MedGen

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]

De Barsy syndrome, or autosomal recessive cutis laxa type III (ARCL3), is characterized by cutis laxa, a progeria-like appearance, and ophthalmologic abnormalities (summary by Kivuva et al., 2008). For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see 219100. Genetic Heterogeneity of de Barsy Syndrome Also see ARCL3B (614438), caused by mutation in the PYCR1 gene (179035) on chromosome 17q25. [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]

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]

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]

Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the presence of low circulating concentrations of sex steroids. IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome) in approximately 60%. IGD can first become apparent in infancy, adolescence, or adulthood. Infant boys with congenital IGD often have micropenis and cryptorchidism. Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination. Adult males with IGD tend to have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth, deepening of the voice), decreased muscle mass, diminished libido, erectile dysfunction, and infertility. Adult females have little or no breast development and primary amenorrhea. Although skeletal maturation is delayed, the rate of linear growth is usually normal except for the absence of a distinct pubertal growth spurt. [from GeneReviews]

De Barsy syndrome, also known as autosomal recessive cutis laxa type III (ARCL3), is a rare autosomal recessive disorder characterized by an aged appearance with distinctive facial features, sparse hair, ophthalmologic abnormalities, intrauterine growth retardation (IUGR), and cutis laxa (summary by Lin et al., 2011). For a phenotypic description and a discussion of genetic heterogeneity of de Barsy syndrome, see 219150. For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see 219200. [from OMIM]

The phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS) is now known to be a continuum that includes the classic phenotype as well as paroxysmal exercise-induced dyskinesia and epilepsy (previously known as dystonia 18 [DYT18]) and paroxysmal choreoathetosis with spasticity (previously known as dystonia 9 [DYT9]), atypical childhood absence epilepsy, myoclonic astatic epilepsy, and paroxysmal non-epileptic findings including intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia. The classic phenotype is characterized by infantile-onset seizures, delayed neurologic development, acquired microcephaly, and complex movement disorders. Seizures in classic early-onset Glut1 DS begin before age six months. Several seizure types occur: generalized tonic or clonic, focal, myoclonic, atypical absence, atonic, and unclassified. In some infants, apneic episodes and abnormal episodic eye-head movements similar to opsoclonus may precede the onset of seizures. The frequency, severity, and type of seizures vary among affected individuals and are not related to disease severity. Cognitive impairment, ranging from learning disabilities to severe intellectual disability, is typical. The complex movement disorder, characterized by ataxia, dystonia, and chorea, may occur in any combination and may be continuous, paroxysmal, or continual with fluctuations in severity influenced by environmental factors such as fasting or with infectious stress. Symptoms often improve substantially when a ketogenic diet is started. [from GeneReviews]

Septooptic dysplasia is a clinically heterogeneous disorder loosely defined by any combination of optic nerve hypoplasia, pituitary gland hypoplasia, and midline abnormalities of the brain, including absence of the corpus callosum and septum pellucidum (Dattani et al., 1998). The diagnosis of this rare congenital anomaly is made when 2 or more features of the classic triad are present. Approximately 30% of patients have complete manifestations, 62% display hypopituitarism, and 60% have an absent septum pellucidum. The disorder is equally prevalent in males and females and is more common in infants born to younger mothers, with a reported incidence of 1 in 10,000 live births (summary by Webb and Dattani, 2010). Also see 516020.0012 for a form of septooptic dysplasia associated with cardiomyopathy and exercise intolerance. [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]

Mal de Meleda (MDM) is a rare autosomal recessive skin disorder characterized by transgressive palmoplantar keratoderma (PPK), keratotic skin lesions, perioral erythema, brachydactyly, and nail abnormalities (summary by Fischer et al., 2001). The PPK in MDM is often accompanied by hyperhidrosis, maceration, fetid odor, and painful fissures (Ward et al., 2003). Some patients exhibiting similar but less severe features of MDM, with milder hyperkeratosis and no nail dystrophy, lichenoid plaques, pachydermia, or distant keratosis, were previously designated as having 'Gamborg Nielsen (Norrbotten) PPK' (see NOMENCLATURE). [from OMIM]

