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Attention deficit hyperactivity disorder(ADHD)

MedGen UID:
220387
Concept ID:
C1263846
Mental or Behavioral Dysfunction
Synonyms: ADHD; Attention deficit; Attention deficit disorder; Attention deficits; Childhood attention deficit/hyperactivity disorder; HYPERACTIVITY OF CHILDHOOD
SNOMED CT: Attention deficit hyperactivity disorder, predominantly hyperactive impulsive type (7461003); Attention deficit hyperactivity disorder (406506008); ADHD - Attention deficit disorder with hyperactivity (406506008); Hyperkinetic disorder (406506008); Hyperkinetic syndrome (406506008); Overactive child syndrome (406506008); Attention deficit hyperkinetic disorder (406506008); Attention deficit hyperactivity disorder, hyperactive impulsive type (7461003)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Genes (locations): DRD4 (11p15.5); DRD5 (4p16.1)
 
HPO: HP:0007018
OMIM®: 143465

Definition

Attention-deficit/hyperactivity disorder (ADHD) is a behavioral disorder that typically begins in childhood and is characterized by a short attention span (inattention), an inability to be calm and stay still (hyperactivity), and poor impulse control (impulsivity). Some people with ADHD have problems with only inattention or with hyperactivity and impulsivity, but most have problems related to all three features.\n\nIn people with ADHD, the characteristic behaviors are frequent and severe enough to interfere with the activities of daily living such as school, work, and relationships with others. Because of an inability to stay focused on tasks, people with inattention may be easily distracted, forgetful, avoid tasks that require sustained attention, have difficulty organizing tasks, or frequently lose items.\n\nHyperactivity is usually shown by frequent movement. Individuals with this feature often fidget or tap their foot when seated, leave their seat when it is inappropriate to do so (such as in the classroom), or talk a lot and interrupt others.\n\nIn most affected individuals, ADHD continues throughout life, but in about one-third of individuals, signs and symptoms of ADHD go away by adulthood.\n\nImpulsivity can result in hasty actions without thought for the consequences. Individuals with poor impulse control may have difficulty waiting for their turn, deferring to others, or considering their actions before acting.\n\nMore than two-thirds of all individuals with ADHD have additional conditions, including insomnia, mood or anxiety disorders, learning disorders, or substance use disorders. Affected individuals may also have autism spectrum disorder, which is characterized by impaired communication and social interaction, or Tourette syndrome, which is a disorder characterized by repetitive and involuntary movements or noises called tics. [from MedlinePlus Genetics]

Clinical features

From HPO
Hyperactivity
MedGen UID:
98406
Concept ID:
C0424295
Finding
Hyperactivity is a state of constantly being unusually or abnormally active, including in situations in which it is not appropriate.
Attention deficit hyperactivity disorder
MedGen UID:
220387
Concept ID:
C1263846
Mental or Behavioral Dysfunction
Attention-deficit/hyperactivity disorder (ADHD) is a behavioral disorder that typically begins in childhood and is characterized by a short attention span (inattention), an inability to be calm and stay still (hyperactivity), and poor impulse control (impulsivity). Some people with ADHD have problems with only inattention or with hyperactivity and impulsivity, but most have problems related to all three features.\n\nIn people with ADHD, the characteristic behaviors are frequent and severe enough to interfere with the activities of daily living such as school, work, and relationships with others. Because of an inability to stay focused on tasks, people with inattention may be easily distracted, forgetful, avoid tasks that require sustained attention, have difficulty organizing tasks, or frequently lose items.\n\nHyperactivity is usually shown by frequent movement. Individuals with this feature often fidget or tap their foot when seated, leave their seat when it is inappropriate to do so (such as in the classroom), or talk a lot and interrupt others.\n\nIn most affected individuals, ADHD continues throughout life, but in about one-third of individuals, signs and symptoms of ADHD go away by adulthood.\n\nImpulsivity can result in hasty actions without thought for the consequences. Individuals with poor impulse control may have difficulty waiting for their turn, deferring to others, or considering their actions before acting.\n\nMore than two-thirds of all individuals with ADHD have additional conditions, including insomnia, mood or anxiety disorders, learning disorders, or substance use disorders. Affected individuals may also have autism spectrum disorder, which is characterized by impaired communication and social interaction, or Tourette syndrome, which is a disorder characterized by repetitive and involuntary movements or noises called tics.

