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Intellectual disability, X-linked 61(TOKAS)

MedGen UID:
924419
Concept ID:
C4283894
Disease or Syndrome
Synonyms: TOKAS; TONNE-KALSCHEUER SYNDROME
 
Gene (location): RLIM (Xq13.2)
 
Monarch Initiative: MONDO:0010506
OMIM®: 300978

Definition

Tonne-Kalscheuer syndrome (TOKAS) is an X-linked recessive multiple congenital anomaly disorder with 2 main presentations. Most patients exhibit global developmental delay apparent from early infancy, impaired intellectual development, speech delay, behavioral abnormalities, and abnormal gait. Affected individuals also have dysmorphic facial features that evolve with age, anomalies of the hands, feet, and nails, and urogenital abnormalities with hypogenitalism. A subset of more severely affected males develop congenital diaphragmatic hernia in utero, which may result in perinatal or premature death. Carrier females may have very mild skeletal or hormonal abnormalities (summary by Frints et al., 2019). Also see Fryns syndrome (229850), an autosomal recessive disorder with overlapping features. [from OMIM]

Clinical features

From HPO
Cryptorchidism
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Decreased testicular size
MedGen UID:
66027
Concept ID:
C0241355
Finding
Reduced volume of the testicle (the male gonad).
Hypospadias
MedGen UID:
163083
Concept ID:
C0848558
Congenital Abnormality
Abnormal position of urethral meatus on the ventral penile shaft (underside) characterized by displacement of the urethral meatus from the tip of the glans penis to the ventral surface of the penis, scrotum, or perineum.
Micropenis
MedGen UID:
1633603
Concept ID:
C4551492
Congenital Abnormality
Abnormally small penis. At birth, the normal penis is about 3 cm (stretched length from pubic tubercle to tip of penis) with micropenis less than 2.0-2.5 cm.
Pes planus
MedGen UID:
42034
Concept ID:
C0016202
Anatomical Abnormality
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.
Brachydactyly
MedGen UID:
67454
Concept ID:
C0221357
Congenital Abnormality
Digits that appear disproportionately short compared to the hand/foot. The word brachydactyly is used here to describe a series distinct patterns of shortened digits (brachydactyly types A-E). This is the sense used here.
Broad thumb
MedGen UID:
140880
Concept ID:
C0426891
Finding
Increased thumb width without increased dorso-ventral dimension.
Abnormal heart morphology
MedGen UID:
6748
Concept ID:
C0018798
Congenital Abnormality
Any structural anomaly of the heart.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Individual Behavior
Behavior or an act aimed at harming a person, animal, or physical property (e.g., acts of physical violence; shouting, swearing, and using harsh language; slashing someone's tires).
Anxiety
MedGen UID:
1613
Concept ID:
C0003467
Finding
Intense feelings of nervousness, tension, or panic often arise in response to interpersonal stresses. There is worry about the negative effects of past unpleasant experiences and future negative possibilities. Individuals may feel fearful, apprehensive, or threatened by uncertainty, and they may also have fears of falling apart or losing control.
Atypical behavior
MedGen UID:
14048
Concept ID:
C0004941
Sign or Symptom
Atypical behavior is an abnormality in a person's actions that can be controlled or modulated by the will of the individual. While abnormal behaviors can be difficult to control, they are distinct from other abnormal actions that cannot be affected by the individual's will.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Excessive shyness
MedGen UID:
20741
Concept ID:
C0037020
Social Behavior
Atypically high degree of awkwardness or apprehension experienced when approaching or being approached by others.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Self-injurious behavior
MedGen UID:
88371
Concept ID:
C0085271
Individual Behavior
Self-aggression.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Broad-based gait
MedGen UID:
167799
Concept ID:
C0856863
Finding
An abnormal gait pattern in which persons stand and walk with their feet spaced widely apart. This is often a component of cerebellar ataxia.
Autistic behavior
MedGen UID:
163547
Concept ID:
C0856975
Mental or Behavioral Dysfunction
Persistent deficits in social interaction and communication and interaction as well as a markedly restricted repertoire of activity and interest as well as repetitive patterns of behavior.
Poor speech
MedGen UID:
341172
Concept ID:
C1848207
Finding
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Congenital diaphragmatic hernia
MedGen UID:
68625
Concept ID:
C0235833
Congenital Abnormality
The presence of a hernia of the diaphragm present at birth.
Malar flattening
MedGen UID:
347616
Concept ID:
C1858085
Finding
Underdevelopment of the malar prominence of the jugal bone (zygomatic bone in mammals), appreciated in profile, frontal view, and/or by palpation.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Pulmonary hypoplasia
MedGen UID:
78574
Concept ID:
C0265783
Congenital Abnormality
A congenital abnormality in which the lung parenchyma is not fully developed. It may be associated with other congenital abnormalities.
Narrow mouth
MedGen UID:
44435
Concept ID:
C0026034
Congenital Abnormality
Distance between the commissures of the mouth more than 2 SD below the mean. Alternatively, an apparently decreased width of the oral aperture (subjective).
Velopharyngeal insufficiency
MedGen UID:
52992
Concept ID:
C0042454
Finding
Inability of velopharyngeal sphincter to sufficiently separate the nasal cavity from the oral cavity during speech.
Convex nasal ridge
MedGen UID:
66809
Concept ID:
C0240538
Finding
Nasal ridge curving anteriorly to an imaginary line that connects the nasal root and tip. The nose appears often also prominent, and the columella low.
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Prominent nose
MedGen UID:
98423
Concept ID:
C0426415
Finding
Distance between subnasale and pronasale more than two standard deviations above the mean, or alternatively, an apparently increased anterior protrusion of the nasal tip.
Narrow face
MedGen UID:
373334
Concept ID:
C1837463
Finding
Bizygomatic (upper face) and bigonial (lower face) width are both more than 2 standard deviations below the mean (objective); or, an apparent reduction in the width of the upper and lower face (subjective).
Widely spaced teeth
MedGen UID:
337093
Concept ID:
C1844813
Finding
Increased spaces (diastemata) between most of the teeth in the same dental arch.
Broad forehead
MedGen UID:
338610
Concept ID:
C1849089
Finding
Width of the forehead or distance between the frontotemporales is more than two standard deviations above the mean (objective); or apparently increased distance between the two sides of the forehead.
Wide nasal bridge
MedGen UID:
341441
Concept ID:
C1849367
Finding
Increased breadth of the nasal bridge (and with it, the nasal root).
Prominent nasal bridge
MedGen UID:
343051
Concept ID:
C1854113
Finding
Anterior positioning of the nasal root in comparison to the usual positioning for age.
Downturned corners of mouth
MedGen UID:
356471
Concept ID:
C1866195
Anatomical Abnormality
A morphological abnormality of the mouth in which the angle of the mouth is downturned. The oral commissures are positioned inferior to the midline labial fissure.
Concave nail
MedGen UID:
66369
Concept ID:
C0221261
Finding
The natural longitudinal (posterodistal) convex arch is not present or is inverted.
Small nail
MedGen UID:
537942
Concept ID:
C0263523
Finding
A nail that is diminished in length and width, i.e., underdeveloped nail.
Fine hair
MedGen UID:
98401
Concept ID:
C0423867
Finding
Hair that is fine or thin to the touch.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Hypotelorism
MedGen UID:
96107
Concept ID:
C0424711
Finding
Interpupillary distance less than 2 SD below the mean (alternatively, the appearance of an decreased interpupillary distance or closely spaced eyes).
Blue irides
MedGen UID:
108297
Concept ID:
C0578626
Finding
A markedly blue coloration of the iris.

