Best practice guidelines for the molecular genetic diagnosis of Type 1 (HFE-related) hereditary haemochromatosis.

Background: Hereditary haemochromatosis (HH) is a recessively-inherited disorder of iron over-absorption prevalent in Caucasian populations. Affected individuals for Type 1 HH are usually either homozygous for a cysteine to tyrosine amino acid substitution at position 282 (C282Y) of the HFE gene, or compound heterozygotes for C282Y and for a histidine to aspartic acid change at position 63 (H63D). Molecular genetic testing for these two mutations has become widespread in recent years.

Malpuech syndrome: facial features in the absence of clefting.

We present a girl with Malpuech syndrome. In addition to the typical features of intrauterine growth retardation, facial dysmorphism, caudal appendage and patent ductus arteriosis, she has an unusual eyebrow pattern with a lateral flare.

The tale of a nail sign in chromosome 4q34 deletion syndrome.

Relatively, few reports of deletions involving the distal long arm of chromosome 4 (4q) exist. Five further cases are described and the findings are compared with those in previous literature reports. Distal 4q deletions may be recognized by the distinctive appearance of the fifth finger, which is stiff with a hypoplastic distal phalanx and a hooked or volar nail.

Genetic conditions in the Irish Roma gypsy population.

Roma gypsy represent a new Irish ethnic minority population with a distinct cultural and racial heritage. There is a strong Roma tradition of consanguinity, which can increase the likelihood of having a child affected by an autosomal recessive disorder. We describe 6 patients from the Roma community who had presented with 4 different autosomal recessive conditions not previously seen in the Irish population, Chronic Granulomatous Disease, HMSN-Russe, and two multiple malformation syndromes.

Clinical and molecular findings in IPEX syndrome.

IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X linked syndrome) is a rare disorder which usually results in death in early infancy or childhood. Clinical awareness remains the cornerstone of diagnosis, and provided that the diagnosis is entertained, mutation analysis for FOXP3 gene mutations can be confirmatory. Two new patients in whom IPEX was diagnosed retrospectively are reported.

3'CBFbeta deletion associated with inv(16) in acute myeloid leukemia.

Recent reports have shown that concomitant submicroscopic deletions can occur in association with chromosomal translocations/inversions in several leukemia subtypes. Detectable by fluorescence in situ hybridization (FISH), these losses of sequence include deletion of the 5' region of the ABL gene and the 3' region of BCR in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL), as well as the 5' region of ETO in acute myeloid leukemia (AML) French-American-British type M2 associated with t(8;21), 3'MLL in AML and ALL, and 3' core-binding factor beta (CBFbeta) in AML associated with inv(16). While it has been widely reported that submicroscopic deletions of the derivative 9 in CML have an adverse prognostic impact, the clinical significance, if any, of deletions associated with t(8;21), inv(16)/t(16;16), or MLL rearrangement is yet to be determined.

Choanal atresia - a recurrent feature of foetal carbimazole syndrome.

Choanal atresia is described as a feature of several congenital anomaly phenotypes. Most cases of choanal atresia arises as an isolated clinical finding. In utero exposure to carbimazole for maternal hyperthyroidism has been reported in five cases of choanal atresia.

Denaturing high-performance liquid chromatography using the WAVE DNA fragment analysis system.

Denaturing high-performance liquid chromatography (DHPLC) is a chromatographic mutation analysis technique that is based on temperature-dependent separation of DNA containing mismatched base pairs from polymerase chain reaction (PCR)-amplified DNA fragments. The WAVE system, developed for DHPLC analysis, allows for unattended analysis of 96 samples directly from a PCR plate under a number of different conditions. It utilizes a Peltier cooling platform to maintain sample integrity.

Non-multifactorial neural tube defects.

Although most neural tube defects (anencephaly, spina bifida) occur as isolated malformations, a substantial proportion are attributable to chromosome anomalies, known teratogens, or component manifestations of multiple anomaly syndromes. This review describes known chromosome alterations and the candidate genes residing in the altered region, as well as syndromes associated with neural tube defects and causative genes, if known.

Molecular cytogenetic analysis of recurrent unbalanced t(11;17) in neuroblastoma.

Loss of 11q material occurs in approximately 30% of advanced stage neuroblastoma and defines a distinct genetic subtype of this disease. These tumors almost always possess unbalanced gain of the 17q, along with many additional recurrent chromosomal imbalances. Loss of 11q and gain of 17q is often the consequence of an unbalanced translocation between the long arms of both chromosomes, but because of the involvement of other chromosomal mechanisms, the actual frequency of t(11;17) is unknown.

Evolution of unbalanced gain of distal chromosome 2p in neuroblastoma.

