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RCAD is associated with a combination of diabetes and kidney or urinary tract abnormalities (unrelated to the elevated blood glucose), most commonly fluid-filled sacs (cysts) in the kidneys. However, the signs and symptoms are variable, even within families, and not everyone with RCAD has both features. Affected individuals may have other features unrelated to diabetes, such as abnormalities of the pancreas or liver or a form of arthritis called gout.

GCK-MODY is a very mild type of the condition. People with this type have slightly elevated blood glucose levels, particularly in the morning before eating (fasting blood glucose). However, affected individuals often have no symptoms related to the disorder, and diabetes-related complications are extremely rare.

HNF1A-MODY and HNF4A-MODY have similar signs and symptoms that develop slowly over time. Early signs and symptoms in these types are caused by high blood glucose and may include frequent urination (polyuria), excessive thirst (polydipsia), fatigue, blurred vision, weight loss, and recurrent skin infections. Over time uncontrolled high blood glucose can damage small blood vessels in the eyes and kidneys. Damage to the light-sensitive tissue at the back of the eye (the retina) causes a condition known as diabetic retinopathy that can lead to vision loss and eventual blindness. Kidney damage (diabetic nephropathy) can lead to kidney failure and end-stage renal disease (ESRD). While these two types of MODY are very similar, certain features are particular to each type. For example, babies with HNF4A-MODY tend to weigh more than average or have abnormally low blood glucose at birth, even though other signs of the condition do not occur until childhood or young adulthood. People with HNF1A-MODY have a higher-than-average risk of developing noncancerous (benign) liver tumors known as hepatocellular adenomas.

The different types of MODY are distinguished by their genetic causes. The most common types are HNF1A-MODY (also known as MODY3), accounting for 50 to 70 percent of cases, and GCK-MODY (MODY2), accounting for 30 to 50 percent of cases. Less frequent types include HNF4A-MODY (MODY1) and renal cysts and diabetes (RCAD) syndrome (also known as HNF1B-MODY or MODY5), which each account for 5 to 10 percent of cases. At least ten other types have been identified, and these are very rare.

Maturity-onset diabetes of the young (MODY) is a group of several conditions characterized by abnormally high levels of blood glucose, also called blood sugar. These forms of diabetes typically begin before age 30, although they can occur later in life. In MODY, elevated blood glucose arises from reduced production of insulin, which is a hormone produced in the pancreas that helps regulate blood glucose levels. Specifically, insulin controls how much glucose (a type of sugar) is passed from the blood into cells, where it is used as an energy source. [from MedlinePlus Genetics]

GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD) is characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of oral administration of levodopa. This disorder typically presents with gait disturbance caused by foot dystonia, later development of parkinsonism, and diurnal fluctuation of symptoms (aggravation of symptoms toward the evening and alleviation of symptoms in the morning after sleep). Initial symptoms are often gait difficulties attributable to flexion-inversion (equinovarus posture) of the foot. Occasionally, initial symptoms are arm dystonia, postural tremor of the hand, or slowness of movements. Brisk deep-tendon reflexes in the legs, ankle clonus, and/or the striatal toe (dystonic extension of the big toe) are present in many affected individuals. In general, gradual progression to generalized dystonia is observed. Intellectual, cerebellar, sensory, and autonomic disturbances generally do not occur. [from GeneReviews]

Ventricular septal defect (VSD) is the most common form of congenital cardiovascular anomaly, occurring in nearly 50% of all infants with a congenital heart defect and accounting for 14 to 16% of cardiac defects that require invasive treatment within the first year of life. Congenital VSDs may occur alone or in combination with other cardiac malformations. Large VSDs that go unrepaired may give rise to cardiac enlargement, congestive heart failure, pulmonary hypertension, Eisenmenger's syndrome, delayed fetal brain development, arrhythmias, and even sudden cardiac death (summary by Wang et al., 2011, 2011). Other congenital cardiac defects caused by mutation in the NKX2-5 gene include atrial septal defect with or without atrioventricular conduction defects (ASD7; 108900), tetralogy of Fallot (see TOF, 187500), conotruncal malformations (see 217095), and hypoplastic left heart syndrome (HLHS2; 614435). For a discussion of genetic heterogeneity of ventricular septal defect, see VSD1 (614429). [from OMIM]

Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine malformation and/or instability), craniofacial features (widely spaced eyes, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant. [from GeneReviews]

