MedGen

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

Bardet-Biedl syndrome is an autosomal recessive and genetically heterogeneous ciliopathy characterized by retinitis pigmentosa, obesity, kidney dysfunction, polydactyly, behavioral dysfunction, and hypogonadism (summary by Beales et al., 1999). Eight proteins implicated in the disorder assemble to form the BBSome, a stable complex involved in signaling receptor trafficking to and from cilia (summary by Scheidecker et al., 2014). Genetic Heterogeneity of Bardet-Biedl Syndrome BBS2 (615981) is caused by mutation in a gene on 16q13 (606151); BBS3 (600151), by mutation in the ARL6 gene on 3q11 (608845); BBS4 (615982), by mutation in a gene on 15q22 (600374); BBS5 (615983), by mutation in a gene on 2q31 (603650); BBS6 (605231), by mutation in the MKKS gene on 20p12 (604896); BBS7 (615984), by mutation in a gene on 4q27 (607590); BBS8 (615985), by mutation in the TTC8 gene on 14q32 (608132); BBS9 (615986), by mutation in a gene on 7p14 (607968); BBS10 (615987), by mutation in a gene on 12q21 (610148); BBS11 (615988), by mutation in the TRIM32 gene on 9q33 (602290); BBS12 (615989), by mutation in a gene on 4q27 (610683); BBS13 (615990), by mutation in the MKS1 gene (609883) on 17q23; BBS14 (615991), by mutation in the CEP290 gene (610142) on 12q21, BBS15 (615992), by mutation in the WDPCP gene (613580) on 2p15; BBS16 (615993), by mutation in the SDCCAG8 gene (613524) on 1q43; BBS17 (615994), by mutation in the LZTFL1 gene (606568) on 3p21; BBS18 (615995), by mutation in the BBIP1 gene (613605) on 10q25; BBS19 (615996), by mutation in the IFT27 gene (615870) on 22q12; BBS20 (619471), by mutation in the IFT172 gene (607386) on 9p21; BBS21 (617406), by mutation in the CFAP418 gene (614477) on 8q22; and BBS22 (617119), by mutation in the IFT74 gene (608040) on 9p21. The CCDC28B gene (610162) modifies the expression of BBS phenotypes in patients who have mutations in other genes. Mutations in MKS1, MKS3 (TMEM67; 609884), and C2ORF86 also modify the expression of BBS phenotypes in patients who have mutations in other genes. Although BBS had originally been thought to be a recessive disorder, Katsanis et al. (2001) demonstrated that clinical manifestation of some forms of Bardet-Biedl syndrome requires recessive mutations in 1 of the 6 loci plus an additional mutation in a second locus. While Katsanis et al. (2001) called this 'triallelic inheritance,' Burghes et al. (2001) suggested the term 'recessive inheritance with a modifier of penetrance.' Mykytyn et al. (2002) found no evidence of involvement of the common BBS1 mutation in triallelic inheritance. However, Fan et al. (2004) found heterozygosity in a mutation of the BBS3 gene (608845.0002) as an apparent modifier of the expression of homozygosity of the met390-to-arg mutation in the BBS1 gene (209901.0001). Allelic disorders include nonsyndromic forms of retinitis pigmentosa: RP51 (613464), caused by TTC8 mutation, and RP55 (613575), caused by ARL6 mutation. [from OMIM]

Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is characterized by pre- and postnatal macrosomia; distinctive craniofacial features (including macrocephaly, coarse facial features, macrostomia, macroglossia, and palatal abnormalities); and commonly, mild-to-severe intellectual disability with or without structural brain anomalies. Other variable findings include supernumerary nipples, diastasis recti / umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and gastrointestinal anomalies. Skeletal anomalies can include vertebral fusion, scoliosis, rib anomalies, and congenital hip dislocation. Hand anomalies can include large hands and postaxial polydactyly. Affected individuals are at increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma, and medulloblastoma. [from GeneReviews]

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. [from GeneReviews]

Aarskog-Scott syndrome is a genetic disorder that affects the development of many parts of the body, most commonly the head and face, the hands and feet, and the genitals and urinary system (genitourinary tract). This condition mainly affects males, although females may have mild features of the syndrome.

People with Aarskog-Scott syndrome often have distinctive facial features, such as widely spaced eyes (hypertelorism), a small nose, a long area between the nose and mouth (philtrum), and a widow's peak hairline. They frequently have mild to moderate short stature during childhood, but their growth usually catches up with that of their peers during puberty. Hand abnormalities are common in this syndrome and include short fingers (brachydactyly), curved pinky fingers (fifth finger clinodactyly), webbing of the skin between some fingers (cutaneous syndactyly), and a single crease across the palm. Affected individuals can also have wide, flat feet with broad, rounded toes. Other abnormalities in people with Aarskog-Scott syndrome include heart defects and a split in the upper lip (cleft lip) with or without an opening in the roof of the mouth (cleft palate).

Most males with Aarskog-Scott syndrome have a shawl scrotum, in which the scrotum surrounds the penis instead of hanging below. Less often, they have undescended testes (cryptorchidism) or a soft out-pouching around the belly-button (umbilical hernia) or in the lower abdomen (inguinal hernia).

