Optic Nerve Hypoplasia With Hypopituitarism Septo-Optic Dysplasia
With
Hypopituitarism
Hawa Patel, MB, MRCP(E); Wah Jun Tze, MD, FRCP(C); John U. Crichton, MB, FRCP(E); Andrew Q. McCormick, MD, FRCP(C); Geoffrey C. Robinson, MD, FRCP(C); Clarissa L. Dolman, MD, FRCP(C)
Four children had optic nerve hypoplasia with hypopituitarism, and their clinical picture varied with age. The newborn had apnea, hypotonia, seizures, hypoglycemia, and prolonged jaundice. The young infant had defective vision, behavioral delay, hypotonia, and seizures. Except for a mildly receding lower jaw and a high-arched palate, the appearance of the patients was not unusual. The fasting blood glucose level was mildly depressed. In two cases the liver was palpable and results of liver function tests were abnormal. The older child, who was blind and mentally retarded, had growth failure. The extent of the pituitary hormone deficiencies was variable, including diabetes insipidus. The septum pellucidum was not invariably absent. Clinical and pathological findings indicate that the brain lesion might be more diffuse than hitherto recognized. Early recognition of this syndrome and timely intervention might diminish serious
sequels. 1941 Reeves1
reported a case of anomaly and agenesis of the septum pellucidum. De Morsier- demonstrated that optic nerve hypoplasia was frequently associated with absence of the septum pelluci¬ dum; he suggested the name "septooptic dysplasia." The review of age¬ nesis of the septum pellucidum by St. John and Reeves' probably contains examples of this syndrome. Recently,
In optic
nerve
Received for publication Nov 9, 1973; accepted 1974. From the departments of paediatrics (Drs. Patel, Tze, Crichton, McCormick, and Robinson), ophthalmology (Dr. McCormick), and pathology (Dr. Dolman), Faculty of Medicine, University of British Columbia, Vancouver General Hospital, and Children's Hospital, Vancouver. Reprint requests to Department of Paediatrics, University of British Columbia, 715 W 12th Ave, Vancouver, British Columbia, Canada (Dr.
July 16,
Patel).
Hoyt and his colleagues4
and
Kaplan
and others" observed that children with optic nerve hypoplasia may have growth retardation associated with
hypopituitarism; logram in four
a
pneumoencepha-
of the nine chil¬ dren showed absent septum pelluci¬ dum.4 5 Brook and others" and Harris and Haas7 have verified four addi¬ tional cases. Billson and Hopkins8 in¬ dicated that absence of the septum pellucidum cannot regularly be pre¬ dicted in such cases; one of the in¬ fants they examined had an intact septum pellucidum. They thus sug¬ gested that the spectrum of associ¬ ated abnormalities in the presence of septo-optic dysplasia and disturbed hypothalamic-pituitary function is variable. During the past four years, we have studied four children with optic nerve hypoplasia; three of them had hypopituitarism. Symptoms in three of our patients appeared in early in¬ fancy, and we wish to verify the clini¬ cal features peculiar to this age group. The recognition of the constel¬ lation of findings in this potentially dangerous syndrome is of clinical im¬
portance. REPORT OF CASES Case 1.—A boy young, unrelated,
was
the first child of
healthy parents. The family history was noncontributory. The pregnancy was complicated by edema, ab¬ dominal pain, and excessive weight gain. He was born normally at term after a 9-%hour labor. The birth weight was 2.98 kg (6.6 lb). He was apneic but was easily re¬ suscitated. Later, he developed apneic spells and seizures. He became icteric on
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the second day and the serum bilirubin level reached a maximum of 20.5 mg/100 ml on the third day. The mother and in¬ fant's blood groups were A Rh-positive, and the direct and indirect Coombs tests were negative. He received phototherapy and an exchange transfusion, along with ampicillin sodium and kanamycin sulfate. The blood glucose level on the third day, measured while he was receiving glucose intravenously, was 27 mg/100 ml. Funduscopic examination showed right optic nerve
hypoplasia.
When
seen
at the age of 3-Vè
months, his
weight, length, and head circumference were 5.6 kg (12.3 lb), 64.5 cm (25.4 in), and 40.8 cm (16.1 in), respectively. The systolic blood pressure was 80 mm Hg. He was alert and responded normally to sounds. The unusual findings were a mildly reced¬ ing lower jaw, high-arched palate, hypo¬ tonia, and mild behavioral delay. He had wandering eye movements, inability to fix¬ ate with either eye, and right optic nerve hypoplasia. The pupillary light reaction was present directly but not consensually on the left, and consensually but not directly on the right. Table 1 shows the clinical details. The hemoglobin level; total and differ¬ ential leukocyte counts; serum bilirubin, electrolyte, and calcium levels; results of liver function tests (serum transaminase, lactic dehydrogenase [LDH], and alkaline phosphatase levels); serum protein electrophoretic pattern; urine amino acid chromatogram; dermatoglyphics; results of chromosomal studies; cerebrospinal fluid (CSF); skull roentgenograms; and bone age were normal. Examination of the urine showed no cytomegalic inclusion bodies, and the serum complement fixation test (CFT) for toxoplasmosis was negative. The electroencephalogram showed only shift¬ ing asymmetry. The pneumoencephalogram demonstrated mild enlargement of the ventricular system, absence of the sep-
slices of brain, demonstrating abnormal development of midline septum pellucidum is thin and the corpus callosum is deficient.
Fig 1.—Coronal
tures. The
struc¬
Fig 2.—Section of supraoptic nucleus, demonstrating abnormal neurones that are deficient in number, small in size, and lack the abundant cytoplasm normally seen in these cells (Luxol fast blue and hematoxylin-eosin, original magnification 254).
