD 30 mm, OCD 67 ram), antimongoloid slanting of palpebral fissures, apparently low set, posteriorly angulated, abnormally narrow and hypoplastie auricles with short upper transverse part of helix, slight hypoplasia of lower part of helix, short tragus and compressed ear canals; hypoplastie tip and alae of nose, short philtral part of septum nasi, a highly arched palate without submueous cleft, short lingual frenulum, pronouneed micrognathia, and mouth breathing facies. There was obstructive breathing and a weak, hoarse, low pitched cry. The neck appeared short, the antero-posterior diameter of the chest increased, and she had a small umbilical hernia. A grade IV/VI systolic murmur was heard over the entire precordium; lungs were normal on physical examination. The liver was enlarged and she had other manifestations of congestive heart failure. A mongolian spot was seen over the lumbosaeral and gluteal area. Arms, hands, fingers and nails were normal; there was slight metatarsus varus bilaterally, a cutaneous syndaetyly between both second and third toes and dorsal dislocation of the fourth toe on the left foot. Flexion creases were normal; dermatoglyphics are listed in Table 1. Muscle tone was somewhat increased with active and symmetrical deep tendon reflexes. There was persistence of primitive reflexes and a tendency to opisthotonie posturing. Psychemotor development seemed to be delayed. t~adiograms of the skull (Fig. 4) showed a small, asymmetric cranial vault with "L/ickenschgdel" appearance in the right temporo-parietal area. Both lambdoid sutures, the posterior part of the sagittal suture, and the lower portion of the right coronal suture were synostosed. The anterior fontanel seemed to be more posteriorly located t h a n normal; the right orbit was smaller t h a n the left, and the mandible was hypoplastic. Chest films revealed an enlarged heart, increased vascularity of the right lung, but diminished vascularity of the left lung. ECG showed right ventrieular hypertrophy; on lung scan there was no evidence of perfusion of the left upper lobe. Cardiac catheterization demonstrated a patent duetus arteriosus which was ligated; following the operation the ehild recovered rapidly from heart failure. Improvement of perfusion of the left lung showed t h a t compression of the left pulmonary artery by the p a t e n t duetus had been present. Auscultation some weeks later still revealed a heart murmur, probably due to a small ventrieular septal defect. Eye examination showed alternating exotropia, hyperopia, vertically oval discs, shallow orbits, and hypertelorism. After recovery from heart surgery the patient had eraniosynosteetomy of the right eoronM and of both ]ambdoid sutures at 6 months. Psychomotor development began to accelerate.
20
G. NeuhEuser et al.
Fig, 4. Lateral view of skull of patient 2 at 3 months. Short base of skull and maxilla, hypoplastic occipital region, increased convolutional markings
Patient 3 ( A D 0 6 1 2 6 9 ; C W C N o . 5 - i 6 9 5 ; U W - H o s p . N o . 6 1 6 6 0 4 ) B o t h parents are healthy, apparently n o t consanguineous and of Irish ancestry. Brothers, born in 1961 a n d 1964, are normal. A t the b i r t h of the patient (1968) father was 41, mother 37 years old. I n addition the m o t h e r h a d one miscarriage. Upper respiratory infections, ankle edema, nausea a n d lack of physical energy were reported during pregnancy; for this the mother was treated symptomatically; weight gain during pregnancy was 9 kg. B i r t h occurred a t term after a n 11 h " m e d i u m to h a r d " labor. B i r t h weight was 3400 g, length 53 era, OFC 39 cm ( > 98th %ile). On the 2nd day the infant turned blue a n d rapid increase of the size of the head was noted; incubator care and oxygen were required. Psychomotor development was slow. Seizures began a t 5 months on the left side, spreading to the right and t h e n to the whole body, recurring every other day, and lasting several minutes. The infant frequently suffered colds and bronchitis. A shunt operation for hydrocephaly was refused a n d the child was a d m i t t e d to Central Wisconsin Colony (CWC). A t 9 months, a Pudenz-Heyer ventriculo-peritoneal s h u n t was finally installed. The child made slow developmental progress; seizures are controlled with appropriate medication. H e a d growth has continued a t t h e 98th~ A t 51/e years s h u n t revision was necessary
Craniofacial Dyssynostosis
