Familial Dwarfism Research Articles

Screening of GHRHR and Npr2 genes as a genetic contributors of dwarfism in familial dwarfism of Khyber Pakhtunkhwa, Pakistan

Screening of GHRHR and Npr2 genes as a genetic contributors of dwarfism in familial dwarfism of Khyber Pakhtunkhwa, Pakistan

Glucose Tolerance and Insulin Secretion in Parents and Children with Familial Dwarfism and High Plasma Immunoreactive Growth Hormone (IR-HGH) and Familial Isolated Growth Hormone Deficiency

Glucose Tolerance and Insulin Secretion in Parents and Children with Familial Dwarfism and High Plasma Immunoreactive Growth Hormone (IR-HGH) and Familial Isolated Growth Hormone Deficiency

Familial Dwarfism due to a Novel Mutation of the Growth Hormone-Releasing Hormone Receptor Gene

Familial Dwarfism due to a Novel Mutation of the Growth Hormone-Releasing Hormone Receptor Gene

Familial dwarfism due to a novel mutation of the growth hormone-releasing hormone receptor gene.

Isolated growth hormone (GH) deficiency (IGHD) is a rare cause of short stature. The same mutation of the gene encoding the growth hormone-releasing hormone receptor (GHRHR) has been identified as the basis for IGHD in three families from the Indian subcontinent. The prevalence and heterogeneity of defects in the GHRHR gene are not known. Twenty-two dwarf members of a large, extended kindred containing at least 105 affected members with autosomal recessive short stature underwent extensive endocrine evaluation, which confirmed markedly reduced or undetectable serum concentrations of GH that did not increase in response to different stimuli. DNA sequences of the 13 exons and intron-exon boundaries of the GHRHR gene were determined in an index patient. A novel homozygous 5' splice site mutation (G-->A at position +1) in IVS1 was found. Thirty of the affected subjects tested were homozygous for this mutation, and 64 clinically unaffected patients were either heterozygous for the mutation (n = 41, including 9 obligate carriers) or homozygous for the wild-type sequence (n = 23). We describe a novel mutation in the GHRHR gene as cause of dwarfism in the largest kindred with familial IGHD described to date.

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.

The Dwarfs of Sindh: severe growth hormone (GH) deficiency caused by a mutation in the GH-releasing hormone receptor gene.

We report the discovery of a cluster of severe familial dwarfism in two villages in the Province of Sindh in Pakistan. Dwarfism is proportionate and occurs in members of a kindred with a high degree of consanguinity. Only the last generation is affected, with the oldest dwarf being 28 years old. The mode of inheritance is autosomal recessive. Phenotype analysis and endocrine testing revealed isolated growth hormone deficiency (GHD) as the reason for growth failure. Linkage analysis for the loci of several candidate genes yielded a high lod score for the growth hormone-releasing hormone receptor (GHRH-R) locus on chromosome 7. Amplification and sequencing of the GHRH-R gene in affected subjects demonstrated an amber nonsense mutation (GAG-->TAG; Glu50-->Stop) in exon 3. The mutation, in its homozygous form, segregated 100% with the dwarf phenotype. It predicts a truncation of the GHRH-R in its extracellular domain, which is likely to result in a severely disabled or non-existent receptor protein. Subjects who are heterozygous for the mutation show mild biochemical abnormalities in the growth hormone-releasing hormone (GHRH)--growth hormone--insulin-like growth factor axis, but have only minimal or no growth retardation. The occurrence of an offspring of two dwarfed parents indicates that the GHRH-R is not necessary for fertility in either sex. We conclude that Sindh dwarfism is caused by an inactivating mutation in the GHRH-R gene, resulting in the inability to transmit a GHRH signal and consequent severe isolated GHD.

Genetic mapping of the human pituitary-specific transcriptional factor gene and its analysis in familial panhypopituitary dwarfism.

