Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases.

Wiedemann-Steiner syndrome (WSS) is a rare syndromic condition in which intellectual disability (ID) is associated with hypertrichosis cubiti, short stature, and characteristic facies. Following the identification of the causative gene (KMT2A) in 2012, only 31 cases of WSS have been described precisely in the literature. We report on 33 French individuals with a KMT2A mutation confirmed by targeted gene sequencing, high-throughput sequencing or exome sequencing. Patients' molecular and clinical features were recorded and compared with the literature data. On the molecular level, we found 29 novel mutations. We observed autosomal dominant transmission of WSS in 3 families and mosaicism in one family. Clinically, we observed a broad phenotypic spectrum with regard to ID (mild to severe), the facies (typical or not of WSS) and associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Hypertrichosis cubiti that was supposed to be pathognomonic in the literature was found only in 61% of our cases. This is the largest series of WSS cases yet described to date. A majority of patients exhibited suggestive features, but others were less characteristic, only identified by molecular diagnosis. The prevalence of WSS was higher than expected in patients with ID, suggesting than KMT2A is a major gene in ID.

ASSOCIATED ANOMALIES IN CASES WITH LIMB REDUCTION DEFICIENCIES.

Infants with limb reduction deficiencies (LRD) often have other associated congenital anomalies. The purpose of this investigation was to assess the prevalence and the types of associated anomalies in a defined population. The associated anomalies in infants with LRD were collected in all livebirths, stillbirths and terminations of pregnancy during 29 years in 387,067 consecutive births in the area covered by our population-based registry of congenital malformations. Of the 317 infants bom with LRD during this period, representing a prevalence of 8.2 per 10,000, 59.9% had associated anomalies. There were 27 (8.5%) cases with chromosomal abnormalities including 17 trisomies 18, and 73 (23.0%) nonchromosomal recognized dysmorphic conditions including 19 VA(C)TER(L) association and 15 Poland syndrome. However, numerous other recognized dysmorphic conditions were registered. Ninety (28.4%) of the cases had multiple congenital anomalies (MCA). Anomalies in the musculoskeletal, the cardiac, the urogenital, and the central nervous system were the most common other anomalies. This study included special strengths: each affected child was examined by a geneticist, all elective terminations were ascertained, and the surveillance for anomalies was continued until 2 years of age. Therefore the overall prevalence of associated anomalies, which was more than one in two infants, emphasizes the need for a thorough investigation of infants with LRD. A routine screening for other anomalies especially in the musculoskeletal system, the cardiovascular system, the urogenital system, the central nervous system, and the digestive system may be considered in infants and in fetuses with LRD.

ASSOCIATED NON DIAPHRAGMATIC ANOMALIES AMONG CASES WITH CONGENITAL DIAPHRAGMATIC HERNIA.

Cases with congenital diaphragmatic hernia (CDH) often have other associated anomalies. The purpose of this investigation was to assess the prevalence and the types of associated anomalies in CDH in a defined population. The anomalies associated with CDH were collected in all live births, stillbirths and terminations of pregnancy during 29 years in 386,088 consecutive pregnancies of known outcome in the area covered by our population based registry of congenital anomalies. Of the 139 cases with CDH born during this period (total prevalence of 3.60 per 10,000), 85 (61.2%) had associated major anomalies. There were 25 (18.0%) cases with chromosomal abnormalities including 12 trisomies 18, and 24 (17.3%) nonchromosomal recognized dysmorphic conditions. There were no predominant recognized dysmorphic conditions, but Fryns syndrome. However, other recognized dysmorphic conditions were registered including fetal alcohol syndrome, de Lange syndrome, sequences (laterality sequence and ectopia cordis), and complexes (limb body wall complex). Thirty six (25.9%) of the cases had non syndromic multiple congenital anomalies (MCA). Anomalies of the cardiovascular system (n = 53, 27.5%), the urogenital system (n = 34, 17.6%), the musculoskeletal system (n = 29, 15.0%), and the central nervous system (n = 19, 9.8%) were the most common other congenital anomalies. We observed specific patterns of anomalies associated with CDH which emphasizes the need to evaluate all patients with CDH for possible associated malformations. In conclusion the overall prevalence of associated anomalies, which was close to two in three infants, emphasizes the need for a thorough investigation of cases with CDH. A routine screening for other anomalies may be considered in infants and in fetuses with CDH. One should be aware that the anomalies associated with CDH can be classified into a recognizable anomaly, syndrome or pattern in more than one out of two cases with CDH.