Term Hierarchy

Conditions with this feature

DiGeorge Syndrome
MedGen UID:
4297
Concept ID:
C0012236
Disease or Syndrome
Individuals with 22q11.2 deletion syndrome (22q11.2DS) can present with a wide range of features that are highly variable, even within families. The major clinical manifestations of 22q11.2DS include congenital heart disease, particularly conotruncal malformations (ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus), palatal abnormalities (velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate), immune deficiency, characteristic facial features, and learning difficulties. Hearing loss can be sensorineural and/or conductive. Laryngotracheoesophageal, gastrointestinal, ophthalmologic, central nervous system, skeletal, and genitourinary anomalies also occur. Psychiatric illness and autoimmune disorders are more common in individuals with 22q11.2DS.
Phenylketonuria
MedGen UID:
19244
Concept ID:
C0031485
Disease or Syndrome
Phenylalanine hydroxylase (PAH) deficiency results in intolerance to the dietary intake of the essential amino acid phenylalanine and produces a spectrum of disorders. The risk of adverse outcome varies based on the degree of PAH deficiency. Without effective therapy, most individuals with severe PAH deficiency, known as classic PKU, develop profound and irreversible intellectual disability. Affected individuals on an unrestricted diet who have phenylalanine levels above normal but below 1,200 µmol/L (20 mg/dL) are at much lower risk for impaired cognitive development in the absence of treatment.
Prader-Willi syndrome
MedGen UID:
46057
Concept ID:
C0032897
Disease or Syndrome
Prader-Willi syndrome (PWS) is characterized by severe hypotonia and feeding difficulties in early infancy, followed in later infancy or early childhood by excessive eating and gradual development of morbid obesity (unless eating is externally controlled). Motor milestones and language development are delayed. All individuals have some degree of cognitive impairment. A distinctive behavioral phenotype (with temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsive characteristics) is common. Hypogonadism is present in both males and females and manifests as genital hypoplasia, incomplete pubertal development, and, in most, infertility. Short stature is common (if not treated with growth hormone); characteristic facial features, strabismus, and scoliosis are often present.
Tourette syndrome
MedGen UID:
21219
Concept ID:
C0040517
Disease or Syndrome
Tourette syndrome is a neurobehavioral disorder manifest particularly by motor and vocal tics and associated with behavioral abnormalities. Tics are sudden, brief, intermittent, involuntary or semi-voluntary movements (motor tics) or sounds (phonic or vocal tics). They typically consist of simple, coordinated, repetitive movements, gestures, or utterances that mimic fragments of normal behavior. Motor tics may range from simple blinking, nose twitching, and head jerking to more complex throwing, hitting, or making rude gestures. Phonic tics include sniffling, throat clearing, blowing, coughing, echolalia, or coprolalia. Males are affected about 3 times more often than females, and onset usually occurs between 3 and 8 years of age. By age 18 years, more than half of affected individuals are free of tics, but they may persist into adulthood (review by Jankovic, 2001).
Cyclical vomiting syndrome
MedGen UID:
57509
Concept ID:
C0152164
Disease or Syndrome
A condition characterized by recurrent, self-limiting episodes of vomiting associated with intense nausea, pallor, and lethargy. It is commonly a migraine precursor.
Adrenoleukodystrophy
MedGen UID:
57667
Concept ID:
C0162309
Disease or Syndrome
X-linked adrenoleukodystrophy (X-ALD) affects the nervous system white matter and the adrenal cortex. Three main phenotypes are seen in affected males: The childhood cerebral form manifests most commonly between ages four and eight years. It initially resembles attention-deficit disorder or hyperactivity; progressive impairment of cognition, behavior, vision, hearing, and motor function follow the initial symptoms and often lead to total disability within six months to two years. Most individuals have impaired adrenocortical function at the time that neurologic disturbances are first noted. Adrenomyeloneuropathy (AMN) manifests most commonly in an individual in his twenties or middle age as progressive stiffness and weakness of the legs, sphincter disturbances, sexual dysfunction, and often, impaired adrenocortical function; all symptoms are progressive over decades. "Addison disease only" presents with primary adrenocortical insufficiency between age two years and adulthood and most commonly by age 7.5 years, without evidence of neurologic abnormality; however, some degree of neurologic disability (most commonly AMN) usually develops by middle age. More than 20% of female carriers develop mild-to-moderate spastic paraparesis in middle age or later. Adrenal function is usually normal.
Aarskog syndrome
MedGen UID:
61234
Concept ID:
C0175701
Disease or Syndrome
Aarskog-Scott syndrome, also known as faciogenital dysplasia, is an X-linked disorder characterized by short stature, hypertelorism, shawl scrotum, and brachydactyly, although there is wide phenotypic variability and other features, such as joint hyperextensibility, short nose, widow's peak, and inguinal hernia, may also occur. Most patients do not have mental retardation, but some may have neurobehavioral features. Carrier females may present with subtle features, such as widow's peak or short stature (summary by Orrico et al., 2010).
Williams syndrome
MedGen UID:
59799
Concept ID:
C0175702
Disease or Syndrome
Williams syndrome (WS) is characterized by cardiovascular disease (elastin arteriopathy, peripheral pulmonary stenosis, supravalvar aortic stenosis, hypertension), distinctive facies, connective tissue abnormalities, intellectual disability (usually mild), a specific cognitive profile, unique personality characteristics, growth abnormalities, and endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism, and early puberty). Feeding difficulties often lead to poor weight gain in infancy. Hypotonia and hyperextensible joints can result in delayed attainment of motor milestones.
FG syndrome 1
MedGen UID:
113106
Concept ID:
C0220769
Disease or Syndrome
The phenotypic spectrum of MED12-related disorders, which is still being defined, includes at a minimum the phenotypes of FG syndrome type 1 (FGS1), Lujan syndrome (LS), and X-linked Ohdo syndrome. FGS1 and LS share the clinical findings of cognitive impairment, hypotonia, and abnormalities of the corpus callosum. FGS1 is further characterized by absolute or relative macrocephaly, tall forehead, downslanted palpebral fissures, small and simple ears, constipation and/or anal anomalies, broad thumbs and halluces, and characteristic behavior. LS is further characterized by large head, tall thin body habitus, long thin face, prominent nasal bridge, high narrow palate, and short philtrum. Carrier females in families with FGS1 and LS are typically unaffected. X-linked Ohdo syndrome (referred to as XLOS in this GeneReview) is characterized by intellectual disability, blepharophimosis, and facial coarsening. A number of individuals with nonsyndromic intellectual disability – including some affected females – have been described.
Sialuria
MedGen UID:
137980
Concept ID:
C0342853
Disease or Syndrome
Sialuria is a rare inborn error of metabolism in which excessive free sialic acid is synthesized. Clinical features include hepatosplenomegaly, coarse facial features, and varying degrees of developmental delay (summary by Enns et al., 2001).
Autism, susceptibility to, X-linked 4
MedGen UID:
162886
Concept ID:
C0795888
Finding
Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypical, and ritualized patterns of interests and behavior (Bailey et al., 1996; Risch et al., 1999). 'Autism spectrum disorder,' sometimes referred to as ASD, is a broader phenotype encompassing the less severe disorders Asperger syndrome (see ASPG1; 608638) and pervasive developmental disorder, not otherwise specified (PDD-NOS). 'Broad autism phenotype' includes individuals with some symptoms of autism, but who do not meet the full criteria for autism or other disorders. Mental retardation coexists in approximately two-thirds of individuals with ASD, except for Asperger syndrome, in which mental retardation is conspicuously absent (Jones et al., 2008). Genetic studies in autism often include family members with these less stringent diagnoses (Schellenberg et al., 2006). Levy et al. (2009) provided a general review of autism and autism spectrum disorder, including epidemiology, characteristics of the disorder, diagnosis, neurobiologic hypotheses for the etiology, genetics, and treatment options.
Attention deficit hyperactivity disorder
MedGen UID:
220387
Concept ID:
C1263846
Mental or Behavioral Dysfunction
Attention-deficit/hyperactivity disorder (ADHD) is a behavioral disorder that typically begins in childhood and is characterized by a short attention span (inattention), an inability to be calm and stay still (hyperactivity), and poor impulse control (impulsivity). Some people with ADHD have problems with only inattention or with hyperactivity and impulsivity, but most have problems related to all three features.\n\nIn people with ADHD, the characteristic behaviors are frequent and severe enough to interfere with the activities of daily living such as school, work, and relationships with others. Because of an inability to stay focused on tasks, people with inattention may be easily distracted, forgetful, avoid tasks that require sustained attention, have difficulty organizing tasks, or frequently lose items.\n\nHyperactivity is usually shown by frequent movement. Individuals with this feature often fidget or tap their foot when seated, leave their seat when it is inappropriate to do so (such as in the classroom), or talk a lot and interrupt others.\n\nIn most affected individuals, ADHD continues throughout life, but in about one-third of individuals, signs and symptoms of ADHD go away by adulthood.\n\nImpulsivity can result in hasty actions without thought for the consequences. Individuals with poor impulse control may have difficulty waiting for their turn, deferring to others, or considering their actions before acting.\n\nMore than two-thirds of all individuals with ADHD have additional conditions, including insomnia, mood or anxiety disorders, learning disorders, or substance use disorders. Affected individuals may also have autism spectrum disorder, which is characterized by impaired communication and social interaction, or Tourette syndrome, which is a disorder characterized by repetitive and involuntary movements or noises called tics.
