Delayed speech and language development, and Meningitis

Medium match AGAMMAGLOBULINEMIA, X-LINKED; XLA

X-linked agammaglobulinemia is an immunodeficiency characterized by failure to produce mature B lymphocytes and associated with a failure of Ig heavy chain rearrangement. The defect in this disorder resides in BTK, also known as BPK or ATK, a key regulator in B-cell development (Rawlings and Witte, 1994). The X-linked form accounts for approximately 85 to 90% of cases of the disorder. Also see {300310}. The remaining 15% of cases constitute a heterogeneous group of autosomal disorders (Lopez Granados et al., 2002; Ferrari et al., 2007). See agammaglobulinemia-1 (AGM1 ) for a discussion of genetic heterogeneity of the autosomal forms of agammaglobulinemia.

AGAMMAGLOBULINEMIA, X-LINKED; XLA Is also known as bruton-type agammaglobulinemia, agammaglobulinemia, x-linked, type 1;agmx1, immunodeficiency 1;imd1;btk-deficiency; bruton type agammaglobulinemia

• Short stature
• Hearing impairment
• Ataxia
• Failure to thrive
• Sensorineural hearing impairment

SOURCES: SCTID OMIM ORPHANET

Medium match HYPEREKPLEXIA 2; HKPX2

• Autosomal recessive inheritance
• Seizures
• Motor delay
• Hyperreflexia
• Hypertonia

SOURCES: OMIM DOID UMLS MONDO

Medium match NEUTROPENIA, SEVERE CONGENITAL, 3, AUTOSOMAL RECESSIVE; SCN3

Severe congenital neutropenia-3 is an autosomal recessive bone marrow failure disorder characterized by low numbers of neutrophils, increased susceptibility to bacterial and fungal infections, and increased risk of developing myelodysplastic syndrome or acute myeloid leukemia. In addition, patients with HAX1 mutations affecting both isoform A and B of the gene develop neurologic abnormalities (summary by Boztug et al., 2010).The Swedish physician Rolf Kostmann (1956) described an autosomal recessive hematologic disorder, termed infantile agranulocytosis, with severe neutropenia with an absolute neutrophil count below 0.5 x 10(9)/l and early onset of severe bacterial infections. The disorder was later termed Kostmann syndrome (Skokowa et al., 2007). Lekstrom-Himes and Gallin (2000) discussed severe congenital neutropenia in a review of immunodeficiencies caused by defects in phagocytes.In addition to Kostmann agranulocytosis, recessively inherited neutropenic syndromes include congenital neutropenia with eosinophilia (OMIM ), Chediak-Higashi syndrome (OMIM ), and Fanconi pancytopenic syndrome (see {227650}).For a phenotypic description and a discussion of genetic heterogeneity of severe congenital neutropenia, see SCN1 (OMIM ).

NEUTROPENIA, SEVERE CONGENITAL, 3, AUTOSOMAL RECESSIVE; SCN3 Is also known as kostmann disease, agranulocytosis, infantile

• Autosomal recessive inheritance
• Intellectual disability
• Seizures
• Global developmental delay
• Hearing impairment

SOURCES: OMIM MONDO ICD10 GARD ORPHANET

Medium match OROTIC ACIDURIA

Orotic aciduria is a rare autosomal recessive disorder characterized by megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. These features respond to appropriate pyrimidine replacement therapy, and most cases appear to have a good prognosis. A minority of cases have additional features, particularly congenital malformations and immune deficiencies, which may adversely affect this prognosis (summary by Webster et al., 2001).Bailey (2009) stated that only 2 cases of orotic aciduria without megaloblastic anemia (OAWA) had been reported.