Professional guidelines

PubMed

Liu S, Li L, Wu H, Pei P, Zheng X, Pan H, Bao X, Qi Y, Ma Y
Mol Genet Genomic Med 2022 Jan;10(1):e1844. Epub 2021 Nov 26 doi: 10.1002/mgg3.1844. PMID: 34826210Free PMC Article
Zahorakova D, Lelkova P, Gregor V, Magner M, Zeman J, Martasek P
J Hum Genet 2016 Jul;61(7):617-25. Epub 2016 Mar 17 doi: 10.1038/jhg.2016.19. PMID: 26984561
Costakos D, Abramson RK, Edwards JG, Rizzo WB, Best RG
Am J Med Genet 1991 Dec 1;41(3):295-300. doi: 10.1002/ajmg.1320410307. PMID: 1789282

Recent clinical studies

Etiology

Sandal S, Verma IC, Mahay SB, Dubey S, Sabharwal RK, Kulshrestha S, Saxena R, Suman P, Kumar P, Puri RD
Indian J Pediatr 2024 Jul;91(7):682-695. Epub 2023 Oct 7 doi: 10.1007/s12098-023-04820-5. PMID: 37804371
Zhang J, Ban T, Zhou L, Ji H, Yan H, Shi Z, Cao B, Jiang Y, Wang J, Wu Y
J Neurol 2020 Sep;267(9):2612-2618. Epub 2020 May 9 doi: 10.1007/s00415-020-09889-y. PMID: 32388833
Ibarluzea N, Hoz AB, Villate O, Llano I, Ocio I, Martí I, Guitart M, Gabau E, Andrade F, Gener B, Tejada MI
Genes (Basel) 2020 Jan 2;11(1) doi: 10.3390/genes11010051. PMID: 31906484Free PMC Article
Ziats CA, Schwartz CE, Gecz J, Shaw M, Field MJ, Stevenson RE, Neri G
Clin Genet 2020 Mar;97(3):418-425. Epub 2019 Nov 24 doi: 10.1111/cge.13667. PMID: 31705537
Jorge P, Oliveira B, Marques I, Santos R
BMC Med Genet 2013 Aug 5;14:80. doi: 10.1186/1471-2350-14-80. PMID: 23914978Free PMC Article

