Giuseppina Zirilli

Subclinical hypothyroidism: The state of the art

Subclinical hypothyroidism (SH) is a common clinical problem, particularly in adulthood and the elderly. Its prevalence is conditioned by several etiological and risk factors. The highest age- and sex-specific rates are in women over 60. SH may be associated with manifestations of mild thyroid failure, which may reverse under levothyroxine (L-T4) therapy. The risk of progression to overt hypothyroidism is distinctly higher in cases with underlying thyroid disease. A population routine screening is not generally recommended, but screening is encouraged in high-risk groups. L-T4 therapy may be indicated in subjects with TSH levels which are repeatedly and consistently elevated (>10 μIU/ml) and may be considered in those with TSH ranging between 4.5–5.5 and 10 μIU/ml, particularly if anti-thyroid antibodies are positive and/or hypothyroid symptoms are present. Treatment should be based, at least initially, on L-T4 low doses.

Clinical presentation of McCune-Albright syndrome in males.

UNLABELLED The aims of this study were: (a) to survey gender prevalence and clinical findings at diagnosis in a series of patients who manifested at the time of this study the classical triad of McCune-Albright syndrome (MAS); (b) to investigate whether clinical presentation of MAS in boys may be different from that in girls; (c) to confirm whether boys with MAS may show a peculiar picture of testicular microlithiasis (TM) by testicular ultrasonography (US). Twenty-six patients (10 boys) with the classical clinical manifestations of MAS were recruited for the present study from the database of the Italian Multicenter Study Group on MAS. Age at diagnosis of MAS was significantly lower in girls than in boys (p < 0.025). Whilst there was no difference in the prevalence of skin and bone fibrous dysplasia for the two groups, a significantly higher prevalence of peripheral precocious puberty (PPP) was found in girls (chi2 = 6.5, p < 0.025). Moreover, PPP onset was earlier in females than in males (2.8 +/- 2.3 vs. 6.9 +/- 2.7 years, p < 0.005). In one boy, aged 2.9 years, the first clinical manifestation of MAS was monolateral testicular enlargement in the context of a picture of classical PPP. US scanning of the testes, at the time of the present study, showed bilateral hyperechogeneic multiple spots, compatible with diagnosis of TM, in 6/10 boys. CONCLUSIONS (a) MAS is slightly more frequent in females. (b) PPP in MAS is significantly more frequent and earlier in girls. (c) PPP in boys with MAS is generally associated with bilateral testicular enlargement, but monolateral macroorchidism may also be seen. (d) TM may be another marker for MAS in males.

Testicular microlithiasis heralding mixed germ cell tumor of the testis in a boy

The clinical implications of the association between testicular microlithiasis (TM) and germ cell tumor (GCT) of the testis are still debated since the natural history of incidentally discovered TM has not been defined. Therefore, it is questionable whether TM can be considered as a precursor of malignancy. We are reporting the case of a 9-yr-old boy with a mixed GCT who had presented 3 yr earlier with TM and hydrocele. This evolution suggests that testicular GCT may develop some years later in a boy with pre-existing and incidentally discovered TM. Our case history and other reports of the literature might suggest a strong association between both conditions, thus vindicating the view that individuals with TM should have clinical and ultrasound follow-up. Longitudinal evaluation may be particularly indicated in the patients with additional testicular dysgenetic features, apart from TM.

Neurocognitive Profile in Turner's syndrome is Not Affected by Growth Impairment

Turners syndrome (TS) is a chromosomal disorder that results from the loss of the entire or a part of the X-chromosome and occurs in 1/2,500 female births. According to the majority of specific reports, intelligence in TS is generally found to be normal and the prevalence of mental retardation does not seem to be increased in TS except for those patients with a small ring X-chromosome. We evaluated 33 girls with TS with chronological age from 6-18 years. Intellectual assessment included the WISC III and the WAIS-R scales. Our results showed: 1) mean full scale intelligence quotient (FSIQ) was significantly lower than expected based on normative data (p < 0.0005); 2) no correlation was present between height and general intellectual ability; 3) mean performance intelligence quotient (PIQ) was significantly lower than both mean verbal intelligence quotient (VIQ) and FSIQ (p < 0.0025 and p < 0.01, respectively), and most patients had a VIQ-PIQ discrepancy; 4) the frequency of mental retardation in our study group was significantly higher than that observed in the general population (15.1% vs 2.3%, p < 0.025); 5) a significant association was found between karyotype and VIQ, and the best score was achieved in the subgroup of patients with structural abnormalities of the X-chromosome. In the light of these findings we conclude that the clinical picture in TS may encompass a slightly reduced FSIQ, VIQ and especially an inadequate PIQ, but this neurocognitive profile is not significantly affected by statural impairment. Since these neurocognitive defects can be responsible for misdiagnosed school difficulties, we suggest that girls with TS should receive specialized educational support and multidisciplinary care.

