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Allan-Herndon-Dudley syndrome(AHDS)

MedGen UID:
208645
Concept ID:
C0795889
Disease or Syndrome
Synonyms: AHDS; Allan-Herndon syndrome; MCT8 (SLC16A2)-Specific Thyroid Hormone Cell Transporter Deficiency; MCT8-Specific Thyroid Hormone Cell-Membrane Transporter Deficiency; Mental retardation and muscular atrophy; Monocarboxylate transporter-8 deficiency; T3 resisitence; T3 RESISTANCE; TRIIODOTHYRONINE RESISTANCE; Triiodothyronine resistence; X-linked mental retardation with hypotonia
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
X-linked recessive inheritance refers to genetic conditions associated with mutations in genes on the X chromosome. A male carrying such a mutation will be affected, because he carries only one X chromosome. A female carrying a mutation in one gene, with a normal gene on the other X chromosome, will be unaffected.
X-linked dominant inheritance
MedGen UID:
376232
Concept ID:
C1847879
Finding
SNOMED CT: Monocarboxylate transporter 8 deficiency (702327009); Allan-Herndon-Dudley syndrome (702327009); Allan-Herndon syndrome (702327009)
 
Gene (location): SLC16A2 (Xq13.2)
OMIM®: 300523
Orphanet: ORPHA59

Disease characteristics

MCT8-specific thyroid hormone cell-membrane transporter deficiency is characterized by severe cognitive deficiency, infantile hypotonia, diminished muscle mass and generalized muscle weakness, progressive spastic quadriplegia, joint contractures, and dystonic and/or athetoid movement with characteristic paroxysms or kinesigenic dyskinesias. Seizures occur in about 25% of cases. Most affected males never sit or walk independently or lose these abilities over time; most never speak or have severely dysarthric speech. Brain MRI obtained in the first few years of life shows transient delayed myelination, which improves by age four years. Although psychomotor findings observed in affected males do not occur in heterozygous females, the latter often have thyroid test abnormalities intermediate between affected and normal individuals. [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  Diagnosis  |  Clinical Characteristics  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  References  |  Chapter Notes
Authors:
Alexandra M Dumitrescu  |  Jiao Fu  |  Melissa A Dempsey, et. al.   view full author information

Additional description

From GHR
Allan-Herndon-Dudley syndrome is a rare disorder of brain development that causes moderate to severe intellectual disability and problems with movement. This condition, which occurs exclusively in males, disrupts development from before birth. Although affected males have impaired speech and a limited ability to communicate, they seem to enjoy interaction with other people. Most children with Allan-Herndon-Dudley syndrome have weak muscle tone (hypotonia) and underdevelopment of many muscles (muscle hypoplasia). As they get older, they usually develop joint deformities called contractures, which restrict the movement of certain joints. Abnormal muscle stiffness (spasticity), muscle weakness, and involuntary movements of the arms and legs also limit mobility. As a result, many people with Allan-Herndon-Dudley syndrome are unable to walk independently and become wheelchair-bound by adulthood.  http://ghr.nlm.nih.gov/condition/allan-herndon-dudley-syndrome