Postnatal phenotype according to prenatal ultrasound features of Noonan syndrome: a retrospective study of 28 cases.

OBJECTIVE: Noonan syndrome is a frequent genetic disorder with autosomal dominant transmission. Classically, it combines postnatal growth restriction with dysmorphic and malformation syndromes that vary widely in expressivity. Lymphatic dysplasia induced during the embryonic stage might interfere with tissue migration. Our hypothesis is that the earlier the edema, the more severe postnatal phenotype. METHOD: This retrospective study analyzed data from all 32 cases of Noonan syndrome diagnosed in the Medical Genetics Department of Hautepierre Hospital in Strasbourg, France, between 1995 and 2011. The postnatal evolution of Noonan syndrome was compared according to the presence of at least one prenatal ultrasound feature of lymphatic dysplasia. RESULTS: The most frequent prenatal ultrasound features found were increased nuchal translucency, cystic hygroma and polyhydramnios; their global prevalence was 46.4%. The presence of these features was not significantly associated with the postnatal phenotype of Noonan syndrome. CONCLUSION: The results of our study indicate that prenatal ultrasound features of lymphatic dysplasia do not predict an unfavorable postnatal prognosis for Noonan syndrome.

Associated malformations among infants with radial ray deficiency.

Infants with radial ray deficiencies very often have other associated congenital anomalies. The reported frequency and types of associated malformations vary between different studies. The purpose of this investigation was to assess the frequency and types of associated malformations among infants with radial ray deficiencies in a geographically well-defined population from 1979 to 2004 of 346,831 consecutive births. Of the 73 infants with radial ray deficiencies born during this period (prevalence at birth of 2.1 per 10,000), 75% had associated malformations. Infants with associated malformation were divided into recognizable conditions (16 (22%) infants with chromosomal and 20 (27%) with non chromosomal conditions), and non recognizable conditions (19 (26%) infants with multiple malformations). Trisomies 18 and autosomal deletions were the most frequent chromosomal abnormalities. VACTERL association, thrombocytopenia absent radii syndrome, Fanconi anemia and Holt-Oram syndrome were most often present in recognizable non chromosomal conditions. Malformations in the musculoskeletal, cardiovascular and urogenital systems were the most common other anomalies in infants with multiple malformations and non recognizable conditions. The frequency of associated malformations in infants with radial ray deficiencies emphasizes the need for a thorough investigation of these infants. Routine screening for other malformations especially musculoskeletal, cardiac and urogenital systems anomalies may need to be considered in infants with radial ray deficiencies, and referral of these infants for genetic evaluation and counseling seems warranted.

X-linked and autosomal recessive Hypohidrotic Ectodermal Dysplasia: genotypic-dental phenotypic findings.

Hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of ectodermal structures and its molecular etiology corresponds to mutations of EDA-EDAR genes. The aim of this study was first to investigate the genotype and dental phenotype associated with HED and second, to explore possible correlations between dental features and molecular defects. A total of 27 patients from 24 unrelated families exhibiting clinical signs of HED (22 XLHED males, 5 autosomal recessive forms) were retrospectively included. In the sample, 25 different mutations on EDA and EDAR genes were detected; 10 were not previously described. EDA and EDAR mutations corresponded respectively to 80.0% and 20.0% of the mutations. The dental phenotype analysis revealed a mean number of primary and permanent missing teeth ranging respectively from 14.5 (4-20) to 22.5 (10-28); the majority of the patients exhibited dysmorphic teeth. Overall, no differential expression in the degree of oligodontia according to either the mutated gene, the mutated functional sub-domains, or the mutation type, could be observed. Nevertheless, the furin group exhibited severe phenotypes unobserved in the TNF group. Significant differences in the number of some primary missing teeth (incisor and canine) related to EDA-EDAR genes defects were detected for the first time between XLHED and autosomal recessive HED, suggesting differential local effects of EDA-EDAR genes during odontogenesis. The present genotypic-phenotypic findings may add to the knowledge of the consequences of the molecular dysfunction of EDA-NF-kB in odontogenesis, and could be helpful in genetic counseling to distinguish autosomal forms from other HED syndromes.

