MedGen

Obesity associated with an identifiable mutation in a single gene. [from NCI]

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]

Prader-Willi syndrome (PWS) is characterized by severe hypotonia, poor appetite, and feeding difficulties in early infancy, followed in early childhood by excessive eating and gradual development of morbid obesity (unless food intake is strictly controlled). Motor milestones and language development are delayed. All individuals have some degree of cognitive impairment. 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). A distinctive behavioral phenotype (temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsive characteristics) is common. Characteristic facial features, strabismus, and scoliosis are often present. [from GeneReviews]

Williams syndrome (WS) is characterized by developmental delay, intellectual disability (usually mild), a specific cognitive profile, unique personality characteristics, cardiovascular disease (supravalvar aortic stenosis, peripheral pulmonary stenosis, hypertension), connective tissue abnormalities, growth deficiency, endocrine abnormalities (early puberty, hypercalcemia, hypercalciuria, hypothyroidism), and distinctive facies. Hypotonia and hyperextensible joints can result in delayed attainment of motor milestones. Feeding difficulties often lead to poor weight gain in infancy. [from GeneReviews]

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]

Angelman syndrome (AS) is characterized by severe developmental delay or intellectual disability, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and unique behavior with an apparent happy demeanor that includes frequent laughing, smiling, and excitability. Microcephaly and seizures are also common. Developmental delays are first noted at around age six months; however, the unique clinical features of AS do not become manifest until after age one year. [from GeneReviews]

Disorders of GNAS inactivation include the phenotypes pseudohypoparathyroidism Ia, Ib, and Ic (PHP-Ia, -Ib, -Ic), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). PHP-Ia and PHP-Ic are characterized by: End-organ resistance to endocrine hormones including parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), gonadotropins (LH and FSH), growth hormone-releasing hormone (GHRH), and CNS neurotransmitters (leading to obesity and variable degrees of intellectual disability and developmental delay); and The Albright hereditary osteodystrophy (AHO) phenotype (short stature, round facies, and subcutaneous ossifications) and brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb). Although PHP-Ib is characterized principally by PTH resistance, some individuals also have partial TSH resistance and mild features of AHO (e.g., brachydactyly). PPHP, a more limited form of PHP-Ia, is characterized by various manifestations of the AHO phenotype without the hormone resistance or obesity. POH and OC are even more restricted variants of PPHP: POH consists of dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia. OC consists of extra-skeletal ossification that is limited to the dermis and subcutaneous tissues. [from GeneReviews]

Alström syndrome is characterized by cone-rod dystrophy, obesity, progressive bilateral sensorineural hearing impairment, acute infantile-onset cardiomyopathy and/or adolescent- or adult-onset restrictive cardiomyopathy, insulin resistance / type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), and chronic progressive kidney disease. Cone-rod dystrophy presents as progressive visual impairment, photophobia, and nystagmus usually starting between birth and age 15 months. Many individuals lose all perception of light by the end of the second decade, but a minority retain the ability to read large print into the third decade. Children usually have normal birth weight but develop truncal obesity during their first year. Sensorineural hearing loss presents in the first decade in as many as 70% of individuals and may progress to the severe or moderately severe range (40-70 db) by the end of the first to second decade. Insulin resistance is typically accompanied by the skin changes of acanthosis nigricans, and proceeds to T2DM in the majority by the third decade. Nearly all demonstrate hypertriglyceridemia. Other findings can include endocrine abnormalities (hypothyroidism, hypogonadotropic hypogonadism in males, and hyperandrogenism in females), urologic dysfunction / detrusor instability, progressive decrease in renal function, and hepatic disease (ranging from elevated transaminases to steatohepatitis/NAFLD). Approximately 20% of affected individuals have delay in early developmental milestones, most commonly in gross and fine motor skills. About 30% have a learning disability. Cognitive impairment (IQ <70) is very rare. Wide clinical variability is observed among affected individuals, even within the same family. [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]

Disorders of GNAS inactivation include the phenotypes pseudohypoparathyroidism Ia, Ib, and Ic (PHP-Ia, -Ib, -Ic), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). PHP-Ia and PHP-Ic are characterized by: End-organ resistance to endocrine hormones including parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), gonadotropins (LH and FSH), growth hormone-releasing hormone (GHRH), and CNS neurotransmitters (leading to obesity and variable degrees of intellectual disability and developmental delay); and The Albright hereditary osteodystrophy (AHO) phenotype (short stature, round facies, and subcutaneous ossifications) and brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb). Although PHP-Ib is characterized principally by PTH resistance, some individuals also have partial TSH resistance and mild features of AHO (e.g., brachydactyly). PPHP, a more limited form of PHP-Ia, is characterized by various manifestations of the AHO phenotype without the hormone resistance or obesity. POH and OC are even more restricted variants of PPHP: POH consists of dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia. OC consists of extra-skeletal ossification that is limited to the dermis and subcutaneous tissues. [from GeneReviews]

