MedGen

Alpha-1 antitrypsin deficiency (AATD) can present with hepatic dysfunction in individuals from infancy to adulthood and with chronic obstructive lung disease (emphysema and/or bronchiectasis), characteristically in individuals older than age 30 years. Individuals with AATD are also at increased risk for panniculitis (migratory, inflammatory, tender skin nodules which may ulcerate on legs and lower abdomen) and C-ANCA-positive vasculitis (granulomatosis with polyangiitis). Phenotypic expression varies within and between families. In adults, smoking is the major factor in accelerating the development of COPD; nonsmokers may have a normal life span, but can also develop lung and/or liver disease. Although reported, emphysema in children with AATD is extremely rare. AATD-associated liver disease, which is present in only a small portion of affected children, manifests as neonatal cholestasis. The incidence of liver disease increases with age. Liver disease in adults (manifesting as cirrhosis and fibrosis) may occur in the absence of a history of neonatal or childhood liver disease. The risk for hepatocellular carcinoma (HCC) is increased in individuals with AATD. [from GeneReviews]

X-linked agammaglobulinemia (XLA) is characterized by recurrent bacterial infections in affected males in the first two years of life. Recurrent otitis is the most common infection prior to diagnosis. Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are also frequently seen. Approximately 60% of individuals with XLA are recognized as having immunodeficiency when they develop a severe, life-threatening infection such as pneumonia, empyema, meningitis, sepsis, cellulitis, or septic arthritis. S pneumoniae and H influenzae are the most common organisms found prior to diagnosis and may continue to cause sinusitis and otitis after diagnosis and the initiation of gammaglobulin substitution therapy. Severe, difficult-to-treat enteroviral infections (often manifest as dermatomyositis or chronic meningoencephalitis) can be prevented by this treatment. The prognosis for individuals with XLA has improved markedly in the last 25 years as a result of earlier diagnosis, the development of preparations of gammaglobulin that allow normal concentrations of serum IgG to be achieved, and more liberal use of antibiotics. [from GeneReviews]

The phenotypic spectrum of ATP8B1 deficiency ranges from severe through moderate to mild. Severe ATP8B1 deficiency is characterized by infantile-onset cholestasis that progresses to cirrhosis, hepatic failure, and early death. Although mild-to-moderate ATP8B1 deficiency initially was thought to involve intermittent symptomatic cholestasis with a lack of hepatic fibrosis, it is now known that hepatic fibrosis may be present early in the disease course. Furthermore, in some persons with ATP8B1 deficiency the clinical findings can span the phenotypic spectrum, shifting over time from the mild end of the spectrum (episodic cholestasis) to the severe end of the spectrum (persistent cholestasis). Sensorineural hearing loss (SNHL) is common across the phenotypic spectrum. [from GeneReviews]

Primary ciliary dyskinesia-14 (CILD14) is an autosomal recessive disorder characterized by recurrent respiratory infections associated with defects in ciliary inner dynein arms and axonemal disorganization (Merveille et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400). [from OMIM]

Primary ciliary dyskinesia-15 (CILD15) is an autosomal recessive disorder characterized by recurrent respiratory infections associated with defects in ciliary inner dynein arms and axonemal disorganization (summary by Becker-Heck et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400). [from OMIM]

NKX2-1-related disorders range from benign hereditary chorea (BHC) to choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress (also known as brain-lung-thyroid syndrome). Childhood-onset chorea, the hallmark of NKX2-1-related disorders, may or may not be associated with respiratory distress syndrome or congenital hypothyroidism. Chorea generally begins in early infancy or about age one year (most commonly) or in late childhood or adolescence, and progresses into the second decade after which it remains static or (rarely) remits. Pulmonary disease, the second most common manifestation, can include respiratory distress syndrome in neonates, interstitial lung disease in young children, and pulmonary fibrosis in older persons. The risk for pulmonary carcinoma is increased in young adults with an NKX2-1-related disorder. Thyroid dysfunction, the result of dysembryogenesis, can present as congenital hypothyroidism or compensated hypothyroidism. The risk for thyroid cancer is unknown and may not be increased. In one review, 50% of affected individuals had the full brain-lung-thyroid syndrome, 30% had involvement of brain and thyroid only, and 13% had isolated chorea only. [from GeneReviews]

Diffuse panbronchiolitis (DPB) is a rare chronic inflammatory obstructive pulmonary disease primarily affecting the respiratory bronchioles. 'Diffuse' refers to the distribution of the lesions throughout both lungs, and 'pan-' refers to the involvement of inflammation in all layers of the respiratory bronchioles. Onset of the disorder occurs in the second to fifth decade of life, and is clinically manifest by chronic cough, exertional dyspnea, and sputum production. Most patients also have chronic paranasal sinusitis. If untreated, the disorder progresses to bronchiectasis, respiratory failure, and death (summary by Poletti et al., 2006). [from OMIM]

Immunodeficiency-20 is a rare autosomal recessive primary immunodeficiency characterized by functional deficiency of NK cells. Patient NK cells are defective in spontaneous cell cytotoxicity, but retain antibody-dependent cellular cytotoxicity. Patients typically present early in childhood with severe herpes viral infections, particularly Epstein Barr virus (EBV), and human papillomavirus (HPV) (summary by Grier et al., 2012). [from OMIM]

Primordial dwarfism-immunodeficiency-lipodystrophy syndrome (PDIL) is characterized by pre- and postnatal growth restriction, with extreme microcephaly, short stature, and absence of subcutaneous fat. There is also significant hematologic/immune dysfunction, with hypo- or agammaglobulinemia, as well as lymphopenia, anemia, and thrombocytopenia, and most affected individuals succumb to infection in early childhood (Parry et al., 2020). [from OMIM]

Recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD) is characterized by neonatal onset of chronic cough, episodic wheezing, recurrent lower respiratory tract infections, chronic diarrhea, and failure to thrive. Despite the resemblance to cystic fibrosis (CF; 219700), these patients have normal sweat chloride and pancreatic elastase tests (Bertoli-Avella et al., 2022). [from OMIM]

A high-pitched whistling sound associated with labored breathing. [from HPO]