Heterozygous IGFALS gene variants in idiopathic short stature and normal children: impact on height and the IGF system.

BACKGROUND: In acid-labile subunit (ALS)-deficient families, heterozygous carriers of IGFALS gene mutations are frequently shorter than their wild-type relatives, suggesting that IGFALS haploinsufficiency could result in short stature. We have characterized IGFALS gene variants in idiopathic short stature (ISS) and in normal children, determining their impact on height and the IGF system. PATIENTS AND METHODS: In 188 normal and 79 ISS children levels of IGF-1, IGFBP-3, ALS, ternary complex formation (TCF) and IGFALS gene sequence were determined. RESULTS: In sum, 9 nonsynonymous or frameshift IGFALS variants (E35Gfs*17, G83S, L97F, R277H, P287L, A330D, R493H, A546V and R548W) were found in 10 ISS children and 6 variants (G170S, V239M, N276S, R277H, G506R and R548W) were found in 7 normal children. If ISS children were classified according to the ability for TCF enhanced by the addition of rhIGFBP-3 (TCF+), carriers of pathogenic IGFALS gene variants were shorter and presented lower levels of IGF-1, IGFBP-3 and ALS in comparison to carriers of benign variants. In ISS families, subjects carrying pathogenic variants were shorter and presented lower IGF-1, IGFBP-3 and ALS levels than noncarriers. CONCLUSIONS: These findings suggest that heterozygous IGFALS gene variants could be responsible for short stature in a subset of ISS children with diminished levels of IGF-1, IGFBP-3 and ALS.

A novel missense mutation in the SH2 domain of the STAT5B gene results in a transcriptionally inactive STAT5b associated with severe IGF-I deficiency, immune dysfunction, and lack of pulmonary disease.

CONTEXT: Signal transducer and activator of transcription 5b (STAT5b) deficiency, first reported in a patient who carried a p.Ala630Pro missense mutation in the Src homology 2 (SH2) domain, results in a rare clinical condition of GH insensitivity (GHI), IGF-I deficiency (IGFD), and severe immune dysregulation manifesting as progressive worsening of pulmonary function. PATIENT: The new patient presented with severe cutaneous eczema, episodic infections in the first years of life, and autoimmune thyroiditis. Immunological evaluation revealed T lymphopenia, but severe pulmonary symptoms were notably absent. She concomitantly exhibited pronounced growth failure, reaching an adult height of 124.7 cm [-5.90 SD score (SDS)]. Endocrine evaluations (normal provocative GH tests; low serum IGF-I, -3.7 SDS, and IGF-binding protein-3, -4.5 SDS) were consistent with GHI and IGFD. RESULTS: Analysis of the STAT5B gene revealed a novel homozygous missense mutation, p.Phe646Ser, located within the ßD' strand of the SH2 domain. Reconstitution studies demonstrated expression of the p.Phe646Ser variant was less robust than wild type but, in contrast to the previously described STAT5B p.Ala630Pro SH2 mutation, could be phosphorylated in response to GH and interferon-γ. The phosphorylated p.Phe646Ser, however, could not drive transcription. CONCLUSION: A novel STAT5B p.Phe646Ser mutation has been identified in a patient with clinical characteristics of STAT5b deficiency. Only the second STAT5B missense mutation identified, its lack of transcriptional activities despite GH-induced phosphorylation, confirms the crucial role of STAT5b for regulating the expression of IGF1 and provides insights into the importance of the SH2 ßD' strand for full STAT5b transcriptional activities. Whether the phosphorylated p.Phe646Ser variant retained functions that prevented pulmonary distress remains unresolved.

Evaluación de los niveles séricos de la proteína de unión de alta afinidad de la hormona de crecimiento humana (GHBP) y del polimorfismo del exón 3 del gen del receptor de GH en niños con talla baja idiopática / Evaluation of serum levels of the high affinity binding protein of human growth hormone (GHBP) and exon 3 polymorphism of the GH receptor gene in children with idiopathic short stature

