Dear Editor,

We read with interest the paper of Kaiser-Rogers et al. [1] in which they describe two cases of androgenetic/biparental mosaicism. In their study both cases exhibited the clinicopathological phenotype of placental mesenchymal dysplasia (PMD) and in both cases the androgenetic cells were almost exclusively restricted to the mesenchymal components of the villi, the overlying trophoblast apparently being derived from normal biparental cells. In these respects the cases in their report differ from those of a previous case of androgenetic/biparental mosaicism described by us [2] and cited by Kaiser-Rogers et al. [1]

We previously reported a case of androgenetic / biparental mosaicism resulting in the live birth of a phenotypically normal girl that, like the present cases, involved only a single sperm. However, in the case described by us, the trophoblast was composed of normal biparental cells in only some villi, the trophoblast of other villi being exclusively androgenetic. In our case the mesenchymal cells within the villus cores had the same genotype as the overlying trophoblast in all areas examined, unlike the present cases in which the mesenchyme and trophoblast from the same villi appear to be genetically different.

Interestingly our case did not show any pathological evidence of PMD but the androgenetic villi showed clear evidence of complete hydatidiform mole phenotype with the biparental villi appearing morphologically normal. The present study [1] suggests that androgenetic/biparental mosaicism may be a cause of PMD but it is clear that it may also have other phenotypic manifestations according to the distribution of the androgenetic cells within the placenta.

In our case the female child, now aged four, has continued to develop normally suggesting that the androgentic lineage was entirely confined to placental tissue or, if present, has no pathological effects. Investigation of these rare cases by molecular techniques may lead to greater understanding of both normal placental development and the pathogenesis of these unusual placental disorders.

Dear Editor,

We read with great interest the paper of Cardinal and colleagues reporting findings of an Australian diagnostic MEN1 genetic testing service.¹ Molecular genetic diagnosis of MEN1 has been possible since the identification of the MEN1 gene in 1997.² In 2001, consensus guidelines outlining clinical criteria for MEN1 mutation testing were published.³ The guidelines recommend genetic testing in a patient meeting clinical criteria for sporadic MEN1 (the presence of at least 2 out of 3 main MEN1-related tumours, i.e. parathyroid, pancreatic and pituitary) or familial MEN1 (as in sporadic MEN1 plus at least one first-degree relative with one or more main MEN1-related tumours), and in a patient suspicious of MEN1 (multiple parathyroid tumours before age 30, recurrent hyperparathyroidism, gastrinoma or multiple islet cell tumours at any age, and familial isolated hyperparathyroidism). These clinical criteria were defined on the basis of initial research findings, and therefore reports of how the criteria apply in routine clinical practice are important. Similar to the study of Cardinal and colleagues, we have also recently reported a large cohort of patients from the UK, who underwent MEN1 genetic testing at our diagnostic molecular genetics laboratory.⁴ Likewise, Klein and colleagues have analysed a large diagnostic laboratory series from the USA.⁵

The MEN1 mutation detection rates in the three diagnostic series are very similar with an overall mutation detection rate of 34% (Table 1). In patients with 2 or more main MEN1-related tumours (i.e., fulfilling clinical criteria for MEN1), the pick up rates were 26% and 68% for sporadic and familial cases, respectively (Table 1). These compare to the pick up rates in research cohorts of 52% in sporadic MEN1 and 87% in familial MEN1.⁴ These findings from the diagnostic laboratory series firmly support the guideline recommendation of MEN1 genetic testing in patients fulfilling the clinical criteria of sporadic or familial MEN1. These series also show that the likelihood of finding a MEN1 mutation increases in the presence of a family history, and also depends upon the clinical features. Patients with 3 main MEN1-related tumours (as compared to those with 2 tumours)⁴ and patients with a combination of parathyroid & pancreatic tumours (as compared to those with parathyroid and pituitary tumours)^4,5 are more likely to yield a positive mutation result.

