Molecular characterization of 6 unrelated Italian patients with 5alpha-reductase type 2 deficiency.

Steroid 5alpha-reductase (5alphaR) deficiency (OMIM number #264600) is a rare 46,XY disorder of sex differentiation caused by mutations in the 5alphaR type 2 gene (SRD5A2) resulting in dihydrotestosterone deficiency during fetal development. We report on the analysis of the SRD5A2 gene in 6 unrelated 46,XY Italian patients with external genitalia morphology ranging from predominantly female to nearly completely male. Three subjects were seen and assessed at birth, 1 patient was referred to us before puberty, and 2 at postpubertal age. Six different causative mutations (5 missense and 1 nonsense) and a rare polymorphism were identified. Four patients presented homozygous single-base substitutions. These SRD5A2 mutations were located in exon 2 (variant Cys133Gly), exon 4 (Gly196Ser and Ala207Asp) and exon 5 (Tyr235Phe). A fifth subject was a compound heterozygote who carried a nonsense mutation in exon 1 (Trp53X) and a second SRD5A2 alteration in exon 5 (Tyr235Phe). The final patient presented a mutation in only 1 allele (Gly34Trp) together with the Ala49Thr variant. The molecular characterization of these patients made it possible to identify novel mutations and to confirm, before gender assignment or any surgical approach, the suspected 5alphaR deficiency in 2 newborns, 1 of whom had inconclusive hormonal data. 5alphaR deficiency in subjects without parental consanguinity and the presence of compound heterozygotic patients suggest that SRD5A2 mutations carrier frequency may be higher than previously thought.

Endocrine and neuropsychological assessment in a child with a novel mutation of thyroid hormone receptor: response to 12-month triiodothyroacetic acid (TRIAC) therapy.

OBJECTIVE: To determine the endocrine, neuropsychological and genetic features of a child with resistance to thyroid hormone (RTH), and his response to long-term triiodothyroacetic acid (TRIAC) therapy. METHODS: Growth, thyroid function, and neuropsychology were assessed at baseline and during 12-month TRIAC therapy. Genetic analysis was performed by PCR and denaturing high performance liquid chromatography. RESULTS: The main clinical finding was the attention deficit-hyperactivity disorder (ADHD). A novel mutation in exon 10 (phenylalanine to isoleucine in codon 455) was found. Long-term TRIAC therapy was effective in the management of the endocrine and neuropsychological manifestations of the syndrome. CONCLUSIONS: ADHD was the only phenotypic manifestation of this novel mutation of thyroid hormone (TH) receptor. TRIAC is an effective and safe drug in the long-term treatment of children with RTH.

Bone mineral density at diagnosis and following successful treatment of pediatric Cushing's disease.

Bone mineral density (BMD) is frequently reduced in children and adolescents with Cushing's disease (CD), but there is little follow-up data after cure. BMD was determined by dual energy X-ray absorptiometry (DEXA) in two groups of patients with CD. Group 1 comprised 8 patients, 5 males and 3 females, aged 12.4 yr (8.2-16.8), assessed at diagnosis. Group 2 comprised 11 subjects, 6 males and 5 females, diagnosed at age 13.3 yr (6.4-17.4), cured by transsphenoidal surgery (TSS) (no.=7) or TSS + pituitary irradiation (no.=4). They had measurement of BMD, at mean age of 18.3 yr (11.1-28.5), i.e. 4.5 yr (0.8-11.4) after cure. Four patients, mean age 20.2 yr (17.6-22.4), had repeated DEXA'scans, 1-4 times, for up to 5.8 yr. After cure, GH deficiency was present in 9 patients and treated with hGH in 8. In Group 1, patients' L2-L4 volumetric (v)BMD Z-score was variable with a mean of -1.04 (-3.21-0.11). L2-L4 vBMD Z-score values correlated negatively with midnight cortisol (p < 0.05). In Group 2, mean L2-L4 vBMD was -0.38 (-1.0-0.13); and in 7/11, mean femoral neck (FN) areal (a)BMD Z-score was 0.14 (-1.62-2.46). FN aBMD Z-score was higher than L2-L4 aBMD Z-score (p < 0.05). In patients with repeated scans, mean change in L2-L4 vBMD Z-score was 0.20 (-0.15-0.45), and mean change in FN aBMD Z-score 0.03 (-0.53-0.38). These findings show variability of BMD at diagnosis and near normal BMD after cure of pediatric CD, suggesting that with appropriate replacement of pituitary hormone deficiency normal peak bone mass is achievable.

Growth in disorders of adrenal hyperfunction.

