Are You Confident of the Diagnosis?
What you should be alert for in the history
Familial dysautonomia (FD) is an autosomal recessive disorder characterized by autonomic and sensory dysfunction. It is classified as a hereditary sensory and autonomic neuropathy (HSAN type III), and is also known as Riley-Day syndrome, which was named for the two doctors who first described it in 1949.
The FD neuropathology results in variable degrees of sensory and autonomic dysfunction affecting most of the organ body systems. Apart from the neurological system, the main systems affected are
– the cardiovascular system, with extreme changes of blood pressure, either high or low. . Postural hypotension or any other hypotension episodes are without compensatory tachycardia. There are variable degrees of arrhythmias.
– the gastrointestinal system, with symptoms including nasopharyngeal dyscoordination with swallowing problems, gastroesophageal reflux (GER), and abnormal gastrointestinal motility.
– the respiratory system, which is affected by recurrent episodes of aspiration, either from fluid or food introduced by the mouth or by aspiration of gastric contents from GER, leading to respiratory distress and chronic lung disease. These patients have decreased CO2 sensitivity and altered O2 sensitivity. Patients may also experience central and obstructive apneas, as well as hypopnea during sleep.
– the skeletal system, which is affected by spinal curvature (scoliosis, kyphosis, lordosis); patients (even those who are young) may experience osteoporosis, increased fractures, avascular necrosis, and deformations of the lower extremities.
– the renal system: there is progressive renal insufficiency as patients get older.
Physical or emotional stress may lead to FD crises, which are manifested by protracted bouts of nausea, vomiting, hypersalivation, high blood pressure, sweating, skin blotching, tachycardia, agitation, and behavioral changes. Some of these manifestations can be seen in Figure 1. See details about clinics below.
Characteristic findings on physical examination
Clinical manifestations include absent or small fungiform papillae on the anterior part of the tongue, absence of overflow tears, increased sweating, decreased skin pain and temperature perception, as well as impaired skeletal pain. However, visceral pain is intact.
There are high incidences of convulsive disorders and developmental delays. The gait is not stable and ataxia is sometimes observed, as is nystagmus and tremor. Corneal and tendon reflexes are diminished. The motor system is also affected, and there is hypotonia, especially during infancy.
The patient’s denervation hypersensitivity to sympathetic and parasympathetic agents is very important, especially during anesthesia. Usually they are considered as “failure to thrive” based on where they fall in the growth percentiles. Emotional instability is sometimes noted. Intelligence is usually normal. (See more details below under Systemic Implications and complications.)
SPECIFIC SKIN CHARACTERISTICS OF FD PATIENTS
See below under diagnostic studies
The skin of FD patients may develop erythematous blotching in patches in part or all over the body, which can be induced by stress, eating, or FD crises. These can fade after a few minutes or more. Blotching tends to become less frequent as the patient grows older. Blotching may resemble an allergic eruption.
Pain and Temperature Sensitivity
There is an impaired perception of pain and temperature, however visceral pain, except in bones, is intact. There may be areas of increased touch perception, especially on the scalp, genitalia, and dorsum of the foot.
Generally, FD patients have increased sweating, especially on the trunk and head, which is intensified by stress and FD crises. The hyperhidrosis appears, despite the reduction of sudomotor fibers and sweat glands associated with this autonomic neuropathy.
This can be explained by the fact that in a disorder with severe sympathetic nerve fiber reduction, sudomotor fibers (but not the sweat gland itself) exhibit chemical hypersensitivity. This might also explain excessive episodic hyperhidrosis in situations with increased central sympathetic outflow.
Due to blood pressure changes (especially hypotension), the skin of the trunk (particularly in the distal extremities) may have poor circulation, which results in a mottled appearance and cutis marmorata, even from infancy. Feet and hands can be cold, red-purple in color (acrocyanosis), and puffy. The hands in a few FD patients can sometimes resemble those of patients with Raynaud syndrome.