Short stature, developmental delay, and congenital heart defects
MedGen UID:
713638
Concept ID:
C1291328
Disease or Syndrome
Schilbach-Rott syndrome
MedGen UID:
371716
Concept ID:
C1834038
Disease or Syndrome
Schilbach-Rott syndrome is an autosomal dominant disorder characterized by hypotelorism, epicanthal folds, cleft palate, dysmorphic facies, and hypospadias in males. The phenotype is variable; mild mental retardation has been reported (summary by Shkalim et al., 2009).
Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation
MedGen UID:
320559
Concept ID:
C1835265
Disease or Syndrome
Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation is an autosomal dominant disorder that involves an overlapping but variable spectrum of central nervous system and ocular developmental anomalies. Microcephaly ranges from mild to severe and is often associated with mild to moderate developmental delay and a characteristic facial phenotype with upslanting palpebral fissures, broad nose with rounded tip, long philtrum with thin upper lip, prominent chin, and prominent ears. Chorioretinopathy is the most common eye abnormality, but retinal folds, microphthalmia, and myopic and hypermetropic astigmatism have also been reported, and some individuals have no overt ocular phenotype. Congenital lymphedema, when present, is typically confined to the dorsa of the feet, and lymphoscintigraphy reveals the absence of radioactive isotope uptake from the webspaces between the toes (summary by Ostergaard et al., 2012). Robitaille et al. (2014) found that MCLMR includes a broader spectrum of ocular disease, including retinal detachment with avascularity of the peripheral retina, and noted phenotypic overlap with familial exudative vitreoretinopathy (FEVR; see EVR1, 133780). Birtel et al. (2017) observed intrafamilial and intraindividual variability in retinal phenotype, and noted that syndromic manifestations in some patients are too subtle to be detected during a routine ophthalmologic evaluation. Variable expressivity and reduced penetrance have also been observed in some families (Jones et al., 2014; Li et al., 2016). Autosomal recessive forms of microcephaly with chorioretinopathy have been reported (see 251270). See also Mirhosseini-Holmes-Walton syndrome (autosomal recessive microcephaly with pigmentary retinopathy and mental retardation; 268050), which has been mapped to chromosome 8q21.3-q22.1.
Primary autosomal recessive microcephaly 5
MedGen UID:
373344
Concept ID:
C1837501
Disease or Syndrome
ASPM primary microcephaly (ASPM-MCPH) is characterized by: (1) significant microcephaly (below -3 SD for age) usually present at birth and always present before age one year and (2) the absence of other congenital anomalies. While developmental milestones are usually normal in young children, older children have variable levels of intellectual disability. Neurologic examination is usually normal except for mild spasticity. Seizures are not common.
Mental retardation, autosomal recessive 2
MedGen UID:
334541
Concept ID:
C1843942
Disease or Syndrome
Creatine transporter deficiency
MedGen UID:
337451
Concept ID:
C1845862
Disease or Syndrome
The cerebral creatine deficiency syndromes (CCDS), inborn errors of creatine metabolism, include the two creatine biosynthesis disorders, guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency, and the creatine transporter (CRTR) deficiency. Intellectual disability and seizures are common to all three CCDS. The majority of individuals with GAMT deficiency have a behavior disorder that can include autistic behaviors and self-mutilation; about 40% have movement disorder. Onset is between ages three months and three years. Only 14 individuals with AGAT deficiency have been reported. The phenotype of CRTR deficiency in affected males ranges from mild intellectual disability and speech delay to severe intellectual disability, seizures, movement disorder, and behavior disorder; age at diagnosis ranges from two to 66 years. Clinical phenotype of females heterozygous for CRTR deficiency ranges from asymptomatic to severe phenotype resembling male phenotype.
Immunodeficiency 61
MedGen UID:
337462
Concept ID:
C1845903
Disease or Syndrome
Immunodeficiency-61 (IMD61) is an X-linked recessive primary immunodeficiency characterized by onset of recurrent infections in early childhood due to impaired antibody production. Affected individuals have normal numbers of circulating B and T cells, but B cells have an intrinsic defect in antibody production (summary by Keller et al., 2018). For a general phenotypic description of X-linked agammaglobulinemia, see 300755.
Spinocerebellar ataxia type 14
MedGen UID:
343106
Concept ID:
C1854369
Disease or Syndrome
Spinocerebellar ataxia type 14 (SCA14) is characterized by slowly progressive cerebellar ataxia, dysarthria, and nystagmus. Axial myoclonus, cognitive impairment, tremor, and sensory loss may also be observed. Parkinsonian features including rigidity and tremor have been described in some families. Findings seen in other ataxia disorders (e.g., dysphagia, dysphonia) may also occur in SCA14. The average age of onset is in the 30s, with a range from childhood to the seventh decade. Life span is not shortened.
Tuberous sclerosis 1
MedGen UID:
344288
Concept ID:
C1854465
Disease or Syndrome
Tuberous sclerosis complex (TSC) involves abnormalities of the skin (hypomelanotic macules, confetti skin lesions, facial angiofibromas, shagreen patches, fibrous cephalic plaques, ungual fibromas); brain (subependymal nodules, cortical dysplasias, and subependymal giant cell astrocytomas [SEGAs], seizures, intellectual disability / developmental delay, psychiatric illness); kidney (angiomyolipomas, cysts, renal cell carcinomas); heart (rhabdomyomas, arrhythmias); and lungs (lymphangioleiomyomatosis [LAM], multifocal micronodular pneumonocyte hyperplasia). Central nervous system tumors are the leading cause of morbidity and mortality; renal disease is the second leading cause of early death.
Williams-Beuren region duplication syndrome
MedGen UID:
347562
Concept ID:
C1857844
Disease or Syndrome
7q11.23 duplication syndrome is characterized by delayed motor, speech, and social skills in early childhood; neurologic abnormalities (hypotonia, adventitious movements, and abnormal gait and station); speech sound disorders including motor speech disorders (childhood apraxia of speech and/or dysarthria) and phonologic disorders; behavior problems including anxiety disorders (especially social anxiety disorder [social phobia]), selective mutism, attention-deficit/hyperactivity disorder, oppositional disorders, physical aggression, and autism spectrum disorder; and intellectual disability in some individuals. Distinctive facial features are common. Cardiovascular disease includes dilation of the ascending aorta. Approximately 30% of individuals have one or more congenital anomalies.
Craniofacial dysmorphism, skeletal anomalies, and mental retardation syndrome
MedGen UID:
347111
Concept ID:
C1859252
Disease or Syndrome
Cerebro-facio-thoracic dysplasia is a rare condition characterized by abnormal development (dysplasia) of the brain (cerebro) and structures in the face (facio) and torso (thoracic). The problems with development lead to the key features of cerebro-facio-thoracic dysplasia, which include severe intellectual disability, distinctive facial features, and abnormalities of the ribs and spinal bones (vertebrae).\n\nIn addition to intellectual disability, individuals with cerebro-facio-thoracic dysplasia have delayed development of speech and movement (motor) skills, and in some, these skills never develop. Nearly one-quarter of affected individuals never learn to speak and almost half are unable to walk. Weak muscle tone (hypotonia) and difficulty feeding occur in some affected infants. People with cerebro-facio-thoracic dysplasia can have behavioral problems, such as anxiety, autism spectrum disorder, or self-injuring behavior; however, many people with the condition are described as friendly and good-natured.\n\nDistinctive facial features common in cerebro-facio-thoracic dysplasia include a wide, short skull (brachycephaly); highly arched eyebrows or eyebrows that grow together in the middle (synophrys); widely spaced eyes (hypertelorism); a wide nasal bridge; low-set ears; an upper lip with pronounced curves (Cupid's bow upper lip); and small teeth (microdontia). Some affected individuals have overgrowth of the gums (gingival hyperplasia), an opening in the roof of the mouth (cleft palate), or a split in the upper lip (cleft lip).\n\nProblems with bone development in the torso (thorax) commonly leads to bone abnormalities such as two or more ribs that are joined together (fused) or ribs that are abnormally shaped with two prongs at one end (bifid ribs). Many people with cerebro-facio-thoracic dysplasia have abnormal side-to-side curvature of the spine (scoliosis) due to malformation of the vertebrae; some vertebrae may also be fused. Additionally, the shoulder blades can be affected in people with this condition.\n\nA wide variety of other features can occur in cerebro-facio-thoracic dysplasia, such as abnormalities involving the eyes, skin, or hair. Heart defects, digestive problems, or genitourinary problems (such as abnormal kidneys or reproductive organs) can also occur. Affected individuals may also have bone or joint abnormalities in other parts of the body.
2-aminoadipic 2-oxoadipic aciduria
MedGen UID:
395350
Concept ID:
C1859817
Finding
Alpha-aminoadipic and alpha ketoadipic aciduria (AAKAD) is an inborn error of lysine, tryptophan, and hydroxylysine metabolism, which is manifested by the accumulation and excretion of 2-aminoadipic, 2-ketoadipic, and 2-hydroxyadipic acids.
Tuberous sclerosis 2
MedGen UID:
348170
Concept ID:
