MedGen

Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-3 (TEBIVANED3) is characterized by global developmental delay with poor overall growth, impaired intellectual development, and speech difficulties. More variable features include hypotonia, microcephaly, and dysmorphic facies. The severity and manifestations of the disorder are highly variable (Tessadori et al., 2022). For a discussion of genetic heterogeneity of Tessadori-Bicknell-van Haaften neurodevelopmental disorder, see TEBIVANED1 (619758). [from OMIM]

Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2) is a highly variable phenotype characterized predominantly by moderate to severe global developmental delay with impaired intellectual development, poor or absent speech, and delayed motor milestones. Most patients have hypotonia, although some have peripheral hypertonia. Common features include variable dysmorphic facial features, oculomotor abnormalities, feeding problems, and nonspecific brain imaging abnormalities. Additional features may include hearing loss, seizures, short stature, and mild skeletal defects (summary by Bryant et al., 2020). For a discussion of genetic heterogeneity of Bryant-Li-Bhoj neurodevelopmental syndrome, see BRYLIB1 (619720). [from OMIM]

Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-1 (TEBIVANED1) is characterized by poor overall growth with short stature, microcephaly, hypotonia, profound global developmental delay often with poor or absent speech, and characteristic dysmorphic facial features, including hypertelorism and abnormal nose. Other variable neurologic and systemic features may also occur (Tessadori et al., 2017). Genetic Heterogeneity of Tessadori-van Haaften Neurodevelopmental Syndrome See also TEBIVANED2 (619759), caused by mutation in the H4C11 gene (602826); TEBIVANED3 (619950), caused by mutation in the H4C5 gene (602830); and TEBIVANED4 (619951), caused by mutation in the H4C9 gene (602833). [from OMIM]

Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-4 (TEBIVANED4) is characterized by global developmental delay with poor overall growth, variably impaired intellectual development, learning difficulties, distal skeletal anomalies, and dysmorphic facies. Some patients have visual or hearing deficits. The severity and manifestations of the disorder are highly variable (Tessadori et al., 2022). For a discussion of genetic heterogeneity of TEBIVANED, see TEBIVANED1 (619758). [from OMIM]

Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-2 (TEBIVANED2) is characterized by poor overall growth, profound global developmental delay with absent speech, and characteristic dysmorphic facial features, including hypertelorism, abnormal nose, and wide mouth (Tessadori et al., 2020). For a discussion of genetic heterogeneity of Tessadori-Bicknell-van Haaften neurodevelopmental syndrome, see TEBIVANED1 (619758). [from OMIM]

Bryant-Li-Bhoj neurodevelopmental syndrome-1 (BRYLIB1) is a highly variable phenotype characterized predominantly by moderate to severe global developmental delay with impaired intellectual development, poor or absent speech, and delayed motor milestones. Most patients have hypotonia, although some have peripheral hypertonia. Common features include abnormal head shape, variable dysmorphic facial features, oculomotor abnormalities, feeding problems, and nonspecific brain imaging abnormalities. Additional features may include hearing loss, seizures, short stature, and mild skeletal defects (summary by Bryant et al., 2020). Genetic Heterogeneity of Bryant-Li-Bhoj Neurodevelopmental Syndrome See also BRYLIB2 (619721), caused by heterozygous mutation in the H3F3B gene (601058). [from OMIM]

Megacystis-microcolon-intestinal hypoperistalsis syndrome-2 (MMIHS2) is characterized by prenatal bladder enlargement, neonatal functional gastrointestinal obstruction, and chronic dependence on total parenteral nutrition and urinary catheterization. The majority of cases have a fatal outcome due to malnutrition and sepsis, followed by multiorgan failure (summary by Wang et al., 2019). For a discussion of genetic heterogeneity of MMIHS, see 249210. [from OMIM]