Associated malformations in cases with congenital diaphragmatic hernia.

The etiology of congenital diaphragmatic hernia (CDH) is unclear and its pathogenesis is controversial. Because previous reports have inconsistently noted the type and frequency of malformations associated with CDH, we assessed these associated malformations ascertained between 1979 and 2003 in 334,262 consecutive births. Of the 115 patients with the most common type of CDH, the posterolateral, or Bochdalek-type hernia, 70 (60.8%) had associated malformations. These included: chromosomal abnormalities (n = 21, 30.0%); non-chromosomal syndromes (Fryns syndrome, fetal alcohol syndrome, De Lange syndrome, CHARGE syndrome, Fraser syndrome, Goldenhar syndrome, Smith-Lemli-Opitz syndrome, multiple pterygium syndrome, Noonan syndrome, and spondylocostal dysostosis); malformation sequences (laterality sequence, ectopia cordis); malformation complexes (limb body wall complex) and non syndromic multiple congenital anomalies (MCA) (n = 30, 42.9%). Malformations of the cardiovascular system (n = 42, 27.5%), urogenital system (n = 27, 17.7%), musculoskeletal system (n = 24, 15.7%), and central nervous system (n = 15, 9.8%) were the most common other congenital malformations. We observed specific patterns of malformations associated with CDH which emphasizes the need to evaluate all patients with CDH for possible associated malformations. Geneticists and pediatricians should be aware that the malformations associated with CDH can often be classified into a recognizable malformation syndrome or pattern (57.1%).

Associated malformations in patients with anorectal anomalies.

Patients with congenital anorectal malformations (ARM) often have other associated congenital defects. The reported incidence and the types of associated malformations vary between different studies. The purpose of this investigation was to assess the prevalences at birth of associated malformations in patients of a geographically defined population with ARM which were collected between 1979 and 2003 in 334, 262 consecutive births. Of the 174 patients with ARM during the study period, 49.4% had associated malformations. Patients with associated malformations were further classified into groups with nonsyndromic multiple congenital anomalies; chromosomal abnormalities; nonchromosomal syndromes including Townes-Brocks, Walker-Warburg, Ivemark, Fetal alcohol, Klippel-Feil, Pallister-Hall, Facio-auriculo-vertebral spectrum, deletion 22q11.2; sequences, including OEIS, Pierre Robin and sirenomelia; and associations including VATER and MURCS. Malformations of the urogenital system (81.1%) and of the skeletal system (45.5%) were the most common other congenital anomalies occurring with ARM in multiply malformed patients without recognized entities, followed by malformations of the cardiovascular system, the digestive system, and the central nervous system. Weight, length, and head circumference of children with ARM and multiple associated malformations were lower than in controls, as was the weight of the placenta. Prenatal detection by fetal ultrasonographic examination was rarely made in isolated ARM. However, even in multiple associated malformations, prenatal detection by fetal ultrasonographic examination had a low sensitivity, 36%. In conclusion the overall prevalence of malformations, which was close to 1 in two infants, emphasizes the need for a thorough investigation of patients with ARM. A routine screening for other malformations may be considered in patients with ARM, and genetic counseling seems warranted in most of these complicated cases.

Clinical, molecular, and genotype-phenotype correlation studies from 25 cases of oral-facial-digital syndrome type 1: a French and Belgian collaborative study.

