Lightwood in 1952 described mild infantile hypercalcemia with failure to thrive, anorexia, vomiting, constipation, polyuria, thirst, recurring dehydration, and muscular hypotonia.1 The syndrome of severe idiopathic hypercalcemia was described by Fanconi in 1952 and consists of growth and mental retardation, irritability, anorexia, vomiting, muscular hypotonia, elfin facies, and generalized osteosclerosis.1 Many of these patients have renal dysfunction, systemic hypertension, and cardiac murmurs. These syndromes may be etiologically related to vitamin D administration and metabolism.3
Supravalvular aortic stenosis is a localized or diffuse narrowing of the ascending aorta just above the level of the coronary arteries at the superior margin of the sinuses of Valsalva. Williams, in 1961, reported four cases of supravalvular aortic stenosis in patients with subnormal intelligence and elfin facies.4
In 1963, two independent groups noted the association between supravalvular aortic stenosis, infantile hypercalcemia, and the elfin facies.5'* The elfin facial features include a high, prominent forehead, hypertelorism, epicanthal folds, underdeveloped bridge of the nose and mandible, and an overhanging upper lip. The upper lip is quite full and may not have a cupid bow. No previous report in the eye literature has been found.
This report describes the ocular manifestations of the supravalvular aortic stenosis syndrome in seven children. Previously reported ocular manifestations include strabismus, corneal and/or lenticular opacities resembling deposition of calcium crystals, prominent epicanthal folds, hypertelorism, and a broad flat nasal base.6-8
Case J - S.G.H. (UAMC No. i8-28-31): This child was born to a gravida 2 para 2 woman on November 16, 1960, after an uncomplicated term pregnancy. The birth weight was six pounds, five ounces. At four months of age, a heart murmur was noted and the infant was referred to the UAMC for evaluation.
Physical findings were those of a small white girl who was in the three percentile in both height and weight. Blood pressure in the right arm was 1 30/70 mm/Hg, and in the left arm, 120/60 mm/Hg. The facies showed prominent epicanthal folds, a flattened nasal bridge, enlarged upper lip, and a high arched palate (Fig. 1). The ocular examination revealed a 12 prism diopter alternating esotropia, and otherwise the findings showed a grade III systolic murmur, heard best at the third left intercostal space, and transmitted through the precordium. The pulmonic second sound was accentuated and palpable. At six years of age, a Stanford- Bin et Intelligence Test showed a mental age of three years, three months, and an Intelligence Quotient of 51.
Fig. I: Case I - Note the flat nasal bridge, enlarged upper lip. small mandible and esotropia.
Fig. 2: Case 2 - The elfin facies are accentuated by the small head and small facial features. Exotropia is present.
The chest film revealed mild cardiomegaly and prominence of the pulmonary outflow trace. The EKG revealed right ventricular hypertrophy. At three years of age, a cardiac catheterization revealed multiple distal pulmonic stenosis and supravalvular aortic stenosis. Serum calcium was not done. This child has not had surgery and has continued to be followed at yearly intervals.
Case 2 - R.K.C. (UAMC No. 21-30-70): This patient was born April 22, 1954, after an uncomplicated term pregnancy with a birth weight of eight pounds, three ounces. His health was good except for frequent colds and slow mental development. His heart murmur was found at seven years of age.
He was in the three percentile in both height and weight. The facies appeared elfin, in which there was a small face, spread- angled teeth, large low-set ears, a small head, hypertelorism, flattened nasal bridge, a thick upper lip and a high arched palate (Fig, 2). No abnormalities were noted of the ocular globe, but a 25 prism diopter alternating exotropia was present. The right arm blood pressure was 125/70 mm/Hg and the left arm 114/64 mm/Hg. A grade IV harsh systolic murmur was heard best in the second right and left intercostal spaces and was transmitted into the carotid vessels. There was left cryptorchidism.