C1860707
Disease or Syndrome
Tuberous sclerosis complex (TSC) involves abnormalities of the skin (hypomelanotic macules, confetti skin lesions, facial angiofibromas, shagreen patches, fibrous cephalic plaques, ungual fibromas); brain (subependymal nodules, cortical dysplasias, and subependymal giant cell astrocytomas [SEGAs], seizures, intellectual disability / developmental delay, psychiatric illness); kidney (angiomyolipomas, cysts, renal cell carcinomas); heart (rhabdomyomas, arrhythmias); and lungs (lymphangioleiomyomatosis [LAM], multifocal micronodular pneumonocyte hyperplasia). Central nervous system tumors are the leading cause of morbidity and mortality; renal disease is the second leading cause of early death.
Muenke syndrome
MedGen UID:
355217
Concept ID:
C1864436
Disease or Syndrome
Muenke syndrome is defined by the presence of the specific FGFR3 pathogenic variant – c.749C>G – that results in the protein change p.Pro250Arg. Muenke syndrome is characterized by considerable phenotypic variability: features may include coronal synostosis (more often bilateral than unilateral); synostosis of other sutures, all sutures (pan synostosis), or no sutures; or macrocephaly. Bilateral coronal synostosis typically results in brachycephaly (reduced anteroposterior dimension of the skull), although turribrachycephaly (a "tower-shaped" skull) or a cloverleaf skull can be observed. Unilateral coronal synostosis results in anterior plagiocephaly (asymmetry of the skull and face). Other craniofacial findings typically include: temporal bossing; widely spaced eyes, ptosis or proptosis (usually mild); midface retrusion (usually mild); and highly arched palate or cleft lip and palate. Strabismus is common. Other findings can include: hearing loss (in 33%-100% of affected individuals); developmental delay (~33%); epilepsy; intracranial anomalies; intellectual disability; carpal bone and/or tarsal bone fusions; brachydactyly, broad toes, broad thumbs, and/or clinodactyly; and radiographic findings of thimble-like (short and broad) middle phalanges and/or cone-shaped epiphyses. Phenotypic variability is considerable even within the same family. Of note, some individuals who have the p.Pro250Arg pathogenic variant may have no signs of Muenke syndrome on physical or radiographic examination.
Legius syndrome
MedGen UID:
370709
Concept ID:
C1969623
Disease or Syndrome
Legius syndrome is characterized by multiple café au lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1 (NF1). Additional clinical manifestations reported commonly include intertriginous freckling, lipomas, macrocephaly, and learning disabilities / attention-deficit/hyperactivity disorder (ADHD) / developmental delays. Current knowledge of the natural history of Legius syndrome is based on the clinical manifestations of fewer than 300 individuals with a molecularly confirmed diagnosis; better delineation of the clinical manifestations and natural history of Legius syndrome will likely occur as more affected individuals are identified.
2p15-16.1 microdeletion syndrome
MedGen UID:
390902
Concept ID:
C2675875
Disease or Syndrome
Chromosome 2p16.1-p15 deletion syndrome is a neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, and variable but distinctive dysmorphic features, including microcephaly, bitemporal narrowing, smooth and long philtrum, hypertelorism, downslanting palpebral fissures, broad nasal root, thin upper lip, and high palate. Many patients have behavioral disorders, including autistic features, as well as structural brain abnormalities, such as pachygyria or hypoplastic corpus callosum. Those with deletions including the BCL11A gene (606557) also have persistence of fetal hemoglobin (HbF), which is asymptomatic and does not affected hematologic parameters or susceptibility to infection (summary by Funnell et al., 2015). Point mutation in the BCL11A gene causes intellectual developmental disorder with persistence of fetal hemoglobin (617101), which shows overlapping features. See also fetal hemoglobin quantitative trait locus-5 (HBFQTL5; 142335).
Thyroid hormone resistance, generalized, autosomal dominant
MedGen UID:
424846
Concept ID:
C2937288
Disease or Syndrome
Chromosome 17q11.2 deletion syndrome, 1.4 MB
MedGen UID:
462278
Concept ID:
C3150928
Disease or Syndrome
Approximately 5 to 20% of all patients with neurofibromatosis type I (162200) carry a heterozygous deletion of approximately 1.4 Mb involving the NF1 gene and contiguous genes lying in its flanking regions (Riva et al., 2000; Jenne et al., 2001), which is caused by nonallelic homologous recombination of NF1 repeats A and C (Dorschner et al., 2000). The 'NF1 microdeletion syndrome' is often characterized by a more severe phenotype than that observed in the majority of NF1 patients. In particular, patients with NF1 microdeletion often show variable facial dysmorphism, mental retardation, developmental delay, an excessive number of early-onset neurofibromas (Venturin et al., 2004), and an increased risk for malignant peripheral nerve sheath tumors (De Raedt et al., 2003).
Fanconi anemia, complementation group D2
MedGen UID:
463627
Concept ID:
C3160738
Disease or Syndrome
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA.
Chromosome 15q11.2 deletion syndrome
MedGen UID:
467404
Concept ID:
C3180937
Disease or Syndrome
A heterozygous deletion of chromosome 15q11.2 may increase the susceptibility to neuropsychiatric or neurodevelopmental problems, including delayed psychomotor development, speech delay, autism spectrum disorder, attention deficit-hyperactivity disorder, obsessive-compulsive disorder, and possibly seizures (summary by Doornbos et al., 2009 and Burnside et al., 2011). See also chromosome 15q11.2 duplication syndrome (608636).
Chromosome 15q25 deletion syndrome
MedGen UID:
481985
Concept ID:
C3280355
Disease or Syndrome
Cognitive impairment with or without cerebellar ataxia
MedGen UID:
482045
Concept ID:
C3280415
Disease or Syndrome
SCN8A-related epilepsy with encephalopathy is characterized by developmental delay, seizure onset in the first 18 months of life (mean 4 months), and intractable epilepsy characterized by multiple seizure types (generalized tonic-clonic seizures, infantile spasms, and absence and focal seizures). Epilepsy syndromes can include Lennox-Gastaut syndrome, West syndrome, and epileptic encephalopathies (e.g., Dravet syndrome). Hypotonia and movement disorders including dystonia, ataxia, and choreoathetosis are common. Psychomotor development varies from normal prior to seizure onset (with subsequent slowing or regression after seizure onset) to abnormal from birth. Intellectual disability, present in all, ranges from mild to severe (in ~50% of affected individuals). Autistic features are noted in some. Sudden unexpected death in epilepsy (SUDEP) of unknown cause has been reported in approximately 10% of published cases. To date SCN8A-related epilepsy with encephalopathy has been reported in the literature in about 50 individuals.
Epilepsy, focal, with speech disorder and with or without mental retardation
MedGen UID:
812732
Concept ID:
C3806402
Disease or Syndrome
GRIN2A-related speech disorders and epilepsy are characterized by speech disorders in all affected individuals and a range of epilepsy syndromes present in about 90%. Severe speech disorders observed can include dysarthria and speech dyspraxia, and both receptive and expressive language delay/regression; more mildly affected individuals may display subtly impaired intelligibility of conversational speech. Epilepsy features include seizure onset usually between ages three and six years, focal epilepsy with language and/or global developmental regression, and electroencephalogram (EEG) showing continuous spike-and-wave discharges in sleep or very active centrotemporal discharges. Seizure types include seizures associated with aura of perioral paresthesia, focal or focal motor seizures (often evolving to generalized tonic-clonic), and atypical absence seizures. Epilepsy syndromes can include: Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), childhood epilepsy with centrotemporal spikes (CECTS), atypical childhood epilepsy with centrotemporal spikes (ACECTS), autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD), and infantile-onset epileptic encephalopathy.
Chromosome 3q13.31 deletion syndrome
MedGen UID:
815820
Concept ID:
C3809490
Disease or Syndrome
The chromosome 3q13.31 deletion syndrome is characterized by marked developmental delay, characteristic facies with a short philtrum and protruding lips, and abnormal male genitalia (Molin et al., 2012). Patients with Primrose syndrome (PRIMS; 259050) exhibit features overlapping those of the chromosome 3q13.31 deletion syndrome but also have ossified ear cartilage, severe muscle wasting, and abnormalities of glucose metabolism resulting in insulin-resistant diabetes mellitus in adulthood. Primrose syndrome is caused by mutation in the ZBTB20 gene (606025) on chromosome 3q13.
Chromosome 22q13 duplication syndrome
MedGen UID:
816174
Concept ID:
C3809844
Disease or Syndrome
Mental retardation with language impairment and with or without autistic features
MedGen UID:
862201
Concept ID:
C4013764
Disease or Syndrome
Mental retardation with language impairment and with or without autistic features is a neurodevelopmental disorder characterized by global developmental delay with moderate to severe speech delay that particularly affects expressive speech. Most patients have articulation defects, but frank verbal dyspraxia is not observed. Common dysmorphic features include broad forehead, downslanting palpebral fissures, short nose with broad tip, relative macrocephaly, frontal hair upsweep, and prominent digit pads. Gross motor skills are also delayed. Some patients have autistic features and/or behavioral problems. All reported cases have occurred de novo (review by Le Fevre et al., 2013).
Mental retardation, autosomal dominant 29
MedGen UID:
863578
Concept ID:
C4015141
Disease or Syndrome
