Chromosomal rearrangements including microdeletion and microduplication are a common cause of morbidity and mortality in the pediatric population.9
Array-based comparative genomic hybridization has revolutionized the early diagnosis and management of these chromosomal abnormalities that often were undetected by routine cytogenetic analysis.4
This report describes the growth pattern, swallow function studies, and associated clinical features in PTLS.
FTT is a frequent finding in individuals with chromosomal disorders and neurological impairment. FTT was diagnosed in 71% of our cohort. Our observations provide additional understanding into the mechanisms that may account for the feeding difficulties and FTT associated with PTLS. Abnormalities of swallowing function were universally present in this cohort suggesting that oropharyngeal dysfunction plays an important role in FTT and PTLS. It is known that hypotonia causes problems with feeding due to the inability to suck or masticate for prolonged periods of time. The observation of infantile hypotonia in 88% of the individuals suggests that hypotonia contributes to the etiology of FTT in PTLS. In addition, other features in PTLS that may influence feeding, such as structural abnormalities of the palate, were observed in 46% of the subjects. Our data also demonstrated that weight but not length deficits were present at birth and persisted throughout infancy and early childhood in persons with PTLS, suggesting that intrinsic genetic factors may also affect growth.
PTLS results from microduplication of chromosome 17 band p11.2.3
The common microduplication is the homologous recombination reciprocal of the 3.7Mb common Smith-Magenis syndrome (SMS) (MIM 182290) microdeletion (deletion 17p11.2).11
Although PTLS and SMS share the same molecular mechanism, the clinical characteristics of individuals with these disorders are distinct. Mouse models of PTLS demonstrate that the growth patterns of these animals are similar to those of human subjects as the heterozygous duplication PTLS mice are underweight from approximately 3 months of age and homozygous duplication animals have more severe weight and growth impairment; however, evidence of inadequate suck or feeding in these animals is lacking.12,13
In contrast, the SMS deletion animal model and the heterozygous Rai1
± knockout animals are overweight compared with wild-type controls,14
a feature common to older children and adults with SMS. Thus, the data derived from animal models of PTLS support that intrinsic genetic factors may also have a major impact on growth in this newly characterized chromosomal microduplication syndrome.
Medical intervention for FTT typically includes nutritional support and feeding therapy. Of the three subjects wherein the duration of nasogastric tube intervention was known, nutritional support ranged between 2 weeks and 6 months. Individuals with gastrostomy tubes had them placed for longer periods, yet details of caloric intake in these subjects are not available. The seven subjects with PTLS who underwent nasogastric or gastrostomy tube feedings remained on their respective linear growth curves and failed to resolve their weight deficits. The short-term intervention and lack of longitudinal data in this cohort precludes establishment of firm conclusions regarding these findings.
Although these are descriptive data and causation cannot be proven, we hypothesize that hypotonia and oropharyngeal dysphagia probably contribute to FTT in PTLS. Although we lack longitudinal follow-up of nutritional, developmental, cognitive, and behavioral outcomes, our preliminary data delineate the growth profile and abnormal swallowing function of individuals with PTLS and substantiate the need for early intervention with nutritional and oromotor therapy. Based on our results, we recommend that patients diagnosed with PTLS undergo an evaluation of oral-motor function by a trained therapist, a swallow function study, and an examination by an otolaryngologist. We anticipate that oral-motor feeding therapies will favorably influence overall nutrition and development in these children.
We conclude that FTT and oropharyngeal dysfunction are common features associated with PTLS. Weight-for-age, weight-for-length, and BMI-for-age in PTLS are significantly lower than those of the reference population and 100% have an element of oropharyngeal dysfunction. Oropharyngeal motor dysfunction and hypotonia are likely to contribute to poor feeding and FTT in PTLS. Our data demonstrate the need for early intervention with nutritional, feeding, and oromotor therapy in PTLS.