Oral-facial-digital syndrome type 1 (OFD1) is characterised by an X linked dominant mode of inheritance with lethality in males. Clinical features include facial dysmorphism with oral, tooth, and distal abnormalities, polycystic kidney disease, and central nervous system malformations. Large interfamilial and intrafamilial clinical variability has been widely reported, and 18 distinct mutations have been previously reported within OFD1. A French and Belgian collaborative study collected 25 cases from 16 families. OFD1 was analysed using direct sequencing and phenotype-genotype correlation was performed using chi2 test. X inactivation studies were performed on blood lymphocytes. In 11 families, 11 novel mutations, including nine frameshift, one nonsense, and one missense mutation were identified, which spanned nine different exons. A combination of our results with previously reported cases showed that the majority of mutations (65.5%) was located in exons 3, 8, 9, 13, and 16. There was phenotype-genotype correlation between (a) polycystic kidney disease and splice mutations; (b) mental retardation and mutations located in exons 3, 8, 9, 13, and 16; and (c) tooth abnormalities and mutations located in coiled coil domains. Comparing the phenotype of the families with a pathogenic mutation to families with absence of OFD1 mutation, polycystic kidneys and short stature were significantly more frequent in the group with no OFD1 mutation, whereas lingual hamartomas were significantly more frequent in the group with OFD1 mutation. Finally, an X inactivation study showed non-random X inactivation in a third of the samples. Differential X inactivation between mothers and daughters in two families with high intrafamilial variability was of particular interest. Slight phenotype-genotype correlations were established, and X inactivation study showed that skewed X inactivation could be partially involved in the pathogenesis of intrafamilial clinical variability.

Associated malformations in cases with neural tube defects.

Infants with neural tube defects (NTDs) may have other associated congenital defects. The reported incidence and the types of associated malformations vary between different studies. The purpose of this investigation was to assess the prevalence of associated malformations in a geographically defined population. The prevalences at birth of associated malformations in infants with NTDs were collected between 1979 and 2003 on all infants born in the area covered by the registry of congenital anomalies of Northeastern France in 334,262 consecutive births. Of the 360 infants with NTDs born during this period, 20.5 % had associated malformations. Associated malformations were more frequent in infants who had encephalocele (37.5 %) than in infants with anencephaly (11.8 %) or infants with spina bifida (23.7 %). Malformations in the face (oral clefts), in the musculoskeletal system, in the renal system, and in the cardiovascular system were the most common other anomalies. In conclusion the overall prevalence of malformations, which was one in five infants, emphasizes the need for a thorough investigation of infants with NTDs. A routine screening for other malformations especially facial clefts, musculoskeletal, renal and cardiac anomalies may need to be considered in infants with NTDs, and genetic counseling seems warranted in most of these complicated cases.

Are the recommendations on the prevention of neural tube defects working?

Many studies showed that reduction by an estimated 80% or more of neural tube defects (NTD) by consumption of folic acid from before conception is achievable. The objectives of this study were to evaluate the effectiveness of recommendations on folic acid aimed at reducing the occurrence of NTD in our region. Cases of NTD were ascertained among liveborn infants, stillbirths, and terminations of pregnancy. Incidences and trends in rates of NTD before and after 1992 (the year of the first recommendations) and before and after 1995 (the year of local recommendations) were obtained. The results showed that the issuing of recommendations on folic acid was followed by no detectable improvement in the trends of incidence of NTD. The rates of NTD per 10,000 were before 1992 9.07, from 1993 to 1995 8.14, and after 1995 10.62, respectively. The incidence rate ratios (IRRs) were not different from 1.00. In conclusion new cases preventable by folic acid continue to accumulate. Recommendations alone did not influence trends in NTD in our country up to 11 years after the confirmation of the effectiveness of folic acid in clinical trials. New strategies are needed.

Parental consanguinity as a cause of increased incidence of birth defects in a study of 131,760 consecutive births.

