181
(59.4%)

progressive familial intrahepatic cholestasis type 1

Conjugated hyperbilirubinemia Jaundice Splenomegaly

Autosomal recessive inheritance

PFIC1, a type of progressive familial intrahepathic cholestasis (PFIC), is an infantile hereditary disorder in bile formation that is hepatocellular in origin and associated with extrahepatic features.

181
(59.4%)

Aagenaes syndrome

Jaundice Lymphedema Splenomegaly

Autosomal recessive inheritance

Cholestasis-lymphedema syndrome is a rare genetic disorder characterized by neonatal intrahepatic cholestasis, often lessening and becoming intermittent with age, and severe chronic lymphedema which mainly affects the lower limbs. Patients often present with fat malabsorption leading to failure to thrive, fat soluble vitamin deficiency with bleeding, rickets, and neuropathy. In 25% of cases, cirrhosis occurs during childhood or later in life.

181
(59.4%)

familial lipoprotein lipase deficiency

Hyperlipidemia Jaundice Lipemia retinalis Splenomegaly

Autosomal recessive inheritance

Familial lipoprotein lipase deficiency is a rare genetic disorder is which a person lacks the enzyme lipoprotein lipase, a protein needed to break down fat molecules. Deficiency of this enzyme prevents affected individuals from properly digesting certain fats. This results in the accumulation of fatty droplets called chylomicrons in the blood and an increase in the blood concentration of triglycerides. Symptoms include episodes of abdominal pain, recurrent inflammation of the pancreas (pancreatitis), abnormal enlargement of the liver and/or spleen (hepatosplenomegaly), and the development of skin lesions known as erruptive xanthomas. Familial lipoprotein lipase deficiency is caused by changes (mutations) in the LPL gene. It is inherited in an autosomal recessive pattern. Treatment aims to control symptoms and blood triglyceride levels with a very low-fat diet. Treatment for individual symptoms (i.e. pancreatitis) involves following established treatment guidelines.

181
(59.4%)

galactose epimerase deficiency

Aminoaciduria Jaundice Sensorineural hearing impairment Splenomegaly

Autosomal recessive inheritance

Galactose epimerase deficiency is a very rare, moderate to severe form of galactosemia characterized by moderate to severe signs of impaired galactose metabolism.

181
(59.4%)

progressive familial intrahepatic cholestasis type 2

Conjugated hyperbilirubinemia Intermittent jaundice Pruritus Splenomegaly

Autosomal recessive inheritance

Progressive familial intrahepatic cholestasis type 2 (PFIC2), a type of progressive familial intrahepatic cholestasis (PFIC), is a severe, neonatal, hereditary disorder in bile formation that is hepatocellular in origin and not associated with extrahepatic features. Initially, PFIC2 was reported under the name Byler syndrome.

181
(59.4%)

cholestasis-pigmentary retinopathy-cleft palate syndrome

Hyperbilirubinemia Jaundice Recurrent urinary tract infections Splenomegaly

Sporadic

Cholestasis- pigmentary retinopathy- cleft palate is a syndrome of multiple congenital malformations, characterized by an association of cleft lip and palate, patchy pigmentary retinopathy (cat's paw), obstructive liver disease (cholestasis, portal hypertension etc.) and obstructive renal disease (ectopic ureteric insertion, obstruction, vesicouretral reflux and hydronephrosis). Gastrointestinal tract involvement (malrotation, gastresophageal reflux etc.) and cardiac involvement (coarctation of aorta, pulmonary artery stenosis etc) have also been reported. An overlap with Kabuki syndrome is debated.

181
(59.4%)

peroxisome biogenesis disorder 5A (Zellweger)

Cryptorchidism Jaundice Palpebral edema Splenomegaly

Autosomal recessive inheritance

181
(59.4%)

COG7-CDG

Hypoglycemia Jaundice Neurogenic bladder Splenomegaly

Autosomal recessive inheritance

COG7-CDG is a congenital disorder of glycosylation characterised by dysmorphism, skeletal dysplasia, hypotonia, hepatosplenomegaly, jaundice, cardiac insufficiency, recurrent infections and epilepsy. To date, it has been described in two infants, both of whom died within the first three months of life. The syndrome is caused by a mutation in the gene encoding COG-7 (chromosome 16), a subunit of the oligomeric Golgi complex.