Naxos disease (NXD) is characterized by arrhythmogenic right ventricular cardiomyopathy associated with abnormalities of the skin, hair, and nails. The ectodermal features are evident from birth or early childhood, whereas the cardiac symptoms develop in young adulthood or later. Clinical variability of ectodermal features has been observed, with hair anomalies ranging from woolly hair to alopecia, and skin abnormalities ranging from mild focal palmoplantar keratoderma to generalized skin fragility or even lethal neonatal epidermolysis bullosa (Protonotarios et al., 1986; Cabral et al., 2010; Pigors et al., 2011; Erken et al., 2011; Sen-Chowdhry and McKenna, 2014). Another syndrome involving cardiomyopathy, woolly hair, and keratoderma (DCWHK; 605676) is caused by mutation in the desmoplakin gene (DSP; 125647). Also see 610476 for a similar disorder caused by homozygous mutation in the DSC2 gene (125645). [from OMIM]

Peutz-Jeghers syndrome (PJS) is characterized by the association of gastrointestinal (GI) polyposis, mucocutaneous pigmentation, and cancer predisposition. PJS-type hamartomatous polyps are most common in the small intestine (in order of prevalence: jejunum, ileum, and duodenum) but can also occur in the stomach, large bowel, and extraintestinal sites including the renal pelvis, bronchus, gall bladder, nasal passages, urinary bladder, and ureters. GI polyps can result in chronic bleeding, anemia, and recurrent obstruction and intussusception requiring repeated laparotomy and bowel resection. Mucocutaneous hyperpigmentation presents in childhood as dark blue to dark brown macules around the mouth, eyes, and nostrils, in the perianal area, and on the buccal mucosa. Hyperpigmented macules on the fingers are common. The macules may fade in puberty and adulthood. Recognition of the distinctive skin manifestations is important especially in individuals who have PJS as the result of a de novo pathogenic variant as these skin findings often predate GI signs and symptoms. Individuals with PJS are at increased risk for a wide variety of epithelial malignancies (colorectal, gastric, pancreatic, breast, and ovarian cancers). Females are at risk for sex cord tumors with annular tubules (SCTAT), a benign neoplasm of the ovaries, and adenoma malignum of the cervix, a rare aggressive cancer. Males occasionally develop large calcifying Sertoli cell tumors of the testes, which secrete estrogen and can lead to gynecomastia, advanced skeletal age, and ultimately short stature, if untreated. [from GeneReviews]

Long QT syndrome (LQTS) is a cardiac electrophysiologic disorder, characterized by QT prolongation and T-wave abnormalities on the EKG that are associated with tachyarrhythmias, typically the ventricular tachycardia torsade de pointes (TdP). TdP is usually self-terminating, thus causing a syncopal event, the most common symptom in individuals with LQTS. Such cardiac events typically occur during exercise and emotional stress, less frequently during sleep, and usually without warning. In some instances, TdP degenerates to ventricular fibrillation and causes aborted cardiac arrest (if the individual is defibrillated) or sudden death. Approximately 50% of untreated individuals with a pathogenic variant in one of the genes associated with LQTS have symptoms, usually one to a few syncopal events. While cardiac events may occur from infancy through middle age, they are most common from the preteen years through the 20s. Some types of LQTS are associated with a phenotype extending beyond cardiac arrhythmia. In addition to the prolonged QT interval, associations include muscle weakness and facial dysmorphism in Andersen-Tawil syndrome (LQTS type 7); hand/foot, facial, and neurodevelopmental features in Timothy syndrome (LQTS type 8); and profound sensorineural hearing loss in Jervell and Lange-Nielson syndrome. [from GeneReviews]

APC-associated polyposis conditions include (classic or attenuated) familial adenomatous polyposis (FAP) and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). FAP is a colorectal cancer (CRC) predisposition syndrome that can manifest in either classic or attenuated form. Classic FAP is characterized by hundreds to thousands of adenomatous colonic polyps, beginning on average at age 16 years (range 7-36 years). For those with the classic form of FAP, 95% of individuals have polyps by age 35 years; CRC is inevitable without colectomy. The mean age of CRC diagnosis in untreated individuals is 39 years (range 34-43 years). The attenuated form is characterized by multiple colonic polyps (average of 30), more proximally located polyps, and a diagnosis of CRC at a later age than in classic FAP. For those with an attenuated form, there is a 70% lifetime risk of CRC and the mean age of diagnosis is 50-55 years. Extracolonic manifestations are variably present and include polyps of the stomach and duodenum, osteomas, dental abnormalities, congenital hypertrophy of the retinal pigment epithelium (CHRPE), benign cutaneous lesions, desmoid tumors, adrenal masses, and other associated cancers. GAPPS is characterized by proximal gastric polyposis, increased risk of gastric adenocarcinoma, and no duodenal or colonic involvement in most individuals reported. [from GeneReviews]

