Delayed speech and language development, and Decreased antibody level in blood

Low match IMMUNODEFICIENCY, DEVELOPMENTAL DELAY, AND HYPOHOMOCYSTEINEMIA; IMDDHH

IMDDHH is a multisystem disorder characterized by immunodeficiency, mildly delayed psychomotor development, poor overall growth from infancy, and hypohomocysteinemia. Additional features, such as congenital heart defects and liver involvement, are more variable (summary by Huppke et al., 2017).

• Intellectual disability
• Seizures
• Global developmental delay
• Short stature
• Pica

SOURCES: OMIM

Low match ECTODERMAL DYSPLASIA, ANHIDROTIC, WITH T-CELL IMMUNODEFICIENCY, AUTOSOMAL DOMINANT

Mutations in the NFKBIA gene result in functional impairment of NFKB1 (OMIM ), a master transcription factor required for normal activation of immune responses. Interruption of NFKB1 signaling results in decreased production of proinflammatory cytokines and certain interferons, rendering patients susceptible to infection (McDonald et al., 2007).

• Autosomal dominant inheritance
• Growth delay
• Failure to thrive
• Delayed speech and language development
• Tics

SOURCES: MESH MONDO OMIM UMLS

Low match OKUR-CHUNG NEURODEVELOPMENTAL SYNDROME; OCNDS

Okur-Chung neurodevelopmental syndrome is an autosomal dominant disorder characterized by delayed psychomotor development, intellectual disability with poor speech, behavioral abnormalities, cortical malformations in some patients, and variable dysmorphic facial features. Additional features, including microcephaly, gastrointestinal problems, and low levels of immunoglobulins, may be observed in some patients (Okur et al., 2016).

• Autosomal dominant inheritance
• Intellectual disability
• Seizures
• Global developmental delay
• Generalized hypotonia

SOURCES: OMIM UMLS MONDO

Low 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

Low match TRICHOTHIODYSTROPHY 1, PHOTOSENSITIVE; TTD1

Trichothiodystrophy (TTD) is a rare autosomal recessive disorder in which patients have brittle, sulfur-deficient hair that displays a diagnostic alternating light and dark banding pattern, called 'tiger tail banding,' under polarizing microscopy. TTD patients display a wide variety of clinical features, including cutaneous, neurologic, and growth abnormalities. Common additional clinical features are ichthyosis, intellectual/developmental disabilities, decreased fertility, abnormal characteristics at birth, ocular abnormalities, short stature, and infections. There are both photosensitive and nonphotosensitive forms of the disorder. TTD patients have not been reported to have a predisposition to cancer (summary by Faghri et al., 2008). Genetic Heterogeneity of TrichothiodystrophyAlso see TTD2 (OMIM ), caused by mutation in the ERCC3/XPB gene (OMIM ); TTD3 (OMIM ), caused by mutation in the GTF2H5 gene (OMIM ); TTD4 (OMIM ), caused by mutation in the MPLKIP gene (OMIM ); TTD5 (OMIM ), caused by mutation in the RNF113A gene (OMIM ); and TTD6 (OMIM ), caused by mutation in the GTF2E2 gene (OMIM ).

TRICHOTHIODYSTROPHY 1, PHOTOSENSITIVE; TTD1 Is also known as trichothiodystrophy, photosensitive;ttdp, ichthyosiform erythroderma with hair abnormality and mental and growth retardation, tay syndrome, trichothiodystrophy with congenital ichthyosis;ichthyosis, congenital, with trichothiodystrophy, pibids syndrome

• Autosomal recessive inheritance
• Intellectual disability
• Global developmental delay
• Short stature
• Pica

SOURCES: OMIM MONDO ORPHANET

Low match IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 4; ICF4

Immunodeficiency-centromeric instability-facial anomalies syndrome-4 is an autosomal recessive disorder characterized by recurrent infections in childhood and variable dysmorphic facial features. Laboratory studies show hypomethylation of certain chromosomal regions. Additional features, including delayed development, are variable (summary by Thijssen et al., 2015).For a discussion of genetic heterogeneity of immunodeficiency-centromeric instability-facial anomalies syndrome, see ICF1 (OMIM ).