Diagnosis

Liu S, Li L, Wu H, Pei P, Zheng X, Pan H, Bao X, Qi Y, Ma Y
Mol Genet Genomic Med 2022 Jan;10(1):e1844. Epub 2021 Nov 26 doi: 10.1002/mgg3.1844. PMID: 34826210Free PMC Article
Saleh S, Beyyumi E, Al Kaabi A, Hertecant J, Barakat D, Al Dhaheri NS, Al-Gazali L, Al Shamsi A
Clin Genet 2021 Nov;100(5):573-600. Epub 2021 Aug 19 doi: 10.1111/cge.14044. PMID: 34374989
Zhang J, Ban T, Zhou L, Ji H, Yan H, Shi Z, Cao B, Jiang Y, Wang J, Wu Y
J Neurol 2020 Sep;267(9):2612-2618. Epub 2020 May 9 doi: 10.1007/s00415-020-09889-y. PMID: 32388833
Ibarluzea N, Hoz AB, Villate O, Llano I, Ocio I, Martí I, Guitart M, Gabau E, Andrade F, Gener B, Tejada MI
Genes (Basel) 2020 Jan 2;11(1) doi: 10.3390/genes11010051. PMID: 31906484Free PMC Article
Jorge P, Oliveira B, Marques I, Santos R
BMC Med Genet 2013 Aug 5;14:80. doi: 10.1186/1471-2350-14-80. PMID: 23914978Free PMC Article

Therapy

van Geest FS, Groeneweg S, van den Akker ELT, Bacos I, Barca D, van den Berg SAA, Bertini E, Brunner D, Brunetti-Pierri N, Cappa M, Cappuccio G, Chatterjee K, Chesover AD, Christian P, Coutant R, Craiu D, Crock P, Dewey C, Dica A, Dimitri P, Dubey R, Enderli A, Fairchild J, Gallichan J, Garibaldi LR, George B, Hackenberg A, Heinrich B, Huynh T, Kłosowska A, Lawson-Yuen A, Linder-Lucht M, Lyons G, Monti Lora F, Moran C, Müller KE, Paone L, Paul PG, Polak M, Porta F, Reinauer C, de Rijke YB, Seckold R, Menevşe TS, Simm P, Simon A, Spada M, Stoupa A, Szeifert L, Tonduti D, van Toor H, Turan S, Vanderniet J, de Waart M, van der Wal R, van der Walt A, van Wermeskerken AM, Wierzba J, Zibordi F, Zung A, Peeters RP, Visser WE
J Clin Endocrinol Metab 2022 Feb 17;107(3):e1136-e1147. doi: 10.1210/clinem/dgab750. PMID: 34679181Free PMC Article
Ziats CA, Schwartz CE, Gecz J, Shaw M, Field MJ, Stevenson RE, Neri G
Clin Genet 2020 Mar;97(3):418-425. Epub 2019 Nov 24 doi: 10.1111/cge.13667. PMID: 31705537
Groeneweg S, Peeters RP, Moran C, Stoupa A, Auriol F, Tonduti D, Dica A, Paone L, Rozenkova K, Malikova J, van der Walt A, de Coo IFM, McGowan A, Lyons G, Aarsen FK, Barca D, van Beynum IM, van der Knoop MM, Jansen J, Manshande M, Lunsing RJ, Nowak S, den Uil CA, Zillikens MC, Visser FE, Vrijmoeth P, de Wit MCY, Wolf NI, Zandstra A, Ambegaonkar G, Singh Y, de Rijke YB, Medici M, Bertini ES, Depoorter S, Lebl J, Cappa M, De Meirleir L, Krude H, Craiu D, Zibordi F, Oliver Petit I, Polak M, Chatterjee K, Visser TJ, Visser WE
Lancet Diabetes Endocrinol 2019 Sep;7(9):695-706. Epub 2019 Jul 31 doi: 10.1016/S2213-8587(19)30155-X. PMID: 31377265Free PMC Article
Loes DJ, Fatemi A, Melhem ER, Gupte N, Bezman L, Moser HW, Raymond GV
Neurology 2003 Aug 12;61(3):369-74. doi: 10.1212/01.wnl.0000079050.91337.83. PMID: 12913200
Schanen NC, Dahle EJ, Capozzoli F, Holm VA, Zoghbi HY, Francke U
Am J Hum Genet 1997 Sep;61(3):634-41. doi: 10.1086/515525. PMID: 9326329Free PMC Article