(a)
21
(b) Fig. 5a and b. Patient 3 at 4 years
because of acutely increased intracranial pressure manifested by irritability and seizures; the postoperative course was uneventful and her condition improved. Examination at 51~ ~ years showed a severely retarded girl with retarded growth (length 89 cm, < 3rd ~oile), a dolichocephaIic, narrow skull, with closed fontanels, OFC of 54 cm (> 98th~oile), relatively flat occipital region (small occipital bone), osseous ridges over lambdoid sutures, and bulging forehead (Fig. 5a and b). There was an occipital hair whorl, hypoplastic supraorbital ridges, hypertelorism (inner canthal distance 33 ram, outer canthal distance 78 ram), slight antimongoloid slant of palpebral fissures, relatively retracted bridge of nose, strabismus, nystagmus, posteriorly angulated auricles (more on the left. than on the right side), relatively short maxilla, normal mouth and palate without submucous cleft, and micrognathia. A ventriculo-peritoneal shunt was functioning well. Heart and lungs were normal on physical examination; liver and spleen were not enlarged. Pectus excavatum, diastasis recti and shallow sacral dimple were noted. Genitalia, hands, fingers and fingernails were normal; the thumb was flexed into the palm bilaterally ("cortical thumb"). She had planovalgus feet and a relatively wide distance between the first and second toes. Dermatoglyphics are listed in Table 1. Muscle tone was markedly diminished; there were normal deep tendon reflexes and no pathologiea!: finger or toes signs; however, she had hcmiplegic weakness on the right. The child was severely retarded, showed stereotyped movements and had only minimal contact with other persons. Roentgenograms at 1 week purportedly showed normal sutures, disproportion between size of calvarium and facial bone and no intracranial calcifications. Ventriculograms, pneumoencephalograms and carotid arteriograms at various ages showed agenesis of the corpus callosum, a mass ( ? lipoma) above the third ventricle (Fig. 6), no ventricular filling after lumbar insufflation of air, dilatation of lateral ventricles (L > R) without filling of third and fourth ventricles, large foramina of Monroe, and several unusual veins in the frontal area. At 5 years the anterior fontanel and metopic sutures were still open. Chest and hip films were normal. An E E G at 1 year showed excessive slowing and epileptogenic activity in several regions with an almost continous spike focus in the left posterior parietal area. The CSF was normal.
Patient 4 (CSM 021164i C W C N o . 5-1517) Parents are of Mexican ancestry and healthy; 6 siblings have developed normally. At the child's birth the father and mother were 32 and 30 years old, respectively.
22
O. Neuh~,user et al.
Fig. 6. Pneumoencephalogram of patient 4 at 9 months: Agenesis of the corpus eallosum, " l i p o m a " of the roof of 3rd ventricle
Mother h a d a " b a d cold" during the first trimester b u t took no medication. Gestation lasted 38 weeks, labor a b o u t 30 min; delivery was normal. B i r t h weight was 3700 g, length 53 era, O~'C 37.5 em (at 98th ~oile). Lens opacity was purportedly n o t e d a t b i r t h ; the child was markedly floppy and h a d sucking difficulties; generalized seizures occurred. Slow development continued: The boy turned over at 2 years and reached for objects a t 21/z years. The left arm was noted to be weak. A t 3 years he was a d m i t t e d to CWC. He has made slow progress and is now able to stand with bilateral support, creep and move a b o u t with a walker. Seizures recur weekly. A t 10 years he was a well nourished, severely retarded, slightly overweight boy with length of 120 em (< 3rd ~oile), dolichocephalic skull with OFC of 55.8 cm (98th ~ ), hypoplastic, flat occipital region a n d bulging forehead, osseous ridge over lambdoid sutures (not over sagittal suture), straight black hair with two hair whorls, hirsutism of t r u n k a n d upper limbs, hyperLelorism (ICD 42 mm, OCD 100 ram), upper epieanthic folds, external strabismus, posteriorly angulated auricles, hypoplasia of lower helix, maxillary overbite, normal palate without submucous cleft, short mandible (Fig. 7) and a shallow sacral dimple. Heart, lungs, liver and spleen a n d genitalia were normal; he h a d normM arms a n d hands, short fifth fingers, a "cortical" t h u m b on the left and planovalgus feet with prominent heels. Dermatoglyphics are listed in Table 1.
