MedGen

Neurodevelopmental disorder with hypotonia and speech delay, with or without seizures (NEDHSS) is characterized by global developmental delay, impaired intellectual development with poor or absent speech, and fine and gross motor delay. Most affected individuals are severely affected and may be unable to walk, have feeding difficulties requiring tube-feeding, and develop early-onset seizures. Additional features may include cortical blindness and nonspecific structural brain abnormalities. Rare individuals present only with hypotonia and mild developmental delay (Paul et al., 2023). [from OMIM]

Immunodeficiency-112 (IMD112) is an autosomal recessive primary immunologic disorder with variable manifestations beginning in early childhood. Some patients have recurrent bacterial, viral, and fungal infections, including disseminated bacillus Calmette-Guerin (BCG)-related infections, whereas at least 1 patient only presented with BCG-related infections. Immunologic workup shows variable abnormalities affecting lymphoid immunity, including hypogammaglobulinemia, lymphopenia or paradoxical lymphocytosis, and defects in B, T, and NK cell differentiation and function mainly due to disruption of the noncanonical NFKB (see 164011) signaling pathway (Willmann et al., 2014; Schlechter et al., 2017). [from OMIM]

Primary ciliary dyskinesia-51 (CILD51) is characterized by male infertility due to multiple morphologic abnormalities of the sperm flagella (MMAF), resulting in severely reduced progressive motility. Some men also have a low sperm count. In addition, affected individuals experience chronic rhinosinusitis and bronchitis, and recurrent upper and lower respiratory infections, and some exhibit dextrocardia and/or situs inversus (Guo et al., 2021). For a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400). [from OMIM]

Infantile-onset multisystem autoimmune disease-3 (ADMIO3) is an autosomal recessive disorder of immune dysregulation characterized by the onset of various systemic autoimmune manifestations in the first months or years of life. Features may include hypothyroidism, type 1 diabetes mellitus, systemic inflammatory manifestations (fever, hepatomegaly), and autoimmune cytopenias. Laboratory studies show normal levels of T, B, and NK cells, but CD4+ (see 186940) T cells demonstrate hyperproliferation when stimulated in vitro (Janssen et al., 2022). For a discussion of genetic heterogeneity of ADMIO, see ADMIO1 (615952). [from OMIM]

Early-onset dystonia-37 with striatal lesions (DYT37) is an autosomal recessive neurologic movement disorder characterized by the onset of progressive dystonia, dysphagia, and choreoathetosis in the first months or years of life. Affected individuals show delayed motor development and may have impaired intellectual development. The disorder is severely disabling; patients lose ambulation and require tube-feeding. Brain imaging shows hyperintense lesions affecting the basal ganglia and striatum (Harrer et al., 2023). [from OMIM]

Epidermolytic palmoplantar keratoderma-2 (EPPK2) is an autosomal dominant skin disorder in which affected individuals have hyperkeratosis restricted to palms and soles present from birth or childhood (Hatsell et al., 2001; Nakamizo et al., 2023). In some individuals with EPPK2, keratoderma involving the palms and soles extends to the dorsal surfaces of the hands and feet and involves the skin over the Achilles tendon (transgrediens), a phenotype known as Greither syndrome (Gach et al., 2005). For a discussion of genetic heterogeneity of epidermolytic palmoplantar keratoderma, and of palmoplantar keratoderma in general, see 144200. [from OMIM]

Autosomal recessive intellectual developmental disorder-79 (MRT79) is characterized by global developmental delay apparent from infancy. Affected individuals have mildly delayed walking with an ataxic gait and severely impaired intellectual development with poor or absent speech. Additional features may include postnatal microcephaly and dysmorphic features (Van Bergen et al., 2022). [from OMIM]

Autosomal dominant auditory neuropathy-2 (AUNA2) is characterized by postlingual onset of progressive bilateral sensorineural hearing loss in the second decade, leading to profound deafness in the fifth decade. Affected individuals show abnormal auditory brainstem responses (ABR) even before the onset of symptoms. Outer hair cell (OHC) function is preserved initially, but declines with age (Lang-Roth et al., 2017). For a discussion of genetic heterogeneity of autosomal dominant auditory neuropathy, see AUNA1 (609129). [from OMIM]

Systemic autoinflammatory disease with vasculitis (SAIDV) is an autosomal dominant disorder that manifests soon after birth with features such as purpuric skin rash, fever, hepatosplenomegaly, and elevated C-reactive protein (CRP; 123260). Laboratory studies may show leukocytosis, thrombocytopenia, and autoantibodies. A subset of patients develop progressive liver involvement that may result in fibrosis. Other systemic features, such as periorbital edema, conjunctivitis, infections, abdominal pain, and arthralgia are usually observed. Mutations occur de novo. De Jesus et al. (2023) referred to this disorder as LAVLI (LYN kinase-associated vasculopathy and liver fibrosis). [from OMIM]