The intellectual development of people with Aarskog-Scott syndrome varies widely. Most individuals with Aarskog-Scott syndrome have normal intelligence; however, some may have mild learning and behavior problems, and in rare cases, severe intellectual disability has been reported. [from MedlinePlus Genetics]

Andersen-Tawil syndrome (ATS) is characterized by a triad of: episodic flaccid muscle weakness (i.e., periodic paralysis); ventricular arrhythmias and prolonged QT interval; and anomalies including low-set ears, widely spaced eyes, small mandible, fifth-digit clinodactyly, syndactyly, short stature, and scoliosis. Affected individuals present in the first or second decade with either cardiac symptoms (palpitations and/or syncope) or weakness that occurs spontaneously following prolonged rest or following rest after exertion. Mild permanent weakness is common. Mild learning difficulties and a distinct neurocognitive phenotype (i.e., deficits in executive function and abstract reasoning) have been described. [from GeneReviews]

Myhre syndrome is a connective tissue disorder with multisystem involvement, progressive and proliferative fibrosis that may occur spontaneously or following trauma or surgery, mild-to-moderate intellectual disability, and in some instances, autistic-like behaviors. Organ systems primarily involved include: cardiovascular (congenital heart defects, long- and short-segment stenosis of the aorta and peripheral arteries, pericardial effusion, constrictive pericarditis, restrictive cardiomyopathy, and hypertension); respiratory (choanal stenosis, laryngotracheal narrowing, obstructive airway disease, or restrictive pulmonary disease), gastrointestinal (pyloric stenosis, duodenal strictures, severe constipation); and skin (thickened particularly on the hands and extensor surfaces). Additional findings include distinctive craniofacial features and skeletal involvement (intrauterine growth restriction, short stature, limited joint range of motion). To date, 55 individuals with molecularly confirmed Myhre syndrome have been reported. [from GeneReviews]

Spondyloperipheral dysplasia is a disorder that impairs bone growth. This condition is characterized by flattened bones of the spine (platyspondyly) and unusually short fingers and toes (brachydactyly), with the exception of the first (big) toes. Other skeletal abnormalities associated with spondyloperipheral dysplasia include short stature, shortened long bones of the arms and legs, exaggerated curvature of the lower back (lordosis), and an inward- and upward-turning foot (clubfoot). Additionally, some affected individuals have nearsightedness (myopia), hearing loss, and intellectual disability. [from MedlinePlus Genetics]

FBXL4-related encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome is a multi-system disorder characterized primarily by congenital or early-onset lactic acidosis and growth failure, feeding difficulty, hypotonia, and developmental delay. Other neurologic manifestations can include seizures, movement disorders, ataxia, autonomic dysfunction, and stroke-like episodes. All affected individuals alive at the time they were reported (median age: 3.5 years) demonstrated significant developmental delay. Other findings can involve the heart (hypertrophic cardiomyopathy, congenital heart malformations, arrhythmias), liver (mildly elevated transaminases), eyes (cataract, strabismus, nystagmus, optic atrophy), hearing (sensorineural hearing loss), and bone marrow (neutropenia, lymphopenia). Survival varies; the median age of reported deaths was two years (range 2 days – 75 months), although surviving individuals as old as 36 years have been reported. To date FBXL4-related mtDNA depletion syndrome has been reported in 50 individuals. [from GeneReviews]

Developmental and epileptic encephalopathy-2 (DEE2) is an X-linked dominant severe neurologic disorder characterized by onset of seizures in the first months of life and severe global developmental delay resulting in impaired intellectual development and poor motor control. Other features include lack of speech development, subtle dysmorphic facial features, sleep disturbances, gastrointestinal problems, and stereotypic hand movements. There is some phenotypic overlap with Rett syndrome (312750), but DEE2 is considered to be a distinct entity (summary by Fehr et al., 2013). For a discussion of genetic heterogeneity of DEE, see 308350. [from OMIM]

Congenital disorder of glycosylation type IIc (CDG2C) is an autosomal recessive disorder characterized by moderate to severe psychomotor retardation, mild dysmorphism, and impaired neutrophil motility. It is a member of a group of disorders with a defect in the processing of protein-bound glycans. For a general overview of congenital disorders of glycosylation (CDGs), see CDG1A (212065) and CDG2A (212066). Frydman (1996) contended that the neutrophil defect in CDG2C, which has been referred to as 'leukocyte adhesion deficiency type II' (LAD2), is a manifestation of the disorder and that there are no cases of 'primary' LAD II. Etzioni and Harlan (1999) provided a comprehensive review of both leukocyte adhesion deficiency-1 (LAD1; 116920) and LAD2. While the functional neutrophil studies are similar in the 2 LADs, the clinical course is milder in LAD2. Furthermore, patients with LAD2 present other abnormal features, such as growth and mental retardation, which are related to the primary defect in fucose metabolism. Delayed separation of the umbilical cord occurs in LAD1. For a discussion of genetic heterogeneity of LAD, see 116920. [from OMIM]

