Journal of Pediatric Ophthalmology and Strabismus

Familial Dysautonomia: Report of a Case in a Non-Jewish Child

John H Mensher, MD

Abstract

When a disease entity or syndrome exists which has a definite and well documented racial predilection, it is of importance to be aware of cases of the same syndrome which, however, present in members of an apparently different racial or genetic pool. The Riley-Day syndrome or familial dysautonomia is inherited in an autosomal recessive manner and is seen almost exclusively in Ashkenazi Jews whose ancestry stems predominantly from Eastern European areas, Galicia, Bukowina, Ukraine, Roumania and Austro-Hungary.* The purpose of this report is to describe a patient whose parentage is non-Jewish but who has been diagnosed as having the Riley-Day syndrome.

CASE REPORT

The patient, LR., is now ten years old. She was first seen in the Department of Ophthalmology in August 1970. This was on referral from another department for treatment of an external eye problem. Subsequent to a workup -in the Pediatrics Department, a diagnosis of congenital Indifference to pain was given and because of her non-Jewish parentage, familial dysautonomia was discounted. On a return visit to the eye clinic several months after her initial visit, this diagnosis, however, was seriously entertained because of her eye findings.

At that exam, it was noted that her acuity was reduced to 6/9 and 6/15 in the right and left eyes respectively. There was a variable exotropia and hypertropia and the patient had reduced elevation of the left eye on versions. Blepharitis of a moderate degree was present. On slit lamp examination there was mild, anterior inferior opacification of the cornea bilaterally with a shallow groove below center on the right side only (Fig. 1). With fluorescein stain, epithelial damage was noted bilaterally. The pupils reacted normally both to light and near stimuli. The fundi were normal without vascular abnormalities. Corneal anesthesia was present Testing for basal secretion tears revealed below normal levels «10 mm after 5 minutes after topical anesthesia). Even without topical anesthesia, there was tear hypofunction. Mecholyl, 2.5 percent solution, produced miosis. Cycloplegic refraction revealed a compound hyperopic astigmatism of a mild degree.

SUMMARY

A case has been presented which fits the diagnostic criteria for inclusion in the Riley-Day or familial dysautonomia syndrome (Table I). Of interest is the fact that this child is of non-Jewish heritage. As such the child is rather unique. Several somewhat similar cases in the literature have been reported. They represent possible variants of the dysautonomia syndrome. The patient I have presented I believe is an authentic Riley-Day and has been examined by pediatricians knowledgeable of this syndrome who agree with the diagnosis. The possibility still exists, of course, that again this patient is a variant and that the only true Riley-Day patients are of Jewish origin. But I think this case is a strong argument against that notion.

A brief discussion of the salient features of the ailment has been given as well as a description of the patient in question. Some other simitar reports have been cited and their relevance to this paper have been noted.

1. Brunt PW, McKusick VA: Familial dysautonomia. A report of genetic and clinical studies with a review of the literature. Medicine 49:343-374, 1970.

2. McKusick VA, Norum RA, Farkas HJ, Brunt PW, Mahloudji M: The Riley-Day syndrome - Observations on genetics and survivorship. An Interim report. Israel J Med Sci 3:372-379, May-June, 1967.

3. Riley CM, Day RL, Greeley DMcL, Langford WS: Central autonomic dysfunction with defective lacrimation. Report of five cases. Pediatrics 3:468-478, 1949.

4. Riley CM: Familial autonomic dysfunction. J Amer Med Assoc 149:1532-1535, 1952.

5. Riley CM: Familial dysautonomia. Advances Pediat 9:157-190, 1957.

6. Smith A: Absence of taste bud papillae in…

When a disease entity or syndrome exists which has a definite and well documented racial predilection, it is of importance to be aware of cases of the same syndrome which, however, present in members of an apparently different racial or genetic pool. The Riley-Day syndrome or familial dysautonomia is inherited in an autosomal recessive manner and is seen almost exclusively in Ashkenazi Jews whose ancestry stems predominantly from Eastern European areas, Galicia, Bukowina, Ukraine, Roumania and Austro-Hungary.* The purpose of this report is to describe a patient whose parentage is non-Jewish but who has been diagnosed as having the Riley-Day syndrome.

