Human growth hormone-releasing hormone (hGH-RH; hGRF) treatment of four patients with GH deficiency

Four patients with GH deficiency aged 6-14 years old were treated with hGRF for 6 months. Before the treatment maximal plasma GH responses to 50 micrograms iv hGRF administration were 48.6, 12.1, 24.3 and 13.0 ng/ml, respectively. Human GRF was administered at a dosage of 50-100 micrograms twice a day subcutaneously. In two patients, the growth rate was increased from 2.4 and 2.0 cm/year to 8.2 and 9.8 cm/year, respectively. In the other two patients, the growth rate did not change with hGRF treatment. Plasma somatomedin C levels increased in one patient but did not change in the other three. Antibody to hGRF was observed in two patients during the treatment, but the presence of antibody did not affect the growth rate.     

Familial type C syndrome of insulin resistance and short stature with possible autosomal dominant transmission

We describe a 17-yr-old girl with insulin resistant diabetes, acanthosis nigricans, hirsutism and short stature. At the age of 14 she was found to have glycosuria and diagnosed as diabetes mellitus. No endocrinological abnormality except transient amenorrhea and exaggerated LH response to LHRH was found. Insulin resistance was demonstrated by fasting hyperinsulinemia, insulin tolerance test and euglycemic glucose clamp test, and large doses of insulin with CSII were not effective in controlling blood glucose. Insulin binding to erythrocytes was normal, suggesting a postbinding defect. The same phenotype of insulin resistant diabetes and short stature was found in her mother who was diagnosed as diabetes mellitus at the age of 31 and died of diabetic nephropathy at the age of 41. Her maternal grandfather and uncle were reportedly affected with the same phenotype. Her father had impaired glucose tolerance, but no hyperinsulinemia. Two sisters had essentially normal glucose tolerance. Insulin binding to erythrocytes of her father and mother was also in the normal range. These results suggest that the present case may be a rare syndrome present together with type C syndrome of insulin resistance, and with short stature which was inherited autosomal dominantly.     

Plasma growth hormone (GH) response to GH-releasing factor (SM-8144) in children of short stature and patients with GH deficiency

Synthetic human GRF (hGRF (1-44) NH2; SM-8144) was administered as an iv bolus to 141 normal children of short stature (NSC), 73 patients with severe idiopathic GH deficiency (IGD; group A), 30 patients with mild idiopathic GH deficiency (IGD; group B), 29 patients with secondary GH deficiency, 3 patients with primary hypothyroidism, 21 patients with Turner's syndrome and 25 patients with various other disease. Their height was below normal for their age and sex, and they were all below 25 years old without obesity. The maximal GH responses (M+SEM) were 39.5 +/- 2.2, 7.2 +/- 0.9, 27.2 +/- 3.7, 5.2 +/- 0.8, 9.7 +/- 4.4, 25.1 +/- 2.8 and 32.3 +/- 4.8 ng/ml, respectively (significance from the NSC, ; p less than 0.05, ; p less than 0.001). The GH responses to hGRF were greater than those elicited by standard pharmacological tests. There was a negative correlation between bone age and peak plasma GH response to hGRF in patients with idiopathic GH deficiency (IGD) but not in normal children (NSC). In twenty-two percent of the patients with IGD in group A the response was above 10 ng/ml and in 57% of the patients with IGD in group B the response was above 20 ng/ml, suggesting that a large percentage of patients with idiopathic GH deficiency lack hypothalamic GRF. The side effect of flushing was observed in 15.2% of all subjects. These results indicate the potential usefulness of hGRF (1-44) NH2 (SM-8144) in inducing GH release from the pituitary.     

Hypochondroplasia due to FGFR3 gene mutation (N540K) and mosaic form of Down syndrome in the same patient

The simultaneous presence of Down syndrome and achondroplasia has rarely been reported in the literature, and our search revealed only six patients with such an association. We are reporting the first case of a patient with Down syndrome and hypochondroplasia. In this patient, Down syndrome was clinically recognised and confirmed by the cytogenetic finding of mosaic karyotype (47,XX,+21/46,XX) shortly after birth. She was subsequently diagnosed with hypochondroplasia at the age of 6 years when disproportional short stature, stocky habitus and macrocephaly were observed. These phenotypic findings were later confirmed by the presence of fibroblast growth factor receptor 3 (FGFR3) gene mutation N540K. The overlapping common clinical features of Down syndrome and hypochondroplasia resulted in delayed diagnosis of hypochondroplasia in our patient and the associated deleterious effect on her linear growth. Her final height is 126.5 cm, which is −3.76 standard deviations (SD) lower than the median height in patients with Down syndrome, and is under the lower borderline of the adult height range for women with hypochondroplasia.     

