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X-linked intellectual disability-psychosis-macroorchidism syndrome(MRXS13)

MedGen UID:
163232
Concept ID:
C0796222
Disease or Syndrome
Synonyms: INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC 13; MRXS13; PPM-X syndrome
SNOMED CT: PPMX - Mental retardation with psychosis, pyramidal signs, and macroorchidism (702356009); X-linked mental retardation, syndromic 13 (702356009); PPM-X syndrome (702356009); X-linked intellectual disability-psychosis-macroorchidism syndrome (702356009); Lindsay Burn syndrome (702356009)
Modes of inheritance:
X-linked dominant inheritance
MedGen UID:
376232
Concept ID:
C1847879
Finding
Source: Orphanet
A mode of inheritance that is observed for dominant traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked dominant disorders tend to manifest very severely in affected males. The severity of manifestation in females may depend on the degree of skewed X inactivation.
 
Gene (location): MECP2 (Xq28)
 
Monarch Initiative: MONDO:0010235
OMIM®: 300055
Orphanet: ORPHA3077

Disease characteristics

Excerpted from the GeneReview: MECP2 Disorders
The spectrum of MECP2-related phenotypes in females ranges from classic Rett syndrome to variant Rett syndrome with a broader clinical phenotype (either milder or more severe than classic Rett syndrome) to mild learning disabilities; the spectrum in males ranges from severe neonatal encephalopathy to pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome to severe syndromic/nonsyndromic intellectual disability. Females: Classic Rett syndrome, a progressive neurodevelopmental disorder primarily affecting girls, is characterized by apparently normal psychomotor development during the first six to 18 months of life, followed by a short period of developmental stagnation, then rapid regression in language and motor skills, followed by long-term stability. During the phase of rapid regression, repetitive, stereotypic hand movements replace purposeful hand use. Additional findings include fits of screaming and inconsolable crying, autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures, and acquired microcephaly. Males: Severe neonatal-onset encephalopathy, the most common phenotype in affected males, is characterized by a relentless clinical course that follows a metabolic-degenerative type of pattern, abnormal tone, involuntary movements, severe seizures, and breathing abnormalities. Death often occurs before age two years. [from GeneReviews]
Authors:
Simranpreet Kaur  |  John Christodoulou   view full author information

Additional description

From OMIM
The MECP2 gene is mutated in Rett syndrome (RTT; 312750), a severe neurodevelopmental disorder that almost always occurs in females. Males with non-RTT mutations in the MECP2 gene can demonstrate a wide variety of phenotypes, including X-linked syndromic intellectual developmental disorder-13, described here, and Lubs-type X-linked syndromic intellectual developmental disorder (MRXSL; 300260). Males with RTT-associated MECP2 mutations have neonatal severe encephalopathy that is usually lethal (300673) (Moog et al., 2003; Villard, 2007).  http://www.omim.org/entry/300055