Stempler et al. concluded in their study that the reduced overall limb perfusion in patients with FD is due to hypertension-induced structural changes to vessel walls, with an increase in resistance vessel rigidity. The exaggerated post-ischemic skin perfusion in FD patients seems to be due to deficient sympathetic innervation of precapillary vessels and arteriovenous shunts, and to denervation hypersensitivity of intradermal small nerve fibers.
During dysautonomic crises, FD patients have hypertensive blood pressure that is presumed to be secondary to episodic vasodilatation as well as swollen hands. Both the reduced limb perfusion and dysfunctional end-organ blood supply may be major contributors to the vasomotor instability, especially during stress. No pitting edema of the extremities can be seen, even without a crisis.
Patients do not usually feel pain when they have fractures or joint injury. The swelling can be the only visible external indicator.
Chicken Pox, Varicella Zoster Virus (VZV), and Herpes (HSV-1) Eruptions
These viruses infect and are reactivated in the periphery through C-type sensory nerve fibers, which are decreased in FD patients. Thus, the clinical manifestations of the typical skin eruption of these viruses in FD patients are diminished and can be very mild.
Ulcers and Healing
The sensory problems of FD patients can cause skin lesions. There is self-mutilation, which can also cause ulcers, skin or tissue loss, as well as short nails. Parents must be taught to protect pediatric patients, and adult patients must protect themselves. Care must be taken to prevent pressure sores and burns, as their healing is slow.
Kyphoscoliosis conservative treatment (which includes physiotherapy and wearing a back brace) can be useful, but if it is ineffective, a spinal fusion operation may be needed. The back brace can cause discomfort before the operation, and the screws of the rods can cause chafing afterwards.
Excessive drooling can cause irritation around the mouth.
Burns can be a complication arising from the expansion of the gastrostomy stoma (due to friction or movement of the tube or button). In some cases, this expansion may allow gastric acid to flow out of the gastrostomy tube and can cause a chemical burn in the surrounding tissue. This may be compounded by a fungal or microbiological infection of the surrounding tissue. The leakage can expand the stoma even more, which can make the size of the tube or button inappropriate for use.
Hair, Scalp, and Ears
There is a tendency for seborrheic dermatitis and dandruff in the scalp and behind the ears. There is also increased cerumen in the ears. The sebaceous glands tend to produce excessive oil.
Pallor and Cyanosis
Pallor is caused by anemia, which is common in FD patients. Cyanosis is caused by hypoxia (due to chronic and/or restrictive lung disease).
Expected results of diagnostic studies
The axon flare response following intradermal histamine injection depends on activation of unmyelinated C fibers, which are deficient in FD. In healthy individuals, intradermal injection of histamine phosphate 1:1000 produces pain, followed within a minute by the development of a wheal surrounded by an axon flare, which is an erythematous area with an undefined boundary that has a radius of 1-3cm. The erythema fades away after 7-10 minutes.
In FD patients, the pain is reduced and there is no normal flare. However, there is sometimes a very narrow (1-2mm) circle of redness surrounding the wheal. This area may (rarely) exhibit pseudopodia patterns. In FD infants, who usually have more sensitive skin, a dilution of 1:10,000 may produce a more clearly abnormal reaction. Such abnormal results are diagnostic for FD, however they can appear in all patients with congenital sensory neuropathy diseases. A control test of intradermal saline is always needed. This phenomenon should also be taken in account when allergy tests are considered for these patients.
The FD gene, IKBKAP (inhibitor of kappa light polypeptide gene enhancer in B cells kinase complex associated protein), is located on the distal long arm of chromosome 9(q31), and in 99.5% of all FD cases, a mutation on intron 20 is found. The most common mutation causes a splicing alteration that leads to reduced protein (IKAP) expression in all tissues, but this reduction is variable and is most severe in the neuronal tissue. The physiological consequences of mutations in this gene are not fully known. Genetic tests have been available since 2001 for the diagnosis of FD patients as well as FD gene carriers.