Comparison of final height in monozygotic twins,one with idiopathic and isolated growth hormone deficiency treated with low dose of growth hormone

OBJECTIVE: We report final heights in a pair of monozygotic twins, one unaffected and the other affected with idiopathic and isolated growth hormone (GH) deficiency treated with human GH, and discuss the effect of GH dosage on the attainment of the genetic height potential in GH deficiency. PATIENTS: Male monozygotic twins were born at 35 weeks of gestation; birth weights were 1,876 g in the unaffected and 1,510 g in the affected twin. At 4.9 years of age, the affected twin was studied for short stature (-3.38 SD) and was diagnosed as having idiopathic and isolated GH deficiency, whereas the unaffected twin was normal in height (+/- 0 SD). GH treatment was started at the age of 5.7 years and continued throughout childhood and adolescence. The average dose of GH administered during the treatment period was 0.35 IU (0.12 mg)/kg/week. The affected twin appeared to grow normally without other hormone replacement and achieved a final height of 165.6 cm (-0.86 SD) compared with that of 166.4 cm (-0.71 SD) in the unaffected twin at 17.5 years of age. CONCLUSION: Our results indicate that a relatively low dose of GH treatment started at an early age may preserve genetic height potential in patients with isolated GH deficiency.     

A Japanese child with geleophysic dysplasia caused by a novel mutation of FBN1

Geleophysic dysplasia (GD) is a rare disorder characterized by severe short stature, short hands and feet, limited joint mobility, skin thickening, characteristic facial features (e.g., a “happy” face), and cardiac valvular disorders that often result in an early death. The genes ADAMTSL2 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif-like 2) and FBN1 (fibrillin 1) were recently identified as causative genes for GD. Here, we describe a 10-year-old Japanese female with GD who was born to non-consanguineous parents. At the age of 11 months, she was referred to our hospital because of very short stature for her age (− 4.4 standard deviations of the age-matched value) and a “happy” face with full cheeks, a shortened nose, hypertelorism, and a long and flat philtrum, characteristic of GD. Her hands and feet were small, her skin was thickened, and her joint mobility was generally limited. She had cardiac valvular disorders and history of recurrent respiratory failure. Mutation analysis revealed no abnormalities in ADAMTSL2. However, analysis of FBN1 revealed a novel heterozygous mutation (c.5161T > T/G) in exon 41, which encodes transforming growth factor-β-binding protein-like domain 5 (TB5). GD is an extremely rare disorder and, to our knowledge, only one case of GD with an FBN1 mutation has been reported in Japan. Similar to the previously reported cases of GD, the mutation in the current patient was located in the TB5 domain, which suggests that abnormalities in this domain of FBN1 are responsible for GD.     

A patient of short stature with idiopathic hypoparathyroidism round face and metacarpal signs

A 16-year old girl of short stature, with round face, mental retardation, and Albright's dimple sign was admitted for evaluation of hypocalcemia. Her serum calcium levels were 6.3-8.0 mg/dl, and phosphorus 6.9-7.8 mg/dl. Although a diagnosis of pseudohypoparathyroidism was initially suggested, her serum iPTH concentration was low (0.1 ng/ml). Furthermore, an injection of synthetic human parathyroid hormone (100 U, hPTH (1-34] was followed by a marked increase in urinary excretion of cyclic AMP and phosphorus. This case suggests that a shortened metacarpal is not a reliable guide in distinguishing between idiopathic hypoparathyroidism and pseudohypoparathyroidism and that a standard Ellsworth-Howard test is a prerequisite to differential diagnosis.     

Psychosocial adaptation to short stature - an indication for growth hormone therapy?

