Molecular, clinical and neuropsychological study in 31 patients with Kabuki syndrome and KMT2D mutations.

Kabuki syndrome (KS-OMIM 147920) is a rare developmental disease characterized by the association of multiple congenital anomalies and intellectual disability. This study aimed to investigate intellectual performance in children with KS and link the performance to several clinical features and molecular data. We recruited 31 children with KMT2D mutations who were 6 to 16 years old. They all completed the Weschler Intelligence Scale for Children, fourth edition. We calculated all indexes: the Full Scale Intellectual Quotient (FSIQ), Verbal Comprehension Index (VCI), Perceptive Reasoning Index (PRI), Processing Speed Index (PSI), and Working Memory Index (WMI). In addition, molecular data and several clinical symptoms were studied. FSIQ and VCI scores were 10 points lower for patients with a truncating mutation than other types of mutations. In addition, scores for FSIQ, VCI and PRI were lower for children with visual impairment than normal vision. We also identified a discrepancy in indexes characterized by high WMI and VCI and low PRI and PSI. We emphasize the importance of early identification and intensive care of visual disorders in patients with KS and recommend individual assessment of intellectual profile.

Fetal phenotypes in otopalatodigital spectrum disorders.

Otopalatodigital spectrum disorders (OPDSD) include OPD syndromes types 1 and type 2 (OPD1, OPD2), Melnick-Needles syndrome (MNS), and frontometaphyseal dysplasia (FMD). These conditions are clinically characterized by variable skeletal dysplasia associated in males, with extra-skeletal features including brain malformations, cleft palate, cardiac anomalies, omphalocele and obstructive uropathy. Mutations in the FLNA gene have been reported in most FMD and OPD2 cases and in all instances of typical OPD1 and MNS. Here, we report a series of 10 fetuses and a neonatally deceased newborn displaying a multiple congenital anomalies syndrome suggestive of OPDSD and in whom we performed FLNA analysis. We found a global mutation rate of 44%. This series allows expanding the clinical and FLNA mutational spectrum in OPDSD. However, we emphasize difficulties to correctly discriminate OPDSD based on clinical criteria in fetuses due to the major overlap between these conditions. Molecular analyses may help pathologists to refine clinical diagnosis according to the type and the location of FLNA mutations. Discriminating the type of OPDSD is of importance in order to improve the genetic counseling to provide to families.

Involvement and alteration of the Sonic Hedgehog pathway is associated with decreased cholesterol level in trisomy 18 and SLO amniocytes.

BACKGROUND: Trisomy 18 and Smith-Lemli-Opitz syndrome are two polymalformative conditions in which a cholesterol defect has been noted. When they occur prenatally, they are associated with a decreased maternal unconjugated estriol (uE(3)) level. Cholesterol plays an essential role in the Sonic Hedgehog pathway, allowing Shh protein maturation leading to its maximal activity. Many malformations in these two syndromes occur in Shh dependent tissues. We thus sought to assess whether a cholesterol defect could affect the Shh pathway and explain some of the observed malformations. MATERIALS AND METHODS: We selected 14 cases of trisomy 18 and 3 cases of SLO in which the maternal uE(3) level was decreased and reported malformations were observed after fetopathological examination. We correlated the number of malformations with maternal uE(3) level. We then carried out cholesterol concentrations in separate culture media consisting of trisomy 18, SLO and control amniocytes. Finally, we analyzed the Shh pathway by testing the gene expression of several Shh components: GLI transcription factors, BMP2, BMP4, TGFß1, COL1A1 and COL1A2. RESULTS AND DISCUSSION: There was an inverse correlation between phenotypic severity and maternal uE(3) levels in SLO and trisomy 18. The cholesterol levels in the amniocyte culture media were correlated with maternal uE3 levels and were significantly lower in T18 and SLO amniocytes, reflecting cholesterol defects. There was an alteration in the Shh pathway since expression of several genes was decreased in T18 and SLO amniocytes. However, these cholesterol defects were not solely responsible for the altered Shh pathway and the malformations observed.

Deep intronic KRIT1 mutation in a family with clinically silent multiple cerebral cavernous malformations.