In FD there is underdevelopment of peripheral unmyelinated and small myelinated neuronal fibers. Histological examinations of the skin have shown severe deficiency of peripheral nerves as well as decreased neurons in the ganglia and spinal cord. There is a deficiency of C fibers, with deficiency of calcitonin gene-related peptide (CGRP), which is a prominent and significant neurotransmitter in these fibers.
Hilz et al. used FD punch-skin biopsies from the calf and back to assess cutaneous nerve fiber loss, in conjunction with studies of temperature and sweating dysfunction. The mean temperature thresholds and baseline sweat rates were elevated in the patients, while total sweat volume and response time did not differ from the controls. Temperature perception was more impaired than sweating. The average density of epidermal nerve fibers was greatly diminished. There was also severe nerve loss from the subepidermal neural plexus (SNP) and deep dermis.
The few sweat glands present within the biopsies had reduced innervation density. Substance P immunoreactive (-ir) and calcitonin gene-related peptide-ir (CGRP-ir) were absent, but vasoactive intestinal peptide-ir (VIP-ir) nerves were present in the SNP. Empty Schwann cell sheaths were observed. Empty Schwann cell sheaths and VIP-ir nerves suggest active denervation and regeneration.
In another study, Hilz et al. showed that sympathetic skin responses (SSR) demonstrated overall integrity of the SSR reflex arc, however the SSR amplitudes were reduced, indicating decreased efferent sympathetic activity. The authors concluded that the reserved response to electrical stimulation and absence of SSR with thermal stimulation reflects afferent small fiber dysfunction.
Bickel et al. used dermal microdialysis to examine sensitivity of skin vessels to noradrenaline (NA) in FD patients and proved that their peripheral blood vessels show a denervation hypersensitivity to catecholamines.
There is evidence of slow progressive sensory degeneration with age.
Who is at Risk for Developing this Disease?
FD has been observed almost exclusively in individuals of Eastern European Jewish descent, with an incidence of 1:3703 in this population.
What is the Cause of the Disease?
FD is an autosomal recessive disorder characterized by autonomic and sensory dysfunction. It is classified as a hereditary sensory and autonomic neuropathy (HSAN type III) disorder.
This is a genetic disease (as above). The physiological consequences of mutations in this gene are not fully known.
Systemic Implications and Complications
Severity among the patients varies. Implications and complications result because most body systems are affected by the defect of the autonomic and sensory nervous systems. These include failure to thrive, fevers (sometimes with no obvious cause), recurrent infections (especially due to aspirations), and insomnia. Due to denervation hypersensitivity of the autonomic nervous system, general anesthesia may produce profound hypotension and vascular instability.
Neurological implications and complications include autonomic dysfunction (e.g. excessive sweating, blotching, postural hypotension, gastrointestinal dyscoordination, and as above), seizures, decreased ability to feel pain and temperature (this leads to excessive injuries), unsteady gait (progressive ataxia), nystagmus, tremor, decreased muscle tone, and decreased deep tendon reflexes. Body temperature regulation may also be altered. Joint position and vibration senses diminish with age. Behavioral and emotional abnormalities, and developmental delay, may be observed. Sometimes speech is slurred.
Cardiovascular implications and complications include orthostatic decrease in blood pressure with no orthostatic tachycardia, syncope, arrhythmias, altered vascular tone (blood vessel spasms, dilations), and altered respiratory sinus arrhythmia.
Gastrointestinal implications and complications include decreased or absent fungiform papillae on the tongue (which alters taste), nasopharyngeal dyscoordination, gastrointestinal dysmotility, gastroesophageal reflux, delayed gastric emptying, vomiting and retching episodes, dysphagia, megaesophagus, constipation, diarrhea, and increased drooling. Eating can induce sweating and blotching.
