Dear Editor

We were very interested in the review article on telomeres by de Vries et al.[1]

The authors comment that all of the 3p terminal deletions reported in the literature were microscopically visible, except for two siblings with an unbalanced familial translocation. We have recently seen a child where we detected a 3p deletion on telomere analysis that was not visible by routine cytogenetics. The child in question was born at 38 weeks weighing 7lb 4 oz. At birth she had dislocated hips and talipes equinovarus. She had marked dimples around her ankles and elbows and deep palmar creases. She had notable facial asymmetry with a right ptosis, mandibular asymmetry and a slightly small right ear. She was a poor feeder requiring a gastrostomy and on follow-up it became clear that she was globally developmentally delayed. Cardiac evaluation revealed atrial and ventricular septal defects. She was referred to the clinical genetics service at 14 months of age when she was noted to have trigonocephaly. She also had small finger and toe nails, especially of the 5th fingers and toes. An MRI scan showed some degree of frontal lobe atrophy and slightly thin corpus callosum.

This case illustrates the value of telomere screening in selected patients. Trigonocephaly has not been a clinical feature highlighted in the discussion about the indications for telomere screening but given the number of chromosome abnormalities that have been associated with this finding, we believe that those children with developmental delay and trigonocephaly should have telomere studies performed if the conventional cytogenetic analysis is normal and there is no other likely cause such as anticonvulsant exposure in utero.

Reference

(1) De Vries BBA, Winter R, Schinzel A, van Ravenswaaij-Arts C. Telomeres: a diagnosis at the end of the chromosomes . J Med Genet 2003;40:385-398.

Dear Editor

We read with interest the report by Lampe AK et al. [1] presenting a patient with Laugier-Hunziker syndrome (LHS) whom had been extensively investigated in order to rule out Peutz-Jeghers syndrome (PJS).

In the case presented by Lampe AK et al.[1] biopsy specimen of the lip was twice mislabled as consistent with PJS, which prompted clinicians to undertake repeated unnecessary investigations. It should be emphasized that while LHS may clinically resemble PJS, histological features are different and distinctive in each condition. Indeed lesions in LHS display increased basal keratinocytes melanin content without melanocytic hyperplasia in addition to superficial pigmentary incontinence with dermal melanophages.[2] In contrast, macules of the Peutz-Jeghers syndrome have the appearance of lentigines on biopsy, showing expansion of the melanocytic population, which accounts for the denomination “periorificial lentiginosis” commonly used to designate the lips and cutaneous lesions of this entity.[3,4] Of note is that questionable cases reported in the literature in whom no PJS or LHS diagnosis could be definitely ascertained had not undergone histological analysis of pigmentary lesions.[5]

While advances in genetics represent exciting breakthroughs and offer valuable tools for modern medicine, we believe that clinicians should refrain from routinely using genetic screening tests for diagnostic purposes when accurate diagnosis can be achieved through careful yet simple anatomo-clinical correlation.

References

(1) Lampe AK, Hampton PJ, Woodford-Richens K, Tomlinson I, Lawrence CM, Douglas FS. Laugier-Hunziker syndrome: an important differential diagnosis for Peutz-Jeghers syndrome. J Med Genet 2003;40:e77.

(2) Dupré A, Viraben R. Laugier’s disease. Dermatologica 1990;181:183-6.

(3) Calnan CD. The Peutz-Jeghers syndrome. Trans St John’s Hosp Dermatol Soc 1960;44:58-64.

(4) Ortonne JP. Les troubles de la pigmentation cutanée. In Dermatologie et maladies sexuellement transmissibles, 3rd edition, Saurat JH, Grosshans E, Laugier P, Lachapelle JM, (Eds). Masson, Paris, 1999:407-426.

(5) Gerbig AW, Hunziker T. Idiopathic lenticular mucocutaneous pigmentation or Laugier-Hunziker syndrome with atypical features. Arch Dermatol 1996;132:844-5.

Dear Editor

Desbuquois dysplasia is a rare autosomal recessive chondrodysplasia characterized by markedly short stature of prenatal onset, joint laxity, facial dysmorphism including round face, prominent bulging eyes and midface hypoplasia.

The radiological findings include a ‘Swedish key’ appearance of the proximal femur, advanced carpal and tarsal bone age and typical hand changes consisting in an extra ossification center distal to the second metacarpal, delta phalanx, bifid distal phalanx of the thumb, and phalangeal dislocations.[1-3] However, those typical hand anomalies are only observed in a third to a half of all Desbuquois patients.[3-4] We have recently reported linkage of a Desbuquois dysplasia disease gene to chromosome 17q25.3 in a group of patients with typical hand abnormalities.[5]

Here, we report on the exclusion of the 17q25.3 locus in three inbred Desbuquois families without typical hand abnormalities. The families originate from Turkey, Asia and Morocco. Two out of the three families had been previously reported.[3,6] Their main clinical and radiological features are summarized in Table 1 (see below).

All affected individuals fulfilled the criteria for Desbuquois dysplasia, namely short stature of prenatal onset, joint laxity, specific facial dysmorphism (see Figure 1), a ‘Swedish key’ appearance of the proximal femur and advanced carpal and tarsal bone age. None of the patients presented any typical hand changes (absence of extra ossification center distal to the second metacarpal, absence of delta phalanx or bifid distal phalanx of the thumb, see Figure 2a).