Loss-of-function mutations in CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10 genes are identified in the vast majority of familial cases with multiple cerebral cavernous malformations (CCMs). However, genomic DNA sequencing combined to large rearrangement screening fails to detect a mutation in 5% of those cases. We report a family in which CCM lesions were discovered fortuitously because of the investigation of a developmental delay in a boy. Three members of the family on three generations had typical multiple CCM lesions and no clinical signs related to CCM. No mutation was detected using genomic DNA sequencing and quantitative multiplex PCR of short fluorescent fragments (QMPSF). cDNA sequencing showed a 99-nucleotide insertion between exons 5 and 6 of CCM1, resulting from a mutation located deep into intron 5 (c.262+132_262+133del) that activates a cryptic splice site. This pseudoexon leads to a premature stop codon. These data highly suggest that deep intronic mutations explain part of the incomplete mutation detection rate in CCM patients and underline the importance of analyzing the cDNA to provide comprehensive CCM diagnostic tests. This kind of mutation may be responsible for apparent sporadic presentations due to a reduced penetrance.

Pediatric outcome of children with the prenatal diagnosis of isolated septal agenesis.

BACKGROUND: Isolated Septal Agenesis (SA) is a rare disease with clinical outcomes (especially neurological outcomes) that are unknown. The purpose of this study was to evaluate the clinical outcome of these children. METHODS: We conducted a retrospective multicenter study of 17 children with an isolated SA or SA combined with a moderate ventricular dilatation (VD) that was diagnosed antenatally and confirmed by a magnetic resonance imaging (MRI) performed in the antenatal period. RESULTS: Of the 17 children, 14 had normal neurological examinations, 2 had language development delay and visuo-spatial dyspraxia, and 3 of the 17 children had behavioral problems. Eight children had neuropsychological evaluations, and the results were normal in six cases. There were 3 cases of septo-optic dysplasia (SOD) diagnosed postnatally, which highlighted the difficulties in assessing the optic tract and hypothalamic-pituitary region in antenatal imaging. Language delay and behavioral disorders were the main abnormalities at follow-up. CONCLUSION: The discovery of an isolated SA reveals the difficulties of prenatal diagnosis to correlate the neurological and functional prognosis to morphological findings. The prognosis seemed to be good. It appears necessary to improve the diagnostic performance of fetal brain imaging and to follow-up these children prospectively to assess their long-term cognitive-behavioral outcomes.

Progressive osseous heteroplasia: a model for the imprinting effects of GNAS inactivating mutations in humans.

CONTEXT: Heterozygous GNAS inactivating mutations are known to induce pseudohypoparathyroidism type 1a when maternally inherited and pseudopseudohypoparathyroidism when paternally inherited. Progressive osseous heteroplasia (POH) is a rare disease of ectopic bone formation, and studies in different families have shown that POH is also caused by paternally inherited GNAS mutations. OBJECTIVE: Our purpose was to characterize parental origin of the mutated allele in de novo cases of POH and to draw phenotype/genotype correlations according to maternal or paternal transmission of a same GNAS mutation. DESIGN AND SETTING: We conducted a retrospective study on patients addressed to our referral center for the rare diseases of calcium and phosphorus metabolism. PATIENTS AND METHODS: We matched 10 cases of POH with cases of pseudohypoparathyroidism type 1a carrying the same GNAS mutations. MAIN OUTCOME MEASURES: The parental origin of the mutated allele was studied using informative intragenic polymorphisms and subcloning of PCR products. RESULTS: Paternal origin of GNAS mutations was clearly demonstrated in eight POH cases including one patient with mutation in exon 1. Genotype/phenotype analyses suggest that there is no direct correlation between the ossifying process and the position of the inactivating GNAS mutation. It is, however, more severe in patients in whom origin of the mutation is paternal. Severe intrauterine growth retardation was clearly evidenced in paternally inherited mutations. CONCLUSIONS: Clinical heterogeneity makes genetic counseling a delicate matter, especially in which paternal inheritance is concerned because it can lead to either a mild expression of pseudopseudohypoparathyroidism or a severe expression of POH.

Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations.