Craniofacial Dyssynostosis
(a)
23
(b) Fig. 7a and b. Patient 4 at 10 years
The patient was hypotonic, had normal deep tendon reflexes and a mild left hemiplegia, affecting the arm more than the leg; he used his right hand exclusively. He was able to follow simple commands, but was somewhat hyperactive. Roentgenograms at 3 weeks purportedly showed normal sutures. A pneumoeneephalogram at 3 years revealed ventricular enlargement more on the left than on the right with moderate subaraehnoid filling. The CSF was normal. At 9 years the skull films were interpreted as showing arrested hydrocephalus with fronto-occipital prominence, hypertelorism, and foramina parietalia (permagna ?). Spine films showed spina biflda oeculta. His karyotype was apparently normal (46,Xu At 91~ years he had a social age (Vineland scale) of 25/12, and a mental age (Cattell scale) of 2 years.
Patient 5 ( E E 200362; C W C No. 5-695, U W - H o s p . No. 652325) Parents are of Puerto-Rican ancestry and apparently not consanguineous; 8 siblings are normal, but one brother requires special education. At the child's birth father and mother were 32 and 27 years old respectively; both are healthy. [Father is one of 5 surviving sibs out of a total 17 children. Details of the fate of the 12 sibs are not known; otherwise the family history is unremarkable. During the last trimester the mother had upper respiratory infections and fever requiring symptomatic medication. Gestation lasted 9 months, labor 45 rain; delivery was normal. Birth weight was 3100 g. The infant had no neonatal problems, but a striking skull deformity with prominent forehead and small occiput was noted and the diagnosis of hydrocephalus was made at 3 days. Development was slow, and the boy was admitted to CWC at 2 years. He has made fairly good progress and is now able to attend a special class for the trainable retarded. At 12 89 years he was a strong, well nourished, cooperative boy with a length of 132 cm (< 3rd ~oile), dolichocephalic skull with OFC of 56 cm (> 50th < 90th %ile), small occipital region and bulging forehead, wavy black hair, hypertelorism (ICD 38 ram, OCD 98 ram), broad and prominent bridge of nose, slight antimongoloid slant of palpebral fissures with upper epicanthic folds, strabismus, posteriorly angulated auricles of normal shape, relatively short maxilla and relatively large mouth, normal palate without submucous cleft, maloc-
24
G. Neuh~user et al.
(a)
(b) Fig. 8a and b. P a t i e n t 5 a t 1 0 ~ years
elusion, micrognathia and hypoplastic tip of nose (Fig. 8). H e a r t and lungs were normal, liver a n d spleen were n o t enlarged. Several depigmented spots were seen on the left side of a b d o m e n ; genitalia were normal. He h a d normal arms, hands and fingers, proximal transverse palmar creases and clinodaetyly of t h e right fifth finger, normal feet and a right convex scoliosis. Dermatoglyphics are listed in Table 1. Muscle tone was normal as were the deep tendon reflexes. He is able to walk independently a n d has clumsy gross and fine body movements. He follows instructions a n d cares for himself. A t 2 years roentgenograms showed an open anterior fontanel, ocular hypertelorism, a very small posterior fossa a n d occipital area; at 11 years closed fontanels, narrowing of suture lines, a very small occipital region and a n unusually shaped sella turciea. Eye examination showed hypertelorism, bilateral sixth nerve palsy, slight refractive error and moderate optic a t r o p h y OU, nystagmus on upward gaze a n d marked visual loss in b o t h eyes. On psychological examination a t 8 years a mental age of 23 m o n t h s (Cattell scale) was determined. Presently he uses some words, is ambulatory, cares for himself, relates well to peers and familiar adults b u t shows m a r k e d impairment of visuo-motor coordination.