At six years of age, he had a mental age of three years and an Intelligence Quotient compatible with an educable retarded level. The chest film was normal, EKG showed a left ventricular hypertrophy and cardiac catheterization revealed a mild supravalvular aortic stenosis. No serum calcium was done, and the chromosome analysis was normal. This child has not had surgery and has continued to be followed at yearly intervals.
Case 3 ~ K.E.G. (UAMC No. 30-02-01): This child had a birth weight of six pounds, ten ounces. The mother had a kidney infection during her first trimester and was treated with Panalba (tetracycline and novobicin). The patient had numerous admissions for nausea, vomiting and diarrhea. She had a hiatal hernia for which she had surgery at both six months and two and one half years of age. The heart murmur was first heard at birth after noting cyanosis.
She was in the ten percentile for both height and weight. The facies consisted of low-set ears, hypertelorism, epicanthal folds, widely spaced maloccluded teeth, a high arched palate, thick smooth upper lip, and mild micrognanthia (Fig. 3). No abnormalities of the globe and extraocular muscles were noted. Cardiac findings revealed a Grade II to III systolic murmur which was most pronounced over the left and right sternal borders and second and third intercostal spaces.
Fig. 3: Case 3 - The smooth upper Up accentuates the micrognathia.
Fig. 4: Case 4 - Epican thai folds are less prominent in this i3-year-old. The esotropia, epican thai folds, and broad nasal base should arouse the ophthalmologist's suspicion of supravalvular aortic stenosis.
The patient has a long neck and sloping shoulders, a dicubitus valgus and curved and shortened fifth digits with hyperextensible fingers. She is an educable trainable mentally retarded child.
Chest film and EKG showed no abnormalities. Cardiac catheterization and serum calcium were not done. She is asymptomatic and is being followed in the cardiac clinic yearly.
Case 4 - S.N. T. (UAMC No. 33-30-98): This child was born October 27, 1968, after a six-month pregnancy with a birth weight of five pounds, fourteen ounces. The pregnancy was marred only by a twoweeks' illness of vomiting, malaise, and uterine cramping at four months of pregnancy. The mother gained 32 pounds of weight during her pregnancy and had considerable edema. Since birth, the child had had pneumonia three times and her motor development was slow.
On physical examination, the child fell below the three percentile for both height and weight. The facies were elfin, with hypertelorism, epicanthal folds, a broad nasal base, and high arched palate (Fig. 4). The mouth had a suggestion of a cupid bow. On ocular examination, the child demonstrated a 40 prism diopters of esotropia which was equal in all fields of gaze and at distance and near. The child demonstrated a 3 diopter hyperopic error and the remainder of the ocular examination was within normal limits. The child had a trial of phospholine iodide 0.125% daily,' which did not alter her strabismus. On November 12, 1970, she had a four millimeter medial rectus recession and fused postoperatively. Cardiovascular examination revealed a Grade II systolic murmur heard best in left second and third intercostal space.
The chest film showed no abnormalities; the EKG demonstrated left ventricular hypertrophy and cardiac catheterization was not done. The serum calcium was 9.6 mgm%.
Case 5 - D.D. (UAMC No. 17-49-72): This child was born September 10, 1951, and had a birth weight of eight pounds. The mother remained anemic throughout pregnancy. The patient suffered frequent upper respiratory infections and his exercise tolerance was diminished. A heart murmur was first heard at three months of age. His height was in the thirty-five percentile for his age and his weight was above the seventy-five percentile for his age.
No abnormalities were noted of the globe or extraocular muscles. The elfin facies demonstrated large ears, a thick upper lip, hypertelorism, and epicanthal folds. He had a large mouth with buck teeth, an enlarged tongue, and a small mandible (Fig. 5). A Grade III systolic murmur was heard best at the second right interspace and radiated to the carotids. The fingers demonstrated hyperextensibility. An Intelligence Quotient of 47 and a mental age of 7 years at 10 years of age was found. He had a very pleasant disposition.
