Growth hormone,suspected gonadotrophin deficiency,and ring 18 chromosome.

A boy with a ring 18 chromosome karyotype was referred because of short stature; he had growth hormone deficiency and possible hypogonadotrophic hypogonadism. Many children with major chromosomal abnormalities are short, but this case emphasises the need to consider growth hormone deficiency in addition.     

Cleft palate and gonadotrophin deficiency.

A boy who had previously had a cleft lip and palate repaired and bilateral orchiopexies presented at 16 years of age with delayed puberty. Isolated gonadotrophin deficiency and testicular hyporesponsiveness to human chorionic gonadotrophin were found. The possibility of bilateral cryptorchidism due to gonadotrophin deficiency should be considered in boys with either cleft lip or palate, or both.     

Growth hormone deficiency in patients with histiocytosis X

Twenty-two patients with biopsy proved histiocytosis X, aged 10 months to 14 years (median 2 years) at the time of diagnosis, were observed for 6 months to 13 years (median 4 years). One patient who had received 3000 rads irradiation directly to the hypothalamic-pituitary area had clinical and biochemical evidence of growth hormone deficiency and responded to GH therapy. Thirteen patients had normal stature, normal growth velocity, and no diabetes insipidus. The GH response to insulin-induced hypoglycemia was studied in three of these 13 patients (group 1), in three children with short stature and no diabetes insipidus (group 2), and in five patients with diabetes insipidus but normal stature and growth velocity (group 3). Peak GH responses were normal (greater than 5 micrograms/L) in all patients in groups 1 and 2, but three of the five patients in group 3 had subnormal GH responses to insulin-induced hypoglycemia and to arginine, L-DOPA/propranolol, and exercise. Their growth rates continue to be normal over 6 to 14 years follow-up. Thus, although impaired GH responses were observed in four of the 12 patients tested, true growth failure occurred only in association with direct hypothalamic-pituitary irradiation. This experience and the observation that GH deficiency was diagnosed in fewer than 1% of children with histiocytosis in Canada during a 15-year period (accounting for less than 1% of all children with GH deficiency) suggest that classic GH deficiency is not a common complication of histiocytosis unless direct hypothalamic-pituitary irradiation has been given.     

Mutation screening in patients with isolated cytochrome c oxidase deficiency

Cytochrome c oxidase (COX) deficiency has been associated with a variety of clinical conditions and can be due to mutations in nuclear or mitochondrial genes. Despite recent progress in our understanding of the molecular bases of COX deficiency, the genetic defect remains elusive in many cases. We performed mutation screening in 30 patients with biochemical evidence of isolated COX deficiency and heterogeneous clinical phenotypes. Sixteen patients had various forms of encephalomyopathy, and six of these had the neuroradiological features of Leigh syndrome. Four patients had encephalohepatopathy, six had hypertrophic cardiomyopathy, and four had other phenotypes. We studied the three mtDNA genes encoding COX subunits, the 22 mtDNA tRNA genes, and seven COX assembly genes: SCO1, SCO2, SURF1, COX10, COX11, COX15, and COX17. We report two novel pathogenic SURF1 mutations in a patient with Leigh syndrome and one novel SCO2 mutation in a patient with hypertrophic cardiomyopathy. These data show that heterogeneous clinical phenotypes are associated with COX deficiency, that mutations in mtDNA COX genes are rare, and that mutations in additional genes remain to be identified.     

Rhizomelic chondrodysplasia punctata with isolated DHAP-AT deficiency.

An infant with the characteristic phenotype of classical rhizomelic chondrodysplasia punctata was found to have an isolated deficiency of the peroxisomal enzyme acyl CoA dihydroxyacetone phosphate acyltransferase (DHAP-AT). All other peroxisomal functions measured were found to be normal. Previously described in one other case report, this confirms the existence of another distinct form of peroxisomal disorder characterised biochemically by a deficiency in de novo plasmalogen biosynthesis only.     

Growth hormone deficiency in patients with sickle cell disease and growth failure

BACKGROUND: Growth disorders are common in children with sickle cell disease (SCD). The etiology for growth disturbances in this population appears to be multifactorial. Recent evidence suggests abnormalities in the growth hormone (GH)/insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) axis may play a role. OBJECTIVE: To measure GH levels through provocative stimulation in a group of patients with SCD with growth failure, and to evaluate response to treatment. PATIENTS AND METHODS: Growth records were reviewed of 79 children with sickle cell hemoglobinopathies to identify children with growth failure. GH levels were measured in patients with SCD with and without growth failure using arginine and L-Dopa as provocative stimulation tests. Treatment with GH was offered to GH-deficient children with SCD and these patients were followed longitudinally over 5 years. RESULTS: Of the 79 patients, 13 (16.5%, all SS) had heights less than -2 SD below the mean or a growth velocity < -2 SD below the mean for age. Seven of the 13 children with growth failure participated in this study. Five patients received GH for 3 or more years and demonstrated significant improvement in their height SDS. One of the two who declined treatment was lost to follow-up and the other had significant worsening of height SDS score. CONCLUSION: GH deficiency may be associated with growth failure in some patients with SCD. These patients may benefit from treatment with GH.     

Growth hormone deficiency associated with the ectrodactyly-ectodermal dysplasia-clefting syndrome and isolated absent septum pellucidum

Two growth hormone-deficient patients with particular developmental defects are presented. One patient had the ectrodactyly-ectodermal dysplasia-clefting syndrome with lobster-claw deformities of the hands; thin, blond, and dry hair and enamel hypoplasia; and a facial raphe on the right side of the philtrum. The other patient had isolated absence of the septum pellucidum. The facial raphe and the absent septum pellucidum are related to cleft lip and septooptic dysplasia, conditions that have been associated with growth hormone failure. The association of the ectrodactyly-ectodermal dysplasia-clefting syndrome with isolated growth hormone deficiency has not been described previously.     

