Duplication 5q and deletion 9p due to a t(5;9)(q34;p23) in 2 cousins with features of Hunter-McAlpine syndrome and hypothyroidism.

We report on 2 similarly affected cousins with a compound imbalance resulting from a familial t(5;9)(q34;p23) and entailing both an ∼17-Mb 5q terminal duplication and an ∼12-Mb 9p terminal deletion as determined by G-banding, subtelomere FISH, and aCGH. The proband's karyotype was 46,XX,der(9)t(5;9)(q34;p23)mat.ish der(9)t(5;9)(q34;p23)(9pter-,5qter+).arr 5q34q35(163,328,000-180,629,000)×3, 9p24p23(194,000-12,664,000)×1. Her cousin had the same unbalanced karyotype inherited from his father. The clinical phenotype mainly consists of a distinct craniofacial dysmorphism featuring microcephaly, flat facies, down slanting palpebral fissures, small flat nose, long philtrum, and small mouth with thin upper lip. Additional remarkable findings were craniosynostosis of several sutures, craniolacunia and preaxial polydactyly in the proband and hypothyroidism in both subjects. The observed clinical constellation generally fits the phenotypic spectrum of the 5q distal duplication syndrome (known also as Hunter-McAlpine syndrome), except for the thyroid insufficiency which can likely be ascribed to the concurrent 9p deletion, as at least 4 other 9pter monosomic patients without chromosome 5 involvement had this hormonal disorder. The present observation further confirms the etiology of the HMS phenotype from gain of the 5q35→qter region, expands the clinical pictures of partial trisomy 5q and monosomy 9p, and provides a comprehensive list of 160 patients with 5q distal duplication.

Polymorphisms C677T and A1298C in the MTHFR gene in Mexican patients with rheumatoid arthritis treated with methotrexate: implication with elevation of transaminases.

Rheumatoid arthritis (RA) is the prototype of the rheumatic diseases worldwide. Methotrexate (MTX) is the drug of first choice in the treatment of this disease due to its immunosuppressant effect. However, side events are present in 30% of the patients. The C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene are involved in the metabolism of MTX. Earlier studies reported an association between these polymorphisms and elevation of hepatic enzymes. We analyzed the frequencies of both polymorphisms and the presence of transaminasemia in 70 Mexican patients with rheumatic arthritis treated with MTX. The 19% (13/70) of patients had an increase in the serum level of transaminases. The A1298C polymorphism was associated with elevation of transaminases (P=0.024). The identification of MTHFR genotypes for C677T and A1298C polymorphisms could lead clinicians to identify patients in risk of elevation of transaminases, and give them an individualized treatment, as is a goal of pharmacogenetics.

Wide clinical spectrum in Zimmermann-Laband syndrome.

Gingival fibromatosis can be present as an isolated form or be part of a genetic disease. The Zimmermann-Laband syndrome (ZLS) is a rare disorder inherited as an autosomal dominant fashion, clinically characterized by gingival fibromatosis, bulbous soft nose, thick floppy ears, nail dysplasia, joint hyperextensibility, hepatosplenomegaly, skeletal anomalies and occasional mental retardation. We studied a girl aged five years with clinical and radiological features of the ZLS, additionally she presented deafness not previously described in the ZLS, as only partial hearing loss was reported in some patients. The father presented some facial features suggestive of ZLS, nevertheless he did not have gingival fibromatosis or hypertrichosis. We suggest that this case supports that ZLS can be part a contiguous genes syndrome or be consequence ofa gene mutation with wide variable expression. The present report supports that ZLS has a wide clinical spectrum.

Zimmermann-Laband syndrome: further clinical delineation.

Zimmermann-Laband syndrome (ZLS) is an autosomal dominant disorder characterized by gingival fibromatosis, absent or dysplastic distal phalanges, vertebral defects, hepatosplenomegaly, hypertrichosis and sometimes mental retardation. We describe two unrelated patients, a girl aged 9 years and a boy 11 months whose clinical and radiological findings permit us to diagnose the ZLS. Body overgrowth, present in both patients, was identified as a main clinical feature not previously reported as well as the presence in neuroimaging studies of a cavernous hemangioma on the frontal and the left cerebellar regions in the boy. The girl also presented important radiological characteristics such as broad medulary canals and metaphyses of long bones, thin cortices, broad ribs, accelerated skeletal maturation as well as high intelligence level. A wide clinical spectrum in ZLS is also considered.