OBJECTIVE: To determine the spectrum of clinical, neuropsychological, and neuroradiologic features in patients with autosomal recessive primary microcephaly (MCPH) due to ASPM gene mutations. METHODS: ASPM was sequenced in 52 unrelated MCPH probands. In patients with ASPM mutations, we evaluated the clinical phenotype, cognition, behavior, brain MRI, and family. RESULTS: We found homozygous or compound heterozygous ASPM loss-of-function mutations in 11 (22%) probands and 5 siblings. The probands harbored 18 different mutations, of which 16 were new. Microcephaly was severe after 1 year of age in all 16 patients, although in 4 patients the occipital-frontal circumference (OFC) at birth was decreased by only 2 SD. The OFC Z score consistently decreased after birth. Late-onset seizures occurred in 3 patients and significant pyramidal tract involvement in 1 patient. Intellectual quotients ranged from borderline-normal to severe mental retardation. Mild motor delay was noted in 7/16 patients. Language development was delayed in all patients older than 3 years. Brain MRI (n = 12) showed a simplified gyral pattern in 9 patients and several malformations including ventricle enlargement (n = 7), partial corpus callosum agenesis (n = 3), mild cerebellar hypoplasia (n = 1), focal cortical dysplasia (n = 1), and unilateral polymicrogyria (n = 1). Non-neurologic abnormalities consisted of short stature (n = 1), idiopathic premature puberty (n = 1), and renal dysplasia (n = 1). CONCLUSIONS: We provide a detailed description of features associated with ASPM mutations. Borderline microcephaly at birth, borderline-normal intellectual efficiency, and brain malformations can occur in ASPM-related primary hereditary microcephaly.

Embryology of neural tube defects: information provided by associated malformations.

OBJECTIVES: To get information about embryologic mechanisms of neural tube defects (NTD), by studying the associated malformations. METHODS: Eighty three cases of NTD, seen at the prenatal diagnosis unit of Rennes University Hospital (France) between May 1999 and December 2002, were retrospectively studied. Cases with chromosomal anomalies (5/83), cases without available karyotype or pathologic examination were excluded. 24 spina bifida, and 27 cephalic forms (anencephalies, exencephalies, and encephaloceles) were thus analyzed. RESULTS: Only 22/51 cases (43%) were strictly isolated NTD. Anomalies of tissues arising from neural crests were noted in 8/51 fetuses (16%), midline or lateralization anomalies in 12/51 (24%), and anomalies of mesoblastic tissues in 17/51 (33%). An already known syndrome was found in 4/51 cases (8%). CONCLUSION: NDT are more extensive congenital damages that would suggest the restrictive terminology. That prompts to assess cautiously prenatal diagnosis of NTD, and to get detailed pathological examination after termination of pregnancy.

[Pseudohypoparathyroidism or hypoparathyroidism? A misleading clinical presentation]. / Pseudohypoparathyroïdie ou hypoparathyroïdie?

We report the case of a 27-year old woman who presented hypocalcemia and hyperphosphoremia during her first pregnancy. Her phenotype was in favor of Albright's hereditary osteodystrophy: short stature, obesity, round face, brachymetacarpy and mental retardation. However, the diagnosis of pseudohypopara thyroidism type Ia was ruled out due to low PTH level (10 pg/ml). The patient's 22q11 microdeletion was suspected and identified because of the association of severe neonatal hypocalcemia, abnormal face and renal malformation in her children. Deletion 22q11 leads to various syndromes, including Di George syndrome, also referred to as CATCH 22 syndrome (Cardiac defect (C), Abnormal face (A), Thymic hypoplasia (T), Cleft palate (C) and Hypocalcemia (H)). Retrospectively, the patient presented with symptoms suggestive of CATCH 22: abnormal face, hypernasal voice suggestive of velopharyngeal insufficiency, mental retardation, recurrent otitis in childhood. It is also noteworthy that there was an idiopathic thrombocytopenic purpura. In conclusion, while the phenotype was suggestive of Albright's hereditary osteodystrophy, the constatation of a low PTH level would cast doubt on this diagnosis. Furthermore, the 22q11 microdeletion should be searched by FISH (Fluorescence In Situ Hybridization) in all patients with hypopara thyroidism of unknown origin, even in the absence of cardiac malformations. Finally, it seems that patients with CATCH 22 would be predisposed to auto-immune disease as a result of thymic dysfunction.

Molecular screening of the CFTR gene in men with anomalies of the vas deferens: identification of three novel mutations.

