Clinical characteristics: Dopamine beta-hydroxylase (DBH) deficiency is characterized by lack of sympathetic noradrenergic function resulting in profound deficits in autonomic regulation of cardiovascular function (orthostatic hypotension) and other autonomic dysfunction (ptosis, nasal stuffiness, sleep difficulties, and impaired ejaculation in males). Although DBH deficiency is present from birth, the diagnosis is often not generally recognized until late childhood. In the perinatal period, DBH deficiency has been complicated by vomiting, dehydration, hypotension, hypothermia, and hypoglycemia requiring repeated hospitalization, and the diagnosis may be identified fortuitously in the neonatal period with investigation of hypoglycemia. Children may report reduced exercise capacity. By early adulthood, individuals have profound orthostatic hypotension, greatly reduced exercise tolerance, ptosis, and nasal stuffiness. Presyncopal symptoms include dizziness, blurred vision, dyspnea, nuchal discomfort, and chest pain; symptoms may worsen in hot environments or after heavy meals or alcohol ingestion. Some individuals have abnormal kidney function, joint laxity, hypotonia, high-arched palate, anemia, and/or hypoglycemia.

Diagnosis/testing: The diagnosis of DBH deficiency is established in a proband with profound neurogenic orthostatic hypotension, minimal or absent plasma concentrations of norepinephrine and epinephrine, a five- to tenfold elevation of plasma dopamine, and biallelic pathogenic variants in DBH identified by molecular genetic testing.

Management: Targeted therapy: Administration of L-threo-3,4-dihydroxyphenylserine (droxidopa) restores plasma norepinephrine concentration and alleviates orthostatic hypotension and other symptoms of abnormal cardiovascular regulation.

Treatment of manifestations: Other treatment options for orthostatic hypotension (fludrocortisone, midodrine) are not as effective as droxidopa; surgical correction of ptosis as needed; standard treatment for nasal stuffiness and reduced kidney function.

Surveillance: Annual evaluation of efficacy of droxidopa and review of adverse events; referral to autonomic specialist prior to surgery or becoming pregnant; measurement of blood urea nitrogen and plasma creatinine to assess kidney function every two years or more often if loss of kidney function is evident; plasma magnesium and potassium every two years.

Agents/circumstances to avoid: Untreated individuals should avoid hot environments, strenuous exercise, standing motionless, and dehydration; nephrotoxic drugs should be avoided.

Pregnancy management: Routine blood pressure monitoring during pregnancy and delivery, with adjustment of droxidopa dosage as needed; extra doses of droxidopa may be required during delivery, and dose adjustment may be required post partum.

Genetic counseling: DBH deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a DBH pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the DBH pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.