Spinocerebellar ataxia-15 (SCA15) is an autosomal dominant, adult-onset, slowly progressive form of cerebellar ataxia. Most patients also have disabling action and postural tremor, and some have pyramidal tract affection, dorsal column involvement, and gaze palsy. Brain imaging shows cerebellar atrophy mainly affecting the vermis (summary by Synofzik et al., 2011). Autosomal dominant 'pure' cerebellar ataxia, classified as ADCA type III by Harding (1983, 1993), is a genetically heterogeneous disorder (see, e.g., 117210). For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

Activated PI3K delta syndrome (APDS) is characterized by a spectrum of clinical manifestations involving the immune system leading to increased susceptibility to infections (e.g., otitis media, sinusitis, bronchitis, and pneumonia), autoimmune/autoinflammatory manifestations including autoimmune cytopenias, gastrointestinal manifestations resembling Crohn-like colitis, intussusception, and lymphoproliferation (e.g., lymphadenopathy, hepatosplenomegaly, and nodular lymphoid hyperplasia), and an increased risk of developing B-cell lymphomas and other malignancies. Short stature, growth delays, and neurodevelopmental delays are also reported. APDS type 1 (APDS1) is caused by a heterozygous pathogenic gain-of-function variant in PIK3CD, and APDS type 2 (APDS2) is caused by a heterozygous loss-of-function pathogenic variant in PIK3R1. The key clinical differences between APDS1 and APDS2 include short stature, frequency of gastrointestinal infections, and characteristic dental findings, which are more prominent in APDS2.

The 10q22.3-q23.2 region is characterized by a complex set of low-copy repeats (LCRs), which can give rise to various genomic changes mediated by nonallelic homologous recombination (NAHR). Recurrent deletions of chromosome 10q22.3-q23.2, including the BMPR1A gene (601299) have been associated with dysmorphic facies, developmental delay, and multiple congenital anomalies. Some patients with deletions that extend distally to include the PTEN gene (601728) have a more severe phenotype with infantile/juvenile polyposis, macrocephaly, dysmorphic facial features, and developmental delay (summary by van Bon et al., 2011).

Craniosynostosis is a primary abnormality of skull growth involving premature fusion of the cranial sutures such that the growth velocity of the skull often cannot match that of the developing brain. This produces skull deformity and, in some cases, raises intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability (summary by Fitzpatrick, 2013). For a discussion of genetic heterogeneity of craniosynostosis, see CRS1 (123100).

Coffin-Siris syndrome (CSS) is classically characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, distinctive facial features, hypotonia, hirsutism/hypertrichosis, and sparse scalp hair. Congenital anomalies can include malformations of the cardiac, gastrointestinal, genitourinary, and/or central nervous systems. Other findings commonly include feeding difficulties, slow growth, ophthalmologic abnormalities, and hearing impairment.

Trichohepatoenteric syndrome (THES), generally considered to be a neonatal enteropathy, is characterized by intractable diarrhea (seen in almost all affected children), woolly hair (seen in all), intrauterine growth restriction, facial dysmorphism, and short stature. Additional findings include poorly characterized immunodeficiency, recurrent infections, skin abnormalities, and liver disease. Mild intellectual disability (ID) is seen in about 50% of affected individuals. Less common findings include congenital heart defects and platelet anomalies. To date 52 affected individuals have been reported.

Hyper-IgE syndrome-4B with recurrent infections (HIES4B) is an autosomal recessive immunologic disorder characterized by early childhood onset of recurrent infections and skeletal abnormalities, including craniosynostosis and scoliosis. Patients are mainly susceptible to bacterial infections that affect the respiratory tract, skin, and eye. Immunologic workup shows increased serum IgE, intermittent eosinophilia, and impaired IL6 (147620) and IL27 (608273) downstream signaling that affects the development and function of certain B- and T-cell populations, as well as the acute-phase response; IL11 (147681) signaling in fibroblasts is also affected (summary by Shahin et al., 2019). For a discussion of genetic heterogeneity of hyper-IgE syndrome, see HIES1 (147060).

Congenital hydrocephalus-4 (HYC4) is characterized by inadequate passage of cerebrospinal fluid (CSF) from its point of production to its point of absorption, in the absence of obstruction (communicating hydrocephalus). Patients undergo surgical shunting at birth because of extreme ventriculomegaly. Patients have neurodevelopmental delay and epilepsy (Furey et al., 2018).

Severe congenital liver disease (SCOLIV) is an autosomal recessive disorder characterized by the onset of progressive hepatic dysfunction usually in the first years of life. Affected individuals show feeding difficulties with failure to thrive and features such as jaundice, hepatomegaly, and abdominal distension. Laboratory workup is consistent with hepatic insufficiency and may also show coagulation defects, anemia, or metabolic disturbances. Cirrhosis and hypernodularity are commonly observed on liver biopsy. Many patients die of liver failure in early childhood (Moreno Traspas et al., 2022).

Tan-Almurshedi syndrome (TANALS) is an autosomal recessive neurodevelopmental disorder characterized by intrauterine growth retardation, poor overall growth with short stature and microcephaly, hypotonia, global developmental delay with impaired intellectual development, poor or absent speech, spasticity, and dysmorphic facial features (Westrip et al., 2023).