201
(57.9%)

familial visceral amyloidosis

Cholestasis Proteinuria Splenomegaly

Autosomal dominant inheritance

201
(57.9%)

short-rib thoracic dysplasia 10 with or without polydactyly

Cholestasis Glucose intolerance Nephronophthisis Splenomegaly

Autosomal recessive inheritance

An asphyxiating thoracic dystrophy that has material basis in homozygous or compound heterozygous mutation in the IFT172 gene on chromosome 2p23.

201
(57.9%)

neonatal diabetes mellitus with congenital hypothyroidism

Cholestasis Diabetes mellitus Polycystic kidney dysplasia Splenomegaly

Autosomal recessive inheritance

A rare genetic disease characterized by intrauterine growth retardation, permanent neonatal diabetes mellitus, and congenital hypothyroidism. Additional manifestations include congenital glaucoma, hepatic disease (hepatitis, fibrosis, and cirrhosis), polycystic kidneys, exocrine pancreatic dysfunction, sensorineural hearing impairment, developmental delay, and mild facial dysmorphism (such as flat nasal bridge, epicanthal folds, long philtrum, and low-set ears), among others

201
(57.9%)

cranioectodermal dysplasia 2

Cholestasis Hydrops fetalis Inguinal hernia Splenomegaly

Autosomal recessive inheritance

Any cranioectodermal dysplasia in which the cause of the disease is a mutation in the WDR35 gene.

205
(57.9%)

combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia

Decreased methylcobalamin Eczema Megaloblastic anemia Vomiting

Autosomal recessive inheritance

205
(57.9%)

methylmalonic aciduria and homocystinuria type cblF

Feeding difficulties in infancy Megaloblastic anemia Methylmalonic acidemia Skin rash

Autosomal recessive inheritance

A form of methylmalonic acidemia with homocystinuria, an inborn error of vitamin B12 (cobalamin) metabolism characterized by megaloblastic anemia, lethargy, failure to thrive, developmental delay, intellectual deficit and seizures. The disorder is caused by mutations in the LMBRD1 gene (6q13) and is transmitted in an autosomal recessive manner.

207
(57.8%)

platelet-type bleeding disorder 19

Anemia Menorrhagia Spontaneous hematomas

Autosomal recessive inheritance

Any isolated hereditary giant platelet disorder in which the cause of the disease is a mutation in the PRKACG gene.

207
(57.8%)

thrombocytopenia 5

Anemia Epistaxis Petechiae

Autosomal dominant inheritance

Any thrombocytopenia in which the cause of the disease is a mutation in the ETV6 gene.

207
(57.8%)

platelet-type bleeding disorder 16

Anemia Petechiae

Autosomal dominant inheritance Autosomal recessive inheritance

An inherited blood coagulation disease characterized by autosomal dominant inheritance with macrothrombocytopenia, platelet anisocytosis, prolonged bleeding time but only mildly increased bleeding tendency that has material basis in heterozygous mutation in the ITGA2B gene on chromosome 17q21.31 or the ITGB3 gene on chromosome 17q21.32.

207
(57.8%)

recessive dystrophic epidermolysis bullosa

Anemia Conjunctivitis Fragile skin Narrow mouth

Autosomal recessive inheritance

Severe generalized recessive dystrophic epidermolysis bullosa (RDEB-sev gen) is the most severe subtype of dystrophic epidermolysis bullosa (DEB), formerly known as the Hallopeau-Siemens type, and is characterized by generalized cutaneous and mucosal blistering and scarring associated with severe deformities and major extracutaneous involvement.

207
(57.8%)

PGM3-CDG

Erythema Hemolytic anemia High palate

Autosomal recessive inheritance

207
(57.8%)

cerebroretinal microangiopathy with calcifications and cysts 1

Anemia Blindness Retinal telangiectasia

Autosomal recessive inheritance

Any Coats plus syndrome in which the cause of the disease is a mutation in the CTC1 gene.

213
(57.7%)

PMM2-CDG

Abnormal subcutaneous fat tissue distribution Hepatomegaly Thrombocytosis Type I transferrin isoform profile

Autosomal recessive inheritance

PMM2-CDG is the most frequent form of congenital disorder of N-glycosylation and is characterized by cerebellar dysfunction, abnormal fat distribution, inverted nipples, strabismus and hypotonia. 3 forms of PMM2-CDG can be distinguished: the infantile multisystem type, late-infantile and childhood ataxia-intellectual disability type (3-10 yrs old), and the adult stable disability type. Infants usually develop ataxia, psychomotor delay and extraneurological manifestations including failure to thrive, enteropathy, hepatic dysfunction, coagulation abnormalities and cardiac and renal involvement. The phenotype is however highly variable and ranges from infants who die in the first year of life to mildly involved adults.

