Calloso-adreno-scrotal agenesis associated with biallelic MAPK-activating death domain protein (MADD) variant: Further phenotypic delineation of MADD deficiency.

MAPK-activating death domain protein (MADD) deficiency is associated with a broad clinical spectrum ranging from mild developmental impairment to fatal multisystem disorder. We report an additional case of severe form with some overlapping and unreported systemic features in a growth-restricted full-term male newborn. The novel findings include corpus callosum agenesis, bilateral adrenal agenesis, scrotal aplasia, and abnormal skin pigmentation. Microscopic changes are only remarkable in thyroid gland that shows decreased, variously sized follicles with absent or non-vacuolated pale colloid. This unique constellation of birth defects is associated with a novel homozygous in-frame MADD gene deletion (NM_003682.4: c.4853_4855delGCT:p.Cys1618del). This case report expands the phenotypic and genetic spectrum of MADD deficiency.

A novel homozygous variant in ATL1 associated with early onset spastic paraplegia 3A: Further evidence for autosomal recessive inheritance.

Spastic paraplegia 3A (SPG3A) has long been considered as an autosomal dominant disorder till the report in 2014 and 2016 of two consanguineous Arabic families, showing that ATL1 mutations may cause autosomal recessive paraplegia. Here, a third report of a consanguineous Arabic family with recessive SPG3A is described. Exome sequencing reveals homozygosity for a novel likely pathogenic ATL1 splice donor variant (c.522+1G>T) in an affected 5-year-old infant whereas the parents, heterozygous carriers, are asymptomatic. The infant's phenotype is consistent with an early onset complicated SPG3A with severe progressive spasticity of the lower limbs and intellectual disability.

CLPB Deficiency Associated Neonatal Cavitating Leukoencephalopathy: A Potential Pathomechanism Underlying Neurologic Disorder.

Caseinolytic peptidase B homolog (CLPB) is a mitochondrial protein which is highly expressed in brain. Its deficiency may be associated with severe neonatal encephalopathy. This report describes a case of fatal neonatal encephalopathy associated with biallelic stop-gain mutation in CLPB (NM_001258392.3:c.1159C>T/p.Arg387*). Neurologic disorder encompasses pre- and post-natal features including polyhydramnios, intrauterine growth restriction, respiratory insufficiency, lethargy, excessive startle reflex, generalized hypertonia, and epileptic seizures. Brain macroscopic examination demonstrates frontal severe periventricular cystic leukoencephalopathy, along with mild ex-vacuo tri-ventricular dilatation. The most striking immunohistopathologic features are striato-thalamic neurodegeneration and deep white matter loss associated with strong reactive astrogliosis. This report supports that CLPB deficiency should be considered among the neurometabolic disorders associated with severe prenatal-onset neurologic impairment that may result from cystic leukoencephalopathy.

Severe Ciliopathy-Like Phenotype in an Infant With a Novel MPDU1 Missense Variant.

Congenital disorders of glycosylation (CDG) are associated with ciliary dysfunction due to altered glycosylation of ciliary glycoproteins. We describe a severe ciliopathy-like phenotype in a female infant associated with a novel homozygous missense variant NM_004870.4(MPDU1):c.503G>A/p.Gly168Glu. Our findings, based on the co-segregation of the variant with the phenotype and in-silico analysis, implicate this MPDU1 missense variant in this disorder. Matched phenotype includes symmetric growth restriction, facial dysmorphism, ichthyosis, hepatomegaly with severe duct plate malformation, renal cortical tubular and glomerular cysts, moderate cerebral tetraventricular dilatation, and severe pontocerebellar hypoplasia. According to this observation, CDG should be included in the workup of infantile ciliopathy-like disorder.

A severe clinicopathologic phenotype of RAF1 Ser257Leu neomutation in a preterm infant without cardiac anomaly.

