MedGen

The phenotypic spectrum of mucopolysaccharidosis IVA (MPS IVA) is a continuum that ranges from a severe and rapidly progressive early-onset form to a slowly progressive later-onset form. Children with MPS IVA typically have no distinctive clinical findings at birth. The severe form is usually apparent between ages one and three years, often first manifesting as kyphoscoliosis, genu valgum (knock-knee), and pectus carinatum; the slowly progressive form may not become evident until late childhood or adolescence, often first manifesting as hip problems (pain, stiffness, and Legg Perthes disease). Progressive bone and joint involvement leads to short stature, and eventually to disabling pain and arthritis. Involvement of other organ systems can lead to significant morbidity, including respiratory compromise, obstructive sleep apnea, valvular heart disease, hearing impairment, visual impairment from corneal clouding, dental abnormalities, and hepatomegaly. Compression of the spinal cord is a common complication that results in neurologic impairment. Children with MPS IVA have normal intellectual abilities at the outset of the disease. [from GeneReviews]

Coffin-Lowry syndrome (CLS) is usually characterized by severe-to-profound intellectual disability in males; less severely impaired individuals have been reported. Neuropsychiatric concerns can include behavioral problems, loss of strength, progressive spasticity or paraplegia, sleep apnea, or stroke. Stimulus-induced drop attacks (SIDAs) in which unexpected tactile or auditory stimuli or excitement triggers a brief collapse but no loss of consciousness are present in approximately 20% of affected individuals. Typically SIDAs begin between mid-childhood and the teens. Characteristic facial features may be more apparent with age. Upper-extremity differences may be subtle and include short, soft, fleshy hands with tapered fingers as well as fleshy forearms. Progressive kyphoscoliosis is one of the most difficult aspects of long-term care. Affected females tend to have intellectual disability in the mild-to-moderate range and may also have the typical facial, hand, and skeletal findings noted in males. [from GeneReviews]

Imerslund-Grasbeck syndrome-2 (IGS2) is an autosomal recessive disorder characterized by onset of megaloblastic anemia associated with decreased serum vitamin B12 (cobalamin, Cbl) in infancy or early childhood. Low molecular weight (LMW) proteinuria is frequently present, but usually occurs later and is usually mild or subclinical. Patients often present with vague symptoms, including failure to thrive, loss of appetite, fatigue, lethargy, and/or recurrent infections. Treatment with vitamin B12 results in sustained clinical improvement of the anemia. The proteinuria is nonprogressive, and affected individuals do not have deterioration of kidney function; correct diagnosis is important to prevent unnecessary treatment. The disorder results from a combination of vitamin B12 deficiency due to selective malabsorption of the vitamin, and impaired reabsorption of LMW proteins in the proximal renal tubule. These defects are caused by disruption of the AMN/CUBN (602997) complex that forms the 'cubam' receptor responsible for intestinal uptake of B12/GIF (CBLIF; 609342). In the kidney, AMN/CUBN interacts with the endocytic receptor megalin (LRP2; 600073), which is important for the reabsorption of plasma proteins (summary by Grasbeck, 2006, De Filippo et al., 2013, and Storm et al., 2013). For a discussion of genetic heterogeneity of Imerslund-Grasbeck syndrome, see 261100. [from OMIM]

SOFM is characterized by marked short stature, oligodontia, mild facial dysmorphism, and motor delay. Endosteal hyperostosis has also been observed, and patients may exhibit some features of progeria (Terhal et al., 2020; Beauregard-Lacroix et al., 2020). [from OMIM]

Atelis syndrome-1 (ATELS1) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay with learning difficulties and poor overall growth with short stature and microcephaly. Most patients have anemia, some have immunologic defects, and some have congenital heart septal defects. More variable features may include hypotonia, dysmorphic facial features, skin pigmentary anomalies, and mild skeletal defects. Patient cells show multiple chromosomal abnormalities due to impaired DNA replication and disrupted mitosis (Grange et al., 2022). See also ATELS2 (620185), caused by mutation in the SMC5 gene (609386) on chromosome 9q21. For a discussion of genetic heterogeneity of MVA, see MVA1 (257300). [from OMIM]

Over curvature of the lumbar region. [from HPO]