214
(57.4%)

Schimke immuno-osseous dysplasia

Anemia Hypermelanotic macule Proteinuria Transient ischemic attack

Autosomal recessive inheritance

Schimke immuno-osseous dysplasia (SIOD) is a multisystem disorder characterized by spondyloepiphyseal dysplasia and disproportionate short stature, facial dysmorphism, T-cell immunodeficiency, and glomerulonephritis with nephrotic syndrome.

214
(57.4%)

Diamond-Blackfan anemia 1

Coarctation of aorta Congenital hypoplastic anemia Elevated red cell adenosine deaminase level Pallor Reticulocytopenia

Autosomal dominant inheritance

Any Diamond-Blackfan anemia in which the cause of the disease is a mutation in the RPS19 gene.

216
(57.3%)

mitochondrial DNA depletion syndrome 15 (hepatocerebral type);

Abnormality of the coagulation cascade Ascites Hypoglycemia Jaundice

Autosomal recessive inheritance

Any mitochondrial DNA depletion syndrome in which the cause of the disease is a mutation in the TFAM gene.

217
(57.2%)

blue rubber bleb nevus

Abnormality of the liver Abnormality of the mouth Iron deficiency anemia

Autosomal dominant inheritance

Blue rubber bleb nevus (BRBNS) is a rare vascular malformation disorder with cutaneous and visceral lesions frequently associated with serious, potentially fatal bleeding and anemia.

217
(57.2%)

nephronophthisis 11

Anemia Hepatic fibrosis Nephronophthisis

Autosomal recessive inheritance

A nephronophthisis that has material basis in homozygous or compound heterozygous mutation in the TMEM67 gene on chromosome 8q22.1.

219
(56.9%)

pericardial effusion, chronic

Flushing Polycythemia Retinal arteriolar tortuosity

Autosomal recessive inheritance

Chronic form of pericardial effusion (disease).

220
(56.9%)

Camurati-Engelmann disease

Anemia Mandibular prognathia Poor appetite Reduced subcutaneous adipose tissue

Autosomal dominant inheritance

Camurati-Englemann disease (CED) is a rare, clinically variable bone dysplasia syndrome characterized by hyperostosis of the long bones, skull, spine and pelvis, associated with severe pain in the extremities, a wide-based waddling gait, joint contractures, muscle weakness and easy fatigability.

221
(56.7%)

isolated neonatal sclerosing cholangitis

Jaundice Splenomegaly

Autosomal recessive inheritance

Isolated neonatal sclerosing cholangitis is a rare, genetic, biliary tract disease characterized by severe neonatal-onset cholangiopathy with patent bile ducts and absence of ichthyosiform skin lesions. Patients present with jaundice, acholic stools, hepatosplenomegaly and high serum gamma-glutamyltransferase activity. Liver histology shows portal fibrosis, ductular proliferation, hepatocellular metallothionein deposits, and intralobular bile-pigment accumulations. Some patients may also have renal disease.

221
(56.7%)

progressive familial intrahepatic cholestasis type 3

Jaundice Splenomegaly

Autosomal recessive inheritance Heterogeneous

Progressive familial intrahepatic cholestasis type 3 (PFIC3), a type of progressive familial intrahepatic cholestasis (PFIC), is a late-onset hereditary disorder in bile formation that is hepatocellular in origin. Onset may occur from infancy to young adulthood.

223
(56.6%)

methylmalonic acidemia with homocystinuria, type cblJ

Anemia Coarctation of aorta Inguinal hernia Methylmalonic acidemia

Autosomal recessive inheritance

224
(56.6%)

Diamond-Blackfan anemia 7

Esophagitis Low levels of vitamin D Macrocytic anemia Tetralogy of Fallot

Autosomal dominant inheritance

Any Diamond-Blackfan anemia in which the cause of the disease is a mutation in the RPL11 gene.

225
(56.5%)

Fanconi anemia complementation group L

Anal atresia Anemia Cafe-au-lait spot Chromosome breakage

Autosomal recessive inheritance

Any Fanconi anemia in which the cause of the disease is a mutation in the FANCL gene.

225
(56.5%)

Cronkhite-Canada syndrome

Anemia Hyperpigmentation of the skin Hypokalemia Vomiting

Sporadic

Cronkhite-Canada syndrome (CCS) is a rare gastrointestinal (GI) polyposis syndrome characterized by the association of non-hereditary GI polyposis with the cutaneous triad of alopecia, nail changes and hyperpigmentation.