The constitutional deletion of chromosome 1p36 results in a syndrome with multiple congenital anomalies and mental retardation (Shapira et al., 1997). Monosomy 1p36 is the most common terminal deletion syndrome in humans, occurring in 1 in 5,000 births (Shaffer and Lupski, 2000; Heilstedt et al., 2003). See also neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH; 616975), which shows overlapping features and is caused by heterozygous mutation in the RERE gene (605226) on proximal chromosome 1p36. See also Radio-Tartaglia syndrome (RATARS; 619312), caused by mutation in the SPEN gene (613484) on chromosome 1p36, which shows overlapping features. [from OMIM]

Cornelia de Lange syndrome (CdLS) encompasses a spectrum of findings from mild to severe. Severe (classic) CdLS is characterized by distinctive facial features, growth restriction (prenatal onset; <5th centile throughout life), hypertrichosis, and upper-limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits). Craniofacial features include synophrys, highly arched and/or thick eyebrows, long eyelashes, short nasal bridge with anteverted nares, small widely spaced teeth, and microcephaly. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS. Across the CdLS spectrum IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Other frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia. [from GeneReviews]

MECP2 duplication syndrome is a severe neurodevelopmental disorder characterized by early-onset hypotonia, feeding difficulty, gastrointestinal manifestations including gastroesophageal reflux and constipation, delayed psychomotor development leading to severe intellectual disability, poor speech development, progressive spasticity, recurrent respiratory infections (in ~75% of affected individuals), and seizures (in ~50%). MECP2 duplication syndrome is 100% penetrant in males. Occasionally females have been described with a MECP2 duplication and a range of findings from mild intellectual disability to a phenotype similar to that seen in males. In addition to the core features, autistic behaviors, nonspecific neuroradiologic findings on brain MRI, mottled skin, and urogenital anomalies have been observed in several affected boys. [from GeneReviews]

Osteoglophonic dysplasia (OGD) is characterized by rhizomelic dwarfism, nonossifying bone lesions, craniosynostosis, prominent supraorbital ridge, and depressed nasal bridge (summary by White et al., 2005). [from OMIM]

The cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are a continuum that includes the following phenotypes: Metaphyseal dysplasia without hypotrichosis (MDWH). Cartilage-hair hypoplasia (CHH). Anauxetic dysplasia (AD). CHH-AD spectrum disorders are characterized by severe disproportionate (short-limb) short stature that is usually recognized in the newborn, and occasionally prenatally because of the short extremities. Other findings include joint hypermobility, fine silky hair, immunodeficiency, anemia, increased risk for malignancy, gastrointestinal dysfunction, and impaired spermatogenesis. The most severe phenotype, AD, has the most pronounced skeletal phenotype, may be associated with atlantoaxial subluxation in the newborn, and may include cognitive deficiency. The clinical manifestations of the CHH-AD spectrum disorders are variable, even within the same family. [from GeneReviews]

Cornelia de Lange syndrome (CdLS) encompasses a spectrum of findings from mild to severe. Severe (classic) CdLS is characterized by distinctive facial features, growth restriction (prenatal onset; <5th centile throughout life), hypertrichosis, and upper-limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits). Craniofacial features include synophrys, highly arched and/or thick eyebrows, long eyelashes, short nasal bridge with anteverted nares, small widely spaced teeth, and microcephaly. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS. Across the CdLS spectrum IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Other frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia. [from GeneReviews]

Cornelia de Lange syndrome (CdLS) encompasses a spectrum of findings from mild to severe. Severe (classic) CdLS is characterized by distinctive facial features, growth restriction (prenatal onset; <5th centile throughout life), hypertrichosis, and upper-limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits). Craniofacial features include synophrys, highly arched and/or thick eyebrows, long eyelashes, short nasal bridge with anteverted nares, small widely spaced teeth, and microcephaly. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS. Across the CdLS spectrum IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Other frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia. [from GeneReviews]

Complex cortical dysplasia with other brain malformations-13 (CDCBM13) is an autosomal dominant neurodevelopmental disorder characterized by global developmental delay with impaired intellectual development. Brain imaging shows variable neuronal migration defects resulting in cortical malformations, including pachygyria. More variable features include early-onset seizures and dysmorphic features. Some patients may also show signs of peripheral neuropathy, such as abnormal gait, hyporeflexia, and foot deformities (summary by Willemsen et al., 2012 and Poirier et al., 2013). For a discussion of genetic heterogeneity of CDCBM, see CDCBM1 (614039). [from OMIM]

MBD5 haploinsufficiency is a neurodevelopmental disorder characterized by developmental delay, intellectual disability, severe speech impairment, seizures, sleep disturbances, and abnormal behaviors. Most children lack speech entirely or have single words, short phrases, or short sentences. Seizures are present in more than 80% of children; onset is usually around age two years. Sleep disturbances, present in about 90%, can result in excessive daytime drowsiness. Abnormal behaviors can include autistic-like behaviors (80%) and self-injury and aggression (>60%). [from GeneReviews]