SHOXHaploinsufficiency and Leri-Weill Dyschondrosteosis: Prevalence and Growth Failure in Relation to Mutation, Sex, and Degree of Wrist Deformity

Abstract

SHOX mutations causing haploinsufficiency were reported in Leri-Weill dyschondrosteosis (LWD), which is characterized by mesomelic short stature and Madelung deformity of the wrists. The aim of this study was to determine the prevalence of SHOX mutations in LWD and to investigate the degree of growth failure in relation to mutation, sex, age of menarche, and wrist deformity. We studied 20 families with 24 affected children (18 females) and nine affected parents (seven females). All patients presented with bilateral Madelung deformity and shortening of the limbs. Height, sitting height, parental height, birth length, age of menarche, and presence of minor abnormalities were recorded. The degree of Madelung deformity was estimated by analysis of left hand radiographs. Microsatellite typing of the SHOX locus was used for detection of SHOX deletions and PCR direct sequencing for the detection of SHOX point mutations. In 14 of 20 families (70%), SHOX mutations were detected, with seven deletions (four de novo) and seven point mutations (one de novo). The latter included five missense mutations of the SHOX homeodomain, one nonsense mutation (E102X) truncating the whole homeodomain, and one point mutation (X293R) causing a C-terminal elongation of SHOX. Median age of the affected children was 13.4 yr (range, 6.1-18.3), mean height sd score (SDS) (sd in parentheses) was -2.85 (1.04), and mean sitting height/height ratio SDS was +3.06 (1.09). Mean birth length SDS was -0.59 (1.26). Growth failure occurred before school age. Height change during a median follow-up of 7.4 yr (range, 2.3-11.3) was insignificant with a mean change in height SDS of -0.10 (0.52). Mean height SDS of affected parents was -2.70 (0.85) vs. -0.91 (1.10) in unaffected parents. Height loss due to LWD was estimated calculating delta height defined by actual height SDS minus target height SDS of the unaffected parent(s). In the children, mean delta height SDS was -2.16 (1.06), the loss being greater in girls at -2.30 (1.02) than in boys at -1.72 (1.09) (P = 0.32). In patients with SHOX deletions, it was -2.14 (1.15) vs. -1.67 (0.73) for the SHOX point mutation group (P = 0.38). Mean delta height SDS was -2.26 (0.68) for the girls with early menarche (<12 yr) vs. -2.08 (0.91) for the other postmenarcheal girls (P = 0.72). Height loss in patients with radiologically severe wrist deformities in comparison with those having milder radiological signs was -2.81 (1.01) vs. -1.70 (1.04) (P = 0.03). GH treatment in five children during a median duration of 3.4 yr (range, 1.5-9.8 yr) with a median dosage of 0.23 mg/kg.wk (range, 0.14-0.25) resulted in a mean height SDS gain of +0.82 (0.34). In conclusion, SHOX defects were the main cause of LWD. Growth failure occurred during the first years of life with a mean height loss of 2.16 SDS whereas pubertal growth may only be mildly or not affected. Children with a severe degree of wrist deformity were significantly shorter than those with mild deformities. No statistically significant effects of type of mutation, age ...

Argentine references for the assessment of body proportions from birth to 17 years of age

“…By this time, clinical and/or radiological signs are evident. [3][4][5][6][7][8][9][10] Many patients with SD have a HC that is normal for their age (between ± 2 Z-scores), but clinically "large" for their height. The term relative macrocephaly is used for cases in whom head circumference is normal for a given age and sex, but "high" for their height.…”

Growth response to growth hormone treatment in patients with SHOX deficiency can be predicted by the Cologne prediction model

“…From numerous studies it appears that SHOX deficiency is the most prevalent monogenic cause of short stature [10]. SHOX anomalies are identified in 2%-15% of patients with short stature [9,[11][12][13][14]. In 2007 a human SHOX allelic variant database was created which can help to distinguish between functional variants and polymorphisms [15].…”

“…In 2007 a human SHOX allelic variant database was created which can help to distinguish between functional variants and polymorphisms [15]. Short children with alterations in SHOX retain a reduced height in adulthood [11,14,16]. Therefore, two studies analyzed the effect of growth hormone (GH) treatment in children with SHOX deficiency [17,18].…”

Referencias argentinas para la evaluación de proporciones corporales desde el nacimiento hasta los 17 años

“…En otras, sin embargo, se necesita de un seguimiento a largo plazo, inclusive hasta la etapa final de crecimiento, momento en el cual los signos clínicos y/o radiológicos son evidentes. [3][4][5][6][7][8][9][10] Muchos niños con DE tienen PC normal para la edad (ent re ± 2 puntuaciones Z) pero clínicamente "alto" para su estatura. El término macrocefalia relativa se utiliza en los casos en los que el PC es normal para la edad y el sexo pero "elevado" para la estatura.…”