Although growth hormone does not clearly improve final height in non-growth-hormone-deficient children with short stature, it leads to a temporary acceleration of growth velocity. It is an ongoing discussion whether this effect supports psychosocial adaptation to short stature and therefore could be an indication for growth hormone treatment in children with short stature without growth hormone deficiency. We have reviewed recent literature concerning psychosocial consequences of short stature. Together with own data we can demonstrate that short people regularly adapt well to their height and have a good self-esteem. On the other hand, we focus on the problem that most studies on this subject suffer from methodical problems. A growth-related questionnaire that evaluates subjective and objective perceptions of being short in patients and peers is not at hand. As a consequence, psychosocial problems due to short stature have not been exactly classified yet and therefore do not represent an indication for growth hormone therapy.     

Severe self-mutilation of hands in a nonpsychotic, nonretarded patient

A case report of a young female teenager with a long history of self-destruction of her hands by chewing, scratching, and gnawing is presented. This habit was related to her successfully repaired cervical meningomyelocele in infancy. Not only did she first present with ulcerations and osteomyelitis, but also with distal autoamputation and severe iron deficiency anemia. A team approach with a pediatrician, neurologist, psychiatrist, and plastic surgeon was employed for her treatment. Behavior modification was moderately successful. Her hands and forearms were reconstructed with arthrodesis, local and distant flaps, and skin grafting without incident. She has been followed now for 4 years.     

Health-Related Quality of Life of Young Adults Treated with Recombinant Human Growth Hormone during Childhood

Background

Since recombinant human growth hormone (rhGH) became available in 1985, the spectrum of indications has broadened and the number of treated patients increased. However, long-term health-related quality of life (HRQoL) after childhood rhGH treatment has rarely been documented. We assessed HRQoL and its determinants in young adults treated with rhGH during childhood.

Methodology/Principal Findings

For this study, we retrospectively identified former rhGH patients in 11 centers of paediatric endocrinology, including university hospitals and private practices. We sent a questionnaire to all patients treated with rhGH for any diagnosis, who were older than 18 years, and who resided in Switzerland at time of the survey. Three hundred participants (58% of 514 eligible) returned the questionnaire. Mean age was 23 years; 56% were women; 43% had isolated growth hormone deficiency, or idiopathic short stature; 43% had associated diseases or syndromes, and 14% had growth hormone deficiency after childhood cancer. Swiss siblings of childhood cancer survivors and the German norm population served as comparison groups. HRQoL was assessed using the Short Form-36. We found that the Physical Component Summary of healthy patients with isolated growth hormone deficiency or idiopathic short stature resembled that of the control group (53.8 vs. 54.9). Patients with associated diseases or syndromes scored slightly lower (52.5), and former cancer patients scored lowest (42.6). The Mental Component Summary was similar for all groups. Lower Physical Component Summary was associated with lower educational level (coeff. -1.9). Final height was not associated with HRQoL.

Conclusions/Significance

In conclusion, HRQoL after treatment with rhGH in childhood depended mainly on the underlying indication for rhGH treatment. Patients with isolated growth hormone deficiency/idiopathic short stature or patients with associated diseases or syndromes had HRQoL comparable to peers. Patients with growth hormone deficiency after childhood cancer were at high risk for lower HRQoL. This reflects the general impaired health of this vulnerable group, which needs long-term follow-up.     

Ac-Tyr1hGRF discriminates between VIP receptors from rat liver and intestinal epithelium

The vasoactive intestinal peptide (VIP) stimulates adenylate cyclase activity in rat liver and intestinal epithelium with low and high efficacy, respectively. The human growth hormone releasing factor (hGRF) derivative with acetylated N-terminus e.g. Ac-Tyr1hGRF binds to VIP receptors in both tissues with a similar affinity. However, Ac-Tyr1hGRF is a partial VIP agonist with high intrinsic activity in liver (50% that of VIP) whereas it behaves as a VIP antagonist in intestine. These results further argue for a possible heterogeneity of VIP receptor-coupled adenylate cyclase among tissues on a pharmacological basis.     