Many studies have shown that congenital absence of the vas deferens (CAVD) is a genital cystic fibrosis transmembrane conductance regulator (CFTR)-mediated phenotype, with a broad spectrum of abnormalities causing male infertility. The genotype of these patients includes mutations in the CFTR gene, e.g. DeltaDeltaF508, R117H and the T5 allele; all of which are commonly found in CAVD. In this study we have screened the entirety of CFTR gene in 47 males with anomalies of the vas deferens: 37 cases of congenital bilateral absence of the vas deferens, three cases of congenital unilateral absence of the vas deferens and seven cases of obstructive azoospermia with hypoplastic vas deferens. Among the 94 chromosomes studied, 65 mutations, of which three are novel (2789+2insA, L1227S, 4428insGA), were identified. The majority of patients (63.8%) had two detectable CFTR gene mutations. Furthermore, high frequencies of the DeltaDeltaF508 mutation (44.7%), the T5 allele (36.2%) and R117H mutation (19.1%) were observed.

Multi-minicore disease--searching for boundaries: phenotype analysis of 38 cases.

Multi-minicore disease (MmD) is a congenital myopathy morphologically defined by the presence of multiple small zones of sarcomeric disorganization and lack of oxidative activity ("minicores") in muscle fibers. The dinical expression of MmD is considered to be greatly variable, and the morphological lesions are nonspecific; therefore, its boundaries are poorly defined, and its molecular bases are not known. To better define the phenotypic characteristics of MmD, we analyzed a large series of 38 patients with multiple minicores in muscle fibers in the absence of any other potential cause. According to clinical features, 4 subgroups were identified. Most patients (30 cases) shared a common highly consistent phenotype marked by the axial predominance of muscle weakness and a high occurrence of severe respiratory insufficiency and scoliosis ("classical" form). Other forms were characterized by pharyngolaryngeal involvement and total lack of head control (2 cases), antenatal onset with arthrogryposis (3 cases), and slowly progressive weakness with marked hand amyotrophy (3 cases). Type 1 fiber predominance and hypotrophy as well as centrally located nuclei were found in every subgroup. MmD is thus phenotypically heterogeneous, but a typical recognizable phenotype does exist. This phenotype classification should be helpful when undertaking research into the molecular defects that cause MmD.

Gastric carcinoma in Sotos syndrome (cerebral gigantism).

We report the first case of the association of Sotos syndrome and gastric carcinoma (containing signet ring cells) in a twin patient. The other-probably monozygous-twin is also affected by the Sotos syndrome. The association of malign tumors in Sotos syndrome and other overgrowth syndromes is discussed.

Heterotaxy-neural tube defect and holoprosencephaly occuring independently in two sib fetuses.

We report on two sib fetuses, products of a consanguineous union, who had multiple and apparently unrelated malformations. The first fetus, a female, had trilobed lungs, a single cardiac ventricle, asplenia, situs ambiguus of the liver, and a lumbosacral meningomyelocele. The brain of this fetus was normal. The second fetus, a male, had bilobed lungs, a single cardiac ventricle, situs solitus of the abdominal organs and spleen, and a semilobar holoprosencephaly. The occurrence of these malformations in sibs of different sexes and the parental consanguinity suggest a recessive mutation in a gene responsible for both heterotaxy and midline defects, including holoprosencephaly.

Unusual fan shaped ossification in a female fetus with radiological features of boomerang dysplasia.

We report on a female fetus of 24 weeks whose clinical and radiological findings were compatible with boomerang dysplasia (BD). However, histopathology was unusual with a lateral fan shaped diaphyseal ossification. This has never been described either in typical atelosteogenesis I (AT-I) or in BD. The purpose of this report is to find out if this condition is a separate lethal bone dysplasia or another histological feature of the nosological group of AT-I and BD.

Central nervous system malformations and early end-stage renal disease in oro-facio-digital syndrome type I: a review.

Intracerebral cysts and porencephaly or arachnoid cysts are rarely but are repeatedly reported in orofaciodigital (OFD) syndrome type 1. We report on 2 families in which OFD syndrome type 1 was observed with central nervous system (CNS) malformations and 3 sporadic cases of OFD with CNS defects, most likely representing fresh mutations for OFD 1. In one case, vermis hypoplasia was present; in another, periventricular heterotopiae were noted. We review the literature on CNS anomalies in OFD syndromes and stress the difficulties in genetic counseling and functional prognosis for children of OFD 1 female carriers prenatally diagnosed with a malformation of the brain. As for CNS malformations, renal cystic disease is an often overlooked complication specific to OFD 1. In 1 family, cystic medullary disease was noted in OFD 1 carriers, leading 1 patient to dialysis by age 35 years and the other to severe renal insufficiency by age 28 years. Longitudinal follow-up of OFD 1 carriers should be performed, and renal function should be assessed in those with cysts because the functional prognosis of this developmental anomaly may be worse than usually reported in the literature.