pellucidum, and large basal cisterns. The left cerebral hemisphere convolutions were small and the sulci large, while over the surface of the right hemisphere no gas was visualized. The fasting blood glucose level was 38 mg/100 ml. Table 2 shows the results of the endocrine studies; for procedures, see "Methods of Hormone Studies." Case 2.-A girl was the first child of un¬ related, healthy, young parents. There was a family history of diabetes mellitus, menturn
tal retardation, and seizures. The preg¬ nancy, lasting 36 weeks, was complicated by edema and a urinary infection that was treated with sulfonamides. After a 2-14hour labor, the infant was born by breech presentation. Her birth weight was 2.25 kg (5.0 lb). She was apneic but was easily re¬ suscitated. She received ampicillin, kanamycin, and sodium bicarbonate and glu¬ cose intravenously. On the second day she was icteric, and the serum bilirubin level reached a maximum of 15 mg/100 ml on
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the third day. The mother and infant's blood groups were O Rh-negative and O Rh-positive, respectively. The direct Coombs test was negative. When examined at the age of 3 months, the weight, length, and head circum¬ ference were 5.9 kg (13.0 lb), 57 cm (22.4 in), and 42.2 cm (16.6 in), respectively. The systolic blood pressure was 90 mm Hg. She was icteric and responded poorly to envi¬ ronmental stimuli, including sounds. She had a mildly receding lower jaw, higharched palate, prominent epicanthic folds, and a firm, nontender liver that was pal¬ pable 1 cm below the costal margin. Other findings included hypotonia, bilateral fifth (motor and sensory) and right seventh cra¬ nial nerve palsies, weakness and ankle clonus of the left limbs, generalized hyper¬ reflexia, and behavior appropriate for a newborn infant. She followed objects with the right eye. The pupillary light reaction was present consensually but not directly on the left, and directly but not consen¬ sually on the right. The left optic nerve head was hypoplastic. Table 1 shows the clinical details. The hemoglobin level, total and differ¬ ential leukocyte counts, serum electrolyte and calcium levels, serum protein electrophoretic pattern, urine amino acid chromatogram, dermatoglyphics, results of chromosomal studies, and skull roentgen¬ ograms were normal. The bone age was at a three-week level. The serum bilirubin level was 5 mg/100 ml, and the serum transaminase levels were elevated (serum glutamic oxaloacetic transaminase [SGOT] level, 97 units, and serum glutamic pyruvic transaminase [SGPT] level, 65 units). The LDH level was also elevated, at 380 units. Examination of the urine showed no cytomegalic inclusion bodies, and the serum CFT for toxoplasmosis and the hemagglutination inhbition test for rubella were negative. The fasting blood glucose level on two occasions was 39 and 28 mg/100 ml. The serum thyroxine (T4) level was normal, and the fasting insulin level in the serum was normal at 5/iU/ml. The 24-hour urine catecholamine execretion was normal at 4fig. The urine specific gravity was 1.003 on one occasion and 1.010 on another. Results of the oral glucose tolerance test were nor¬ mal, with blood glucose levels of 57, 84, and 50 mg per 100 ml at zero, 90, and 180 min¬ utes, respectively, after the glucose load. Results of the leucine sensitivity test were satisfactory, the blood glucose levels being 80,49, and 39 mg per 100 ml at zero, 45, and 60 minutes, respectively, after the load. Results of the glucagon test were normal with adequate mobilization of glycogen stores, the blood glucose levels being 40 and 75 mg/100 ml at zero and 30 minutes,
pupillary light response directly and con¬ sensually in both eyes, and bilateral optic nerve hypoplasia. Table 1 shows the clini¬
Table 1.—Clinical Details of Four Patients Patient & Sex
Age Groups Newborn period
Clinical Findings Birth weight, kg (Ib)
1, M 2.98
(6.6)
2.25
3.95
(5.0)
(8.7)
+
Apnea
3-3 y2
mo
27
(13.0)
(9.9)
(in)
64.5
57
58
(25.4)
(22.4)
(22.8)
circumference,
40.8
42.2
41.0
(16.1)
(16.6)
(16.1)
+ + +
Nil
Poor
Poor
Delayed
Delayed
Nil
+
+
Right
Left
Bilateral
(in)
Seizures
Palpable, firm liver Responsiveness to
environment Behavioral development
5 yr
Hypotonia Hyperreflexia Optic nerve hypoplasia Height, cm (in)
Nil Nil Normal
Slight delay
4.5
+
(41.4) Delayed
Hyperreflexia Visual defect The
Bilateral
plus sign signifies that these details were present.
respectively, after the injection. The insu¬ lin sensitivity test results were abnormal, the blood glucose levels being 90 and 39 mg/100 ml at zero and 15 minutes, respec¬ tively, after the load; the blood glucose level failed to return to the normal control level at 60 minutes. Results of the metyra¬ pone test were normal. Although growth hormone studies were not available, these findings suggested that growth hormone deficiency might possibly account for the
hypoglycemia. Case 3.—A girl was the first child of un¬ related, healthy, young parents. The mother's family history disclosed diabetes mellitus and two of her brothers had nys¬
tagmus. During pregnancy she had ane¬ mia, hypoproteinemia, and vomiting that was treated with antiemetics. Labor was induced at 44 weeks' gestation and lasted 13 hours. The small placenta was calcified and infarcted. The infant was born nor¬ mally and weighed 3.95 kg (8.7 lb). She was apneic but was easily resuscitated. Twelve hours later the blood glucose level was 12 mg/100 ml. She received glucose intrave-
roentgenogram
globin
level
were
normal. The hemo¬
8.8
gm/100 ml, and the 15,000/cu mm, with
was
leukocyte count was lymphocytes. The
mone
105
Seizures Behavioral development
*
level, serum protein electrophoretic pattern, dermatoglyphics, results of chromosomal studies, urine amino acid chromatogram, CSF, and skull
serum sodium and chloride levels were elevated at 147 to 155 and 110 to 120 mEq/liter, respectively. The transaminase and LDH levels in the serum were raised (SGOT level, 98 units; SGPT level, 83 units; LDH level, 450 units). Hemagglutination inhibition test for rubella and CFTs for cytomegalovirus, herpes simplex, and toxoplasmosis in the serum were negative. The EEG showed sharp wave activity in the left central region. The pneumoencephalogram demonstrated excessive gas over the hemispheres, large basal cisterns, and dilatation of the ven¬ tricular system. The blood glucose level was 82 mg/100 ml after a four-hour fast. The urine specific gravity was 1.002. Table 2 shows the results of the endocrine stud¬ ies; for procedures, see "Methods of Hor¬
Nil
Receding lower jaw High-arched palate Jaundice
+
12
5.9
cm
(8.6)
cal details. The serum bilirubin
67%
(12.3)
Length, cm
+
5.6
Weight, kg (lb)
Head
+ +
3.9
+ +
Hypotonia Resuscitation Seizures Jaundice Blood glucose level, mg/100 ml
4, M
3, F
2, F
nously, along with ampicillin
and kanamycin. She became icteric on the third day and the serum bilirubin level reached a maximum of 16 mg/100 ml on the fifth day, returning to normal at 10 weeks of age. The mother and infant's blood groups were O Rh-positive and A Rh-negative, respec¬ tively. The direct Coombs test was nega¬ tive. Examination at the age of 3 months showed that the temperature was 39.5 C (103.1 F) and the weight, length, and head circumference were 4.5 kg (9.9 lb), 58 cm (22.8 in), and 41.0 cm (16.1 in), respectively. The systolic blood pressure was 70 mm Hg. She was pale and had a slightly receding lower jaw, coccygeal dimple, and a firm, nontender liver that was palpable 1 cm below the costal margin. Other findings in¬ cluded minimal spontaneous activity, di¬ minished response to environmental stim¬ uli, exaggerated Moro reflex, hypotonia, symmetrical hyperreflexia, and behavioral development appropriate for a 1-month-old infant. She had roving eye movements, inability to fixate on objects, absence of
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Studies."
For the diabetes insipidus, the patient received vasopressin injection (Pitressin) with good results: the urinary output de¬ creased, and the temperature returned to normal. She made very little progress in behavioral development. At the age of 16 months, her condition suddenly deteri¬ orated and she died. Autopsy showed a grossly malformed, microcephalic brain. The right cerebral hemisphere was smaller than the left; microgyri and heterotopic nodules were prominent in the cerebral hemispheres. The olfactory bulbs and tracts were ab¬ sent. The corpus callosum was deficient an¬ teriorly, but a thin septum pellucidum was present (Fig 1). The optic nerves were at¬ tenuated and, on microscopy, only a few myelinated fibers were seen. The optic chiasm was also severely atrophie. The lat¬ eral geniculate bodies were small, the cells were diminished, and the fibers of the optic radiation were missing. On the right no calcarine fissure was seen. The anterior lobe of the pituitary gland was normal. The posterior lobe of the pituitary gland was not identified even after extensive ex¬ amination of tissue from the area of the sella turcica. In the anterior part of the hy¬ pothalamus, the tissue was distorted and small clusters of primitive cells and foci of heterotopic gray matter were present. The cells of the supraoptic and paraventricular nuclei were abnormally small and few in
number
Table 2.—Studies of Endocrine Function in Four Patients
Fasting
Range
ng/ml
2.5 4.9
...
