Allan-Herndon-Dudley Syndrome

Clinical characteristics: Allan-Herndon-Dudley syndrome (AHDS), an X-linked disorder, is characterized in males by neurologic findings (hypotonia and feeding difficulties in infancy, developmental delay / intellectual disability ranging from mild to profound) and later-onset pyramidal signs, extrapyramidal findings (dystonia, choreoathetosis, paroxysmal movement disorder, hypokinesia, masked facies), and seizures, often with drug resistance. Additional findings can include dysthyroidism (manifest as poor weight gain, reduced muscle mass, and variable cold intolerance, sweating, elevated heart rate, and irritability) and pathognomonic thyroid test results. Most heterozygous females are not clinically affected but may have minor thyroid test abnormalities.

Diagnosis/testing: The diagnosis of AHDS is established in a male proband with suggestive findings and a hemizygous SLC16A2 pathogenic variant identified by molecular genetic testing, and in a female proband by identification of a heterozygous pathogenic variant in SLC16A2.

Management: Treatment of manifestations: Multidisciplinary team to provide standard care for hypotonia, poor feeding, DD/ID, spasticity, and extrapyramidal movement disorders. Standard treatment with anti-seizure medication by an experienced neurologist. Thyroid hormone replacement therapy during childhood has no beneficial effect and could be dangerous by worsening dysthyroidism.

Surveillance: In children, assess the following every six months until age four years, then once a year: developmental progress & educational needs; neurologic examination for new manifestations (e.g., seizures, changes in tone, movement disorders); spine for scoliosis and hips for dislocation; mobility and self-help skills.

Agents/circumstances to avoid: Administration of L-T₄ or L-T₃ alone can exacerbate the high serum T₃ levels and the resulting hypermetabolism.

Therapies under investigation: A T₃ analog TRIAC (acide 3,3',5-triiodothyroacetique) has been tested for a maximum of one year in an international multicentric study of 46 individuals with AHDS. The main objective, normalization of the free T₃ blood level, was achieved. Other favorable findings were increased body weight; decreased heart rate, systolic blood pressure, and hypertension; and improved development in seven children, two of whom had started TRIAC treatment before age four years and achieved independent sitting and full head control after 12 months of treatment.

Genetic counseling: AHDS is inherited in an X-linked manner. If the mother of a proband has an SLC16A2 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the variant will be heterozygotes (carriers) and usually will not be clinically affected but may have minor thyroid test abnormalities. Once the SLC16A2 pathogenic variant has been identified in an affected family member, carrier testing of at-risk female relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.