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Intellectual disability, autosomal dominant 43(MRD43)

MedGen UID:
934738
Concept ID:
C4310771
Mental or Behavioral Dysfunction
Synonyms: INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 43; MRD43
 
Gene (location): HIVEP2 (6q24.2)
 
Monarch Initiative: MONDO:0014858
OMIM®: 616977

Definition

HIVEP2-related intellectual disability is a neurological disorder characterized by moderate to severe developmental delay and intellectual disability and mild physical abnormalities (dysmorphic features). Early symptoms of the condition include weak muscle tone (hypotonia) and delayed development of motor skills, such as sitting, standing, and walking. After learning to walk, many affected individuals continue to have difficulty with this activity; their walking style (gait) is often unbalanced and wide-based. Speech is also delayed, and some people with this condition never learn to talk. Most people with HIVEP2-related intellectual disability also have unusual physical features, such as widely spaced eyes (hypertelorism), a broad nasal bridge, or fingers with tapered ends, although there is no characteristic pattern of such features among affected individuals. Many people with the condition exhibit neurodevelopmental disorders, such as hyperactivity, attention deficit disorder, aggression, anxiety, and autism spectrum disorder, which is a group of developmental disorders characterized by impaired communication and social interaction.

Other features of HIVEP2-related intellectual disability include mild abnormalities in the structure of the brain and an abnormally small brain and head size (microcephaly). Less common health problems include seizures; recurrent ear infections; and eye disorders, such as eyes that do not look in the same direction (strabismus), "lazy eye" (amblyopia), and farsightedness (hyperopia). Some people with HIVEP2-related intellectual disability have gastrointestinal problems, which can include backflow of acidic stomach contents into the esophagus (gastroesophageal reflux) and constipation. [from MedlinePlus Genetics]