Growth is disturbed by adrenal hypersecretion of androgens or cortisol. Androgen excess in virilizing adrenal tumours causes advanced growth and bone age. In 9 girls with virilizing tumours, mean heights at diagnosis and final heights were 1.23 +/- 0.42 and 1.3 +/- 0.37 SDS respectively. In poorly controlled CAH, excess androgens cause early epiphyseal fusion and adult short stature. Increased growth occurs only after 18 months of age, even in untreated CAH, i.e. hydrocortisone >10 mg/m(2)/day is not generally required and may suppress infantile growth, affecting childhood and adult height. Growth was studied in 19 patients, aged 6.4-17.8 years, with Cushing's disease (CD). At diagnosis, mean height SDS was -1.81 (1.2 to -4.17), 53% < -1.8 SDS, height velocity in 6 was 0.9-3.8 cm/year and mean BMI SDS 2.29 (0.7-5.06). From 1983 to 2001, CD was cured in 18 patients (61%) by transsphenoidal surgery (TSS) alone and 39% by TSS plus pituitary irradiation (RT). In 13 patients, growth hormone (GH) was assessed by ITT/glucagons at 1-108 months after cure. Four had severe GH deficiency (<9 mU/l), 7 subnormal (10-29 mU/l) and 2 normal (>30 mU/l) GH status. Subnormal GH was present in 7 subjects >2 years after TSS or RT cure. In 10 subjects, aged 12.9 +/- 3.4 years, growth after cure was studied for 9.1 +/- 5.0 years. Nine had no catch-up growth in the interval of 0.3-1.1 years after cure (mean HV 5.3 +/- 2.4 cm/year). All these had GH deficiency peak GH 0.5-20.9 mU/l, and received hGH 2.7 mg/m(2)/week, 3 with GnRHa. All 10 showed long-term catch-up growth with mean delta SDS at diagnosis (Ht SDS-target Ht SDS) -1.72 +/- 1.26 improving to -0.83 +/- 1.08 (p = 0.0005) at latest of final Ht. At diagnosis, virilization was present in 82% of 17 patients with CD. Mean SDS values of serum androstenedione, DHEA-S and testosterone were normal, i.e. 0.72 (-2.9 to 3.0), -0.8 (6.0 to 2.2), 0.7 (-7.9 to 9.5) respectively, whereas SHBG was reduced at -2.1 (-5.3 to 1.2), increasing free androgen levels. Bone age (BA) was delayed (mean 1.46 years) in 14/16 patients, suggesting cortisol excess contributed more then androgen effect to skeletal maturation. In conclusion, most paediatric patients with CD had subnormal linear growth with delayed BA. After cure by TSS or pituitary irradiation, GH deficiency was frequent and persisted for many years. Treatment with hGH induced significant long-term catch-up growth leading to reasonable final height.

[Diagnosis of Prader-Willi syndrome. Considerations on a case of erroneous diagnosis]. / L'iter diagnostico della sindrome di Prader-Willi. Considerazioni su un caso di diagnosi errata.

Prader-Willi syndrome is a genetic disease, which is clinically characterized by neonatal hypotonia, feeding problems in the first year of life, excessive eating with severe obesity from the second year of life, developmental delay, hypogonadism, typical facial features, short stature, behaviour problems, mental retardation. It is caused by a genomic imprinting disorder, i.e., lacking expression of paternally derived genes located on the long arm of chromosome 15. We present a case of a child with a neonatal diagnosis of Prader-Willi syndrome, founded on some facial dysmorphic features and a partial deletion of 15q, which we belied thanks to an anamnestic and clinical revaluation, and a metilation test. We also present main topics about Prader-Willi syndrome diagnosis, including clinical and endocrinological features, scoring system, and genetics.

Alloimmune neonatal neutropenia treated with rHuG-CSF.

Infants with alloimmune neonatal neutropenia (ANN) may be at risk of life-threatening infection. Various modalities of treatment have been attempted but with differing results. We describe a case treated with rHuG-CSF. The use of rHuG-CSF should be considered in children with ANN especially when associated with life-threatening infection.

[Rhabdoid tumor of the kidney: a rare malignant neoplasm of infancy. A case report and review of the literature]. / Tumore rabdoide del rene: una rara neoplasia maligna infantile. Descrizione di un caso e revisione della letteratura.

Rhabdoid tumor of the kidney (RTK) is a quite rare malignant neoplasm of early childhood. It has a very unfavourable prognosis, since it tends to give early metastases and shows a poor response to chemotherapy regimens. We report a case of an infant with RTK, who had a rapidly progressive course. Based upon our case and the review of the literature, we would like to stress the importance of a differential diagnosis with another kidney cancer, namely Wilms tumor, which is more frequent and has by far a better prognosis.

[Haemophilus influenzae disease in childhood. Comment about case reports of meningitis]. / Patologia da Haemophilus influenzae in età pediatrica. Considerazioni su una casistica di meningiti.

The authors describe a series of Haemophilus influenzae meningitis in childhood, obtained with a retrospective analysis of the cases of bacterial meningitis admitted to Isolamento Pediatrico department of "A. Gemelli" Polyclinic in Rome, from January 1, 1970 to December 31, 1994. Haemophilus influenzae resulted the second agent in frequency (first was Neisseria meningitidis). Main features were: no patient was older than 5 years, and most of them were less than 2 years old; clinical feature was aspecific in the first year of life, it was typical of bacterial meningitis in older children; blood culture and detection of bacterial antigens in cerebrospinal fluid (CSF) were useful for etiological diagnosis, supporting CSF culture; clinical course was characterized by many complications, but no case was lethal and incidence of sequelae at discharge was low; C reactive protein was effective as index of inflammation and as indicator of arising complications; chosen antibiotics were efficacious, but frequency of antibiotic resistance, especially to beta-lactams, was found to be increasing; results of dexamethasone therapy were not of univocal interpretation. The authors are in favour of spreading of vaccination against Haemophilus influenzae in Italy, too, in order to eradicate this disease, as experiences in other countries are successful, and of setting up of the combined vaccines, in order to increase parents' compliance to vaccinal practices.

[Intracranial hemorrhage in Schoenlein-Henoch syndrome]. / Emorragia endocranica nella sindrome di Schoenlein-Henoch.

Henoch-Schoenlein syndrome (HSS) is one of the most common vasculitis in childhood. It is characterized by non-thrombocytopenic purpura, arthritis, abdominal pain, and sometimes intestinal haemorrhage and renal involvement. It may be complicated by haemorrhages in uncommon sites, such as lungs, testicles, bladder, and central nervous system. Neurological involvement in HSS is often underestimated, usually occurring with headache, irritability, and behavioural alterations, whereas endocranial haemorrhage is quite rare. We report a case of endocranial haemorrhage in a child with HSS.