Visceral myopathy-2 (VSCM2) is characterized by gastrointestinal symptoms resulting from intestinal dysmotility and paresis, including abdominal distention, pain, nausea, and vomiting. Some patients exhibit predominantly esophageal symptoms, with hiatal hernia and severe reflux resulting in esophagitis and stricture, whereas others experience chronic intestinal pseudoobstruction. Bladder involvement resulting in megacystis and megaureter has also been observed and may be evident at birth (Dong et al., 2019; Gilbert et al. (2020)). [from OMIM]

Megacystis-microcolon-intestinal hypoperistalsis syndrome-4 (MMIHS4) is a severe early-onset disorder characterized by impaired smooth muscle contractility in the bladder and intestines (Kandler et al., 2020). For a discussion of genetic heterogeneity of MMIHS, see 249210. [from OMIM]

Individuals with PPP1R12A-related urogenital and/or brain malformation syndrome (UBMS) usually present with multiple congenital anomalies, commonly including brain and/or urogenital malformations. The brain abnormalities are variable, with the most severe belonging to the holoprosencephaly spectrum and associated with moderate-to-profound intellectual disability, seizures, and feeding difficulties. In individuals without brain involvement, variable degrees of developmental delay and/or intellectual disability may be present, although normal intelligence has been seen in a minority of affected individuals. Eye abnormalities and skeletal issues (kyphoscoliosis, joint contractures) can also be present in individuals of either sex. Regardless of the presence of a brain malformation, affected individuals with a 46,XY chromosome complement may have a disorder of sex development (DSD) with gonadal abnormalities (dysgenetic gonads or streak gonads). Individuals with a 46,XX chromosome complement may have varying degrees of virilization (clitoral hypertrophy, posterior labial fusion, urogenital sinus). [from GeneReviews]

MYH9-related disease (MYH9-RD) is characterized in all affected individuals by hematologic features present from birth consisting of platelet macrocytosis (i.e., >40% of platelets larger than 3.9 µm in diameter), thrombocytopenia (platelet count <150 x 109/L), and aggregates of the MYH9 protein in the cytoplasm of neutrophil granulocytes. Most affected individuals develop one or more additional extrahematologic manifestations of the disease over their lifetime, including sensorineural hearing loss, renal disease (manifesting initially as glomerular nephropathy), presenile cataracts, and/or elevation of liver enzymes. [from GeneReviews]

EDFAOB is characterized by linear hypopigmentation and craniofacial asymmetry in association with ocular, dental, and acral anomalies. Brain imaging has revealed some abnormalities, including diffuse cystic leukoencephalopathy and mildly enlarged lateral ventricles, but patients show no intellectual or neurologic impairment (Vabres et al., 2019). [from OMIM]

Familial thoracic aortic aneurysm and dissection (familial TAAD) involves problems with the aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body. Familial TAAD affects the upper part of the aorta, near the heart. This part of the aorta is called the thoracic aorta because it is located in the chest (thorax). Other vessels that carry blood from the heart to the rest of the body (arteries) can also be affected.

In familial TAAD, the aorta can become weakened and stretched (aortic dilatation), which can lead to a bulge in the blood vessel wall (an aneurysm). Aortic dilatation may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection), allowing blood to flow abnormally between the layers. These aortic abnormalities are potentially life-threatening because they can decrease blood flow to other parts of the body such as the brain or other vital organs, or cause the aorta to break open (rupture).

The occurrence and timing of these aortic abnormalities vary, even within the same affected family. They can begin in childhood or not occur until late in life. Aortic dilatation is generally the first feature of familial TAAD to develop, although in some affected individuals dissection occurs with little or no aortic dilatation.

Aortic aneurysms usually have no symptoms. However, depending on the size, growth rate, and location of these abnormalities, they can cause pain in the jaw, neck, chest, or back; swelling in the arms, neck, or head; difficult or painful swallowing; hoarseness; shortness of breath; wheezing; a chronic cough; or coughing up blood. Aortic dissections usually cause severe, sudden chest or back pain, and may also result in unusually pale skin (pallor), a very faint pulse, numbness or tingling (paresthesias) in one or more limbs, or paralysis.