CASE REPORT

The patient, LR., is now ten years old. She was first seen in the Department of Ophthalmology in August 1970. This was on referral from another department for treatment of an external eye problem. Subsequent to a workup -in the Pediatrics Department, a diagnosis of congenital Indifference to pain was given and because of her non-Jewish parentage, familial dysautonomia was discounted. On a return visit to the eye clinic several months after her initial visit, this diagnosis, however, was seriously entertained because of her eye findings.

At that exam, it was noted that her acuity was reduced to 6/9 and 6/15 in the right and left eyes respectively. There was a variable exotropia and hypertropia and the patient had reduced elevation of the left eye on versions. Blepharitis of a moderate degree was present. On slit lamp examination there was mild, anterior inferior opacification of the cornea bilaterally with a shallow groove below center on the right side only (Fig. 1). With fluorescein stain, epithelial damage was noted bilaterally. The pupils reacted normally both to light and near stimuli. The fundi were normal without vascular abnormalities. Corneal anesthesia was present Testing for basal secretion tears revealed below normal levels «10 mm after 5 minutes after topical anesthesia). Even without topical anesthesia, there was tear hypofunction. Mecholyl, 2.5 percent solution, produced miosis. Cycloplegic refraction revealed a compound hyperopic astigmatism of a mild degree.

Fig. 1. Mild opacification of the right cornea with a shallow groove.

Fig. 1. Mild opacification of the right cornea with a shallow groove.

Further examination of the child revealed a "bird-like" facial structure (Fig. 2), absence of fungiform papi II i (confirmed by the Oral Surgery Department) and atrophic circumvallate papi I II (Fig. 3), and a scoliosis which required bracing (Figs. 4A and 4B). In addition, the child wore a bib because of persistant drooling. Her hands bore the scars of repeated trauma Fig. 5). Her knees showed evidence of possible early Charcot changes (Fig. 6). She was moderately dysarthrlc with a nasal quality to her voice. In tests for recognition of painful stimuli, the child was found Insensitive. Deep tendon reflexes were absent Taste discrimination was impaired. She was moderately incoordinated being both clumsy with her upper extremities and stumbling with an unsteady gait Intradermal histamine (0.05 cc of a 1:1,000 solution) produced a wheal but no flare. An EEG has not been performed and because of some problems in collection, determinations of urine HVA and VMA have not been performed. A history of feeding problems early in the child's life was present The child would not swallow properly and persists In this. When the child became excited, skin blotching occurred. There was a history of high fevers of an unexplained etiology. The mother had had one spontaneous abortion previously but had two other female offspring both older than the patient and both entirely normal. The patient's maternal grandmother had a child who died suddenly at an early age without a cause being ascertained. The patient's mother is not of Jewish extraction and her family roots are in the British isles. The patient's father likewise is not of Jewish parentage but his roots are in Eastern Europe.

Fig. 2. Characteristic physiognomy notad In the patient.

Fig. 2. Characteristic physiognomy notad In the patient.

Fig. 3. Absence of fungiform and atrophy of clrcumvallate papillae noted In the patient.

Fig. 3. Absence of fungiform and atrophy of clrcumvallate papillae noted In the patient.

Since the patient's early visits and treatment in the Department of Ophthalmology, she has done well from an ophthalmologic point of view. Artificial tears of various makeup have been used. Most of the time, gelatin in Locke's solution has been used. One year after her initial treatment the child had an acute worsening of her corneal problem requiring patching and bland ointments. This may have coincided with a viral Illness. At her most recent visit to the clinic, ner acuity was 6/6 and 6/7.5 in the right and left eyes respectively. There was still the mild opacification of the epithelium below center on the right side and there was epithelial staining which was most prominent on the left side. She has recently been found to have broken her left leg and right arm. Diagnosis of these injuries was delayed because of the patient's lack of symptomatology, I.e., no pain at all.

