301
(54.2%)

ALG1-CDG

Hepatomegaly Hypogonadism Splenomegaly Type I transferrin isoform profile

Autosomal recessive inheritance

A severe form of congenital disorders of N-linked glycosylation characterized by severe developmental and psychomotor delay, muscular hypotonia, intractable early-onset seizures, and microcephaly. Additional features include altered blood coagulation with a high probability of hemorrhages or thromboses, nephrotic syndrome, ascites, hepatomegaly, cardiomyopathy, ocular manifestations (strabismus, nystagmus), and immunodeficiency. The disease is caused by loss-of-function mutations in the gene ALG1 (16p13.3).

302
(54.0%)

breath-holding Spells

Behavioral abnormality Cyanosis Iron deficiency anemia

Autosomal dominant inheritance

303
(53.9%)

arteriosclerosis, severe juvenile

Abnormality of the skin Anemia Arteriosclerosis Hypertension

Autosomal recessive inheritance

304
(53.8%)

familial benign copper deficiency

Anemia Decreased circulating copper concentration Seborrheic dermatitis

Autosomal dominant inheritance X-linked inheritance

Familial benign copper deficiency is a rare disorder of mineral absorption and transport characterized by hypocupremia that manifests as failure to thrive, mild anemia, repeated seizures, hypotonia, and seborrheic skin. Spurring of the femur and tibia are also noted on radiographic imaging. Symptoms are reversible or improve with supplements of oral copper. There have been no further descriptions in the literature since 1982.

304
(53.8%)

immunodeficiency, common variable, 12

Decreased circulating antibody level Hemolytic anemia Recurrent skin infections

Autosomal dominant inheritance

Any common variable immunodeficiency in which the cause of the disease is a mutation in the NFKB1 gene.

304
(53.8%)

Majeed syndrome

Inflammatory abnormality of the skin Microcytic anemia Osteomyelitis Recurrent fever

Autosomal recessive inheritance

Majeed syndrome is a rare genetic multisystemic disorder characterized by the triad of chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, and variable transient inflammatory dermatosis.

307
(53.8%)

thrombocythemia, X-linked

Hepatomegaly Splenomegaly Thrombocytosis

307
(53.8%)

sea-blue histiocyte syndrome

Abnormality of the eye Cirrhosis Splenomegaly Thrombocytopenia

Autosomal recessive inheritance

A rare, inherited or acquired syndrome characterized by the presence of histiocytes in the bone marrow which contain granules stained blue with hematoxylin-eosin stain, mild thrombocytopenia and purpura, and splenomegaly.

307
(53.8%)

hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency

Portal hypertension Seizure Splenomegaly Venous thrombosis

Autosomal recessive inheritance

The combination of a propensity for venous thrombosis and seizures has been reported in two unrelated kindreds. Transmission is autosomal recessive. It results from a point mutation of PIGM, which reduces transcription of PIGM and blocks mannosylation of glycosylphosphatidylinositol (GPI), leading to partial but severe deficiency of GPI.

307
(53.8%)

acute erythroleukemia, familial

Acute myeloid leukemia Hepatomegaly Splenomegaly

Autosomal dominant inheritance

An instance of acute erythroleukemia that is caused by an inherited modification of the individual's genome.

307
(53.8%)

idiopathic hypereosinophilic syndrome

Abnormality of the nervous system Eosinophilia Hepatomegaly Splenomegaly

Somatic mutation Sporadic

307
(53.8%)

severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, NK cell-positive

Hepatomegaly Oral ulcer Splenomegaly T lymphocytopenia

Autosomal recessive inheritance

A severe combined immunodeficiency characterized by being T cell-negative, B cell-positive and natural killer cell-positive and that has material basis in homozygous or compound heterozygous mutation in the IL7R gene on chromosome 5p13 or the CD45 gene on chromosome 1q31.