Peak After insulin
Fasting
Normal
>5
load, ng/ml
1.6
.
Peak_>5_3.5 ...
Thyroid function
Serum T4, ¿jg/lOO ml "i| uptake, % At4hr At 24 Adrenocorticotrophic hormone
4-12
1.5 2.4
...
.
7.5
8.6
20
hr_10-35_12
Metyrapone test: urinary 17-ketogenic steroids, mg/24 hr
activity
Base line level Maximum response
7.0
1.3 1.2 0.5 1.5 1.7
...
0.5 0.5
...
>twofold rise
0.6 2.1
0.2 0.7
plasma cortisol,
8 am 4 pm Antidiuretic hormone activity Water deprivation test: urine, mOsm/kg water Base line level Maximum response After vasopressin injection with µ /hour: urine, mOsm/kg water Base line level Maximum response Serum insulin After glucose load, ¿tU/ml Base line level
8.0
...
.
_.___6.0 ...
35 310
>350 ...
...
.
.
.
40 240
50 760
.
5.7*
6-12
510
intravenously. orally.
Table 3.—Summary of
Findings
6.2t
.
.
.
.
.
in Patients With
30.2
Optic
Nerve
Hypoplasia
With
Absent Authors
No. of Patients
Age, Male
Female
yr
Kaplan
étais Brook et al6
4.5-7.2
Harris &
5.5
Haas7 Billson &
0.25
was
lost
At the age of 3 months he had defective vision and sluggish pupillary light re¬ sponses, and on funduscopic examination he was thought to have bilateral optic at¬ rophy. The pneumoencephalogram showed an excessive amount of gas in the basal cisterns and over the surfaces of the cere¬ bral hemisphere and cerebellum. The cere¬ bral sulci were widened. The ventricles ap¬ peared dilated. The septum pellucidum was present. There was a suggestion of a suprasellar cyst. At operation the right optic nerve was very thin. At 2 years of age he developed focal and generalized cortical
.
.
Glucose administered t Glucose administered
...
.
...
_Peak_350
but it
ing 42 weeks, was complicated by vaginal bleeding, excessive weight gain, and edema that was treated orally with diuret¬ ics. He was delivered by cesarean section because of cephalopelvic disproportion. At birth he weighed 3.9 kg (8.6 lb). After 12 hours he became apneic and hypotonie, and he had seizures. The blood glucose level was 9 mg/100 ml.
1.6 1.4
Circadian rhythm:
/ig/100 ml
area
failure. He was the first child of a young mother who later was found to be prediabetic. There was no consanguinity. There was a family history of seizures and mental retardation. The pregnancy, last¬
6.9 6.0
5 15
...
...
in the tuberai
glial tissue. The posterior part of the hy¬ pothalamus was normal. The small thyroid and adrenal glands were normal on micro¬ scopical examination. The pancreas was normal. The thymus was atrophie, but oc¬ casional Hassall corpuscles were seen and numerous hyalinized vessels were noted. The lungs, liver, kidneys, and spleen were normal except for congestion. Case 4.—A 5-year-old boy was admitted for seizures and was noted to have growth in
Patients Test Growth hormone After arginine infusion,
(Fig 2). The beginning of the stalk
was seen
Admission Findings Short stature, visual defect Visual defect, short stature Short stature
Septum
Pellucidum 3 of 4
Hypopituitarism Pituitary Hormone Deficiencies
ADH*
MTHt
Panhypopituitarism
GHÍ
1 of 2
Hopkins8 Present series
• ADH signifies antidiuretic hormone. t MTH signifies multiple trophic hormones. t GH signifies growth hormone. § The fourth patient also probably had growth
0.25-5.0
hormone
Delayed development, hypotonia, visual defect, pyrexia (1 child), short stature
deficiency.
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1 of 3
3§
seizures. He was blind and mentally re¬ tarded. At the age of 5 years the height was 105 cm (41.4 in). The systolic blood pressure was 90 mm Hg. The previously noted re¬ ceding lower jaw was less apparent, as was the hyperreflexia. He responded to envi¬ ronmental stimuli, including sounds. Mild mental retardation was noted. He had bi¬ lateral absence of the pupillary light re¬ flexes consensually and directly. The fundi were difficult to visualize because of severe searching nystagmus. Table 1 shows the clinical details. The hemoglobin level, total leukocyte and differential counts, serum calcium level, and urine amino acid chromatogram were normal. The serum sodium and chlo¬ ride levels were 132 and 98 mEq/liter, re¬ spectively. The urine specific gravity was 1.010. The EEG showed spike wave activity in the left occipital region with syn¬ chronous focus on the right. Later there was, in addition, an area of slow wave ac¬ tivity in the right midtemporal region. The fasting blood glucose level was 57 mg/100 ml. Table 2 shows the results of the endo¬ crine studies. See "Methods of Hormone Studies" for procedures. The results of the endocrine studies of patients studied by us and by other au¬ thors are summarized in Table 3.
Methods of Hormone Studies
The growth hormone level was esti¬ mated by radioimmunoassay. The T4 level was estimated by the MurphyPattee method. The Zimmerman re¬ action was used for measuring uri¬ nary 17-ketogenic steroid levels. For the metyrapone test, 24-hour urine collections were done two days before and one day after metyrapone admin¬ istration and the 17-ketogenic steroid levels were estimated. Dosage of me¬ tyrapone was 100 mg/kg weight. The
freezing point depression, measured by osmometer, was used for urine osmolality. The immunoreactive insulin level was measured by double-anti¬ body radioimmunoassay technique. COMMENT
The syndrome of optic nerve hypo¬ plasia with hypopituitarism is proba¬ bly more common than is generally recognized. The paucity of recorded cases might be related to the diffi¬ culty of diagnosis, especially in early
life. The cause is unknown. Kaplan and others'' found a negative family his-
tory for identical cases, and this was also noted in the present series. How¬ ever, two uncles of
tagmus, the
cause
child had nys¬ of which is un¬
one
known to us. The family history was positive for mental retardation in two cases. The pregnancies in the present series were complicated by anemia,
urinary infection, edema, hypoprotein-
emia, and medications that included sulfonamides, diuretics, and antiemetics. The patient of Harris and Haas7
born after a normal preg¬ Our patients were all first¬ nancy. born children of young mothers and this has been noted once before.7 Both boys and girls are affected; seven of the ten previously reported patients5-7 were girls. Clustering of cases in time and place has not been a feature. The dermatoglyphics, chromosomes, and urine amino acid levels in this syn¬ drome would appear not to have been studied before, but in our patients these were normal. A temporary cystathioninuria in one case was thought to be due to a dietary deficiency. In three of our patients, tests for cytomegalovirus and toxoplasmosis were negative; in two of them, stud¬ ies for rubella were negative; and in one, studies for herpes simplex were negative. Similar studies have not previously been documented. Pro¬ longed neonatal jaundice was a fea¬ ture noted in three of our cases; this has been observed once before.7 While this might have been related to hy¬ poglycemia,9 the presence of jaundice at a later age, together with a nontender, firm, palpable liver and abnor¬ mal results of liver function tests, might possibly suggest that a toxic or infective process is operative. Although little is known of the fac¬ tors responsible for the syndrome, several factors are known to account for the eye defect. Mothers ingesting quinine have given birth to infants with optic nerve hypoplasia and sometimes with deafness.10 The optic nerves were absent in the offspring of pregnant rats who received hy¬ poglycémie sulfonamides.11 Familial optic nerve hypoplasia has been veri¬ fied.12 It is of interest to note that op¬ tic nerve hypoplasia is more common among first-born children." The insult presumably occurs at was