The diagnosis from all signs and symptoms would appear to be familial dysautonomia, RileyDay syndrome. That the patient Is not of Jewish background poses a problem in the diagnosis but in fact makes this patient rather unique In view of available information pointing to the incidence of this syndrome only in Ashkenazl Jewish children.

DISCUSSION

The Riley-Day or familial dysautonomia syndrome is a multlfaceted one. According to McKusick, et al 2 the incidence is one in 10,000 to 20,000 live births among American Jews. It is inherited as an autosomal recessive, and It is seen equally in the sexes. When Riley and Day, et al3 described the first five cases, they set forth a long list of characteristics they found most commonly in these five Individuals. The list included mild anxiety problems, excessive sweating and salivation, red blotching of the skin, transient increases in blood pressure, decreased tear production, cyclic vomiting spells, hypoactive deep tendon reflexes, mental retardation, motor incoordination, cold extremities, speech difficulty, electroencephalographic abnormality, frequent pulmonary infections and Jewish parentage. Later in 1952 Riley4 published a more extensive work compiling 33 cases. To the above list of signs and symptoms he added relative indifference to pain, frequent unexplained fevers, breath holding spells, convulsions and an eye sign, corneal ulceration. Ten of the 33 cases had died, eight of them as a result of aspiration pneumonia. At that time, however, Riley suggested, with respect to longevity in these patients or their prognosis, that there was "nothing in the basic condition incompatible with long life so that is seems probable that as knowledge of the syndrome becomes more widespread more adult examples of it will be found."4 In 1957, Riley5 expanded on his finding of pain insensitivity. The affected patient, although unable to experience pain, could identify a pinprick not as a noxious stimulus but as a sensation of touch which, Riley asserted, remained intact. Various emotional problems including the possibility of a psychic relation to cyclic vomiting were also described.5 In addition, the characteristic bird-like facies, retarded growth and scoliosis were noted.

Fig. 4A and 4B. (two photos - front and back view) Presence of a scoliosis requiring a Milwaukee type brace.

Fig. 4A and 4B. (two photos - front and back view) Presence of a scoliosis requiring a Milwaukee type brace.

Fig. 5. Evidence of repeated trauma to the hands.

Fig. 5. Evidence of repeated trauma to the hands.

Fig. 6. Possible early hypertrophic changes In the knees.

Fig. 6. Possible early hypertrophic changes In the knees.

Smith reported the patient's inability to discern tastes and showed associated tongue changes: absence of fungiform papillae which, in the normal tongue, are concentrated on the tip and lateral surfaces, and absence of the circumvallate papillae which normally are located posteriorly, seven to 15 in number, organized in a V-shape with its apex pointed posteriorly. Interestingly, Henkin and Kopin7 in 1964 published a report on the increased taste thresholds and showed that with systemic injection of mecholyl the affected patient's taste sensitivity could be normalized. Topically administered mecholyl had no effect Pearson, et al" were unable to find nerve fibers traveling to rudimentary papillae which they examined microscopically. What taste sensation exists in Riley-Day patients is probably accounted for by olfaction abilities.

Drooling is noted clinically and may be related to an excessive rate of salivation. However, this problem may be related to a swallowing difficulty these patients have. Margulies, et al * described this using cineradiography techniques. They found a delay in the opening of the cricopharyngeal sphincter which led to a difficulty in the initiation of the pharyngeal phase of deglutition. Thus, the subsequent movement of ingested foods or saliva, for instance, from the pharynx into the esophagus was hampered. The feeding difficulties noted in infancy in dysautonomic children, the incidence of aspiration pneumonia, and drooling, may all be related to this malfunction.

Dysarthric speech is notable as has been described by Halpern, et al. · This may be due, they suggest, to a lack of both gross and fine motor control. The affected child's speech has a monotonous, nasal quality and there Is lack of loudness and rate control.