Respiratory implications and complications include aspiration of fluids, food introduced orally, or gastric contents, which results in recurrent pneumonia and chronic lung disease with interstitial changes, as well as atelectasis and bronchiectasis. There is also restrictive lung disease, which is caused by kyphoscoliosis, decreased CO2 sensitivity, and altered O2 sensitivity, resulting in apnea and periodic breathing during sleep. Coupling of low blood pressure and hypoxia can cause syncope or cardiorespiratory arrest. There are breath-holding spells.
Skeletal implications and complications include kyphoscoliosis, lordosis, osteoporosis, recurrent fractures (with decreased bone pain), delayed bone age, feet deformations, avascular necrosis, and neuropathic joints.
Renal implications and complications include progressive renal insufficiency, frequently prerenal in nature, delayed urine control, and sometimes nocturia.
Ophthalmological implications and complications include no overflow tears, corneal ulcers and scars, risk of blindness, decreased corneal reflex, and optic atrophy progressing with age.
Patients may present with delayed sexual maturation. Some of the patients get married and have children.
Treatment considerations are summarized in Table I.
|General||All patients should be referred to a tertiary care center that has experience in treating FD patients|
|Dermatological- general||Protection from skin trauma (burning, painful contact injuries)||Burns and traumatic skin injuries are treated in the same way as injuries in patients who do not have FD.|
|Dermatological- blotching||No specific therapy required|
|Dermatological- ulcers||Avoid pressure sores by using an inflatable mattress and change of positions; apply antibiotic ointment when necessary.|
|Dermatological- burns and infections||Keep the area surrounding the tube clean and dry to prevent infection. Apply ointment containing zinc or thick Maalox to treat a chemical burn. Apply antibiotic and antifungal ointments when necessary. Replacement of the gastrostomy tube or button should be considered.|
|Dermatological-cold extremities||Attempt to prevent hypotension with fluids, medications, and avoidance of postural hypotension. Gloves should be worn in cold weather and constrictive socks and cuffs should be avoided.|
|Dermatological-swelling, orthopedic||Swelling can be the only indicator of a fracture or joint injury.||Referral to orthopedics and to a physical therapist who has experience with FD patients|
|Dermatological- sweating||Keep environment cool and wear light clothing during sleep|
|Dermatological- hair, scalp, and ears||Frequent ketoconazole shampoo and ointment for the scalp and skin (caution that the soap should not get into the eyes). Clean deep cerumen in the ears with caution.|
|Gastrointestinal||Referral to gastroenterologist who has experience with FD patients|
|Ophthalmological||Referral to ophthalmologist who has experience with FD patients|
|Neurological||Referral to neurologist who has experience with FD patients|
|Respiratory||Referral to pulmonologist who has experience with FD patients|
|Behavioral||Referral to a psychologist or psychiatrist who has experience with FD patients|
Optimal Therapeutic Approach for this Disease
Prevention of ulcers and irritations, and hot or painful stimuli, is essential. Ventilate environment and wear light clothing to reduce perspiration.
Advise patient to consult an FD center that specializes in treating the disease.
Initiate immediate aggressive treatment for any skin infection to prevent systemic infection, sepsis, and necrosis.
A multidisciplinary approach is essential for patients with FD. Ideally, patients should be treated in a tertiary care center staffed by physicians who have familiarity with the disorder. Since the autonomic and sensory systems affect most organ systems, the treatment of various systemic conditions is beyond the scope of this chapter. See the first two references for additional systemic implications, complications, workup information, and management advice.
Unusual Clinical Scenarios to Consider in Patient Management
In two cases, self-mutilation by repeated friction to the nose with the finger caused loss of ala nasi in one side. One patient underwent several cosmetic surgical procedures that required skin flaps to correct the defect.
A protruding screw from the rods in a spinal fusion caused prolonged skin infection in the back with an abscess.
In a few cases, an infected pressure sore caused sepsis, and in others, this was also complicated by osteomyelitis.
What is the Evidence?
Gold-von Simson, G, Axelrod, FB. “Familial dysautonomia: Update and recent advances”. Curr Probl Pediatr Adolesc Health Care. vol. 36. 2006. pp. 218-37. (This article discusses clinical manifestations and updates therapeutic options up to 2006.)