The risk for birth defects in the offspring of first cousin parents is substantially higher than in the offspring of non-consanguineous parents. As a general decline in the frequency of consanguineous marriages was observed in this century, one wonders whether consanguinity is still a factor in the appearance of birth defects in developed countries. Based on our registry of congenital anomalies, we think that the answer to this question is "yes." In the population studied in Northeastern France, consanguineous matings were known in 1.08% of the cases with congenital anomalies, vs. 0.28% in controls (P < 0.001). The frequency of the malformations recorded paralleled the degree of consanguinity: out of 38 malformed children, 24 were seen in first cousin matings (10.5 times more frequent than in offspring of nonconsanguineous couples), 8 in second cousin marriages, and 6 in more distantly consanguineous matings. Consanguineous mothers were more often pregnant than nonconsanguineous mothers (P < 0.01) and they had more stillbirths than nonconsanguineous mothers. These results must be taken into account when counseling consanguineous couples.

Ventricular extrasystoles with syncopal episodes, perodactyly, and Robin in sequence in three generations: a new inherited MCA syndrome?

We observed the combination of the Robin sequence with perodactyly (hypoplasia and/or agenesis of the distal phalanx of the toes) and cardiac arrhythmia (ventricular extrasystoles occurring as bigemini or multifocal tachycardia with syncopal episodes) in 6 relatives in 3 generations. This familial association has not been reported before and probably represents a previously unrecognized heritable malformation syndrome.

Dandy-Walker variant malformation, spastic paraplegia, and mental retardation in two sibs.

Two sibs, a boy and a girl, had both hypoplasia of the cerebellar hemispheres and partial agenesis of the cerebellar vermis with normal communication between the fourth ventricle and arachnoid spaces, i.e., the manifestations of the Dandy-Walker variant malformation associated with agenesis of the corpus callosum. Both sibs were mentally retarded and had spastic paraplegia. The occurrence of a distinct and similar pattern of congenital anomalies in sibs born to healthy parents points toward a "new" syndrome caused by the homozygous state of an autosomal recessive gene. Prenatal ultrasonographic diagnosis is possible at least for the more severe form of the brain anomalies.

Linkage analysis suggests at least two loci for X-linked non-specific mental retardation.

Epidemiological studies have suggested that non-specific X-linked mental retardation (XLMR) might be at least as frequent as the fragile X syndrome. The identification of all mutations causing XLMR would thus appear of prime importance. In the absence of other clinical signs the problem of genetic heterogeneity is acute. This can be partly overcome by the analysis of large families. We have been able to perform linkage analysis in 3 such families. The condition in family 1 was described as clinically resembling the fra (X) syndrome by Proops et al [1983]: the kindred includes 7 affected males in 3 sibships. Family 2 from Denmark has affected males in 4 generations; however, several affected relatives in this extended pedigree are deceased. Family 3 from France counts 6 affected males in two sibships. The families were analysed with about 25 X-linked markers. Linkage with markers in Xp22.2-p22.3 was found in family 1: z(theta) = 2.62 at theta = 0.06 for DXS85 (probe 782). Suggestion of linkage was found in family 2 with both the Duchenne muscular dystrophy region (DXS164 in Xp21.2) and with DXS1 (Xq11-q12). In family 3, DXS159 (Xq12-q13) gave a lod score of 2.53 at theta = 0; results were compatible with localisation of the putative XLMR locus in this family proximal to DXYS1 (Xq21). These data suggest that at least two non-specific XLMR loci could exist, one in Xp22 and the other in the q12-q13 region.

Probable localisation of the Coffin-Lowry locus in Xp22.2-p22.1 by multipoint linkage analysis.

The Coffin-Lowry syndrome (McKusick No. 30360) is a rare genetically transmitted disorder characterized by severe mental retardation, "coarse" facial appearance, thick soft skin, tapering fingers, and progressive skeletal abnormalities. X-linked inheritance is implied since the males are severely affected with variably mild manifestations in carrier women. We have performed a linkage analysis with many X-linked RFLP markers in 4 families. Positive two-point lod scores were obtained with DXS28 (z(theta) = 2.00 at theta = 0.05) and DXS41 (z(theta) = 1.26 at theta = 0.10). We performed a 5-point linkage analysis using the LINKMAP program assuming that DXS16 and DXS43 are a single locus and using the following fixed map (distances in centimorgans): DXS85 - 18cM - (DXS16, DXS43) - 13cM - DXS41 - 5cM -DXS28. This gave a multipoint lod score of 3.41 for a localisation in Xp22.2-p22.1, between DXS43 and DXS41.

