SHOX haploinsufficiency presenting with isolated short long bones in the second and third trimester

Abstract

Haploinsufficiency of the transcription factor short stature homeobox (SHOX) manifests as a spectrum of clinical phenotypes, ranging from disproportionate short stature and Madelung deformity to isolated short stature. Here, we describe five infants with molecularly confirmed diagnoses of SHOX haploinsufficiency who presented in utero with short long bones during routine antenatal scanning from as early as 19 weeks gestation. Other foetal growth parameters were normal. The molecular basis of SHOX haploinsufficiency was distinct in each case. In four cases, SHOX haploinsufficiency was inherited from a previously undiagnosed parent. In our de novo case, SHOX haploinsufficiency reflected the formation of a derivative sex chromosome during paternal meiosis. Final adult height in the SHOX-deficient parents ranged from -1.9 to -1.2 SDS. All affected parents had disproportionately short limbs and two affected mothers had bilateral Madelung deformity. To our knowledge, SHOX haploinsufficiency has not previously been reported to present in utero. Our experience illustrates that SHOX deficiency should form part of the differential diagnosis of foetal short long bones and suggests a low threshold for genetic testing. This should be particularly targeted at, but not limited to, families with a history of features suggestive of SHOX deficiency. Data on the postnatal growth of our index cases is presented which demonstrates that antenatal presentation of SHOX haploinsufficiency is not indicative of severe postnatal growth restriction. Early identification of SHOX deficiency will enable accurate genetic counselling reflecting a good postnatal outcome and facilitate optimal initiation of growth hormone therapy.

Disruptive natural selection by male reproductive potential prevents underexpression of protein-coding genes on the human Y chromosome as a self-domestication syndrome

“…In the order of discussion, three rightmost columns of Table S 1 cite a clinical report [ 44 ] on SHOX deficiency as a known physiological marker of Madelung deformity and disproportionate short stature in newborns, as found in the PubMed database in its “Keyword search” mode [ 45 ] (hereinafter: see Supplementary Keyword Search, Additional file 3 ). That is why there is a down arrow (↓) in the “♂” column, which means a candidate SNP marker for a decrease in male reproductive potential, as predicted here, within the applicability limits described in ref.…”

New developments in the genetic diagnosis of short stature

“…SHOX deficiency should be considered if the family history shows an autosomal dominant inheritance pattern of disproportionate short stature (increased sitting height index or increased upper to lower body segment ratio), short 4 th metacarpal bones and/or Madelung deformity. Recently, Ramachandrappa et al reported that SHOX haploinsufficiency may be detected during routine antenatal ultrasound as early as 19-weeks of gestation [18]. However, it did not seem that antenatal presentation of SHOX haploinsufficiency was indicative of severe postnatal growth restriction [18].…”

“…Recently, Ramachandrappa et al reported that SHOX haploinsufficiency may be detected during routine antenatal ultrasound as early as 19-weeks of gestation [18]. However, it did not seem that antenatal presentation of SHOX haploinsufficiency was indicative of severe postnatal growth restriction [18].…”

How often do we identify fetal abnormalities during routine third‐trimester ultrasound? A systematic review and meta‐analysis

“…The second group includes abnormalities that can only be seen with fetal maturation, such as certain malformations of cortical development, microcephaly or hydrocephaly, gastrointestinal abnormalities relating to intestinal obstruction, urinary tract abnormalities that change over time such as renal pelvis dilation and some skeletal dysplasias. [16][17][18][19][20] There are some important considerations when detecting abnormalities in late pregnancy. These include factors at the level of the individual, such as ensuring appropriate consent prior to growth scans; anxiety provoked given the limited time to carry out full investigations, and referral for appropriate fetal/neonatal care; and implications at the level of the health system, such as the need for efficient late referral pathways and the associated costs of growth screening.…”