MedGen

Lacrimoauriculodentodigital syndrome-1 (LADD1) is a multiple congenital anomaly disorder mainly affecting lacrimal glands and ducts, salivary glands and ducts, ears, teeth, and distal limb segments (summary by Rohmann et al., 2006). Genetic Heterogeneity of Lacrimoauriculodentodigital Syndrome LADD syndrome-2 (LADD2; 620192) is caused by mutation in the FGFR3 gene (134934) on chromosome 4p16, and LADD syndrome-3 (LADD3; 620193) is caused by mutation in the FGF10 gene, an FGFR ligand, on chromosome 5p12. [from OMIM]

Lacrimoauriculodentodigital syndrome-3 (LADD3) is a multiple congenital anomaly disorder characterized by aplasia, atresia or hypoplasia of the lacrimal and salivary systems, cup-shaped ears, hearing loss, and dental and digital anomalies (summary by Milunsky et al., 2006). [from OMIM]

Any gingival fibromatosis in which the cause of the disease is a mutation in the SOS1 gene. [from MONDO]

Schimmelpenning-Feuerstein-Mims syndrome, also known as linear sebaceous nevus syndrome, is characterized by sebaceous nevi, often on the face, associated with variable ipsilateral abnormalities of the central nervous system, ocular anomalies, and skeletal defects (summary by Happle, 1991 and Ernst et al., 2007). The linear sebaceous nevi follow the lines of Blaschko (Hornstein and Knickenberg, 1974; Bouwes Bavinck and van de Kamp, 1985). All cases are sporadic. The syndrome is believed to be caused by an autosomal dominant lethal mutation that survives by somatic mosaicism (Gorlin et al., 2001). [from OMIM]

Hyperphosphatemic familial tumoral calcinosis is a rare autosomal recessive metabolic disorder characterized by the progressive deposition of basic calcium phosphate crystals in periarticular spaces, soft tissues, and sometimes bone (Chefetz et al., 2005). The biochemical hallmark of tumoral calcinosis is hyperphosphatemia caused by increased renal absorption of phosphate due to loss-of-function mutations in the FGF23 or GALNT3 (601756) gene. The term 'hyperostosis-hyperphosphatemia syndrome' is sometimes used when the disorder is characterized by involvement of the long bones associated with the radiographic findings of periosteal reaction and cortical hyperostosis. Although some have distinguished HHS from FTC by the presence of bone involvement and the absence of skin involvement (Frishberg et al., 2005), Ichikawa et al. (2010) concluded that the 2 entities represent a continuous spectrum of the same disease, best described as familial hyperphosphatemic tumoral calcinosis. HFTC is considered to be the clinical converse of autosomal dominant hypophosphatemic rickets (ADHR; 193100), an allelic disorder caused by gain-of-function mutations in the FGF23 gene and associated with hypophosphatemia and decreased renal phosphate absorption (Chefetz et al., 2005; Ichikawa et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of HFTC, see 211900. [from OMIM]

Nonmedullary thyroid cancer (NMTC) comprises thyroid cancers of follicular cell origin and accounts for more than 95% of all thyroid cancer cases. The remaining cancers originate from parafollicular cells (medullary thyroid cancer, MTC; 155240). NMTC is classified into 4 groups: papillary, follicular, Hurthle cell (607464), and anaplastic. Approximately 5% of NMTC is hereditary, occurring as a minor component of a familial cancer syndrome (e.g., familial adenomatous polyposis, 175100, Carney complex, 160980) or as a primary feature (familial NMTC or FNMTC). Papillary thyroid cancer (PTC) is the most common histologic subtype of FNMTC, accounting for approximately 85% of cases (summary by Vriens et al., 2009). Follicular thyroid cancer (FTC) accounts for approximately 15% of NMTC and is defined by invasive features that result in infiltration of blood vessels and/or full penetration of the tumor capsule, in the absence of the nuclear alterations that characterize papillary carcinoma. FTC is rarely multifocal and usually does not metastasize to the regional lymph nodes but tends to spread via the bloodstream to the lung and bones. An important histologic variant of FTC is the oncocytic (Hurthle cell, oxyphilic) follicular carcinoma composed of eosinophilic cells replete with mitochondria (summary by Bonora et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of NMTC, see NMTC1 (188550). [from OMIM]