Maternal trace elements, vitamin B12, vitamin A, folic acid, and fetal malformations.

The demonstrated teratogenicity of maternal zinc deficiency in rats has led to burgeoning interest in zinc and other trace elements as important factors in embryonic development. Levels of zinc, copper, manganese, magnesium, folic acid, vitamin B12 and vitamin A were evaluated at the beginning of pregnancy in the plasma of pregnant women who later delivered a malformed newborn. Fetal chromosomal anomalies and recognizable nonchromosomal syndromes were excluded. The results were compared to control women who delivered normal babies. One hundred seventy mothers had malformed children. The more frequent congenital malformations were congenital heart diseases (72 cases including 24 VSD), musculoskeletal malformations (21 cases), urogenital malformations (23 cases), spina bifida (6 cases), hydrocephaly (6 cases), and labial cleft (14 cases). Maternal plasma concentrations of zinc, copper, magnesium, manganese, folate, vitamin B12, and vitamin A of malformed children did not differ from controls. Thus vitamin profiles do not form a suitable means for identifying women at risk for having a child with congenital malformations.

Oto-palato-digital syndrome type II.

We report a patient with a sporadic case of oto-palato-digital (OPD) syndrome type II. Parents and five previous sibs are normal. At 26 years of age the patient had conductive hearing impairment, cleft palate, a prominent forehead, a flat facies, and a broad nasal base resulting in the characteristic "pugilistic" appearance. Extension and supination were limited at the elbows; thumbs and halluces were broad. Many radiological abnormalities were noted: malformations of the cervical spine, pelvic abnormalities, bilateral coxa valga, genu valgum, small fibulae, pes equino varus, and 15 carpal bones. IQ improved dramatically from 65 to 95.

A boy with neurofibromatosis 1 and Poland anomaly.

Von Recklinghausen neurofibromatosis (NF1) is one of the most common autosomal dominant disorders and has one of the highest mutation rates of a single human locus. The NF1 gene has recently been mapped to proximal 17q. Poland anomaly consists of the combination of unilateral aplasia of the sternal head of the pectoralis major muscle and an ipsilateral anomaly of the hand. Although other defects may occur in patients with Poland anomaly, neurofibromatosis 1 has not been reported. We have seen a boy with these two disorders.

Brachydactyly type E in two sibs with increased bone density and mental retardation. A new autosomal recessive syndrome?

Brachydactyly type E in two sibs with increased bone density and mental retardation. A new autosomal recessive syndrome?: We report on two sibs, a boy and a girl, with syndromic brachydactyly type E. Parents were first cousins. Facial dysmorphia was characterized by a flat occiput, a large forehead, hypertelorism, a long triangular nose, an everted lower lip, downslanting palpebral fissures and strabismus. They had marked shortening of the third, fourth and fifth fingers and of the third, fourth, and fifth toes. IQ was 16 in the boy, 63 in the girl. In both sibs ophtalmologic examination showed strabismus, absence of cataract and normal fundus and radiological findings disclosed increased bone density involving the skull, the vertebrae and the corticalis of the long bones. Neither ectopic calcifications, nor exostosic, nor osteomalacia, and nor osteotis fibrosa cystica were present. Investigations revealed that plasma calcium, phosphate, vitamine D, parathyroid hormone (PTH), response to exogenous PTH, and Gs activity were normal as well as renal and thyroid function. Molecular genetic studies failed to identify mutations in the GNAS 1 gene, in the PTH receptor gene and in the HOX D13 gene. Analysis of 2q showed that there was no deletion 2q37. Other known syndromes with brachydactyly type E and mental retardation were excluded. In conclusion we suggest that these two sibs with a combination of brachydactyly, mental retardation and increased bone density have a specific autosomal recessive syndrome.