Clinical features

Narrow face
MedGen UID:
373334
Concept ID:
C1837463
Finding
Narrow forehead
MedGen UID:
326408
Concept ID:
C1839127
Finding
Microcephaly
MedGen UID:
337454
Concept ID:
C1845868
Finding
Open mouth
MedGen UID:
346627
Concept ID:
C1857628
Finding
Proptosis
MedGen UID:
350667
Concept ID:
C1862425
Finding
Abnormality of the neck
MedGen UID:
424994
Concept ID:
CN000433
Finding
An abnormality of the neck.
Upslanted palpebral fissure
MedGen UID:
504509
Concept ID:
CN000546
Finding
The palpebral fissure inclination is more than two standard deviations above the mean for age (objective); or, the inclination of the palpebral fissure is greater than typical for age.
Drooling
MedGen UID:
505191
Concept ID:
CN002095
Finding
Habitual flow of saliva out of the mouth.
Cheekbone underdevelopment
MedGen UID:
430039
Concept ID:
CN009495
Finding
Underdevelopment of the zygomatic bone. That is, a reduction in size of the zygomatic process of the temporal bone of the skull, which forms the middle and lateral inferior orbital margin.
Abnormal conjugate eye movement
MedGen UID:
337198
Concept ID:
C1845274
Finding
Proptosis
MedGen UID:
350667
Concept ID:
C1862425
Finding
Ptosis
MedGen UID:
504471
Concept ID:
CN000475
Finding
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Rotary nystagmus
MedGen UID:
504862
Concept ID:
CN001442
Finding
A form of nystagmus in which the eyeball makes rotary motions around the axis.
Prominent antihelix
MedGen UID:
335147
Concept ID:
C1845272
Finding
Macrotia
MedGen UID:
349900
Concept ID:
C1860838
Finding
Stahl ear
MedGen UID:
451410
Concept ID:
CN116914
Finding
The presence of a supernumerary, i.e. third, crus of the helix (FMA:61024) in the helix, arising at or above the normal bifurcation of the antihelix.
Irritability
MedGen UID:
5898
Concept ID:
C0022107
Finding
Abnormal or excessive excitability with easily triggered anger, annoyance, or impatience.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
A reflex found in normal infants consisting of dorsiflexion of the HALLUX and abduction of the other TOES in response to cutaneous stimulation of the plantar surface of the FOOT. In adults, it is used as a diagnostic criterion, and if present is a NEUROLOGIC MANIFESTATION of dysfunction in the CENTRAL NERVOUS SYSTEM.
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
IQ 20-34.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Cerebral calcification
MedGen UID:
124360
Concept ID:
C0270685
Finding
Inability to walk
MedGen UID:
107860
Concept ID:
C0560046
Finding
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Sign or Symptom
A finding referring to walking difficulties.
Dysarthria
MedGen UID:
333395
Concept ID:
C1839743
Finding
Involuntary writhing movements
MedGen UID:
375616
Concept ID:
C1845265
Finding
Microcephaly
MedGen UID:
337454
Concept ID:
C1845868
Finding
Intellectual disability, progressive
MedGen UID:
337397
Concept ID:
C1846149
Finding
Spastic paraplegia
MedGen UID:
335468
Concept ID:
C1846589
Finding
Cognitive impairment
MedGen UID:
383844
Concept ID:
C1856145
Finding
Incoordination
MedGen UID:
351047
Concept ID:
C1864113
Finding
Ataxia
MedGen UID:
504767
Concept ID:
CN001146
Finding
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- oder overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Neurological speech impairment
MedGen UID:
446437
Concept ID:
CN001964
Finding
Clonus
MedGen UID:
505137
Concept ID:
CN001966
Finding
A series of rhythmic and involuntary muscle contractions (at a frequency of about 5 to 7 Hz) that occur in response to an abruptly applied and sustained stretch.
Delayed CNS myelination
MedGen UID:
500919
Concept ID:
CN001984
Finding
Delayed myelination in the central nervous system.
Drooling
MedGen UID:
505191
Concept ID:
CN002095
Finding
Habitual flow of saliva out of the mouth.
Leukodystrophy
MedGen UID:
505231
Concept ID:
CN002194
Finding
Leukodystrophy refers to deterioration of white matter of the brain resulting from degeneration of myelin sheaths in the CNS. Their basic defect is directly related to the synthesis and maintenance of myelin membranes.
Spastic tetraplegia
MedGen UID:
505258
Concept ID:
CN002281
Finding
Spastic paralysis affecting all four limbs.
Thyroid-stimulating hormone excess
MedGen UID:
507088
Concept ID:
CN002646
Finding
Overproduction of thyroid-stimulating hormone (TSH) by the anterior pituitary gland.
Severe global developmental delay
MedGen UID:
506566
Concept ID:
CN167072
Finding
A severe delay in the achievement of motor or mental milestones in the domains of development of a child.
Type I diabetes mellitus
MedGen UID:
334999
Concept ID:
C1844664
Finding
Hypothyroidism
MedGen UID:
413085
Concept ID:
C2750951
Finding
Thyroid-stimulating hormone excess
MedGen UID:
507088
Concept ID:
CN002646
Finding
Overproduction of thyroid-stimulating hormone (TSH) by the anterior pituitary gland.
Cerebral calcification
MedGen UID:
124360
Concept ID:
C0270685
Finding
Microcephaly
MedGen UID:
337454
Concept ID:
C1845868
Finding
Hallux valgus
MedGen UID:
338251
Concept ID:
C1847526
Finding
Pectus excavatum
MedGen UID:
504591
Concept ID:
CN000721
Finding
A defect of the chest wall characterized by a depression of the sternum, giving the chest (\
Flexion contracture
MedGen UID:
504817
Concept ID:
CN001256
Finding
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Limitation of joint mobility
MedGen UID:
446405
Concept ID:
CN001260
Finding
A reduction in the freedom of movement of one or more joints.
Abnormality of the rib cage
MedGen UID:
428272
Concept ID:
CN001412
Finding
A morphological anomaly of the rib cage.
Scoliosis
MedGen UID:
427922
Concept ID:
CN002409
Finding
The presence of an abnormal lateral curvature of the spine.
Cheekbone underdevelopment
MedGen UID:
430039
Concept ID:
CN009495
Finding
Underdevelopment of the zygomatic bone. That is, a reduction in size of the zygomatic process of the temporal bone of the skull, which forms the middle and lateral inferior orbital margin.
Camptodactyly of finger
MedGen UID:
451844
Concept ID:
CN117383
Finding
The distal interphalangeal joint and/or the proximal interphalangeal joint of the fingers cannot be extended to 180 degrees by either active or passive extension.
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Single transverse palmar crease
MedGen UID:
362624
Concept ID:
C1873502
Finding
Type I diabetes mellitus
MedGen UID:
334999
Concept ID:
C1844664
Finding
Neonatal hypotonia
MedGen UID:
331807
Concept ID:
C1834679
Finding
Spastic paraplegia
MedGen UID:
335468
Concept ID:
C1846589
Finding
Flexion contracture
MedGen UID:
504817
Concept ID:
CN001256
Finding
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Spastic tetraplegia
MedGen UID:
505258
Concept ID:
CN002281
Finding
Spastic paralysis affecting all four limbs.
Skeletal muscle atrophy
MedGen UID:
505481
Concept ID:
CN002890
Finding
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
Generalized amyotrophy
MedGen UID:
505577
Concept ID:
CN003344
Finding
Generalized (diffuse, unlocalized) amyotrophy (muscle atrophy) affecting multiple muscles.
Camptodactyly of finger
MedGen UID:
451844
Concept ID:
CN117383
Finding
The distal interphalangeal joint and/or the proximal interphalangeal joint of the fingers cannot be extended to 180 degrees by either active or passive extension.
Flexion contracture
MedGen UID:
504817
Concept ID:
CN001256
Finding
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Camptodactyly of finger
MedGen UID:
451844
Concept ID:
CN117383
Finding
The distal interphalangeal joint and/or the proximal interphalangeal joint of the fingers cannot be extended to 180 degrees by either active or passive extension.
Hallux valgus
MedGen UID:
338251
Concept ID:
C1847526
Finding
Single transverse palmar crease
MedGen UID:
362624
Concept ID:
C1873502
Finding
Pes planus
MedGen UID:
427894
Concept ID:
CN001603
Finding
A foot where the longitudinal arch of the foot is in contact with the ground or floor when the individual is standing; or, in a patient lying supine, a foot where the arch is in contact with the surface of a flat board pressed against the sole of the foot by the examiner with a pressure similar to that expected from weight bearing; or, the height of the arch is reduced.
Camptodactyly of finger
MedGen UID:
451844
Concept ID:
CN117383
Finding
The distal interphalangeal joint and/or the proximal interphalangeal joint of the fingers cannot be extended to 180 degrees by either active or passive extension.