about four to six weeks' gestation when the ganglion cells of the retina are developing. The main structures involved in this syndrome are the op¬ tic nerves, the septum pellucidum, and the pituitary gland. The findings in our patients demonstrate that the process might affect other areas of the brain, including the brain stem. Indeed, it might involve the brain dif¬ fusely. The septum pellucidum need not be absent. The syndrome may be related to the spectrum of forebrain malformations,1417 which have some features in common; perhaps it is the more "benign" expression of the series. The clinical picture is apparently related to the age groups, and this might be related to the severity and extent of the pathological process. In the newborn period there may be apnea, hypotonia, hypoglycemia with or without seizures, and hyper¬ bilirubinemia. Except for the jaun¬ dice, this clinical picture resembles that observed among newborns with hypopituitarism and secondary adre¬ nal failure.18"22 At the age of 3 months, patients have hypotonia, psychomotor retarda¬ tion, defective visual fixation, and sei¬ zures. A firm, nontender liver may be palpable and, in one case, there was mild jaundice. A receding lower jaw
and, occasionally, a high-arched pal¬ ate may be present. The general ap¬
pearance is otherwise normal. The fasting blood glucose level may be mildly depressed, and results of liver function tests may be abnormal. The older child in this series had psychomotor retardation, growth fail¬ ure, defective vision, and seizures. He resembled the patients described by other authors.4-7 One of the three cardinal features of this syndrome merits further com¬ ment. Growth failure was present in one of our patients but could not as yet be demonstrated in the three in¬ fants. The fasting blood glucose level was depressed in three of the pa¬ tients, and in two of them results of the glucagon and leucine tolerance tests were normal, indicating that glycogenoses and leucine sensitivity were not responsible for the low blood glucose level. The immunoreactive in-
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sulin levels during the glucose load measured in two cases demonstrated no evidence of hyperinsulinism. The low growth hormone level and de¬ pressed function of the pituitary-ad¬ renal axis implied that this accounted for the hypoglycemia. All three cases studied for growth hormone secretion showed subnormal response to provocative stimulation. One of them demonstrated vasopressin-responsive diabetes insipidus, and another had asymptomatic, partial antidiuretic hormone deficiency with a subnormal response to metyrapone inhibition, suggesting adrenocorticotrophic hormone deficiency; one of the three appeared to have adrenocorticotrophic hormone deficiency and hypothyroidism, the latter conceiv¬ ably due to thyrotropin deficien¬ cy. These observations compare with with those of other authors who found the extent of the endocrine deficiency varied from isolated growth hormone
insufficiency to panhypopituitarism.58 In the syndrome of optic nerve hypo¬ plasia with hypopituitarism, just as in some cases of idiopathic hypopituitar¬ ism, the hypothalamic neurohypophy-
seal control of the
pituitary hormone secretions seems important.5-2 Kap¬ lan and others5 suggested that the hypopituitarism in this syndrome was ascribable to a diencephalic lesion that resulted in deficiency of hypothalamic-releasing factors, and, in some cases, vasopressin. The autopsy findings in our patient are thus of great interest. The diagnosis of optic nerve hypo¬ plasia with hypopituitarism may be '
difficult, especially in early life; in fact, in our patients initial diagnoses included idiopathic neonatal hypogly¬ cemia, hypoxia, and hepatitis. In one case the importance of the optic nerve hypoplasia was not recognized. In one child the appearance of the optic disc
wrongly interpreted as optic at¬ rophy. However, the appearance of the disc with an inner hypoplastic margin and an outer halo should serve to differentiate it from optic at¬ rophy.24 Unilateral hypoplasia has been diagnosed as simple esotropia or strabismic amblyopia.22-24 Visual de¬
is normal and vi¬ sual evoked responses that are absent might be helpful in the diagnosis. The physician should be aware of this relatively common syndrome of optic nerve hypoplasia with hypo¬ pituitarism, the variable clinical pic¬ ture dependent on the age groups, and the diagnostic pitfalls. Agenesis
troretinogram that
of the septum pellucidum, initially thought to be an integral part of this syndrome, is inconstant and not es¬ sential. A careful examination of the fundus permits correct diagnosis and timely assessment of the endocrine status so that the deleterious effects of hormone deficiencies might be avoided, and the prognosis of these children improved.
was
fect is hard to assess in infants, espe¬ cially if psychomotor retardation is also present. In such cases, the elee-
Henry G. Dunn, MB, FRCP, gave encour¬ agement and advice; George D. M. Kettyls, MD, and John H. Sturdy, MD, provided pathology re¬ ports; and Edward G. Cook, MB, MRCP, and Ju¬ dith C. Naylor, MB, FRCP(C), referred the pa¬ tients to
us.
Nonproprietary
Name and Trademarks of Drug
Ampicillin sodium-^ipera-iV, Amcill-S, Omnipen-N, Penbritin-S.
References 1. Reeves DL: Congenital absence of septum pellucidum. Johns Hopkins Med J 69:61-71, 1941.
2. de Morsier G: \l=E'\tudessur les dysraphies cr\l=a^\nio-enc\l=e'\phaliques:III. Ag\l=e'\n\l=e'\siedu septum lucidum avec malformation du tractus optique: La dysplasie septooptique. Schweiz Arch Neurol Psychiatr 77:267-292, 1956. 3. St. John JR, Reeves DL: Congenital absence of the septum pellucidum: A review of the literature with case report. Am J Surg 94:974-980, 1957. 4. Hoyt WF, Kaplan SL, Grumbach MM, et al: Septo-optic dysplasia with pituitary dwarfism. Lancet 1:893-894, 1970. 5. Kaplan SL, Grumbach MM, Hoyt WF: A syndrome of hypopituitary dwarfism, hypoplasia of optic nerves and malformation of prosencephalon. Pediatr Res 4:480\x=req-\ 481, 1970. 6. Brook CGD, Sanders MD, Hoare RD: Septo-optic dysplasia. Br Med J 3:811-813, 1972. 7. Harris RJ, Haas L: Septo-optic dysplasia with growth hormone deficiency (de Morsier syndrome). Arch Dis Child 47:973\x=req-\
976, 1972.
8. Billson F, Hopkins IJ: Optic hypoplasia and hypopituitarism. Lancet 1:905,
1972. 9. Yeung CY: Blood sugar changes in neonatal and phenobarbitone therapy. Arch Dis Child 47:246\x=req-\ 249, 1972. 10. McKinna AJ: Quinine induced hypoplasia of the optic nerve. Can J Ophthalmol 1:261-265, 1966. 11. Duke-Elder S: System of Ophthalmology. London, Henry Kimpton Publishers, 1964, vol 3, p 668. 12. Kytila J, Miettinen P: On bilateral aplasia of the optic nerve. Acta Ophthalmol 39:416-419, 1961. 13. Walton DS, Robb RM: Optic nerve hypoplasia. Arch Ophthalmol 84:572-578, 1970. 14. DeMyer W, Zeman W, Palmer CG: The face predicts the brain: Diagnostic significance of median facial anomalies for (arhinencephaly). Pediatrics 34:256-263, 1964. 15. Loesser JD, Ellsworth CA: Agenesis of the corpus callosum. Brain 91:553-570, 1968. 16. Gorlin RJ, Yunis J, Anderson VE: Short arm deletion of chromosome 18 in ceAm J Dis Child 115:473-476, bocephaly. 1968. 17. Patel H, Dolman CL, Byrne MA:
hyperbilirubinaemia
holoprosencephaly
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Holoprosencephaly with median cleft lip: Clinical, pathological, and echoencephalographic study. Am J Dis Child 124:217-221, 1972. 18. Blizzard RM, Alberts A: Hypopituitarism, hypoadrenalism and hypogonadism in the newborn infant. J Pediatr 48:782\x=req-\
792, 1956.