Prognosis

van Geest FS, Groeneweg S, van den Akker ELT, Bacos I, Barca D, van den Berg SAA, Bertini E, Brunner D, Brunetti-Pierri N, Cappa M, Cappuccio G, Chatterjee K, Chesover AD, Christian P, Coutant R, Craiu D, Crock P, Dewey C, Dica A, Dimitri P, Dubey R, Enderli A, Fairchild J, Gallichan J, Garibaldi LR, George B, Hackenberg A, Heinrich B, Huynh T, Kłosowska A, Lawson-Yuen A, Linder-Lucht M, Lyons G, Monti Lora F, Moran C, Müller KE, Paone L, Paul PG, Polak M, Porta F, Reinauer C, de Rijke YB, Seckold R, Menevşe TS, Simm P, Simon A, Spada M, Stoupa A, Szeifert L, Tonduti D, van Toor H, Turan S, Vanderniet J, de Waart M, van der Wal R, van der Walt A, van Wermeskerken AM, Wierzba J, Zibordi F, Zung A, Peeters RP, Visser WE
J Clin Endocrinol Metab 2022 Feb 17;107(3):e1136-e1147. doi: 10.1210/clinem/dgab750. PMID: 34679181Free PMC Article
Shibata Y, Matsushima M, Matsukawa T, Ishiura H, Tsuji S, Yabe I
J Hum Genet 2021 May;66(5):535-537. Epub 2020 Oct 30 doi: 10.1038/s10038-020-00866-x. PMID: 33127985
Remerand G, Boespflug-Tanguy O, Tonduti D, Touraine R, Rodriguez D, Curie A, Perreton N, Des Portes V, Sarret C; RMLX/AHDS Study Group
Dev Med Child Neurol 2019 Dec;61(12):1439-1447. Epub 2019 Aug 13 doi: 10.1111/dmcn.14332. PMID: 31410843
Groeneweg S, Peeters RP, Moran C, Stoupa A, Auriol F, Tonduti D, Dica A, Paone L, Rozenkova K, Malikova J, van der Walt A, de Coo IFM, McGowan A, Lyons G, Aarsen FK, Barca D, van Beynum IM, van der Knoop MM, Jansen J, Manshande M, Lunsing RJ, Nowak S, den Uil CA, Zillikens MC, Visser FE, Vrijmoeth P, de Wit MCY, Wolf NI, Zandstra A, Ambegaonkar G, Singh Y, de Rijke YB, Medici M, Bertini ES, Depoorter S, Lebl J, Cappa M, De Meirleir L, Krude H, Craiu D, Zibordi F, Oliver Petit I, Polak M, Chatterjee K, Visser TJ, Visser WE
Lancet Diabetes Endocrinol 2019 Sep;7(9):695-706. Epub 2019 Jul 31 doi: 10.1016/S2213-8587(19)30155-X. PMID: 31377265Free PMC Article
Semmler A, Bao X, Cao G, Köhler W, Weller M, Aubourg P, Linnebank M
J Neurol 2009 Aug;256(8):1277-80. Epub 2009 Apr 8 doi: 10.1007/s00415-009-5114-6. PMID: 19353223

Clinical prediction guides

Gras M, Heide S, Keren B, Valence S, Garel C, Whalen S, Jansen AC, Keymolen K, Stouffs K, Jennesson M, Poirsier C, Lesca G, Depienne C, Nava C, Rastetter A, Curie A, Cuisset L, Des Portes V, Milh M, Charles P, Mignot C, Héron D
J Med Genet 2024 Jan 19;61(2):103-108. doi: 10.1136/jmg-2023-109203. PMID: 37879892
Sandal S, Verma IC, Mahay SB, Dubey S, Sabharwal RK, Kulshrestha S, Saxena R, Suman P, Kumar P, Puri RD
Indian J Pediatr 2024 Jul;91(7):682-695. Epub 2023 Oct 7 doi: 10.1007/s12098-023-04820-5. PMID: 37804371
Zhang J, Ban T, Zhou L, Ji H, Yan H, Shi Z, Cao B, Jiang Y, Wang J, Wu Y
J Neurol 2020 Sep;267(9):2612-2618. Epub 2020 May 9 doi: 10.1007/s00415-020-09889-y. PMID: 32388833
Ibarluzea N, Hoz AB, Villate O, Llano I, Ocio I, Martí I, Guitart M, Gabau E, Andrade F, Gener B, Tejada MI
Genes (Basel) 2020 Jan 2;11(1) doi: 10.3390/genes11010051. PMID: 31906484Free PMC Article
Jorge P, Oliveira B, Marques I, Santos R
BMC Med Genet 2013 Aug 5;14:80. doi: 10.1186/1471-2350-14-80. PMID: 23914978Free PMC Article

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