307
(53.8%)

primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency

Hepatomegaly Lymphoproliferative disorder Microcephaly Splenomegaly

Autosomal recessive inheritance

The primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency is characterised by a specific natural-killer (NK) cell deficiency and susceptibility to viral diseases. It has been described in four children from a large inbred kindred. Three out of the four children reported developed a viral illness. The mode of transmission is most likely autosomal recessive. The causative gene has been localised to within a 12-Mb region on chromosome 8p11.23-q11.21.

307
(53.8%)

Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome

Hepatomegaly Hydrocephalus Pancytopenia Splenomegaly

Autosomal recessive inheritance

Gaucher disease - ophthalmoplegia - cardiovascular calcification is a variant of Gaucher disease, also known as a Gaucher-like disease that is characterized by cardiac involvement.

307
(53.8%)

Aicardi-Goutieres syndrome 4

Hepatosplenomegaly Hydrocephalus Splenomegaly Thrombocytopenia

Autosomal recessive inheritance

Any Aicardi-Goutieres syndrome in which the cause of the disease is a mutation in the RNASEH2A gene.

307
(53.8%)

Hermansky-Pudlak syndrome 10

Hepatomegaly Microcephaly Neutropenia Splenomegaly

Autosomal recessive inheritance

Any Hermansky-Pudlak syndrome in which the cause of the disease is a mutation in the AP3D1 gene.

307
(53.8%)

Roifman syndrome

Eosinophilia Hepatomegaly Splenomegaly Thin upper lip vermilion

Autosomal recessive inheritance

307
(53.8%)

Hermansky-Pudlak syndrome 2

Hepatomegaly Splenomegaly Thin upper lip vermilion Thrombocytopenia

Autosomal recessive inheritance

Hermansky-Pudlak syndrome type 2 (HPS-2) is a type of Hermansky-Pudlak syndrome (HPS), a multi-system disorder characterized by oculocutaneous albinism, bleeding diathesis and neutropenia.

319
(53.7%)

Adams-Oliver syndrome 5

Aplasia cutis congenita Inguinal hernia Portal vein thrombosis Splenomegaly

Autosomal dominant inheritance

Any Adams-Oliver syndrome in which the cause of the disease is a mutation in the NOTCH1 gene.

319
(53.7%)

Proteus syndrome

Deep venous thrombosis Hyperkeratosis Open mouth Splenomegaly

Somatic mutation Sporadic

Proteus syndrome (PS) is a very rare and complex hamartomatous overgrowth disorder characterized by progressive overgrowth of the skeleton, skin, adipose, and central nervous systems.

321
(53.5%)

congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome

Brittle hair Lactic acidosis Lymphopenia Sideroblastic anemia

Autosomal recessive inheritance

Congenital sideroblastic anemia -B cell immunodeficiency- periodic fever-developmental delay syndrome is a form of constitutional sideroblastic anemia, characterized by severe microcytic anemia, B-cell lymphopenia, panhypogammaglobulinemia and variable neurodegeneration. The disease presents in infancy with recurrent febrile illnesses, gastrointestinal disturbances, developmental delay, seizures, ataxia and sensorineural deafness. Most patients require regular blood transfusion, iron chelation, and intravenous immunoglobulin (IVIG) replacement. Stem cell transplantation has been reported to be successful.

322
(53.5%)

orotic aciduria

Hematuria Impaired T cell function Poikilocytosis Pyrimidine-responsive megaloblastic anemia

Autosomal recessive inheritance

An extremely rare autosomal recessive inherited disorder caused by mutations in the UMPS gene. It is characterized by deficiency of the activity of the pyrimidine pathway enzyme uridine 5'-monophosphate (UMP) synthase. Clinical manifestations include growth retardation, anemia, and increased excretion of orotic acid in the urine.

