Frontal bossing, and Proximal muscle weakness

Multiple epiphyseal dysplasia due to collagen 9 anomaly is a rare primary bone dysplasia disorder characterized by normal or mild short stature, early-onset pain and/or stiffness of the joints (mainly affecting knees but also elbows, wrists, ankles and fingers, with relative sparing of the hips) and early degenerative joint disease. Other skeletal anomalies (incl. varus or valgus deformities, osteochondritis dissecans, abnormal carpal shape, free articular bodies) and mild myopathy have also been reported.

• Short stature
• Muscle weakness
• Pain
• Depressed nasal bridge
• Gait disturbance

SOURCES: OMIM ORPHANET MESH MENDELIAN

Camurati-Englemann disease (CED) is a rare, clinically variable bone dysplasia syndrome characterized by hyperostosis of the long bones, skull, spine and pelvis, associated with severe pain in the extremities, a wide-based waddling gait, joint contractures, muscle weakness and easy fatigability. Camurati-Englemann disease (CED) is a rare, clinically variable bone dysplasia syndrome characterized by hyperostosis of the long bones, skull, spine and pelvis, associated with severe pain in the extremities, a wide-based waddling gait, joint contractures, muscle weakness and easy fatigability.

CAMURATI-ENGELMANN DISEASE Is also known as diaphyseal dysplasia 1, progressive|engelmann disease|progressive diaphyseal dysplasia|dpd1|ced|pdd

• Hearing impairment
• Scoliosis
• Ataxia
• Muscle weakness
• Abnormal facial shape

SOURCES: OMIM ORPHANET MENDELIAN

Cowden syndrome (CS) is a difficult to recognize, under-diagnosed genodermatosis characterized by the presence of multiple hamartomas in various tissues and an increased risk for malignancies of the breast, thyroid, endometrium, kidney and colorectum. When CS is accompanied by germline PTEN mutations, it belongs to the PTEN hamartoma tumor syndrome (PHTS; see this term) group.

COWDEN SYNDROME Is also known as bzs|cowden disease|bbrs|macrocephaly, multiple lipomas, and hemangiomata|pten hamartoma tumor syndrome with granular cell tumor|bannayan-zonana syndrome|macrocephaly, pseudopapilledema, and multiple hemangiomata|cs|cd|mham|pten hamartoma tumor syndrome|ri

• Intellectual disability
• Seizures
• Global developmental delay
• Short stature
• Generalized hypotonia

SOURCES: ORPHANET OMIM MENDELIAN

An autosomal recessive form of rickets caused by inactivating mutation(s) in the CYP2R1 gene, encoding vitamin D 25-hydroxylase, the hepatic enzyme that converts vitamin D to 25-hydroxyvitamin D, the precursor of 1,25-dihydroxyvitamin D (calcitriol). The condition is characterized by reduced serum concentrations of 25-hydroxyvitamin D, hypophosphatemia, hypocalcemia with secondary hyperparathyroidism and elevated serum alkaline phosphatase, and by failure to thrive, seizures, muscle weakness, and rickets.

VITAMIN D HYDROXYLATION-DEFICIENT RICKETS, TYPE 1B; VDDR1B Is also known as 25-hydroxyvitamin d3 deficiency, selective|pseudovitamin d3 deficiency rickets due to 25-hydroxylase deficiency|vitamin d-dependent rickets, type 1b

• Generalized hypotonia
• Growth delay
• Failure to thrive
• Muscle weakness
• Muscular hypotonia

SOURCES: OMIM MESH MENDELIAN

Sclerosteosis is a severe sclerosing bone dysplasia characterized by progressive skeletal overgrowth. Syndactyly is a variable manifestation. The disorder is rare and the majority of affected individuals have been reported in the Afrikaner population of South Africa (summary by Brunkow et al., 2001).For a discussion of genetic heterogeneity of sclerosteosis, see SOST1 (OMIM ).