FISH characterisation of dynamic mosaicism involving an inv dup(15) in a patient with mental retardation.

We report on a man with mental retardation and a complex karyotype with cells containing up to three morphologically distinct supernumerary marker chromosomes (SMCs) in most metaphases. Fluorescence in situ hybridisation studies using chromosome 15-specific probes characterised the presence of seven SMCs all derived from chromosome 15. The results suggest that the patient originally had a large inv dup(15) containing two copies of the Prader-Willi/Angelman critical region which became mitotically unstable, and by a process of dynamic mosaicism various morphologically distinct SMCs arose.

Floating-Harbor syndrome. A neuropsychological approach.

We describe a six year old Mexican girl whose clinical picture (short stature with delayed bone age, language difficulties and triangular face with prominent nose) was compatible with the diagnosis of Floating-Harbor Syndrome (FHS). A neuropsychological evaluation disclosed a mild mental retardation, a constructive apraxia, a comprehensive and expressive language impairment. The analysis of the present case and sixteen patients previously described establishes that the FHS is mainly characterized by proportionate short stature with significantly delayed bone age, delayed expressive language and peculiar face.

A variant example of familial Floating-Harbor syndrome?

The Floating-Harbor syndrome (FHS) is clinically characterized by short stature, retarded speech development, delayed bone age, typical facies, bulbous nose, wide columella, thin lips. Four cases with celiac disease have been described previously. In two other cases, autosomal dominant inheritance has been suggested. We describe a boy aged 2 years 11 months with clinical features of FHS and celiac disease. His mother also presents minor phenotypical characteristics, suggesting that the present observation corresponds to a variant example of familial FHS.

Guadalajara camptodactyly type III: a new probably autosomal dominant syndrome.

A Mexican family is presented with the main clinical features of camptodactyly, a distinctive facial appearance because of ocular hypertelorism, telecanthus, symblepharon and spinal defects. Other clinical manifestations included: multiple nevi, simplified ears, retrognathia, congenital shortness of the sternocleidomastoid muscle, thin hands and feet, a small penis and mild mental retardation. Radiographic studies revealed spina bifida occulta at cervical and dorso-lumbar levels, increased bone trabeculae, cortical thickening and delayed bone age. The presence of five affected members through four generations suggests autosomal dominant inheritance although no male-to-male transmission was documented. The authors propose this as a new entity, and have designated it Guadalajara camptodactyly type III.

A non-sense mutation in the corneodesmosin gene in a Mexican family with hypotrichosis simplex of the scalp.

BACKGROUND: Hypotrichosis simplex of the scalp (HSS; MIM 146520) is a rare autosomal dominant form of non-syndromic alopecia that affects men and women equally. Up to now, only a small number of families with HSS have been reported. The affected individuals experience a diffuse progressing hair loss from childhood to adulthood that is confined to the scalp. Recently, HSS has been mapped to the short arm of chromosome 6 (6p21.3), allowing mutations in the corneodesmosin gene (CDSN) to be identified as the cause of the disorder. To date, two stop mutations have been found in three unrelated families with HSS of different ethnic origin. OBJECTIVES: To describe the first HSS-family with Latin American (Mexican) background comprising 6 generations and to identify a mutation in the CDSN gene. PATIENTS/METHODS: The patients were examined by a clinician and blood samples were taken. After DNA extraction, sequencing analysis of the CDSN gene and restriction enzyme analysis with PsuI were performed. RESULTS: By direct sequencing of the two exons of the CDSN gene, a nonsense mutation was identified in the index patient in exon 2, resulting in a premature stop codon (Y239X). The mutation co-segregates perfectly in the family with the disease and was not found in 300 control chromosomes using a restriction enzyme analysis with PsuI. CONCLUSIONS: A nonsense mutation was identified in the first family with HSS of Latin American ethnical background. Our data provide molecular genetic evidence for a 3rd stop mutation in exon 2 of the CDSN gene being responsible for HSS. All to date known nonsense mutations responsible 3 for HSS are clustered in a region of 40 amino acids which is in accordance with a dominant negative effect conferred by aggregates of truncated CDSN proteins.

Methylenetetrahydrofolate reductase C677T polymorphism and Factor V Leiden variant in Mexican women with preeclampsia/eclampsia.

