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MC Ferrari, R Parini, MD Di Rocco, G Radetti, P Beck-Peccoz and L Persani

OBJECTIVE: The congenital disorders of glycosylation (CDGs) are progressive multisystemic disorders characterized by a heterogeneous deficiency of the carbohydrate moieties in various structural and circulating glycoproteins, representing a natural model for glycoprotein hormone studies. Here, we studied the carbohydrate moiety of circulating glycoprotein hormones in four patients with a clinical suspicion of CDGs. METHODS: The diagnosis of CDG-I was confirmed in two out of the four cases by transferrin isoelectrofocusing (IEF) and/or carbohydrate-deficient transferrin (CDT) test. The carbohydrate moiety of serum endocrine-related glycoproteins was investigated by means of Ricin (immunopurified thyrotropin (TSH)) and Concanavalin A (Con-A) (TSH, follicle-stimulating hormone, alpha-subunit and thyroglobulin) lectin affinity chromatography measurement. RESULTS: CDT concentrations were very high in the two patients with CDG-I and moderately enhanced in the remaining two. In the two CDG-I patients, Ricin analysis of immunopurified TSH showed a severe impairment of lectin binding, both before and after neuroaminidase treatment, indicating a nearly complete lack of terminal sialic acid and galactose residues. In these two cases, Con-A analysis showed a significant prevalence of firmly bound isoforms with poorly processed carbohydrate chains. In the remaining two cases with unknown CDG classification, TSH binding pattern to Ricin was modestly affected and Con-A analysis showed the prevalence of weakly bound glycoprotein isoforms. CONCLUSIONS: The results of Ricin analyses in all four patients were consistent with the CDT test and/or serum transferrin IEF. The severe alteration of TSH binding pattern to Ricin seems to be characteristic of CDG-I. Nevertheless, TSH biological properties are not severely altered, as normal thyroid function was found in both cases.

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CY Hayashida, RG Gondo, C Ferrari, SP Toledo, R Salvatori, MA Levine, MC Ezabella, N Abelin, D Gianella-Neto and BL Wajchenberg

OBJECTIVE: To characterize clinically and hormonally the syndrome of autosomal recessive familial growth hormone deficiency (FGHD) recently identified in Itabaianinha, Sergipe, Brazil, caused by a novel mutation (mt) that inactivates the growth hormone-releasing hormone receptor (GHRH-R) gene. DESIGN: Clinical and hormonal evaluations were performed in 21 FGHD individuals (mt/mt group) aged 8 to 63 years, 13 heterozygotes for the GHRH-R mutation (wt/mt group) and 5 homozygotes for the wild type (wt) allele (wt/wt group), identified by genotyping of peripheral blood leukocyte DNA. METHODS: Clinical and hormonal characterization included physical examination and measurement of GH, IGF-I, IGF binding protein-3 (IGFBP-3), cortisol, prolactin, LH, FSH, and free thyroxine (FT4). RESULTS: Clinical features were consistent with isolated growth hormone deficiency. Height was significantly reduced in the mt/mt group compared with the wt/mt group (mean height standard deviation score (SDS) +/- s.d.: -7.35+/-1.37 vs -1.84+/-1.44 respectively, P<0. 0001), and the wt/wt group (-1.85 +/- 0.81, P=0.0007). The height of the 13 wt/mt subjects did not differ from the 5wt/wt individuals. Serum GH, IGF-I, IGF-I SDS, IGFBP-3 and IGFBP-3 SDS were all significantly lower in the mt/mt group than in the wt/mt and wt/wt groups. Two affected children treated with GH for 1 year showed a normal growth response. Serum IGF-I and IGF-I SDS were lower in wt/mt compared with wt/wt group, but did not reach statistical significance. IGF-I and IGF-I SDS correlated inversely with age in wt/mt group. CONCLUSIONS: FGHD due to an autosomal recessive GHRH-R gene mutation leads to marked dwarfism, phenotypically and hormonally indistinguishable from other forms of isolated GH deficiency. Heterozygotes for the GHRH-R mutation appear to have a partial defect in the GH/IGF axis, with no apparent height impairment.