Whilst the importance of genetic testing in patients fulfilling clinical criteria for sporadic or familial MEN1 is generally accepted, it remains uncertain as to which of the patients with isolated MEN1-related tumours should be screened for an MEN1 mutation. Sporadic isolated MEN1-related tumours (such as parathyroid and pituitary) are fairly common in the general population, and it is not feasible to perform expensive and laborious MEN1 genetic testing in all such cases. Although we did not find MEN1 mutations in the 10 patients with sporadic hyperparathyroidism in our series, Cardinal and colleagues found a MEN1 mutation in one (out of 11) patient with sporadic hyperparathyroidism, suggesting that MEN1 genetic testing should be carried out in patients with early onset, multiglandular parathyroid tumours. Clearly, further studies with much larger cohorts of patients are necessary to establish clinical criteria for MEN1 genetic testing in patients with various sporadic isolated MEN1-related tumours or rarer combinations of different MEN1-related tumours. In many countries molecular genetic testing for MEN1 is carried out by a single national laboratory or a small number of nominated regional centres. This should allow the collection of clinical information from large cohorts of patients undergoing MEN1 mutation analysis, which is likely to facilitate the further definition of clinical criteria for MEN1 genetic testing.

B Vaidya¹, AT Hattersley¹ & S Ellard²

Departments of ¹Endocrinology and ²Molecular Genetics, Royal Devon & Exeter NHS Foundation Trust, Peninsula Medical School, Exeter, UK

References:

1. Cardinal JW, Bergman L, Hayward N, Sweet A, Warner J, Marks L, Learoyd D, Dwight T, Robinson B, Epstein M, Smith M, Teh BT, Cameron DP, Prins JB. A report of a national mutation testing service for the MEN1 gene: clinical resentations and implications for mutation testing. J Med Genet 2005;42:69-74.

2. Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Crabtree JS, Wang Y, Roe BA, Weisemann J, Boguski MS, Agarwal SK, Kester MB, Kim YS, Heppner C, Dong Q, Spiegel AM, Burns AL, Marx SJ. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 1997;276:404-7.

3. Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG, Libroia A, Lips CJ, Lombardi G, Mannelli M, Pacini F, Ponder BA, Raue F, Skogseid B, Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells SA, Marx SJ. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001;86:5658-71.

4. Ellard S, Hattersley AT, Brewer CM, Vaidya, B. Detection of an MEN1 gene mutation depends on clinical features and supports current referral criteria for diagnostic molecular genetic testing. Clin Endocrinol 2005; 62:169-175.

5. Klein RD, Salih S, Bessoni J, Bale AE. Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. Genet Med 2005;7:131-8.

Table 1. MEN1 mutation detection rates in large diagnostic laboratory series

Dear Editor,

The conclusions of Rauch et al. [1] with respect to positive genotype-phenotype correlations in 22q11 Deletion Syndrome (22qDS) must be viewed with caution. They report on extensive fluorescence in situ hybridization (FISH) studies of 350 patients with features of 22qDS ascertained from 3 sources. Based on a case series of 3 subjects found to have distal (atypical) deletions that would not have been detected using commonly used clinical probes (TUPLE1 or N25), they draw provocative conclusions about genotype-phenotype associations. The methods used and data presented do not justify the generalizations made, however.

We have calculated 95% confidence intervals (CIs) (see Table 1.) for the Rauch et al. data presented since percentages alone may be misleading. CIs allow for an assessment of statistical significance while accounting for sample size and rarity of events.[2] All of these CIs are non-significant, that is contain expected values, such as ~18% for positive clinical FISH in conotruncal congenital heart defect (ctCHD).[3] In addition, the 95% CI for finding three distal deletions in 350 subjects (0.86%) is 0.18-2.5%, which overlaps the 0-5% frequency reported in the literature, as would the results if only the sample of genetics referrals with features suggestive of 22qDS were used as the denominator: 3/77 (3.9%, 95% CI 0.8-8.3%).