323
(53.5%)

midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis

Anemia Elliptocytosis Hypercalciuria Patent foramen ovale Renal dysplasia

X-linked recessive inheritance

324
(53.4%)

hydrops fetalis, nonimmune, and/or atrial septal defect, susceptibility to

Abdominal distention Anemia Facial edema Varicose veins

Autosomal dominant inheritance

324
(53.4%)

hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome

Decreased liver function Lactic acidosis Patent ductus arteriosus Sideroblastic anemia

Autosomal recessive inheritance

324
(53.4%)

hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome

Anemia Feeding difficulties Proteinuria Pulmonary arterial hypertension

Autosomal recessive inheritance

324
(53.4%)

Wolfram syndrome 1

Diabetes mellitus Dysphagia Megaloblastic anemia Stroke-like episode

Autosomal recessive inheritance

Any Wolfram syndrome in which the cause of the disease is a mutation in the WFS1 gene.

328
(53.2%)

pancreatitis, sclerosing cholangitis, and sicca complex

Hepatomegaly Jaundice Xerostomia

Autosomal recessive inheritance

328
(53.2%)

peroxisome biogenesis disorder 8A (Zellweger)

Glossoptosis Hepatomegaly Jaundice

Autosomal recessive inheritance

328
(53.2%)

peroxisome biogenesis disorder 7A (Zellweger)

Hepatomegaly High palate Jaundice

Autosomal recessive inheritance

328
(53.2%)

peroxisome biogenesis disorder 13A (Zellweger)

Hepatomegaly Jaundice Large fontanelles

Autosomal recessive inheritance

332
(53.2%)

hereditary neutrophilia

Elevated leukocyte alkaline phosphatase Hepatosplenomegaly Myelodysplasia

Autosomal dominant inheritance

A leukocyte disease characterized by autosomal dominant inheritance of lifelong, persistent elevated neutrophil counts primarily consisting of segmented neutrophils that has material basis in heterozygous mutation in the CSF3R gene on chromosome 1p34.

332
(53.2%)

severe combined immunodeficiency due to CD70 deficiency

Decreased circulating antibody level Hepatomegaly Lymphoproliferative disorder

Autosomal recessive inheritance

332
(53.2%)

combined oxidative phosphorylation deficiency 34

Hepatic steatosis Hepatomegaly Hypoglycemia Pancytopenia

Autosomal recessive inheritance

332
(53.2%)

Nezelof syndrome

Hepatosplenomegaly Lymphopenia Reduced delayed hypersensitivity

Autosomal recessive inheritance

332
(53.2%)

familial hemophagocytic lymphohistiocytosis 5

Hemophagocytosis Hepatosplenomegaly Recurrent fever

Autosomal recessive inheritance

Any genetic hemophagocytic lymphohistiocytosis in which the cause of the disease is a mutation in the STXBP2 gene.

332
(53.2%)

peroxisome biogenesis disorder type 3B

Abnormal bleeding Hepatomegaly Hypocholesterolemia

Autosomal recessive inheritance

A genetic disorder characterized by abnormalities in the breakdown of phytanic acid. It results in accumulation of phytanic acid in the blood, brain and other tissues. Signs and symptoms include retinitis pigmentosa which may lead to blindness, hearing problems and deafness, hypotonia, ataxia, nystagmus, facial deformities, and mental and growth retardation.

332
(53.2%)

TMEM165-CDG

Hepatomegaly Thrombocytopenia Unexplained fevers

Autosomal recessive inheritance

TMEM165-CDG is a form of congenital disorders of N-linked glycosylation characterized by a psychomotor delay-dysmorphism (pectus carinatum, dorsolumbar kyphosis and severe sinistroconvex scoliosis, short distal phalanges, genua vara, pedes planovalgi syndrome) with postnatal growth deficiency and major spondylo-, epi-, and metaphyseal skeletal involvement. Additional features include facial dysmorphism (midface hypoplasia, internal strabism of the right eye, low-set ears, moderately high arched palate, small teeth), nephrotic syndrome, cardiac defects, and feeding problems. The disease is caused by mutations in the gene TMEM165 (4q12).