225
(56.5%)

Nijmegen breakage syndrome

Autoimmune hemolytic anemia Cafe-au-lait spot Diarrhea Dysgammaglobulinemia

Autosomal recessive inheritance

Nijmegen breakage syndrome is a rare genetic disease presenting at birth with microcephaly, dysmorphic facial features, becoming more noticeable with age, growth delay, and later-onset complications such as malignancies and infections.

225
(56.5%)

short stature, microcephaly, and endocrine dysfunction

Acanthosis nigricans Anemia Diabetes mellitus Inguinal hernia

Autosomal recessive inheritance

229
(56.4%)

methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

Hepatomegaly Methylmalonic acidemia Thrombocytopenia

Autosomal recessive inheritance

Vitamin B12-unresponsive methylmalonic acidemia is an inborn error of vitamin B12 (cobalamin) metabolism characterized by recurrent ketoacidotic crises or transient vomiting, dehydration, hypotonia and intellectual deficit, which does not respond to administration of vitamin B12. There are two types of vitamin B12-unresponsive methylmalonic acidemia: mut0 and mut-.

230
(56.4%)

von Hippel-Lindau disease

Abnormality of the liver Polycythemia Tinnitus

Autosomal dominant inheritance

Von Hippel-Lindau disease (VHL) is a familial cancer predisposition syndrome associated with a variety of malignant and benign neoplasms, most frequently retinal, cerebellar, and spinal hemangioblastoma, renal cell carcinoma (RCC), and pheochromocytoma.

231
(56.3%)

optic nerve edema-splenomegaly syndrome

Pancytopenia Splenomegaly Urticaria Visual loss

Autosomal dominant inheritance

Optic nerve edema-splenomegaly syndrome is a rare presumably genetic disorder characterized by idiopathic massive splenomegaly with pancytopenia and childhood-onset chronic optic nerve edema with slowly progressive vision loss. Additional reported features include anhidrosis, urticaria and headaches.

231
(56.3%)

gray platelet syndrome

Bruising susceptibility Menorrhagia Splenomegaly

Autosomal recessive inheritance

Gray platelet syndrome (GPS) is a rare inherited bleeding disorder characterized by macrothrombocytopenia, myelofibrosis, splenomegaly and typical gray appearance of platelets on Wright stained peripheral blood smear.

233
(56.0%)

TFRC-related combined immunodeficiency

Anemia Chronic oral candidiasis Conjunctivitis Decreased circulating antibody level

Autosomal recessive inheritance

233
(56.0%)

thiamine-responsive megaloblastic anemia syndrome

Abnormality of the skin Diabetes mellitus Sideroblastic anemia Stroke

Autosomal recessive inheritance

Thiamine-responsive megaloblastic anemia (TRMA) is characterized by a triad of megaloblastic anemia, non-type I diabetes mellitus, and sensorineural deafness.

233
(56.0%)

Wiskott-Aldrich syndrome, autosomal dominant form

Decreased specific anti-polysaccharide antibody level Eczema Hemolytic anemia Large vessel vasculitis

Autosomal dominant inheritance Autosomal recessive inheritance

236
(56.0%)

congenital intrinsic factor deficiency

Malabsorption Malabsorption of Vitamin B12 Megaloblastic anemia

Autosomal recessive inheritance

Congenital intrinsic factor deficiency (IFD) is a rare disorder of vitamin B12 (cobalamin) absorption that is characterized by megaloblastic anemia and neurological abnormalities.

236
(56.0%)

methylcobalamin deficiency type cblG

Decreased methylcobalamin Feeding difficulties in infancy Megaloblastic anemia

Autosomal recessive inheritance

Methylcobalamin deficiency cbl G type is a rare condition that occurs when the body is unable to process certain amino acids (building blocks of protein) properly. In most cases, signs and symptoms develop during the first year of life; however, the age of onset can range from infancy to adulthood. Common features of the condition include feeding difficulties, lethargy, seizures, poor muscle tone (hypotonia), developmental delay, microcephaly (unusually small head size), and megaloblastic anemia. Methylcobalamin deficiency cbl G type is caused by changes (mutations) in the MTR gene and is inherited in an autosomal recessive manner. Treatment generally includes regular doses of hydroxycobalamin (vitamin B12). Some affected people may also require supplementation with folates and betaine.

236
(56.0%)

methylmalonic aciduria and homocystinuria type cblC

Feeding difficulties in infancy Megaloblastic anemia Methylmalonic acidemia

Autosomal recessive inheritance

A form of methylmalonic acidemia with homocystinuria, an inborn error of vitamin B12 (cobalamin) metabolism characterized by megaloblastic anemia, lethargy, failure to thrive, developmental delay, intellectual deficit and seizures. cblC type methylmalonic acidemia with homocystinuria is caused by mutations in the MMACHC gene (1p36.3) and is transmitted in an autosomal recessive manner.