• Hearing impairment
• Hypertelorism
• Macrocephaly
• Gait disturbance
• Frontal bossing

SOURCES: OMIM MENDELIAN

Hypermethioninemia encephalopathy due to adenosine kinase deficiency is a rare inborn error of metabolism disorder characterized by persistent hypermethioninemia with increased levels of S-adenosylmethionine and S-adenosylhomocysteine which manifests with encephalopathy, severe global developmental delay, mild to severe liver dysfunction, hypotonia and facial dysmorphism (most significant is frontal bossing, macrocephaly, hypertelorism and depressed nasal bridge). Epileptic seizures, hypoglycemia and/or cardiac defects (pulmonary stenosis, atrial and/or ventricular septal defect, coarctation of the aorta) may be associated. Clinical picture may range from neurological symptoms only to multi-organ involvement.

HYPERMETHIONINEMIA ENCEPHALOPATHY DUE TO ADENOSINE KINASE DEFICIENCY Is also known as mental retardation, autosomal recessive 8, formerly|adk hypermethioninemia|mrt8, formerly|hypermethioninemia encephalopathy due to adk deficiency

• Seizures
• Global developmental delay
• Generalized hypotonia
• Hearing impairment
• Hypertelorism

SOURCES: ORPHANET MESH OMIM MENDELIAN

Hereditary hypophosphatemic rickets with hypercalciuria is a rare autosomal recessive disorder characterized by the presence of hypophosphatemia secondary to renal phosphate wasting, radiographic and/or histologic evidence of rickets, limb deformities, muscle weakness, and bone pain. HHRH is distinct from other forms of hypophosphatemic rickets in that affected individuals present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption (summary by Bergwitz et al., 2006).

HYPOPHOSPHATEMIC RICKETS WITH HYPERCALCIURIA, HEREDITARY; HHRH Is also known as hypercalciuric rickets

• Short stature
• Generalized hypotonia
• Growth delay
• Failure to thrive
• Muscle weakness

SOURCES: OMIM MENDELIAN

The musculocontractural type of Ehlers-Danlos syndrome is characterized by progressive multisystem fragility-related manifestations, including joint dislocations and deformities; skin hyperextensibility, bruisability, and fragility, with recurrent large subcutaneous hematomas; cardiac valvular, respiratory, gastrointestinal, and ophthalmologic complications; and myopathy, featuring muscle hypoplasia, muscle weakness, and an abnormal muscle fiber pattern in histology in adulthood, resulting in gross motor developmental delay (summary by Muller et al., 2013).For a discussion of genetic heterogeneity of the musculocontractural type of Ehlers-Danlos syndrome, see EDSMC1 (OMIM ).

• Global developmental delay
• Hypertelorism
• Muscle weakness
• Abnormal facial shape
• Pain

SOURCES: OMIM MENDELIAN

Molybdenum cofactor deficiency (MOCOD) is a rare autosomal recessive metabolic disorder characterized by onset in infancy of poor feeding, intractable seizures, and severe psychomotor retardation. Characteristic biochemical abnormalities include decreased serum uric acid and increased urine sulfite levels due to the combined enzymatic deficiency of xanthine dehydrogenase (XDH ) and sulfite oxidase (SUOX ), both of which use molybdenum as a cofactor. Most affected individuals die in early childhood (summary by Reiss, 2000; Reiss et al., 2011). Genetic Heterogeneity of Molybdenum Cofactor DeficiencySee also MOCOD, complementation group B (MOCODB ), caused by mutation in the MOCS2 gene (OMIM ) on chromosome 5q11; and MOCOD, complementation group C (MOCODC ), caused by mutation in the GPHN gene (OMIM ) on chromosome 14q24.

SULFITE OXIDASE DEFICIENCY DUE TO MOLYBDENUM COFACTOR DEFICIENCY TYPE A Is also known as sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase, combined deficiency of|combined deficiency of sulfite oxidase, xanthine dehydrogenase and aldehyde oxidase type a|mocod type a

• Intellectual disability
• Seizures
• Global developmental delay
• Generalized hypotonia
• Microcephaly

SOURCES: ORPHANET OMIM MESH MENDELIAN

Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and death usually in the first years of life. It represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1 ), collectively known as 'dystroglycanopathies' (summary by Roscioli et al., 2012).For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (OMIM ).

MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 7; MDDGA7 Is also known as walker-warburg syndrome or muscle-eye-brain disease, ispd-related

• Intellectual disability
• Generalized hypotonia
• Cataract
• Low-set ears
• Macrocephaly

SOURCES: OMIM MENDELIAN