Familial partial lipodystrophy (FPLD) is a metabolic disorder characterized by abnormal subcutaneous adipose tissue distribution beginning in late childhood or early adult life. Affected individuals gradually lose fat from the upper and lower extremities and the gluteal and truncal regions, resulting in a muscular appearance with prominent superficial veins. In some patients, adipose tissue accumulates on the face and neck, causing a double chin, fat neck, or cushingoid appearance. Metabolic abnormalities include insulin-resistant diabetes mellitus with acanthosis nigricans and hypertriglyceridemia; hirsutism and menstrual abnormalities occur infrequently. Familial partial lipodystrophy may also be referred to as lipoatrophic diabetes mellitus, but the essential feature is loss of subcutaneous fat (review by Garg, 2004). The disorder may be misdiagnosed as Cushing disease (see 219080) (Kobberling and Dunnigan, 1986; Garg, 2004). Genetic Heterogeneity of Familial Partial Lipodystrophy Familial partial lipodystrophy is a clinically and genetically heterogeneous disorder. Types 1 and 2 were originally described as clinical subtypes: type 1 (FPLD1; 608600), characterized by loss of subcutaneous fat confined to the limbs (Kobberling et al., 1975), and FPLD2, characterized by loss of subcutaneous fat from the limbs and trunk (Dunnigan et al., 1974; Kobberling and Dunnigan, 1986). No genetic basis for FPLD1 has yet been delineated. FPLD3 (604367) is caused by mutation in the PPARG gene (601487) on chromosome 3p25; FPLD4 (613877) is caused by mutation in the PLIN1 gene (170290) on chromosome 15q26; FPLD5 (615238) is caused by mutation in the CIDEC gene (612120) on chromosome 3p25; FPLD6 (615980) is caused by mutation in the LIPE gene (151750) on chromosome 19q13; FPLD7 (606721) is caused by mutation in the CAV1 gene (601047) on chromosome 7q31; FPLD8 (620679), caused by mutation in the ADRA2A gene (104210) on chromosome 10q25; and FPLD9 (620683), caused by mutation in the PLAAT3 gene (613867) on chromosome 11q12. [from OMIM]

Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is characterized by distinctive craniofacial features, genital anomalies, hypotonia, and mild-to-profound developmental delay / intellectual disability (DD/ID). Craniofacial abnormalities include small head circumference, telecanthus or widely spaced eyes, short triangular nose, tented upper lip, and thick or everted lower lip with coarsening of the facial features over time. While all affected individuals have a normal 46,XY karyotype, genital anomalies comprise a range from hypospadias and undescended testicles, to severe hypospadias and ambiguous genitalia, to normal-appearing female external genitalia. Alpha-thalassemia, observed in about 75% of affected individuals, is mild and typically does not require treatment. Osteosarcoma has been reported in a few males with germline pathogenic variants. [from GeneReviews]

Myhre syndrome is a multisystem progressive connective tissue disorder that often results in significant complications. The highly distinctive (and often severe) findings of joint stiffness, restrictive lung and cardiovascular disease, progressive and proliferative fibrosis, and thickening of the skin usually occur spontaneously. Some proliferation such as abnormal scarring or adhesions may follow trauma, invasive medical procedures, or surgery. Effusions of the heart, airways, lungs, uterus, and peritoneum may occur and can progress to fibrosis. Most affected individuals have characteristic facial features (short palpebral fissures, deeply set eyes, maxillary underdevelopment, short philtrum, thin vermilion of the upper lip, narrow mouth, and prognathism) and developmental delay / cognitive disability, typically in the mild-to-moderate range. Neurobehavioral issues may include autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and/or anxiety. Although immunoglobulin (Ig) G and IgA deficiency are rare, affected individuals can experience recurrent infections (including otitis media, sinusitis, mastoiditis, or croup). Hearing loss can progress over time. Growth may be impaired in early life. Most adolescents develop obesity. Eye findings can include refractive errors, astigmatism, corectopia, and optic nerve anomalies. Gastrointestinal (GI) issues may include gastroesophageal reflux disease, constipation, and encopresis. Less commonly, stenosis of the GI tract, Hirschsprung disease, and/or metabolic dysfunction-associated liver disease may be observed. [from GeneReviews]