SETBP1 disorder is a condition that involves speech and language problems, intellectual disability, and distinctive facial features.\n\nIn people with SETBP1 disorder, problems with expressive language skills (vocabulary and the production of speech) are generally more severely affected than receptive language skills (the ability to understand speech). Speech development may be limited to a few words or no speech. Affected individuals often communicate using gestures or by mimicking the expressions of others.\n\nIndividuals with SETBP1 disorder have intellectual disability that can range from mild to moderate. They may also have behavioral problems, such as attention-deficit/hyperactivity disorder (ADHD) or autistic behaviors that affect communication and social interaction. Affected individuals may have weak muscle tone (hypotonia); delayed development of motor skills, such as sitting, standing, and walking; or recurrent seizures (epilepsy).\n\nDistinctive facial features in people with SETBP1 disorder can include a long face, a high forehead, eyebrows that grow together in the middle (synophrys), short eye openings (short palpebral fissures), skin folds covering the inner corner of the eyes (epicanthal folds), droopy eyelids (ptosis), puffiness of the skin around the eyes (periorbital fullness), small nostrils, a high nasal bridge, a broad tip of the nose, a thin upper lip, a high arch in the roof of the mouth (high-arched palate), and a small chin.
Desanto-shinawi syndrome
MedGen UID:
908218
Concept ID:
C4225239
Disease or Syndrome
WAC-related intellectual disability (ID) is typically characterized by variable degrees of developmental delay and/or intellectual disability. Behavioral abnormalities including anxiety, attention-deficit/hyperactivity disorder, and/or autism spectrum disorder are observed in the majority of older children and adults. Most affected infants have significant but nonspecific features at birth such as neonatal hypotonia and feeding problems. Some affected individuals come to medical attention with respiratory or vision problems. Facial features may be mildly dysmorphic, but are nonspecific. To date, 18 individuals have been identified with WAC-related ID.
Mental retardation, X-linked, syndromic 33
MedGen UID:
895979
Concept ID:
C4225418
Disease or Syndrome
X-linked syndromic mental retardation-33 is an X-linked recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, and characteristic facial features (summary by O'Rawe et al., 2015).
Language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmia
MedGen UID:
934645
Concept ID:
C4310678
Disease or Syndrome
LADCI is an autosomal recessive neurodevelopmental disorder characterized by severe expressive and receptive language delay apparent from early childhood. Affected individuals have additional developmental or behavioral abnormalities, including attention deficit, hyperactivity, or mild intellectual disability. Some patients develop cardiac arrhythmias reminiscent of sick sinus syndrome (summary by Lodder et al., 2016 and Shamseldin et al., 2016).
Okur-chung neurodevelopmental syndrome
MedGen UID:
934706
Concept ID:
C4310739
Disease or Syndrome
Okur-Chung neurodevelopmental syndrome is an autosomal dominant disorder characterized by delayed psychomotor development, intellectual disability with poor speech, behavioral abnormalities, cortical malformations in some patients, and variable dysmorphic facial features. Additional features, including microcephaly, gastrointestinal problems, and low levels of immunoglobulins, may be observed in some patients (Okur et al., 2016).
Mental retardation, autosomal dominant 44
MedGen UID:
934707
Concept ID:
C4310740
Disease or Syndrome
TRIO-related intellectual disability (ID) is characterized by delay in acquisition of motor and language skills, mild to borderline intellectual disability, and neurobehavioral problems (including autistic traits or autism spectrum disorder, attention-deficit/hyperactivity disorder, and/or aggression). Neonatal or infantile feeding difficulties including poor suck, impaired bottle feeding, and failure to thrive are common and are often the presenting finding. Other findings can include microcephaly, variable hand and dental abnormalities, and suggestive facial features. Only ten of the 20 individuals with a TRIO pathogenic variant reported to date had sufficient information to make preliminary generalizations about clinical manifestations; it is anticipated that the phenotype of this newly described disorder will continue to evolve.
Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart
MedGen UID:
934739
Concept ID:
C4310772
Disease or Syndrome
RERE-related disorders are characterized by neurodevelopmental problems with or without structural anomalies of the eyes, heart, kidneys, and genitourinary tract and mild sensorineural hearing loss. Hypotonia and feeding problems are common among affected individuals. Developmental delay and intellectual disability range from mild to profound. Behavior problems may include attention-deficit/hyperactivity disorder, self-injurious behavior, and autism spectrum disorder. A variety of eye anomalies (coloboma, optic nerve anomalies, microphthalmia, and/or Peter's anomaly) and vision issues (myopia, anisometropia, astigmatism, exotropia, esotropia) have been reported. Congenital heart defects, most commonly septal defects, have also been described. Genitourinary abnormalities include vesicoureteral reflux, and cryptorchidism and hypospadias in males. Sensorineural hearing loss can be unilateral or bilateral.
Witteveen-kolk syndrome
MedGen UID:
934771
Concept ID:
C4310804
Disease or Syndrome
15q24 microdeletion is a chromosomal change in which a small piece of chromosome 15 is deleted in each cell. The deletion occurs on the long (q) arm of the chromosome at a position designated q24.\n\n15q24 microdeletion is associated with mild to moderate intellectual disability and delayed speech development. Other common signs and symptoms include short stature, weak muscle tone (hypotonia), and skeletal abnormalities including loose (lax) joints. Affected males may have genital abnormalities, which can include an unusually small penis (micropenis) and the opening of the urethra on the underside of the penis (hypospadias). Affected individuals also have distinctive facial features such as a high front hairline, broad eyebrows, widely set eyes (hypertelorism), outside corners of the eyes that point downward (downslanting palpebral fissures), a broad nasal bridge, a full lower lip, and a long, smooth space between the upper lip and nose (philtrum).
Hyperphenylalaninemia, mild, non-bh4-deficient
MedGen UID:
1391882
Concept ID:
C4479270
Disease or Syndrome
Mild non-BH4-deficient hyperphenylalaninemia (HPANBH4) is an autosomal recessive disorder characterized by increased serum phenylalanine (HPA) usually detected by newborn screening and associated with highly variable neurologic defects, including movement abnormalities, such as dystonia, and variably impaired intellectual development. Laboratory analysis shows dopamine and serotonin deficiencies in the cerebrospinal fluid, and normal tetrahydrobiopterin (BH4) metabolism. Evidence suggests that treatment with BH4 and neurotransmitter precursors can lead to clinical improvement or even prevent the neurologic defects if started in infancy (summary by Anikster et al., 2017). The phenotype is highly variable: some patients may present with later onset of juvenile or young adult nonprogressive dopa-responsive parkinsonism reminiscent of early-onset Parkinson disease (168600). These patients benefit from treatment with L-dopa (summary by Straniero et al., 2017). In a review of HPA, Blau et al. (2018) noted that molecular screening for DNAJC12 mutations should be mandatory in patients in whom deficiencies of PAH (612349) and BH4 metabolism have been excluded.
Intellectual developmental disorder with gastrointestinal difficulties and high pain threshold
MedGen UID:
1385744
Concept ID:
C4479517
Disease or Syndrome
Jansen-de Vries syndrome (JDVS) is an autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability with speech delay, and behavioral abnormalities. Most patients have variable additional features, including feeding and gastrointestinal difficulties, high pain threshold and/or hypersensitivity to sound, and dysmorphic features, including mild facial abnormalities, strabismus, and small hands and feet (summary by Jansen et al., 2017).
Intellectual disability, X-linked, syndromic, Houge type
MedGen UID:
1624740
Concept ID:
C4538788
Mental or Behavioral Dysfunction
The Houge type of X-linked syndromic mental retardation is characterized by delayed development, intellectual disability, speech and language delay, and early-onset seizures. EEG tends to show continuous spike-wave activity or centrotemporal spikes. Some patients may have remission of seizures by adolescence. Carrier females may be mildly affected (summary by Damiano et al., 2017).
Intellectual disability, autosomal dominant 45
MedGen UID:
1616472
Concept ID:
C4539848
Mental or Behavioral Dysfunction
Developmental and epileptic encephalopathy, 56
MedGen UID:
1621755
Concept ID:
C4540034
Disease or Syndrome
Developmental and epileptic encephalopathy-56 (DEE56) is a neurodevelopmental disorder characterized by early-onset seizures in most patients, followed by impaired intellectual development, variable behavioral abnormalities, and sometimes additional neurologic features, such as ataxia (summary by Guella et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Coffin-Siris syndrome 6
MedGen UID:
1615540
Concept ID:
C4540499
Disease or Syndrome
Coffin-Siris syndrome-6 is characterized by short stature, sparse hair, mild to severe intellectual disability, coarse facial features, and variable behavioral anomalies. Some patients have fifth digit clinodactyly with small nails. Other congenital anomalies and seizures may be present. This description is based on reports of 7 unrelated patients (Shang et al., 2015; Van Paemel et al., 2017; Bramswig et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (135900).
Intellectual disability, autosomal dominant 56
MedGen UID:
1638835
Concept ID:
C4693389
Mental or Behavioral Dysfunction
Neurodevelopmental disorder with or without seizures and gait abnormalities
MedGen UID:
1645968
Concept ID:
C4693391
Disease or Syndrome