Patient 6 ( W V 0 8 0 7 6 8 ; U W - H o s p . N o . 701770) Parents are of Caucasian ancestry; at the child's b i r t h mother and father were 26 and 29 years old respectively. Parents have no close Spanish ancestors a n d are not consanguineous. A n older sister is healthy. Bleeding occurred during the 3rd and 4 t h months of pregnancy. After premature rupture of membranes b i r t h occurred at t e r m following several a t t e m p t s a t induction. Labor lasted "for a b o u t 5 d a y s " ; breech delivery was difficult because the child h a d a n arm around the neck; the left arm was broken a n d paralyzed; b i r t h weight was 3000 g. Respiratory distress was n o t e d immediately after birth. R e t a r d e d motor a n d mental development was apparent a t 12 m o n t h s ; the boy sat without support a t 2 years, walked at 21/2 years, spoke words a t 21/2--3 years a n d was toilet trained a t 4 years. I-Ie attends a preschool class for handicapped children. At 3i/2 years spells were n o t e d which recurred four times in intervals of 6 months: He would fall, sleep, complain of abdominal pain, and vomit. B e is easily startled by loud noises a n d sounds. A t 6 years he was a quiet, alert, cooperative, well nourished boy with a length of 106 cm (< 3rd~oile), weight of 16 kg (< 3rd~ a seaphoeephalic, narrow head with a n OFC of 55 cm (> 98th ~/oile), bulging forehead, a flat, narrow occiput and a ridge over the posterior
Craniofaeial Dyssynostosis
(a)
25
(b) Fig. 9a and b. Patient 7 at 4 days
part of the sagittal suture, broad bridge of nose, antimongoloid slant of palpebral fissures, posteriorly angulated aurieles and a high-pitched voice, paralysis and hypotrophy of the left arm and the left anterior chest wall (hypoplastic left peetoralis muscle and left scapula), hypesthesia over the left arm, and a clumsy, slightly widely based gait; otherwise the neurological examination was normal. Roentgenograras showed no intraeranial calcifications, a normal sella tureica, synostosis of the posterior part of the sagittal suture on tangential views, a normal ehest, delayed bone age (3--3 89 years) and osteoporosis and flexion deformity at the left elbow. CBC and urinalysis were normal. An E E G showed focal epilepgogenie disturbance of cerebral function in the right Rolandie region. The EMG demonstrated total left braehial plexus palsy: The left upper and middle truneus seemed to be more affected than the lower. A hearing test was normal. Eye examination showed intermittent right hypertropia and mixed astigmatism OU. I-Ie functioned at a 21/2--3 year level in fine motor, adaptive and gross motor abilities, and at a 3 ~ - - 4 year level in personal-social and language areas. Expressive language skills (articulation and conception) were impaired; he used stereotyped phrases. But the language skills were better than non-verbal performance and visual-perceptual abilities and problem solving (visual memory, figure copying, form perception) ; he was unable to solve verbal or performance tasks of the WISC. Visual-perceptual deficits were also shown in the Merry and Buktenieka test of visual motor integration and in the Goodenough Draw-a-man test. The impression was that of mild mental retardation.
Patient 7 ( K M c C 031075) was born after a normal, 41 week gestation, spontaneous onset of labor and a normal, spontaneous vertex, vaginal delivery, with weight, length, and OFC of 2250 g, 48.5 and 35.5 em, respectively. ?r took birth control pills for 3 weeks after conception and had nausea and vomiting for the first 3 months of pregnancy. Patient's brother (240670) is normal but was also small at term (2177 g and 43 era). A second pregnancy ended (131074) in a spontaneous abortion at 12 weeks. Mother (100850) and father (241247) are normal, not consanguineous, deny Spanish ancestry and have an unremarkable family history except for one of father's sisters who has a cleft palate and borderline intelligence. At 4 days the infant began to regurgitate feedings, was unusually jittery and became hyponatremic (serum Na 122 mE@l). She was found to be normal except for eraniofaeial dyssynostosis with apparent hypertelorism, broad, prominent and bulging forehead, dolichocephaly with relatively narrow and prominent oceiput (Fig. 9a and b), eraniosynostosis of posterior sagittal and lambdoid sutures (confirmed roentgenologieally), large and full anterior fontanel, slight bulging above each ear, and Babinsky reflexes, DeLange's sign, jitteriness,
26
G. Neuhguser et al.
irritability, increased muscle tone, hyperreflexia, and regurgitation. Feeding and neurological status improved and by 3 weeks she had gained 155 g and her OFC had increased 2 cm. Computerized axial tomographic brain scans at 7 days and 21/2 months showed grossly normal brain structure and ventricular size. Craniosynosteetomy of sagittal and lambdoid sutures was performed at 21/2 months when she had an OFC of 41 cm (> 98th ~ Her course since then has been uneventful, and her growth, neurological status and psychomotor development are normal. Parents have been counseled a 25O/orecurrence risk.