The smallest of the small

Microcephalic Osteodysplastic Primordial Dwarfism (MOPD) II has recently been defined as a PCNT gene defect. Historically, it has been a disorder of interest because of the severe intrauterine growth restriction and postnatal short stature. The very shortest/smallest mature human being undoubtedly had this disorder. Maria Zarate lived between 1864 and 1890 and traveled in sideshows to England and all over North America. Her exceeding short stature was well documented in photographs and by a group of physicians in England. She was Mexican and also had an affected brother. A museum, Museo Casa Grande, about her still exists in Cempoala, Mexico.     

A case of Turner syndrome with congenital hypothyroidism untreated until age 38 years

OBJECTIVE AND METHODS: The effect of thyroid hormone on human growth and maturation is considered 'permissive'. To evaluate the effect of a prolonged thyroid hormone defect, especially in the pubertal period, a woman with untreated congenital hypothyroidism underwent studies of thyroid function and bone maturation for the first time at age 38 years 10 months and received thyroid hormone replacement. RESULTS: The karyotype was 45,X/46,XX. Menstruation had occurred for 10 years, from menarche until she was about 31 years old. Epiphyseal closure of the left hand was incomplete. The serum thyroid hormone level was virtually undetectable, and her thyroid gland was not detectable in the normal position by ultrasonography. Her height increased by 3.5 cm in the first 9 months after starting thyroid hormone replacement; after 11 months, closure of the epiphysis was complete. CONCLUSION: Thyroid hormone is necessary to achieve bone maturation and epiphyseal closure, but its role is only permissive.     

Maternal Height and Preterm Birth: A Study on 192,432 Swedish Women

BackgroundThere is increasing evidence that lower maternal stature is associated with shorter gestational length in the offspring. We examined the association between maternal height and the likelihood of delivering preterm babies in a large and homogeneous cohort of Swedish women.MethodsThis study covers antenatal data from the Swedish Medical Birth Register on 192,432 women (aged 26.0 years on average) born at term, from singleton pregnancies, and of Nordic ethnicity. Continuous associations between women''s heights and the likelihood of preterm birth in the offspring were evaluated. Stratified analyses were also carried out, separating women into different height categories.ResultsEvery cm decrease in maternal stature was associated with 0.2 days shortening of gestational age in the offspring (p<0.0001) and increasing odds of having a child born preterm (OR 1.03), very preterm (OR 1.03), or extremely preterm (OR 1.04). Besides, odds of all categories of preterm birth were highest among the shortest women but lowest among the tallest mothers. Specifically, women of short stature (≤155 cm or ≤-2.0 SDS below the population mean) had greater odds of having preterm (OR 1.65) or very preterm (OR 1.47) infants than women of average stature (-0.5 to 0.5 SDS). When compared to women of tall stature (≥179 cm), mothers of short stature had even greater odds of giving birth to preterm (OR 2.07) or very preterm (OR 2.16) infants.ConclusionsAmong Swedish women, decreasing height was associated with a progressive increase in the odds of having an infant born preterm. Maternal short stature is a likely contributing factor to idiopathic preterm births worldwide, possibly due to maternal anatomical constraints.     

Challenges of Securing Growth Hormone Coverage for Idiopathic Short Stature: Review of the 7-Year Experience at one Institution

Objective: Despite U.S. Food & Drug Administration (FDA) approval of growth hormone (GH) for idiopathic short stature (ISS), many providers face challenges obtaining insurance coverage. We reviewed the insurance coverage experience for ISS at our hospital to identify factors predictive of approval or denial.Methods: We reviewed charts of patients who underwent GH stimulation testing from July 1, 2009, to April 30, 2017, to identify ISS patients (height <-2.25 SD, subnormal predicted adult height (PAH) and peak GH >10 ng/mL).Results: Eighty-seven patients met ISS criteria, of whom 47 (29 male/18 female) had a GH request submitted to insurance. Mean age, height, and growth velocity were 8.6 ± 2.7 years, 2.83 ± 0.4 SD, and 4.4 ± 1.7 cm/year, respectively. Mean PAH based on bone age was -2.50 ± 0.9 SD, equaling 62 inches for males and 58 inches for females. Most had private managed care insurance (74%). Overall, 17/47 (36%) received treatment approval, 7 immediately and 10 more on appeal. There were no differences in age, height SD, growth rate, insurance type, or PAH between the 17 who were approved and the 30 denied. For 21 patients who were treated, a mean increase in 0.6 SD in height was seen after 1 year.Conclusion: At our institution, GH coverage requests for ISS included very short children mostly ages 6 to 11, with heights well below -2.25 SD and poor PAH. Only 36% were approved even after appeal. This highlights the challenge in our area to secure GH treatment for a FDA-approved indication. Collaboration between pediatric endocrinologists and insurers focusing on height SD and PAH, may improve cost-effective coverage to deserving short children who meet FDA guidelines for ISS treatment.Abbreviations: FDA = Food and Drug Administration; GH = growth hormone; IGF-1 = insulin-like growth factor 1; ISS = idiopathic short stature; PAH = predicted adult height     

