Alström syndrome is characterized by cone-rod dystrophy, obesity, progressive bilateral sensorineural hearing impairment, acute infantile-onset cardiomyopathy and/or adolescent- or adult-onset restrictive cardiomyopathy, insulin resistance / type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), and chronic progressive kidney disease. Cone-rod dystrophy presents as progressive visual impairment, photophobia, and nystagmus usually starting between birth and age 15 months. Many individuals lose all perception of light by the end of the second decade, but a minority retain the ability to read large print into the third decade. Children usually have normal birth weight but develop truncal obesity during their first year. Sensorineural hearing loss presents in the first decade in as many as 70% of individuals and may progress to the severe or moderately severe range (40-70 db) by the end of the first to second decade. Insulin resistance is typically accompanied by the skin changes of acanthosis nigricans, and proceeds to T2DM in the majority by the third decade. Nearly all demonstrate hypertriglyceridemia. Other findings can include endocrine abnormalities (hypothyroidism, hypogonadotropic hypogonadism in males, and hyperandrogenism in females), urologic dysfunction / detrusor instability, progressive decrease in renal function, and hepatic disease (ranging from elevated transaminases to steatohepatitis/NAFLD). Approximately 20% of affected individuals have delay in early developmental milestones, most commonly in gross and fine motor skills. About 30% have a learning disability. Cognitive impairment (IQ <70) is very rare. Wide clinical variability is observed among affected individuals, even within the same family.

DICER1 tumor predisposition (DICER1) is characterized by an increased risk for pleuropulmonary blastoma (PPB), pulmonary cysts, thyroid gland neoplasia (multinodular goiter, adenomas, and/or thyroid cancer), ovarian tumors (Sertoli-Leydig cell tumor, gynandroblastoma, and sarcoma), and cystic nephroma. Less commonly observed tumors include ciliary body medulloepithelioma, nasal chondromesenchymal hamartoma, embryonal rhabdomyosarcoma, pituitary blastoma, pineoblastoma, central nervous system (CNS) sarcoma, other CNS tumors, and presacral malignant teratoid tumor. The majority of tumors occur in individuals younger than age 40 years. PPB typically presents in infants and children younger than age six years. Ovarian sex cord-stromal tumors are most often diagnosed before age 40 years. Cystic nephroma generally presents in young children but has also been reported in adolescents. Additional clinical features that may be seen include macrocephaly, ocular abnormalities, structural anomalies of the kidney and collecting system, and dental anomalies (bulbous crowns).

CAPOK syndrome (CAPOK) is characterized by onset of symptoms in the first year of life, with the development of progressive alopecia, hypo- and hyperpigmented macular skin lesions, palmoplantar keratoderma, and nail dystrophy. Beginning in the third decade of life, patients develop recurrent squamous cell carcinomas. Some patients may have brittle teeth resulting in tooth loss, and multinodular goiter has been observed (Courcet et al., 2015).

Mosaic variegated aneuploidy syndrome-7 with inflammation and tumor predisposition (MVA7) is an autosomal recessive disorder characterized by increased susceptibility to benign and malignant neoplasms beginning in early childhood. Affected individuals show dysmorphic facies and may have early developmental delay. Patient cells show a high level of aneuploidy due to defects in cell division (Villarroya-Beltri et al., 2022). For a discussion of genetic heterogeneity of MVA, see MVA1 (257300).