239
(56.0%)

MPI-CDG

Abnormal bleeding Cirrhosis Hepatomegaly Type I transferrin isoform profile

Autosomal recessive inheritance

MPI-CDG is a form of congenital disorders of N-linked glycosylation, characterized by cyclic vomiting, profound hypoglycemia, failure to thrive, liver fibrosis, gastrointestinal complications (protein-losing enteropathy with hypoalbuminaemia, life-threatening intestinal bleeding of diffuse origin), and thrombotic events (protein C and S deficiency, low anti-thrombine III levels), whereas neurological development and cognitive capacity is usually normal. The clinical course is variable even within families. The disease is caused by loss of function of the gene MPI (15q24.1).

239
(56.0%)

RFT1-CDG

Abnormal isoelectric focusing of serum transferrin Abnormality of the coagulation cascade Hepatomegaly

Autosomal recessive inheritance

RFT1-CDG is a form of congenital disorders of N-linked glycosylation characterized by poorly coordinated suck resulting in difficulty feeding and failure to thrive; myoclonic jerks with hypotonia and brisk reflexes progressing to a seizure disorder; roving eyes; developmental delay; poor to absent visual contact; and sensorineural hearing loss. Additional features that may be observed include coagulation factor abnormalities, inverted nipples and microcephaly. The disease is caused by mutations in the gene RFT1 (3p21.1).

241
(55.9%)

persistent polyclonal B-cell lymphocytosis

Decreased circulating total IgM Hepatomegaly Lymphocytosis Splenomegaly

Autosomal dominant inheritance

Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare, generally benign, lymphoproliferative hematological disease characterized by: chronic, stable, persistent, polyclonal lymphocytosis of memory B-cell origin, the presence of binucleated lymphocytes in the peripheral blood, and a polyclonal increase in serum immunoglobulin M (IgM). Patients are most frequently asymptomatic or may present with mild splenomegaly.

241
(55.9%)

Farber lipogranulomatosis

Hepatomegaly Joint swelling Lipogranulomatosis Splenomegaly

Autosomal recessive inheritance

Farber disease is a rare sphingolipid disorder characterized by a spectrum of clinical signs ranging from the classical triad of painful and progressively deformed joints, subcutaneous nodules, and progressive hoarseness (due to laryngeal involvement) that presents in infancy, to varying phenotypes with respiratory and neurologic involvement.

241
(55.9%)

Niemann-Pick disease type B

Hepatomegaly Hypertriglyceridemia Sea-blue histiocytosis Splenomegaly

Autosomal recessive inheritance

Niemann-Pick disease type B is a mild subtype of Niemann-Pick disease, an autosomal recessive lysosomal disease, and is characterized clinically by onset in childhood with hepatosplenomegaly, growth retardation, and lung disorders such as infections and dyspnea

241
(55.9%)

macrocephaly-autism syndrome

Decreased circulating antibody level Hepatomegaly Lymphopenia Splenomegaly

Autosomal dominant inheritance

An autosomal dominant disease characterized by macrocephaly, facial phenotypes including square outline with frontal bossing, 'dished-out' midface, biparietal narrowing, and long philtrum, developmental delay and autism that has material basis in heterozygous mutation in the PTEN gene on chromosome 10q23.

241
(55.9%)

lymphoproliferative syndrome 2

Aplastic anemia Fever Hepatomegaly Splenomegaly

Autosomal recessive inheritance

Any lymphoproliferative syndrome in which the cause of the disease is a mutation in the CD27 gene.

241
(55.9%)

lysosomal acid lipase deficiency

Cirrhosis Hypertriglyceridemia Splenomegaly Vacuolated lymphocytes

Autosomal recessive inheritance

Lysosomal acid lipase deficiency is a lipid storage disease that can result in 1) an early-onset severe form, Wolman disease, or 2) a less severe form, cholesteryl ester storage disease, of cholesteryl ester accumulation in the body (liver, spleen, macrophages). Wolman disease is characterized by neonatal abdominal distension, major or even massive hepatosplenomegaly and calcified adrenal glands, cholesteryl ester storage disease presents with microvesicular steatosis leading to hepatomegaly and hypercholesterolaemia with subsequent liver failure and accelerated atherosclerosis.