In Sicilian ethnic group non-classical congenital adrenal hyperplasia is frequently associated with a very mild genotype

The spectrum of mutated alleles in non-classical congenital adrenal hyperplasia (NC-CAH) has been recently reported to be very large and haplotypes may significantly differ in the different ethnic groups. In order to confirm that population differences may exist in the genetic basis of this disease, we have analyzed the genetic presentation of NC-CAH in a Sicilian cohort of symptomatic patients and compared our findings with the ones reported in other studies of different ethnic groups. In 38 NC-CAH patients coming from two regions of Sicily and born of Sicilian parents, we found that 84.2% of the chromosomes examined bore only mild mutations and only the remaining 15.8% of the chromosomes bore at least 1 severe mutation. The overall predominant mutation was V281L, which was detected in 73.7% of alleles and in 89.5% of patients. About 58% of the patients were homozygotes for this mutation. V281L allele and homozygote frequencies were higher in the present series than in other European and Italian reports. In our NC-CAH population, which is one of the largest ever reported, the patients with two mild mutations exhibited a less severe impairment of both clinical and endocrine phenotype. On the basis of these results we can conclude that: a) in Sicilian ethnic groups NC-CAH is frequently associated with a very mild genotype; b) the most frequent genotype in our series is V281L homozygosis; c) clinical and biochemical expression of NC-CAH is more marked in the patients bearing a severe mutation; d) no correlations between genotype and phenotype were found in our patients affected by NC-CAH.

Early Discrimination between Transient and Permanent Congenital Hypothyroidism in Children with Eutopic Gland

Aim: To analyze the factors that might allow an early discrimination between permanent (P) and transient (T) congenital hypothyroidism (CH). Methods: Clinical, biochemical and imaging data of 64 children with eutopic gland, who were positively screened and treated for CH during the period 1998-2011, were retrospectively analyzed. Results: During a 3-year treatment period, the mean doses of L-thyroxine (L-T4) per kilogram of body weight at various times were significantly lower in the 46 children with T CH than in the remaining 18 with P CH. No patients with T CH had required any increment of the doses of L-T4 per kilogram of body weight to maintain normal thyroid-stimulating hormone levels over time, whereas 16/18 children with P CH during the same period had needed some dose increments (p < 0.0001). Conclusions: (a) L-T4 requirements >4.9 µg/kg/day at 12 months or >4.27 µg/kg/day at 24 months are highly suggestive of P CH, irrespective of gland ultrasonography; (b) L-T4 requirements <1.7 µg/kg/day at 12 months or <1.45 µg/kg/day at 24 months are highly suggestive of T CH, at least in the cases with eutopic gland, and (c) the analysis of L-T4 requirements during the first years of treatment might allow an early discrimination between T and P CH in the cases with eutopic gland.

Analysis of the factors affecting the evolution over time of subclinical hypothyroidism in children

Aim of this commentary is to report the most recent views about natural history of subclinical hypothyroidism (SH) according to the different etiologies. In children with idiopathic SH the natural evolution is often favourable, with a high percentage of cases reverting to euthyroidism or remaining SH even after a prolonged follow-up. By contrast, the risk of a significant deterioration of thyroid status is distinctly higher in the SH children with Hashimoto’s thyroiditis (HT). This risk is even higher in the cases with both HT-related SH and chromosomal abnormalities, such as Turner or Down’s syndrome.