Hypoplasia of the pituiReport of occursiblings and autopsy find-
19. Mosier HD:
tary and adrenal rence
in twin
cortex:
ings. J Pediatr 48:633-639, 1956. 20. Brewer DB: Congenital absence of the pituitary gland and its consequences. J PatholBacteriol 73:59-67, 1957. 21. Reid JD: Congenital absence of the pituitary gland. J Pediatr 56:658-664,1960. 22. Moncrieff MW, Hill DS, Archer J, et al: Congenital absence of pituitary gland and adrenal hypoplasia. Arch Dis Child 47:136-137, 1972. 23. Costom BE, Grumbach MM, Kaplan SL: Effect of thyrotropin-releasing factor on serum thyroid-stimulating hormone. J Clin Invest 50:2219-2225, 1971. 24. Edwards WC, Layden WE: Optic nerve hypoplasia. Am J Ophthalmol 70:950-959, 1970.
With
Hypopituitarism
Hawa Patel, MB, MRCP(E); Wah Jun Tze, MD, FRCP(C); John U. Crichton, MB, FRCP(E); Andrew Q. McCormick, MD, FRCP(C); Geoffrey C. Robinson, MD, FRCP(C); Clarissa L. Dolman, MD, FRCP(C)
Four children had optic nerve hypoplasia with hypopituitarism, and their clinical picture varied with age. The newborn had apnea, hypotonia, seizures, hypoglycemia, and prolonged jaundice. The young infant had defective vision, behavioral delay, hypotonia, and seizures. Except for a mildly receding lower jaw and a high-arched palate, the appearance of the patients was not unusual. The fasting blood glucose level was mildly depressed. In two cases the liver was palpable and results of liver function tests were abnormal. The older child, who was blind and mentally retarded, had growth failure. The extent of the pituitary hormone deficiencies was variable, including diabetes insipidus. The septum pellucidum was not invariably absent. Clinical and pathological findings indicate that the brain lesion might be more diffuse than hitherto recognized. Early recognition of this syndrome and timely intervention might diminish serious
sequels. 1941 Reeves1
reported a case of anomaly and agenesis of the septum pellucidum. De Morsier- demonstrated that optic nerve hypoplasia was frequently associated with absence of the septum pelluci¬ dum; he suggested the name "septooptic dysplasia." The review of age¬ nesis of the septum pellucidum by St. John and Reeves' probably contains examples of this syndrome. Recently,
In optic
nerve
Received for publication Nov 9, 1973; accepted 1974. From the departments of paediatrics (Drs. Patel, Tze, Crichton, McCormick, and Robinson), ophthalmology (Dr. McCormick), and pathology (Dr. Dolman), Faculty of Medicine, University of British Columbia, Vancouver General Hospital, and Children's Hospital, Vancouver. Reprint requests to Department of Paediatrics, University of British Columbia, 715 W 12th Ave, Vancouver, British Columbia, Canada (Dr.
July 16,
Patel).
Hoyt and his colleagues4
and
Kaplan
and others" observed that children with optic nerve hypoplasia may have growth retardation associated with
hypopituitarism; logram in four
a
pneumoencepha-
of the nine chil¬ dren showed absent septum pelluci¬ dum.4 5 Brook and others" and Harris and Haas7 have verified four addi¬ tional cases. Billson and Hopkins8 in¬ dicated that absence of the septum pellucidum cannot regularly be pre¬ dicted in such cases; one of the in¬ fants they examined had an intact septum pellucidum. They thus sug¬ gested that the spectrum of associ¬ ated abnormalities in the presence of septo-optic dysplasia and disturbed hypothalamic-pituitary function is variable. During the past four years, we have studied four children with optic nerve hypoplasia; three of them had hypopituitarism. Symptoms in three of our patients appeared in early in¬ fancy, and we wish to verify the clini¬ cal features peculiar to this age group. The recognition of the constel¬ lation of findings in this potentially dangerous syndrome is of clinical im¬
portance. REPORT OF CASES Case 1.—A boy young, unrelated,
was
the first child of
healthy parents. The family history was noncontributory. The pregnancy was complicated by edema, ab¬ dominal pain, and excessive weight gain. He was born normally at term after a 9-%hour labor. The birth weight was 2.98 kg (6.6 lb). He was apneic but was easily re¬ suscitated. Later, he developed apneic spells and seizures. He became icteric on
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the second day and the serum bilirubin level reached a maximum of 20.5 mg/100 ml on the third day. The mother and in¬ fant's blood groups were A Rh-positive, and the direct and indirect Coombs tests were negative. He received phototherapy and an exchange transfusion, along with ampicillin sodium and kanamycin sulfate. The blood glucose level on the third day, measured while he was receiving glucose intravenously, was 27 mg/100 ml. Funduscopic examination showed right optic nerve
hypoplasia.
When
seen
at the age of 3-Vè
months, his
weight, length, and head circumference were 5.6 kg (12.3 lb), 64.5 cm (25.4 in), and 40.8 cm (16.1 in), respectively. The systolic blood pressure was 80 mm Hg. He was alert and responded normally to sounds. The unusual findings were a mildly reced¬ ing lower jaw, high-arched palate, hypo¬ tonia, and mild behavioral delay. He had wandering eye movements, inability to fix¬ ate with either eye, and right optic nerve hypoplasia. The pupillary light reaction was present directly but not consensually on the left, and consensually but not directly on the right. Table 1 shows the clinical details. The hemoglobin level; total and differ¬ ential leukocyte counts; serum bilirubin, electrolyte, and calcium levels; results of liver function tests (serum transaminase, lactic dehydrogenase [LDH], and alkaline phosphatase levels); serum protein electrophoretic pattern; urine amino acid chromatogram; dermatoglyphics; results of chromosomal studies; cerebrospinal fluid (CSF); skull roentgenograms; and bone age were normal. Examination of the urine showed no cytomegalic inclusion bodies, and the serum complement fixation test (CFT) for toxoplasmosis was negative. The electroencephalogram showed only shift¬ ing asymmetry. The pneumoencephalogram demonstrated mild enlargement of the ventricular system, absence of the sep-
slices of brain, demonstrating abnormal development of midline septum pellucidum is thin and the corpus callosum is deficient.
