MedGen

HTRA1 disorder is a phenotypic spectrum in which some individuals have few to no symptoms and others manifest with the more severe CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) phenotype. Those who have a heterozygous HTRA1 pathogenic variant may have mild neurologic findings (sometimes identified only on neuroimaging) or mild-to-moderate neurologic signs and symptoms of CARASIL. In this chapter, the term "classic CARASIL" refers to the more severe phenotype associated with biallelic pathogenic variants, and "HTRA1 cerebral small vessel disease" (HTRA1-CSVD) refers to the milder phenotype associated with a heterozygous HTRA1 pathogenic variant. Classic CARASIL is characterized by early-onset changes in the deep white matter of the brain observed on MRI, and associated neurologic findings. The most frequent initial symptom is gait disturbance from spasticity beginning between ages 20 and 40 years. Forty-four percent of affected individuals have stroke-like episodes before age 40 years. Mood changes (apathy and irritability), pseudobulbar palsy, and cognitive dysfunction begin between ages 20 and 50 years. The disease progresses slowly following the onset of neurologic symptoms. Scalp alopecia and acute mid- to lower-back pain (lumbago) before age 30 years are characteristic. The most frequent initial symptom in individuals with HTRA1-CSVD is slowly progressive gait disturbance after age 40 years, which may be followed by the development of mood changes and cognitive dysfunction. A majority of affected individuals have a stroke-like episode after age 40 years. Spondylosis and alopecia are seen in a minority of individuals with HTRA1-CSVD. [from GeneReviews]

Any familial thoracic aortic aneurysm and aortic dissection in which the cause of the disease is a mutation in the MYH11 gene. [from MONDO]

Sitosterolemia is characterized by: Hypercholesterolemia (especially in children) which (1) shows an unexpected significant lowering of plasma cholesterol level in response to low-fat diet modification or to bile acid sequestrant therapy; or (2) does not respond to statin therapy; Tendon xanthomas or tuberous (i.e., planar) xanthomas that can occur in childhood and in unusual locations (heels, knees, elbows, and buttocks); Premature atherosclerosis, which can lead to angina, aortic valve involvement, myocardial infarction, and sudden death; Hemolytic anemia, abnormally shaped erythrocytes (stomatocytes), and large platelets (macrothrombocytopenia). On occasion, the abnormal hematologic findings may be the initial presentation or the only clinical feature of this disorder. Arthritis, arthralgias, and splenomegaly may sometimes be seen and one study has concluded that "idiopathic" liver disease could be undiagnosed sitosterolemia. The clinical spectrum of sitosterolemia is probably not fully appreciated due to underdiagnosis and the fact that the phenotype in infants is likely to be highly dependent on diet. [from GeneReviews]

Ehlers-Danlos syndrome classic-like-2 (EDSCLL2) is characterized by severe joint and skin laxity, osteoporosis involving the hips and spine, osteoarthritis, soft redundant skin that can be acrogeria-like, delayed wound healing with abnormal atrophic scarring, and shoulder, hip, knee, and ankle dislocations. Variable features include gastrointestinal and genitourinary manifestations, such as bowel rupture, gut dysmotility, cryptorchidism, and hernias; vascular complications, such as mitral valve prolapse and aortic root dilation; and skeletal anomalies (Blackburn et al., 2018). See 606408 for another classic-like EDS syndrome. For a discussion of the classification of EDS, see 130000. [from OMIM]

Grange syndrome (GRNG) is a rare early-onset disease characterized by hypertension and multifocal stenoocclusive lesions of renal, cerebral, and abdominal arteries. Bone fragility, syndactyly, brachydactyly, congenital heart defects, and learning disabilities have been reported with variable expressivity and incomplete penetrance (summary by Rath et al., 2019). [from OMIM]

Narrowing of the carotid arteries. [from HPO]