To support their assertion of a genotype-phenotype correlation, the authors compared the frequency of atypical distal deletions in a sub-sample (n=63) from the 77 genetics referrals to that in 3 other samples. However, using a selected partial sample prevents a proper interpretation of results, and limits applicability to other populations. If the 22qDS phenotype were the issue, the 77-subject genetics referral sample should be used, since these subjects had multiple features consistent with 22qDS, as compared to those with a single feature such as ctCHD. On the other hand, if the issue were whether "typical" 22qDS facial features were related to atypical distal deletions then the relevant comparison should be between the 14 subjects with "typical" 22qDS facies and the 63 without these facies from the same ascertainment source. As illustrated in Table 2, the frequency of distal deletions is significantly different (p<_0.05 no="no" correction="correction" for="for" multiple="multiple" comparisons="comparisons" in="in" only="only" _3="_3" non-overlapping="non-overlapping" all="all" of="of" which="which" involve="involve" deletions="deletions" distal="distal" to="to" the="the" _3mb="_3mb" region.="region." conclusion="conclusion" one="one" can="can" draw="draw" from="from" these="these" results="results" is="is" that="that" a="a" _22q11.2="_22q11.2" deletion="deletion" more="more" likely="likely" be="be" found="found" subjects="subjects" with="with" than="than" feature="feature" _22qds.="_22qds." _="_" p="p"/>

The assessment of atypicality of phenotypic expression is challenging in the phenotypically diverse condition 22qDS. Terms such as "atypical" should be used with caution as phenotype will vary with age, completeness of assessment, assessors, and ascertainment.[4] Mild learning difficulties may not be noticeable until later childhood, and absence of psychosis could not be truly determined until well into adulthood (in contrast to Table 3. of Rauch et al. where infants are indicated to have no psychosis). Hyperactivity is a common feature in children with 22qDS.[5] The sister from the affected sibpair with two different length 22q11.2 deletions may thus be considered to have typical neurobehavioural features of 22qDS.

Larger sample sizes and detailed consideration of phenotypic and statistical methodology will be needed before one can conclude that there is “a significant correlation between deletion site and phenotypic expression” in 22qDS.

Anne S. Bassett, MD, FRCPC^1,2
Rosanna Weksberg, PhD, MD, FRCPC^{3, 4}
Eva W.C. Chow, MD, MPH, FRCPC^1,2

¹Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
²Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
³Division of Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, Ontario, Canada
⁴Department of Molecular & Medical Genetics, University of Toronto, Toronto, Ontario, Canada

Table 1. Frequencies from Rauch et al. with percentages and 95% CI

^*Where the frequency is 0, the 95% CI is one-sided

Table 2. Comparisons of frequency of distal deletions in different samples from Rauch et al. using Fisher’s exact testing*

*Statistically significant results are bolded

References

1. Rauch A, Zink S, Zweier C, Thiel CT, Koch A, Rauch R, Lascorz J, Huffmeier U, Weyand M, Singer H, Hofbeck M. Systematic assessment of atypical deletions reveals genotype-phenotype correlation in 22q11.2. J Med Genet 2005.

2. Richardson WS, Wilson MC, Williams JWJ, Moyer VA, Naylor CD. Users' guides to the medical literature: XXIV. How to use an article on the clinical manifestations of disease. J Am Med Assoc 2000;284:869-875.

3. Goldmuntz E, Clark BJ, Mitchell LE, Jawad AF, Cuneo BF, Reed L, McDonald-McGinn D, Chien P, Feuer J, Zackai EH, Emanuel BS, Driscoll DA. Frequency of 22q11 deletions in patients with conotruncal defects. J Am Coll Cardiol 1998;32:492-498.

4. Cohen E, Chow EWC, Weksberg R, Bassett AS. Phenotype of adults with the 22q11 Deletion Syndrome: A review. Am J Med Genet 1999;86:359-365.

5. Feinstein C, Eliez S, Blasey C, Reiss AL. Psychiatric disorders and behavioral problems in children with velocardiofacial syndrome: Usefulness as phenotypic indicators of schizophrenia risk. Biol Psychiatry 2002;51:312-318.

Dear Editor,

I read with interest the article by Muroya et al. [1].

