FOXL2 copy number changes in the molecular pathogenesis of BPES: unique cohort of 17 deletions.

Blepharophimosis Syndrome (BPES) is an autosomal dominant developmental disorder of the eyelids with or without ovarian dysfunction caused by FOXL2 mutations. Overall, FOXL2deletions represent 12% of all genetic defects in BPES. Here, we have identified and characterized 16 new and one known FOXL2 deletion combining multiplex ligation-dependent probe amplification (MLPA), custom-made quantitative PCR (qPCR) and/or microarray-based copy number screening. The deletion breakpoints could be localized for 13 out of 17 deletions. The deletion size is highly variable (29.8 kb - 11.5 Mb), indicating absence of a recombination hotspot. Although the heterogeneity of their size and breakpoints is not reflected in the uniform BPES phenotype, there is considerable phenotypic variability regarding associated clinical findings including psychomotor retardation (8/17), microcephaly (6/17), and subtle skeletal features (2/17). In addition, in all females in whom ovarian function could be assessed, FOXL2 deletions proved to be associated with variable degrees of ovarian dysfunction. In conclusion, we present the largest series of BPES patients with FOXL2 deletions and standardized phenotyping reported so far. Our genotype-phenotype data can be useful for providing a prognosis (i.e. occurrence of associated features) in newborns with BPES carrying a FOXL2 deletion.

Isodisomy of chromosome 6 in a newborn with methylmalonic acidemia and agenesis of pancreatic beta cells causing diabetes mellitus.

Isodisomy (ID) is a genetic anomaly defined as the inheritance of two copies of the same genetic material from one parent. ID in an offspring is a rare cause of recessive genetic diseases via inheritance of two copies of a mutated gene from one carrier parent. We studied a newborn female with a mut(o) of methylmalonic acidemia and complete absence of insulin-producing beta cells in otherwise normal-appearing pancreatic islets, causing insulin-dependent diabetes mellitus. The patient died 2 wk after birth. Serotyping of the HLA antigens, DNA typing of HLA-B and HLA class II loci, study of polymorphic DNA markers of chromosome 6, and cytogenetic analysis demonstrated paternal ID, involving at least a 25-centiMorgan portion of the chromosome pair that encompasses the MHC. ID probably caused methylmalonic acidemia by duplication of a mutated allele of the corresponding gene on the chromosome 6 inherited from the father. It is also very likely that ID was etiologically related to the agenesis of beta cells and consequent insulin-dependent diabetes mellitus in our patient. We thus speculate on the existence of a gene on chromosome 6 involved in beta cell differentiation.

The phenotypic spectrum in patients with arginine to cysteine mutations in the COL2A1 gene.

BACKGROUND: The majority of COL2A1 missense mutations are substitutions of obligatory glycine residues in the triple helical domain. Only a few non-glycine missense mutations have been reported and among these, the arginine to cysteine substitutions predominate. OBJECTIVE: To investigate in more detail the phenotype resulting from arginine to cysteine mutations in the COL2A1 gene. METHODS: The clinical and radiographic phenotype of all patients in whom an arginine to cysteine mutation in the COL2A1 gene was identified in our laboratory, was studied and correlated with the abnormal genotype. The COL2A1 genotyping involved DHPLC analysis with subsequent sequencing of the abnormal fragments. RESULTS: Six different mutations (R75C, R365C, R519C, R704C, R789C, R1076C) were found in 11 unrelated probands. Each mutation resulted in a rather constant and site-specific phenotype, but a perinatally lethal disorder was never observed. Spondyloarthropathy with normal stature and no ocular involvement were features of patients with the R75C, R519C, or R1076C mutation. Short third and/or fourth toes was a distinguishing feature of the R75C mutation and brachydactyly with enlarged finger joints a key feature of the R1076C substitution. Stickler dysplasia with brachydactyly was observed in patients with the R704C mutation. The R365C and R789C mutations resulted in classic Stickler dysplasia and spondyloepiphyseal dysplasia congenita (SEDC), respectively. CONCLUSIONS: Arginine to cysteine mutations are rather infrequent COL2A1 mutations which cause a spectrum of phenotypes including classic SEDC and Stickler dysplasia, but also some unusual entities that have not yet been recognised and described as type II collagenopathies.

