Characteristics of Sotos syndrome
Boer, L. de
Citation
Boer, L. de. (2005, April 28). Characteristics of Sotos syndrome. Retrieved from https://hdl.handle.net/1887/4565
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis in theInstitutional Repository of the University of Leiden Downloaded from: https://hdl.handle.net/1887/4565
CHAPTER 5
$X[RORJLFDOGDWDLQSDWLHQWVFOLQLFDOO\VXVSHFWHGRI
6RWRVV\QGURPHZLWK16'JHQHDOWHUDWLRQV
L. de Boer1, S. le Cessie2, J.M. Wit1
Department of Paediatrics1, Department of Medical Statistics2, Leiden University Medical Center, Leiden, the Netherlands
$EVWUDFW
$LP
Nuclear receptor binding SET domain containing protein 1 (NSD1) gene mutations and deletions (NSD1+/-) are the major cause of Sotos syndrome. The aim was to investigate which auxology parameters relate to NSD1+/- in patients clinically suspected of Sotos
syndrome. 0HWKRGV
In 32 patients clinically suspected of Sotos syndrome, we compared auxology parameters between NSD1+/- patients and patients without NSD1 gene alterations (NSD1+/+). The statistical performance of these parameters to predict NSD1+/- was assessed.
5HVXOWV
Arm span for height standard deviation score (SDS) and hand length SDS were significantly higher in NSD1+/- patients.
&RQFOXVLRQ
Arm span for height and hand length are discriminating parameters between NSD1 +/-and NSD1+/+.
Sotos syndrome is an overgrowth syndrome, characterised by macrocephaly, advanced bone age, developmental delay and typical facial features as frontal bossing, pointed chin, high hair line, antimongoloid slant of palpebral fissures, dolichocephaly and a high palate (1, 2). In 2002 NSD1 gene alterations were discovered as the major cause of Sotos syndrome (3). According to earlier reports, auxological measures as arm span, hand length and foot length are increased in Sotos syndrome (2, 4), hand and foot length were even large when corrected for height (2), and upper to lower segment body ratios are decreased (4). These auxological measurements have not yet been related to NSD1 gene alterations.
92
Table 1. Auxology data (SDS) of patients with and without NSD1 gene alterations, mean (95% CI)
NSD+/+ NSD+/- t-test
Number of patients (number < 15 years) 19 (15) 13 (7) Age Mean (range) in years 14.1 (1.8-48.4) 13.3 (2.1-36.3)
Sex Male/Female 14/5 8/5
Birth parameters length 0.8 (0.2-1.4) 1.4 (0.2-2.5) 0.32 for gestational age weight 0.2 (-0.4-0.8) 0.3 (-0.6-1.3) 0.78 head circumference 1.0 (0.3-1.7) 1.2 (0.2-2.1) 0.78
Height Height for age 1.4 (0.7-2.1) 1.9 (1.1-2.6) 0.40 only patients < 15 years 1.8 (1.3-2.4) 2.4 (1.0-3.8) 0.32 Height – target height 0.9 (0.3-1.6) 1.8 (1.1-2.5) 0.06 only patients < 15 years 1.1 (0.4-1.7) 2.0 (0.9-3.2) 0.10
Sitting height and Sitting height for age 1.4 (0.5-2.2) 1.0 (0.3-1.7) 0.49 leg length Leg length for age 1.6 (1.2-2.1) 1.9 (1.2-2.6) 0.46 Sitting height/height -0.9 (-1.6--0.2) -1.0 (-1.6--0.4) 0.91
Arm span Arm span for age 1.0 (0.2-1.8) 2.0 (1.3-2.6) 0.09 Arm span for height -0.3 (-1.0-0.5) 1.6 (0.2-3.1)
Hand and foot Hand length for age 0.8 (0.1-1.7) 2.3 (1.5-3.1) length Foot length for age 0.7 (-0.3-1.6) 2.1 (0.8-3.4) 0.06 Foot length for height -1.2 (-2.3--0.1) 0.4 (-1.3-2.0) 0.09
Head
circumference Head circumference for age 2.2 (1.5-2.8) 2.6 (1.9-3.4) 0.32
BMI 1.0 (0.2-1.7) 1.0 (0.1-1.9) 0.98
NSD1+/+ = no NSD1 gene alteration
NSD1+/- = NSD1 gene mutation or deletion
CI = confidence interval
Table 2. Statistical characteristics of four auxology parameters at optimal cut-off limits for discriminating between patients with and without NSD1 gene alteration