The etiology of preeclampsia is still a matter of controversy. An association between hyperhomocysteinemia and preeclamptic patients has been described. A common missense mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with increased plasma homocysteine concentrations. In addition, the polymorphism of gene encoding for Factor V Leiden G1691A is associated with a prothrombotic state in heterozygous subjects. Both mutations in these thrombophilic proteins appear to have different prevalence in the general population and in patients with preeclampsia/eclampsia (PE/E). We studied single nucleotide polymorphisms for MTHFR C677T and coagulation Factor V Leiden in 33 Mexican patients with PE/E as a genetic risk factor for these diseases, comparing with a normotensive pregnant control group. The genotype and allele frequencies of MTHFR C677T and Factor V Leiden mutations between Mexican women with PE/E and healthy controls were not different. We conclude that these polymorphisms do not contribute in the etiology of PE/E as it has been reported in other populations.

inv(9)(p24q13) in three sterile brothers.

Only nine non-polymorphic constitutional pericentric inversions of chromosome 9 have been described. We report on a familial inv(9)(p24q13) associated with sterility in three brothers. The mother's chromosomes were normal in blood lymphocytes (n=130); the father was already deceased and his karyotype unknown. However, the presence of any of the maternal chromosomes 9 (as assessed by C-banding) in her carrier children is inconsistent with the assumption of maternal mosaicism. Two single sisters were also carriers. The same rearranged chromosome 9 in the three sterile brothers can hardly be regarded as a fortuitous association, especially when the breakpoints are almost identical to those of the sole inversion previously found in an azoospermic male. If their father was a carrier, the observed sterility may be the result of 'chromosome anticipation', a phenomenon already invoked for certain familial chromosomal rearrangements.

Alphoidless centromere of a familial unstable inverted Y chromosome.

We report on a 3-generation pedigree in which an inverted unstable Y chromosome had no phenotypical or reproductive repercussion despite a sizable proportion of secondary aneuploidies (mainly 45, X cells) in lymphocytes. This chromosome was metacentric and had a single Cd-positive primary constriction, but occasionally assumed a normal acrocentric aspect. FISH using the probe DYZ3 revealed a single strong signal; unexpectedly, the signal was outside the primary constriction and appeared to map in the middle of p, that is, at the usual centromeric localisation. Therefore, this chromosome should be regarded as a remarkable pseudodicentric because the major alphoid array was located at the inactive centromere but not at the active one. This chromosome may have resulted from a) a transcentric inversion with the 48 bp satellite array of proximal Yq being relocated next to the Yq heterochromatin, or b) an intrachromosomal insertion of nonalphoid centromeric sequences.

Reproductive history in mothers of children with neural tube defects.

The reproductive history of 100 women with at least 1 child with a neural tube defect (NTD) has been studied. The data analyzed correspond to the period previous to their first visit to a genetic counseling service. A total of 204 pregnancies resulted in 205 outcomes. Of the 100 sibships, 14 (14%) had more than 1 affected member. The pregnancy was shorter than 28 weeks in 56/205 (27%) of the total outcomes. Of 104 evaluable previous outcomes, 34 corresponded to short pregnancies, positioned before an affected (23/60, 38%), a healthy (2/18, 11%), or an undiagnosed product (9/26, 35%). Short pregnancies subsequent to affected outcomes were also increased. The inter-gestational interval varied according to diagnosis: it was longer in the affected group than in the healthy one (0.1 > p > 0.05) and the subsequent intervals were shorter for the affected group (p < 0.05). An increased number of abortions adjacent to affected offspring and a changing fertility pattern, depending on the product diagnosis, point to an environmental etiological component in this high-risk NTD group of mothers.

The C677T polymorphism of the methylenetetrahydrofolate reductase gene in Mexican mestizo neural-tube defect parents, control mestizo and native populations.

The C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene, associated with the thermolabile form of the enzyme, has reportedly been found to be increased in neural-tube defects (NTD), though this association is still unclear. A group of 107 mestizo parents of NTD children and five control populations: 101 mestizo (M), 50 Huichol (H), 38 Tarahumara (T), 21 Purepecha (P) and 20 Caucasian (C) individuals were typed for the MTHFR C677T variant by the PCR/RFLP (HinfI) method. Genotype frequencies were in agreement with the Hardy-Weinberg expectations in all six populations. Allele frequency (%) of the C677T variant was 45 in NTD, 44 in M, 56 in H, 36 in T, 57 in P, 35 in C. Pairwise inter-population comparisons of allele frequency disclosed a very similar distribution between NTD and M groups (exact test, P=0.92). Among controls, differences between M and individual native groups were NS (0.06