241
(55.9%)

immunodeficiency, common variable, 1

Decreased circulating IgA level Hepatomegaly Neutropenia in presence of anti-neutropil antibodies Splenomegaly

Autosomal recessive inheritance

241
(55.9%)

X-linked lymphoproliferative disease due to XIAP deficiency

Aplastic anemia Fever Hepatomegaly Splenomegaly

X-linked inheritance X-linked recessive inheritance

A condition of decreased or absent presence of baculoviral IAP repeat-containing protein 4. Deficiency of this protein is associated with X-linked lymphoproliferative syndrome 2.

241
(55.9%)

Gaucher disease type III

Decreased beta-glucocerebrosidase level Hepatomegaly Splenomegaly Thrombocytopenia

Autosomal recessive inheritance

Gaucher disease type 3 is the subacute neurological form of Gaucher disease (GD) characterized by progressive encephalopathy and associated with the systemic manifestations (organomegaly, bone involvement, cytopenia) of GD type 1.

241
(55.9%)

immunodeficiency, common variable, 2

Decreased circulating IgA level Hepatomegaly Lymphoma Splenomegaly

Autosomal dominant inheritance Autosomal recessive inheritance

241
(55.9%)

granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1

Decreased activity of NADPH oxidase Granulomatosis Hepatomegaly Splenomegaly

Autosomal recessive inheritance

Any chronic granulomatous disease in which the cause of the disease is a mutation in the NCF1 gene.

241
(55.9%)

granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2

Decreased activity of NADPH oxidase Granulomatosis Hepatomegaly Splenomegaly

Autosomal recessive inheritance

Any chronic granulomatous disease in which the cause of the disease is a mutation in the NCF2 gene.

241
(55.9%)

granulomatous disease, chronic, X-linked

Decreased activity of NADPH oxidase Granulomatosis Hepatomegaly Splenomegaly

X-linked recessive inheritance

241
(55.9%)

granulomatous disease, chronic, autosomal recessive, cytochrome b-negative

Decreased activity of NADPH oxidase Granulomatosis Hepatomegaly Splenomegaly

Autosomal recessive inheritance

241
(55.9%)

Aicardi-Goutieres syndrome 7

Hepatomegaly Increased circulating antibody level Splenomegaly Thrombocytopenia

Autosomal dominant inheritance

Any Aicardi-Goutieres syndrome in which the cause of the disease is a mutation in the IFIH1 gene.

241
(55.9%)

tyrosinemia type I

Abnormal bleeding Cirrhosis Hypoglycemia Splenomegaly

Autosomal recessive inheritance

Tyrosinemia type 1 (HTI) is an inborn error of tyrosine catabolism caused by defective activity of fumarylacetoacetate hydrolase (FAH) and is characterized by progressive liver disease, renal tubular dysfunction, porphyria-like crises and a dramatic improvement in prognosis following treatment with nitisinone.

241
(55.9%)

sialidosis type 2

Hepatomegaly Proteinuria Splenomegaly Vacuolated lymphocytes

Autosomal recessive inheritance

Sialidosis type 2 (ST-2) is a rare lysosomal storage disease, and the severe, early onset form of sialidosis characterized by a progressively severe mucopolysaccharidosis-like phenotype (coarse facies, dysostosis multiplex, hepatosplenomegaly), macular cherry-red spots as well as psychomotor and developmental delay. ST-2 displays a broad spectrum of clinical severity with antenatal/congenital, infantile and juvenile presentations.

241
(55.9%)

free sialic acid storage disease, infantile form

Hepatomegaly Hydrops fetalis Splenomegaly Vacuolated lymphocytes

Autosomal recessive inheritance

241
(55.9%)

autosomal recessive familial Mediterranean fever

Hepatomegaly Leukocytosis Renal amyloidosis Splenomegaly

Autosomal recessive inheritance

Autosomal recessive form of familial Mediterranean fever.

241
(55.9%)

sarcoidosis, susceptibility to, 1

Fever Hepatomegaly Pancytopenia Splenomegaly

Autosomal dominant inheritance Sporadic

Any sarcoidosis in which the cause of the disease is a mutation in the HLA-DRB1 gene.

241
(55.9%)

H syndrome

Diabetes mellitus Hepatomegaly Histiocytosis Splenomegaly

Autosomal recessive inheritance

H syndrome is a systemic inherited histiocytosis, with characteristic cutaneous findings accompanying systemic manifestations. H syndrome refers to the major clinical findings of hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, low height, and occasionally, hyperglycemia/diabetes mellitus. Due to overlapping clinical features, H syndrome is now considered to include pigmented hypertrichosis with insulin dependent diabetes mellitus syndrome (PHID), Faisalabad histiocytosis (FHC) and familial sinus histiocytosis with massive lymphadenopathy (FSHML).