Brunt11 described a dysautonomic patient with destructive joint disease of the neuropathic or Charcot type. Without appropriate afferent sensory input this is inevitable. The extremities show multiple scars of unfelt injuries and the fingers may be especially mutilated. Various attempts at discovering the reason for the sensory deficit have led only to speculation.7'1*''3 Both an anatomical defect11 and a pharmacologic or humoral abnormality13 have been proposed as the causal factors involved.

The EEG has been reported as abnormal by Niedermeyer, et al u with spike and wave changes without a focal quality. A metabolic basis was proposed to account for the alterations found.

Sak, et al ls have refuted the claim that the children are mentally retarded. They described motor retardation and usually the affected patients were in the dull normal range. There was emotional immaturity which prevented appropriate interpersonal relationships and consistent school attendance and participation.

There is peripheral Insensitivity to increased blood levels of CO 2 and the presence of hypoxia.16 Blood pressure control is inadequate and orthostatic hypotension is noted as a result17 With peripheral mechanisms for homeostasis not being effective, general anesthesia can be a definite hazard.'8'" In fact, Goldln and Harris20 reported their reluctance to place a 6-year-old Riley-Day patient under general anesthesia for skin grafting necessitated by burns the patient received. Because of the child's Insensitivity to pain the graft was done without anesthesia other than sedation with meperidine. Smith and Dancis21 noted supersensitivity to infused norepinephrine. This has been confirmed by Dancis" and Jones.23 Autonomic dysfunction is a factor in this phenomenon and general anesthesia may potentiate this.

Aguayo, et al M have studied nerve conduction velocities and EMG responses in a dysautonomic patient Motor nerve conduction velocities were slower than normal but muscle action potentials were normal. When sensory conduction was tested results showed reduced amplitudes in some nerves and absent or unrecordable amplitudes in others. EMG studies were normal. Phase microscopy revealed irregularity of the fiber shape as compared with normal control specimens. In addition, large diameter myelinated nerve fibers were absent On EM examination there was a decrease in the number of unmyelinated fibers but no evidence of demyelinization, axon degeneration or remyelinization could be found. Post-ganglionic autonomic fibers are for the most part unmyelinated. A decrease or absence of these could explain postural hypotension, altered excretion of catecholamine metabolites, poor temperature control, skin blotching, defective lacrimation, mecholyl sensitivity and other of the signs and symptoms of the disease. Loss of the deep tendon reflexes could be related to absence of large, myelinated fibers. Peripheral sensation and homeostatlc mechanism impairment and the absent flare after intradermal histamine may be explained by loss of unmyelinated fibers. The authors24 suggest an arrest in development of unmyelinated and large myelinated fibers in peripheral nerves and question the presence of an abnormal nerve growth factor.

Smith and Hui M have also examined unmyelinated nerve fibers in these patients studying them in tongue, extraocular muscle and lacrimal gland. Because mecholyl infused system ica My has the effect of normalizing taste and deep tendon reflexes, the defect is presumed to be not an anatomical one. The innervation is normal, but there is a functional defect both in the sensory and parasympathetic systems. These authors felt the difficulty might lie with acetylcholine synthesis, storage and/or release."

There is also an abnormality of the adrenergic function as shown by the shift to an increased dopamine metabolism away from norepinephrine. Dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxy-tyramine and 3methoxy-4-hydroxyphenylacetic acid (HVA) are increased. By O-methylation DOPAC converts to HVA and by the action of MAO 3-methoxy-tyramine also converts to HVA. This metabolite, then, is found in increased amounts in the urine of dysautonomics. The metabolites of norepinephrine, 3methoxy-4-hydroxy mandelic acid and vanilmandelic acid (VMA), are decreased. It is possible that there is, through a genetic inborn error, a defect in the enzyme system which is involved in the norepinephrine system.26 Dancis and Smith27 showed an increased HVA excretion in dysautonomics while the VMA level remained normal in this group. The enzyme dopamine-B-hydroxylase, which is localized in catecholamine-containing vesicular structures in sympathetic nerves and in chromaffin granules in the adrenal medulla, is found to be reduced in the plasma of dysautonomic patients.28 This enzyme is released with catecholamines and its low plasma level may reflect a defect in maturation of sympathetic nerves.