Renal hypodysplasia/aplasia belongs to a group of perinatally lethal renal diseases, including bilateral renal aplasia, unilateral renal agenesis with contralateral dysplasia (URA/RD), and severe obstructive uropathy. Renal aplasia falls at the most severe end of the spectrum of congenital anomalies of the kidney and urinary tract (CAKUT; 610805), and usually results in death in utero or in the perinatal period. Families have been documented in which bilateral renal agenesis or aplasia coexists with unilateral renal aplasia, renal dysplasia, or renal aplasia with renal dysplasia, suggesting that these conditions may belong to a pathogenic continuum or phenotypic spectrum (summary by Joss et al., 2003; Humbert et al., 2014). For a discussion of genetic heterogeneity of renal hypodysplasia/aplasia, see RHDA1 (191830). [from OMIM]

Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia, has been reported in some individuals. [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]

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]

Bent bone dysplasia syndrome-1 (BBDS1) is a perinatal lethal skeletal dysplasia characterized by poor mineralization of the calvarium, craniosynostosis, dysmorphic facial features, prenatal teeth, hypoplastic pubis and clavicles, osteopenia, and bent long bones (Merrill et al., 2012). Genetic Heterogeneity of Bent Bone Dysplasia Syndrome BBDS2 (620076) is caused by mutation in the LAMA5 gene (601033) on chromosome 20q13. [from OMIM]

Panitumumab is a monoclonal antibody used for the treatment of metastatic colorectal cancer (mCRC). Panitumumab is an epidermal growth factor receptor (EGFR) antagonist, which works by blocking the growth of cancer cells. It is administered every 14 days as an intravenous (IV) infusion, often with chemotherapy. Panitumumab is approved for first-line therapy with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) and as monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy. The location of the primary tumor correlates whether an individual with mCRC is likely respond to anti-EGFR therapy. Individuals with left-sided tumors are more likely to respond well to anti-EGFR therapy and have a better prognosis. Individuals with right-sided tumors have a worse prognosis and respond poorly to anti-EGFR therapy. However, only the genetic variation status of the tumor, and not the location of the tumor, is discussed in the FDA drug label’s dosing recommendations. Resistance to panitumumab is associated with specific RAS mutations. The RAS is a family of oncogenes that includes the KRAS and NRAS genes. When mutated, these genes have the ability to transform normal cells into cancerous cells by providing a continual growth stimulus to cells. The KRAS mutations are particularly common, being detectable in 40% of metastatic colorectal tumors. The KRAS mutations often lead to constitutive activation of the EGFR and are associated with resistance to anti-EGFR drugs such as panitumumab. Mutations in NRAS and another gene, BRAF, have also been associated with poor response to anti-EGFR therapy. The 2017 FDA-approved label states that panitumumab is indicated for wild-type RAS (no mutations in either KRAS or NRAS) mCRC. The label states that an FDA-approved test must be used to confirm the absence of RAS mutations before starting panitumumab, and that panitumumab is not indicated for the treatment of individuals with colorectal cancer with RAS mutations (in either NRAS or KRAS), or when the RAS genetic variation status is unknown. Similarly, the 2015 Update from the American Society of Clinical Oncology (ASCO) states that anti-EGFR therapy should only be considered for the treatment of individuals whose tumor is determined to not have variations detected after extended RAS testing. The 2020 National Comprehensive Cancer Network (NCCN) guideline also strongly recommends KRAS/NRAS genotyping of tumor tissue in all individuals with mCRC. In addition, the guideline states the V600E mutation in the BRAF gene makes a response to panitumumab highly unlikely, unless given with a BRAF inhibitor. [from Medical Genetics Summaries]