332
(53.2%)

glycogen storage disease due to glucose-6-phosphatase deficiency type IA

Abnormal bleeding Hepatocellular carcinoma Hepatomegaly Proteinuria

Autosomal recessive inheritance

Glycogenosis due to glucose-6-phosphatase deficiency (G6P) type a, or glycogen storage disease (GSD) type 1a, is a type of glycogenosis due to G6P deficiency.

332
(53.2%)

carnitine palmitoyl transferase II deficiency, neonatal form

Antenatal intracerebral hemorrhage Hepatomegaly Macrovesicular hepatic steatosis Nonketotic hypoglycemia

Autosomal recessive inheritance

The neonatal form of carnitine palmitoyltransferase II (CPT II) deficiency, an inherited disorder that affects mitochondrial oxidation of long chain fatty acids (LCFA), is the lethal form of the disease which presents with multisystem failure.

332
(53.2%)

Greenberg dysplasia

Extramedullary hematopoiesis Hepatosplenomegaly Nonimmune hydrops fetalis

Autosomal recessive inheritance

A very rare lethal skeletal dysplasia characterized by fetal hydrops, short limbs and abnormal chondro-osseous calcification. The disease is characterized by early in utero lethality and affected fetuses are considered as nonviable.

342
(53.1%)

methemoglobinemia due to deficiency of methemoglobin reductase

Cyanosis Microcephaly Polycythemia

Autosomal recessive inheritance

343
(53.1%)

epidermolysis bullosa simplex with muscular dystrophy

Anemia Keratitis Palmoplantar hyperkeratosis

Autosomal recessive inheritance

Epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) is a basal subtype of epidermolysis bullosa simplex (EBS) characterized by generalized blistering associated with muscular dystrophy.

343
(53.1%)

WT limb-blood syndrome

Cryptorchidism Hypoplastic anemia Irregular hyperpigmentation Leukemia

Autosomal dominant inheritance

WT limb-blood syndrome is characterised by haematological anomalies (Fanconi anaemia, leukaemia and lymphoma) often appearing during childhood. Anomalies of the limbs and hands are also present: bifid or hypoplastic thumbs, cutaneous syndactyly, and ulnar and radial defects. The syndrome has been described in several families. Transmission is autosomal dominant.

345
(53.0%)

combined immunodeficiency due to CD3gamma deficiency

Abnormal intestine morphology Autoimmune hemolytic anemia Eczema Recurrent otitis media

Autosomal recessive inheritance

Combined immunodeficiency due to CD3gamma deficiency is an extremely rare genetic combined primary immunodeficiency characterized by a selective partial lymphopenia (T+/-B+NK+) phenotype and decreased CD3 complex resulting in a variable but usually mild clinical presentation ranging from asymptomatic until adulthood to high susceptibility to infections from early infancy with predominant automimmune manifestations.

345
(53.0%)

cartilage-hair hypoplasia

Brachycephaly Macrocytic anemia Malabsorption Neoplasm of the skin

Autosomal recessive inheritance

Cartilage-hair hypoplasia is a disease affecting the bone metaphyses causing small stature from birth.

347
(53.0%)

congenital generalized lipodystrophy type 3

Diabetes mellitus Primary amenorrhea Reduced subcutaneous adipose tissue Splenomegaly

Autosomal recessive inheritance

Any congenital generalized lipodystrophy in which the cause of the disease is a mutation in the CAV1 gene.

347
(53.0%)

hemochromatosis type 1

Azoospermia Diabetes mellitus Splenomegaly Telangiectasia

Autosomal recessive inheritance

Hemochromatosis type 1 (classic) is the most common form of hereditary hemochromatosis (HH), a group of diseases characterized by excessive tissue iron deposition. Due to its incidence (1/200-1/1000), it is not considered as a rare disease, unlike the other subforms of the disease

347
(53.0%)

congenital generalized lipodystrophy type 1

Hyperinsulinemia Labial hypertrophy Reduced subcutaneous adipose tissue Splenomegaly

Autosomal recessive inheritance Heterogeneous

Any congenital generalized lipodystrophy in which the cause of the disease is a mutation in the AGPAT2 gene.