NEDSGA is an autosomal dominant disorder characterized by global developmental delay apparent from infancy or early childhood, resulting in variable intellectual disability that can range from profound with absent speech to mild with an ability to attend special schools. Most affected individuals show irritability, stiffness, and hypertonia early in life, which progresses to spasticity and impaired gait later. Some patients may develop seizures of variable severity early in life (summary by Martin et al., 2017).
Microcephaly 20, primary, autosomal recessive
MedGen UID:
1641618
Concept ID:
C4693572
Congenital Abnormality
Developmental delay, intellectual disability, obesity, and dysmorphic features
MedGen UID:
1641154
Concept ID:
C4693860
Disease or Syndrome
Chung-Jansen syndrome (CHUJANS) is characterized by global developmental delay apparent from infancy, impaired intellectual development or learning difficulties, behavioral abnormalities, dysmorphic features, and obesity. The severity of the phenotype and additional features are variable (summary by Jansen et al., 2018).
Intellectual disability, autosomal dominant 57
MedGen UID:
1648280
Concept ID:
C4748003
Disease or Syndrome
MRD57 is an autosomal dominant neurodevelopmental disorder with a highly variable phenotype. Most affected individuals have delayed psychomotor development apparent in infancy or early childhood, language delay, and behavioral abnormalities. Additional features may include hypotonia, feeding problems, gastrointestinal issues, and dysmorphic facial features (summary by Reijnders et al., 2018).
Periventricular nodular heterotopia 8
MedGen UID:
1648287
Concept ID:
C4748602
Disease or Syndrome
Periventricular nodular heterotopia-8 (PVNH8) is a neurologic disorder characterized by abnormal neuronal migration during brain development, resulting in delayed psychomotor development. Three patients have been reported (Ge et al., 2016). For a phenotypic description and a discussion of genetic heterogeneity of periventricular heterotopia, see PVNH1 (300049).
Intellectual disability, autosomal recessive 66
MedGen UID:
1648460
Concept ID:
C4748732
Disease or Syndrome
MRT66 is a nonsyndromic autosomal recessive intellectual developmental disorder with delayed speech development, neuropsychiatric symptoms, and relatively normal life span (Philips et al., 2017).
Mullegama-Klein-Martinez syndrome
MedGen UID:
1683985
Concept ID:
C5193008
Disease or Syndrome
Microcephaly 25, primary, autosomal recessive
MedGen UID:
1674123
Concept ID:
C5193046
Disease or Syndrome
Turnpenny-fry syndrome
MedGen UID:
1683283
Concept ID:
C5193060
Disease or Syndrome
Turnpenny-Fry syndrome (TPFS) is characterized by developmental delay, impaired intellectual development, impaired growth, and recognizable facial features that include frontal bossing, sparse hair, malar hypoplasia, small palpebral fissures and oral stoma, and dysplastic 'satyr' ears. Other common findings include feeding problems, constipation, and a range of brain, cardiac, vascular, and skeletal malformations (Turnpenny et al., 2018).
Intellectual developmental disorder, autosomal recessive 70
MedGen UID:
1679317
Concept ID:
C5193077
Disease or Syndrome
MRT70 is characterized primarily by impaired intellectual development. Mild facial dysmorphism, febrile seizures, and behavioral abnormalities have been reported in some patients (Maddirevula et al., 2018; Perez et al., 2018).
Neurodevelopmental disorder with microcephaly and structural brain anomalies
MedGen UID:
1677276
Concept ID:
C5193123
Disease or Syndrome
Intellectual developmental disorder, autosomal recessive 71
MedGen UID:
1673448
Concept ID:
C5193133
Disease or Syndrome
Shukla-Vernon syndrome
MedGen UID:
1674076
Concept ID:
C5193146
Disease or Syndrome
Shukla-Vernon syndrome (SHUVER) is an X-linked recessive neurodevelopmental disorder characterized by global developmental delay, variably impaired intellectual development, and behavioral abnormalities, including autism spectrum disorder and ADHD. Dysmorphic features are common and may include tall forehead, downslanting palpebral fissures, and tapering fingers. Some patients may have seizures and/or cerebellar atrophy on brain imaging. Carrier mothers may have mild manifestations, including learning disabilities (summary by Shukla et al., 2019).
Hypothyroidism, congenital, nongoitrous, 8
MedGen UID:
1684717
Concept ID:
C5231395
Disease or Syndrome
Congenital nongoitrous hypothyroidism-8 (CHNG8) is characterized by relatively mild central hypothyroidism, which may be accompanied by hearing loss in some patients (Heinen et al., 2016).
Intellectual developmental disorder 61
MedGen UID:
1684867
Concept ID:
C5231400
Disease or Syndrome
Autosomal dominant intellectual developmental disorder-61 (MRD61) is characterized by global developmental delay apparent in infancy with mildly impaired intellectual development, expressive speech delay, and behavioral abnormalities, including autism spectrum disorder and attention deficit-hyperactivity disorder (ADHD). Most affected individuals learn to walk on time or with some mild delay. Additional features are highly variable and may include nonspecific dysmorphic features, obstipation, ocular anomalies, and poor overall growth (Snijders Blok et al., 2018).
Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies
MedGen UID:
1684792
Concept ID:
C5231448
Disease or Syndrome
Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA) is a global neurodevelopmental disorder with highly variable features. Patients often show poor feeding, poor overall growth, and hypotonia from early infancy, followed by mildly delayed motor development, poor language acquisition, and behavioral abnormalities. Intellectual development varies from severe with absent speech to mild with the ability to attend special schools. Common features include dysmorphic facial features with notable eye anomalies, joint hypermobility, and mild skeletal anomalies of the hands and feet (summary by Carapito et al., 2019).
Intellectual developmental disorder, autosomal recessive 72
MedGen UID:
1684805
Concept ID:
C5231452
Disease or Syndrome
Intellectual developmental disorder with short stature and behavioral abnormalities
MedGen UID:
1684812
Concept ID:
C5231462
Disease or Syndrome
Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures
MedGen UID:
1684757
Concept ID:
C5231470
Disease or Syndrome
Neurodevelopmental disorder with nonspecific brain abnormalities is a highly variable syndrome characterized by impaired intellectual development and behavioral abnormalities associated with structural changes on brain imaging. Some patients have seizures, hypotonia, and scoliosis/kyphosis. Cognitive function ranges from severely impaired to the ability to attend schools with special assistance (summary by Fischer-Zirnsak et al., 2019).
Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures
MedGen UID:
1684850
Concept ID:
C5231476
Disease or Syndrome
Patients with intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures (IDDBCS) have impaired intellectual development or developmental delay of varying severity with impaired motor skills and language delay. Macrocephaly, obesity, and overgrowth are frequently seen. Approximately half of patients experience seizures, and neurobehavioral disorders including autism are usually present (Hamanaka et al., 2019; Kim et al., 2019).
Intellectual developmental disorder with hypotonia and behavioral abnormalities
MedGen UID:
1684709
Concept ID:
C5231489
Disease or Syndrome
Intellectual developmental disorder with hypotonia and behavioral abnormalities (IDDHBA) is a neurodevelopmental disorder characterized by onset of hypotonia and variably impaired global developmental delay in infancy. Affected individuals tend to have learning disability, usually requiring special schooling, as well as behavioral abnormalities, such as autistic features and attention deficit-hyperactivity disorder (ADHD). Additional more variable features may include nonspecific dysmorphic facial features, congenital heart defects, visual or ocular movement anomalies, and poor feeding and/or gastroesophageal reflux (summary by Calpena et al., 2019).
Catifa syndrome
MedGen UID:
1684686
Concept ID:
C5231492
Disease or Syndrome
CATIFA syndrome is characterized by global developmental delay and impaired intellectual development ranging from mild to severe, with most patients exhibiting attention-deficit hyperactivity disorder (ADHD). Patients show an elongated face with long philtrum and small ears. Ocular anomalies include congenital cataracts, strabismus, and amblyopia, which may be associated with reduced vision; other anomalies include cleft lip and/or palate and misaligned teeth with extensive caries (Unlu et al., 2020).
Intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type
MedGen UID:
1716269
Concept ID:
C5393302
Disease or Syndrome
Hackmann-Di Donato-type X-linked syndromic intellectual developmental disorder (MRXSHD) is an X-linked recessive phenotype characterized by global developmental delay with hypotonia, delayed speech, and mildly delayed walking associated with somatic marfanoid features, including tall stature, long fingers, and mildly dysmorphic facies. Some patients may have cardiac defects, such as mitral valve regurgitation, as well as other anomalies related to connective tissue defects, such as scoliosis (summary by Fiordaliso et al., 2019).
Beck-Fahrner syndrome
MedGen UID:
1711894
Concept ID:
C5394097
Disease or Syndrome
Beck-Fahrner syndrome (BEFAHRS) is a developmental disorder characterized by global developmental delay with variably impaired intellectual development. Affected individuals often have behavioral abnormalities, such as autistic features or attention deficit-hyperactivity disorder (ADHD), as well as learning disabilities. Most patients have hypotonia and dysmorphic facies. Some may have growth abnormalities, including overgrowth or poor growth, poor feeding, and rarely, seizures. Although both monoallelic and biallelic mutations have been reported, some heterozygous carriers in autosomal recessive families may have milder symptoms; thus, both groups are included in this entry (summary by Beck et al., 2020).
Genitourinary and/or brain malformation syndrome
MedGen UID:
1720440
Concept ID:
C5394158
Disease or Syndrome
Genitourinary and/or brain malformation syndrome (GUBS) is characterized by variable genitourinary anomalies, including disorders of sex differentiation, and brain abnormalities ranging from agenesis of the corpus callosum to anencephaly. Other variable congenital anomalies have been observed, including omphalocele and gastrointestinal tract atresia with aberrant vessels (Hughes et al., 2020).
