MedGen

Phenylalanine hydroxylase (PAH) deficiency results in intolerance to the dietary intake of the essential amino acid phenylalanine and produces a spectrum of disorders. The risk of adverse outcome varies based on the degree of PAH deficiency. Without effective therapy, most individuals with severe PAH deficiency, known as classic PKU, develop profound and irreversible intellectual disability. Affected individuals on an unrestricted diet who have phenylalanine levels above normal but below 1,200 µmol/L (20 mg/dL) are at much lower risk for impaired cognitive development in the absence of treatment. [from GeneReviews]

Distance between the inner canthi more than two standard deviations above the mean (objective); or, apparently increased distance between the inner canthi. [from HPO]

Distance between nasal base and midline upper lip vermilion border more than 2 SD above the mean. Alternatively, an apparently increased distance between nasal base and midline upper lip vermilion border. [from HPO]

The palpebral fissure inclination is more than two standard deviations above the mean for age (objective); or, the inclination of the palpebral fissure is greater than typical for age. [from HPO]

Body temperature elevated above the normal range. [from HPO]

Width of the forehead or distance between the frontotemporales is more than two standard deviations above the mean (objective); or apparently increased distance between the two sides of the forehead. [from HPO]

Sotos syndrome is characterized by a distinctive facial appearance (broad and prominent forehead with a dolichocephalic head shape, sparse frontotemporal hair, downslanting palpebral fissures, malar flushing, long and narrow face, long chin); learning disability (early developmental delay, mild-to-severe intellectual impairment); and overgrowth (height and/or head circumference =2 SD above the mean). These three clinical features are considered the cardinal features of Sotos syndrome. Major features of Sotos syndrome include behavioral problems (most notably autistic spectrum disorder), advanced bone age, cardiac anomalies, cranial MRI/CT abnormalities, joint hyperlaxity with or without pes planus, maternal preeclampsia, neonatal complications, renal anomalies, scoliosis, and seizures. [from GeneReviews]

Silver-Russell Syndrome (SRS) is typically characterized by asymmetric gestational growth restriction resulting in affected individuals being born small for gestational age, with relative macrocephaly at birth (head circumference =1.5 SD above birth weight and/or length), prominent forehead usually with frontal bossing, and frequently body asymmetry. This is followed by postnatal growth failure, and in some cases progressive limb length discrepancy and feeding difficulties. Additional clinical features include triangular facies, fifth-finger clinodactyly, and micrognathia with narrow chin. Except for the limb length asymmetry, the growth failure is proportionate and head growth normal. The average adult height in untreated individuals is ~3.1±1.4 SD below the mean. The Netchine-Harbison Clinical Scoring System (NH-CSS) is a sensitive diagnostic scoring system. Clinical diagnosis can be established in an individual who meets at least four of the NH-CSS clinical criteria – prominent forehead/frontal bossing and relative macrocephaly at birth plus two additional findings – and in whom other disorders have been ruled out. [from GeneReviews]

Distance between subnasale and pronasale more than two standard deviations above the mean, or alternatively, an apparently increased anterior protrusion of the nasal tip. [from HPO]

Inclination of the anterior surface of the forehead from the vertical more than two standard deviations above the mean (objective); or apparently excessive posterior sloping of the forehead in a lateral view. [from HPO]

Facial height (length) is more than 2 standard deviations above the mean (objective); or, an apparent increase in the height (length) of the face (subjective). [from HPO]

Penile length more than 2 SD above the mean for age. [from HPO]