Clinical features

From HPO
Macroorchidism
MedGen UID:
224727
Concept ID:
C1263023
Finding
The presence of abnormally large testes.
Small hand
MedGen UID:
108279
Concept ID:
C0575802
Finding
Disproportionately small hand.
Pes cavus
MedGen UID:
675590
Concept ID:
C0728829
Congenital Abnormality
An increase in height of the medial longitudinal arch of the foot that does not flatten on weight bearing (i.e., a distinctly hollow form of the sole of the foot when it is bearing weight).
Obesity
MedGen UID:
18127
Concept ID:
C0028754
Disease or Syndrome
Accumulation of substantial excess body fat.
Macrotia
MedGen UID:
488785
Concept ID:
C0152421
Congenital Abnormality
Median longitudinal ear length greater than two standard deviations above the mean and median ear width greater than two standard deviations above the mean (objective); or, apparent increase in length and width of the pinna (subjective).
Apraxia
MedGen UID:
8166
Concept ID:
C0003635
Mental or Behavioral Dysfunction
A defect in the understanding of complex motor commands and in the execution of certain learned movements, i.e., deficits in the cognitive components of learned movements.
Bruxism
MedGen UID:
676
Concept ID:
C0006325
Mental or Behavioral Dysfunction
Bruxism is characterized by the grinding of the teeth including the clenching of the jaw and typically occur during sleep, but also can occur while the affected individual is awake.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
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- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
Psychotic disorder
MedGen UID:
19568
Concept ID:
C0033975
Mental or Behavioral Dysfunction
A condition characterized by changes in personality and thought patterns, often accompanied by hallucinations and delusional beliefs, is known as psychosis.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
Severe mental retardation is defined as an intelligence quotient (IQ) in the range of 20-34.
Spastic paraplegia
MedGen UID:
20882
Concept ID:
C0037772
Disease or Syndrome
Spasticity and weakness of the leg and hip muscles.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Choreoathetosis
MedGen UID:
39313
Concept ID:
C0085583
Disease or Syndrome
Involuntary movements characterized by both athetosis (inability to sustain muscles in a fixed position) and chorea (widespread jerky arrhythmic movements).
Emotional lability
MedGen UID:
39319
Concept ID:
C0085633
Mental or Behavioral Dysfunction
Unstable emotional experiences and frequent mood changes; emotions that are easily aroused, intense, and/or disproportionate to events and circumstances.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Spastic gait
MedGen UID:
115907
Concept ID:
C0231687
Finding
Spasticity is manifested by increased stretch reflex which is intensified with movement velocity. This results in excessive and inappropriate muscle activation which can contribute to muscle hypertonia. Spastic gait is characterized by manifestations such as muscle hypertonia, stiff knee, and circumduction of the leg.
Shuffling gait
MedGen UID:
68545
Concept ID:
C0231688
Finding
A type of gait (walking) characterized by by dragging one's feet along or without lifting the feet fully from the ground.
Bradykinesia
MedGen UID:
115925
Concept ID:
C0233565
Sign or Symptom
Bradykinesia literally means slow movement, and is used clinically to denote a slowness in the execution of movement (in contrast to hypokinesia, which is used to refer to slowness in the initiation of movement).
Resting tremor
MedGen UID:
66697
Concept ID:
C0234379
Sign or Symptom
A resting tremor occurs when muscles are at rest and becomes less noticeable or disappears when the affected muscles are moved. Resting tremors are often slow and coarse.
Delayed ability to walk
MedGen UID:
66034
Concept ID:
C0241726
Finding
A failure to achieve the ability to walk at an appropriate developmental stage. Most children learn to walk in a series of stages, and learn to walk short distances independently between 12 and 15 months.
Parkinsonism
MedGen UID:
66079
Concept ID:
C0242422
Disease or Syndrome
Characteristic neurologic anomaly resulting from degeneration of dopamine-generating cells in the substantia nigra, a region of the midbrain, characterized clinically by shaking, rigidity, slowness of movement and difficulty with walking and gait.
Spastic tetraplegia
MedGen UID:
98433
Concept ID:
C0426970
Disease or Syndrome
Spastic paralysis affecting all four limbs.
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.
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.
Persistent head lag
MedGen UID:
256151
Concept ID:
C1141883
Finding
The Premie-Neuro and the Dubowitz Neurological Examination score head lag in the same manner. Scoring for both is as follows
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
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.
Restlessness
MedGen UID:
854457
Concept ID:
C3887611
Sign or Symptom
A state of unease is characterized by diffuse motor activity or motion, which is subject to limited control, nonproductive, or disorganized behavior.
EEG with generalized slow activity
MedGen UID:
866862
Concept ID:
C4021217
Finding
Diffuse slowing of cerebral electrical activity recorded along the scalp by electroencephalography (EEG).
Delayed ability to sit
MedGen UID:
1368737
Concept ID:
C4476710
Finding
A failure to achieve the ability to sit at an appropriate developmental stage. Most children sit with support at 6 months of age and sit steadily without support at 9 months of age.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Flexion contracture
MedGen UID:
83069
Concept ID:
C0333068
Anatomical Abnormality
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.
Wrist flexion contracture
MedGen UID:
592338
Concept ID:
C0409345
Acquired Abnormality
A chronic loss of wrist joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevent normal movement of the joints of the wrist.
Kyphoscoliosis
MedGen UID:
154361
Concept ID:
C0575158
Anatomical Abnormality
An abnormal curvature of the spine in both a coronal (lateral) and sagittal (back-to-front) plane.
Facial hypotonia
MedGen UID:
336889
Concept ID:
C1845251
Finding
Reduced muscle tone of a muscle that is innervated by the facial nerve (the seventh cranial nerve).
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Apnea
MedGen UID:
2009
Concept ID:
C0003578
Sign or Symptom
Lack of breathing with no movement of the respiratory muscles and no exchange of air in the lungs. This term refers to a disposition to have recurrent episodes of apnea rather than to a single event.
Drooling
MedGen UID:
8484
Concept ID:
C0013132
Finding
Habitual flow of saliva out of the mouth.
Excessive salivation
MedGen UID:
11419
Concept ID:
C0037036
Disease or Syndrome
Excessive production of saliva.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Male hypogonadism
MedGen UID:
57480
Concept ID:
C0151721
Disease or Syndrome
Familial male hypogonadism is a highly heterogeneous category from which some disorders such as Reifenstein syndrome (312300), Kallmann syndrome (see 308700), isolated gonadotropin deficiency, and some other entities can be separated. The presence of an autosomal recessive form is suggested by the occurrence of parental consanguinity (Nowakowski and Lenz, 1961).
Gynecomastia
MedGen UID:
6694
Concept ID:
C0018418
Disease or Syndrome
Abnormal development of large mammary glands in males resulting in breast enlargement.
Juvenile cataract
MedGen UID:
137062
Concept ID:
C0302254
Anatomical Abnormality
A type of cataract that is not apparent at birth but that arises in childhood or adolescence.