Clinical features

From HPO
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.
Tapered finger
MedGen UID:
98098
Concept ID:
C0426886
Finding
The gradual reduction in girth of the finger from proximal to distal.
Pulmonic stenosis
MedGen UID:
408291
Concept ID:
C1956257
Disease or Syndrome
A narrowing of the right ventricular outflow tract that can occur at the pulmonary valve (valvular stenosis), below the pulmonary valve (infundibular stenosis), or above the pulmonary valve (supravalvar stenosis).
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
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.
Chronic constipation
MedGen UID:
98325
Concept ID:
C0401149
Sign or Symptom
Constipation for longer than three months with fewer than 3 bowel movements per week, straining, lumpy or hard stools, and a sensation of anorectal obstruction or incomplete defecation.
Gastroesophageal reflux
MedGen UID:
1368658
Concept ID:
C4317146
Finding
A condition in which the stomach contents leak backwards from the stomach into the esophagus through the lower esophageal sphincter.
Microtia
MedGen UID:
57535
Concept ID:
C0152423
Congenital Abnormality
Underdevelopment of the external ear.
Attached earlobe
MedGen UID:
867017
Concept ID:
C4021375
Finding
Attachment of the lobe to the side of the face at the lowest point of the lobe without curving upward.
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.
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.
Impulsivity
MedGen UID:
43850
Concept ID:
C0021125
Mental or Behavioral Dysfunction
Acting on the spur of the moment in response to immediate stimuli; acting on a momentary basis without a plan or consideration of outcomes; having difficulty establishing or following plans; experiencing a sense of urgency and engaging in self-harming behavior when under emotional distress.
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.
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.
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
Hyperactivity
MedGen UID:
98406
Concept ID:
C0424295
Finding
Hyperactivity is a condition characterized by constant and unusually high levels of activity, even in situations where it is deemed inappropriate.
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.
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.
Frontal cortical atrophy
MedGen UID:
870517
Concept ID:
C4024965
Anatomical Abnormality
Atrophy of the frontal cortex.
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.
Delayed ability to crawl
MedGen UID:
1772845
Concept ID:
C5421628
Finding
A failure to achieve the ability to crawl at an appropriate developmental stage. Normal infant motor development is marked by a series of postural milestones including learning to crawl on hands and knees between the ages of 6 and 10 months.
Thin corpus callosum
MedGen UID:
1785336
Concept ID:
C5441562
Anatomical Abnormality
An abnormally thin corpus callous, due to atrophy, hypoplasia or agenesis. This term is intended to be used in situations where it is not known if thinning of the corpus callosum (for instance, as visualized by magnetic resonance tomography) is due to abnormal development (e.g. a leukodystrophy) or atrophy following normal development (e.g. neurodegeneration).
Umbilical hernia
MedGen UID:
9232
Concept ID:
C0019322
Anatomical Abnormality
Protrusion of abdominal contents through a defect in the abdominal wall musculature around the umbilicus. Skin and subcutaneous tissue overlie the defect.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Poor head control
MedGen UID:
322809
Concept ID:
C1836038
Finding
Difficulty to maintain correct position of the head while standing or sitting.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Developmental dysplasia of the hip
MedGen UID:
1640560
Concept ID:
C4551649
Congenital Abnormality
Congenital dysplasia of the hip (CDH) is an abnormality of the seating of the femoral head in the acetabulum. Its severity ranges from mild instability of the femoral head with slight capsular laxity, through moderate lateral displacement of the femoral head, without loss of contact of the head with the acetabulum, up to complete dislocation of the femoral head from the acetabulum. It is one of the most common skeletal congenital anomalies (summary by Sollazzo et al., 2000). Acetabular dysplasia is an idiopathic, localized developmental dysplasia of the hip that is characterized by a shallow hip socket and decreased coverage of the femoral head. Its radiologic criteria include the center-edge angle of Wiberg, the Sharp angle, and the acetabular roof obliquity. Most patients with acetabular dysplasia develop osteoarthritis (165720) after midlife, and even mild acetabular dysplasia can cause hip osteoarthritis (summary by Mabuchi et al., 2006). CDH occurs as an isolated anomaly or with more general disorders represented by several syndromes and with chromosomal abnormalities such as trisomy 18 (Wynne-Davies, 1970). Genetic Heterogeneity of Developmental Dysplasia of the Hip Developmental dysplasia of the hip-1 (DDH1) maps to chromosome 13q22; DDH2 (615612) maps to chromosome 3p21. DDH3 (620690) is caused by mutation in the LRP1 gene (107770) on chromosome 12q13.
Drooling
MedGen UID:
8484
Concept ID:
C0013132
Finding
Habitual flow of saliva out of the mouth.
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).
High forehead
MedGen UID:
65991
Concept ID:
C0239676
Finding
An abnormally increased height of the forehead.
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).
Increased overbite
MedGen UID:
539656
Concept ID:
C0266063
Disease or Syndrome
Maxillary teeth cover the mandibular teeth when biting to an increased degree. The feature is defined as a vertical overlap of the maxillary incisors over the mandibular incisors that exceeds 2 mm.
Gingival overgrowth
MedGen UID:
87712
Concept ID:
C0376480
Finding
Hyperplasia of the gingiva (that is, a thickening of the soft tissue overlying the alveolar ridge. The degree of thickening ranges from involvement of the interdental papillae alone to gingival overgrowth covering the entire tooth crown.
Upslanted palpebral fissure
MedGen UID:
98390
Concept ID:
C0423109
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.
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
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.
Low hanging columella
MedGen UID:
344656
Concept ID:
C1856119
Finding
Columella extending inferior to the level of the nasal base, when viewed from the side.
Short philtrum
MedGen UID:
350006
Concept ID:
C1861324
Finding
Distance between nasal base and midline upper lip vermilion border more than 2 SD below the mean. Alternatively, an apparently decreased distance between nasal base and midline upper lip vermilion border.
Thin upper lip vermilion
MedGen UID:
355352
Concept ID:
C1865017
Finding
Height of the vermilion of the upper lip in the midline more than 2 SD below the mean. Alternatively, an apparently reduced height of the vermilion of the upper lip in the frontal view (subjective).
Hirsutism
MedGen UID:
42461
Concept ID:
C0019572
Disease or Syndrome
Abnormally increased hair growth referring to a male pattern of body hair (androgenic hair).
Synophrys
MedGen UID:
98132
Concept ID:
C0431447
Congenital Abnormality
Meeting of the medial eyebrows in the midline.
Hypermetropia
MedGen UID:
43780
Concept ID:
C0020490
Disease or Syndrome
An abnormality of refraction characterized by the ability to see objects in the distance clearly, while objects nearby appear blurry.
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).