We have analyzed the human pituitary-specific transcription factor (Pit-1) gene using PCR amplification of DNA fragments that span intron III and contain portions of exons III and IV. A PCR restriction fragment length polymorphism (PCRFLP) was detected in intron III by RsaI digestion, which was used to assign the human Pit-1 locus to chromosome 3p by linkage analysis of the CEPH panel. Analysis of corresponding Pit-1 segments from six nonrelated probands with familial panhypopituitary dwarfism (FPD) did not reveal any alterations in size and co-segregation of Pit-1, or a tightly linked microsatellite marker (D3S1559), and FPD was excluded in all six kindreds. Our data (1) assign Pit-1 to human chromosome 3p by linkage, (2) provide a PCRFLP and identify a variety of tightly linked markers, for analysis of FPD, and (3) exclude Pit-1 defects as the basis of at least one form of FPD.

Secretion of growth hormone in children with familial dwarfism

Thirty-two patients with familial dwarfism were examined. Stimulated and spontaneous secretion of growth hormone was studied in all of them. Stimulated secretion was assessed in two standard pharmacologic tests, spontaneous one was examined during the first 3 h of night sleep. Analysis of the results showed an irregular pattern of growth hormone secretion. Disorders of the hormone secretion of the neurosecretory dysfunction type with a partial deficit of growth hormone were revealed in the majority (20 out of 32) patients, which may be the cause of growth retardation. In twelve patients the levels of both stimulated and spontaneous secretion were normal.

Radioimmunological determination of somatomedin B in healthy children and in children with growth disturbances.

Serum somatomedin B levels were determined by radioimmunoassay in 209 healthy boys and girls from one month to 16 years of age. Low values were found up to the second year life. In the first year the mean level was 13.8 mg/l in girls and 11.5 mg/l in boys. In older children the values increased to levels between 13 and 22 mg/l in boys and between 13 and 18.5 mg/l in girls. They were independent of the stage of pubertal development. Somatomedin B levels were normal in 71 children with constitutional growth delay, primordial dwarfism, familial dwarfism and other forms of growth disturbance. The mean levels were between 12.1 and 14.4 mg/l. Values below 6 mg/l were present only in children with hGH deficiency. In these patients we could find an increase of the mean level from 4.3 mg/l without therapy to 9.4 mg/l under treatment. Thus the determination of somatomedin B seems to be useful for the diagnosis of hGH deficiency.

Pituitary function in 8 patients with familial pituitary dwarfism

Pituitary function was studied in four pairs of familial pituitary dwarfs (two sisters 28 and 20 years old, two brothers 15 and 11 years old, one sister aged 19 and her brother aged 6 and one sister aged 9 6/12 and her brother 3 6/12), by performing 1-dopa test, TRH-test ,LHRH-test, sulpiride-test and by measuring basal concentrations of ACTH and Cortisol (F). It was found that all patients had abnormal responses of GH to 1-dopa test, and of prolactin to sulpiride-test but there was an intra-and interfamilial variability as regards the response of TSH to TRH, of FSH and LH to LHRH and the basal levels of ACTH and F.

308 DWARFISM DUE TO IMMUNOREACTIVE BUT BIOLOGICALLY INACTIVE GROWTH HORMONE

In the syndrome of familial dwarfism with high plasma immunoreactive growth hormone (GH)(Laron Syndrome), elevated levels of GH are associated with low levels of plasma somatomedin that do not increase following administration of GH. These patients do not respond to treatment with GH.The two subjects of this report were three-year-old boys with dwarfism (height ages 1 3/12 and 1 6/12 years) and delayed bone ages (1 3/12 and 1 9/12 years). Both had normal GH response after stimulation associated with undetectable levels of somatomedin. However, unlike patients with Laron Syndrome, the two patients generated normal levels of somatomedin after intra-muscular administration of GH. Treatment with GH (2 IU every other day) brought a significant increase in the growth rate of both patients. The growth rate of the first patient increased from 2 cm/year before treatment, to 16 cm/year on therapy. The growth rate of the second patient was 4.5 cm/year before treatment, and 11.0 cm/year while on treatment.The two cases represent a new syndrome of dwarfism due to biologically inactive, immunoreactive GH. If erroneously diagnosed as having Laron Syndrome, these patients may be denied the benefit of treatment.

Cephalometric measurements of familial dwarfism and high plasma immunoreactive growth hormone

Cephalometric measurements of familial dwarfism and high plasma immunoreactive growth hormone

Immunological behaviour of HGH from plasma of patients with familial dwarfism and high IR-HGH in a radioimmunoassay system using the cross-reaction between HGH and HCS.

