Allan-Herndon-Dudley Syndrome
Summary
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 antiepileptic drugs 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.
Diagnosis
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
Craniofacial. Common facial findings that may be attributed to prenatal and infantile hypotonia include ptosis, open mouth, and a tented upper lip. Ear length is above the 97th centile in about half of adults. Cup-shaped ears, thickening of the nose and ears, upturned earlobes, and a decrease in facial creases and a long face are also reported.
Laboratory Findings
Males with AHDS have pathognomonic thyroid test results (Figure 1) including the following:
Figure 1.
Thyroid profiles of 24 patients with AHDS (black triangles) compared to 25 male patients with other genetically defined intellectual disability (gray circles). Serum levels of: A. TSH *
- High serum 3,3',5-triiodothyronine (usually free T3) concentration and low serum 3,3',5'-triiodothyronine (reverse T3, or rT3) concentrationNote: All males with SLC16A2 pathogenic variants had high serum T3 concentration and, when obtained, low serum rT3 concentration. This holds true for both total and free hormone concentrations in serum.
- Serum tetraiodothyronines (total T4 and free T4) concentration are often reduced, but may be within the low normal range
- Free T3/T4 ratio >0.75 (expressed as mmol/mmol) [Remerand et al 2019]
- Serum TSH concentrations that are normal or slightly elevated (Figure 1) [Refetoff & Dumitrescu 2007, Dumitrescu & Refetoff 2009, Remerand et al 2019]
Imaging
Brain MRI in children under age five years usually shows severely delayed myelination mimicking hypomyelination, which subsequently improves over time (Figure 2) [Holden et al 2005, Kakinuma et al 2005, Sijens et al 2008, Vaurs-Barrière et al 2009, Gika et al 2010, Tsurusaki et al 2011, Tonduti et al 2013, Remerand et al 2019].
Figure 2.
(A) T2-weighted sequences of the brain MRI of a child age 12 months with AHDS showing diffusely abnormal white matter; (B) same child at age 7 years showing improved myelination with time
Note: Early reports of normal brain MRI findings in this disorder were from older individuals. Cerebral atrophy is also a frequent sign associated with hypomyelination.
Establishing the Diagnosis
Male proband. The diagnosis of AHDS is established in a male proband with suggestive findings and a hemizygous SLC16A2 pathogenic variant identified by molecular genetic testing (see Table 1).
Female proband. The diagnosis of AHDS is usually established in a female proband by identification of a heterozygous pathogenic variant in SLC16A2 by molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of AHDS is broad, individuals with the distinctive clinical and laboratory findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of AHDS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
Single-gene testing. Sequence analysis of SLC16A2 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants. If no pathogenic variant is found, gene-targeted deletion/duplication analysis is usually performed next to detect intragenic deletions or duplications. Note: Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
An intellectual disability, leukodystrophy, or abnormal movement disorder multigene panel that includes SLC16A2 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Allan-Herndon-Dudley Syndrome
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| SLC16A2 | Sequence analysis 3, 4 | ~85 5 |
| Gene-targeted deletion/duplication analysis 6 | ~15% 5, 7 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
- 5.
García-de Teresa et al [2015], Remerand et al [2019]
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
Due to the presence of repetitive elements, deletions of exon 1 with varying breakpoints are frequently observed [García-de Teresa et al 2015].
Clinical Characteristics
Clinical Description
Allan-Herndon-Dudley syndrome (AHDS), an X-linked disorder, is characterized in males by neurologic findings (hypotonia and feeding difficulties in infancy, developmental delay [DD] / intellectual disability [ID]) and later-onset pyramidal signs, extrapyramidal findings, and seizures, often with drug resistance. Dysthyroidism can manifest as poor weight gain, reduced muscle mass and variable cold intolerance, sweating, elevated heart rate, irritability, and pathognomonic thyroid test results. Most heterozygous females are not clinically affected but may have minor thyroid test abnormalities.
Affected Males
To date, information on about 200 individuals with a pathogenic variant in SLC16A2 has been published [Groeneweg et al 2019, Remerand et al 2019]. The following description of the phenotypic features associated with this condition is based on the report by Remerand et al [2019].
Table 2.