The dysautonomic patient is described as being uncoordinated with a peculiar stumbling gait There is an increased incidence of scoliosis and fractures. The scoliosis is reported most often between the T-2 and L-1 segments. With progression of the scoliosis, kyphoscoliotic cardiopulmonary decompensation may ensue.29 Osteochondritis is noted as is hip dysplasia. Many of the patients have been found to have some degree of demineralization with osteoporosis. Soft tissue contractures especially of the Achilles tendon and the hip are also seen. The Milwaukee brace that is utilized in control of the scoliosis may produce pressure ulceration. Because of lack of deep sensation fractures may occur without the knowledge of the individual. With repeated trauma to joint structures "Charcot" changes are possible.

In diagnosis, intradermal histamine (0.03 to 0.05 ml of a 1:1,000 concentration) is utilized.30 Normally a wheal is produced by the injection of histamine and an axon flare will ensue and cover about three to five cm of skin surface. Although a wheal is produced in the dysautonomic patient, no flare but only a small erythematous areola of one to two mm is observed. Absence of an afferent arc, with no pain sensation, is offered as an explanation.

The inability to produce adequate lacrimation is a problem in dysautonomics. Kroop 3I showed the response of overflow tearing to systemic methacholine. The pupil, which normally does respond to light well, becomes miotic with low concentrations of the cholinergic activator, methacholine (2.5 percent).32 Normally the pupil does not respond to this dose unless denervation is present as in Adie's tonic pupil.

The lack of appropriate tearing can lead to drying of the cornea with ulceration and visual loss.33 Because of the lack of corneal sensation, the affected individual does not blink and thus the problem is compounded. Tarsorrhaphy, though undesirable in young children, is, in some instances, indicated.34'33 Gunderson flaps have also been utilized.3*

Goldberg, et al37 in 1968 published a review of the ophthalmologic aspects of familial dysautonomia. In their series the acuities ranged from 6/6 to 6/60 with the median 6/12 and mode 6/6. On slit lamp examination corneal nerves were visible but sensation was impaired. Fifty percent of their patients had corneal ulcerations. Basal secretion of tears was impaired as was stimulated tear function. Of interest, 25 percent of the parents tested also had abnormally low tear production. Myopia was present in 80 percent of the individuals tested and anisometropia was also common. Exodeviations were present in two-thirds of the patients, the deviation measuring from 20 to 58 prism diopters. Two-thirds of the patients had retinal vascular tortuosity with engorgement, hemorrhage, exudates or papilledema. The reason for the tortuosity is not known but may relate to systemic hypoxia, blood-gas abnormalities, e.g., cyanosis retinae. There was no evidence of adrenergic denervation on testing with four percent cocaine. Twenty percent of the patients had an anisocoria, more than the incidence in the normal population. Intraocular pressures were normal.

The miotic response of the dysautonomic pupil to 2.5 percent mecholyl which was discussed previously is not a supersensitive one of the type seen in the Adie or tonic pupil. It is not a question of local denervation supersensitivity because the light and near responses of the pupil in familial dysautonomia are entirely intact Rather, it must be said that the miosis elicited is an apparent sign of systemic supersensitivity to the cholinergic substance.38

In the literature there are reports of cases of familial dysautonomia wJth non-Jewish ancestry. Aronson, et al3' have reported that the Riley-Day patients all have ancestors in southern provinces of Eastern Europe including Hungary, Rumania, Moldavia, Bucovina, Krakow and Lwow. The progenitors, they stated, stemmed from Gatician, Balkan and Ukranian Jewish enclaves.

