MedGen

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. [from GeneReviews]

Kleefstra syndrome is characterized by intellectual disability, autistic-like features, childhood hypotonia, and distinctive facial features. The majority of individuals function in the moderate-to-severe spectrum of intellectual disability although a few individuals have mild delay and total IQ within low-normal range. While most have severe expressive speech delay with little speech development, general language development is usually at a higher level, making nonverbal communication possible. A complex pattern of other findings can also be observed; these include heart defects, renal/urologic defects, genital defects in males, severe respiratory infections, epilepsy / febrile seizures, psychiatric disorders, and extreme apathy or catatonic-like features after puberty. [from GeneReviews]

Darier-White disease (DAR), also known as keratosis follicularis, is an autosomal dominant skin disorder characterized by warty papules and plaques in seborrheic areas (central trunk, flexures, scalp, and forehead), palmoplantar pits, and distinctive nail abnormalities (Sakuntabhai et al., 1999). Onset is usually before the third decade, and penetrance is complete in adults, although expressivity is variable. Involvement may be severe, with widespread itchy malodorous crusted plaques, painful erosions, blistering, and mucosal lesions. Secondary infection is common. Sun, heat, and sweating exacerbate the symptoms. Darier disease never remits, but oral retinoids may reduce hyperkeratosis. Neuropsychiatric abnormalities, including mild mental retardation and epilepsy, have been described in association with Darier disease in a few families (Burge and Wilkinson, 1992); whether this is an association based on pleiotropism of the mutant gene or reflects coincidence is not clear. Histologic findings are (1) mild nonspecific perivascular infiltration in the dermis; (2) dermal villi protruding into the epidermis; (3) suprabasal detachment of the spinal layer leading to the formation of lacunae containing acantholytic cells; (4) in the more superficial epidermis, dyskeratotic round epidermal cells ('corps ronds'), the most distinctive feature; and (5) in the stratum corneum, 'grains' that resemble parakeratotic cells embedded in a hyperkeratotic horny layer. Electron microscopy reveals loss of desmosomal attachments, perinuclear aggregations of keratin filaments, and cytoplasmic vacuolization. Ultrastructural and immunologic studies suggest the disease results from an abnormality in the desmosome-keratin filament complex leading to a breakdown in cell adhesion. [from OMIM]

CLCN4-related neurodevelopmental disorder (CLCN4-NDD), an X-linked disorder, is characterized in the 36 males reported to date by developmental delay or intellectual disability, behavioral/mental health issues (e.g., autism spectrum disorder, anxiety, hyperactivity, and bipolar disorder), epilepsy, and gastrointestinal dysfunction. The five heterozygous females with a de novo CLCN4 variant reported to date had findings very similar to those of affected males. Twenty-two of 25 heterozygous females identified in family studies following identification of an affected male were unaffected or had only mild specific learning difficulties and/or mental health concerns, whereas three were more severely affected. [from GeneReviews]

Primary familial brain calcification (PFBC) is a neurodegenerative disorder with characteristic calcium deposits in the basal ganglia and other brain areas visualized on neuroimaging. Most affected individuals are in good health during childhood and young adulthood and typically present in the fourth to fifth decade with a gradually progressive movement disorder and neuropsychiatric symptoms. The movement disorder first manifests as clumsiness, fatigability, unsteady gait, slow or slurred speech, dysphagia, involuntary movements, or muscle cramping. Neuropsychiatric symptoms, often the first or most prominent manifestations, range from mild difficulty with concentration and memory to changes in personality and/or behavior, to psychosis and dementia. Seizures of various types occur frequently, some individuals experience chronic headache and vertigo; urinary urgency or incontinence may be present. [from GeneReviews]

Gomez-Lopez-Hernandez syndrome (GLHS), also known as cerebellotrigeminal dermal dysplasia, is a rare neurocutaneous syndrome classically characterized by the triad of rhombencephalosynapsis, trigeminal anesthesia, often giving rise to corneal opacities, and bilateral parietal or parietooccipital alopecia. However, trigeminal anesthesia is an inconsistent finding (summary by Sukhudyan et al., 2010). [from OMIM]

Dystonia-30 (DYT30) is an autosomal dominant neurologic disorder characterized by the onset of symptoms in the first decades of life. Patients present with oromandibular, cervical, bulbar, or upper limb dystonia, and usually show slow progression to generalized dystonia. Some patients may lose ambulation. A subset of patients may also have neurocognitive impairment, including mild intellectual disability or psychiatric manifestations (summary by Steel et al., 2020). In a review of the pathogenesis of disorders with prominent dystonia, Monfrini et al. (2021) classified DYT30 as belonging to a group of neurologic disorders termed 'HOPS-associated neurologic disorders' (HOPSANDs), which are caused by mutations in genes encoding various components of the autophagic/endolysosomal system, including VPS16. [from OMIM]

Autosomal dominant intellectual developmental disorder-67 (MRD67) is characterized by global developmental delay with variably impaired intellectual development apparent from infancy or early childhood. Additional features may include behavioral abnormalities, such as autism spectrum disorder (ASD) and ADHD, as well as language and sleeping difficulties. Brain imaging is normal (Ismail et al., 2022). [from OMIM]

Lissencephaly-10 (LIS10) is a neurologic disorder characterized by variably delayed development with mildly to moderately impaired intellectual development and language delay, as well as seizures, which are often intractable. There is a spectrum of severity, with some patients having normal early development and only borderline to mild cognitive impairment. Brain imaging shows features consistent with neuronal migration defects, including posterior-predominant lissencephaly, pachygyria, agyria, and subcortical band heterotopia (summary by Tsai et al., 2020). For a general description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (607432). [from OMIM]

Bipolar disorder is an illness of mood characterized by alternating episodes of elevated and depressed moods, which are interspersed with euthymic periods. [from HPO]