• Autosomal recessive inheritance
• Intellectual disability
• Global developmental delay
• Hypertelorism
• Motor delay

SOURCES: UMLS OMIM MONDO DOID

Low match MANNOSIDOSIS, ALPHA B, LYSOSOMAL; MANSA

Alpha-mannosidosis is an autosomal recessive lysosomal storage disease characterized by mental retardation, coarse facial features, skeletal abnormalities, hearing impairment, neurologic motor problems, and immune deficiency. Expression of the disease varies considerably, and there is a wide spectrum of clinical findings and severity. Affected children are often normal at birth and during early development. They present in early childhood with delayed psychomotor development, delayed speech, and hearing loss. Additional features include large head with prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, widely spaced teeth, dysostosis multiplex, and motor impairment (summary by Malm and Nilssen, 2008). Classification SystemsTwo classification systems have been used to describe the clinical presentation of alpha-mannosidosis. The earlier system delineated a more severe 'type I,' which shows infantile onset, rapid mental deterioration, hypotonia, splenomegaly, severe dysostosis multiplex, and severe recurrent infections, often resulting in death by age 8 years. Individuals with the less severe 'type II' show normal early development with later childhood development of mental retardation, hearing loss, coarse facies, neurologic deterioration, and survival well into adulthood (summary by Desnick et al., 1976 and Gotoda et al., 1998). A later classification system delineated 3 clinical types. Type 1 is the mildest form, with onset after age 10 years, without skeletal abnormalities and very slow progression. Type 2 is a moderate form, with onset before age 10 years, presence of skeletal abnormalities, and slow progression with development of ataxia by age 20 to 30 years. Type 3 is the severe form, with onset in early infancy, skeletal abnormalities, and obvious progression leading to early death from primary central nervous system involvement or myopathy. Most patients belong to clinical type 2 (summary by Malm and Nilssen, 2008). Despite the clinical heterogeneity of the disorder, there are no apparent genotype/phenotype correlations (Berg et al., 1999; Riise Stensland et al., 2012).

MANNOSIDOSIS, ALPHA B, LYSOSOMAL; MANSA Is also known as alpha-mannosidosis, lysosomal alpha-d-mannosidase deficiency, alpha-mannosidase b deficiency

• Autosomal recessive inheritance
• Intellectual disability
• Global developmental delay
• Generalized hypotonia
• Pica

SOURCES: OMIM ORPHANET SCTID

Low match RITSCHER-SCHINZEL SYNDROME 1; RTSC1

The 3C syndrome, also known as Ritscher-Schinzel syndrome, is a developmental malformation syndrome characterized by craniofacial abnormalities, congenital heart defects, and cerebellar brain malformations. Facial features include prominent occiput, prominent forehead, low-set ears, downslanting palpebral fissures, depressed nasal bridge, and micrognathia. Cardiac defects can include septal defects and aortic stenosis, among others, and brain imaging shows Dandy-Walker malformation, cerebellar vermis hypoplasia, posterior fossa cysts, and ventricular dilatation. Affected individuals have severe developmental delay (summary by Leonardi et al., 2001; Seidahmed et al., 2011). Genetic Heterogeneity of Ritscher-Schinzel SyndromeSee also RTSC2 (OMIM ), caused by mutation in the CCDC22 gene (OMIM ) on chromosome Xp11.

RITSCHER-SCHINZEL SYNDROME 1; RTSC1 Is also known as craniocerebellocardiac dysplasia, 3c syndrome, dandy-walker-like malformation with atrioventricular septal defect;craniocerebellocardiac dysplasia; ritscher-schinzel syndrome

• Autosomal recessive inheritance
• Intellectual disability
• Global developmental delay
• Short stature
• Generalized hypotonia

SOURCES: SCTID UMLS OMIM MONDO DOID ORPHANET

Low match OSTEOPETROSIS, AUTOSOMAL RECESSIVE 7; OPTB7

Osteopetrosis-hypogammaglobulinemia syndrome is an extremely rare primary bone dysplasia with increased bone density disorder characterized by severe osteoclast-poor osteopetrosis associated with hypogammaglobulinemia. Patients typically present infantile malignant osteopetrosis (manifesting with increased bone density, bone fractures, abnormal eye movements/visual loss, nystagmus), hematologic abnormalities with bone marrow failure (e.g. anemia, hepatosplenomegaly) and immunological deficiency (manifesting as recurrent respiratory infections) associated with reduced immunoglobulin levels due to impaired peripheral B cell differentiation.

OSTEOPETROSIS, AUTOSOMAL RECESSIVE 7; OPTB7 Is also known as osteopetrosis, osteoclast-poor, with hypogammaglobulinemia;autosomal recessive osteoclast-poor osteopetrosis with hypogammaglobulinemia; autosomal recessive osteopetrosis type 7

• Autosomal recessive inheritance
• Global developmental delay
• Nystagmus
• Anemia
• Fever

SOURCES: MONDO ORPHANET OMIM MESH UMLS DOID GARD

Low match IMMUNODEFICIENCY 36; IMD36

IMD36 is a primary immunodeficiency with a highly heterogeneous clinical phenotype, characterized primarily by recurrent respiratory tract infections, lymphoproliferation, and antibody deficiency. Other features include growth retardation, mild neurodevelopmental delay, and autoimmunity. The major complication is development of B-cell lymphoma (Elkaim et al., 2016).

• Autosomal dominant inheritance
• Global developmental delay
• Growth delay
• Splenomegaly
• Diarrhea

SOURCES: MONDO UMLS OMIM