Clinical Guidance

It has been repeatedly reported that the severity of the clinical phenotype is related to the residual transport capacity of the mutated MCT8 protein. Large deletions in SLC16A2 are assumed to result in complete inactivation of MCT8 and a consequently severe phenotype. While the most frequent large SLC16A2 deletions are of exon 1, deletions of exons 2-4, exons 2-6, exon 3, exons 3-4, and exon 6 have also been reported [, , , , , , , , , , ]. Several SLC16A2 pathogenic missense variants and an in-frame single amino-acid deletion have been associated with considerable residual MCT8 thyroid hormone transport capacity and a milder clinical phenotype, including some speech development, some reading/writing ability, and/or the ability to walk with or without support [, , , , , , , , ].

Source: GeneReviews — "Allan-Herndon-Dudley Syndrome"

Diagnostic Criteria

Formal diagnostic criteria for Allan-Herndon-Dudley syndrome have not been established.

Suggestive Findings

Allan-Herndon-Dudley syndrome (AHDS) should be considered in males with the following clinical findings, brain imaging, and thyroid hormone profiles.

Clinical Findings

Neurologic

• Onset before age two years often with hypotonia and feeding difficulties

• Developmental delay/ intellectual disability ranging from mild to profound intellectual disability

• Extrapyramidal findings: dystonia, choreoathetosis, paroxysmal movement disorder, hypokinesia, hypomimia (masked facies)

• Pyramidal signs

• Late-onset seizures, often with drug resistance

Dysthyroidism

• Poor weight gain

• Reduced muscle mass

• Variably present: cold intolerance, sweating, elevated heart rate, irritability

Source: GeneReviews — "Allan-Herndon-Dudley Syndrome"

Differential Diagnosis

Many disorders demonstrate hypotonia and severe intellectual disability in an X-linked or autosomal recessive inheritance pattern. The main differential diagnoses, described in , also demonstrate dystonia, spasticity, seizures, or other features that overlap with the neurologic phenotype of Allan-Herndon-Dudley syndrome. More widely, all diseases leading to X-linked intellectual disability, hypomyelinating leukodystrophies or precocious dystonia should be considered as differential diagnoses. Table 3. Genes of Interest in the Differential Diagnosis of Allan-Herndon-Dudley Syndrome (AHDS)

Management Guidelines

No current published guidelines exist to establish the extent of disease or proper management in an individual diagnosed with Allan-Herndon-Dudley syndrome (AHDS). The following recommendations are based on current literature and the authors' experience. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Allan-Herndon-Dudley syndrome (AHDS), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with Allan-Herndon-Dudley Syndrome

Clinical Guidance

Administration of L-T4 or L-T3 alone can exacerbate the high serum T3 levels and the resulting hypermetabolism.

Source: GeneReviews — "Allan-Herndon-Dudley Syndrome"

Therapies Under Investigation

Recently, an T3 analog TRIAC (acide 3,3',5-triiodothyroacetique) has been tested in an international multicentric study, coordinated by the Erasmus University (Rotterdam, Netherlands) ; 46 persons with AHDS were included and treated with a maximum of one year of TRIAC. The main objective was the normalization of the free T3 blood level; T3 concentration declined significantly (reduction of 61% of baseline). Other findings: a mean increase of body weight of 2.7 kg, a mean decrease of heart rate over 24 hours of five beats per minute, a mean decrease of systolic blood pressure from the 78th centile to the 61st centile, and a mean decrease of hypertension from 34% to 9%.

Source: GeneReviews — "Allan-Herndon-Dudley Syndrome"

Surveillance Guidelines

Table 6. Recommended Surveillance for Individuals with Allan-Herndon-Dudley Syndrome

Source: GeneReviews — "Allan-Herndon-Dudley Syndrome"