Fig 1.—Coronal
tures. The
struc¬
Fig 2.—Section of supraoptic nucleus, demonstrating abnormal neurones that are deficient in number, small in size, and lack the abundant cytoplasm normally seen in these cells (Luxol fast blue and hematoxylin-eosin, original magnification 254).
pellucidum, and large basal cisterns. The left cerebral hemisphere convolutions were small and the sulci large, while over the surface of the right hemisphere no gas was visualized. The fasting blood glucose level was 38 mg/100 ml. Table 2 shows the results of the endocrine studies; for procedures, see "Methods of Hormone Studies." Case 2.-A girl was the first child of un¬ related, healthy, young parents. There was a family history of diabetes mellitus, menturn
tal retardation, and seizures. The preg¬ nancy, lasting 36 weeks, was complicated by edema and a urinary infection that was treated with sulfonamides. After a 2-14hour labor, the infant was born by breech presentation. Her birth weight was 2.25 kg (5.0 lb). She was apneic but was easily re¬ suscitated. She received ampicillin, kanamycin, and sodium bicarbonate and glu¬ cose intravenously. On the second day she was icteric, and the serum bilirubin level reached a maximum of 15 mg/100 ml on
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the third day. The mother and infant's blood groups were O Rh-negative and O Rh-positive, respectively. The direct Coombs test was negative. When examined at the age of 3 months, the weight, length, and head circum¬ ference were 5.9 kg (13.0 lb), 57 cm (22.4 in), and 42.2 cm (16.6 in), respectively. The systolic blood pressure was 90 mm Hg. She was icteric and responded poorly to envi¬ ronmental stimuli, including sounds. She had a mildly receding lower jaw, higharched palate, prominent epicanthic folds, and a firm, nontender liver that was pal¬ pable 1 cm below the costal margin. Other findings included hypotonia, bilateral fifth (motor and sensory) and right seventh cra¬ nial nerve palsies, weakness and ankle clonus of the left limbs, generalized hyper¬ reflexia, and behavior appropriate for a newborn infant. She followed objects with the right eye. The pupillary light reaction was present consensually but not directly on the left, and directly but not consen¬ sually on the right. The left optic nerve head was hypoplastic. Table 1 shows the clinical details. The hemoglobin level, total and differ¬ ential leukocyte counts, serum electrolyte and calcium levels, serum protein electrophoretic pattern, urine amino acid chromatogram, dermatoglyphics, results of chromosomal studies, and skull roentgen¬ ograms were normal. The bone age was at a three-week level. The serum bilirubin level was 5 mg/100 ml, and the serum transaminase levels were elevated (serum glutamic oxaloacetic transaminase [SGOT] level, 97 units, and serum glutamic pyruvic transaminase [SGPT] level, 65 units). The LDH level was also elevated, at 380 units. Examination of the urine showed no cytomegalic inclusion bodies, and the serum CFT for toxoplasmosis and the hemagglutination inhbition test for rubella were negative. The fasting blood glucose level on two occasions was 39 and 28 mg/100 ml. The serum thyroxine (T4) level was normal, and the fasting insulin level in the serum was normal at 5/iU/ml. The 24-hour urine catecholamine execretion was normal at 4fig. The urine specific gravity was 1.003 on one occasion and 1.010 on another. Results of the oral glucose tolerance test were nor¬ mal, with blood glucose levels of 57, 84, and 50 mg per 100 ml at zero, 90, and 180 min¬ utes, respectively, after the glucose load. Results of the leucine sensitivity test were satisfactory, the blood glucose levels being 80,49, and 39 mg per 100 ml at zero, 45, and 60 minutes, respectively, after the load. Results of the glucagon test were normal with adequate mobilization of glycogen stores, the blood glucose levels being 40 and 75 mg/100 ml at zero and 30 minutes,
pupillary light response directly and con¬ sensually in both eyes, and bilateral optic nerve hypoplasia. Table 1 shows the clini¬
Table 1.—Clinical Details of Four Patients Patient & Sex
Age Groups Newborn period
Clinical Findings Birth weight, kg (Ib)
1, M 2.98
(6.6)
2.25
3.95
(5.0)
(8.7)
+
Apnea
3-3 y2
mo
27
(13.0)
(9.9)
(in)
64.5
57
58
(25.4)
(22.4)
(22.8)
circumference,
40.8
42.2
41.0
(16.1)
(16.6)
(16.1)
+ + +
Nil
Poor
Poor
Delayed
Delayed
Nil
+
+
Right
Left
Bilateral
(in)
Seizures
Palpable, firm liver Responsiveness to
environment Behavioral development
5 yr
Hypotonia Hyperreflexia Optic nerve hypoplasia Height, cm (in)
Nil Nil Normal
Slight delay
4.5
+
(41.4) Delayed
Hyperreflexia Visual defect The
Bilateral
plus sign signifies that these details were present.
respectively, after the injection. The insu¬ lin sensitivity test results were abnormal, the blood glucose levels being 90 and 39 mg/100 ml at zero and 15 minutes, respec¬ tively, after the load; the blood glucose level failed to return to the normal control level at 60 minutes. Results of the metyra¬ pone test were normal. Although growth hormone studies were not available, these findings suggested that growth hormone deficiency might possibly account for the
hypoglycemia. Case 3.—A girl was the first child of un¬ related, healthy, young parents. The mother's family history disclosed diabetes mellitus and two of her brothers had nys¬
tagmus. During pregnancy she had ane¬ mia, hypoproteinemia, and vomiting that was treated with antiemetics. Labor was induced at 44 weeks' gestation and lasted 13 hours. The small placenta was calcified and infarcted. The infant was born nor¬ mally and weighed 3.95 kg (8.7 lb). She was apneic but was easily resuscitated. Twelve hours later the blood glucose level was 12 mg/100 ml. She received glucose intrave-
roentgenogram
globin
level
were
normal. The hemo¬
8.8
gm/100 ml, and the 15,000/cu mm, with
was
leukocyte count was lymphocytes. The
mone
105
Seizures Behavioral development
*
level, serum protein electrophoretic pattern, dermatoglyphics, results of chromosomal studies, urine amino acid chromatogram, CSF, and skull
serum sodium and chloride levels were elevated at 147 to 155 and 110 to 120 mEq/liter, respectively. The transaminase and LDH levels in the serum were raised (SGOT level, 98 units; SGPT level, 83 units; LDH level, 450 units). Hemagglutination inhibition test for rubella and CFTs for cytomegalovirus, herpes simplex, and toxoplasmosis in the serum were negative. The EEG showed sharp wave activity in the left central region. The pneumoencephalogram demonstrated excessive gas over the hemispheres, large basal cisterns, and dilatation of the ven¬ tricular system. The blood glucose level was 82 mg/100 ml after a four-hour fast. The urine specific gravity was 1.002. Table 2 shows the results of the endocrine stud¬ ies; for procedures, see "Methods of Hor¬
Nil
Receding lower jaw High-arched palate Jaundice
+
12
5.9
cm
(8.6)
cal details. The serum bilirubin
67%
(12.3)
Length, cm
+
5.6
Weight, kg (lb)
Head
+ +
3.9
+ +
Hypotonia Resuscitation Seizures Jaundice Blood glucose level, mg/100 ml
4, M
3, F
2, F
nously, along with ampicillin
and kanamycin. She became icteric on the third day and the serum bilirubin level reached a maximum of 16 mg/100 ml on the fifth day, returning to normal at 10 weeks of age. The mother and infant's blood groups were O Rh-positive and A Rh-negative, respec¬ tively. The direct Coombs test was nega¬ tive. Examination at the age of 3 months showed that the temperature was 39.5 C (103.1 F) and the weight, length, and head circumference were 4.5 kg (9.9 lb), 58 cm (22.8 in), and 41.0 cm (16.1 in), respectively. The systolic blood pressure was 70 mm Hg. She was pale and had a slightly receding lower jaw, coccygeal dimple, and a firm, nontender liver that was palpable 1 cm below the costal margin. Other findings in¬ cluded minimal spontaneous activity, di¬ minished response to environmental stim¬ uli, exaggerated Moro reflex, hypotonia, symmetrical hyperreflexia, and behavioral development appropriate for a 1-month-old infant. She had roving eye movements, inability to fixate on objects, absence of
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Studies."