Discussion
Etiologic Considerations The 7 patients may represent Hippokratic syndromy, i.e., an etiologically heterogeneous but pathogenetieally similar group of -> 2 disorders. However, Spanish ancestry in 4 of 7 patients, and familial (i.e. sib) occurrence in 1 of these 4 families suggests that at least the Spanish ancestry patients have a causally identical condition, and that sporadic occurrence in two of them actually represents chance isolated occurrence of an autosomal recessive trait. We think that the condition of the 3 non-Spanish ancestry patients is so similar to that of the other 4, that we would feel remiss in not counseling their parents a 25% recurrence risk. I f the hypothesis of a high gene frequency in people of Spanish descent is correct, then a cursory search through neurosurgery flies and institutions for the retarded should yield a large number of similar cases in Spanish speaking countries in this hemisphere but perhaps also in Spain, unless the gene emigrated from Spain as apparently happened with Brazilian acheiropodia which is absent from Portugal. Holland and Ireland, the ancestral countries of 2 of our other patients, have also had more or less close contact with Spain, which is less true of Scotland, the ancestral country of patient 7. I f the presence of the gene in these latter 3 populations does not reflect gene flow from Spain, then it must be a very common gene indeed, a supposition supported by the fact that the parents of none of our patients were consanguineous.
Phenotypic Considerations The combination of craniosynostosis with cranio-facial dysostosis-like manifestations have caused us to coin the term eranio/acial dyssynostosis (CFDS) for the condition in our patients. W h a t pathogenetic/prognostic inferences concerning the nature of this condition does phenotype analysis permit ? All but one patient had actual ridging of the posterior sagittal and/or lambdoid sutures, and in patient 5 the former presence of such ridging as indication of premature suture closure is inferred from the characteristic skull shape. I n patient 2 the right coronal suture was also involved. Depending on the time of onset and the site of the closure(s), and the relative rates of lambdoid and sagittal suture closure one might expect variations of skull shape ranging from dolichocephaly with occipital prominence to re]ative brachycephaly with a rather flat and hypoplastic oceiput, in either case with a high, broad/bulging forehead with hypertelorism. Variations of both of these types are present in our patient group. Hypoplasia of maxilla, with high and/or narrowly arched palate, relative nasal obstruction and mouth breathing in almost every case suggest an additional craniofacia] dysostosis-like process, a surmise supported by roentgenological evi-
Craniofaeial Dyssynostosis
27
deuce of short base of skull and relatively steep slope of base of anterior fossa in several cases. We suppose t h a t the MR, seizures, squint, spasticity and/or hypotonia in several of our patients represents secondary brain damage due to increased intracranial pressure associated in several cases by roentgenological or brain scan evidence of increased ventricular size. Early ( ? prenatal) onset of such increased pressure and rapid, untreated progression of suture closure probably resulted in the permanent severe impairment of CNS function in cases 3 - - 6 and prompted us to urge craniosynostotomy in patients 1, 2 and 7. So far, p~tients 1 and 7 show normal CNS function 3 years and 2 months after surgery respectively; however, patient 2, who m a y have suffered prenatM brain dan?age, is recovering slowly and has not reached a normal rate of psychomotor development 8 months after the operation. In all who have not had craniosynostectomy the increased pressure/ hydrocephaly seems to arrest itself spontaneously (cases 4--6); in patient 3 a Pudenz valve was inserted and required revision at 5 89 years due to malfunction resulting in acutely increased pressure. In patients 3--7 the OFC has stayed over the 50th percentile, and in 4 of them it is still around the 98th percentile. Is CFDS a multiple congenital anomaly (MCA) or MCA/MR syndrome ? At this time we are inclined to the view (which m a y change) that it is not, and t h a t CFDS represents