Professional guidelines

PubMed

León NY, Harley VR
Hum Genet 2021 Dec;140(12):1625-1634. Epub 2021 Sep 15 doi: 10.1007/s00439-021-02361-5. PMID: 34524523
Magini P, Palombo F, Boito S, Lanzoni G, Mongelli P, Rizzuti T, Baccarin M, Pippucci T, Seri M, Lalatta F
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Verpelli C, Galimberti I, Gomez-Mancilla B, Sala C
Dev Neurobiol 2014 Feb;74(2):197-206. Epub 2013 Jul 19 doi: 10.1002/dneu.22093. PMID: 23695997

Recent clinical studies

Etiology

Lui JC, Baron J
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Wang YR, Xu NX, Wang J, Wang XM
World J Pediatr 2019 Dec;15(6):528-535. Epub 2019 Oct 5 doi: 10.1007/s12519-019-00309-4. PMID: 31587141
Niturad CE, Lev D, Kalscheuer VM, Charzewska A, Schubert J, Lerman-Sagie T, Kroes HY, Oegema R, Traverso M, Specchio N, Lassota M, Chelly J, Bennett-Back O, Carmi N, Koffler-Brill T, Iacomino M, Trivisano M, Capovilla G, Striano P, Nawara M, Rzonca S, Fischer U, Bienek M, Jensen C, Hu H, Thiele H, Altmüller J, Krause R, May P, Becker F; EuroEPINOMICS Consortium, Balling R, Biskup S, Haas SA, Nürnberg P, van Gassen KLI, Lerche H, Zara F, Maljevic S, Leshinsky-Silver E
Brain 2017 Nov 1;140(11):2879-2894. doi: 10.1093/brain/awx236. PMID: 29053855
Laxova R
Adv Pediatr 1994;41:305-42. PMID: 7992687

Diagnosis

Pascual-Alonso A, Martínez-Monseny AF, Xiol C, Armstrong J
Int J Mol Sci 2021 Sep 4;22(17) doi: 10.3390/ijms22179610. PMID: 34502518Free PMC Article
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Therapy

Pereira G, Dória S
J Genet 2021;100 PMID: 34553695
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Chakrabarti A, Oehme I, Witt O, Oliveira G, Sippl W, Romier C, Pierce RJ, Jung M
Trends Pharmacol Sci 2015 Jul;36(7):481-92. Epub 2015 May 23 doi: 10.1016/j.tips.2015.04.013. PMID: 26013035
Mégarbané H, Mégarbané A
Orphanet J Rare Dis 2011 May 21;6:29. doi: 10.1186/1750-1172-6-29. PMID: 21600032Free PMC Article
Laxova R
Adv Pediatr 1994;41:305-42. PMID: 7992687

Prognosis

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El-Hattab AW, Scaglia F
Cell Calcium 2016 Sep;60(3):199-206. Epub 2016 Mar 4 doi: 10.1016/j.ceca.2016.03.003. PMID: 26996063

Clinical prediction guides

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De Luca C, Race V, Keldermans L, Bauters M, Van Esch H
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Piché J, Van Vliet PP, Pucéat M, Andelfinger G
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Shah A, Bapna M, Al-Saif H, Li R, Couser NL
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