Select Features of Allan-Herndon-Dudley Syndrome in Affected Males
| Feature 1 | % of Persons w/Feature | |
|---|---|---|
| Prenatal/ neonatal findings | Weak fetal movements | 1.4%-16.6% |
| Fetal arrhythmia | 0%-1.4% | |
| Neonatal hypotonia | 4.4%-9.4% | |
| Premature birth | 0%-0.7% | |
| Neonatal hypotrophy | 0%-4.2% | |
| Congenital microcephaly | 0%-0.7% | |
| Congenital macrocephaly | 0%-0.7% | |
| Hydramnios | 0%-1.4% | |
| Neonatal jaundice | 0%-20.8% | |
| Growth | Weight gain deficiency | 33.3% |
| Low weight | 37%-66.6% | |
| Short stature | 12.6%-29.1% | |
| Microcephaly | 10%-33.3% | |
| DD/ID | ID | 100% 2 |
| Severe-to-profound ID | 37.5%-83.3% 2 | |
| Mild-to-moderate ID | 16.6%-62.5% 2 | |
| Oral language | 19.9%-69% | |
| Walking | 19.9%-62% | |
| Neuromuscular | Axial hypotonia | 74%-100% |
| Amyotrophy | 34.5%-88% | |
| Spasticity/hyperreflexia | 70.8%-94% | |
| Dystonia | 0%-75% | |
| Choreoathetosis | 0%-50% | |
| Paroxysms or kinesigenic dyskinesias | 0%-9% | |
| Ataxia | 0%-60% | |
| Seizures | 14.8%-29.1% | |
| Nystagmus | 0%-16.6% | |
| Skeletal | Pectus excavatum | 9.1%-58% |
| Kyphoscoliosis | 21.1%-53.0% | |
| Flat feet with valgus | 4.3%-77% | |
| Other | Narrow/elongated myopathic face | 31%-75% |
| Cryptorchidism | 2.8%-33.3% | |
| Peripheral dysthyroidism | 27.9%-66.6% | |
| Brain MRI | Severely delayed myelination | 33.1%-79.1% |
| Myelination improvement | 8.4%-62.4% | |
| Brain atrophy | 17%-41.6% | |
DD = developmental delay; ID = intellectual disability
- 1.
Features and percentages of persons with feature were evaluated from the cohorts of Schwartz et al [2005], Remerand et al [2019], and the entire literature reporting individuals with AHDS. Variation in percentages can be attributed to either the non-evaluation or lack of systematic evaluation of features in different reports.
- 2.
Expressed as % of all males with AHDS. All affected individuals had ID ranging from mild to profound.
Prenatal/neonatal findings. Infants with AHDS have normal length, weight, and head circumference at birth. Hypotonia, feeding difficulties and early weight gain deficiency can appear in the first weeks or months of life. Prolonged neonatal jaundice has recently been reported.
Growth. Weight gain lags behind linear growth; low weight is a frequent feature Linear growth is frequently normal initially, but between 10 and 30% of males with time have short stature; microcephaly becomes apparent with age.
Developmental delay / intellectual disability. Most affected males have profound-to-severe intellectual disability with no acquisition of walking; most affected males never speak or may develop only garbled sounds secondary to severely dysarthric speech.
Less frequently, affected males have mild-to-moderate intellectual disability, and develop the ability to walk (with or without aid) and use of language allowing academic learning with aid.
Neuromuscular. Truncal hypotonia, a main feature of AHDS, persists into adulthood. Adults are described with "limber neck" or poor head control.
Progressive hypertonicity of the limbs with brisk reflexes, ankle clonus, and extensor plantar responses (Babinski sign) leads to spastic quadriplegia and joint contractures.
Overall muscle mass (particularly proximally) is reduced and associated with generalized muscle weakness.
It is common for affected males to experience purposeless movements described as dystonic and/or athetoid and characteristic paroxysms or kinesigenic dyskinesias [Brockmann et al 2005, Fuchs et al 2009]. These can be triggered by somatosensory stimuli, including changing clothes or diaper, or lifting the affected child. During attacks, the body extends and the mouth opens; stretching or flexing of the limbs lasts as long as one to two minutes.
Some authors also reported abnormal movements as ataxia [Schwartz et al 2005].
Seizures typically begin during infancy or early childhood. Drug resistance is common [Schwartz & Stevenson 2007, Remerand et al 2019].
Rotary nystagmus and disconjugate eye movements have been reported but are not common [Dumitrescu et al 2004, Remerand et al 2019].
Skeletal. Pectus excavatum and kyphoscoliosis are most likely the result of hypotonia and reduced muscle mass.
Behavior. Generally, affected individuals are attentive, friendly, and docile. They are not aggressive or destructive.