189
(59.4%)

microcytic anemia with liver iron overload

Abnormality of metabolism/homeostasis Abnormality of the liver Decreased mean corpuscular volume Hypochromia

Autosomal recessive inheritance

Congenital hypochromic microcytic anemia with progressive liver iron overload paradoxically associated with normal to moderately elevated serum ferritin levels has been described in three unrelated patients.

189
(59.4%)

atransferrinemia

Abnormality of the liver Atransferrinemia Hypochromic anemia

Autosomal recessive inheritance

Congenital atransferrinemia is a very rare hematologic disease caused by a transferrin (TF) deficiency and characterized by microcytic, hypochromic anemia (manifesting with pallor, fatigue and growth retardation) and iron overload, and that can be fatal if left untreated.

189
(59.4%)

3-methylglutaconic aciduria type 5

Glutaric aciduria Microvesicular hepatic steatosis Normochromic microcytic anemia

Autosomal recessive inheritance

Dilated cardiomyopathy with ataxia (DCMA) is characterized by severe early onset (before the age of three years) dilated cardiomyopathy (DCM) with conduction defects (long QT syndrome), non-progressive cerebellar ataxia, testicular dysgenesis, and 3-methylglutaconic aciduria.

192
(58.9%)

autoimmune pulmonary alveolar proteinosis

Cyanosis Pneumonia Polycythemia

Sporadic

Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by the accumulation of a lipoproteinaceous substance in the distal air spaces which positively stains with periodic acid-Schiff (PAS).

193
(58.8%)

retinitis pigmentosa and erythrocytic microcytosis

Anemia Decreased serum iron Elliptocytosis Optic disc pallor Pallor

Autosomal recessive inheritance

194
(58.6%)

neonatal ichthyosis-sclerosing cholangitis syndrome

Abnormality of blood and blood-forming tissues Hepatomegaly Jaundice Sparse eyelashes

Autosomal recessive inheritance

Neonatal ichthyosis-sclerosing cholangitis (NISCH syndrome) is a very rare complex ichthyosis syndrome characterized by scalp hypotrichosis, scarring alopecia, ichthyosis and sclerosing cholangitis.

195
(58.5%)

Seckel syndrome 10

Diabetes mellitus Elevated hemoglobin A1c Hepatic steatosis

Autosomal recessive inheritance

Any Seckel syndrome in which the cause of the disease is a mutation in the NSMCE2 gene.

196
(58.4%)

primary myelofibrosis

Fever Purpura Splenomegaly

Somatic mutation

Myelofibrosis with myeloid metaplasia is a myeloproliferative disease with annual incidence of approximately 1 case per 100,000 individuals and age at diagnosis around 60 (an increased prevalence is noted in Ashkenazi Jews). Clinical manifestations depend on the type of blood cell affected and may include anemia, pallor, splenomegaly, hypermetabolic state, petechiae, ecchymosis, bleeding, lymphadenopathy, hepatomegaly, portal hypertension.

196
(58.4%)

familial cold autoinflammatory syndrome 2

Lymphocytosis Recurrent fever Splenomegaly Urticaria

Autosomal dominant inheritance

An autoinflammatory disease caused by mutations in the NLRP12 gene. It is characterized by periodic fevers beginning in the first year of life that are triggered by cold exposure. Episodes occur more than once per month.

196
(58.4%)

GM1 gangliosidosis type 1

Angiokeratoma corporis diffusum Decreased beta-galactosidase activity Splenomegaly Vacuolated lymphocytes

Autosomal recessive inheritance

GM1 gangliosidosis type 1 is the severe infantile form of GM1 gangliosidosis with variable neurological and systemic manifestations.

196
(58.4%)

fucosidosis

Angiokeratoma Oligosacchariduria Splenomegaly Vacuolated lymphocytes

Autosomal recessive inheritance

Fucosidosis is an extremely rare lysosomal storage disorder characterized by a highly variable phenotype with common manifestations including neurologic deterioration, coarse facial features, growth retardation, and recurrent sinopulmonary infections, as well as seizures, visceromegaly, angiokeratoma and dysostosis.

200
(58.1%)

Pearson syndrome

Diabetes mellitus Pancreatic fibrosis Refractory sideroblastic anemia

Mitochondrial inheritance

Pearson syndrome is characterized by refractory sideroblastic anemia, vacuolization of bone marrow precursors and exocrine pancreatic dysfunction.

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).