Schaaf-Yang syndrome (SYS) is a rare neurodevelopmental disorder that shares multiple clinical features with the genetically related Prader-Willi syndrome. It usually manifests at birth with muscular hypotonia in all and distal joint contractures in a majority of affected individuals. Gastrointestinal/feeding problems are particularly pronounced in infancy and childhood, but can transition to hyperphagia and obesity in adulthood. Respiratory distress is present in many individuals at birth, with approximately half requiring intubation and mechanical ventilation, and approximately 20% requiring tracheostomy. Skeletal manifestations such as joint contractures, scoliosis, and decreased bone mineral density are frequently observed. All affected individuals show developmental delay, resulting in intellectual disability of variable degree, from low-normal intelligence to severe intellectual disability. Other findings may include short stature, seizures, eye anomalies, and hypogonadism. [from GeneReviews]

A distinct syndromic type of frontonasal malformation with characteristics of hypertelorism, wide nasal bridge, broad columella, widened philtrum, widely separated narrow nares, poor development of nasal tip, midline notch of the upper alveolus, columella base swellings and a low hairline. Additional features reported in some include upper eyelid ptosis and midline dermoid cysts of craniofacial structures and philtral pits or rugose folding behind the ears. [from SNOMEDCT_US]

Cytosolic phosphoenolpyruvate carboxykinase deficiency causes a defect in gluconeogenesis that results in a 'biochemical signature' of fasting hypoglycemia with high tricarboxylic acid cycle intermediate excretion, particularly of fumarate. Other biochemical anomalies that may be seen during metabolic crisis include ketonuria, dicarboxylic aciduria, and urea cycle dysfunction (Vieira et al., 2017). See PCKDM (261650) for a discussion of mitochondrial PCK (PEPCK2; 614095) deficiency. [from OMIM]

Immunodeficiency-104 (IMD104) is an autosomal recessive disorder characterized by the onset of recurrent infections in early infancy. Manifestations may include oral thrush, fever, and failure to thrive. Some patients have lymphadenopathy and hepatosplenomegaly, whereas others have absence of lymph nodes and lack a thymic shadow. Laboratory studies show decreased or absent numbers of nonfunctional T cells, normal or increased levels of B cells, variable hypogammaglobulinemia, and normal NK cells. The disorder is caused by a defect in IL7 (146660) signaling due to a mutant IL7 receptor. Hematopoietic stem cell transplantation may be curative (Roifman et al., 2000 and Giliani et al., 2005). Giliani et al. (2005) provided a detailed review of IL7R deficiency, including discussion of the IL7R gene and its function in the immune system, clinical features of the disorder, and experiences with hematopoietic stem cell transplant as treatment. For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive SCID, see 601457. [from OMIM]

Autoimmune interstitial lung, joint, and kidney disease is an autosomal dominant systemic autoimmune disorder characterized by interstitial lung disease, inflammatory arthritis, and immune complex-mediated renal disease. Laboratory studies show high-titer autoantibodies. Symptoms appear in the first 2 decades of life, but there is incomplete penetrance (summary by Watkin et al., 2015). [from OMIM]

DYRK1A syndrome is characterized by intellectual disability including impaired speech development, autism spectrum disorder including anxious and/or stereotypic behavior problems, and microcephaly. Affected individuals often have a clinically recognizable phenotype including a typical facial gestalt, feeding problems, seizures, hypertonia, gait disturbances, and foot anomalies. The majority of affected individuals function in the moderate-to-severe range of intellectual disability; however, individuals with mild intellectual disability have also been reported. Other medical concerns relate to febrile seizures in infancy; the development of epilepsy with seizures of the atonic, absence, and generalized myoclonic types; short stature; and gastrointestinal problems. Ophthalmologic, urogenital, cardiac, and/or dental anomalies have been reported. [from GeneReviews]

A rare autosomal recessive primary immunodeficiency characterized by infancy onset of severe inflammatory bowel disease with life-threatening diarrhea and failure to thrive, oral aphthous ulcers, and recurrent severe upper and lower respiratory tract infections with finger clubbing. Laboratory examination reveals increased IgE and decreased IgG levels, as well as reduced numbers of circulating CD19+ B-cells including IgM+ naive and class-switched IgG memory B-cells, with a concomitant increase in transitional B-cells, while T-cell numbers and function are normal. [from SNOMEDCT_US]

Bardet-Biedl syndrome-22 (BBS22) is an autosomal recessive ciliopathy described in a single patient and characterized by retinitis pigmentosa, obesity, polydactyly, hypogonadism, and intellectual disability (Lindstrand et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (209900). [from OMIM]