Axelrod, FB, Rimoin, DL, Connor, JM, Pyeritz, RE, Korf, BR. “Principles and Practice of Medical Genetics”. Autonomic and sensory disorders. vol. vol 3. 2007. pp. 2802-16. (Review of the autonomic system in depth and discussion of the various diseases of this system. A comprehensive review of familial dysautonomia [clinical and therapeutic].)
Riley, CM, Day, RL, Greely, DM, Langford, WS. “Central autonomic dysfunction with defective lacrimation: report of 5 cases”. Pediatrics. vol. 3. 1949. pp. 464-77. (First description of the disease by Dr. Riley and Dr. Day. Landmark article in FD that discusses five patients with autonomic dysfunction. This disease is named Riley-Day syndrome after these two doctors.)
Bickel, A, Axelrod, FB, Marthol, H, Schmelz, M, Hilz, MJ. “Sudomotor function in familial dysautonomia”. J Neurosurg Psychiatry. vol. 75. 2004; Feb. pp. 275-9. (This study found that normal direct- and axon-reflex-mediated sweat output in FD patients supports the hypothesis that, in a disorder with severe sympathetic nerve fiber reduction, sudomotor fibers [but not the sweat glands themselves] exhibit chemical hypersensitivity.)
Stempler, B, Axelrod, FB, Marthol, H, Brown, C, Brys, M, Welsch, G, Hilz, MJ. “Terminal vessel hyperperfusion despite organ hypoperfusion in familial dysautonomia”. Clin Science. vol. 105. 2003; Sep. pp. 295-301. (This study showed that reduced overall limb perfusion in FD patients is due to hypertension-induced structural changes to vessel walls with an increase in resistance vessel rigidity.)
Maayan, C, Nimrod, A, Morag, A, Becker, Y. “Herpes simplex virus-1 and varicella virus infection in familial dysautonomia patients”. J Med Virol. vol. 54. 1998. pp. 158-61. (The clinical presentation of varicella virus injection is mild, although the rate is the same for patients and controls. The rate of herpes simplex virus 1 infection means that infection risk is low and reactivation is rare. This can be due to decreased type C fibers in FD patients.)
Slaugenhaupt, SA, Blumenfeld, A, Gill, SP, Leyne, M, Mull, J, Cuajungco, MP. “Tissue-specific expression of a slicing mutation in the IKBKAP gene causes familial dysautonomia”. Am J Hum Genetics. vol. 8. 2001. pp. 598-605. (The authors identified the defective FD gene that encodes IKB kinase complex associate of protein [IKBKAP], which results in the skipping of exon 20, and thereby encodes a truncated protein. They found this major mutation in 99.5% of the patients, and found another mutation of missense change in exon 19 in four patients. The authors also examined the ratio of the wild type to mutant IKBKAP transcript and found it to be different in EBV-transformed lymphoblast and postmortem tissues from FD patients.)
Anderson, SL, Coli, R, Daly, IW, Kichula, EA, Rork, MJ, Volpi, SA. “Familial dysautonomia is caused by mutations of the IKAP gene”. Am J Hum Gene. vol. 68. 2001. pp. 753-8. (Codiscovery by another research group of the FD gene, the genetic mutation, and the function of the encoded protein. This mutation results in defective phosphorylation of IKAP.)
Pearson, J, Pytel, BA. “Quantitative studies of sympathetic ganglia and spinal cord intermedio-lateral gray columns in familial dysautonomia”. J Neurol Sci. vol. 39. 1978. pp. 47-59. (Histopathological results showed severe deficiency of neurons [about 34% of controls].)
Pearson, J, Pytel, BA. “Quantitative studies of ciliary and sphenopalatine ganglia in familial dysautonomia”. J Neurol Sci. vol. 39. 1978. pp. 123-30. (The total number of neurons was reduced.)