Professional guidelines

PubMed

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Recent clinical studies

Etiology

Billiet B, Amati-Bonneau P, Desquiret-Dumas V, Guehlouz K, Milea D, Gohier P, Lenaers G, Mirebeau-Prunier D, den Dunnen JT, Reynier P, Ferré M
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Brain Dev 2021 Jan;43(1):144-151. Epub 2020 Aug 11 doi: 10.1016/j.braindev.2020.07.015. PMID: 32798076
Davidson YS, Raby S, Foulds PG, Robinson A, Thompson JC, Sikkink S, Yusuf I, Amin H, DuPlessis D, Troakes C, Al-Sarraj S, Sloan C, Esiri MM, Prasher VP, Allsop D, Neary D, Pickering-Brown SM, Snowden JS, Mann DM
Acta Neuropathol 2011 Dec;122(6):703-13. Epub 2011 Oct 4 doi: 10.1007/s00401-011-0879-y. PMID: 21968532
Sammour ZM, Gomes CM, Duarte RJ, Trigo-Rocha FE, Srougi M
J Urol 2006 Apr;175(4):1472-6. doi: 10.1016/S0022-5347(05)00666-X. PMID: 16516025
Fitch N, Becker R, Heller A
Ann Neurol 1988 Jan;23(1):14-9. doi: 10.1002/ana.410230104. PMID: 2964224

Diagnosis

Lv X, Yang X, Li L, Yue F, Zhang H, Wang R
Medicine (Baltimore) 2023 Oct 27;102(43):e34852. doi: 10.1097/MD.0000000000034852. PMID: 37904428Free PMC Article
Valverde de Morales HG, Wang HV, Garber K, Cheng X, Corces VG, Li H
Am J Med Genet A 2023 Mar;191(3):718-729. Epub 2022 Dec 1 doi: 10.1002/ajmg.a.63065. PMID: 36454652Free PMC Article
Simmers R, Goodwin A, Al Saif H, Couser N
Ophthalmic Genet 2022 Oct;43(5):699-702. Epub 2022 Jun 27 doi: 10.1080/13816810.2022.2089358. PMID: 35762114
Matsumoto A, Kojima K, Miya F, Miyauchi A, Watanabe K, Iwamoto S, Kawai K, Kato M, Takahashi Y, Yamagata T
Brain Dev 2021 Sep;43(8):857-862. Epub 2021 Jun 3 doi: 10.1016/j.braindev.2021.05.005. PMID: 34092403
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Therapy

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Clinical prediction guides

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Lin SJ, Vona B, Porter HM, Izadi M, Huang K, Lacassie Y, Rosenfeld JA, Khan S, Petree C, Ali TA, Muhammad N, Khan SA, Muhammad N, Liu P, Haymon ML, Rüschendorf F, Kong IK, Schnapp L, Shur N, Chorich L, Layman L, Haaf T, Pourkarimi E, Kim HG, Varshney GK
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Hum Mutat 2022 Jan;43(1):3-15. Epub 2021 Oct 11 doi: 10.1002/humu.24287. PMID: 34618388
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Eur J Med Genet 2010 Jan-Feb;53(1):19-22. Epub 2009 Oct 4 doi: 10.1016/j.ejmg.2009.08.007. PMID: 19808103

Recent systematic reviews

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