Carmela Ingegnosi

Skin and subcutaneous thickness at injecting sites in children with diabetes: ultrasound findings and recommendations for giving injection

Children who inject insulin need clear guidelines as to the length of needle best for them. We studied the distance from surface to muscle in children in order to make needle choices which are evidence‐based.

Gerstmann-Sträussler-Scheinker disease with P102L-V129 mutation: a case with psychiatric manifestations at onset.

Gerstmann-Sträussler-Scheinker disease (GSS) is an adult onset, rare, genetically determined autosomal dominant prion disease. Clinically, it is characterized predominantly by slowly progressive spino-cerebellar dysfunction with ataxia, absent reflexes in the legs and cognitive impairment. Onset is usually in the fifth decade and in the early phase, ataxia is predominant. Mutations in the prion protein gene (PRNP) had been identified and the most important of these is at codon 129. A genotype-phenotype relationship with genetic polymorphism at residue 129 between methionine and valine has been supposed. We describe a patient with GSS and P102L-V129 mutation in which the onset with prominent psychiatric features characterized by apathy and depression and not with cerebellar sign and the clinical course with seizures, nor observed in P102L-V129 cases, allow us to confirm observations that the GSS caused by the 102 mutation is influenced by the codon 129 polymorphism with a specific genotype-phenotype influence, but probably other additional factors might be considered as background for phenotypic variability.

Mosaic trisomy 20: Considerations for genetic counseling

Trisomy 20 is one of the most common types of mosaic trisomy detected on prenatal diagnosis, whether by amniocentesis or chorionic villus sampling. Many of the prenatally detected cases are not fetal trisomy as the trisomic cells found on amniocentesis or chorionic villus sampling in these cases, originate from and are restricted to the placenta or other extra embryonic tissue. Even if few cases with congenital abnormalities have been reported, more than 90% of cases were associated with healthy babies. Factors predictive of outcome in the case of prenatally diagnosed trisomy 20 mosaicism have been proposed and include the presence of uniparental disomy (UPD), origin and level of trisomy. Moreover, firm conclusions for genetic counseling are not evident. Recently, Willis et al. [2008] reported three patients with mosaic trisomy 20, two of whom were identified prenatally and suggest that with long term follow up a subtle phenotype does exist and includes spinal abnormalities (spinal stenosis, vertebral fusion, and kyphosis), hypotonia, lifelong constipation, sloped shoulders, and significant learning disabilities despite normal intelligence. Some of these findings may be overlooked on routine history and physical exam or assumed to be standard pediatric problems. No dysmorphic features have been reported. On the basis of these observations, we think that, in the absence of specific guidelines for prenatal genetic counseling, some considerations may be useful for genetic management. Based on available literature and personal experience we have proposed [Bianca et al., 2005] that in the cases of prenatally detected trisomy 20, it is important to tell the parents that: (1) a second invasive sample to confirm the presence of a true fetal mosaicism does not provide conclusive remarks and risks spontaneous abortion; (2) fetal blood sampling is not helpful, as the trisomic cells do not appear in blood even in the cases with abnormal outcome; (3) UPD study is not useful because UPD cases do not differ substantially with trisomy mosaicism; (4) trisomy mosaicism levels do not influence the outcome; (5) second-level ultrasonography at 20–22 gestational weeks may exclude severe congenital anomalies and intrauterine growth retardation (IUGR) and may be useful, when normal, in providing some reassurance to parents. Thus, in absenceof severe structural anomalies and even though a mild phenotype cannot be excluded as suggested by Willis et al. [2008], it is important to reassure the parents about the unlikelihood of severe mental retardation and dysmorphic appearance, findings that often are the most important components in the decision of voluntary termination the pregnancy in the absence of structural anomalies on prenatal ultrasonography. Finally we agree with Willis et al. [2008] in the opportunity to long term follow up mosaic trisomy 20 patients with special attention to spinal evaluation even if in the majority

Hyperglycemia in celiac disease: not always pretype 1 diabetes?

Abstract:  Celiac disease (CD) is a T‐cell‐mediated enteropathy, triggered in genetically susceptible individuals by the ingestion of wheat gluten or related rye and barley proteins, whose clinical picture disease is considerably heterologous. Patients with CD are at high risk of autoimmune disorders; similarly, CD is frequent in patients with type 1 diabetes mellitus (T1DM), a disorder characterized by the immune‐mediated β‐cell destruction, with the cooperation of environmental factors in genetically susceptible individuals. The immunological markers of β‐cell destruction are the autoantibodies to insulin, glutamic acid decarboxylase, and the protein tyrosine phosphatase. In absence of these markers, incidental hyperglycemia in children and adolescents appears unlikely to be associated with the progression to T1DM. We report a girl with CD and incidental hyperglycemia, without immunological markers of T1DM, with a family history for hyperglycemia, and diagnosed as maturity‐onset diabetes of the young. We present this case as evidence that the possibility of monogenic forms of diabetes must be suspected in children with incidental hyperglycemia, a family history for mild hyperglycemia or diabetes, and absence of markers of β‐cell destruction, even if the patients are affected by an autoimmune disease.

Multiple aneuploidy recurrence risk.