Immunological behaviour of HGH from plasma of patients with familial dwarfism and high IR-HGH in a radioimmunoassay system using the cross-reaction between HGH and HCS.

Immunoreactive properties of the plasma hGH from patients with the syndrome of familial dwarfism and high plasma IR-hGH.

ABSTRACT The dilution curves of plasma hGH from 22 patients with the syndrome of familial dwarfism and high plasma IR-hGH were tested by radioimmunoassay with 3 different antisera. No significant differences were observed between the shape of the dilution curves of these samples and those of plasma hGH from healthy children, newborns and acromegalic patients.

Skull changes in pituitary dwarfism and the syndrome of familial dwarfism with high plasma immunoreactive growth hormone--a Roentgenologic study.

Skull changes in pituitary dwarfism and the syndrome of familial dwarfism with high plasma immunoreactive growth hormone--a Roentgenologic study.

SMALL ACETABULAR AND ILIAC ANGLES AND ASSOCIATED DISEASES

A review of the literature on the evaluation of the acetabular and iliac angles in health and disease is presented. Small angles in two newly described conditions, “broad thumbs and great toes, facial abnormalities and mental retardation” syndrome and “congenital familial dwarfism with cephaloskeletal dysplasia,” are discussed. Narrow acetabular or iliac angles in some skeletal dysplasias and several other unrelated conditions are shown.

19 Familial Growth Hormone (GH) Deficiency

Isolated GH deficiency has been observed in a number of instances, but its occurrence as a recessively inherited defect has been previously documented only in adult members of two families. The present study concerns a family of 9 in which the father and 4 siblings had growth retardation, truncal obesity, facial infantilism and impaired glucose tolerance. Plasma GH responsiveness to insulin-induced hypoglycemia and to bacterial pyrogen administration was absent in those whose growth was retarded, but indirect studies of thyrotropin and adrenocorticotropin demonstrated the presence of these pituitary factors in all members of the family. Human GH administration to the 18-year-old, dwarfed, sexually infantile, female sibling resulted in objective changes in sexual maturation, alterations in fat distribution and greatly accelerated growth. The similarly treated 9-year-old male sibling experienced marked increase in the rate of statural growth, but remained sexually infantile. No discernable change in urinary corticoid responsiveness to adrenocorticotropin and no measurable change in gonadotropin excretion occurred during the therapeutic period. Studies of glucose tolerance and plasma insulin responsiveness in 4 of the dwarfs revealed an increase in peripheral resistance to insulin during GH administration. It is concluded that this form of familial dwarfism is related to GH deficiency and that the defect is monotropic. The patients described clearly illustrate the natural course of the condition, wherein delayed adolescence is the rule rather than the exception. Observations presented support the possibility that GH alters responsiveness of endocrine end-organ tissues. Serious doubts are raised regarding the validity of diagnoses which exclude hypopituitarism in patients with retarded growth on the basis of eventual sexual maturation. (APS)

FAMILIAL DWARFISM AND "STIFF JOINTS".

REPORTS of familial dwarfism associated with limitation of joint motion are rare in the North American literature. This paper describes six members of three generations of a family showing short stature, stiff joints, normal intelligence, and varying degrees of hyperopia, glaucoma, asthmatic bronchitis, and hepatomegaly. The pedigree (Fig 1) suggests an autosomal dominant pattern of inheritance. Report of Case Case III, 2.* —The proband (MGH No. 123-79-74) was 45 years old when he entered the Massachusetts Eye and Ear Infirmary in 1962 because of decreasing vision. At 38 he had had a serious retinal detachment of the left eye. Glaucoma developed at age 43 and was treated with drugs and two operations, the latter achieving normal pressures. A retinal detachment in the right eye with spontaneous reattachment occurred in 1961, and a cataract extraction was done on the right eye in June of 1962. A further retinal detachment occurred, however,

A case of familial dwarfism, with choroideremia, myopia, posterior polar cataract, and zonular cataract.

A case of familial dwarfism, with choroideremia, myopia, posterior polar cataract, and zonular cataract.