241
(55.9%)

alpha-mannosidosis

Decreased circulating antibody level Hepatomegaly Splenomegaly Vacuolated lymphocytes

Autosomal recessive inheritance

Alpha-mannosidosis is an inherited lysosomal storage disorder characterized by immune deficiency, facial and skeletal abnormalities, hearing impairment, and intellectual deficit.

263
(55.9%)

benign recurrent intrahepatic cholestasis type 2

Conjugated hyperbilirubinemia Hepatomegaly Jaundice

Autosomal recessive inheritance

263
(55.9%)

benign recurrent intrahepatic cholestasis type 1

Conjugated hyperbilirubinemia Hearing impairment Hepatomegaly Intermittent jaundice

Autosomal recessive inheritance

Benign recurrent intrahepatic cholestasis 1 (BRIC1) is characterized by episodes of liver dysfunction called cholestasis, during which the liver cells have a reduced ability to release a digestive fluid called bile. These episodes can last from weeks to months, and the time between them, during which there are usually no symptoms, can vary from weeks to years.Most people with BRIC1have their first episode of cholestasisintheir teens or twenties. Symptoms oftenpresent with severe itchiness, followed by yellowing of the skin and whites of the eyes (jaundice) a few weeks later. BRIC1 is caused by mutations in the ATP8B1 gene. This condition is inherited in an autosomal recessive pattern.BRIC1generally does not cause lasting damage to the liver. However, in rare cases, episodes of liver dysfunction may develop into a more severe, permanent form of liver disease known as progressive familial intrahepatic cholestasis (PFIC). BRIC and PFIC are sometimes considered to be part of a spectrum of intrahepatic cholestasis disorders of varying severity.

263
(55.9%)

extrahepatic biliary atresia

Hepatomegaly Increased total bilirubin Jaundice

A disorder of infants in which there is progressive obliteration or discontinuity of the extrahepatic biliary system, resulting in obstruction of bile flow.

263
(55.9%)

multiple acyl-CoA dehydrogenase deficiency

Abnormality of the genital system Hepatomegaly Hypoglycemia Jaundice

Autosomal recessive inheritance

A disorder of fatty acid and amino acid oxidation, caused by mutations in ETFDH, ETFA, or ETFB, and is a clinically heterogeneous disorder ranging from a severe neonatal presentation with metabolic acidosis, cardiomyopathy and liver disease, to a mild childhood/adult disease with episodic metabolic decompensation, muscle weakness, and respiratory failure.

263
(55.9%)

Navajo neurohepatopathy

Hepatomegaly Hypoglycemia Prolonged neonatal jaundice Recurrent corneal erosions

Autosomal recessive inheritance

263
(55.9%)

peroxisome biogenesis disorder 2A (Zellweger)

Aminoaciduria Cryptorchidism Hepatomegaly Jaundice

Autosomal recessive inheritance

263
(55.9%)

peroxisome biogenesis disorder 1A (Zellweger)

Aminoaciduria Cryptorchidism Hepatomegaly Prolonged neonatal jaundice

Autosomal recessive inheritance Heterogeneous

270
(55.8%)

poikiloderma with neutropenia

Elevated serum creatine kinase Neutropenia Poikiloderma Splenomegaly

Autosomal recessive inheritance

A skin disease characterized by poikiloderma, hyperkeratotic nails, generalized hyperkeratosis on palms and soles, neutropenia, short stature, and recurrent pulmonary infections. It has material basis in mutation in the C16ORF57 gene on chromosome 16q13.

270
(55.8%)

hyperimmunoglobulinemia D with periodic fever

Hypermelanotic macule Increased circulating IgA level Leukocytosis Splenomegaly

Autosomal recessive inheritance

Hyperimmunoglobinemia D with periodic fever (HIDS) is a rare autoinflammatory disease characterized by periodic attacks of fever and a systemic inflammatory reaction (cervical lymphadenopathy, abdominal pain, vomiting, diarrhea, arthralgias and skin signs).

272
(55.6%)

pseudo-TORCH syndrome 2

Hepatomegaly Lactic acidosis Petechiae

Autosomal recessive inheritance

272
(55.6%)

aspartylglucosaminuria

Abnormality of metabolism/homeostasis Angiokeratoma corporis diffusum Hepatomegaly Neutropenia

Autosomal recessive inheritance

Aspartylglycosaminuria (AGU) is an autosomal recessive lysosomal storage disease belonging to the oligosaccharidosis group (also called glycoproteinosis).

274
(55.6%)

systemic lupus erythematosus (disease)

Cutaneous photosensitivity Hemolytic anemia Nephritis

Autosomal dominant inheritance

An autoimmune multi-organ disease typically associated with vasculopathy and autoantibody production. Most patients have antinuclear antibodies (ANA). The presence of anti-dsDNA or anti-Smith antibodies are highly-specific.

