The Frequency of Germline BRCA and Non-BRCA HR-Gene-Variants in a Cohort of Pancreatic Cancer Patients.

Germline DNA alterations affecting homologous recombination pathway genes have been associated with pancreatic cancer (PC) risk. BRCA2 is the most studied gene and affects the management of PC patients and their families. Even though recent reports have suggested a similar role of germline ATM pathogenic variants (PV) in familial PC, there is still a disagreement between experts on how it could affect patient management given the lack of proper PC risk estimates. We retrospectively analyzed the germline data of 257 PC patients among whom nearly 50% were sporadic cases. We showed similar frequencies of BRCA2 (4.9%) and ATM (4.4%) PV or likely pathogenic variants, which were not related to familial history. Based on our findings and that of the literature, we suggest including ATM gene among the panel of genes analyzed in PC patients pending the publication of prospective studies.

[Griscelli syndrome type 3: A new case]. / Syndrome de Griscelli de type 3 : un nouveau cas.

INTRODUCTION: Griscelli syndrome (GS) is a rare autosomal-recessive genetic disease characterized by hypopigmentation of skin and hair. We report a case of GS type 3 with late diagnosis. OBSERVATION: A 31-year-old female patient had presented depigmentation of the hair and eyebrows as well as diffuse skin hypopigmentation during childhood. Microscopic analysis of a hair shaft revealed irregularly distributed clumps of melanin. DNA sequencing showed a homozygous C103T (R35W) transition in exon 1 of MLPH, confirming Griscelli syndrome type 3. DISCUSSION: Three clinical phenotypes of GS have been described based on the underlying genetic defect. GS type 1 and 2 are associated respectively with a central nervous system dysfunction and an immune defect. GS type 3 is an isolated cutaneous form. Diagnosis is confirmed on microscopic examination of hair shafts. 15 cases of GS type 3 have been reported: 9 in males and 6 in females. Mean age at diagnosis is around 12 years. Nine of the reported patients were of Arab origin, four of Turkish origin, and one of Indian origin. R35W mutation was described in 9 cases and E98X and R35Q mutations were each found in one case. CONCLUSION: GS should be suspected in patients presenting gray silvery hair, particularly when these patients are of Arab or Turkish origin.

Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, Eastern France: implications for clinical management.

While Friedreich's ataxia (FRDA) and ataxia telangiectasia (AT) are known to be the two most frequent forms of autosomal recessive cerebellar ataxia (ARCA), knowledge on the other forms of ARCA has been obtained only recently, and they appear to be rarer. Little is known about the epidemiological features and the relative frequency of the ARCAs and only few data are available about the comparative features of ARCAs. We prospectively studied 102 suspected ARCA cases from Eastern France (including 95 from the Alsace region) between 2002 and 2008. The diagnostic procedure was based on a sequential strategic scheme. We examined the clinical, paraclinical and molecular features of the large cohort of patients and compared features and epidemiology according to molecular diagnosis. A molecular diagnosis could be established for 57 patients; 36 were affected with FRDA, seven with ataxia plus oculomotor apraxia type 2 (AOA2), four with AT, three with ataxia plus oculomotor apraxia type 1 (AOA1), three with Marinesco-Sjögren syndrome, two with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), one with ataxia with vitamin E deficiency (AVED) and one with autosomal recessive cerebellar ataxia type 2 (ARCA2). The group of patients with no identified mutation had a significantly lower spinocerebellar degeneration functional score corrected for disease duration (SDFS/DD ratio; p = 0.002) and comprised a significantly higher proportion of cases with onset after 20 years (p < 0.01). Extensor plantar reflexes were rarer and cerebellar atrophy was more frequent in the group of patients with a known non-Friedreich ARCA compared to all other patients (p < 0.0001 and p = 0.0003, respectively). Lower limb areflexia and electroneuromyographic evidences of peripheral neuropathy were more frequent in the Friedreich ataxia group than in the group with a known non-Friedreich ataxia and were more frequent in the later group than in the group with no identified mutation (p = 0.0001 and p = 0.01, respectively). The overall prevalence of ARCA in Alsace is 1/19,000. We can infer the prevalence of FRDA in Alsace to be 1/50,000 and infer that AT is approximately eight times less frequent than FRDA. MSS, AOA2 and ARSACS appear only slightly less frequent than AT. Despite the broad variability of severity, Friedreich ataxia patients are clinically distinct from the other forms of ARCA. Patients with no identified mutation have more often a pure cerebellar degenerative disease or a spastic ataxia phenotype. It appears that ARCA cases can be divided into two major groups of different prognosis, an early-onset group with a highly probable genetic cause and an adult-onset group with better prognosis for which a genetic cause is more difficult to prove but not excluded. ARCAs are rare, early-disabling and genetically heterogeneous diseases dominated by FRDA. Several of the recently identified ARCAs, such as AVED, ARSACS, AOA1, AOA2 and MSS, have a prevalence close to AT and should be searched for extensively irrespective of ethnic origins. The strategic scheme is a useful tool for the diagnosis of ARCAs in clinical practice.

Intrachromosomal triplication for the distal part of chromosome 15q.

We report the case of a boy whose karyotype at birth showed additional material on one chromosome 15. He underwent treatment for unilateral nephroblastoma at 6 years old. At 23 years old, he presented with body asymmetry, facial dysmorphism, arachnodactyly, severe scoliosis, and mental retardation. Molecular cytogenetic analyses of peripheral lymphocytes demonstrated a complex mosaic with three clones. A major cell lineage (68%) showed a chromosome 15 with additional material fused to its telomere long arm that was constituted by an inverted duplicated 15q24.3-qter segment. Therefore, the resulting add(15)(q) harbored an intrachromosomal triplication with the middle segment being inverted in orientation. A minor cell lineage (7%) showed an abnormal chromosome 3 resulting from a telomeric fusion between its short arm and an inverted duplicated 15q24.3-qter segment. The third cell lineage (25%) showed a normal 46,XY constitution. Finally, this resulted in tetrasomy for the distal 15q24.3-qter region in 75% of the patient's lymphocytes. To our knowledge, distal 15q tetrasomy is rare and only eight cases have been reported in the literature, all due to a supernumerary analphoid marker consisting of an inverted duplication. We report here the first observation of distal 15q tetrasomy associated with a 46 chromosomes constitution. We compare the phenotype of our patient to previous cases of distal tetrasomy 15q and discuss the mechanisms underlying this chromosomal rearrangement.

Two cousins with partial trisomy 12q and monosomy 12p recombinants of a familial pericentric inversion of the chromosome 12.

Partial trisomy 12q and monosomy 12p lead to multiple malformation syndromes. Instead of trisomy 12q that has been reported as a clinically identifiable syndrome, monosomy 12p is characterized by a wide phenotypic spectrum. We report two cousins suffering from severe mental retardation, seizures, and dysmorphic features related to a trisomy 12q24.3-->qter and a monosomy 12p13-->pter resulting from a familial pericentric inversion of chromosome 12. In an attempt to improve the clinical delineation of these two syndromes, we compared our two patients with previous reports of these aneusomies. This review emphasizes the high frequency of familial translocations, including a breakpoint at 12q24 involved in trisomy 12q whereas monosomy 12p occurs most frequently de novo. Despite the poor specificity of the signs, this comparison allowed us to determine the clinical features present in more than 20% of patients with trisomy 12q or monosomy 12p. We particularly emphasize some consistent leading features of monosomy 12p, including microcephaly, dental, cardio-vascular, extremity, and sensorial abnormalities, initially not reported as recurrent in this syndrome.