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At a glance

An inherited disorder with brachycephaly, short stature, and hands and feet. This syndrome has distinct facies with a small, broad nose and flat nasal bridge, prominent mandible, and microstomia. Other abnormalities affect the musculoskeletal system, genitals, skin, and teeth. Mental retardation is present in 90% of children and can be severe.

Synonyms

Arkless-Graham Syndrome; Maroteaux-Malamut Syndrome.

Incidence

Unknown, but less than 100 cases have been reported. The disorder affects individuals of different ethnic background and affects both sexes equally.

Genetic inheritance

Chromosomal studies are normal. Beside autosomal dominant inheritance pattern in two families, sporadic cases have also been described. The average parental age seems slightly increased (2-3 years) compared to the general parent population, which could suggest that advanced parental age is a risk factor for the condition. AD 1 is most likely caused by recurrent mutations in the gene encoding PRKAR1A (cyclic-AMP (cAMP)-dependent regulatory subunit of protein kinase A), which has been mapped to chromosome 17q24.2. In AD 2, the genetic defect results from heterozygous missense mutations of the PDE4D gene (cyclic-AMP-specific phosphodiesterase 4D), which has been mapped to chromosome 5q11.2-q12.1. Clinically, the two types of acrodysostosis are difficult to distinguish. However, it seems that in general hormone resistances are more common and neurocognitive impairment less severe in AD 1 than in AD 2.

Diagnosis

Based on the clinical features. Epiphyseal stippling on radiologic examination is a constant finding in infancy.

Clinical aspects

The most common manifestations include mental retardation (in about three-quarters of patients), learning difficulties and/or behavioral issues (of variable degree), brachycephaly, frontal bossing, hypertelorism, hypoplasia of the nose (short, broad, and upturned nose with depressed nasal bridge), and the maxilla (often with prognathism and increased mandibular angle) and small mouth. Poor growth results in brachymelic dwarfism in more than half of the patients. Severe brachydactyly, secondary to shortening of the tubular bones of hands and feet, and acromesomelic brachymelia are common. Other common skeletal features may include peripheral dysostosis, hyperplasia of the first ray of the foot, and decreased interpedicular distance of the lumbar vertebrae with predisposition to spinal canal stenosis. On radiologic examination, advanced skeletal maturation is seen in combination with cone-shaped epiphyses (hands and feet), epiphyseal stippling (very common in the first year of life), peripheral dysostosis, and abnormal metacarpophalangeal pattern profile. Marked hearing loss has been reported in about two-thirds of patients. Endocrine anomalies are common in AD 1 (but rare in AD 2) and may present as resistance to multiple hormones, including parathyroid hormone, thyrotropin (thyroid stimulating hormone [TSH]; with normal or low thyroxine [T4] plasma concentrations), calcitonin, impaired secretory response of growth hormone after a growth hormone-releasing hormone challenge, and gonadotropin (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) with hypogonadism in males (cryptorchidism and hypoplastic genitalia), ...

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