Growth in Phelan–McDermid syndrome

Phelan–McDermid syndrome (or 22q13.3 deletion syndrome, OMIM #606232) results from a deletion in the terminal region of the long arm of chromosome 22 [Phelan et al., 2001]. Characteristic traits include hypotonia, developmental delay, and severely delayed or absent speech. Minor dysmorphic features are often present, and include long eyelashes, abnormal external ears, large fleshy hands, and hypoor dysplastic toenails [Phelan, 2008]. The growth aspect of the clinical picture of this syndrome is not welldefined. We report growth data on a cohort of 55 patients with terminal 22q13 deletions. Our results help delineate the clinical picture ofPhelan–McDermid syndromeanddemonstrate thenovel observation of occasional undergrowth. The postulation that ‘‘accelerated’’ growth may be a feature of Phelan–McDermid syndrome can be traced to an early report of seven patients with 22q13.3 deletions [Nesslinger et al., 1994]. This assertion was partially based on the observation that while none of the seven patients was undergrown, one had tall stature, one had large hands and feet, and three hadmacrocephaly. Of the three who had macrocephaly, two of their fathers did as well, suggesting the macrocephaly may have been inherited [Weaver and Christian, 1980] independently of the de novo 22q13.3 deletions. One of the two patients with familial macrocephaly was also the patient with tall stature, and head circumference is a known correlate of stature [Bushby et al., 1992], raising furtherquestionof a true associationof overgrowth with the deletion. On the other hand, most previous reports of short stature occurred in patients with ring chromosome 22, so growth failure was dismissed as a phenomenon of any autosomal ring structure rather than deletion of 22q13 [Luciani et al., 2003; Dhar et al., 2010]. Thus, ambiguous and subjective references to advanced or accelerated growth have often been repeated among the list of features of Phelan–McDermid syndrome [Phelan et al., 2001; Jones, 2006; Cusmano-Ozog et al., 2007; Phelan, 2008], although objective evidence has been weak. Wehave collected the largest set of clinical and laboratory data to date on patients with Phelan–McDermid syndrome. Most growth measurements were gathered from physical examinations at Phelan–McDermid Syndrome Foundation conferences in 1998, 2000, 2004, 2006, and 2008; measurements for two additional patients were derived from medical records. This study and the consent forms were approved by the Institutional Review Board of Self Regional Healthcare in Greenwood, South Carolina. After excluding patients with all but terminal deletions of 22q13 (i.e., rings, translocations, interstitial deletions, etc.), the study included growth data on 55 patients (26 males, 29 females) between 10 months and 40 years of age (median age 5.17 years). In five cases where multiple measurements were available from the same patient, only the most recent measurements were used. A total of 45 length/height measurements (19 males, 26 females) and 53 head circumference measurements (25 males, 28 females) were compared by deriving their centiles from the most recent growth references for the United States population [Kuczmarski et al., 2002; Rollins et al., 2010]. One-sample t-tests performed using Stata SE/10 (StataCorp, College Station, TX) revealed that average length-for-age, staturefor-age, andhead circumference-for-age centiles of our patients did not differ significantly from the expected value of 50 (Table I). However, the data appeared to be heavily weighted in the tails; the Chi-square goodness of fit test, also performed using Stata, revealed that the proportion of measurements falling above and below the respective cutoffs for tall and short stature (>95th centile and<5th centile, respectively) was significantly different than expected (P1⁄4 0.0239). The number of patients with short stature equalled