Cetuximab is a monoclonal antibody used in the treatment of metastatic colorectal cancer (mCRC) and cancer of the head and neck. Cetuximab is an epidermal growth factor receptor (EGFR) antagonist, which works by blocking the growth of cancer cells. It is administered as a weekly intravenous (IV) infusion, but in practice, is often given every other week to coincide with chemotherapy (for example, FOLFIRI or FOLFOX). Cetuximab has several off-label uses as well, which include non-small cell lung cancer, squamous cell carcinoma of the skin, and Menetrier’s disease. Interestingly, for colorectal cancer, the location of the primary tumor influences whether an individual with mCRC will respond to anti-EGFR therapy, and influences prognosis. Individuals with left-sided tumors are more likely to respond well to anti-EGFR therapy and have a better prognosis. Individuals with right-sided tumors have a worse prognosis and respond poorly to anti-EGFR therapy. However, currently only the mutation status of the tumor, and not the location of the tumor, is discussed in the drug label’s dosing recommendations. Resistance to cetuximab is associated with specific RAS mutations. The RAS family of oncogenes includes the KRAS and NRAS genes. When mutated, these genes have the ability to transform normal cells into cancerous cells. The KRAS mutations are particularly common, being detectable in 40% of metastatic colorectal tumors. The KRAS mutations often lead to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and are associated with resistance to anti-EGFR drugs such as cetuximab. In addition, mutations in NRAS and another gene, BRAF, have been associated with poor response to anti-EGFR therapy; however, BRAF mutation does not explicitly preclude anti-EGFR therapy. Combination therapies targeting both BRAF and EGFR have shown to improve survival for individuals with wild-type RAS and mutant BRAF. The 2018 FDA-approved drug label for cetuximab states that for mCRC, cetuximab is indicated for K- and N-RAS wild-type (no mutation), EGFR-expressing tumors. The label states that an FDA-approved test must be used to confirm the absence of a RAS mutation (in either KRAS or NRAS) prior to starting cetuximab. While the FDA label also states that EGFR expression should also be confirmed by an approved test prior to starting therapy for mCRC, this is largely not implemented in practice, nor is it recommended by professional oncology society guidelines. Similarly, the 2015 Update from the American Society of Clinical Oncology (ASCO) states that anti-EGFR therapy should only be considered for the treatment of individuals whose tumor is determined to not have mutations detected after extended RAS testing. The 2020 National Comprehensive Cancer Network (NCCN) guideline also strongly recommends KRAS/NRAS genotyping of tumor tissue in all individuals with mCRC. In addition, the guideline states the V600E mutation in the BRAF gene makes a response to cetuximab (and panitumumab) highly unlikely unless given a BRAF inhibitor. [from Medical Genetics Summaries]

Cytochrome P450 oxidoreductase deficiency (PORD) is a disorder of steroidogenesis with a broad phenotypic spectrum including cortisol deficiency, altered sex steroid synthesis, disorders of sex development (DSD), and skeletal malformations of the Antley-Bixler syndrome (ABS) phenotype. Cortisol deficiency is usually partial, with some baseline cortisol production but failure to mount an adequate cortisol response in stress. Mild mineralocorticoid excess can be present and causes arterial hypertension, usually presenting in young adulthood. Manifestations of altered sex steroid synthesis include ambiguous genitalia/DSD in both males and females, large ovarian cysts in females, poor masculinization and delayed puberty in males, and maternal virilization during pregnancy with an affected fetus. Skeletal malformations can manifest as craniosynostosis, mid-face retrusion with proptosis and choanal stenosis or atresia, low-set dysplastic ears with stenotic external auditory canals, hydrocephalus, radiohumeral synostosis, neonatal fractures, congenital bowing of the long bones, joint contractures, arachnodactyly, and clubfeet; other anomalies observed include urinary tract anomalies (renal pelvic dilatation, vesicoureteral reflux). Cognitive impairment is of minor concern and likely associated with the severity of malformations; studies of developmental outcomes are lacking. [from GeneReviews]

Any multiple synostoses syndrome in which the cause of the disease is a mutation in the FGF9 gene. [from MONDO]

Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population. [from GeneReviews]

RAS-associated leukoproliferative disorder is characterized by lymphadenopathy, splenomegaly, and variable autoimmune phenomena, including autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, and neutropenia. Laboratory studies show an expansion of lymphocytes due to defective apoptosis, as well as significant autoantibodies. Some patients have recurrent infections, and there may be an increased risk of hematologic malignancy (summary by Oliveira, 2013 and Niemela et al., 2010). The disorder shows significant overlap with autoimmune lymphoproliferative syndrome (ALPS; 601859) and was originally designated ALPS IV. [from OMIM]

Beare-Stevenson cutis gyrata syndrome (BSTVS) is an autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities, and early death (summary by Przylepa et al., 1996). [from OMIM]