primarily the action of the homozygous state of the CFDS mutation on the posterior sagittal and lambdoid sutures and basal synchondroses with secondary brain damage. Presently we cannot answer the quest/on wI~et1~er the brain ma/formLttion (i.e. agenesis of the corpus eallosum-presumed interventrieular Iipoma) of patient 3 is an independent primary developmental effect of the CFDS trait on the CNS or a secondary effect. The only other anomaly t h a t has been noted in this condition is the congenital heart disease in patient 2 (PDA and ? small VSD), anomalies of incomplete differentiation. Thus only 2 of the 7 patients have had one additional anomaly, different in the 2 cases, and to our mind insufficient evidence to assert t h a t these patients have a true MCA syndrome. We interpret minor anomalies, such as posterior augulation of auricles and antimongoloid slant of palpebral fissures as secondary to the primary major defect, and other manifestations such as anteversion of nostrils, inverted V shape of the upper lip and mierognathia as secondary symptomatic manifestations of mouth breathing and hypotonia, r t is of interest t h a t all but the youngest patient in this group had shortness of stature ( < 3rd ~oile for age), a common non-specific manifestation in autosomal recessive disorders. Premature closure of cranial sutures most commonly affects the sagittal and/or the coronal suture causing dolichocephaly (scaphocephaly) or (braehy)turricephaly respectively. Synostosis of lambdoid sutures with or without synostosis of the posterior part of the sagittal suture seems to be very rare. Bolk (eit. Burkhardt, 1970) in a study of 1820 skulls found synostosis of lambdoid sutures in only 0.25~o compared to synostosis of the sagittal suture in 3,8~ and of the coronal sutures in 0.6 %. Shillito and Matson (1968) reviewed 530 patients (mostly children) with craniosynostosis, and found 2.2% with synostosis of one (7 cases) or both (5 cases)/ambdoid sutures; Anderson and Gaiter (1965) found 1.5% (3 e~ses) of sagittal and (uni- or bilateral) lambdoid suture synostosis in their 204: patients.
28
G. Neuh~user et aL
l n g r a h a m et al. (1948) reported among 50 cases 3 patients with synostosis of lambdoid sutures ; all of them had been retarded before the operation, and craniosynostectomy did not change the developmental delay; however, it is not evident from the reports if the craniosynostosis in these patients was part of an MCA/MR syndrome. The type of craniosynostosis seen in our patients can be distinguished from the scaphoeephaly of complete sagittal synostosis because of the structure of the occiput which in sagittal synostosis is far more protruding; further, the occipital bone is usually normal, but it was hypoplastic in most of our patients. I t also differs from the turricephaly of coronal synostosis because of the bulging forehead ; in turricephaly the forehead tends to be flat and frequently receding. Conclusions We report prenatal onset of premature closure of the posterior sagittal and lambdoid sutures, the basal synchondroses and in 1 case of coronal suture(s) with head enlargement, mental retardation and other signs of brain damage, shortness of stature in 7 patients, and CHD and agenesis of the corpus callosum with interventricular lipoma in 1 patient each, as an autosomal recessive trait with a high gene frequency in people of Spanish descent. Most patients show signs of increased intracranial pressure soon after birth, and we think t h a t craniosynostotomy is indicated in all cases in early infancy to prevent mental retardation and other signs of brain damage. References Anderson, F. M., Geiger, L. : Craniosynostosis: A survey of 204 cases. J. Neurosurg. 22, 229-240 (1965) Burkhardt, L. : Pathologische Anatomic des Sch~del. In: Handbuch der speziellen Pathologischen Anatomic und Histologie, Vol. IX/7. Berlin-Heidelberg-New York: Springer 1974 Ingraham, F. D., Alexander, E., Matson, D. D. : Clinical studies in craniosynostosis: Analysis of 50 cases and description of a method of surgical treatment. Surgery 24, 518--541 (1948) Shillito, J., Matson, D. D. : Craniosynostosis: A review of 519 surgical patients. Pediatrics 41, 829--853 (1968) John M. Opitz, M.D. University of Wisconsin - - Madison 109 Genetics Madison, Wise. 53706, USA