Pearson, J, Dancis, J, Axelrod, F, Grover, N. “The sural nerve in familial dysautonomia”. J Neuropath Exp Neurol. 1975. pp. 34-413. (The sural nerve, which is a sensory nerve, was small in transverse area and deficient of axons. There was diminution of myelinated axons, particularly those of small caliber, and a severe depletion in non-myelinated axons.)
Pearson, J, Pytel, BA, Grover-Jonson, N. “Quantitative studies of dorsal root ganglia and neuropathological observations on spinal cords in familial dysautonomia”. J Neurol Sci. vol. 35. 1978. pp. 77-9. (This study used microscopic examination to show a diminution of neurons and the fact that the dorsal root ganglia were grossly reduced in size. Neurons in dorsal root ganglia showed further depletion with age.)
Aguayo, AJ, Nair, CPV, Bray, GM. “Peripheral nerve abnormalities in the Riley-Day syndrome. Findings in the sural nerve biopsy”. Arch Neurol. vol. 24. 1971. pp. 106-16. (This study also proved that the sural nerve of dysautonomic patients is small and deficient in axons.)
Maayan, C, Becker, Y, Gesundheit, B, Girgis, S. “Calcitonin gene related peptide in familial dysautonomia”. Neuropeptide. vol. 35. 2001. pp. 189-95. (This study shows that CGRP, which is a prominent neurotransmitter in C fibers, is deficient in FD patients. This is consistent with the depletion of C fibers and can explain some of the patients' symptoms.)
Hilz, MJ, Axelrod, FB, Bickel, A, Stempler, B, Brys, M, Wendelchafer-Crabb, G. “Assessing function and pathology in familial dysautonomia: assessment of temperature perception, sweating and cutaneous innervation”. Brain. vol. 127. 2004. pp. 2090-8. (Temperature thresholds and baseline sweat rate were elevated in the patients, while total sweat volume and response time did not differ from controls. Temperature perception was more impaired than sweating.)
Hilz, MJ, Axelrod, FB, Schweibold, G, Neuner, I, Glorius, SE, Kolodney, EH. “Sympathetic skin response (SSR) to thermal stimulation in familial dysautonomia: an objective indicator of sensory small fiber neuropathy”. 1994. (Sympathetic skin responses [SSR] demonstrated overall integrity of the SSR reflex arc; however, the SSR amplitudes were reduced, indicating decreased efferent sympathetic activity. The authors concluded that the reserved response to electrical stimulation, and absence of SSR with thermal stimulation, reflects afferent small fiber dysfunction.)
Bickel, A, Axelrod, FB, Schmelz, M, Marthol, H, Hilz, MJ. “Dermal microdialysis provides evidence for hypersensitivity to noradrenalin in patients with familial dysautonomia”. J Neurol Neurosurg Psychiatry. vol. 73. 2002. pp. 299-302. (This study showed, through the use of dermal microdialysis to examine sensitivity of the skin vessels to noradrenaline [NA] in patients with familial dysautonomia, that the reaction of these patients to NA was more prominent and prolonged, as shown by a larger zone of skin blanching around the microdialysis membrane and delayed reduction in protein content in the dialysate after termination of NA application. This supports the hypothesis that peripheral blood vessels of patients with FD show a denervation hypersensitivity to catecholamines.)
Axelrod, FB, Iyer, K, Fish, I. “Progressive sensory loss in familial dysautonomia”. Pediatrics. vol. 67. 1981. pp. 517-22. (This study showed that older FD patients had a greater tendency towards increased dysfunction in pain sensations, joint position, Romberg's sign, and vibratory sense.)
Maayan, C, Kaplan, E, Shachar, S. “Incidence of familial dysautonomia in Israel 1977-1981”. Clin Genet. vol. 32. Aug 1987. pp. 106-8. (Review of familial dysautonomia. Discusses the epidemiology over a 5-year period in Israel. The incidence of FD in Ashkenazi Jews was found to be 1:3703 [years 1977-1981]; the carrier incidence was found to be 1:32.)
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