From Australia comes a report of two cases described in 1966 by Burke.40 Although one of them was Jewish, the other was not The latter had most of the clinical signs and symptoms associated with the syndrome but had normal deep tendon reflexes, and a normal HVA: VMA ratio. Mecholyl, 2.5 percent, constricted the pupil, the histamine skin test was positive, no fungiform papillae were present, and there was a feeding difficulty with achalasia. Alacrima, flushing, orthostatic hypotension, and reduced pain sensation, also were evident. Hutchinson and Hamilton41 reported two Scottish children of non-Jewish heritage who were siblings and to whom they gave the diagnosis of familial dysautonomia. The basic clinical presentation was generalized hypotonia, with inability to suck or swallow. In addition, the corneal sensation was reduced as was the tear function. Skin blotching was noticed. Both died before the age of two. The diagnosis of familial dysautonomia is possible but doubtful in this case based on the description. Andersson, et al42 described a non-Jewish six-year-old child from Goteborg, Sweden whom they felt was a Riley-Day patient. Their presentation centered mainly on biochemical aspects of the syndrome and the diagnosis was made because of those abnormalities.

Grossman, et al4J described megacolon as a part of the dysautonomia syndrome presenting the case of a non-Jewish child with this diagnosis. The patient on exam had some but not all the stigmata classically outlined. Of interest on the paternal side there was a history of paraplegia and early demise of the grandmother's siblings. Linde44 presented a non-Jewish familial dysautonomic patient although there was the distinct possibility upon tracing the heritage that indeed Jewish ancestry may have existed. Again one year later, Linde ** presented two other cases who had some but not many signs of familial dysautonomia. Esterly, et al46 reported on a patient with Pupillotonie, hyporeflexia and segmental hypohodrosis. Although some of the findings could be associated with the Riley-Day Syndrome such as absence of fungiform papillae, most of the described anomalies did not fit the classical description. Rüssel and Avery47 published three cases of dysautonomia one of which occurred in a non-Jewish patient However, many of the clinical findings do not fit the diagnosis. Riley, et al * found one non-Jewish variant in a series of 48 cases and claimed it a possible forme fruste. Ginsberg, et al49 described a black child with a dysautonomia syndrome again with many of the basic findings of the Riley-Day syndrome. The child appeared to have an anhidrotic condition of the eye and mouth with marked dessication of the eye and accompanying poor vision. While there were signs compatible In part with a diagnosis of the Riley-Day syndrome, others were not Possibly, again, this represents a variant

In the case presented in this paper the signs and symptoms appear classical for an accurate diagnosis of familial dysautonomia despite the fact of the apparent absence of Jewish ancestry (Table I). There will be, as Ginsberg, et al 49 stated, gene mutations with incomplete penetration to explain the findings in cases not wholly typical. Thus, gene mutations or variations may explain the presence of the Riley-Day or a Ri ley-Day- 1 ike syndrome of autonomic dysfunction in non-Jewish individuals. An enzyme deficiency has been postulated as the basic defect in this syndrome.28 Possibly, then, from a different gene pool a different enzyme defect may be present accounting for a similar condition. This is speculation. And, of course, as Brunt and McKusick in their extensive review of familial dysautonomia noted "the complete absence of Jewish blood in any ancestry is always difficult or impossible to prove."1 Of importance, I believe, is the fact that one should not (simply on the basis of a lack of Jewish background) rule out a diagnosis of familial dysautonomia when the clinical presentation fits the described picture.

Table

TABLE 1SIGNS AND SYMPTOMS FOUND IN PATIENT

TABLE 1

SIGNS AND SYMPTOMS FOUND IN PATIENT

SUMMARY

A case has been presented which fits the diagnostic criteria for inclusion in the Riley-Day or familial dysautonomia syndrome (Table I). Of interest is the fact that this child is of non-Jewish heritage. As such the child is rather unique. Several somewhat similar cases in the literature have been reported. They represent possible variants of the dysautonomia syndrome. The patient I have presented I believe is an authentic Riley-Day and has been examined by pediatricians knowledgeable of this syndrome who agree with the diagnosis. The possibility still exists, of course, that again this patient is a variant and that the only true Riley-Day patients are of Jewish origin. But I think this case is a strong argument against that notion.

