Coffin-Lowry Syndrome

A syndrome of mental retardation and osteocartilaginous abnormalities with peculiar facies.

Coffin-Siris-Wegienka Syndrome (do not confuse with Coffin-Siris Syndrome, which is a different disease); Soft Hands Syndrome.

First described by Grange S. Coffin, an American pediatrician, Evelyn Siris, an American radiologist, and Laurence C. Wegienka, an American physician, in 1966. However, to avoid (further) confusions with Coffin-Siris Syndrome, it was decided to name the syndrome described here as Coffin Lowry Syndrome (after Robert Bryan Lowry, a British medical geneticist, who described a fourth family with the same findings in 1971).

1:50,000-100,000 live births. No sexual predilection, but the disease is more severe in males.

X-linked semidominant inherited disorder caused by mutations in the gene coding for the RSK2 (ribosomal s6 kinase 2), a growth factor-regulated serine-threonine protein kinase (involved in promotion of mitosis and activation of genes) that has been mapped to Xp22.2-p22.1. However, research shows that only a minority of patients with this disorder actually have a mutation in the RSK2 gene.

Abnormal proteodermatan sulfate, glycolipid-like lysosomal granules, and vacuoles have been found in cultured skin fibroblasts. Accumulation of hyaluronate and hyperprolinemia have been reported in some patients.

Based on the clinical association of growth and psychomotor retardation with hypotonia, progressive skeletal deformations, characteristic facial dysmorphism, and large soft hands.

There is a wide variability in the expression of the features of the syndrome. Involvement of the head and neck can present as thickened calvarium, small sinuses paranasales, flat occiput, delayed suture closure with large anterior fontanelle, prominent supraorbital ridges with bushy brows, downwardly slanted palpebral fissures, hypertelorism, blepharoptosis, large and prominent ears, large nose with broad base and elongated philtrum, mandibular prognathism, maxillary/midfacial hypoplasia, large mouth with big lips, and longitudinally furrowed tongue with a dorsal groove. The facial features are generally not present at birth, but become apparent by the second year of life, after which they become more pronounced. Dental anomalies are numerous and may include congenital absence of some teeth, delayed eruption, enamel hypoplasia, caries, early loss of teeth, abnormal size and shape, malposition, malalignments, and periodontal disease. Involvement of the musculoskeletal system presents as short thorax, bifid sternum, pectus excavatum or carinatum, vertebral dysplasia, kyphosis, scoliosis, delayed bone age, ligamental calcifications, hyperextensible joints, muscle atrophy, large and soft hands with simian crease, and tapering of the fingers. Cardiovascular involvement is frequent, with features including atrial septal defects, persistent ductus arteriosus, valvular anomalies (mitral valve prolapse, mitral regurgitation, tricuspid insufficiency), impaired cardiac function, right ventricular hypertrophy, restrictive cardiomyopathy, endomyocardial fibroelastosis, and ventricular arrhythmias. Central nervous system features consist of generalized hypotonia, which may be the earliest presenting sign and related to paroxysmal drop attacks (cataplexy or hyperexplexia). In addition, seizures, hydrocephalus, agenesis of the corpus callosum, abnormal gyration, faulty cortical lamination, calcification of the falx cerebri, sensorineural hearing loss, mental retardation, a tendency to obsessive-compulsive behavior, and cervical radiculopathy (secondary to calcification of the ligamentum flavum and consequent stenosis of the spinal canal) have been described. Inguinal and umbilical hernias and rectal and uterine prolapse appear to be common in these patients. Liver cirrhosis, recurrent respiratory infections, and emphysema have been described. Most of the clinical findings become more pronounced with increasing age.

Structural and functional cardiac abnormalities should be identified preoperatively (echocardiogram, electrocardiogram, chest radiograph) because they are responsible for fatal outcome. Endomyocardial fibroelastosis may be asymptomatic, and a high index of clinical suspicion is needed with respect to cardiac involvement. Evaluate neurologic function (clinically, review electroencephalogram, computed tomography scans, and/or magnetic resonance images). Evaluate intubation anatomy and document dental anomalies. Assess liver, renal, and pulmonary function, although pulmonary function tests may be of limited value because of decreased patient compliance. Laboratory investigations should include a complete blood count, serum levels of electrolytes, creatinine, and blood urea nitrogen, and arterial blood gas analysis in selected patients. Frequent or chronic pulmonary infections combined with emphysema may require prolonged mechanical ventilation postoperatively. Developmental delay may limit patient cooperation. Sedative and/or anxiolytic premedication and the presence of the primary caregiver during induction of anesthesia may be helpful.

The facial features suggest airway management may be difficult. Cardiac involvement may warrant specific anesthesia techniques and invasive monitoring. Special attention is needed for the teeth. Patients are prone to seizures. Controlled ventilation with normocapnia or mild hypocapnia is recommended in the presence of untreated hydrocephalus. Careful intraoperative positioning is needed because of musculoskeletal involvement. Regional anesthesia is not contraindicated per se, but central neuraxial blockade may be difficult to perform and should be avoided in the presence of radiculopathy or hydrocephalus.

Chronic use of many antiseizure medications may alter the metabolism of certain anesthetic agents. Subacute bacterial endocarditis prophylaxis may be required as indicated. In the presence of renal and/or hepatic insufficiency, drugs should be selected and dosed accordingly.

Fragile X Syndrome: A syndrome comprising X-linked mental retardation in children with prognathism, hypotonia, and autism and a characteristic, but variable facies (long face, high arched palate, malocclusion). Additional abnormalities may include hyperlordosis, heart defects, pectus excavatum, shortening of the tubular bones of the hands, and joint laxity.

Sotos Syndrome: Characterized by excessively rapid growth during the first year of life, acromegalic craniocerebral features (macrocephaly, prominent forehead) and a nonprogressive cerebral disorder with mental retardation. Other features include high arched palate and prognathism with premature eruption of teeth, hypotonia, hyperthyroidism or hypothyroidism, and delayed motor and cognitive development.

Williams Syndrome: A syndrome characterized by peculiar elfin facies associated with infantile hypercalcemia, cardiac defects, and mild mental retardation. High frequency of sudden death.

Alpha Thalassemia: The clinical signs of this disorder are a result of hemolysis and chronic anemia. The clinical features include hepatosplenomegaly, bone deformations, and cardiac failure. Strict asepsis is needed.