275
(55.3%)

Kabuki syndrome 1

Cafe-au-lait spot Coarctation of aorta Cryptorchidism Hemolytic anemia

Autosomal dominant inheritance

276
(55.2%)

methemoglobinemia type 4

Abnormality of metabolism/homeostasis Cyanosis Male pseudohermaphroditism Methemoglobinemia

Autosomal recessive inheritance

Any methemoglobinemia in which the cause of the disease is a mutation in the CYB5A gene.

277
(55.2%)

nephronophthisis 19

Cholestasis Nephronophthisis Splenomegaly

Autosomal recessive inheritance

Any nephronophthisis in which the cause of the disease is a mutation in the DCDC2 gene.

278
(55.2%)

Fanconi anemia complementation group G

Abnormality of chromosome stability Anemia Multiple cafe-au-lait spots Neutropenia

Fanconi anemia caused by mutations of the FANCG gene.

278
(55.2%)

bone marrow failure syndrome 4

Anemia Decreased circulating antibody level Dry skin Eczema

Autosomal recessive inheritance

278
(55.2%)

stiff-person syndrome

Anemia Autoimmunity Diabetes mellitus Vitiligo

Sporadic

Stiff-man syndrome (SMS) is a rare neurological disorder comprising fluctuating trunk and limb stiffness, painful muscle spasms, task-specific phobia, an exaggerated startle response, and ankylosing deformities such as fixed lumbar hyperlordosis.

281
(55.1%)

hereditary pediatric Behçet-like disease

Colitis Hemolytic anemia Recurrent fever Skin rash

Autosomal dominant inheritance

281
(55.1%)

autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome

Autoimmune hemolytic anemia Diabetes mellitus Diarrhea Eczema

Autosomal dominant inheritance

Autoimmune enteropathy and endocrinopathy-susceptibility to chronic infections syndrome is an extremely rare, autosomal dominant immunological disorder characterized by variable enteropathy, endocrine disorders (e.g. type 1 diabetes mellitus, hypothyroidism), immune dysregulation with pulmonary and blood-borne bacterial infections, and fungal infections (chronic mucocutaneous candidiasis) developing in infancy. Other manifestations include short stature, eczema, hepatosplenomegaly, delayed puberty, and osteoporosis/osteopenia.

281
(55.1%)

STAT3-related early-onset multisystem autoimmune disease

Autoimmune hemolytic anemia Celiac disease Diabetes mellitus Eczema

Autosomal dominant inheritance

284
(55.1%)

DPAGT1-CDG

Jaundice Reduced antithrombin III activity Type I transferrin isoform profile

Autosomal recessive inheritance

DPAGT1-CDG is a form of congenital disorders of N-linked glycosylation characterized by hypotonia, intractable seizures, developmental delay, microcephaly and severe fetal hypokinesia. Additional features that may be observed include apnea and respiratory deficiency, cataracts, joint contractures, vermian hypoplasia, dysmorphic features (esotropia, arched palate, micrognathia, finger clinodactyly, single flexion creases) and feeding difficulties. The disease is caused by loss-of-function mutations in the gene DPAGT1 (11q23.3).

285
(54.8%)

encephalomyopathy, mitochondrial, due to voltage-dependent anion channel deficiency

Anemia Ketonuria Small nail Umbilical hernia

Sporadic

286
(54.7%)

phosphoenolpyruvate carboxykinase deficiency, cytosolic

Cyanosis Hepatomegaly Hypoglycemia Optic atrophy

Autosomal recessive inheritance

PEPCK1 deficiency is a rare inborn error of metabolism disorder, characterized by the deficiency of the enzyme PEPCK1, one of the enzymes needed for gluconeogenesis, the process by which organisms produce sugars (namely glucose) from non-carbohydrate precursors (such as amino acids). The symptoms described in the few cases reported in the medical literature suggest that there may be variation in the severity of the symptoms ranging from severe early-onset cases, to milder late-onset presentations. In severe cases symptoms may include persistent and very low levels of blood's sugar in newborns (neonatal hypoglycemia), failure to thrive, build-up of lactic acid in the blood (lactic acidosis), liver enlargement (hepatomegaly) and liver failure leading to neurological degeneration. Milder cases present during childhood with fewer and less serious liver problems. Infections and fasting may trigger the symptoms. PEPCK1 deficiency inheritance is autosomal recessive. It is caused by mutations in the PEPCK1 gene. Some researchers believe that the severity of the disease depend upon the mutations resulting in less or more PEPCK1 activity (the more active the enzyme is, the less severe the disease is, and vice versa). Treatment depend on the symptoms and may include giving extra carbohydrates during heavy exercise and illness or other times of fasting (formal sick day regimen) by the dietitian.PEPCK1 is the cytosolic form of the phosphoenolpyruvate carboxykinase (PEPCK) enzyme, the other being the mitochondrial (PEPCK2).