La talla baja idiopática (TBI) incluye a un grupo heterogéneo de pacientes con fallas en su crecimiento. Una causa probable de TBI puede ser la insensibilidad a la GH (IGH). La proteína de unión de GH de alta afinidad (GHBP) se genera por el clivaje proteolítico de la porción extracelular del receptor de GH (GHR) y su determinación se propone como un marcador periférico del nivel de GHR en los tejidos. El objetivo de este trabajo fue evaluar los niveles de GHBP circulantes y su asociación con factores de crecimiento y el polimorfismo del exón 3 del gen GHR en niños con TBI. Los niños con TBI presentaron talla, IMC, IGF-I, IGFBP-3, ALS y niveles de GHBP significativamente más bajos que un grupo de niños de edad comparable (p<0.001). El genotipo del exón 3 del GHR no fue un factor determinante de las diferencias observadas. La máxima respuesta de GH de los tests de estímulo de secreción correlacionó negativa y significativamente con los niveles de GHBP (r= -0.28, p= 0.012). Los perfiles de distribución de la concentración de GHBP, IGF-I, ALS y BP3 expresadas en score de desvío estándar (SDE) en la TBI, mostraron un sesgo hacia niveles bajos. En conclusión, los marcadores de acción de GH y los niveles de GHBP fueron bajos en la TBI, independientemente del genotipo del exón 3 del gen GHR. En un subgrupo de niños con TBI, niveles disminuidos de GHBP y de componentes del sistema de los IGFs, colaborarían en la evaluación de la IGH sugiriendo la búsqueda de defectos en el GHR.

Idiopathic Short Stature (ISS) includes a heterogeneous group of children with growth failure. One possible explanation for the growth failure is a reduced responsiveness to growth hormone (GH). Human circulating GH is partially bound to a highaffinity binding protein (GHBP) which is derived from proteolytical cleavage of the extracellular domain of the GH receptor. Many reports have demonstrated a close relationship between GHBP and liver GH receptor status in physiological conditions and diseases. Moreover, serum GHBP measurement has been proposed as an useful peripheral index of GH receptor abundance. Our objective was the evaluation of serum GHBP levels and its probable association with serum growth factors (IGF-I, IGFBP-3 and ALS) and the exon 3 polymorphism of the extracellular domain of the GHR gene in ISS children. Children with ISS presented significantly lower height SDS, BMI SDS, serum components of the IGFs system and GHBP concentration as compared to an age-matched control group of normal children (p<0.001). Interestingly, exon 3 genotype did not influence the differences observed in these parameters. The maximal GH response obtained after two GH provocative tests inversely and significantly correlated to GHBP serum levels (r= -0.28, p= 0.012). A frequency study showed a deviation to low SDS values of serum GHBP, IGF-I, IGFBP-3 and ALS. Conclusion: 1- in children with ISS the exon 3 genotype of the GHR gene is not a factor that could explain the lower levels observed in circulating GHBP concentration and components of the IGFs system; 2- low serum GHBP together with low IGF-I, IGFBP-3 or ALS levels would help pointing to GH insensitivity due to GH receptor gene abnormalities in ISS.

Normal growth spurt and final height despite low levels of all forms of circulating insulin-like growth factor-I in a patient with acid-labile subunit deficiency.

BACKGROUND: In a recently described patient with acid-labile subunit (ALS) deficiency, the inability to form ternary complexes resulted in a marked reduction in circulating total insulin-like growth factor (IGF)-I, whereas skeletal growth was only marginally affected. To further study the role of circulating versus locally produced IGF-I in skeletal growth in this patient, we now describe in detail growth changes and their relationship with several components of the circulating IGF system. DESIGN AND METHODS: We followed growth and development up to the final height in a patient with complete ALS deficiency and determined both spontaneous and growth hormone (GH)-stimulated changes in the IGF system, including measurements of total, free and bioactive IGF-I, total IGF-II and insulin-like growth factor binding protein (IGFBP)-1, IGFBP-2 and IGFBP-3. RESULTS: The patient had a delayed growth and pubertal onset. Six months of GH treatment had no effect on growth. At the age of 19.3 years, he spontaneously completed puberty and had a normal growth spurt for a late adolescent (peak height velocity of 8.4 cm/year). A normal final height was attained at 21.3 years (167.5 cm; -0.78 SDS). During as well as after puberty, basal levels of total, free and bioactive IGF-I were low, as were total IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3. GH treatment for 6 months normalized free IGF-I and increased bioactive IGF-I, but had no effect on growth velocity. CONCLUSIONS: This case story shows that in the presence of complete ALS deficiency, a height within normal limits can be obtained despite low levels of all forms of circulating IGF-I. Furthermore, the patient presented a delayed but normal growth spurt without any marked increment of circulating IGF-I.

