[Long-term follow-up of isolated-growth hormone deficiency typeIA: the clinical analysis of 2-sister cases].

OBJECTIVE: To elucidate the curative and adverse effect of recombinant human growth hormone (rhGH) in 2 patients with isolated-growth hormone deficiency type IA (IGHDIA), to track sexual development and pregnancy, and reassess the quality of life in the adulthood. METHOD: The authors summarized the data of 2-sister cases with IGHDIA; followed up for assessment of height, weight, blood pressure and sexual development; detected fasting blood lipids, glucose, insulin, insulin growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3); made an investigation of education and occupation, and so on. RESULT: After 6.2 and 7.3 years treatment with rhGH, the two sisters had considerably improved height from -7.8 SDS, -8.8 SDS to -2.6 SDS and -1.3 SDS respectively. No evident side effect was observed. They had normal sexual development and pregnancy. The levels of IGF-1 and IGFBP-3 were still low, in the elder sister they were 46.6 µg/L, 2460 µg/L, and in the younger 52.4 µg/L, 2430 µg/L. No hyperlipidemia, diabetes or obesity occurred. CONCLUSION: Long term therapy with rhGH may improve final adult height of individuals with IGHDIA. They can have normal sexual development and pregnancy. Metabolic syndrome did not occur during the follow-up period.

Genetics of growth hormone deficiency.

When a child is not following the normal, predicted growth curve, an evaluation for underlying illness and central nervous system abnormalities is required and appropriate consideration should be given to genetic defects causing growth hormone (GH) deficiency. This article focuses on the GH gene, the various gene alterations, and their possible impact on the pituitary gland. Transcription factors regulating pituitary gland development may cause multiple pituitary hormone deficiency but may present initially as GH deficiency. The role of two most important transcription factors, POU1F1 (Pit-1) and PROP 1, is discussed.

Phenotype and genetic analysis of a syndrome caused by an inactivating mutation in the growth hormone-releasing hormone receptor: Dwarfism of Sindh.

We report, in detail, a new form of familial dwarfism, including its phenotypic features, hormonal profile, and molecular basis. Following a newspaper report of severe dwarfism in two villages in the province of Sindh, Pakistan, we organized an expedition to study its clinical, genetic, and molecular characteristics. We identified 18 dwarfs (15 male, 3 female), all members of a consanguineous kindred, ranging in age from newborn to 28 yr. Mean height was 7.2 SD below the norm, with mean adult heights of 130 cm for males and 113.5 cm for females. Body proportions and habitus were normal; but head circumference was 4.1 SD, and blood pressure approximately 3 SD below the norm. There was no dysmorphism, no microphallus, and no history of hypoglycemia. Serum GH did not respond to provocative stimuli (GHRH, L-dopa, or clonidine). Insulin-like growth factor I (IGF-I) and IGF-binding protein 3 were low (5.2 +/- 2.0 ng/mL and 0.42 +/- 0.13 microg/mL, respectively; mean +/- SD) but rose normally with GH treatment. One affected, dwarfed couple had a son, demonstrating fertility in both sexes. Clinical and endocrinological evidence suggested isolated GH deficiency with a recessive inheritance pattern. The GH-N gene was found to be intact. Linkage analysis of microsatellite chromosomal markers near other candidate genes yielded a high LOD score (6.26) for the GHRH receptor (GHRH-R) locus. DNA sequencing revealed a nonsense mutation (Glu50-->Stop) in the extracellular domain of the GHRH-R. This mutation predicts a severely truncated GHRH-R; it is identical to that recently reported in four patients from two other families. Inheritance is autosomal recessive (chromosome 7p) with a high degree of penetrance. Relatives heterozygous for the mutation had moderately decreased IGF-I levels and slightly blunted GH responses to GHRH and L-dopa, but they showed only minimal or no height deficit. This syndrome represents the human homologue of the little (lit/lit) mouse and closely resembles its phenotype. It demonstrates the absolute requirement of GHRH signaling for pituitary GH secretion and postnatal growth in humans, and its relatively minor (but discernible) biological importance in extrapituitary sites. The syndrome is distinct from other forms of GH deficiency with respect to microcephaly, asymptomatic hypotension, and absence of features such as facial dysplasia, significant truncal obesity, microphallus, or hypoglycemia. Its discovery raises the possibility of milder mutations in the GHRH-R gene as potential causes for partial GH insufficiency and idiopathic short stature.

Magnetic resonance images of 91 children with different causes of short stature: pituitary size reflects growth hormone secretion.

