Udo Heinrich

Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome

Growth retardation resulting in short stature is a major concern for parents and due to its great variety of causes, a complex diagnostic challenge for clinicians. A major locus involved in linear growth has been implicated within the pseudoautosomal region (PAR1) of the human sex chromosomes. We have determined an interval of 170 kb of DNA within PAR1 which was deleted in 36 individuals with short stature and different rearrangements on Xp22 or Yp11.3. This deletion was not detected in any of the relatives with normal stature or in a further 30 individuals with rearrangements on Xp22 or Yp11.3 with normal height. We have isolated a homeobox-containing gene (SHOX} from this region, which has at least two alternatively spliced forms, encoding proteins with different patterns of expression. We also identified one functionally significant SHOX mutation by screening 91 individuals with idiopathic short stature. Our data suggest an involvement of SHOX in idiopathic growth retardation and in the short stature phenotype of Turner syndrome patients.

Tri-iodothyronine treatment in children after cardiac surgery: a double-blind, randomised, placebo-controlled study

BACKGROUND Serum thyroid hormone concentrations decline transiently during critical illness and after surgical procedures. We investigated prospectively the endocrine and haemodynamic effects of tri-iodothyronine treatment after cardiopulmonary bypass operations in children with congenital cardiac malformations. METHODS We did a randomised, double-blind, placebo-controlled trial, in which 40 children (median age 0.6 years; range 2 days to 10.4 years) were randomly assigned placebo (saline) or one daily infusion of tri-iodothyronine (2 microg/kg bodyweight on day 1 after surgery and 1 microg/kg bodyweight on subsequent postoperative days up to 12 days after surgery. Before and 2 h, 24 h, and 72 h after the first infusion, plasma concentrations of thyroid hormones were measured by RIA, and systolic cardiac function was evaluated by echocardiography. During the postoperative course intensive-care measures were assessed by use of the therapeutic intervention scoring system. FINDINGS In all patients, postoperative plasma concentrations of thyrotropin, thyroxine, free thyroxine, tri-iodothyronine were abnormally low and plasma concentrations of reverse tri-iodothyronine were raised. After start of treatment, tri-iodothyronine was significantly higher in patients given tri-iodothyronine than in those receiving placebo, whereas thyrotropin, thyroxine, free thyroxine, and reverse tri-iodothyronine remained similar in the two groups. At discharge, thyroid hormones of all patients were within the normal range, but thyrotropin secretion increased to plasma concentrations higher than those seen before treatment. The mean change of cardiac index was significantly higher in children given tri-iodothyronine (20.4% [SD 19.6] vs 10.0% [15.2]; p=0.004). Systolic cardiac function improved most in patients given tri-iodothyronine after longer cardiopulmonary bypass operations. Overall, patients given tri-iodothyronine had significantly lower mean treatment scores. INTERPRETATION Treatment of children with tri-iodothyronine after cardiopulmonary bypass operations raises tri-iodothyronine plasma concentrations and improves myocardial function especially in patients with low postoperative cardiac output without adverse events, and without delaying postoperative recovery of thyroid function. Furthermore, tri-iodothyronine reduces the need for postoperative intensive care.

Phenotypic classification of male pseudohermaphroditism due to steroid 5α‐reductase 2 deficiency

Conversion of testosterone (T) to dihydrotestosterone (DHT) in genital tissue is catalysed by the enzyme 5 alpha-reductase 2, which is encoded by the SRD5A2 gene. The potent androgen DHT is required for full masculinization of the external genitalia. Mutations of the SRD5A2 gene inhibit enzyme activity, diminish DHT formation, and hence cause masculinization defects of varying degree. The classical syndrome, formerly described as pseudovaginal perineoscrotal hypospadias, is characterized by a predominantly female phenotype at birth and significant virilization without gynecomastia at puberty. We investigated nine patients with steroid 5 alpha-reductase 2 deficiency (SRD). Phenotypes, which were classified according to the severity of the masculinization defect, varied between completely female (SRD type 5), predominantly female (SRD type 4), ambiguous (SRD type 3), predominantly male with micropenis and hypospadias (SRD type 2), and completely male without overt signs of undermasculinization (SRD type 1). T/DHT-ratios were highly increased ( > 50) in the classical syndrome (SRD type 5), but variable in the less severe affected patients (SRD types 1-4) (14-35). Mutations in the SRD5A2 gene had been characterized using PCR-SSCP analysis and direct DNA sequencing. A small deletion was encountered in two patients, while all other patients had single base mutations which result in amino acid substitutions. We conclude that phenotypes may vary widely in patients with SRD5A2 gene mutations spanning the whole range from completely female to normal male without distinctive clinical signs of the disease. Hence, steroid 5 alpha-reductase deficiency should be considered not only in sex reversed patients with female or ambiguous phenotypes, but also in those with mild symptoms of undermasculinization as encountered in patients with hypospadias and/or micropenis. A classification based on the severity of the masculinization defect may be used for correlation of phenotypes with enzyme activities and genotypes, and for comparisons of phenotypes between different patients as the basis for clinical decisions to be made in patients with pseudohermaphroditism due to steroid 5 alpha-reductase 2 deficiency.