The cardiac catheterization revealed a supravalvular aortic stenosis (Fig. 6). The EKG demonstrated left ventricular hypertrophy. The chest film revealed no abnormalities; the serum calcium was not done. Findings from chromosome studies were normal. In August, I960, he underwent surgical repair of the supravalvular aortic stenosis and has done quite well since that time.
Case 6 - L.M.B. (UAMC No. 23-36-75): This patient was born December 14, 1954, after an uncomplicated term pregnancy and a birth weight of four pounds. He had frequent upper respiratory infections and at 6 years of age had a tonsillectomy. At 10 years of age a heart murmur was detected on routine physical examination.
The child was cooperative and friendly. He had large protuberant ears, a small receding mandible, protuberant crowded teeth with the two front incisors broken, elfin facies, and a microcephaly. No abnormalities were noted of the globe and extraocular muscles. Chest examination revealed a Grade III systolic murmur, heard best at the second right intercostal space and radiating to the carotids. The blood pressure in the right arm was 1 16/80 mm/Hg, and in the left arm was 106/80 mm/Hg. At 10 years of age, he had a mental age of 6 years and a mental retardation at an educable level. He was below the three percentile in both height and weight. (Fig. 7)
Findings from the chest film were normal and the EKG had nonspecific ST-T changes. Cardiac catheterization was not done. The serum calcium was 10.1%. X-rays of the heart revealed slight evidence of left ventricular preponderance. Chromosome studies revealed a normal karyotype. The child is followed yearly in the cardiac clinic.
Case 7 - T.H. (ÜAMC No. 21-70-22): This child was the product of a term pregnancy on April 20, 1958, with a birth weight of six and a half pounds. The child did not breathe spontaneously at birth and required artificial respiration and resuscitation. The cardiac murmur was first heard at three years of age. At three years of age, he had aspiration pneumoniae secondary to ingestion of floor polish. He had frequent upper respiratory infections.
Physical findings included a peculiar facies of epicanthal folds, hypertelorism, low-set ears, flat nasal bridge, and pouting lips (Fig. 8). The mouth showed widely spaced teeth and a high arched palate. No abnormalities were noted of the globes, but a marked right esotropia with amblyopia was present. The chest revealed a Grade III systolic murmur heard best at the second left intercostal space and radiated to the neck. The child was hyperactive and very friendly. At six years of age, he had a mental age of a three-year-old and an Intelligence Quotient of 75.
Fig. 5: Case 5 - Almost all these children demonstrate a pleasant personality.
Fig. 6: Case 5 - Lateral chest x-ray of cardiac catheterization with retrograde aortography. Catheter is in left ventricle. Note constriction of aorta at site of supravalvular aortic stenosis.
Fig. 7: Case 6 - Child's supravalvular aortic stenosis required surgery.
Fig. 8: Case 7 - Esotropia, epicanthal folds, and broad nasal base are prominent in this case. The upper lid demonstrates the cupid bow that may be seen.
Chest films revealed a right ventricular prominence with decreased pulmonary vascularity. The EKG was normal. The cardiac catheterization in April, 1965, revealed peripheral stenosis of the left pulmonary artery and mild supravalvular aortic stenosis. The serum calcium was 10.3 mgm%. His cardiac difficulty was not severe enough to warrant surgery and he is to be followed yearly on an outpatient basis. He has not yet had ocular surgery.
All but one of the children presented as a problem in cardiac diagnosis. Frequently, elevated serum calcium is not present at an older age when the syndrome of elfin facies and supravalvular aortic stenosis is recognized. No serum calciums were elevated in this series.
The cardiac lesion of supravalvular aortic stenosis can occur as an uncomplicated entity,9 or associated with mental retardation, elfin facies, defective dentition, and ocular findings.4 The past history may suggest the syndrome of infantile hypercalcemia.* Early clinical detection of this syndrome is infrequent which implies that the metabolic disturbance is generally not severe or that the facial features are not completely developed, thus suggesting the diagnosis.