Developmental and epileptic encephalopathy-31B (DEE31B) is an autosomal recessive neurologic disorder with early-onset epilepsy, generalized muscular hypotonia, visual impairment, and severe neurodevelopmental delay (Yigit et al., 2022). [from OMIM]

C1q deficiency (C1QD) is a rare autosomal recessive disorder characterized by recurrent skin lesions, chronic infections, and an increased risk of autoimmune diseases, particularly systemic lupus erythematosus (SLE; see 152700) or SLE-like diseases. It has also been associated with chronic glomerulonephritis and renal failure. C1q deficiency presents in 2 different forms, absent C1q protein or presence of a dysfunctional molecule (summary by Topaloglu et al., 1996 and Vassallo et al., 2007). For a discussion of genetic heterogeneity of C1q deficiency, see 613652. [from OMIM]

C1q deficiency (C1QD) is a rare autosomal recessive disorder characterized by recurrent skin lesions, chronic infections, and an increased risk of autoimmune diseases, particularly systemic lupus erythematosus (SLE; see 152700) or SLE-like diseases. It has also been associated with chronic glomerulonephritis and renal failure. C1q deficiency presents in 2 different forms, absent C1q protein or presence of a dysfunctional molecule (summary by Topaloglu et al., 1996 and Vassallo et al., 2007). For a discussion of genetic heterogeneity of C1q deficiency, see 613652. [from OMIM]

Oocyte/zygote/embryo maturation arrest-17 (OZEMA17) is characterized by female infertility due to arrest of the embryo after the first rounds of cleavage or failure to establish pregnancy after implantation (Wang et al., 2023). For a discussion of genetic heterogeneity of OZEMA, see 615774. [from OMIM]

Autoinflammation with pulmonary and cutaneous vasculitis (AIPCV) is a disorder of immune dysregulation manifest as skin lesions (petechiae and purpura) appearing soon after birth followed by progressive pulmonary involvement causing restrictive lung disease and respiratory insufficiency. Other features may include hepatosplenomegaly and anemia (Kanderova et al., 2022). [from OMIM]

Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures (NEDLBAS), is characterized by global developmental delay with variably impaired intellectual development apparent from infancy or early childhood. Affected individuals have significant speech delay, and most demonstrate behavioral abnormalities, including autistic features. About half of patients develop seizures, which may be controlled or refractory. More variable features include hypotonia, feeding difficulties, and subtle facial dysmorphism (Schalk et al., 2022). [from OMIM]

Immunodeficiency-109 with EBV-induced lymphoproliferation (IMD109) is an autosomal recessive primary immune disorder characterized by onset of recurrent sinopulmonary infections in childhood. Affected individuals are susceptible to infection with EBV and develop EBV viremia and EBV-associated lymphoproliferative disease or B-cell lymphoma. Immunologic work-up shows normal levels of T, B, and NK cells, with defective CD8+ T cell function after stimulation. Some patients may have hypogammaglobulinemia and poor antibody response to stimulation (Alosaimi et al., 2019). [from OMIM]

Oocyte/zygote/embryo maturation arrest-14 (OZEMA14) is characterized by female infertility due to oocyte maturation arrest, fertilization failure, and/or early embryonic arrest. The rare fertilized embryos that are transferred to the uterus fail to establish pregnancy after transfer (Zhao et al., 2020, Zhao et al., 2021, Huang et al., 2021, Xu et al., 2021). For a discussion of genetic heterogeneity of OZEMA, see 615774. [from OMIM]

Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities (NEDSMB) is an autosomal recessive disorder characterized by global developmental delay and severely impaired intellectual development with aggressive behavior. Mild dysmorphic features and hypodontia are also present (Faqeih et al., 2023). [from OMIM]

PPP2R5D-related neurodevelopmental disorder is characterized by mild to severe neurodevelopmental delay. Pronounced hypotonia with delay in gross motor skills is common. Onset of independent walking varies widely and ataxia is reported. All reported individuals have speech impairment, with a wide range of abilities. Autism spectrum disorder is reported in six individuals. Macrocephaly is common. Seizures and ophthalmologic abnormalities are reported in fewer than half of individuals. Additional anomalies include skeletal, endocrine, and cardiac malformations, each reported in a few individuals. To date, 23 individuals with PPP2R5D-related neurodevelopmental disorder have been reported. [from GeneReviews]