Informed consent and blood samples were obtained from the probant and other family members when available. Genomic DNA was purified from peripheral blood leukocytes according to standard techniques. Microsatellite DNA markers from the 17q25.3 region were used at an average spacing of 2 cM and were chosen from the Généthon map. PCR analyses were performed using a single set of primers in each amplification reaction. The homozygosity mapping strategy was based on the assumption that affected individuals of the same kindred are homozygous by descent.[7] The three affected individuals from families 1-3 were heterozygous for the 17q25.3 region (see Figure 3). These results allow us to exclude this region as the disease locus in Desbuquois families with no hand anomalies and demonstrate a genetic heterogeneity. Reviewing the 6 sibship reported in the literature with Desbuquois dysplasia,[1,2,8] we found a complete intrafamilial concordance regarding the presence or absence of typical hand anomalies. Indeed, those anomalies were present in all individuals within the 2 sibships reported by Puissan and in the 3 sibships reported by Shohat.[8] Moreover, they were absent in the sibpair reported by Desbuquois. Those findings together with our molecular results suggests that the presence or absence of hands anomalies define two distinct entities within Desbuquois dysplasia. These results emphasise the importance of defining subgroups prior to any linkage analyses. Additional families will be necessary to confirm this result.

Electronic-Database
Human Genome working Draft, http://genome.ucsc.edu/

Table 1

Figures

Figure 1
[View Figure 1]
Clinical presentation of patient 1 at age 1 and age 11. Note typical facial dysmorphism (round and flat face, prominent bulging eyes and midface hypoplasia), prominent sternum, micromelia and brachydactyly.

Figure 2
[View Figure 2]
(a,b) X-rays of the hands of patient 2 (a) and 3 (b), respectively at age 5 years and 15 days. Note the advanced bone age and the generalised brachydactyly but the absence of typical hand changes (ie extra ossification center distal to the second metacarpal, delta phalanx, bifid distal phalanx of the thumb.)
(c) X-rays of the pelvis in patient 2 at 6 years of age. Note the typical 'Swedish key' appearance of the proximal femur.

Figure 3
[View Figure 3]
Pedigrees and haplotypes of the 17q25.3 region in families 1-3. The microsatellite polymorphic markers were placed according to the Généthon and the Human Genome working Draft databases, from D17S802 to D17S784, centromere to telomere. Genetic intervals between following markers were respectively of 4.1, 1.7, 1.4, 2.3 and 0 cM. Two additional microsatellite DNA markers were chosen on clones AC016182 and AC099804 between D17S802 and D17S1847 in order to establish heterozygosity for the 17q25.3 region in family 1.

References

(1) Desbuquois G, Grenier B, Michel J, Rossignol C. Nanisme chondrodystrophique avec ossification anarchique et polymalformations chez deux sœurs. Arch Fr Pediatr 1966; 23: 573-587.

(2) Puissan C, Maroteaux P, Castroviejo I, Risbourg B. Dysplasie osseuse avec nanisme et altérations squelettiques diffuses. Six observations. Arch Fr Pediatr 1975;32:541-550.

(3) Gillessen-Kaesbach G, Meinecke P, Ausems MGEM, Nöthen M, Albrecht B, Beemer FA, Zerres K. Desbuquois syndrome: three further cases and review of the literature. Clin Dysmorphol 1995;4:136-144.

(4) Faivre L, Cormier-Daire V, Eliot A, Field F, Munnich A, Maroteaux P, Le Merrer M, Lachman R. Desbuquois dysplasia, a reevaluation with abnormal and “ normal ” hands : Radiographic manifestations. Am J Med Genet; in press.

(5) Faivre L, Le Merrer M, Al Gazali LI, Aussems MGEM, Bitoun P, Munnich A, Cormier-Daire V. Homozygosity mapping of a Desbuquois dysplasia locus to chromosome 17q25.3. J Med Genet 2003;40:282-284.

(6) Le Merrer M, Young ID, Stanescu V, Maroteaux P. Desbuquois syndrome. Eur J Pediatr 1991;150:793-796.

(7) Lander ES, Botstein D. Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children. Science 1987;236:1567-1570.

(8) Shohat M, Lachman R, Gruber HE, Hsia YE, Golbus MS, Witt DR, Bodell A, Bryke CR, Hogge WA, Rimoin DL. Desbuquois syndrome: clinical, radiographic, and morphologic characterization. Am J Med Genet 1994;52:9-18.

Dear Editor

One of the interesting findings in this study is the lack of a change in length of survival over the study period. It appears that modern intensive care has not made any impact. Indeed, rapid and accurate diagnosis with early withdrawal of care following discussion with the parents may reduce the survival period. It is interesting that, Dr Rassmusen from the CDC in Atlanta presented new population based data at the recent ASHG meeting suggesting that there is a reduction rather than an increase in survival over time. I fully agree that we need more information in this area and I would encourage all neonatal intensive care units to record the actual cause of death (e.g. central apnoea, respiratory disress, cariac failure etc) in addition to accurate cateloging of associated major malformations.