Autism, susceptibility to, 20
MedGen UID:
1717195
Concept ID:
C5394226
Finding
Diets-Jongmans syndrome
MedGen UID:
1714920
Concept ID:
C5394263
Disease or Syndrome
Diets-Jongmans syndrome (DIJOS) is an autosomal dominant disorder characterized by mild to moderately impaired intellectual development with a recognizable facial gestalt (summary by Diets et al., 2019).
Skeletal dysplasia, mild, with joint laxity and advanced bone age
MedGen UID:
1711043
Concept ID:
C5394341
Disease or Syndrome
CSGALNACT1 deficiency is characterized by mild skeletal dysplasia, joint hypermobility, and advanced bone age. Shortness of long bones is evident prenatally, and patients exhibit short stature and relative macrocephaly. Advanced carpotarsal bone age and monkey-wrench appearance of the femur observed in infancy may disappear with age (Mizumoto et al., 2020).
Nizon-Isidor syndrome
MedGen UID:
1715748
Concept ID:
C5394350
Disease or Syndrome
Nizon-Isidor syndrome (NIZIDS) is a neurodevelopmental disorder characterized by global developmental delay, mildly delayed walking, poor speech and language, variably impaired intellectual development, and behavioral abnormalities, such as autistic features or attention deficit-hyperactivity disorder (ADHD). Some patients may have additional features, including nonspecific facial dysmorphism, gastrointestinal difficulties, distal hand anomalies, and thin corpus callosum on brain imaging (summary by Nizon et al., 2019).
Microcephaly, developmental delay, and brittle hair syndrome
MedGen UID:
1718781
Concept ID:
C5394425
Disease or Syndrome
Microcephaly, developmental delay, and brittle hair syndrome (MDBH) is a multisystem disorder with clinical variability. Affected individuals show cognitive and motor disabilities, as well as some degree of fine, brittle hair with microscopic shaft abnormalities. Other shared features include failure to thrive in early childhood and short stature, with some patients exhibiting feeding difficulties and hepatic steatosis (Kuo et al., 2019).
Intellectual developmental disorder with autistic features and language delay, with or without seizures
MedGen UID:
1715081
Concept ID:
C5394447
Disease or Syndrome
Intellectual developmental disorder with autistic features and language delay, with or without seizures (IDDALDS), is a neurodevelopmental disorder characterized by global developmental delay, variable intellectual disability, impaired speech development, and behavioral abnormalities, most commonly on the autism spectrum. About half of patients develop seizures; brain imaging is typically normal. Additional features are highly variable, but may include chronic constipation, walking difficulties, and dysmorphic facial features (summary by Guo et al., 2019).
Periventricular nodular heterotopia 9
MedGen UID:
1718470
Concept ID:
C5394503
Disease or Syndrome
Periventricular nodular heterotopia-9 (PVNH9) is an autosomal dominant neurologic disorder characterized as a malformation of cortical development. Anterior predominant PVNH, thin corpus callosum, and decreased white matter volume are found on brain imaging, but the clinical effects are variable. Most patients have impaired intellectual development and cognitive defects associated with low IQ (range 50 to 80), learning disabilities, and behavior abnormalities. Some patients develop seizures that tend to have a focal origin. However, some mutation carriers may be less severely affected with borderline or even normal IQ, suggesting incomplete penetrance of the phenotype (summary by Heinzen et al., 2018, Walters et al., 2018). For a discussion of genetic heterogeneity of periventricular nodular heterotopia, see 300049.
Agenesis of corpus callosum, cardiac, ocular, and genital syndrome
MedGen UID:
1718475
Concept ID:
C5394523
Disease or Syndrome
Agenesis of corpus callosum, cardiac, ocular, and genital syndrome (ACOGS) is a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, corpus callosum agenesis or hypoplasia, craniofacial dysmorphisms, and ocular, cardiac, and genital anomalies (Accogli et al., 2019).
Li-Ghorbani-Weisz-Hubshman syndrome
MedGen UID:
1763263
Concept ID:
C5436525
Disease or Syndrome
Li-Ghorbani-Weisz-Hubshman syndrome (LIGOWS) is a neurodevelopmental disorder characterized by global developmental delay, mild to moderately impaired intellectual development with language delay, and mild dysmorphic features. Affected individuals may have behavioral abnormalities and difficulties with numbers and understanding certain concepts, such as money. Some patients have seizures. Brain imaging often shows enlarged ventricles, thin corpus callosum, and gray matter nodular heterotopia, suggesting abnormal cortical brain development. More variable additional features may be present (summary by Li et al., 2020).
Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia
MedGen UID:
1776912
Concept ID:
C5436585
Disease or Syndrome
Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia (NEDDISH) is an autosomal recessive disorder characterized by global developmental delay and mildly to severely impaired intellectual development with poor speech and language acquisition. Some patients may have early normal development with onset of the disorder in the first years of life. More variable neurologic abnormalities include hypotonia, seizures, apnea, mild signs of autonomic or peripheral neuropathy, and autism. Aside from dysmorphic facial features and occasional findings such as scoliosis or undescended testes, other organ systems are not involved (summary by Schneeberger et al., 2020).
Neurodevelopmental disorder with alopecia and brain abnormalities
MedGen UID:
1775930
Concept ID:
C5436741
Disease or Syndrome
Bachmann-Bupp syndrome (BABS) is a neurometabolic disorder associated with global developmental delay, ectodermal abnormalities including alopecia, absolute or relative macrocephaly, dysmorphic features, and characteristic neuroimaging features (summary by Rodan et al., 2018).
Noonan syndrome 13
MedGen UID:
1761918
Concept ID:
C5436773
Disease or Syndrome
Noonan syndrome-13 (NS13) is a neurodevelopmental disorder characterized by developmental delay and impaired intellectual development of variable severity, associated with behavioral problems. Affected individuals also exhibit reduced postnatal growth and craniofacial anomalies, including ptosis, hypertelorism, low-set posteriorly rotated ears, and short webbed neck. Other features include congenital heart defects and mild skeletal defects (Motta et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of Noonan syndrome, see NS1 (163950).
Neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities
MedGen UID:
1777442
Concept ID:
C5436821
Disease or Syndrome
Neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities (NEDFASB) is a syndromic disorder with multisystemic involvement. Affected individuals have severe global developmental delay with severely impaired intellectual development, poor or absent language, behavioral abnormalities, seizures, and sleep disturbances. Craniofacial dysmorphisms, while variable, include round face, prognathism, depressed nasal bridge, and cleft or high-arched palate. Brain imaging shows dysgenesis of the corpus callosum and progressive cerebellar atrophy. Additional features may include genitourinary tract anomalies, hearing loss, and mild distal skeletal defects (summary by Humbert et al., 2020).
Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities
MedGen UID:
1750805
Concept ID:
C5436848
Disease or Syndrome
Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (NEDCASB) is an autosomal recessive multisystemic disorder characterized by global neurodevelopmental delay, severely impaired intellectual development, poor overall growth, and spasticity of the lower limbs resulting in gait difficulties. Most affected individuals also develop progressive hypertrophic cardiomyopathy in childhood or have cardiac developmental anomalies. Additional more variable features include dysmorphic facies and axonal sensory peripheral neuropathy. Brain imaging tends to show thin corpus callosum and polymicrogyria (summary by Garcia-Cazorla et al., 2020).
Lessel-Kreienkamp syndrome
MedGen UID:
1762595
Concept ID:
C5436892
Disease or Syndrome
Lessel-Kreienkamp syndrome (LESKRES) is a neurodevelopmental disorder characterized by global developmental delay with intellectual disability and speech and language delay apparent from infancy or early childhood. The severity of the disorder is highly variable: some patients have mildly delayed walking and mild cognitive deficits, whereas others are nonambulatory and nonverbal. Most have behavioral disorders. Additional features, including seizures, hypotonia, gait abnormalities, visual defects, cardiac defects, and nonspecific dysmorphic facial features may also be present (summary by Lessel et al., 2020).
AMED syndrome, digenic
MedGen UID:
1754257
Concept ID:
C5436906
Disease or Syndrome
AMED syndrome (AMEDS) is an autosomal recessive digenic multisystem disorder characterized by global developmental delay with impaired intellectual development, onset of bone marrow failure and myelodysplastic syndrome (MDS) in childhood, and poor overall growth with short stature (summary by Oka et al., 2020). For a discussion of genetic heterogeneity of bone marrow failure syndrome (BMFS), see BMFS1 (614675).
Neurodevelopmental disorder with or without early-onset generalized epilepsy
MedGen UID:
1737097
Concept ID:
C5436914
Disease or Syndrome
Neurodevelopmental disorder with or without early-onset generalized epilepsy (NEDEGE) is characterized by global developmental delay apparent from infancy or early childhood. Affected individuals have variably impaired intellectual development, speech delay, and behavioral abnormalities. About half of patients develop early-onset generalized epilepsy with different seizure types; myoclonic seizures and myoclonic-atonic epilepsy are commonly observed. The seizures may remit with age or remain refractory to treatment. Brain imaging is essentially normal and there are no significant accompanying neurologic or systemic abnormalities (summary by Mulhern et al., 2018).