Acrocallosal syndrome in an Algerian boy born to consanguineous parents: review of the literature and further delineation of the syndrome.

We present a 17-month-old boy with the acrocallosal syndrome. He was born to consanguineous parents. Abnormal findings included agenesis of the corpus callosum, a ventricular septal defect (VSD), postaxial polydactyly of fingers, cleft soft palate, intestinal malrotation, large anterior fontanelle, prominent forehead, hypertelorism, epicanthic folds, short nose and mandible and preauricular skin tags, mixed hearing loss, laryngomalacia, and growth and severe motor and mental retardation. A review of previous reports on the acrocallosal syndrome shows considerable clinical variability; minimal diagnostic criteria are proposed. A developmental field defect with disturbance of midline development is suggested.

Feingold syndrome: report of a new family and review.

Feingold syndrome (or oculodigitoesophagoduodenal syndrome; Microcephaly, Mesobrachyphalangy, Tracheo-esophageal fistula syndrome) is a dominantly inherited combination of hand and foot abnormalities, microcephaly, esophageal/duodenal atresia, short palpebral fissures and learning disabilities, first reported in 1975 (MIM 164280). We report on the seventh family with Feingold syndrome. The propositus is a male infant with esophageal and duodenal atresia, brachymesophalangy of the fifth fingers, bilateral syndactyly of toes 4-5 (and 2-3), relative microcephaly, and facial anomalies. His mother also has microcephaly, similar facial appearance, short fifth fingers with single flexion crease, syndactyly of toes 4-5, and learning disabilities. The maternal sister, brother, and grandmother of the propositus have the same phenotype. The 7 families with Feingold syndrome are reviewed. Intestinal (esophageal/duodenal) atresia/obstruction occurs in approximately 1/3 of the patients with Feingold syndrome.

Further evidence for autosomal dominant inheritance and ectodermal abnormalities in Kabuki syndrome.

Most cases with Kabuki syndrome (KS) were reported sporadically. Recently, a few familial cases of KS were reported. This report provides further evidence that the KS is inherited as a dominant trait with variable expressivity. The proposita is an 18-month-old girl with facial findings characteristic of Kabuki syndrome, prominent fingertip-pads, a midsagittal cleft of vertebral body D4, hypotonia, and psychomotor retardation. Her mother had a similar facial appearance, prominent, cup-shaped ears, an abnormal dentition, early breast development, and low-normal intelligence. Because mother and daughter both had evident Kabuki syndrome, we conclude that KS in this family is inherited as a dominant trait. Further family history supports this finding. Microscopic examination of the hair of the proposita shows abnormalities consisting of trichorrhexis nodosa, twisting of the hairshafts, and irregularity of the diameter of the hair, as was described recently in a patient with KS. This could be another occasional finding in this syndrome, but further studies are required. The presence of abnormal hair, nails, and the commonly described tooth abnormalities in KS further suggest ectodermal involvement in this syndrome.

Interstitial deletion 2q33.3-q34 in a boy with a phenotype resembling the Seckel syndrome.

A boy presented at 5 weeks with a syndrome of pre- and postnatal growth retardation, microcephaly, muscular hypotonia, and facial anomalies resembling those seen in Seckel syndrome or microcephalic primordial dwarfism I. Analysis of prometaphase chromosomes, fluorescent in situ hybridization (FISH), and molecular studies showed the presence of a de novo chromosome 2 deletion that could be defined as del(2)(q33.3q34)pat. Parental chromosomes were normal, except for the presence of a paternal supernumerary marker identified by FISH as der(15). On follow-up of the patient during the next months length development appeared normal and the diagnosis of Seckel syndrome was withdrawn. Clinical findings of previously published cases with interstitial deletion of at least 2q33.3-q34, the deletion present in the propositus, are reviewed and include pre- and postnatal growth retardation, psychomotor retardation, microcephaly, micrognathia, and abnormal/low-set ears; findings also present in the propositus. These findings resemble those described in the Seckel syndrome. Noteworthy is the finding that 2/3 of the 60 reviewed cases originally reported as having Seckel syndrome apparently belong to a heterogeneous group of low birth weight microcephalic dwarfism I yet to be clearly defined. In these patients no chromosome 2q deletion has been reported so far. Retrospective analysis could show if a subgroup of these patients carry submicroscopic deletions at 2q33.3-q34. Alternatively, molecular analysis of this region may be warranted in newly diagnosed patients with Seckel syndrome-like manifestations.