Recent clinical studies

Etiology

Philips AK, Sirén A, Avela K, Somer M, Peippo M, Ahvenainen M, Doagu F, Arvio M, Kääriäinen H, Van Esch H, Froyen G, Haas SA, Hu H, Kalscheuer VM, Järvelä I
Orphanet J Rare Dis 2014 Apr 11;9:49. doi: 10.1186/1750-1172-9-49. [Epub ahead of print] PMID: 24721225Free PMC Article
Kersseboom S, Kremers GJ, Friesema EC, Visser WE, Klootwijk W, Peeters RP, Visser TJ
Mol Endocrinol 2013 May;27(5):801-13. Epub 2013 Apr 2 doi: 10.1210/me.2012-1356. [Epub ahead of print] PMID: 23550058
Zung A, Visser TJ, Uitterlinden AG, Rivadeneira F, Friesema EC
Eur J Endocrinol 2011 Nov;165(5):823-30. Epub 2011 Sep 6 doi: 10.1530/EJE-11-0358. [Epub ahead of print] PMID: 21896621
Kinne A, Kleinau G, Hoefig CS, Grüters A, Köhrle J, Krause G, Schweizer U
J Biol Chem 2010 Sep 3;285(36):28054-63. Epub 2010 Jul 13 doi: 10.1074/jbc.M110.129577. [Epub ahead of print] PMID: 20628049Free PMC Article
Schwartz CE, May MM, Carpenter NJ, Rogers RC, Martin J, Bialer MG, Ward J, Sanabria J, Marsa S, Lewis JA, Echeverri R, Lubs HA, Voeller K, Simensen RJ, Stevenson RE
Am J Hum Genet 2005 Jul;77(1):41-53. Epub 2005 May 11 doi: 10.1086/431313. [Epub ahead of print] PMID: 15889350Free PMC Article