Identification of the first patient with a confirmed mutation of the JAK-STAT system.

Growth hormone insensitivity (GHI) has been attributable, classically, to mutations in the gene for the GH receptor. After binding to the GH receptor, GH initiates signal transduction through a number of pathways, including the JAK-STAT pathway. We describe the first patient reported with a mutation in the gene for STAT5b, a protein critical for the transcriptional regulation of insulin-like growth factor-I.

Peripheral venous thrombosis in children and adolescents with adipsic hypernatremia secondary to hypothalamic tumors.

OBJECTIVE: To determine the clinical presentation and laboratory follow-up in patients with the syndrome of adipsic hypernatremia complicated with a peripheral thrombosis event. METHODS: Report of 3 patients (6-19 years old) with chronic hypernatremia with sustained difficulties to normalize their serum osmolality levels. RESULTS: During post-surgical management the 3 patients developed a peripheral venous thrombotic event as a complication of their chronic hyperosmolality. CONCLUSIONS: Chronic hypernatremia in patients with prolonged immobilization is associated with an increased risk for development of deep venous thrombosis.

The C105fs114X is the prevalent thyrotropin beta-subunit gene mutation in Argentinean patients with congenital central hypothyroidism.

BACKGROUND: Congenital isolated thyrotropin (TSH) deficiency is an unusual condition characterized by low levels of thyroid hormones and TSH, usually presenting early typical signs of severe hypothyroidism. Five different beta-TSH mutations have been described so far. While 4 of them affect only consanguineous families, a frameshift mutation in exon 3 (C105fs114X) has been found also in nonconsanguineous families. OBJECTIVE: The aim of the present study was to characterize beta-TSH mutations in Argentinean patients with congenital central hypothyroidism (CCH) and to emphasize the importance of early biochemical and molecular diagnosis of this disorder. PATIENTS AND METHODS: We investigated 8 Argentinean children (3 boys, 5 girls) from 7 unrelated families with CCH based upon low levels of T(4) and T(3), and low basal and stimulated TSH levels. Mutation characterizations for the beta-TSH gene were performed by PCR amplification followed by sequence and restriction enzyme analysis with SNABI in the patients, 9 parents and in 100 newborn children. RESULTS: All patients presented the same homozygous mutation in exon 3 of the beta-TSH gene (C105fs114X), the 9 studied parents were heterozygous for the same mutation and 1 carrier was found in the 100 studied newborns. CONCLUSION: Our findings show that the C105fs114X mutation is prevalent in our population and may constitute a hot spot at codon 105 in the beta-TSH gene. Since this mutation is easily demonstrable by a SNABI digestion in DNA amplified from dried blood spots, its investigation would be indicated in patients in our milieu with clinical and biochemical features of CCH, allowing early L-thyroxine (LT(4)) replacement and genetic counseling of the family.

Congenital secondary hypothyroidism due to a mutation C105Vfs114X thyrotropin-beta mutation: genetic study of five unrelated families from Switzerland and Argentina.

We identified five patients with congenital secondary hypothyroidism with isolated thyrotropin (TSH) deficiency originating from three and two unrelated Argentinean and Swiss families, respectively. The affected patients presented with both low TSH as well as low thyroid hormone levels. Further, TSH-releasing hormone (TRH) stimulation failed to increase serum TSH, whereas prolactin increased adequately. These affected children were homozygous for a 1-bp deletion (822delT) in the TSH-beta subunit gene leading to a cysteine 105 to valine conversion (C105V) and to a frameshift with a premature stop codon at position 114 (C105Vfs114X). In a total of 22 families five different mutations located within the coding region of the TSH-beta subunit gene responsible for congenital secondary hypothyroidism have been reported so far (E12X; G29R; Q49X; IVS2 +5, G --> A; C105Vfs114X). Importantly, out of 13 families, including our five families, the C105Vfs114X mutation has been described in 12 unrelated and non-consanguineous families, whereas the remaining four TSH-beta subunit gene mutations have been described in consanguineous families only. Therefore the C105Vfs114X mutation within the TSH-beta subunit gene is the most frequent alteration causing congenital secondary hypothyroidism (13 of 22; 59%) and occurs mainly in unrelated and non-consanguineous families (12 of 13; 92%). As we could exclude a common ancestry by microsatellite marker analysis in our five independent families we concluded that the codon 105 in the TSH-beta subunit gene might be a "hot spot," although a founder effect has been reported in certain cases clustered in a highly specific and restricted geographical area.