Transient Secondary Hypothyroidism in Children after Cardiac Surgery

Thyroid hormone status was assessed in 132 children with congenital heart defects undergoing cardiac surgery (median age 3.1 y; range 2 d to 16.2 y). Plasma TSH, thyroxine (T4), free thyroxine (fT4), triiodothyronine (T3), reverse triiodothyronine (rT3), thyroglobulin (Tg), and urinary iodine excretion were measured before and every other day after cardiac surgery (d 1-21). After surgery we observed strikingly low plasma concentrations of TSH (0.4 mU/L; 0.2-1.3), T3(0.6 nmol/L; 0.3-1.2), T4 (48.9 nmol/L; 12.9-82.4), fT4 (12.9 pmol/L; 5.1-19.3), and Tg (9.4 μg/L; 1.5-20.6), whereas rT3 plasma concentrations increased (0.13 pmol/L; 0.05-0.3; n = 40). The maximal postoperative changes of TSH and rT3 preceded changes of T3, T4, fT4, and Tg. Postoperative urinary iodine excretion increased significantly (n = 109). Thyroid hormone plasma concentrations were lowest after cardiopulmonary bypass operations and in patients treated with dopamine. In patients with postoperative T3 plasma concentrations less than 0.6 nmol/L (n = 52) the period of mechanical ventilation and intensive care treatment was significantly prolonged. Furthermore, the cumulative doses of inotropic and vasoactive catecholamines and furosemide were significantly higher in this patient group. Our results demonstrate transient secondary hypothyroidism in children after cardiac surgery that may contribute to postoperative cardiac and respiratory dysfunction and may delay recovery. Possible benefits of thyroid hormone replacement therapy need to be thoroughly examined.

Lymphocytic hypophysitis with central diabetes insipidus and consequent panhypopituitarism preceding a multifocal, intracranial germinoma in a prepubertal girl

Abstract We report the clinical course of a prepubertal girl with central diabetes insipidus (DI) and consequent panhypopituitarism evolving over a period of 10 years due to lymphocytic hypophysitis and subsequent germinoma. Two years after the diagnosis of central DI was established, MRI revealed a thickened pituitary stalk. Later pituitary enlargement and increasing thickening of the pituitary stalk impinging on the optic chiasm required a trans-sphenoidal biopsy which disclosed active hypophysitis with lymphocytic infiltrates and necrosis. High dose dexamethasone treatment only temporarily halted the disease process. Therefore, stereotactic radiation therapy was performed as a rescue treatment and MRI findings almost reversed. However, the subsequent MRI showed multiple intracranial lesions identified histologically as a germinoma and a standard chemotherapy and radiation was performed. Conclusion The diagnosis of diabetes insipidus in children requires long-term follow up beyond the pubertal age in order to establish the underlying cause. In contrast to lymphocytic hypophysitis in adults, lymphocytic hypophysitis in prepubertal children may represent the first sign of a host reaction to an occult germinoma.

Growth Analysis in Patients with 21-Hydroxylase Deficiency Influence of Glucocorticoid Dosage, Age at Diagnosis, Phenotype and Genotype on Growth and Height Outcome

Objective: To evaluate the impact of hydrocortisone dosage, age at diagnosis, compliance, genotype and phenotype on growth and height outcome in 21-hydroxylase-deficient patients. Methods: We analyzed 37 patients with 21-hydroxylase deficiency (17 had completed growth, 20 still growing). Final (FH)/predicted final height (pFH) and loss of height potential related to target height (TH) were calculated and the impact of 4 hydrocortisone (HC) dosage regimens on height outcome and growth velocities was evaluated. Mean FH SDS and pFH SDS were analyzed in accordance to age at diagnosis, compliance, genotype and phenotype. Results: Mean (FH SDS, pFH SDS) was –1.8 ± 1.06 SD, with 35.1% of all 37 patients exhibiting short stature. Doses >20 mg/m2/day during the first year and >15 mg/m2/day during age 1–5 and at puberty resulted in significantly lower FH SDS, pFH SDS and greater height losses. Age at diagnosis, compliance, genotype and phenotype played only a minor role in growth development. Conclusions: Hydrocortisone substitution in 21-hydroxylase-deficient patients should be kept at the lowest efficient level, if possible <20 during the first year and <15 mg/m2/day until age 5 and during puberty. Normal growth and not complete androgen suppression should be aimed for.