Prenatal detection of a congenital pancreatic cyst and Beckwith-Wiedemann syndrome.

We report a case of congenital pancreatic cyst detected prenatally by ultrasound in a fetus with evidence for a diagnosis of Beckwith-Wiedemann syndrome (BWS). Neonatal hypoglycaemia was prevented. The cyst was managed by internal drainage. This is the second reported case of BWS associated with pancreatic cystic dysplasia and the first time that this association has been detected prenatally. Differential diagnosis of cystic abdominal lesions occurring in utero should take pancreatic cysts into consideration. This case suggests that pancreatic cysts should be included in the BWS phenotype.

[Spontaneous abortion of male fetuses with incontinentia pigmenti (apropos of a family)]. / L'interruption spontanée des grossesses de foetus mâles atteints dans l'incontinentia pigmenti (a propos d'une famille).

We report a family with incontinentia pigmenti. One affected woman had seven pregnancies, seven miscarriages; a prenatal diagnosis by molecular biology was undertaken in the last four cases (two males, two females). In the last two males, a miscarriage occurred at the beginning of the second trimester with cystic hygroma in a case. In the first two males a miscarriage was observed also at the beginning of the second trimester after chorionic biopsy or amniocentesis. These two miscarriages would not be a complication of prenatal diagnosis but spontaneous abortion of an affected male. The date of the miscarriage of affected males (the beginning of the second trimester) and the role of a cystic hygroma for the diagnosis of incontinentia pigmenti in this mother of a fetus karyotyped 46,XY are discussed.

Isolated X-linked thrombocytopenia in two unrelated families is associated with point mutations in the Wiskott-Aldrich syndrome protein gene.

The Wiskott-Aldrich syndrome (WAS) is characterized by defective platelet and lymphocyte function associated with eczema and increased susceptibility to malignancies. It is caused by mutations of the WAS protein-encoding gene (WASP). X-lined thrombocytopenia, defined by low platelet counts and volume, may be an allelic variant of WAS. In patients with XLT from two unrelated families, WASP gene defects were identified by single-strand conformational polymorphism and by sequencing. Point mutations in exon 2 of the WASP gene were found in the patients from both families in which XLT segregated. Several obligate heterozygote female members of these families display a random pattern of X inactivation in their peripheral blood leukocytes. This study shows that XLT may be caused by mutations of the WASP, thus representing an allelic variant of WAS.

[Reflections on 10 years of medically induced abortions in Ille-et-Vilaine]. / Réflexions sur 10 ans d'interruptions médicales de grossesse (IMG) en Ille-et-Vilaine.

The medical files of 532 patients who underwent medically induced abortion over a 10-year period (1982-1991) in the French department of Ille-et-Vilaine were studied in order to evaluate the indications and outcomes. Among the patients, 358 resided in the department (67%). Comparatively with the number of births during the 10-year period, there was a relative increase in the number of medically induced abortions from 3.5/1000 to 5.5/1000. This parameter was taken into consideration for the interpretation of a parallel decrease in the perinatal mortality during the same period, from 5.9/1000 to 5.1/1000. There was a maternal indication in 91 cases which correspond to the former category of therapeutic induced abortions. There was a clear increase in 1991 corresponding to abortions induced because of extremely premature rupture of the membranes which were formerly allowed to continue to dead births. Foetal indications were frequent: 441 cases (83%). Exogenous causes were lower (15.6%), particularly due to the disappearance of indications resulting from maternal irradiation. For indications related to infection, the vaccination against rubella and improved prenatal diagnosis resulted in the disappearance of rubella as an indication during the last three years of the study and a clear decrease in the number of toxoplasmosis indications. There were few indications due to maternal infection by human immunodeficiency virus (4 cases). Chromosomal abnormalities were the main cause of medically induced abortion among the foetal indications (27.7%).(ABSTRACT TRUNCATED AT 250 WORDS)