Prenatal diagnosis of a constitutional interstitial deletion of chromosome 5 (q15q31.1) presenting with features of congenital contractural arachnodactyly.

Prenatal diagnosis of a constitutional interstitial deletion of chromosome 5 (q15q31.1) in a 30-year-old woman is reported. At 21 weeks of pregnancy, routine fetal ultrasounds showed the presence of apparently isolated bilateral club feet. Fetal karyotyping documented an interstitial deletion of the long arm of chromosome 5: 46,XX,del(5) (q15q31) in all 50 analyzed metaphases. Because such deletion is associated with severe psychomotor retardation, the pregnancy was terminated. Postmortem karyotyping of skin fibroblasts confirmed the presence of this interstitial de novo deletion in all mitoses. The breakpoints on 5q were analyzed by fluorescent in situ hybridization and were localized at 5q15 and q31.1. This case illustrates the importance of fetal karyotyping in cases of isolated club feet. At autopsy, the fetus presented had minor anomalies and contractures of knee and hip joints. These clinical findings could fit the diagnosis of congenital contractural arachnodactyly (CCA) or Beals syndrome. CCA is caused by a defect in the fibrillin-2 (FBN2) gene. This gene was previously mapped on 5q23-31. Our molecular studies of both parents and the fetus, using an intragenic polymorphic GT repeat, showed that the FBN2 gene was deleted in the fetus and that the de novo interstitial deletion occurred on the paternally inherited chromosome 5. Thus, CCA may be caused by a loss of function of the FBN2 gene. Clinical findings in this fetus and those of other described cases with interstitial 5q deletions are reviewed, and similarities with CCA are stressed.

Proximal deletion of chromosome 21 confirmed by in situ hybridization and molecular studies.

Foetal blood sampling was performed at 35 weeks of gestation due to abnormal foetal ultrasound findings. There was apparent monosomy 21 (45,XX,-21) in all mitoses analyzed. The infant died at 37 weeks during delivery. Examination disclosed facial anomalies, clubfeet, hypoplasia of the left urogenital tract, agenesis of corpus callosum, ventricular dilatation, and heterotopias. Reevaluation of the karyotype showed an unbalanced translocation t(1;21) (q44;q22.11) which resulted from a maternal balanced translocation. These findings were confirmed by fluorescence in situ hybridization and molecular studies with chromosome 21 specific markers. The latter showed a proximal deletion of the maternally derived chromosome 21 including all loci from centromere down to the D21S210 locus. This case illustrates the need for complementary cytogenetic and molecular investigations in cases of apparent monosomy 21.

New syndrome or severe expression of Gordon syndrome? A case report.

A boy with multiple congenital anomalies including median cleft palate, bilateral hearing loss, clino- and camptodactyly, bilateral single palmar flexion creases, severe hypotonia with kyphoscoliosis and respiratory insufficiency, failure to thrive, bilateral cryptorchidism and facial dysmorphism (epicanthus, a flat nasal bridge, a small mouth, a small nose with anteverted nostrils, low-set ears, a prominent forehead, microretrognathia) is presented. His mother has a median cleft palate, bilateral hearing loss, single palmar flexion creases, and short stature. An autosomal or X-linked dominant syndrome with more severe expression in the proband than in his mother is suggested.

A probable case of Wiedemann-Rautenstrauch syndrome or neonatal progeroid syndrome and review of the literature.

A boy with features suggesting the diagnosis of Wiedemann-Rautenstrauch syndrome (WRS) or neonatal progeroid syndrome is presented. Abnormal findings included a generalized virtual absence of subcutaneous fat, sparse scalp hair, prominence of veins and muscles, a large and persistent anterior fontanelle and facial dysmorphism (triangular aged face, prominent eyes and scalp veins). Until now, only 13 cases (including one prenatal diagnosis) of this syndrome have been described. Since the borderlines of this syndrome are not very exact, we reviewed the previous reports in order to further delineate this rare syndrome.