Growth Hormone Induced Rise in Glomerular Filtration Rate Is Not Obliterated by Angiotensin-Converting Enzyme Inhibitors

In 8 healthy normotensive probands with normal glomerular filtration rate, the effect of recombinant human growth hormone (rhGH) on inulin clearance (Cin) was examined in an open study with intraindividual crossover with or without enalapril pretreatment (20 mg/day). rhGH was administered by subcutaneous injection (4.5 U twice daly) for 3 days. On the following day Cin was measured with an enzymatic steady state infusion technique. Systemic hemodynamics and potential metabolic effects of rhGH, i.e., inulin-like growth factors I and II, somatomedin-binding protein, glucagon, C peptide, amino acid pattern, etc., were monitored. On controlled dietary intake of protein, the median Cin rose 72 h after start of rhGh administration from 114 (range 91-158) to 135 (108-167) ml/min/1.73 m2 without enalapril pretreatment (p less than 0.01) and from 111 (88-153) to 131 (100-173 ml/min/1.73 m2 with enalapril pretreatment (p less than 0.02). The results confirm that (1) rhGH increases Cin to a similar extent as extractive GH and (2) further demonstrate that this action is not obliterated by blocking the circulating converting enzyme.

Atrial Natriuretic Peptide in Infants and Children

Atrial natriuretic peptide (ANP) was measured in the plasma of 192 normal infants and children aged 1 day to 18 years. Plasma ANP was high during postnatal adaptation, particularly in premature infants. In 96 infants and children aged 4 months to 18 years, plasma ANP was similar to values obtained in 7 healthy adult volunteers (23.9 +/- 11.9 vs. 25.7 +/- 4.6 fmol/ml). There was no significant relationship between ANP and age. ANP is elevated about twofold in full-term neonates being 3-4 days of age, and returned to normal thereafter. It is concluded that ANP is raised during the postnatal adaptation. This hormone is possibly involved in the postnatal volume contraction and may antagonize vasoconstrictor hormones that are elevated during the postnatal period.

Three new 46,XX male patients: A clinical, cytogenetic and molecular analysis

BACKGROUND XX males range phenotypically from completely masculinised individuals to true hermaphrodites and include a subset of SRY negative patients. The correlation between genotype (SRY+/-) and phenotype is still unclear. AIM To report three new patients with this rare condition, one of whom was diagnosed prenatally and another was SRY negative, and to verify in our patients whether the presence of SRY results in a more masculinised phenotype. PATIENTS AND METHODS We present two phenotypically normal XX male patients (10 and 13.5 years) and one 3.1 years old XX male with ambiguous external male genitalia Prader IV. The patients were diagnosed by clinical, hormonal, sonographic, genetic and histological criteria. RESULTS Basal hormonal status was normal for phenotype but an excessive response to GnRH testing was noticed in the second patient together with insufficient hCG stimulation in all three patients. Pelvic ultrasound displayed male structures without Müllerian ducts; testicular biopsy, performed only in the intersex patient, showed Sertoli and Leydig cell hypoplasia. Chromosome analysis confirmed 46,XX karyotype. FISH analysis and molecular analysis by PCR were positive for Yp fragments/SRY gene on Xp in two patients and negative in the patient with ambiguous external genitalia. CONCLUSIONS In our observation Y chromosome-specific material containing the SRY gene translocated to the X chromosome results in a completely masculinised phenotype. In the intersex patient, incomplete masculinisation without SRY suggests a mutation of one or more downstream non-Y testis-determining genes.

Short-term, high-dose testosterone treatment fails to reduce adult height in boys with constitutional tall stature.

Abstract Height predictions based on three different methods (Bayley-Pinneau [BP], Tanner-Whitehouse Mark II [TW II], Roche-Wainer-Thissen [RWT]) were compared to adult heights in 19 males with constitutional tall stature previously treated with high-dose testosterone oenanthate for 6 months (group A) and 25 untreated tall males (group B). Their chronological ages (CA) at the initial evaluation of tall stature ranged from 12.1 to 16.6 years in group A and from 10.4 to 15.7 years in group B; at the time of assessment of adult height ages ranged from 18.0 to 26.5 years and from 18.4 to 25.1 years, respectively. Height measurements and predicted adult heights were expressed as height standard deviation scores (height SDS) for chronological age using the tables of Reinken and van Oost [14]. Height SDS in group A were 2.8 (range = 1.8–5.4) before testosterone treatment, 3.0 (range = 2.0–4.8) thereafter and finally 3.0 (range = 2.1–4.2) (P=NS) and in group B 2.7 (range = 0.5–4.3) and 2.4 (range = 1.3–3.5) (P=NS). A significant difference between adult height SDS and predicted height SDS according to BP was detected both in group A (3.0; range = 2.1–4.2 vs 3.6; range = 2.4–5.0; P≤0.004) and group B (2.4; range = 1.3–3.5 vs 3.0; range = 2.0–4.9; P≤0.0002), whereas no significant difference between adult height SDS and predicted height SDS according to TW II and RWT was found in either group. These data indicate that BP height predictions overestimated adult height in our patient group of treated and untreated males with constitutional tall stature. In contrast, the TW II and RWT methods were more accurate in predicting adult height in these patients, but also failed to demonstrate that testosterone therapy in boys with constitutional tall stature can be limited to a 6-month period in order to reduce adult height. Conclusion The widely used height prediction method of BP is inaccurate in boys with constitutional tall stature. High dose testosterone treatment fails to reduce adult height in these individuals when discontinued before complete closure of the epiphyses.