Importancia de la gonadectomía temprana en pacientes con síndrome de Turner portadoras de cromosoma Y / Importance of early gonadectomy in patients with Turner syndrome with presence of Y chromosome material

Introducción: la presencia de material del cromosoma Y en mujeres con Síndrome de Turner se asocia con el desarrollo de tumores gonadales, teniendo un incremento del riesgo relacionado con la edad. Objetivo: investigar la correlación entre la presencia de cromosoma Y ó secuencias específicas del Y y los hallazgos histopatológicos de las gónadas en pacientes con Síndrome de Turner. Material y métodos: se estudiaron cinco niñas con síndrome de Turner, con edades comprendidas entre los 4.4 y 13.4 años de edad. En todas las pacientes se realizó el análisis cromosómico con bandeo G y técnicas de alta resolución, tales como análisis molecular por PCR amplificando las secuencias específicas del cromosoma Y (SRT, DYZ1, DYZ3 y AMGL). Tres niñas tenían un cariotipo conteniendo el cromosoma Y, mientras que en las otras dos niñas restantes fueron detectadas secuencias del cromosoma Y por análisis molecular. En todas la niñas fue realizada la gonadectomía bilateral con técnica laparoscópica. Resultados: el procedimiento laparoscópico fue adecuado y bien tolerado por las niñas. Tres de las pacientes (de 5.4, 8 y 13.4 años de edad) que tenían cromosoma Y presentaron tumores gonadales: gonadoblastoma uni o bilateral, y en una de ellas se encontró un disgerminoma. En las dos niñas restantes se encontraron las típicas gónadas tipo "streak" del Síndrome de Turner, sin tejido neoplásico. Conclusión: el hallazgo de tumores gonadales en 3 de las 5 niñas con Síndrome de Turner refuerza la importancia de la indicación de la gonadectomía a edades tempranas cuando las pacientes son portadoras de material del Y en sus cromosomas. La técnica laparoscópica es una elección adecuada para el tratamiento

Importancia de la gonadectomía temprana en pacientes con síndrome de Turner portadoras de cromosoma Y / Importance of early gonadectomy in patients with Turner syndrome with presence of Y chromosome material

Introducción: la presencia de material del cromosoma Y en mujeres con Síndrome de Turner se asocia con el desarrollo de tumores gonadales, teniendo un incremento del riesgo relacionado con la edad. Objetivo: investigar la correlación entre la presencia de cromosoma Y ó secuencias específicas del Y y los hallazgos histopatológicos de las gónadas en pacientes con Síndrome de Turner. Material y métodos: se estudiaron cinco niñas con síndrome de Turner, con edades comprendidas entre los 4.4 y 13.4 años de edad. En todas las pacientes se realizó el análisis cromosómico con bandeo G y técnicas de alta resolución, tales como análisis molecular por PCR amplificando las secuencias específicas del cromosoma Y (SRT, DYZ1, DYZ3 y AMGL). Tres niñas tenían un cariotipo conteniendo el cromosoma Y, mientras que en las otras dos niñas restantes fueron detectadas secuencias del cromosoma Y por análisis molecular. En todas la niñas fue realizada la gonadectomía bilateral con técnica laparoscópica. Resultados: el procedimiento laparoscópico fue adecuado y bien tolerado por las niñas. Tres de las pacientes (de 5.4, 8 y 13.4 años de edad) que tenían cromosoma Y presentaron tumores gonadales: gonadoblastoma uni o bilateral, y en una de ellas se encontró un disgerminoma. En las dos niñas restantes se encontraron las típicas gónadas tipo "streak" del Síndrome de Turner, sin tejido neoplásico. Conclusión: el hallazgo de tumores gonadales en 3 de las 5 niñas con Síndrome de Turner refuerza la importancia de la indicación de la gonadectomía a edades tempranas cuando las pacientes son portadoras de material del Y en sus cromosomas. La técnica laparoscópica es una elección adecuada para el tratamiento (AU)