UNLABELLED: In order to validate an association between pituitary size and severity of growth hormone deficiency (GHD) we evaluated the magnetic resonance images (MRI) of 107 children with different causes of short stature. Ninety-one MRIs were evaluable (64 male, 27 female; age: 9.1 +/- 3.9 years). The levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3), and tests of GH stimulation and spontaneous secretion, led to the following subgroups: severe isolated GHD (SIGHD) (GH < 7 ng/ml) (n = 21); partial, isolated GHD (GH 7-10 ng/ml) (n = 22); multiple pituitary hormone deficiency (MPHD) (n = 13); neurosecretory dysfunction (n = 10); non-classifiable diagnosis (NC) (n = 13); idiopathic short stature (n = 9); and intra-uterine growth retardation (n = 3). Pituitary height (PHT) was measured and hypoplasia was assumed when PHT was < -2 SDS. An ectopic posterior pituitary with missing stalk and a hypoplastic anterior pituitary was present in 12 (57%) SIGHD cases, 12 (92%) MPHD cases and 1 patient from the NC group. An isolated hypoplastic anterior pituitary was observed in 15%-33% of the other groups. PHT (mm; mean, SD) in MPHD (1.7 +/- 0.5) was lower than in SIGHD (2.7 +/- 1.0, P < 0.05), with PHT of both groups being lower than in all the other groups (3.8 +/- 0.9, P < 0.0001). PHT SDS correlates with IGF-I SDS (r = 0.48, P < 0.0001), IGFBP-3 SDS (r = 0.46, P < 0.0001) and the highest peaks in tests of GH stimulation and GH spontaneous secretion (r = 0.36, P < 0.0001). In contrast to all the other groups, no correlation with age was observed in MPHD and SIGHD. Breech delivery was recorded in up to 26% of patients in all seven groups. Surprisingly, only 1 out of 23 patients with an ectopic posterior pituitary was born by breech delivery, suggesting that ectopia of the posterior lobe is not necessarily related to breech delivery. CONCLUSION: PHT is significantly correlated with GH secretion in several types of short stature. Patients with ectopic posterior pituitary, missing stalk and hypoplastic anterior pituitary either suffer from SIGHD or MPHD, and this anatomical defect is not necessarily related to breech delivery.

Twenty-four-hour osteocalcin, carboxyterminal propeptide of type I procollagen, and aminoterminal propeptide of type III procollagen rhythms in normal and growth-retarded children.

The relationships between spontaneous variations in serum 24-h osteocalcin (OC), carboxyterminal propeptide of type I procollagen (PICP), and aminoterminal propeptide of type III procollagen (PIIINP) concentrations and GH secretion, measured as GH response to provocative pharmacologic stimuli and spontaneous GH secretion during 24 h, were evaluated in prepubertal normal children and in GH-deficient and GH-secreting short normal children (SNC). All the subjects showed a circadian rhythm in smoothed 24-h OC and PICP mean data with higher nocturnal values in comparison with diurnal values. Conversely, serum PIINP concentrations did not vary throughout the day. In children with classic GH deficiency and nonclassic GH deficiency, mean 24-h serum levels and smoothed 24-h mean data for OC, PICP, and PIIINP were significantly reduced (p < 0.001) with respect to age-matched controls. SNC showed mean 24-h OC concentrations similar (p = NS) to those we found in age-matched controls, but they had significantly lower (p < 0.001) diurnal 12-h mean data in comparison with controls. SNC also showed both 24-h PICP and PIIINP mean data and smoothed 24-h PICP and PIIINP mean data significantly lower (from p < 0.02 to p < 0.001) at all the time points of measurement in comparison with controls. Twenty-four-hour PICP and PIIINP mean data were positively related to spontaneous 24-h GH concentrations (r = 0.77, p < 0.005 and r = 0.69, p < 0.005, respectively) and growth velocity (r = 0.85, p < 0.005, and r = 0.70, p < 0.005, respectively), whereas 24-h OC mean data were not.(ABSTRACT TRUNCATED AT 250 WORDS)

Occurrence of four types of growth hormone-related dwarfism in Israeli communities.

Data are presented on 121 dwarfed patients belonging to 98 Israeli families with 4 types of dwarfism related to deficiency or in activity of human growth hormone (hGH): isolated growth hormone deficiency (IGHD), partial hGH deficiency (pIGHD), multiple pituitary hormone deficiencies (MPHD) and Laron-type dwarfism (LTD). These series are believed to comprise most of the dwarfs of these types in Israel; however, their distribution among the various ethnic communities varies greatly: LTD (15 families) is confined to a few communities of Oriental Jews; only 3 of 30 families with IGHD, but 7 of 10 families with pIGHD, are Ashkenazi, whereas the clinic distribution of 42 families with MPHD corresponds roughly to that of the general population. These data seem to reflect the role of genetic factors in the etiology of the various types of dwarfism: the stronger the genetic component, the greater is its deviation from random occurrence among the various communities.

X-linked congenital panhypopituitarism.

Two half brothers with panhypopituitary dwarfism are reported who have the same mother and different, unrelated fathers. The subject of hereditary panhypopituitarism is reviewed briefly. It is concluded that there are at least two forms of hereditary panhypopituitary dwarfism, one of which may be X-linked.

Genetic forms of pituitary dwarfism.

Pituitary dwarfism represents a genetically heterogeneous group of disorders which may be classified on the basis of: associated developmental anomalies or degenerative disease; deficiency of, or peripheral insensitivity to HGH; the number of deficient hormones; the associated metabolic disturbances; and the mode of inheritance. Hereditary forms of pituitary dwarfism include: congenital absence of the pituitary, panhypopituitary dwarfism (autosomal and X-linked recessive forms), isolated HGH deficiency (Types I and II), Laron type of dwarfism, and peripheral unresponsiveness to HGH (the African Pygmies).