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Familial dysautonomia

ORPHA1764
Synonym(s) HSAN3
Hereditary sensory and autonomic neuropathy type 3
Riley-Day syndrome
Prevalence <1 / 1 000 000
Inheritance Autosomal recessive
Age of onset Infancy
Neonatal
ICD-10
  • G90.1
OMIM
UMLS
  • C0013364
MeSH
  • D004402
MedDRA
  • 10039179

Summary

Hereditary sensory and autonomic neuropathy, type 3 (HSAN3) is an inherited disorder characterized by sensory dysfunction and severe impairment of the autonomic nervous system activity, resulting in multisystem dysfunction. HSAN3 is almost exclusive to individuals of Eastern European Jewish extraction, with incidence of 1 per 3,600 live births. Both sexes are affected. The disease is present at birth and is progressive. Initial symptoms (from birth to 3 years) include swallowing problems, aspiration pneumonia, hypotonia, temperature instability, and delayed development. No obvious dysmorphism is present at birth, but a characteristic facial expression may develop over time. Severe kyphoscoliosis and short stature are common. Absence of tears with emotional crying is one of the cardinal features of the disorder, but this sign may not be immediately recognized (since lack of overflow tears is normal until about seven months of age). Thus, the earliest sign of autonomic dysfunction usually is feeding difficulties due to gastrointestinal dysmotility (oropharyngeal incoordination, abnormal esophageal peristalsis, erratic gastric emptying, gastroesophageal reflux and episodes of protracted vomiting attacks termed 'dysautonomic crises''). Chronic lung disease (secondary to repeated aspirations), restrictive lung disease (imposed by scoliosis), muscle weakness, and chemoreceptor dysfunction (resulting in blunted responses to hypoxemia) are frequent. Orthostatic hypotension without compensatory tachycardia is common. Patients can also experience episodic hypertension in response to emotional stress or visceral pain. Negative personality changes range from irritability and withdrawal to general excitation. Forty percent of the patients manifest a cyclical crisis pattern with frequencies that can occur daily, weekly, or monthly and follows morning arousal. Pain and temperature perception are decreased, but not absent. Vibration sense is normal. Deep tendon reflexes are decreased in almost all patients. Absent axon flare (following intradermal histamine) and lack of fungiform papilla on the tongue are characteristic features of HSAN3. The disease is transmitted as an autosomal recessive trait. The HSAN3 (IKBKAP) gene is localized to the long arm of chromosome 9 (9q31). Diagnosis is based upon clinical recognition of both sensory and autonomic dysfunction. The 'cardinal'' criteria include alacrima, absent fungiform papillae, depressed patellar reflexes, and abnormal histamine test. DNA molecular diagnostics should be performed to provide a definitive diagnosis. Differential diagnosis includes the other hereditary sensory and autonomic neuropathies. Management should be tailored for each patient, as the clinical expression varies considerably. It is supportive and mainly directed towards alacrima, gastrointestinal dysfunction, respiratory dysfunction, and blood pressure lability.

Expert reviewer(s)

  • Pr Felicia B. AXELROD
  • Dr Gabrielle GOLD-VON SIMSON

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Detailed information

Review article
  • EN (2007)
Clinical genetics review
  • EN (2010)
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