For the diabetes insipidus, the patient received vasopressin injection (Pitressin) with good results: the urinary output de¬ creased, and the temperature returned to normal. She made very little progress in behavioral development. At the age of 16 months, her condition suddenly deteri¬ orated and she died. Autopsy showed a grossly malformed, microcephalic brain. The right cerebral hemisphere was smaller than the left; microgyri and heterotopic nodules were prominent in the cerebral hemispheres. The olfactory bulbs and tracts were ab¬ sent. The corpus callosum was deficient an¬ teriorly, but a thin septum pellucidum was present (Fig 1). The optic nerves were at¬ tenuated and, on microscopy, only a few myelinated fibers were seen. The optic chiasm was also severely atrophie. The lat¬ eral geniculate bodies were small, the cells were diminished, and the fibers of the optic radiation were missing. On the right no calcarine fissure was seen. The anterior lobe of the pituitary gland was normal. The posterior lobe of the pituitary gland was not identified even after extensive ex¬ amination of tissue from the area of the sella turcica. In the anterior part of the hy¬ pothalamus, the tissue was distorted and small clusters of primitive cells and foci of heterotopic gray matter were present. The cells of the supraoptic and paraventricular nuclei were abnormally small and few in
number
Table 2.—Studies of Endocrine Function in Four Patients
Fasting
Range
ng/ml
2.5 4.9
...
Peak After insulin
Fasting
Normal
>5
load, ng/ml
1.6
.
Peak_>5_3.5 ...
Thyroid function
Serum T4, ¿jg/lOO ml "i| uptake, % At4hr At 24 Adrenocorticotrophic hormone
4-12
1.5 2.4
...
.
7.5
8.6
20
hr_10-35_12
Metyrapone test: urinary 17-ketogenic steroids, mg/24 hr
activity
Base line level Maximum response
7.0
1.3 1.2 0.5 1.5 1.7
...
0.5 0.5
...
>twofold rise
0.6 2.1
0.2 0.7
plasma cortisol,
8 am 4 pm Antidiuretic hormone activity Water deprivation test: urine, mOsm/kg water Base line level Maximum response After vasopressin injection with µ /hour: urine, mOsm/kg water Base line level Maximum response Serum insulin After glucose load, ¿tU/ml Base line level
8.0
...
.
_.___6.0 ...
35 310
>350 ...
...
.
.
.
40 240
50 760
.
5.7*
6-12
510
intravenously. orally.
Table 3.—Summary of
Findings
6.2t
.
.
.
.
.
in Patients With
30.2
Optic
Nerve
Hypoplasia
With
Absent Authors
No. of Patients
Age, Male
Female
yr
Kaplan
étais Brook et al6
4.5-7.2
Harris &
5.5
Haas7 Billson &
0.25
was
lost
At the age of 3 months he had defective vision and sluggish pupillary light re¬ sponses, and on funduscopic examination he was thought to have bilateral optic at¬ rophy. The pneumoencephalogram showed an excessive amount of gas in the basal cisterns and over the surfaces of the cere¬ bral hemisphere and cerebellum. The cere¬ bral sulci were widened. The ventricles ap¬ peared dilated. The septum pellucidum was present. There was a suggestion of a suprasellar cyst. At operation the right optic nerve was very thin. At 2 years of age he developed focal and generalized cortical
.
.
Glucose administered t Glucose administered
...
.
...
_Peak_350
but it
ing 42 weeks, was complicated by vaginal bleeding, excessive weight gain, and edema that was treated orally with diuret¬ ics. He was delivered by cesarean section because of cephalopelvic disproportion. At birth he weighed 3.9 kg (8.6 lb). After 12 hours he became apneic and hypotonie, and he had seizures. The blood glucose level was 9 mg/100 ml.
1.6 1.4
Circadian rhythm:
/ig/100 ml
area
failure. He was the first child of a young mother who later was found to be prediabetic. There was no consanguinity. There was a family history of seizures and mental retardation. The pregnancy, last¬
6.9 6.0
5 15
...
...
in the tuberai
glial tissue. The posterior part of the hy¬ pothalamus was normal. The small thyroid and adrenal glands were normal on micro¬ scopical examination. The pancreas was normal. The thymus was atrophie, but oc¬ casional Hassall corpuscles were seen and numerous hyalinized vessels were noted. The lungs, liver, kidneys, and spleen were normal except for congestion. Case 4.—A 5-year-old boy was admitted for seizures and was noted to have growth in
Patients Test Growth hormone After arginine infusion,
(Fig 2). The beginning of the stalk
was seen
Admission Findings Short stature, visual defect Visual defect, short stature Short stature
Septum
Pellucidum 3 of 4
Hypopituitarism Pituitary Hormone Deficiencies
ADH*
MTHt
Panhypopituitarism
GHÍ
1 of 2
Hopkins8 Present series
• ADH signifies antidiuretic hormone. t MTH signifies multiple trophic hormones. t GH signifies growth hormone. § The fourth patient also probably had growth
0.25-5.0
hormone
Delayed development, hypotonia, visual defect, pyrexia (1 child), short stature
deficiency.
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1 of 3
3§
seizures. He was blind and mentally re¬ tarded. At the age of 5 years the height was 105 cm (41.4 in). The systolic blood pressure was 90 mm Hg. The previously noted re¬ ceding lower jaw was less apparent, as was the hyperreflexia. He responded to envi¬ ronmental stimuli, including sounds. Mild mental retardation was noted. He had bi¬ lateral absence of the pupillary light re¬ flexes consensually and directly. The fundi were difficult to visualize because of severe searching nystagmus. Table 1 shows the clinical details. The hemoglobin level, total leukocyte and differential counts, serum calcium level, and urine amino acid chromatogram were normal. The serum sodium and chlo¬ ride levels were 132 and 98 mEq/liter, re¬ spectively. The urine specific gravity was 1.010. The EEG showed spike wave activity in the left occipital region with syn¬ chronous focus on the right. Later there was, in addition, an area of slow wave ac¬ tivity in the right midtemporal region. The fasting blood glucose level was 57 mg/100 ml. Table 2 shows the results of the endo¬ crine studies. See "Methods of Hormone Studies" for procedures. The results of the endocrine studies of patients studied by us and by other au¬ thors are summarized in Table 3.
