Generalized hypotonia, and Chronic myelogenous leukemia

High match ACHONDROPLASIA; ACH

Achondroplasia is the most frequent form of short-limb dwarfism. Affected individuals exhibit short stature caused by rhizomelic shortening of the limbs, characteristic facies with frontal bossing and midface hypoplasia, exaggerated lumbar lordosis, limitation of elbow extension, genu varum, and trident hand (summary by Bellus et al., 1995).

• Intellectual disability
• Short stature
• Generalized hypotonia
• Hearing impairment
• Scoliosis

SOURCES: MESH OMIM MENDELIAN

High match MEVALONIC ACIDURIA

Mevalonic aciduria (MVA) is a rare, very severe form of mevalonate kinase deficiency (MKD; see this term) characterized by dysmorphic features, failure to thrive, psychomotor delay, ocular involvement, hypotonia, progressive ataxia, myopathy, and recurrent inflammatory episodes.

MEVALONIC ACIDURIA Is also known as mva|complete mevalonate kinase deficiency

• Intellectual disability
• Seizures
• Global developmental delay
• Short stature
• Generalized hypotonia

SOURCES: OMIM ORPHANET MENDELIAN

Medium match JUVENILE MYELOMONOCYTIC LEUKEMIA

Juvenile myelomonocytic leukemia is an aggressive pediatric myelodysplastic syndrome (MDS)/myeloproliferative disorder (MPD) characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny (Loh et al., 2009). JMML constitutes approximately 30% of childhood cases of myelodysplastic syndrome and 2% of leukemia (Hasle et al., 1999). Although JMML is a progressive and often rapidly fatal disease without hematopoietic stem cell transplantation (HSCT), some patients have been shown to have a prolonged and stable clinical course without HSCT (Niemeyer et al., 1997). Chronic myelomonocytic leukemia (CMML) is a similar disorder with later onset. Both JMML and CMML have a high frequency of mutations affecting the RAS signaling pathway and show hypersensitivity to stimulation with GM-CSF, which causes STAT5 (OMIM ) hyperphosphorylation (Loh et al., 2009). Genetic Heterogeneity of Juvenile Myelomonocytic LeukemiaIn up to 60% of cases of JMML, the RAS/MAPK pathway is deregulated due to somatic mutations in the PTPN11 (OMIM ), KRAS (OMIM ), and NRAS (OMIM ) genes. Additionally, both germline and somatic mutations in the CBL gene have been found in patients with JMML, indicating a frequency of 10 to 15% of JMML patients overall (Loh et al., 2009). Somatic disruptions of the GRAF gene (ARHGAP26 ) have also been found in patients with JMML.About 10 to 15% of JMML cases arise in children with neurofibromatosis type I (NF1 ) due to germline mutations in the NF1 gene (OMIM ). In addition, patients with Noonan syndrome (NS1, {163950}; NS3, {609942}) or Noonan syndrome-like disorder (NSLL ) due to germline mutations in the PTPN11, KRAS2, and CBL genes, respectively, also have an increased risk of developing JMML. Genetic Heterogeneity of Chronic Myelomonocytic LeukemiaSomatic mutations in the CBL, ASXL1 (OMIM ), TET2 (OMIM ), and SF3B1 (OMIM ) genes have been found in patients with CMML.

JUVENILE MYELOMONOCYTIC LEUKEMIA Is also known as juvenile chronic myelomonocytic leukemia|jmml|leukemia, juvenile myelomonocytic

• Generalized hypotonia
• Abnormal facial shape
• Anemia
• Anteverted nares
• Splenomegaly

SOURCES: ORPHANET MESH OMIM MENDELIAN

Medium match ATAXIA-TELANGIECTASIA

Ataxia-telangiectasia is the association of severe combined immunodeficiency (affecting mainly the humoral immune response) with progressive cerebellar ataxia. It is characterised by neurological signs, telangiectasias, increased susceptibility to infections and a higher risk of cancer.

ATAXIA-TELANGIECTASIA Is also known as at1|louis-bar syndrome

• Intellectual disability
• Seizures
• Short stature
• Microcephaly
• Scoliosis

SOURCES: ORPHANET OMIM MENDELIAN

Medium match NOONAN SYNDROME 6; NS6

• Intellectual disability
• Global developmental delay
• Short stature
• Generalized hypotonia
• Hearing impairment

SOURCES: OMIM MESH MENDELIAN

Low match CARDIOFACIOCUTANEOUS SYNDROME 4; CFC4

Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomaly disorder in which individuals have characteristic craniofacial features, cardiac defects, ectodermal anomalies, gastrointestinal dysfunction, and neurocognitive delay (summary by Rauen et al., 2010).

• Global developmental delay
• Short stature
• Generalized hypotonia
• Scoliosis
• Nystagmus

SOURCES: OMIM MENDELIAN

Low match 3-METHYLGLUTACONIC ACIDURIA TYPE 7

3-Methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MEGCANN) is an autosomal recessive inborn error of metabolism characterized primarily by increased levels of 3-methylglutaconic acid (3-MGA) associated with neurologic deterioration and neutropenia. The phenotype is highly variable: most patients have infantile onset of a progressive encephalopathy with various movement abnormalities and delayed psychomotor development, although rare patients with normal neurologic development have been reported. Other common, but variable, features include cataracts, seizures, and recurrent infections (summary by Wortmann et al., 2015 and Saunders et al., 2015).For a general phenotypic description and a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA1 (OMIM ).

3-METHYLGLUTACONIC ACIDURIA TYPE 7 Is also known as 3-methylglutaconic aciduria-cataract-neurologic involvement-neutropenia syndrome|mga7|mgca7|3-methylglutaconic aciduria, type vii

• Intellectual disability
• Seizures
• Global developmental delay
• Generalized hypotonia
• Microcephaly

SOURCES: ORPHANET OMIM MENDELIAN

Low 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 hemophagocytic reticulosis, familial|hlh1|hemophagocytic lymphohistiocytosis, familial|erythrophagocytic lymphohistiocytosis, familial|reticulosis, familial histiocytic|hplh1|fhl|fhlh|hplh|fel

• Seizures
• Global developmental delay
• Generalized hypotonia
• Ataxia
• Neoplasm

SOURCES: OMIM MENDELIAN

Low match POLYHYDRAMNIOS-MEGALENCEPHALY-SYMPTOMATIC EPILEPSY SYNDROME

POLYHYDRAMNIOS-MEGALENCEPHALY-SYMPTOMATIC EPILEPSY SYNDROME Is also known as pmse syndrome

• Intellectual disability
• Seizures
• Global developmental delay
• Generalized hypotonia
• Hypertelorism

SOURCES: MESH OMIM ORPHANET MENDELIAN

Low match KNOBLOCH SYNDROME

Knobloch syndrome (KS) is defined by vitreoretinal and macular degeneration, and occipital encephalocele.

KNOBLOCH SYNDROME Is also known as retinal detachment and occipital encephalocele|knobloch-layer syndrome|retinal detachment-occipital encephalocele syndrome|kno

• Seizures
• Global developmental delay
• Generalized hypotonia
• Ataxia
• Nystagmus

SOURCES: OMIM MESH ORPHANET MENDELIAN