A thickening of the skin thickness in the posterior aspect of the fetal neck. A nuchal fold (NF) measurement is obtained in a transverse section of the fetal head at the level of the cavum septum pellucidum and thalami, angled posteriorly to include the cerebellum. The measurement is taken from the outer edge of the occiput bone to the outer skin limit directly in the midline. An NF measurement greater than 5 mm at 14 to 17+6 weeks of gestation, or 6 mm at 18 to 28 weeks has been associated with a markedly increased risk for Down syndrome. [from HPO]

The association of a range of ocular anomalies (anophthalmia, microphthalmia and retinal abnormalities) with variable developmental delay and central nervous system malformations. Less than 20 cases have been reported in the literature so far. The clinical picture is highly variable, even between affected members of the same family. Severe developmental delay was noted in some patients, whilst others showed normal cognitive development. Pituitary dysfunction, leading to growth hormone deficiency and short stature, or combined pituitary hormone deficiency, has also been reported. The syndrome is caused by heterozygous mutations in the OTX2 gene (14q22.3). [from SNOMEDCT_US]

Adiponectin is an adipocyte-derived hormone that exerts pleiotropic effects that promote insulin sensitivity, inhibit cell death, and decrease inflammation. Adiponectin forms an obligate trimer and circulates as trimers, hexamers, and high molecular weight multimers that target multiple tissues and cell types including liver, kidney, cardiac myocytes, and pancreatic beta cells. Levels of adiponectin are decreased in obesity and may lead to insulin resistance, type 2 diabetes, myocardial infarction, nonalcoholic steatohepatitis, and kidney disease. The antiapoptotic, insulin-sensitizing, antiinflammatory, and antisteatotic effects have been linked to its role in sphingolipid metabolism and its receptor-mediated activation of ceramidase activity which reduces levels of lipotoxic ceramides (summary by Simeone et al., 2022). Genetic Heterogeneity of Quantitative Trait Loci for Serum Level of Adiponectin Additional quantitative trait loci for serum level of adiponectin have been mapped to chromosome 5 (ADIPQTL2; 606770), chromosome 14 (ADIPQTL3; 606771), chromosome 11 (ADIPQTL4; 612629), and chromosome 16q (ADIPQTL5; 613836). [from OMIM]

Dyskeratosis congenita and related telomere biology disorders (DC/TBD) are caused by impaired telomere maintenance resulting in short or very short telomeres. The phenotypic spectrum of telomere biology disorders is broad and includes individuals with classic dyskeratosis congenita (DC) as well as those with very short telomeres and an isolated physical finding. Classic DC is characterized by a triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia, although this may not be present in all individuals. People with DC/TBD are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome or acute myelogenous leukemia, solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), taurodontism, liver disease, gastrointestinal telangiectasias, and avascular necrosis of the hips or shoulders. Although most persons with DC/TBD have normal psychomotor development and normal neurologic function, significant developmental delay is present in both forms; additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome and Coats plus syndrome). Onset and progression of manifestations of DC/TBD vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF. [from GeneReviews]

Focal segmental glomerulosclerosis (FSGS) is a pathologic entity associated clinically with proteinuria, the nephrotic syndrome (NPHS), and progressive loss of renal function. It is a common cause of end-stage renal disease (ESRD) (Meyrier, 2005). Dominant intermediate Charcot-Marie-Tooth disease E and focal segmental glomerulonephritis (CMTDIE; 614455) is also caused by heterozygous mutation in the INF2 gene. For a general phenotypic description and a discussion of genetic heterogeneity of focal segmental glomerulosclerosis and nephrotic syndrome, see FSGS1 (603278). [from OMIM]

An autosomal recessive inherited skin disorder caused by mutations in the genes encoding keratins 5 and 14, collagen VII or laminin 5. It is characterized by skin fragility and the formation of blisters. The blisters may become large and ulcerated, resulting in skin infections and loss of body fluids. [from NCI]