Recent clinical studies

Etiology

Holst LM, Kronborg JB, Jepsen JRM, Christensen JØ, Vejlstrup NG, Juul K, Bjerre JV, Bilenberg N, Ravn HB
Cardiol Young 2020 Feb;30(2):180-187. Epub 2020 Jan 13 doi: 10.1017/S1047951119003184. PMID: 31928549
Ashjazadeh N, Sahraeian A, Sabzgolin I, Asadi-Pooya AA
Epilepsy Behav 2019 Dec;101(Pt A):106543. Epub 2019 Nov 4 doi: 10.1016/j.yebeh.2019.106543. PMID: 31698258
Wang K, Xu M, Ji Y, Zhang L, Du X, Li J, Luo Q, Li F
Aust N Z J Psychiatry 2019 Aug;53(8):760-771. Epub 2019 Mar 7 doi: 10.1177/0004867419836031. PMID: 30843728
Gou X, Wang Y, Tang Y, Qu Y, Tang J, Shi J, Xiao D, Mu D
Aust N Z J Psychiatry 2019 Mar;53(3):195-206. Epub 2019 Jan 17 doi: 10.1177/0004867418823276. PMID: 30654621
Costa DS, de Paula JJ, Malloy-Diniz LF, Romano-Silva MA, Miranda DM
J Pediatr (Rio J) 2019 Nov - Dec;95(6):736-743. Epub 2018 Sep 17 doi: 10.1016/j.jped.2018.06.014. PMID: 30236592

Diagnosis

Sasaki H, Jono T, Fukuhara R, Yuki S, Ishikawa T, Boku S, Takebayashi M
BMC Psychiatry 2020 Nov 23;20(1):550. doi: 10.1186/s12888-020-02949-7. PMID: 33228586Free PMC Article
Holst LM, Kronborg JB, Jepsen JRM, Christensen JØ, Vejlstrup NG, Juul K, Bjerre JV, Bilenberg N, Ravn HB
Cardiol Young 2020 Feb;30(2):180-187. Epub 2020 Jan 13 doi: 10.1017/S1047951119003184. PMID: 31928549
Wang K, Xu M, Ji Y, Zhang L, Du X, Li J, Luo Q, Li F
Aust N Z J Psychiatry 2019 Aug;53(8):760-771. Epub 2019 Mar 7 doi: 10.1177/0004867419836031. PMID: 30843728
Kentrou V, de Veld DM, Mataw KJ, Begeer S
Autism 2019 May;23(4):1065-1072. Epub 2018 Sep 24 doi: 10.1177/1362361318785171. PMID: 30244604Free PMC Article
Costa DS, de Paula JJ, Malloy-Diniz LF, Romano-Silva MA, Miranda DM
J Pediatr (Rio J) 2019 Nov - Dec;95(6):736-743. Epub 2018 Sep 17 doi: 10.1016/j.jped.2018.06.014. PMID: 30236592

Therapy

Johnson J, Morris S, George S
Br J Hosp Med (Lond) 2020 Mar 2;81(3):1-11. Epub 2020 Mar 16 doi: 10.12968/hmed.2019.0188. PMID: 32240011
Roy A, Garner AA, Epstein JN, Hoza B, Nichols JQ, Molina BSG, Swanson JM, Arnold LE, Hechtman L
J Am Acad Child Adolesc Psychiatry 2020 Aug;59(8):952-963. Epub 2019 Aug 22 doi: 10.1016/j.jaac.2019.08.007. PMID: 31445873
van den Dries MA, Guxens M, Pronk A, Spaan S, El Marroun H, Jusko TA, Longnecker MP, Ferguson KK, Tiemeier H
Environ Int 2019 Oct;131:105002. Epub 2019 Jul 29 doi: 10.1016/j.envint.2019.105002. PMID: 31369979Free PMC Article
Gou X, Wang Y, Tang Y, Qu Y, Tang J, Shi J, Xiao D, Mu D
Aust N Z J Psychiatry 2019 Mar;53(3):195-206. Epub 2019 Jan 17 doi: 10.1177/0004867418823276. PMID: 30654621
Naguy A
Pediatr Neurol 2018 May;82:7-12. Epub 2017 Sep 27 doi: 10.1016/j.pediatrneurol.2017.09.010. PMID: 29678368

Prognosis

Johnson J, Morris S, George S
Br J Hosp Med (Lond) 2020 Mar 2;81(3):1-11. Epub 2020 Mar 16 doi: 10.12968/hmed.2019.0188. PMID: 32240011
Roy A, Garner AA, Epstein JN, Hoza B, Nichols JQ, Molina BSG, Swanson JM, Arnold LE, Hechtman L
J Am Acad Child Adolesc Psychiatry 2020 Aug;59(8):952-963. Epub 2019 Aug 22 doi: 10.1016/j.jaac.2019.08.007. PMID: 31445873
So R, Makino K, Hirota T, Fujiwara M, Ocho K, Ikeda S, Tsubouchi S, Inagakip M
J Autism Dev Disord 2019 Nov;49(11):4515-4522. doi: 10.1007/s10803-019-04169-9. PMID: 31410697
Costa DS, de Paula JJ, Malloy-Diniz LF, Romano-Silva MA, Miranda DM
J Pediatr (Rio J) 2019 Nov - Dec;95(6):736-743. Epub 2018 Sep 17 doi: 10.1016/j.jped.2018.06.014. PMID: 30236592
Mulraney M, Zendarski N, Mensah F, Hiscock H, Sciberras E
Aust N Z J Psychiatry 2017 Apr;51(4):393-402. Epub 2016 Aug 20 doi: 10.1177/0004867416659365. PMID: 27514404

Clinical prediction guides

Sasaki H, Jono T, Fukuhara R, Yuki S, Ishikawa T, Boku S, Takebayashi M
BMC Psychiatry 2020 Nov 23;20(1):550. doi: 10.1186/s12888-020-02949-7. PMID: 33228586Free PMC Article
Holst LM, Kronborg JB, Jepsen JRM, Christensen JØ, Vejlstrup NG, Juul K, Bjerre JV, Bilenberg N, Ravn HB
Cardiol Young 2020 Feb;30(2):180-187. Epub 2020 Jan 13 doi: 10.1017/S1047951119003184. PMID: 31928549
Roy A, Garner AA, Epstein JN, Hoza B, Nichols JQ, Molina BSG, Swanson JM, Arnold LE, Hechtman L
J Am Acad Child Adolesc Psychiatry 2020 Aug;59(8):952-963. Epub 2019 Aug 22 doi: 10.1016/j.jaac.2019.08.007. PMID: 31445873
Kentrou V, de Veld DM, Mataw KJ, Begeer S
Autism 2019 May;23(4):1065-1072. Epub 2018 Sep 24 doi: 10.1177/1362361318785171. PMID: 30244604Free PMC Article
Costa DS, de Paula JJ, Malloy-Diniz LF, Romano-Silva MA, Miranda DM
J Pediatr (Rio J) 2019 Nov - Dec;95(6):736-743. Epub 2018 Sep 17 doi: 10.1016/j.jped.2018.06.014. PMID: 30236592

Recent systematic reviews

Praveena SM, Munisvaradass R, Masiran R, Rajendran RK, Lin CC, Kumar S
Environ Sci Pollut Res Int 2020 Dec;27(36):44757-44770. Epub 2020 Sep 7 doi: 10.1007/s11356-020-10652-z. PMID: 32895790
Cosmo C, DiBiasi M, Lima V, Grecco LC, Muszkat M, Philip NS, de Sena EP
J Affect Disord 2020 Nov 1;276:1-13. Epub 2020 Jul 14 doi: 10.1016/j.jad.2020.06.054. PMID: 32697687Free PMC Article
Thrower E, Bretherton I, Pang KC, Zajac JD, Cheung AS
J Autism Dev Disord 2020 Mar;50(3):695-706. doi: 10.1007/s10803-019-04298-1. PMID: 31732891
Grünblatt E, Werling AM, Roth A, Romanos M, Walitza S
J Neural Transm (Vienna) 2019 Apr;126(4):517-529. Epub 2019 Mar 28 doi: 10.1007/s00702-019-01998-x. PMID: 30923918Free PMC Article
Villas-Boas CB, Chierrito D, Fernandez-Llimos F, Tonin FS, Sanches ACC
Int Clin Psychopharmacol 2019 Mar;34(2):57-64. doi: 10.1097/YIC.0000000000000243. PMID: 30422834

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