Medulloblastoma is the most common brain tumor in children. It accounts for 16% of all pediatric brain tumors, and 40% of all cerebellar tumors in childhood are medulloblastoma. Medulloblastoma occurs bimodally, with peak incidences between 3 and 4 years and 8 and 9 years of age. Approximately 10 to 15% of medulloblastomas are diagnosed in infancy. Medulloblastoma accounts for less than 1% of central nervous system (CNS) tumors in adults, with highest incidence in adults 20 to 34 years of age. In 1 to 2% of patients, medulloblastoma is associated with Gorlin syndrome (109400), a nevoid basal carcinoma syndrome. Medulloblastoma also occurs in up to 40% of patients with Turcot syndrome (see 276300). Medulloblastoma is thought to arise from neural stem cell precursors in the granular cell layer of the cerebellum. Standard treatment includes surgery, chemotherapy, and, depending on the age of the patient, radiation therapy (Crawford et al., 2007). Millard and De Braganca (2016) reviewed the histopathologic variants and molecular subgroups of medulloblastoma. Pretreatment prognosis of medulloblastoma has been refined by histopathologic subclassification into the following variants: large-cell medulloblastoma, anaplastic medulloblastoma, desmoplastic/nodular medulloblastoma, and medulloblastoma with extensive nodularity (MBEN). The latter 2 groups have been shown to have a significantly superior prognosis as compared to the large cell and anaplastic groups in young children. At the molecular level, medulloblastomas have been categorized into the following subgroups: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4. Each subgroup is characterized by a unique set of genetics and gene expression as well as demographic and clinical features. [from OMIM]

A rare autosomal recessive inherited syndrome. It is characterized by xeroderma pigmentosum, mental retardation, dwarfism, hypogonadism, and neurologic abnormalities. [from NCI]

DFNX2, also known as DFN3, is an X-linked recessive disorder characterized by progressive conductive and sensorineural hearing loss and a pathognomonic temporal bone deformity that includes dilatation of the inner auditory canal and a fistulous connection between the internal auditory canal and the cochlear basal turn, resulting in a perilymphatic fluid 'gusher' during stapes surgery (summary by de Kok et al., 1995 and Song et al., 2010). See also choroideremia, deafness, and mental retardation (303110), a contiguous gene deletion syndrome involving the POU3F4 and CHM (300390) genes on Xq21; isolated choroideremia (303100) is caused by mutation in the CHM gene. [from OMIM]

Congenital myopathy-2A (CMYO2A) is an autosomal dominant disorder of the skeletal muscle characterized by infantile- or childhood-onset myopathy with delayed motor milestones and nonprogressive muscle weakness. Of the patients with congenital myopathy caused by mutation in the ACTA1 gene, about 90% carry heterozygous mutations that are usually de novo and cause the severe infantile phenotype (CMYO2C; 620278). Some patients with de novo mutations have a more typical and milder disease course with delayed motor development and proximal muscle weakness, but are able to achieve independent ambulation. Less frequently, autosomal dominant transmission of the disorder within a family may occur when the ACTA1 mutation produces a phenotype compatible with adult life. Of note, intrafamilial variability has also been reported: a severely affected proband may be identified and then mildly affected or even asymptomatic relatives are found to carry the same mutation. The severity of the disease most likely depends on the detrimental effect of the mutation, although there are probably additional modifying factors (Ryan et al., 2001; Laing et al., 2009; Sanoudou and Beggs, 2001; Agrawal et al., 2004; Nowak et al., 2013; Sewry et al., 2019; Laitila and Wallgren-Pettersson, 2021). The most common histologic finding on muscle biopsy in patients with ACTA1 mutations is the presence of 'nemaline rods,' which represent abnormal thread- or rod-like structures ('nema' is Greek for 'thread'). However, skeletal muscle biopsy from patients with mutations in the ACTA1 gene can show a range of pathologic phenotypes. These include classic rods, intranuclear rods, clumped filaments, cores, or fiber-type disproportion, all of which are nonspecific pathologic findings and not pathognomonic of a specific congenital myopathy. Most patients have clinically severe disease, regardless of the histopathologic phenotype (Nowak et al., 2007; Sewry et al., 2019). ACTA1 mutations are the second most common cause of congenital myopathies classified histologically as 'nemaline myopathy' after mutations in the NEB gene (161650). ACTA1 mutations are overrepresented in the severe phenotype with early death (Laing et al., 2009). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000). For a discussion of genetic heterogeneity of nemaline myopathy, see NEM2 (256030). [from OMIM]