Any secretory diarrhea in which the cause of the disease is a mutation in the SLC9A3 gene. [from MONDO]

Familial hypercholanemia-1 (FHCA1) is an autosomal recessive disorder characterized by elevated concentrations of bile acids (usually conjugated), itching, and fat malabsorption, leading to poor overall growth and deficiencies of fat-soluble vitamins. Vitamin D deficiency results in rickets, and vitamin K deficiency results in a coagulopathy (Morton et al., 2000; Shneider et al., 1997; summary by Carlton et al., 2003). See also bile acid conjugation defect-1 (BACD1; 619232), which can also show increased bile acid levels, although the bile acids in BACD1 are unconjugated. Genetic Heterogeneity of FHCA See FHCA2 (619256), caused by mutation in the SLC10A1 gene (182396) on chromosome 14q24. [from OMIM]

Any secretory diarrhea in which the cause of the disease is a mutation in the SPINT2 gene. [from MONDO]

X-linked lymphoproliferative disease (XLP) has two recognizable subtypes, XLP1 and XLP2. XLP1 is characterized predominantly by one of three commonly recognized phenotypes: Inappropriate immune response to Epstein-Barr virus (EBV) infection leading to hemophagocytic lymphohistiocytosis (HLH) or severe mononucleosis. Dysgammaglobulinemia. Lymphoproliferative disease (malignant lymphoma). XLP2 is most often characterized by HLH (often associated with EBV), dysgammaglobulinemia, and inflammatory bowel disease. HLH resulting from EBV infection is associated with an unregulated and exaggerated immune response with widespread proliferation of cytotoxic T cells, EBV-infected B cells, and macrophages. Dysgammaglobulinemia is typically hypogammaglobulinemia of one or more immunoglobulin subclasses. The malignant lymphomas are typically B-cell lymphomas, non-Hodgkin type, often extranodal, and in particular involving the intestine. [from GeneReviews]

Familial myoclonus-2 is an autosomal dominant neurologic condition characterized by childhood onset of isolated action-induced nonepileptic myoclonus affecting the upper limbs. The disorder is nonprogressive (Wagnon et al., 2018). [from OMIM]

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]

Obesity due to mutation in the MC4R gene is the most common cause of monogenic obesity. Patients have early-onset severe obesity and hyperphagia (Farooqi et al., 2003). [from OMIM]

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]

ASXL3-related disorder is characterized by developmental delay or intellectual disability, typically in the moderate to severe range, with speech and language delay and/or absent speech. Affected individuals may also display autistic features. There may be issues with feeding. While dysmorphic facial features have been described, they are typically nonspecific. Affected individuals may also have hypotonia that can transition to spasticity resulting in unusual posture with flexion contractions of the elbows, wrists, and fingers. Other findings may include poor postnatal growth, strabismus, seizures, sleep disturbance, and dental anomalies. [from GeneReviews]

Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is characterized by the presence of multiple small (1-2 cm in diameter) capillary malformations mostly localized on the face and limbs. Some affected individuals also have associated arteriovenous malformations (AVMs) and/or arteriovenous fistulas (AFVs), fast-flow vascular anomalies that typically arise in the skin, muscle, bone, spine, and brain; life-threatening complications of these lesions can include bleeding, congestive heart failure, and/or neurologic consequences. Symptoms from intracranial AVMs/AVFs appear to occur early in life. Several individuals have Parkes Weber syndrome (multiple micro-AVFs associated with a cutaneous capillary stain and excessive soft-tissue and skeletal growth of an affected limb). [from GeneReviews]

In Alport syndrome (AS) a spectrum of phenotypes ranging from progressive renal disease with extrarenal abnormalities to isolated hematuria with a non-progressive or very slowly progressive course is observed. Approximately two thirds of AS is X-linked (XLAS); approximately 15% is autosomal recessive (ARAS), and approximately 20% is autosomal dominant (ADAS). In the absence of treatment, renal disease progresses from microscopic hematuria (microhematuria) to proteinuria, progressive renal insufficiency, and end-stage renal disease (ESRD) in all males with XLAS, and in all males and females with ARAS. Progressive sensorineural hearing loss (SNHL) is usually present by late childhood or early adolescence. Ocular findings include anterior lenticonus (which is virtually pathognomonic), maculopathy (whitish or yellowish flecks or granulations in the perimacular region), corneal endothelial vesicles (posterior polymorphous dystrophy), and recurrent corneal erosion. In individuals with ADAS, ESRD is frequently delayed until later adulthood, SNHL is relatively late in onset, and ocular involvement is rare. [from GeneReviews]