A brief discussion of the salient features of the ailment has been given as well as a description of the patient in question. Some other simitar reports have been cited and their relevance to this paper have been noted.

REFERENCES

1. Brunt PW, McKusick VA: Familial dysautonomia. A report of genetic and clinical studies with a review of the literature. Medicine 49:343-374, 1970.

2. McKusick VA, Norum RA, Farkas HJ, Brunt PW, Mahloudji M: The Riley-Day syndrome - Observations on genetics and survivorship. An Interim report. Israel J Med Sci 3:372-379, May-June, 1967.

3. Riley CM, Day RL, Greeley DMcL, Langford WS: Central autonomic dysfunction with defective lacrimation. Report of five cases. Pediatrics 3:468-478, 1949.

4. Riley CM: Familial autonomic dysfunction. J Amer Med Assoc 149:1532-1535, 1952.

5. Riley CM: Familial dysautonomia. Advances Pediat 9:157-190, 1957.

6. Smith A: Absence of taste bud papillae in familial dysautonomia. Science 147:10401041, 1965.

7. Henkin R, Kopln I: Taste-smell thresholds. Life Sci 3:1319-1325, 1964.

8. Pearson J, Finegold M, Budzilovfch G: The tongue and taste In familial dysautonomia. Pediatrics 45:739-745, 1970.

9. Margulies SI, Brunt PW, Donner MW, Silbiger ML: Familial dysautonomia. A cl ne radiographic study of the swallowing mechanism. Radiology 112, 1968.

10. Halpern H, Hochberg I, Rees N: Speech and hearing characteristics In familial dysautonomia. J Speech Hearing Res 10:361366, 1967.

11. Brunt PW: Unusual case of Charcot joints in early adolescence (Riley-Day syndrome). Brit Med J 4:277-278, 1967.

12. Brown JC, Johns RJ: Nerve conduction In familial dysautonomia, (Riley-Day syndrome). J Amer Med Assoc 201:200-202, 1967.

13. Winkelmann RK, Bourland A, Smith AA: Nerves in the skin of a patient with familial dysautonomia (Riley-Day syndrome). Pediatrics 38:1060-1062, 1966.

14. Niedermeyer E, McKusick VA, Brunt PW, Mahloudji M: The EEG in familial dysautonomia. Electroenceph Clin Neurophysiol 22:473-475, 1967.

15. Sak HG, Smith AA, Dancis J: Psychometric evaluation of children with familial dysautonomia. Amer J Psychiat 124:682-687, 1967.

16. Filler J, Smith AA, Stone S, Dancis J: Respiratory control in familial dysautonomia. J Pediat 66:509-516, 1965.

17. Mason DT, Kopin IJ, Braunwald E: Abnormality in reflex control of the circulation in familial dysautonomia. Effects of posture on venous and arterial constrictions in normals and In a patient with dysautonomia. Amer J Med 41:898-909, 1966.

18. McCaughey TJ: Familial dysautonomia as an anesthetic hazard. Canad Anesth Soc J 12:358-368, 1965.

19. Bartels J, MazzlaV: Familial dysa,. tonomia. J Amer Med Assoc 212:318-319, 1970.

20. Goldln JH. Harris RJ: A case of familial dysautonomia: Cutting skin grafts without anesthesia. Brit J Plastic Surg 26:184-185, 1973.

21. Smith AA, Dancis J: Exaggerated response to infused norepinephrine in familial dysautonomia. New Engl J Med 270:704-707, 1964.

22. Dancis J: Altered drug response in familial dysautonomia. J Ann ? Y Acad Sci 151:876879. 1968.

23. Jones WP: Circulatory collapse associated with defective catecholamine metabolism. Hawaii Med J 25:101-105, 1965.

24. Aquayo A, Nalr C, Bray G: Peripheral nerve abnormalities in the Riley-Day syndrome. Findings in a sural nerve biopsy. Arch Neurol 24:106-116, 1971.