Familial TAAD may not be associated with other signs and symptoms. However, some individuals in affected families show mild features of related conditions called Marfan syndrome or Loeys-Dietz syndrome. These features include tall stature, stretch marks on the skin, an unusually large range of joint movement (joint hypermobility), and either a sunken or protruding chest. Occasionally, people with familial TAAD develop aneurysms in the brain or in the section of the aorta located in the abdomen (abdominal aorta). Some people with familial TAAD have heart abnormalities that are present from birth (congenital). Affected individuals may also have a soft out-pouching in the lower abdomen (inguinal hernia), an abnormal curvature of the spine (scoliosis), or a purplish skin discoloration (livedo reticularis) caused by abnormalities in the tiny blood vessels of the skin (dermal capillaries). However, these conditions are also common in the general population. Depending on the genetic cause of familial TAAD in particular families, they may have an increased risk of developing blockages in smaller arteries, which can lead to heart attack and stroke. [from MedlinePlus Genetics]

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. [from OMIM]

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay and moderate to severe intellectual disability, as well as variable other manifestations, such as macro- or microcephaly, epilepsy, hypotonia, behavioral problems, stereotypic movements, and facial dysmorphism (including arched eyebrows, long palpebral fissures, prominent nasal bridge, upturned nose, dysplastic ears, and broad mouth), among others. Brain imaging may show cerebellar anomalies, hypoplastic corpus callosum, enlarged ventricles, polymicrogyria, or white matter abnormalities. [from ORDO]

An inherited condition caused by autosomal dominant mutation(s) in the PPP1CB gene, encoding serine/threonine-protein phosphatase PP1-beta catalytic subunit. The condition is characterized by facial features similar to those seen in Noonan syndrome but may also include short stature, cognitive deficits, relative macrocephaly, small posterior fossa resulting in Chiari I malformation, hypernasal voice, cardiac defects, and ectodermal abnormalities, which typically presents as slow-growing, sparse, and/or unruly hair. [from NCI]

Palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome is a rare, genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, axial hypotonia, palate abnormalities (including cleft palate and/or high and narrow palate), dysmorphic facial features (including prominent forehead, hypertelorism, downslanting palpebral fissures, wide nasal bridge, thin lips and widely spaced teeth), and short stature. Additional manifestations may include digital anomalies (such as brachydactyly, clinodactyly, and hypoplastic toenails), a single palmar crease, lower limb hypertonia, joint hypermobility, as well as ocular and urogenital anomalies. [from ORDO]

Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome is a rare, syndromic genetic deafness characterized by a combination of muscle weakness, chronic neuropathic and myopathic features, hoarseness and sensorineural hearing loss. A wide range of disease onset and severity has been reported even within the same family. [from ORDO]

Hypospadias is a common congenital malformation of the penis, affecting approximately 1 in 750 births in Europe. Due to developmental arrest of urethral fusion, the urethral opening is displaced along the ventral side of the penis. The opening can be located glanular, penile, or even more posterior in the scrotum or perineum. Although most children with this condition undergo surgery in their second year of life, serious medical, social, and sexual problems may still exist later in life (summary by van der Zanden et al., 2011). Hypospadias is a feature of several syndromic disorders, including the androgen insensitivity syndrome (300068) and Opitz syndrome (300000). Genetic Heterogeneity of Hypospadias See also HYSP2 (300758), caused by mutation in the MAMLD1 gene (300120) on chromosome Xq28; HYSP3 (146450), a familial form which has been mapped to chromosome 7q32.2-q36.1; and HYSP4 (300856), a susceptibility locus mapped to chromosome Xp11.22 and associated with variation in the DGKK gene (300837). [from OMIM]

Any autosomal dominant nonsyndromic deafness in which the cause of the disease is a mutation in the MYH9 gene. [from MONDO]