OROTIC ACIDURIA Is also known as orotic aciduria i, orotate phosphoribosyltransferase and orotidylic decarboxylase deficiency, oprt and odc deficiency, orotidylic pyrophosphorylase and orotidylic decarboxylase deficiency, uridine monophosphate synthase deficiency, ump synthase deficiency, umps deficiency;oroticaciduria; orotidylic decarboxylase deficiency; uridine monophosphate synthetase deficiency

• Autosomal recessive inheritance
• Global developmental delay
• Hypertelorism
• Failure to thrive
• Anemia

SOURCES: DOID ORPHANET NCIT GARD SCTID OMIM MONDO

Medium match HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2; FHL2

Familial hemophagocytic lymphohistiocytosis-2 (FHL2) is an autosomal recessive disorder of immune dysregulation with onset in infancy or early childhood. It is characterized clinically by fever, edema, hepatosplenomegaly, and liver dysfunction. Neurologic impairment, seizures, and ataxia are frequent. Laboratory studies show pancytopenia, coagulation abnormalities, hypofibrinogenemia, and hypertriglyceridemia. There is increased production of cytokines, such as gamma-interferon (IFNG ) and TNF-alpha (OMIM ), by hyperactivation and proliferation of T cells and macrophages. Activity of cytotoxic T cells and NK cells is reduced, consistent with a defect in cellular cytotoxicity. Bone marrow, lymph nodes, spleen, and liver show features of hemophagocytosis. Chemotherapy and/or immunosuppressant therapy may result in symptomatic remission, but the disorder is fatal without bone marrow transplantation (summary by Dufourcq-Lagelouse et al., 1999, Stepp et al., 1999, and Molleran Lee et al., 2004).For a general phenotypic description and a discussion of genetic heterogeneity of FHL, see {267700}.

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2; FHL2 Is also known as hplh2, hlh2

• Autosomal recessive inheritance
• Seizures
• Global developmental delay
• Generalized hypotonia
• Ataxia

SOURCES: GARD DOID OMIM UMLS MESH MONDO

Medium match HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 1; FHL1

Zur Stadt et al. (2005) summarized the clinical features of hemophagocytic lymphohistiocytosis (HLH), a rare autosomal recessive disorder characterized by massive infiltration of several organs by activated lymphocytes and macrophages. The clinical features of the disease include fever, hepatosplenomegaly, cytopenia, and less frequently central nervous system involvement. In FHL, the familial form of the disease, first episodes occur mostly during infancy, with a rapidly fatal outcome if untreated. Diagnostic criteria also include low fibrinogen and high triglyceride and ferritin levels. Chemoimmunotherapy based on corticosteroids, epipodophyllotoxins, and cyclosporin succeeds in controlling the disease in the majority of patients, although remission is rarely obtained (Henter et al., 2002). Most patients suffer an early death unless they are treated by hematopoietic stem cell transplantation (Durken et al., 1999). Genetic Heterogeneity of Familial Hemophagocytic LymphohistiocytosisFamilial hemophagocytic lymphohistiocytosis exhibits genetic heterogeneity. In some families, familial hemophagocytic lymphohistiocytosis has been found to be linked to chromosome 9q (HPLH1, FHL1). FHL2 (OMIM ) is caused by mutation in the PRF1 gene (OMIM ) on chromosome 10q22; FHL3 (OMIM ) is caused by mutation in the UNC13D gene (OMIM ) on chromosome 17q25; FHL4 (OMIM ) is caused by mutation in the syntaxin-11 gene (STX11 ) on chromosome 6q24; and FHL5 (OMIM ) is caused by mutation in the syntaxin-binding protein-2 (STXBP2 ), which is an interaction partner of STX11, on chromosome 19p13.Furthermore, before the identification of mutations in the RAG1 (OMIM ) and RAG2 (OMIM ) genes, both of which map to 11p, Omenn syndrome (familial reticuloendotheliosis with eosinophilia; {603554}) was not thought to be clearly distinct from other reported cases of hemophagocytic lymphohistiocytosis.