The authors mention that the inherited condition of hypoparathyroidism, sensorineural deafness and renal dysplasia has been recognized as a distinct clinical entity since the report by Bilous et al. in 1992. In fact, this syndrome was described for the first time in 1977 by Barakat et al. [2]. The syndrome with presumed autosomal recessive inheritance was later named the “Barakat syndrome” [3-5]. In 1992 Bilous et al. [6] described a phenotypically similar syndrome in one family with autosomal dominant inheritance. The mode of inheritance may not be a fundamental difference, and the disorder in the two families described by Barakat and Bilous may be due to different mutations in the same gene [7]. Inheritance in the family described by Barakat et al. could also be autosomal dominant with reduced penetrance [7]. In 1997 Hasegawa et al. [8] described a Japanese girl with this syndrome and a de novo deletion of 10p13. They suggested the name “HDR syndrome”. Subsequently, a few more patients were reported.

Other synonyms for Barakat syndrome include “Hypoparathyroidism, sensorineural deafness and renal dysplasia”, “HDR syndrome”, and “Nephrosis, nerve deafness and hypoparathyroidism” [7]. The syndrome should then consist of hypoparathyroidism, sensorineural deafness and renal disease, since various renal abnormalities have been described including nephrotic syndrome, renal dysplasia, hypoplasia and unilateral renal agenesis, vesicoureteral reflux, pelvicalyceal deformity, hydronephrosis, and chronic renal failure.

First described by Barakat et al. in 1977, Barakat syndrome is a rare condition consisting of hypoparathyroidism, sensorineural deafness and renal disease. The defect is on chromosome 10p15,10p15.1-p14, with haploinsufficiency or mutation of the GATA3 gene being the underlying cause of the syndrome [7,9].

References

1. Muroya, K, Hasegawa,T, Ito,Y, Nagai,T. Isotani,H, Iwata,Y, Yamamoto,K, Fujimoto,S, Seishu,S, Fukushima,Y, Hasegawa,Y, Ogata,T. GATA3 abnormalities and the phenotypic spectrum of HDR syndrome. J Med Genet 2001;38:374-80.

2. Barakat, AY, D'Albora, JB, Martin, MM, Jose, PA. Familial nephrosis, nerve deafness, and hypoparathyroidism. J. Pediat 1977; 91: 61- 4.

3. McKusick V. Mendalian Inheritance in Man, 12th Edition, Volume 2, Baltimore,The Johns Hopkins University Press, l998.

4. Magnalini SI, et al: Dictionary of Medical Syndromes, 4th edition,Philadelphia, J.B. Lippencott-Raven, 1997, p 73.

5. Rimoin DL, Connor, JM, Pyeritz RE, Korf BR. Emery and Rimoin’s Principles and Practice of Medical Genetics. Fourth Edition, Volume 2, London, Churchill Livingstone, 2002, p2217.

6. Bilous, RW, Murty, G, Parkinson, DB, Thakker, RV, Coulthard, MG, Burn, J, Mathias, D, Kendall-Taylor, P. Btief report: Autosomal dominant familial hypoparathyroidism, sensorineural deafness, and renal dysplasia. New Eng J Med 1992; 327: 1069-74.

7. Online Mendelian Inheritance in Man, Johns Hopkins University #146255.

8. Hasegawa,T, Hasegawa, Y, Aso, T.; Koto, S, Nagai, T, Tsuchiya, Y, Kim, K, Ohashi, H, Wakui, K, Fukushima, Y. HDR syndrome (hypoparathyroidism, sensorineural deafness, renal dysplasia) associated with del(10)(p13). Am J Med Genet 1997; 73: 416-8.

9. Van Esch, H, Groenen, P, Nesbit, MA, Schuffenhauer, S, Lichtner, P, Vanderlinden, G, Harding, B, Beetz, R, Bilous, RW, Holdaway, I, Shaw, NJ, Fryns, J.-P, Van de Ven, W, Thakker, RV, Devriendt, K. GATA3 haplo- insufficiency causes human HDR syndrome. Nature 2000; 406: 419-22.