We have recently observed four families that requested genetic counseling about reproductive recurrence risks. Two of these families showed a multiple aneuploidy recurrence and the other two showed a reproductive history characterized by two sequent pregnancies with prenatal diagnosis of trisomy 21 in the first and neural tube defects (NTDs) in the second, respectively. Family 1 had a reproductive history characterized by three spontaneous pregnancy losses with trisomy 9, monosomy X, and triploidy, respectively. Family 2 had two voluntary therapeutic abortions for trisomy 21 and trisomy 18 and a monosomy X spontaneously aborted pregnancy. In both cases the women were younger than 35 years. Even if the chromosomal anomalies represent one of the most common causes of spontaneous abortion, the recurrence risk for subsequent pregnancy after a spontaneous abortion with a de novo chromosomal anomaly is generally low. Except for advanced age at conception, maternal risk factors for meiotic nondisjunction are not well established and parental germline mosaicism had been proposed to explain recurrence chromosomal risk. Morris et al. [2005] demonstrated with a large dataset that women who have had a previous DS pregnancy have a constant absolute excess risk (the difference between the risk of a DS pregnancy after a previous affected pregnancy minus the expected age-related risk) above their maternal age-related risk of having a subsequent affected pregnancy. This absolute excess risk is determined by the age at which the affected pregnancy occurred and is higher for younger than for older women. Recurrence of trisomy in the same couple could occur for several reasons: (1) chance alone, due to the maternal age-associated risk, (2) parental gonadal mosaicism for trisomy, or (3) factors associated with an increased risk of meiotic error. Moreover gonadal mosaicism cannot explain an increased recurrence risk for a different trisomy (heterotrisomy). Warburton et al. [2004] reported significantly increased risk for heterotrisomy that supports the hypothesis that some women have a risk for nondisjunction higher than do others of the same age. Cavalli and Luongo [2005] recently reported a case of multiple aneuploidy recurrence and concluded that a recurrence of aneuploidies should be considered as a likely consequence of parental germline mosaicism and, as in the reported case, both genetic predisposition and environmental factors (mesalazine periconceptional exposure) should also be considered. We do not agree with the proposed role of mesalazine and/or Crohn disease as risk factors, in fact as in our experience (four pregnancy exposed cases) and in the literature [Diav-Citrin et al., 1998] there is no evidence of increased teratogenic risk; on the contrary untreated Crohn disease increases the risk of spontaneous abortion. Regarding our other two families a link between trisomy 21 and NTDs was posited [Barkai et al., 2003] from epidemiological evidence of a coexistence of the two conditions in the same family; however, other authors do not confirm this [Amorim et al., 2004]. There is evidence that mutations in 5, 10 methylenetetrahydrofolate reductase (MTHFR) gene, that is involved in folate metabolism, may play a role in the pathogenesis of NTD [Posey et al., 1996] and trisomy 21 [James et al., 1999]; however, while the link

Hypospadias and Robertsonian Translocation

terone or adrenal steroid hormones, receptor defects, syndrome-associated hypospadias, chromosomal anomalies, defects in other genetic factors or exogenous forms [5] . Recently Kilic et al. [6] reported a case of severe hypospadias in a boy with paternally inherited 45,XY,t(13q;14q) RT and concluded that even if no such association has been reported so far, the severe hypospadias in this case might be associated with this translocation. Genotype-phenotype relationships for chromosomal anomalies are often diffi cult to establish. One of the classical approaches is based on the molecular characterisation of chromosomal break points associated with abnormal phenotypes. Thus diseaseassociated balanced chromosome rearrangements that truncate, delete or otherwise inactivate specifi c genes have been instrumental in the positional cloning of many disease genes [7] . We agree that a classical chromosome approach alone is not enough to detect submicroscopic rearrangements, and that the use of other methods (i.e. FISH or molecular approach) is necessary in the study of apparently balanced translocation with phenotypic effects. The conclusions of Kilic et al. [6] , if confi rmed, strongly suggest genetic counseling: paternally inherited balanced RT 13; 14 incurs a risk of severe hypospadias. If true, geneticists should inform their patients about this conclusion. Moreover we think that without a molecular demonstraAutosomal reciprocal balanced translocations and inversions occur in approximately 0.1% of newborns [1], and the estimated frequency of de novo balanced rearrangements in the general population, as determined from newborn screening series and prenatal diagnosis, is 0.0283% [2] . Robertsonian translocations (RT) are the most frequent structural chromosomal abnormalities in humans. They occur with a prevalence of about 1 in 1,000 in the general population [3] and can affect fertility, with various degrees of sperm alterations in men or the pregnancy outcome of the carriers. The most common RT is between chromosomes 13 and 14. This D/D translocation makes up approximately 75% of all Robertsonians [3] . Balanced RT incurs a very low risk of congenital malformations in the carrier, and the empirical reproductive risks for male carriers of 13; 14 RT are also very low. Hypospadias, a midline fusion defect of the male ventral urethra, is a relatively common genital anomaly occurring in 0.3–7 of 1,000 live male births. It is considered a complex disorder with both genetic and environmental factors involved in the pathogenesis [4] . Besides a higher incidence in consanguineous families and a suggested recessive inheritance, in other families a dominant transmission is likely. The recurrence risk in the next generation seems to be correlated with the severity of hypospadias. Only 30% of severe hypospadias can be attributed to defects in the synthesis of testosReceived: November 7, 2005 Accepted: March 9, 2006 Internationalis Urologia