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 1; FHL1 Is also known as hplh1, hlh1, hemophagocytic lymphohistiocytosis, familial;fhl;fhlh;hplh, reticulosis, familial histiocytic, hemophagocytic reticulosis, familial, erythrophagocytic lymphohistiocytosis, familial;fel

• Autosomal recessive inheritance
• Seizures
• Global developmental delay
• Generalized hypotonia
• Ataxia

SOURCES: NCIT DOID MONDO ORPHANET ICD10 OMIM

Medium match IMMUNODEFICIENCY, COMMON VARIABLE, 10; CVID10

Common variable immunodeficiency-10 is an autosomal dominant primary immunodeficiency characterized by childhood-onset of recurrent infections, hypogammaglobulinemia, and decreased numbers of memory and marginal zone B cells. Some patients may develop autoimmune features and have circulating autoantibodies. An unusual feature is central adrenal insufficiency (summary by Chen et al., 2013).For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (OMIM ).

IMMUNODEFICIENCY, COMMON VARIABLE, 10; CVID10 Is also known as immunodeficiency, common variable, with central adrenal insufficiency, deficit in anterior pituitary function and variable immunodeficiency;david

• Autosomal dominant inheritance
• Global developmental delay
• Spasticity
• Gait disturbance
• Dysphagia

SOURCES: OMIM UMLS

Medium match CINCA SYNDROME; CINCA

Chronic infantile neurologic cutaneous and articular (CINCA) syndrome is a severe chronic inflammatory disease of early onset, characterized by cutaneous symptoms, central nervous system involvement, and arthropathy (Feldmann et al., 2002).See also familial cold autoinflammatory syndrome-1 (FCAS1, CAPS1; {120100}), an allelic disorder with a less severe phenotype.

CINCA SYNDROME; CINCA Is also known as chronic neurologic cutaneous and articular syndrome, multisystem inflammatory disease, neonatal-onset;nomid, cryopyrin-associated periodic syndrome 3;caps3;chronic infantile neurological cutaneous articular syndrome; iomid syndrome; infantile-onset multisystem inflammatory disease; nomid syndrome; neonatal-onset multisystem inflammatory disease; prieur-griscelli syndrome

• Autosomal dominant inheritance
• Intellectual disability
• Global developmental delay
• Pica
• Hearing impairment

SOURCES: OMIM ORPHANET

Medium match MIRAGE SYNDROME; MIRAGE

MIRAGE syndrome is a form of syndromic adrenal hypoplasia, characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. The condition is often fatal within the first decade of life, usually as a result of invasive infection (Narumi et al., 2016).

MIRAGE SYNDROME; MIRAGE Is also known as myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy;myelodysplasia-infection-restriction of growth-adrenal hypoplasia-genital anomalies-enteropathy syndrome; myelodysplasia-infection-restriction of growth-adrenal hypoplasia-genital phenotypes-enteropathy syndrome

• Autosomal dominant inheritance
• Seizures
• Global developmental delay
• Short stature
• Scoliosis

SOURCES: ORPHANET UMLS NCIT OMIM MONDO GARD

Medium match GAUCHER DISEASE, TYPE III

Gaucher disease type III is the subacute form of neuronopathic Gaucher disease. It has later onset and slower progression compared to the acute form of neuronopathic Gaucher disease, type II.Patterson et al. (1993) suggested that there are 2 phenotypic subgroups of Gaucher disease type III: type IIIA, which is characterized by myoclonus and dementia, and type IIIB, characterized by early onset of isolated horizontal supranuclear gaze palsy and aggressive systemic disease. See also Gaucher disease type IIIC (OMIM ), which is associated with cardiovascular calcifications.

GAUCHER DISEASE, TYPE III Is also known as gd iii, gaucher disease, subacute neuronopathic type, gaucher disease, chronic neuronopathic type, gaucher disease, juvenile and adult, cerebral;cerebral juvenile and adult form of gaucher disease; chronic neuronopathic gaucher disease; gaucher disease, subacute neuronopathic type

• Autosomal recessive inheritance
• Seizures
• Short stature
• Pica
• Ataxia

SOURCES: ORPHANET UMLS GARD OMIM DOID MONDO SCTID