Diagnosis

Fu J, Dumitrescu AM
Best Pract Res Clin Endocrinol Metab 2014 Mar;28(2):189-201. Epub 2013 Jul 9 doi: 10.1016/j.beem.2013.05.014. [Epub ahead of print] PMID: 24629861Free PMC Article
Azzolini S, Nosadini M, Balzarin M, Sartori S, Suppiej A, Mardari R, Greggio NA, Toldo I
Brain Dev 2014 Sep;36(8):716-20. Epub 2013 Nov 19 doi: 10.1016/j.braindev.2013.10.009. [Epub ahead of print] PMID: 24268987
Boccone L, Dessì V, Meloni A, Loudianos G
Eur J Med Genet 2013 Apr;56(4):207-10. Epub 2013 Feb 16 doi: 10.1016/j.ejmg.2013.02.001. [Epub ahead of print] PMID: 23419639
Verma S
Indian J Pediatr 2008 Apr;75(4):402-4. PMID: 18589880
Schwartz CE, Stevenson RE
Best Pract Res Clin Endocrinol Metab 2007 Jun;21(2):307-21. doi: 10.1016/j.beem.2007.03.009. PMID: 17574010Free PMC Article

Therapy

Verge CF, Konrad D, Cohen M, Di Cosmo C, Dumitrescu AM, Marcinkowski T, Hameed S, Hamilton J, Weiss RE, Refetoff S
J Clin Endocrinol Metab 2012 Dec;97(12):4515-23. Epub 2012 Sep 19 doi: 10.1210/jc.2012-2556. [Epub ahead of print] PMID: 22993035Free PMC Article
Zung A, Visser TJ, Uitterlinden AG, Rivadeneira F, Friesema EC
Eur J Endocrinol 2011 Nov;165(5):823-30. Epub 2011 Sep 6 doi: 10.1530/EJE-11-0358. [Epub ahead of print] PMID: 21896621
Namba N, Etani Y, Kitaoka T, Nakamoto Y, Nakacho M, Bessho K, Miyoshi Y, Mushiake S, Mohri I, Arai H, Taniike M, Ozono K
Eur J Pediatr 2008 Jul;167(7):785-91. Epub 2007 Sep 25 doi: 10.1007/s00431-007-0589-6. [Epub ahead of print] PMID: 17899191

Prognosis

Zung A, Visser TJ, Uitterlinden AG, Rivadeneira F, Friesema EC
Eur J Endocrinol 2011 Nov;165(5):823-30. Epub 2011 Sep 6 doi: 10.1530/EJE-11-0358. [Epub ahead of print] PMID: 21896621
Kinne A, Kleinau G, Hoefig CS, Grüters A, Köhrle J, Krause G, Schweizer U
J Biol Chem 2010 Sep 3;285(36):28054-63. Epub 2010 Jul 13 doi: 10.1074/jbc.M110.129577. [Epub ahead of print] PMID: 20628049Free PMC Article
Verma S
Indian J Pediatr 2008 Apr;75(4):402-4. PMID: 18589880

Clinical prediction guides

Goto M, Ito K, Okamoto N, Sato N, Sasaki M
Clin Nucl Med 2013 Jun;38(6):e276-8. doi: 10.1097/RLU.0b013e31827082d8. PMID: 23235483
Kinne A, Kleinau G, Hoefig CS, Grüters A, Köhrle J, Krause G, Schweizer U
J Biol Chem 2010 Sep 3;285(36):28054-63. Epub 2010 Jul 13 doi: 10.1074/jbc.M110.129577. [Epub ahead of print] PMID: 20628049Free PMC Article
Wirth EK, Roth S, Blechschmidt C, Hölter SM, Becker L, Racz I, Zimmer A, Klopstock T, Gailus-Durner V, Fuchs H, Wurst W, Naumann T, Bräuer A, de Angelis MH, Köhrle J, Grüters A, Schweizer U
J Neurosci 2009 Jul 29;29(30):9439-49. doi: 10.1523/JNEUROSCI.6055-08.2009. PMID: 19641107
Frints SG, Lenzner S, Bauters M, Jensen LR, Van Esch H, des Portes V, Moog U, Macville MV, van Roozendaal K, Schrander-Stumpel CT, Tzschach A, Marynen P, Fryns JP, Hamel B, van Bokhoven H, Chelly J, Beldjord C, Turner G, Gecz J, Moraine C, Raynaud M, Ropers HH, Froyen G, Kuss AW
Eur J Hum Genet 2008 Sep;16(9):1029-37. Epub 2008 Apr 9 doi: 10.1038/ejhg.2008.66. [Epub ahead of print] PMID: 18398436
Bialer MG, Lawrence L, Stevenson RE, Silverberg G, Williams MK, Arena JF, Lubs HA, Schwartz CE
Am J Med Genet 1992 Apr 15-May 1;43(1-2):491-7. PMID: 1605231

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