Premature ovarian failure-14 (POF14) is characterized by amenorrhea, hypoestrogenism, and elevated gonadotropin levels (Franca et al., 2018). For a general phenotypic description and discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360). [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 (188470), Hurthle cell (607464), and anaplastic. Approximately 5% of NMTC is hereditary, occurring as a 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). PTC is characterized by distinctive nuclear alterations including pseudoinclusions, grooves, and chromatin clearing. PTCs smaller than 1 cm are referred to as papillary microcarcinomas. These tumors have been identified in up to 35% of individuals at autopsy, suggesting that they may be extremely common although rarely clinically relevant. PTC can also be multifocal but is typically slow-growing with a tendency to spread to lymph nodes and usually has an excellent prognosis (summary by Bonora et al., 2010). Genetic Heterogeneity of Susceptibility to Nonmedullary Thyroid Cancer Other susceptibilities to nonmedullary thyroid cancer include NMTC2 (188470), caused by mutation in the SRGAP1 gene (606523); NMTC3 (606240), mapped to chromosome 2q21; NMTC4 (616534), caused by mutation in the FOXE1 gene (602617); and NMTC5 (616535), caused by mutation in the HABP2 gene (603924). A susceptibility locus for familial nonmedullary thyroid carcinoma with or without cell oxyphilia (TCO; 603386) has been mapped to chromosome 19p. [from OMIM]

Meckel syndrome-14 (MKS14) is a lethal disorder characterized by occipital encephalocele, postaxial polydactyly of the hands and feet, and polycystic kidneys. Stillbirth has been reported, as well as death within hours in a live-born affected individual (Shaheen et al., 2016; Ridnoi et al., 2019). For a general phenotypic description and discussion of genetic heterogeneity of Meckel syndrome, see MKS1 (249000). [from OMIM]

Laing distal myopathy is characterized by early-onset weakness (usually before age 5 years) that initially involves the dorsiflexors of the ankles and great toes and then the finger extensors, especially those of the third and fourth fingers. Weakness of the neck flexors is seen in most affected individuals and mild facial weakness is often present. After distal weakness has been present for more than ten years, mild proximal weakness may be observed. Life expectancy is normal. [from GeneReviews]

Spastic paraplegia 15 (SPG15), typically an early-onset complex hereditary spastic paraplegia, is characterized by progressive spasticity that begins in the lower extremities and is associated with several manifestations resulting from central and peripheral nervous system dysfunction. While onset of spasticity is typically in mid- to late childhood or adolescence (i.e., between ages 5 and 18 years), other manifestations, such as developmental delay or learning disability, may be present earlier, often preceding motor involvement. Individuals with adult onset have also been reported. [from GeneReviews]

Any autosomal dominant Emery-Dreifuss muscular dystrophy in which the cause of the disease is a mutation in the SYNE2 gene. [from MONDO]

People with the mild form may have very mild anemia or sometimes have no symptoms. People with the moderate form typically have anemia, jaundice, and splenomegaly. Many also develop gallstones. The signs and symptoms of moderate hereditary spherocytosis usually appear in childhood. Individuals with the moderate/severe form have all the features of the moderate form but also have severe anemia. Those with the severe form have life-threatening anemia that requires frequent blood transfusions to replenish their red blood cell supply. They also have severe splenomegaly, jaundice, and a high risk for developing gallstones. Some individuals with the severe form have short stature, delayed sexual development, and skeletal abnormalities.

There are four forms of hereditary spherocytosis, which are distinguished by the severity of signs and symptoms. They are known as the mild form, the moderate form, the moderate/severe form, and the severe form. It is estimated that 20 to 30 percent of people with hereditary spherocytosis have the mild form, 60 to 70 percent have the moderate form, 10 percent have the moderate/severe form, and 3 to 5 percent have the severe form.

Hereditary spherocytosis is a condition that affects red blood cells. People with this condition typically experience a shortage of red blood cells (anemia), yellowing of the eyes and skin (jaundice), and an enlarged spleen (splenomegaly). Most newborns with hereditary spherocytosis have severe anemia, although it improves after the first year of life. Splenomegaly can occur anytime from early childhood to adulthood. About half of affected individuals develop hard deposits in the gallbladder called gallstones, which typically occur from late childhood to mid-adulthood. [from MedlinePlus Genetics]

A precursor lymphoid neoplasm which is composed of B-lymphoblasts and carries a translocation between the IL3 gene on chromosome 5 and the IGH locus on chromosome 14, (q31.1;q32.3). It results in eosinophilia. [from NCI]

Distal myopathy-5 (MPD5) is an autosomal recessive, slowly progressive muscle disorder characterized by adolescent onset of distal muscle weakness and atrophy predominantly affecting the lower limbs. Other features include facial weakness and hyporeflexia. Patients remain ambulatory even after long disease duration (summary by Park et al., 2016). [from OMIM]