25. Smith AA, Hui F: Unmyelinated nerves in familial dysautonomia. Neurol (Minneapolis), 23:8-11. 1973.

26. Goodall McC. Gitlow SE, Alton H: Decreased noradrenaline (norepinephrine) synthesis in familial dysautonomia. J Clin I nvest 50:27342740, 1971.

27. Dancis J, Smith AA: Current Concepts: Familial dysautonomia. New Engl J Med 274:207-209, 1966.

28. Weinshilboum R, Axelrod J: Reduced plasma dopamine-B-hydroxylase activity in familial dysautonomia. New Engl J Med 285:938-942, 1971.

29. Yoslow W, Becker M , Bartels J, Thompson W: Orthopedic defects in familial dysautonomia. J Bone Joint Surg (Arn) 53-A: 1541 -1550, 1971.

30. Smith AA, Danois J: Response to intradermal histamine in familial dysautonomia: A diagnostic sign. J Pediat 63:889-894, 1963.

31. Kroop IG: The production of tears in familial dysautonomia - preliminary report J Pediat 48:326-329, 1956.

32. Smith AA, Danois J, Breinin G: Ocular responses to autonomic drugs In familial dysautonomia. Invest Ophthalmol 4:358-361, 1965.

33. Keith CG: Riley-Day syndrome, congenital familial dysautonomia. Br J Ophthalmol 49:667-672, 1965.

34. Dunnlngton JH: Congenital alacrima In familial dysautonomic dysfunction. Arch Ophthalmol 52:925-931, 1954.

35. Liebman SD: Riley-Day syndrome: Long term ophthalmologic observations. Trans Amer Ophthal Soc 66:95-116, 1968.

36. Boruchotf SA, Dohlman CH: The Riley-Day syndrome: Ocular manifestations In a 35year-old patient Am J Ophthalmol 63:523-524, 1967.

37. Goldberg MF, Payne JW, Brunt PW: Ophthalmologic studies of familial dysautonomia, the Riley-Day syndrome. Arch Ophthalmol (Chicago), 80:732-743, 1968.

38. Thompson HS: Personal communication. University of Iowa Department of Ophthalmology, 1971.

39. Aronson S, Herzog M, Brunt ?, McKusIck V, Myrianthopoulos N: Inherited neurologic diseases of Ashkenazic Jewry: Demographic data suggesting non-random gene frequencies. Trans Am Neurol Assoc 92:117121, 1967.

40. Burke, V: Familial dysautonomia. Austral Pediat J. 2:58, 1966.

41. Hutchison JH, Hamilton W: Familial dysautonomia in two siblings. Lancet 1:1216, 1962.

42. Andersson H, Hagne I, Roos BE: Homovanillic acid and 5-hydroxy-indolacetic acid in cerebrospinal fluid of a child with familial dysautonomia. Acta Paedlatr Scand 62:46-48, 1973.

43. Grossman HJ, Limosani MA, Shore M: Megacolon as a manifestation of familial autonomic dysfunction. J Pediat 49:289, 1956.

44. Linde LM: Dysautonomia. Case report of a variant J Pediat 46:453, 1955.

45. Linde LM: Diagnosis and management of dysautonomia. Pediatrics 18:692, 1956.

46. Esterly NB, Cantollno SJ, Alter BP, Brusilow SW: Pupillotonie, hyporeflexla and segmental hypohidrosis: Autonomic dysfunction in a child. J Pediat 73:852, 1968.

47. Russell A, Avery H: Familial dysautonomia with other anomalies (Riley-Day syndrome): Three examples. Proc Roy Soc Med 56:291, 1963.

48. Riley CM, Freedman AM Langford WS: Further observations on familial dysautonomia. Pediatrics 14:475, 1954.

49. Ginsberg S, Polack F, Ravin M: Autonomic dysfunction syndrome. Am J Ophthalmol 74:1121-1125, 1972.

TABLE 1

SIGNS AND SYMPTOMS FOUND IN PATIENT

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