A child with severe iron-deficiency anemia and a complex TMPRSS6 genotype

ABSTRACT Objectives: We report a case of a 7-year-old girl with severe hypochromic microcytic anemia, who was unresponsive to classical iron supplements. We suspected IRIDA, iron-refractory iron-deficiency anemia, a genetic iron metabolism disorder, caused by TMPRSS6 variations. TMPRSS6 encodes matriptase-2, a negative regulator of hepcidin, and its pathological variants are related to normal to high levels of hepcidin. We analyzed the TMPRSS6 gene and we improved clinical management of the patient, selecting the appropriate supplementation therapy. Intervention & Technique: The parenteral iron therapy was started, but the patient was only partially responsive and the anemia persisted. To confirm the diagnosis, the TMPRSS6 gene sequence was analyzed by DNA sequencing and other relevant biochemical parameters were evaluated. Results: The TMPRSS6 sequence analysis showed a complex genotype with a rare heterozygous missense variant, in addition to other common polymorphisms. The serum hepcidin value was normal. We unexpectedly observed a normalization of patient’s hemoglobin (Hb) levels only after liposomal iron treatment. Discussion and Conclusion: The proband was symptomatic for IRIDA during a critical phase of growth and development, but we did not find a clearly causative genotype. A long-term result, improving stably patient’s Hb levels, was obtained only after liposomal iron supplementation. Children may be at greater risk for iron deficiency and the degree of anemia as well as the response to the iron supplements varies markedly patient to patient. Here, we show the importance of comprehensive study of these patients in order to collect useful information about genotype–phenotype association of genes involved in iron metabolism.

Long-term auxological and pubertal outcome of patients with hereditary insulin-like growth factor-I deficiency (Laron and growth hormone-gene deletion syndrome) treated with recombinant human insulin-like growth factor-I.

Background: GH-IGF-I axis is mainly involved in the complex process of somatic growth but emerging evidence suggests that it also influences hypothalamic-pituitary-gonadal (HPG) function. Subjects: We report some data regarding long-term auxological and pubertal outcome of five female patients with hereditary forms of GH-IGF-I deficiency (Laron and GH-gene deletion syndrome) and a mean age of 23.4±5.3 yr (range 19–32). Methods: All the patients received recombinant human IGF-I (rhIGF-I, Pharmacia and Upjohn, Stockholm, Sweden, and rhIGF-I, Genentech, San Francisco, CA, USA) from a mean age of 8.6 yr (range 3.2–14.2) up to the final height. Results: Final height was very disappointing (≤ − 5.0 SD scores) and lower than target height in all the patients. Pubertal onset was delayed in most of them but menarche occurred spontaneously in all the patients. Median age at menarche was 15.1 yr. Menstrual cycles were regular for several years. Median duration of gynecological follow-up was 8.3 yr with the longest span of 17.2 yr. Conclusion: We can assert that GH-IGF-I axis has an essential role in promoting linear growth in humans and its physiological action cannot be replaced by pharmacological treatment in most patients with hereditary forms of IGF-I insufficiency as demonstrated by their subnormal final height. Our clinical observations can also support an essential role of IGF-I in genitalia growth but not in the function of HPG axis as demonstrated by the maintenance of regular menstrual cycles in the presence of subnormal levels of IGF-I after treatment discontinuation.

Post vaccine acute disseminated encephalomyelitis as the first manifestation of chromosome 22q11.2 deletion syndrome in a 15-month old baby: A case report

We describe a case of a 15-month-old female child admitted to our hospital because of fever, rash, neurological signs (oscillation between states of irritability and drowsiness), palpebral edema and drooping eyelid, appeared 10 days after the vaccination for measles, mumps and rubella. Brain MRI images showed multiple bilateral hyperintense lesions in the white matter typical of acute disseminated encephalomyelitis (ADEM), an autoimmune demyelinating disorder with inflammatory lesions of the central nervous system, due to viral antigens or vaccines. In the mean time, because of patients vague phenotypic manifestations, suggestive of a genetic defect, array comparative genomic hybridization was carried out which showed the presence of a microdeletion 22q11.21, linked to the DiGeorge syndrome. Our case suggests that pediatric cases of post-vaccination ADEM, in which neurological signs persist, should be investigated for genetic phenotypical features, in order to exclude the presence of a genetic syndrome or disease.