Methods of Hormone Studies
The growth hormone level was esti¬ mated by radioimmunoassay. The T4 level was estimated by the MurphyPattee method. The Zimmerman re¬ action was used for measuring uri¬ nary 17-ketogenic steroid levels. For the metyrapone test, 24-hour urine collections were done two days before and one day after metyrapone admin¬ istration and the 17-ketogenic steroid levels were estimated. Dosage of me¬ tyrapone was 100 mg/kg weight. The
freezing point depression, measured by osmometer, was used for urine osmolality. The immunoreactive insulin level was measured by double-anti¬ body radioimmunoassay technique. COMMENT
The syndrome of optic nerve hypo¬ plasia with hypopituitarism is proba¬ bly more common than is generally recognized. The paucity of recorded cases might be related to the diffi¬ culty of diagnosis, especially in early
life. The cause is unknown. Kaplan and others'' found a negative family his-
tory for identical cases, and this was also noted in the present series. How¬ ever, two uncles of
tagmus, the
cause
child had nys¬ of which is un¬
one
known to us. The family history was positive for mental retardation in two cases. The pregnancies in the present series were complicated by anemia,
urinary infection, edema, hypoprotein-
emia, and medications that included sulfonamides, diuretics, and antiemetics. The patient of Harris and Haas7
born after a normal preg¬ Our patients were all first¬ nancy. born children of young mothers and this has been noted once before.7 Both boys and girls are affected; seven of the ten previously reported patients5-7 were girls. Clustering of cases in time and place has not been a feature. The dermatoglyphics, chromosomes, and urine amino acid levels in this syn¬ drome would appear not to have been studied before, but in our patients these were normal. A temporary cystathioninuria in one case was thought to be due to a dietary deficiency. In three of our patients, tests for cytomegalovirus and toxoplasmosis were negative; in two of them, stud¬ ies for rubella were negative; and in one, studies for herpes simplex were negative. Similar studies have not previously been documented. Pro¬ longed neonatal jaundice was a fea¬ ture noted in three of our cases; this has been observed once before.7 While this might have been related to hy¬ poglycemia,9 the presence of jaundice at a later age, together with a nontender, firm, palpable liver and abnor¬ mal results of liver function tests, might possibly suggest that a toxic or infective process is operative. Although little is known of the fac¬ tors responsible for the syndrome, several factors are known to account for the eye defect. Mothers ingesting quinine have given birth to infants with optic nerve hypoplasia and sometimes with deafness.10 The optic nerves were absent in the offspring of pregnant rats who received hy¬ poglycémie sulfonamides.11 Familial optic nerve hypoplasia has been veri¬ fied.12 It is of interest to note that op¬ tic nerve hypoplasia is more common among first-born children." The insult presumably occurs at was
about four to six weeks' gestation when the ganglion cells of the retina are developing. The main structures involved in this syndrome are the op¬ tic nerves, the septum pellucidum, and the pituitary gland. The findings in our patients demonstrate that the process might affect other areas of the brain, including the brain stem. Indeed, it might involve the brain dif¬ fusely. The septum pellucidum need not be absent. The syndrome may be related to the spectrum of forebrain malformations,1417 which have some features in common; perhaps it is the more "benign" expression of the series. The clinical picture is apparently related to the age groups, and this might be related to the severity and extent of the pathological process. In the newborn period there may be apnea, hypotonia, hypoglycemia with or without seizures, and hyper¬ bilirubinemia. Except for the jaun¬ dice, this clinical picture resembles that observed among newborns with hypopituitarism and secondary adre¬ nal failure.18"22 At the age of 3 months, patients have hypotonia, psychomotor retarda¬ tion, defective visual fixation, and sei¬ zures. A firm, nontender liver may be palpable and, in one case, there was mild jaundice. A receding lower jaw
and, occasionally, a high-arched pal¬ ate may be present. The general ap¬
pearance is otherwise normal. The fasting blood glucose level may be mildly depressed, and results of liver function tests may be abnormal. The older child in this series had psychomotor retardation, growth fail¬ ure, defective vision, and seizures. He resembled the patients described by other authors.4-7 One of the three cardinal features of this syndrome merits further com¬ ment. Growth failure was present in one of our patients but could not as yet be demonstrated in the three in¬ fants. The fasting blood glucose level was depressed in three of the pa¬ tients, and in two of them results of the glucagon and leucine tolerance tests were normal, indicating that glycogenoses and leucine sensitivity were not responsible for the low blood glucose level. The immunoreactive in-
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sulin levels during the glucose load measured in two cases demonstrated no evidence of hyperinsulinism. The low growth hormone level and de¬ pressed function of the pituitary-ad¬ renal axis implied that this accounted for the hypoglycemia. All three cases studied for growth hormone secretion showed subnormal response to provocative stimulation. One of them demonstrated vasopressin-responsive diabetes insipidus, and another had asymptomatic, partial antidiuretic hormone deficiency with a subnormal response to metyrapone inhibition, suggesting adrenocorticotrophic hormone deficiency; one of the three appeared to have adrenocorticotrophic hormone deficiency and hypothyroidism, the latter conceiv¬ ably due to thyrotropin deficien¬ cy. These observations compare with with those of other authors who found the extent of the endocrine deficiency varied from isolated growth hormone
insufficiency to panhypopituitarism.58 In the syndrome of optic nerve hypo¬ plasia with hypopituitarism, just as in some cases of idiopathic hypopituitar¬ ism, the hypothalamic neurohypophy-
seal control of the
pituitary hormone secretions seems important.5-2 Kap¬ lan and others5 suggested that the hypopituitarism in this syndrome was ascribable to a diencephalic lesion that resulted in deficiency of hypothalamic-releasing factors, and, in some cases, vasopressin. The autopsy findings in our patient are thus of great interest. The diagnosis of optic nerve hypo¬ plasia with hypopituitarism may be '
difficult, especially in early life; in fact, in our patients initial diagnoses included idiopathic neonatal hypogly¬ cemia, hypoxia, and hepatitis. In one case the importance of the optic nerve hypoplasia was not recognized. In one child the appearance of the optic disc
wrongly interpreted as optic at¬ rophy. However, the appearance of the disc with an inner hypoplastic margin and an outer halo should serve to differentiate it from optic at¬ rophy.24 Unilateral hypoplasia has been diagnosed as simple esotropia or strabismic amblyopia.22-24 Visual de¬
is normal and vi¬ sual evoked responses that are absent might be helpful in the diagnosis. The physician should be aware of this relatively common syndrome of optic nerve hypoplasia with hypo¬ pituitarism, the variable clinical pic¬ ture dependent on the age groups, and the diagnostic pitfalls. Agenesis
troretinogram that
of the septum pellucidum, initially thought to be an integral part of this syndrome, is inconstant and not es¬ sential. A careful examination of the fundus permits correct diagnosis and timely assessment of the endocrine status so that the deleterious effects of hormone deficiencies might be avoided, and the prognosis of these children improved.
was
fect is hard to assess in infants, espe¬ cially if psychomotor retardation is also present. In such cases, the elee-
Henry G. Dunn, MB, FRCP, gave encour¬ agement and advice; George D. M. Kettyls, MD, and John H. Sturdy, MD, provided pathology re¬ ports; and Edward G. Cook, MB, MRCP, and Ju¬ dith C. Naylor, MB, FRCP(C), referred the pa¬ tients to
us.
Nonproprietary
Name and Trademarks of Drug
Ampicillin sodium-^ipera-iV, Amcill-S, Omnipen-N, Penbritin-S.
References 1. Reeves DL: Congenital absence of septum pellucidum. Johns Hopkins Med J 69:61-71, 1941.
2. de Morsier G: \l=E'\tudessur les dysraphies cr\l=a^\nio-enc\l=e'\phaliques:III. Ag\l=e'\n\l=e'\siedu septum lucidum avec malformation du tractus optique: La dysplasie septooptique. Schweiz Arch Neurol Psychiatr 77:267-292, 1956. 3. St. John JR, Reeves DL: Congenital absence of the septum pellucidum: A review of the literature with case report. Am J Surg 94:974-980, 1957. 4. Hoyt WF, Kaplan SL, Grumbach MM, et al: Septo-optic dysplasia with pituitary dwarfism. Lancet 1:893-894, 1970. 5. Kaplan SL, Grumbach MM, Hoyt WF: A syndrome of hypopituitary dwarfism, hypoplasia of optic nerves and malformation of prosencephalon. Pediatr Res 4:480\x=req-\ 481, 1970. 6. Brook CGD, Sanders MD, Hoare RD: Septo-optic dysplasia. Br Med J 3:811-813, 1972. 7. Harris RJ, Haas L: Septo-optic dysplasia with growth hormone deficiency (de Morsier syndrome). Arch Dis Child 47:973\x=req-\
976, 1972.
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