The vascular lesions have been produced by experimental hypercalcemia in both the fetus and young and mature animals.,ß,l, A tendency to low birth weight has been noted.4'7 Vitamin D intoxication in the pregnant woman might possibly account for the manifestation of the supravalvular aortic stenotic syndrome in human infants. It has been postulated but not proven by other studies that an excessive intake of vitamin D in mothers or infants after birth has caused the metabolic derangement.8 It is very difficult to trace all causes of possible exogenous sources, such as enriched food materials, self- medication, and vitamin D dietary supplementation. An alternate possibility is that subtoxic doses of vitamin D, either in the mother or infant with a metabolic error, would be the cause of an infantile hypercalcemia.3 ,,z This has not been supported by any evidence thus far. It appears unlikely then that impaired excretion or inactivation of vitamin D as the basis of the metabolic error is responsible for the abnormalities in these children.'
A satisfactory alternative to the vitamin D - hypercalcemia hypothesis is not currently available. The action of a single mutant gene has been proposed in familial supravalvular aortic stenosis. Chromosome aberrations, however, have not been found.13 No chromosome abnormalities were demonstrated in these patients.
Patients with supravalvular aortic stenosis and mental retardation have a characteristic facial appearance. The features are a high prominent forehead, hypertelorism, epicanthal folds, underdeveloped bridge of the nose and mandible, overhanging upper lip, strabismus, and anomalous dental findings. Hypertelorism, epicanthal folds, and underdeveloped bridge of the nose were present in all seven children. Three children had esotropia. No corneal or lenticular calcium deposits were present in this series. Their characteristic appearance should lead to prompt suspicion of the cardiovascular anomaly. As an ophthalmologist, one should consider this entity when the characteristic facies is noted in a mentally retarded child.
The cardiac physical findings demonstrate a Grade II to III systolic ejection murmur which is heard best in the second to third right intercostal spaces and is transmitted to the neck. The aortic closure sound is frequently accentuated. Frequently stenosis of the peripheral pulmonary arteries is found in association with the aortic supravalvular obstruction as was found in our Case 1 and 7. The blood pressure is frequently higher in the right arm than in the left arm.
The EKG generally reveals left ventricular hypertrophy when the obstruction is severe and is similar to that seen in other forms of obstruction to left ventricular outflow. With marked peripheral pulmonary artery stenosis coexisting, the EKG may also show right ventricular hypertrophy. A definitive diagnosis of supravalvular aortic stenosis is established by retrograde aortic catheterization, demonstrating a pressure gradient just above the aortic valve, and a constriction in the region by aortography. If supravalvular aortic stenosis is diagnosed in infancy, prompt treatment of the metabolic disorder may retard the progression of the cardiovascular lesion. Surgical treatment of supravalvular aortic stenosis usually consists of an insertion of a plastic prosthesis in the supravalvular aorta. Many times the aorta is also hypoplastic above this area and extensive resection of the aorta or a prosthesis is needed to widen the aorta. In view of the technical difficulties encountered many times, the indications for surgery are stricter than for other forms of congenital cardiac lesions. Operation is deferred in an asymptomatic patient with milder obstruction. Only one patient in this series had surgery.
Ocular manifestations of seven cases of supravalvular aortic stenosis and assumed infantile hypercalcemia are described. Ocular manifestations consist of prominent epicanthal folds, hypertelorism, strabismus, usually esotropia, and corneal and/or lenticular opacities. The ocular findings with characteristic facies which consist of a high prominent forehead, underdeveloped bridge of the nose and mandible, and overhanging upper lip should suggest this syndrome to the ophthalmologist.
Acknowledgment: Dr. F. Henry, Jr. of Little Rock furnished the data of Case 6 and Dr. S. R. McEwen of Fort Smith in Case 1 .
300 East Roosevelt Road
Little Rock, Arkansas 72205
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