347
(53.0%)

congenital generalized lipodystrophy type 2

Hyperinsulinemia Labial hypertrophy Reduced subcutaneous adipose tissue Splenomegaly

Autosomal recessive inheritance Heterogeneous

Any congenital generalized lipodystrophy in which the cause of the disease is a mutation in the BSCL2 gene.

347
(53.0%)

Cockayne syndrome type 1

Cryptorchidism Cutaneous photosensitivity Proteinuria Splenomegaly

Autosomal recessive inheritance Heterogeneous

Cockayne syndrome caused by mutation(s) in the ERCC8 gene, encoding DNA excision repair protein ERCC-8.

347
(53.0%)

Cockayne syndrome type 2

Cryptorchidism Cutaneous photosensitivity Proteinuria Splenomegaly

Autosomal recessive inheritance

Cockayne syndrome caused by mutation(s) in the ERCC6 gene, encoding DNA excision repair protein ERCC-6.

353
(52.7%)

Diamond-Blackfan anemia 15 with mandibulofacial dysostosis

Epicanthus Feeding difficulties Macrocytic anemia Sparse and thin eyebrow

Autosomal dominant inheritance

Any Diamond-Blackfan anemia in which the cause of the disease is a mutation in the RPS28 gene.

353
(52.7%)

specific granule deficiency 2

Anemia Diarrhea Hirsutism Low-set ears

Autosomal recessive inheritance

Specific granule deficiency-2 is an autosomal recessive immunologic disorder characterized by recurrent infections due to defective neutrophil development. Bone marrow findings include hypercellularity, abnormal megakaryocytes, and features of progressive myelofibrosis with blasts. The disorder is apparent from infancy, and most patients die in early childhood unless they undergo hematopoietic stem cell transplantation. Some patients may have additional findings, including delayed development, mild dysmorphic features, and distal skeletal anomalies (summary by {2:Witzel et al., 2017}).nnFor a discussion of genetic heterogeneity of SGD, see SGD1 (OMIM:245480).

355
(52.5%)

intrinsic factor and r binder, combined congenital deficiency of

Abnormality of metabolism/homeostasis Absence of intrinsic factor Megaloblastic anemia

Autosomal recessive inheritance

355
(52.5%)

porphyria due to ALA dehydratase deficiency

Elevated urinary delta-aminolevulinic acid Hemolytic anemia Vomiting

Autosomal recessive inheritance

Porphyria of doss or deficiency of delta-aminolevulinic acid dehydratase (DALAD) is an extremely rare form of acute hepatic porphyria characterized by neuro-visceral attacks without cutaneous manifestations.

355
(52.5%)

generalized juvenile polyposis/juvenile polyposis coli

Abdominal pain Anemia Hypokalemia

355
(52.5%)

Fanconi anemia complementation group B

Abnormality of chromosome stability Anemia Tracheoesophageal fistula

X-linked recessive inheritance

Fanconi anemia caused by mutations of the FANCB gene. This gene encodes the protein for complementation group B.

355
(52.5%)

pyridoxal phosphate-responsive seizures

Anemia Feeding difficulties in infancy Metabolic acidosis

Autosomal recessive inheritance

Pyridoxal phosphate-responsive seizures is a very rare neonatal epileptic encephalopathy disorder characterized clinically by onset of severe seizures within hours of birth that are not responsive to anticonvulsants, but are responsive to treatment with pyridoxal phosphate.

355
(52.5%)

transcobalamin II deficiency

Decreased circulating IgA level Macrocytic anemia Reticulocytopenia Vomiting

Autosomal recessive inheritance

Transcobalamin deficiency (TC) is a disorder of cobalamin transport that usually presents during the first few months of life and is characterized by megaloblastic anemia, failure to thrive, vomiting, weakness and pancytopenia.