Hand length SDS Arm span for Height
SDS Height-target height SDS Patients < 15 yrs Head circumference SDS AUC 0.737 0.732 0.705 0.632 Optimal cut-off limit > 1.5 SDS > 0.25 SDS > 2 SDS > 2 SDS Sensitivity 0.85 0.73 0.57 0.77 Specificity 0.72 0.72 0.87 0.63 + LR (95%CI) 3.05 (1.40-6.65) 2.62 (1.14-5.99) 4.29 (1.01-18) 2.09 (1.08-4.04) PPV (95%CI) 0.69 (0.50-0.83) 0.62 (0.41-0.79) 0.67 (0.32-0.89) 0.59 (0.42-0.73) - LR (95% CI) 0.21 (0.06-0.79) 0.38 (0.14-1.03) 0.49 (0.21-1.19) 0.37 (0.13-1.04) NPV (95%CI) 0.87 (0.64-0.96) 0.81 (0.61-0.92) 0.81 (0.64-0.91) 0.80 (0.58-0.92)
AUC=area under the curve, CI= confidence interval, +LR= Likelihood ratio for a positive test result, PPV= positive predictive value, -LR= Likelihood ratio for a negative test result, NPV= negative predictive value
length), > 2.0 SDS (height - TH, patients < 15 yrs) and > 2.1 SDS (head circumference). The rounded values are shown in table 2. Hand length SDS and arm span for height SDS combined (using results of logistic regression) in a ROC curve yield an AUC of 0.840. All four parameters showed a significantly elevated positive likelihood ratio. Hand length showed a significantly decreased negative likelihood ratio.
In all patients suspected of Sotos syndrome (NSD1+/+ and NSD1+/- patients), the results show an increased mean arm span and, as described before (2), increased hand length. Foot length corrected for height was not significantly elevated in both subgroups. In agreement with another study (4), decreased sitting height/height ratios were found, which means leg length contributes most to the increased height. If both subgroups are compared, arm span in NSD1+/- patients is disproportional, meaning that after height correction still an increased value is found, in contrast to the findings in NSD1+/+ patients. Hand length above 1.5 SDS is a good discriminating parameter for NSD1+/-. No significant differences were found between the two groups for the sitting height/height ratio.
94
$FNQRZOHGJHPHQWV
Thanks are due to Liselore van Esch for assisting in collection of the data.
5HIHUHQFHV
1. Sotos JF, Dodge PR, Muirhead D, Crawford JD, Talbot NB: Cerebral gigantism
in childhood. A syndrome of excessively rapid growth with acromegalic features and a nonprogressive neurologic disorder. N Engl J Med 1964; 271:109-116
2. Cole TR, Hughes HE: Sotos syndrome: a study of the diagnostic criteria and
natural history. J Med Genet 1994; 31(1):20-32
3. Kurotaki N, Imaizumi K, Harada N, Masuno M, Kondoh T, Nagai T:
Haploinsufficiency of NSD1 causes Sotos syndrome. Nat Genet 2003; 30:365-366
4. Agwu JC, Shaw NJ, Kirk J, Chapman S, Ravine D, Cole TR: Growth in Sotos
syndrome. Arch Dis Child 1999; 80(4):339-342
5. Fredriks AM, van Buuren S, Burgmeijer RJ, Meulmeester JF, Beuker RJ,
Brugman E et al: Continuing positive secular growth change in The Netherlands 1955-1997. Pediatr Res 2000; 47(3):316-323
6. Fredriks AM, van Buuren S, Wit JM, Verloove-Vanhorick SP: Body index
measurements in 1996-7 compared with 1980. Arch Dis Child 2000; 82(2):107-112
7. Gerver WJM, de Bruin R: Paediatric Morphometrics, A Reference Manual.
Utrecht: Wetenschappelijke uitgeverij Bunge, 1996
8. Niklasson A, Ericson A, Fryer JG, Karlberg J, Lawrence C, Karlberg P: An
update of the Swedish reference standards for weight, length and head circumference at birth for given gestational age (1977-1981). Acta Paediatr Scand 1991; 80(8-9):756-762