Disorders of GNAS inactivation include the phenotypes pseudohypoparathyroidism Ia, Ib, and Ic (PHP-Ia, -Ib, -Ic), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). PHP-Ia and PHP-Ic are characterized by: End-organ resistance to endocrine hormones including parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), gonadotropins (LH and FSH), growth hormone-releasing hormone (GHRH), and CNS neurotransmitters (leading to obesity and variable degrees of intellectual disability and developmental delay); and The Albright hereditary osteodystrophy (AHO) phenotype (short stature, round facies, and subcutaneous ossifications) and brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb). Although PHP-Ib is characterized principally by PTH resistance, some individuals also have partial TSH resistance and mild features of AHO (e.g., brachydactyly). PPHP, a more limited form of PHP-Ia, is characterized by various manifestations of the AHO phenotype without the hormone resistance or obesity. POH and OC are even more restricted variants of PPHP: POH consists of dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia. OC consists of extra-skeletal ossification that is limited to the dermis and subcutaneous tissues. [from GeneReviews]

BBS2 is an autosomal recessive ciliopathy characterized by retinal degeneration, polydactyly, renal disease, hypogonadism, obesity, dysmorphic features, and variable degrees of cognitive impairment (Innes et al., 2010). Mutation in the BBS2 gene is the third most frequent cause of BBS, accounting for approximately 8% of cases (Zaghloul and Katsanis, 2009). For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (209900). [from OMIM]

Leptin deficiency or dysfunction (LEPD) is characterized by severe early-onset obesity, hyperphagia, hypogonadotropic hypogonadism, and neuroendocrine/metabolic dysfunction (Ozata et al., 1999). [from OMIM]

BBS10 is characterized by progressive retinal dystrophy, obesity, polydactyly, cognitive impairment, and renal dysplasia (Stoetzel et al., 2006). BBS10 represents a major locus for BBS, with mutations in the BBS10 gene accounting for approximately 20% of BBS patients (Stoetzel et al., 2006; Zaghloul and Katsanis, 2009). For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (209900). [from OMIM]

Spastic paraplegia 11 (SPG11) is characterized by progressive spasticity and weakness of the lower limbs frequently associated with the following: mild intellectual disability with learning difficulties in childhood and/or progressive cognitive decline; peripheral neuropathy; pseudobulbar involvement; and increased reflexes in the upper limbs. Less frequent findings include: cerebellar signs (ataxia, nystagmus, saccadic pursuit); retinal degeneration; pes cavus; scoliosis; and parkinsonism with characteristic brain MRI features that include thinning of the corpus callosum. Onset occurs mainly during infancy or adolescence (range: age 1-31 years) and in rare cases as late as age 60 years. Most affected individuals become wheelchair bound one or two decades after disease onset. [from GeneReviews]

BBS12 is a clinically pleiotropic autosomal recessive ciliopathy. The patients with BBS12 studied by Stoetzel et al. (2007) and Harville et al. (2010) met the diagnostic criteria of Beales et al. (1999), which required the presence of either 4 primary features, including rod-cone dystrophy, polydactyly, obesity, learning disabilities, hypogonadism (in males), and/or renal anomalies; or 3 primary plus 2 secondary features (e.g., developmental delay, ataxia, cataracts). For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (209900). [from OMIM]

PAX6-related aniridia occurs either as an isolated ocular abnormality or as part of the Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome. Aniridia is a pan ocular disorder affecting the cornea, iris, intraocular pressure (resulting in glaucoma), lens (cataract and lens subluxation), fovea (foveal hypoplasia), and optic nerve (optic nerve coloboma and hypoplasia). Individuals with aniridia characteristically show nystagmus and impaired visual acuity (usually 20/100 - 20/200); however, milder forms of aniridia with subtle iris architecture changes, good vision, and normal foveal structure do occur. Other ocular involvement may include strabismus and occasionally microphthalmia. Although the severity of aniridia can vary between and within families, little variability is usually observed in the two eyes of an affected individual. WAGR syndrome. The risk for Wilms tumor is 42.5%-77%; of those who develop Wilms tumor, 90% do so by age four years and 98% by age seven years. Genital anomalies in males can include cryptorchidism and hypospadias (sometimes resulting in ambiguous genitalia), urethral strictures, ureteric abnormalities, and gonadoblastoma. While females typically have normal external genitalia, they may have uterine abnormalities and streak ovaries. Intellectual disability (defined as IQ <74) is observed in 70%; behavioral abnormalities include attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder. Other individuals with WAGR syndrome can have normal intellect without behavioral issues. [from GeneReviews]