Born too soon

In this Letter, the author walks through 'Memory Lane'. She reflects upon the birth, growth and developmental trajectory of her third child who was born too soon, in a major Hospital in London. Her aim is to share her knowledge and experiences with other parents and professionals. The author acknowledges the feelings which is so common amongst mothers of preterm babies i.e. that the baby does not belong to them. Moreover, she reflects upon her participation in caring for her daughter, how overwhelming it all was and her joy when her child left hospital and is a healthy teenager.     

Normal progression of testicular size in boys with idiopathic short stature and isolated growth hormone deficiency treated with growth hormone: experience from the KIGS

BACKGROUND: The aim of this retrospective analysis was to evaluate the effects of growth hormone (GH) treatment on testicular development in boys with idiopathic short stature (ISS) and isolated GH deficiency (IGHD) followed in the KIGS (Pharmacia International Growth Database). METHODS: For inclusion in the study, the patients had to have received more than 1 year of prepubertal GH treatment, at least 4 consecutive years of GH treatment in total, and to have attained their final height, defined as a height velocity of less than 2 cm/year. Data on 107 boys in the KIGS database have been analyzed. RESULTS: No significant differences in duration of GH treatment and testicular volume at the start of treatment or at final height were found between the boys with ISS and those with IGHD. The progression of testicular volume in boys with ISS or IGHD during GH treatment did not differ from the reference population. CONCLUSIONS: This analysis shows that GH treatment does not alter testicular growth in boys with ISS or IGHD. However, prospective controlled studies are needed to rule out moderate attenuating or stimulating effects.     

Precocious Puberty Due to Rathke Cleft Cyst in a Child

ObjectiveTo report a case of a child with precocious puberty attributable to Rathke cleft cyst (RCC).MethodsThe clinical features, laboratory results, and findings on ultrasonography of the pelvis and magnetic resonance imaging of the pituitary gland are presented.ResultsA 16-month-old child had breast enlargement, height increase, and an increase in growth velocity. On examination, she was found to have Tanner stage 3 breast development, and her vaginal mucosa was estrogenized. Her height was above the 97th percentile. Biochemically, she was diagnosed as having central precocious puberty, and magnetic resonance imaging of her pituitary gland disclosed RCC. Treatment with leuprolide resulted in normalization of her growth rate and regression of the breast development; the vaginal mucosa also became unestrogenized.ConclusionAlthough RCC is a relatively common finding, it is a rare cause of precocious puberty. Magnetic resonance imaging of the pituitary gland should be performed in all children younger than 6 years of age who have precocious puberty, in an effort to detect any organic lesions. (Endocr Pract. 2009;15:134-137)     

A new clinical presentation associated with pontine clefting, hyperpigmentation and short stature in addition to craniofacial, cardiac and developmental anomalies

We report on a 13-year-old girl who was the first child of nonconsanguineous parents, and who suffered from short stature accompanied with mental retardation, generalized hyperpigmentation of the skin and craniofacial findings. Her cardiological examination revealed atrial septal defect, mitral valve prolapsus and atrial septal aneurysm. Brain scans revealed dilatation of the third and lateral ventricles and a pontine cleft. Growth hormone (GH) deficiency was observed during the evaluation of GH/IGF-I axis. All the laboratory tests performed including metabolic screening, conventional karyotype and oligonucleotide array were normal. Mutation analysis of the C2ORF3 7 gene revealed no mutation. The clinical signs seen in this patient likely represent a new dysmorphological syndrome which has not been previously described.