Multiplex ligation-dependent probe amplification to detect subtelomeric rearrangements in routine diagnostics.

Subtelomeric rearrangements are believed to be responsible for 5-7% of idiopathic mental retardation cases. Due to the relative complexity and high cost of the screening methods used till now, only preselected patient populations including mostly the more severely affected cases have been screened. Recently, multiplex ligation-dependent probe amplification (MLPA) has been adapted for use in subtelomeric screening, and we have incorporated this technique into routine diagnostics of our laboratory. Since the evaluation of MLPA as a screening method, we tested 275 unselected patients with idiopathic mental retardation and detected 12 possible subtelomeric aberrations: a der(11)t(11;20)(qter;qter), a 19pter duplication, a der(18)t(18;10)(qter; pter), a 15qter deletion, a 8pter deletion, a 6qter deletion, a der(X)t(X;1)(pter;qter), a der(X)t(X;3)(pter;pter), a 5qter duplication, a 3pter deletion, and two 3qter duplications. The patients can be subdivided into two groups: the first containing de novo rearrangements that are likely related to the clinical presentation of the patient and the second including aberrations also present in one of the parents that may or may not be causative of the mental retardation. In our patient cohort, five (1.8%) subtelomeric rearrangements were de novo, three (1.1%) rearrangements were familial and suggestively disease causing, and four (1.5%) were possible polymorphisms. This high frequency of subtelomeric abnormalities detected in an unselected population warrants further investigation about the feasibility of routine screening for subtelomeric aberrations in mentally retarded patients.

Oculocerebral hypopigmentation syndrome (Cross syndrome) in a Gipsy child.

A boy aged 2 years, born prematurely to Gipsy parents, presented with hypopigmentation severe encephalopathy with athetoid movements, bilateral ocular anomalies including cloudy corneas, iris atrophy and cataracts, as well as dental defects. Ultrastructural examination of the skin disclosed scare melanosomes. Although the neurologic and ocular anomalies might have been accounted for by his extreme prematurity, their association with hypomelanogenesis and dental defects support, in this patient the diagnosis of the oculocerebral hypopigmentation syndrome (Cross syndrome).

Maternal diabetes and fetal malformations: a case associating cardiovascular, facial and skeletal malformations.

Maternal diabetes is known to be a condition associated with a high frequency of fetal malformations. However, pathogenic factors for these malformations and their possible classification into different entities are not yet well established. We present the case of an infant born to a diabetic mother and affected by several malformations. This report consolidates different hypotheses put forward in recent years.

Hermansky-Pudlak syndrome: a case report and discussion.

Hermansky-Pudlak syndrome is a rare, inherited, autosomal recessive disease. Diagnosis is based on a triad of signs: oculocutaneous albinism, a hemorrhagic tendency due to a platelet disorder, and an accumulation of lipopigments in different organs, particularly the medullary macrophages. We describe a child with the characteristic findings of this syndrome, which often goes unrecognized because of the discrete nature of the cutaneous and hemorrhagic manifestations. This diagnosis is important because of the risk not only of hemorrhage but also of granulomatous colitis and long-term pulmonary fibrosis.

Pre- and perinatal findings in partial trisomy 7q resulting from balanced parental translocations t(7;21) and t(4;7).

We report on a fetus and a newborn, both with partial trisomy 7q21-->qter due to different familial translocations, t(7;21)(q21.2;p12) and t(4;7)(q35;q21.2). Postmortem examination of the 19-week-old female fetus disclosed dysmorphic features, cleft palate, anomalies of the great vessels, intestinal malrotation and uterus bicornis. The newborn girl revealed a pattern of minor anomalies, cleft palate, cerebellar hypoplasia, and anomalies of pancreas, gall bladder and appendix. The clinical findings in three other reported fetuses with partial trisomy 7q described so far are reviewed. A duplication 7q21-->qter, as found in the propositi, has only been described in 11 patients who all had a concurrent partial monosomy. Patient 1 is particularly interesting since she is, to our knowledge, the first reported case with pure trisomy 7q21/22-->qter. We reviewed the phenotype of the previously described patients, compared it with the propositae, and summarized the clinical features of pure trisomy 7q21/22-->qter.