287
(54.6%)

BENTA disease

Decreased circulating total IgM Lymphocytosis Splenomegaly

Autosomal dominant inheritance

BENTA disease (B cell Expansion with N F-N:B and T cell Anergy) is a very rare congenital immune deficiency disorder. The main symptoms include spleen enlargement (splenomegalia) and frequent ear, sinus, and lung infections early in life. Some patients can present with molluscum contagiosum or chronic Epstein-Barr virus (EBV) infection. Blood exams show alterations of several immune cells with very high numbers of polyclonal B cell lymphocytos (above 2200/N

287
(54.6%)

splenomegaly syndrome with splenic Germinal center hypoplasia and reduced circulating T helper cells

Cutaneous anergy Pancytopenia Splenomegaly

Autosomal dominant inheritance

287
(54.6%)

immunodeficiency 14

Increased circulating IgM level Splenomegaly T lymphocytopenia

Autosomal dominant inheritance

287
(54.6%)

immunodeficiency 36

Decreased circulating antibody level Lymphopenia Splenomegaly

Autosomal dominant inheritance

287
(54.6%)

periodic fever-infantile enterocolitis-autoinflammatory syndrome

Fever Pancytopenia Splenomegaly

Autosomal dominant inheritance

287
(54.6%)

lymphedema, hereditary, type III

Deep venous thrombosis Facial edema Splenomegaly

Autosomal recessive inheritance

293
(54.6%)

glycogen storage disease IXc

Bile duct proliferation Hypotonia Ketosis Splenomegaly

Autosomal recessive inheritance

A liver PhK deficiency caused by variants in the PHKG2 gene

293
(54.6%)

trichohepatoneurodevelopmental syndrome

Cholelithiasis Elevated alkaline phosphatase Macroglossia Splenomegaly

Autosomal recessive inheritance

293
(54.6%)

Meckel syndrome, type 1

Bile duct proliferation Cryptorchidism Elevated amniotic fluid alpha-fetoprotein Splenomegaly

Autosomal recessive inheritance

Any Meckel syndrome in which the cause of the disease is a mutation in the MKS1 gene.

296
(54.4%)

hepatoencephalopathy due to combined oxidative phosphorylation defect type 1

Cholestasis Hepatomegaly Metabolic acidosis Microcephaly

Autosomal recessive inheritance

Hepatoencephalopathy due to combined oxidative phosphorylation deficiency type 1 is a rare, inherited mitochondrial disorder due to a defect in mitochondrial protein synthesis characterized by intrauterine growth retardation, metabolic decompensation with recurrent vomiting, persistent severe lactic acidosis, encephalopathy, seizures, failure to thrive, severe global developmental delay, poor eye contact, severe muscular hypotonia or axial hypotonia with limb hypertonia, hepatomegaly and/or liver dysfunction and/or liver failure, leading to fatal outcome in severe cases. Neuroimaging abnormalities may include corpus callosum thinning, leukodystrophy, delayed myelination and basal ganglia involvement.

296
(54.4%)

leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

Cholestasis Cleft palate Hepatomegaly Increased serum lactate

Autosomal recessive inheritance

Leukoencephalopathy-thalamus and brainstem anomalies-high lactate (LTBL) syndrome is a rare, genetic neurological disorder defined by early-onset of neurologic symptoms, biphasic clinical course, unique MRI features (incl. extensive, symmetrical, deep white matter abnormalities), and increased lactate in body fluids. The severe form is characterized by delayed psychomotor development, seizures, early-onset hypotonia, and persistently increased lactate levels. The mild form usually presents with irritability, psychomotor regression after six months of age, and temporary high lactate levels, with overall clinical improvement from the second year onward.

298
(54.4%)

congenital nongoitrous hypothryoidism 6

Anemia Dry skin Macroglossia Omphalocele

Autosomal dominant inheritance

Any hypothyroidism, congenital, nongoitrous in which the cause of the disease is a mutation in the THRA gene.

298
(54.4%)

myelodysplasia, immunodeficiency, facial dysmorphism, short stature, and psychomotor delay

Anemia Steatorrhea Thin skin Vesicoureteral reflux

Autosomal recessive inheritance

298
(54.4%)

craniofacial dysplasia - osteopenia syndrome

Hypochromic anemia Inguinal hernia Preauricular skin tag

Autosomal recessive inheritance