Growth hormone deficiency in Sturge-Weber syndrome.

Sturge-Weber syndrome (SWS) is a disorder involving central nervous system abnormalities that may increase the risk of hypothalamic-pituitary dysfunction. Records of 19 patients with suspected growth hormone deficiency (GHD), identified from a registry of 1653 patients with SWS, were reviewed; nine patients with GHD were found.     

Growth of infants with neonatal growth hormone deficiency.

In view of contradictory reports on the growth hormone dependency of early postnatal growth we studied the growth curves of 15 infants with neonatal growth hormone deficiency. In seven infants the growth curve was parallel to the standards of the infancy-childhood-puberty (ICP) model (group 1), but in the remaining infants there was an immediate deviation of the growth curve (group 2). In this group the mean (SD) at 4 and 9 months of age was -3.3 (1.1) and -4.9 (1.4), respectively, when compared with the ICP model. The mean birth length in both groups was decreased and five out of 15 had a birth length of less than -2 SD. Serial measurements of the growth hormone response to provocation tests in two patients in group 2 showed decreasing concentrations, while four patients with documented complete growth hormone deficiency belonged to group 2. We conclude that growth hormone is needed for early infant growth and that the normal growth pattern in some infants with neonatal pituitary dysfunction is due to incomplete insufficiency.     

Depot testosterone in boys with anorchia or gonadotrophin deficiency: effect on growth rate and adult height.

Eleven teenage boys with bilateral anorchia and 12 with gonadotrophin deficiency were treated by injections of testosterone ester (enanthate) at an initial dose of 100 mg every six to eight weeks, rising to 250 mg every four weeks after three to four years. In the anorchic boys average adult height was 177.1 cm, compared with a mean mid-parental height of 174.4 cm, and mean predicted adult heights of 177.0 cm (Tanner-Whitehouse method) and 178.0 cm (Bayley-Pinneau method). In the patients with gonadotrophin deficiency, mean adult height was 176.9 cm, compared with a mean mid-parental height of 176.1 cm, and mean predicted adults heights of 174.0 cm (Tanner-Whitehouse method) and 177.3 cm (Bayley-Pinneau method). We conclude that this testosterone regimen allows achievement of full growth potential in such patients.     

Growth retardation in children with IgA deficiency

We evaluated the clinical and immunological manifestations of 14 children with IgA deficiency. Four of the patients were asymptomatic, and ten were symptomatic, with recurrent sinopulmonary infections, allergic disease, recurrent intestinal giardiasis or celiac disease. Growth retardation was the second important feature in our patients. One of the seven patients with growth retardation had partial growth hormone deficiency. The levels of serum IgG and IgM were high in five and three patients, respectively. Cellular immunity was normal.     

Rhizomelic chondrodysplasia punctata with isolated DHAP-AT deficiency

An infant with the characteristic phenotype of classical rhizomelic chondrodysplasia punctata was found to have an isolated deficiency of the peroxisomal enzyme acyl CoA dihydroxyacetone phosphate acyltransferase (DHAP-AT). All other peroxisomal functions measured were found to be normal. Previously described in one other case report, this confirms the existence of another distinct form of peroxisomal disorder characterised biochemically by a deficiency in de novo plasmalogen biosynthesis only.     

Antibody deficiency and isolated growth hormone deficiency in a girl with Mulibrey nanism

A combination of humoral immunodeficiency and isolated growth hormone deficiency was observed in a girl with Mulibrey nanism. The humoral immunodeficiency consisted of subnormal concentration of serum IgG, in particular IgG2 and IgG4, and low concentration of serum IgM. Serum IgA and IgD were elevated, IgE was absent. Antibody response in vivo was very low or absent and opsonization in vitro was defective. Total B-cell number was low. In addition, the serum kappa/lambda light chain ratios within the immunoglobulin classes G, A, and M were abnormal. The defective anti-body response may be linked to the abnormal kappa/lambda light chain ratios. Endocrine functions were normal except for isolated growth hormone deficiency. Therapy with human growth hormone resulted in increased growth velocity but did not improve humoral immune functions.     

Growth hormone deficiency in patients with 22q11.2 deletion: expanding the phenotype

The list of findings associated with the 22q11.2 deletion is quite long and varies from patient to patient. The hallmark features include: conoruncal cardiac anomalies, palatal defects, thymic aplasia or hypoplasia, T cell abnormalities, mild facial dysmorphia, and learning disabilities. The 22q11.2 deletion has been seen in association with the DiGeorge sequence, velocardiofacial syndrome (VCFS), conotruncal anomaly face syndrome, isolated conotruncal cardiac anomalies, and some cases of autosomal dominant Optiz G/BBB syndrome. Short stature has been seen in one to two thirds of children reported in the literature with a diagnosis of VCFS, but growth hormone deficiency (GHD) has not been described in conjunction with this diagnosis. We present 4 patients with a 22q11.2 deletion and short stature who were found to have abnormalities in the growth hormone-insulin-like growth factor I axis. All had growth factors less than -2 SD for age and failed provocative growth hormone testing. Two patients were found to have abnormal pituitary anatomy. In our population, the incidence of GHD in 4 or 95 children with 22q11 deletion is significantly greater than the estimated incidence of GHD in the general population. Children with a 22q11.2 deletion appear to be at a greater risk for pituitary abnormalities. Therefore, those children with the 22q11.2 deletion and short stature or poor growth should be evaluated for GHD, as replacement growth hormone therapy may improve their growth velocity and final height prediction.