Other. Peripheral dysthyroidism can be expressed as cold intolerance, sweating, intestinal transit disorders, tachycardia, high blood pressure, and sleep disorders.
Life span. Early death has occurred in some individuals, usually caused by recurrent infections and/or aspiration pneumonia. In a few instances survival beyond age 70 years has been reported.
Affected Heterozygous Females
Heterozygous females are generally asymptomatic and have no specific phenotypic findings. About 25% of heterozygous female have an abnormal thyroid profile with elevated T3 levels without any neurologic manifestations [Ramos et al 2011, García-de Teresa et al 2015].
Developmental delay and intellectual disability have been reported in heterozygous females in rare instances, perhaps due to skewed X-chromosome inactivation [Dumitrescu et al 2004, Schwartz et al 2005, Herzovich et al 2007, García-de Teresa et al 2015]. One female had typical features of AHDS with a de novo translocation disrupting SLC16A2 and unfavorable nonrandom X-chromosome inactivation [Frints et al 2008]. One exception of note was the finding in one female of a whole or partial deletion of one X chromosome and a SLC16A2 pathogenic variant on the other X chromosome. However, whether a causative relationship exists between SLC16A2 pathogenic variants and cognitive impairments in heterozygous females has yet to be proven [Schwartz et al 2005].
Genotype-Phenotype Correlations
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 [Friesema et al 2004, Jansen et al 2007, Vaurs-Barrière et al 2009, Visser et al 2009, Friesema et al 2010, Gika et al 2010, Zung et al 2011, Yamamoto et al 2013, Anık et al 2014, García-de Teresa et al 2015, Remerand et al 2019].
Several SLC16A2 pathogenic missense variants and an in-frame single amino-acid deletion (Table 7) 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 [Schwartz et al 2005, Jansen et al 2008, Vaurs-Barrière et al 2009, Visser et al 2009, Visser et al 2013, Philips et al 2014, Novara et al 2017, Masnada et al 2019, Remerand et al 2019]. Independent walking and speech development are unusual in affected males with other pathogenic variants.
Nomenclature
This condition was named MCT8-specific thyroid hormone cell-membrane transporter deficiency following identification of the causative gene, SLC16A2, and the defect in thyroid hormone metabolism.
Because of the overlap of clinical findings in individuals with an SLC16A2 pathogenic variant and Allan-Herndon-Dudley syndrome (AHDS), Schwartz et al [2005] analyzed SLC16A2 and identified variants in six families with MCT8-specific thyroid hormone cell-membrane transporter deficiency. Thus, AHDS and MCT8-specific thyroid hormone cell-membrane transporter deficiency are synonyms.
Prevalence
Prevalence of Allan-Herndon-Dudley syndrome (AHDS) is unknown; however, the identification of more than 160 affected individuals in approximately 15 years suggests that the syndrome is more common than previously thought.
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 Table 3, 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)
| Gene 1 | Differential Diagnosis Disorder | MOI | Clinical Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/AHDS | Distinguishing from AHDS | |||
| GJC2 | Pelizaeus-Merzbacher-like disease 2 | AR | PMD-like | Normal free T3/T4 ratio |
| MECP2 | MECP2 duplication syndrome | XL | In males: infantile hypotonia, severe ID, absent speech, progressive spasticity, & seizures | |
| PLP1 | Pelizaeus-Merzbacher disease (see PLP1 Disorders) | XL |
| |
| THRA | Nongoitrous congenital hypothyroidism 6 (OMIM 614450) | AD |
|
|
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; PMD-like = Pelizaeus-Merzbacher–like disease; XL = X-linked
- 1.
Genes are in alphabetic order
- 2.
Of note, in one study SLC16A2 pathogenic variants were reported in 11% of 53 families with a severe form of Pelizaeus-Merzbacher-like disease with an unusual improvement in myelination with age [Vaurs-Barrière et al 2009].
Management
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 Table 4 (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
| System/Concern | Evaluation | Comment |
|---|---|---|
| Constitutional | Measure height, weight, BMI, head circumference | To be regularly followed |
| Neurologic | Neurologic evaluation |
|
| Development | Developmental assessment |
|
| Musculoskeletal | Orthopedic, physical medicine & rehabilitation, PT, & OT evaluation | To include assessment of:
|
| Osteoporosis evaluation in non-ambulatory patients |
| |
| Gastrointestinal/ Feeding | Gastroenterology, nutrition, & feeding team evaluation |
|