Neuroblastoma, one of the most common tumors of childhood, presents at diagnosis with a vast number of recurrent chromosomal imbalances that include hyperdiploidy for whole chromosomes, partial loss of 1p, 3p, 4p, 11q, 14q, partial gain of 1q, 7q, 17q and amplification of MYCN. These abnormalities are nonrandomly distributed in neuroblastoma as loss of 3p and 11q rarely occur in MYCN amplified neuroblastomas. Here, we report on a patient who had a non-MYCN amplified 3p-/11q- neuroblastoma at diagnosis who subsequently developed a high level of MYCN amplification in bone marrow metastases 41 months after induction of complete remission.

Oligonucleotide microarray analysis of gene expression in neuroblastoma displaying loss of chromosome 11q.

A number of distinct subtypes of neuroblastoma exist with different genetic abnormalities that are predicative of outcome. Whole chromosome gains are usually associated with low stage disease and favourable outcome, whereas loss of 1p, 3p and 11q, unbalanced gain of 17q and MYCN amplification (MNA) are indicative of high stage disease and unfavourable prognosis. Although MNA and loss of 11q appear to represent two distinct genetic subtypes of advanced stage neuroblastoma, a detailed understanding of how these subtypes differ in terms of global gene expression is still lacking.

Moebius sequence and hypogonadotrophic hypogonadism.

A distinct form of Moebius sequence is associated with hypogonadotrophic hypogonadism. There have been five such cases to date. We now add a further case with detailed neurologic, endocrine, and autopsy findings and offer a hypothesis drawing parallels with the already established basis of hypogonadotrophic hypogonadism in the X-linked form of Kallman syndrome.

Deafness associated with bilateral facial diplegia, ptosis and hypermobile joints--A new autosomal recessive condition?

We report the combination of sensorineural deafness with facial diplegia, ptosis and hypermobile joints. Observed in a sister and brother, comparison with other reports has failed to identify an established syndrome with this clinical profile. We propose that these siblings share a unique phenotype, representing a new autosomal recessive trait.

Congenital ptosis with esotropia in brothers.

Two brothers are reported with congenital ptosis and esotropia, one of whom also has polythelia. This particular constellation of clinical features has not previously been described, although comparison with recorded families does show significant overlap with the pedigree reported by Frydman et al.

Are gains of chromosomal regions 7q and 11p important abnormalities in neuroblastoma?

Neuroblastoma exhibiting deletion of a segment of the long arm of chromosome 11 represents a genetic subtype of tumor that is distinct from those exhibiting MYCN amplification or 1p deletion. The 11q- genetic subtype is further characterized by gain of 17q and loss of distal 3p material. Gain of 11p material has also been reported in neuroblastoma with 11q loss, but at a considerably lower frequency than gain of 17q or loss of the distal 3p region.

Broad thumbs and halluces with deafness: a patient with Keipert syndrome.

Clinical, radiological, and audiological features are described in a boy whose condition closely parallels the profile of patients previously described with Keipert syndrome. This case represents the fourth report of this rare disorder.

Genitopatellar syndrome: a recognizable phenotype.

Genitopatellar syndrome is a newly described condition, subject of a single literature report to date. The condition comprises absent patellae, genital and renal malformations, joint dislocation, and mental retardation. Recurrence has been recorded in two kindreds, consistent with autosomal recessive inheritance.

Genetic abnormalities in a pre and post-chemotherapy hepatoblastoma.

Comparative genomic hybridization (CGH) analysis was performed on both a pre- and post-chemotherapy hepatoblastoma from a 24-month-old female patient. The diagnostic sample obtained from a tru-cut biopsy was a mixed epithelial-mesenchymal tumor with both fetal and embryonal patterns present. In contrast, the post-chemotherapy tumor exhibited a prominent anaplastic large cell population focally reminiscent of pleomorphic hepatocellular carcinoma (HCC).

Double vagina with sex reversal, congenital diaphragmatic hernia, pulmonary and cardiac malformations--another case of Meacham syndrome.

We report a female infant of 42 weeks gestation with a left sided diaphragmatic hernia and a hypoplastic left heart. A true double vagina, absent uterus and abnormal male gonads were found in the presence of normal external female genitalia. Conventional G band karyotyping of skin samples revealed a normal male karyotype.

A novel germline mutation of the PTEN gene in a patient with macrocephaly, ventricular dilatation, and features of VATER association.

Mutations of the PTEN gene are associated with hamartoma-neoplasia syndromes. While germline mutations at this chromosome 10q22-23 locus have been observed in patients with Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR), both of which phenotypes are associated with hamartomata and neoplasia, somatic mutation of PTEN has been established in a wide variety of sporadically occurring neoplasia. CS and BRR share some clinical features, specifically hamartomata and lipomatosis.

An atypical case suggesting the possibility of overlap between Malpuech and Juberg-Hayward syndromes.

Malpuech syndrome and Juberg-Hayward syndrome are considered to be distinct disorders of orofacial clefting. We present details of a patient whose clinical presentation closely resembles the profile of Malpuech syndrome, but whose radiological features are more in keeping with published observations in Juberg-Hayward patients.