Quigley (1993) reviewed adult-onset primary open angle glaucoma, which combines a particular abnormal appearance of the optic disc (optic nerve head) with a slowly progressive loss of visual sensitivity. Many patients with glaucoma have intraocular pressures above the normal range, although this cannot be considered part of the definition of the disease, since some patients have normal intraocular pressures. Changes in the optic disc, either inherited or acquired, contribute to the development of the disorder, which leads to visual loss from increasing nerve fiber layer atrophy. Quigley et al. (1994) stated that POAG should be reviewed as a multifactorial disorder. Genetic Heterogeneity of Primary Open Angle Glaucoma Other forms of primary open angle glaucoma include GLC1A (137750), caused by mutation in the MYOC gene (601652) on chromosome 1q24; GLC1B (606689) on chromosome 2cen-q13; GLC1C (601682) on chromosome 3q21-q24; GLC1D (602429) on chromosome 8q23; GLC1F (603383), caused by mutation in the ASB10 gene (615054) on chromosome 7q36; GLC1G (609887), caused by mutation in the WDR36 gene (609669) on chromosome 5q22; GLC1H (611276), caused by mutation in the EFEMP1 gene (601548) on chromosome 2p16; GLC1I (609745) on chromosome 15q11-q13; GLC1J (608695) on chromosome 9q22; GLC1K (608696) on chromosome 20p12; GLC1L (see 137750) on chromosome 3p22-p21; GLC1M (610535) on chromosome 5q22; GLC1N (611274) on chromosome 15q22-q24; GLC1O (613100), caused by mutation in the NTF4 gene (162662) on chromosome 19q13; GLC1P (177700), caused by an approximately 300-kb duplication on chromosome 12q24, most likely involving the TBK1 gene (604834). Nail-patella syndrome (NPS; 161200), which is caused by mutation in the LMX1B gene (602575) on chromosome 9q34, has open angle glaucoma as a pleiotropic feature. Other Forms of Glaucoma For a general description and a discussion of genetic heterogeneity of congenital forms of glaucoma, see GLC3A (231300). See 606657 for a discussion of normal tension glaucoma (NTG) or normal pressure glaucoma (NPG), a subtype of POAG. See 618880 for a discussion of primary closed-angle glaucoma. [from OMIM]

Supravalvular aortic stenosis (SVAS) is a heart defect that develops before birth. This defect is a narrowing (stenosis) of the large blood vessel that carries blood from the heart to the rest of the body (the aorta). The condition is described as supravalvular because the section of the aorta that is narrowed is located just above the valve that connects the aorta with the heart (the aortic valve). Some people with SVAS also have defects in other blood vessels, most commonly stenosis of the artery from the heart to the lungs (the pulmonary artery). An abnormal heart sound during a heartbeat (heart murmur) can often be heard during a chest exam. If SVAS is not treated, the aortic narrowing can lead to shortness of breath, chest pain, and ultimately heart failure.

The severity of SVAS varies considerably, even among family members. Some affected individuals die in infancy, while others never experience symptoms of the disorder. [from MedlinePlus Genetics]

Increased thickness of the lower lip, leading to a prominent appearance of the lower lip. The height of the vermilion of the lower lip in the midline is more than 2 SD above the mean. Alternatively, an apparently increased height of the vermilion of the lower lip in the frontal view (subjective). [from HPO]

The classic phenotype of megalencephalic leukoencephalopathy with subcortical cysts (MLC) is characterized by early-onset macrocephaly, often in combination with mild gross motor developmental delay and seizures; gradual onset of ataxia, spasticity, and sometimes extrapyramidal findings; and usually late onset of mild mental deterioration. Macrocephaly, observed in virtually all individuals, may be present at birth but more frequently develops during the first year of life. The degree of macrocephaly is variable and can be as great as 4 to 6 SD above the mean in some individuals. After the first year of life, head growth rate normalizes and growth follows a line parallel to and usually several centimeters above the 98th centile. Initial mental and motor development is normal in most individuals. Walking is often unstable, followed by ataxia of the trunk and extremities, then minor signs of pyramidal dysfunction and brisk deep-tendon stretch reflexes. Almost all individuals have epilepsy from an early age. The epilepsy is typically well controlled with anti-seizure medication, but status epilepticus occurs relatively frequently. Mental deterioration is late and mild. Disease severity ranges from independent walking for a few years only to independent walking in the fifth decade. Some individuals have died in their teens or twenties; others are alive in their fifties. An improving phenotype has a similar initial presentation with delayed mental or motor development, followed by an improving clinical course: macrocephaly usually persists, but some children become normocephalic; motor function improves or normalizes; hypotonia and clumsiness may persist in some or neurologic examination may become normal. Some have intellectual disability that is stable, with or without autism. Epilepsy and status epilepticus may occur. [from GeneReviews]

Distance between the hairline (trichion) and the glabella (the most prominent point on the frontal bone above the root of the nose), in the midline, more than two SD below the mean. Alternatively, an apparently decreased distance between the hairline and the glabella. [from HPO]

Interalar distance more than two standard deviations above the mean for age, i.e., an apparently increased width of the nasal base and alae. [from HPO]

An increased creatine kinase level more than 50X above the upper normal level. [from HPO]

An increased CPK level between 4X and 50X above the upper normal level. [from HPO]