Tall stature and poor breast development after estrogen replacement in a hypergonadotrophic hypogonadic patient with a 45,X/46,X,der(X) karyotype with SHOX gene overdosage

Abstract

SHOX is exclusively expressed in the developing distal limb bones of human embryos and in the fi rst and second pharyngeal arches. It works as a promoter for linear growth and as a repressor of growth plate fusion. It was reported, recently, that SHOX overdosage and gonadal estrogen defi ciency have led to tall stature due to continued growth. We report, in the present study, a female patient with 45,X/46,X, psu idic(X)(pter→q21::q21→pter) karyotype, tall stature, and hypergonadotrophic hypogonadism without Turner stigmas. She did not present breast development even after long term therapy with high estrogen doses. Fluorescence in situ hybridization depicted the presence of three copies of SHOX gene. Microsatellite studies showed paternal origin of der(X). Further studies in similarly affected patients will clarify if the absence of breast development, despite previous high-dose estrogen treatment, is associated to triple copy of SHOX gene. O gene SHOX é expresso, exclusivamente, no primeiro e no segundo arcos faríngeos, assim como nas extremidades dos ossos dos membros em embriões humanos. SHOX normalmente atua como um promotor para o crescimento linear e como um repressor do fechamento da placa de crescimento. Recentemente, foi descrito que o excesso da proteína SHOX associada à defi ciência estrogênica gonadal leva à estatura alta devido ao contínuo crescimento. Neste estudo descrevemos uma paciente do sexo feminino com cariótipo 45,X/46,X,psu idic(X)(pter→q21::q21→pter), estatura alta, hipogonadismo hipergonadotrófi co e sem estigmas de Turner. A paciente não apresentou desenvolvimento de mamas, mesmo depois do tratamento prolongado com altas doses de estrógenos. FISH evidenciou a presença de três cópias do SHOX. Estudo de microssatélites demonstrou a origem paterna do der(X). Estudos futuros em pacientes com semelhanças clínicas esclarecerão se a ausência de desenvolvimento de mamas, apesar do tratamento com altas doses de estrógenos, está associada à tripla cópia do SHOX.

The Klinefelter syndrome is associated with high recurrence of copy number variations on the X chromosome with a potential role in the clinical phenotype

“…In contrast, the occurrence of SHOX duplications is apparently rare, with only few cases reported so far (Grigelioniene et al ., ; Tachdjian et al ., ; Roos et al ., ; Thomas et al ., ; D'Haene et al ., ; Gervasini et al ., ) and no direct relationship with any specific phenotype has yet been defined, also because it has been reported in association with normal to tall stature (Ogata et al ., ; Adamson et al ., ). Short stature in Turner's syndrome is caused by haploinsufficiency of SHOX , whereas an effect of SHOX overdosage was reported in females with supernumerary X chromosomes (Adamson et al ., ; Kanaka‐Gantenbein et al ., ; Alvarez‐Vázquez et al ., ; Nishi et al ., ) Consequently, the tall stature in KS may not be only due to hypogonadism, but may well be caused by excessive expression of SHOX .…”

Trisomy of the Short Stature Homeobox-Containing Gene (SHOX) due to Duplication/Deletion of the X Chomosome: Clinical Implications on the Stature

“…That combination was the key to diagnosis, suggesting that SHOX gene functions as a repressor of growth plate fusion, counteracting the skeletal-maturing effects of estrogens [22,23]. In 2008 a new patient with tall stature, gonadal dysgenesis, no Turner stigmata, poor breast development after estrogen replacement and a karyotype with an extra copy of the SHOX gene was described [24]. On the other hand, Adamson et al [25] reported the case of a woman with normal stature, gonadal dysgenesis and trisomy of the SHOX gene resulting from a crossover event of one maternal X chromosome containing balanced pericentric inversion (p21q21).…”

Bringing endocrine basic science and physician investigators together

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