Phenotype analysis of the Noonan syndrome (NS) related to RAF1 mutations demonstrates that a high proportion of cases exhibit severe lymphatic dysplasia and congenital heart disease, especially hypertrophic cardiomyopathy. Because of the difficulty of fetal phenotypic assessment, the percentage of cases with multisystemic prenatal presentation as well as the phenotypic variability may be underestimated. We describe a 35 weeks male preterm infant presenting with de novo missense mutation NM_002880.4(RAF1):c.770C>T (p.Ser257Leu), whose death occurred following birth. Antenatal ultrasound showed polyhydramnios, severe ascites, and tongue protrusion. Autopsy revealed multiple congenital anomalies including intrauterine growth restriction, hydrops fetalis, characteristic facial dysmorphia, short and webbed neck, hypertrichosis, severe lungs hypoplasia, thymic hyperplasia, hepato-splenomegaly, bilateral mild uretero-hydronephrosis, and mild pontocerebellar hypoplasia. Histology revealed increased hepatic hematopoiesis and iron deposits. This report confirms that NS may be associated with multisystem involvement and provides further evidence for the wide phenotypic variability associated with RAF1 variants.

Value of Placental Examination in the Diagnostic Evaluation of Stillbirth.

ObjectiveThe aim was to assess the contribution of placental examination in the etiologic investigation of stillbirth. Materials and Methods: A retrospective review of stillbirths that occurred after 14 weeks gestation was conducted for a one-year period. Twin pregnancies and fetuses without placentas were excluded. According to the fetoplacental examination, stillbirths were classified into etiologic groups. Results: A total of 147 stillbirths were selected. They were associated with placental, materno-fetal, fetal and multiple causes in 89 cases (61%), 23 cases (16%), 14 cases (9%) and 13 cases (9%), respectively. Unexplained stillbirths were observed in 8 cases (5%). Placental abnormalities were identified in 132/147 cases (90%). They were consistent with vascular, inflammatory and developmental lesions in 82/132 cases (61%), 28/132 cases (21%) and 18/132 cases (13%), respectively. Conclusion: Placental lesions were the main causes of stillbirth and were predominantly of vascular type including chronic villous hypoxia-ischemia and funicular anomalies.

Fetal Skeletal Dysplasias: Radiologic-Pathologic Classification of 72 Cases.

ObjectiveThe aim of this study was to classify the fetal skeletal dysplasias (FSD) in a series of affected fetuses based on radio-pathologic criteria. Materials and methods: We gathered clinicopathologic data of 72 cases which were diagnosed among 5995 autopsies performed over a 8-year period. Results: The prevalence of FSD was 1.2:100 autopsies. The overall sex ratio (M:F) was 1.25. Gestational age was between 17 and 24 weeks in 60% of cases. The FSD were classified into 13 distinct pathologic groups. Four major groups were identified: (1) Osteogenesis imperfecta (21 cases, 29%); (2) FGFR3 chondrodysplasia (18 cases, 25%); (3) Ciliopathies (9 cases, 12%); and (4) Sulfation disorders (7 cases, 10%). Thanatophoric dysplasia type 1 and lethal osteogenesis imperfecta were the most common skeletal dysplasias. Conclusion: Our study demonstrates the usefulness of the radio-pathologic examination in the diagnosis and accurate classification of the FSD, thus enabling better targeting of genetic counseling.

Luckenschadel Associated with Chiari Type II Malformation: An Autopsy Case Report.

Background Luckenschadel is commonly associated with Chiari II malformation and myelomeningocele. The aim of this case report was to revisit this entity. Case report: Antenatal imaging performed at 32 weeks gestation showed severe hydrocephalus with brain parenchymal thinning, cerebellar hypoplasia and lumbar myelomeningocele, suggestive of Chiari type II malformation. Stillbirth occurred before the pregnancy termination. X-rays showed a characteristic honeycomb appearance of the skull. The female 34-week-old stillborn was severely macerated and presented with thin and fenestrated skull, ruptured lumber myelomeningocele and diastematomyelia. Hydrocephalus could not be confirmed because of cerebral maceration. Histological examination did not reveal any significant visceral alteration. Conclusion: This case report highlights two key points. Luckenschadel should be kept in mind when Chiari II malformation is diagnosed. Autopsy with radiographic assessment is very useful in revealing this congenital defect which may escape prenatal detection.

Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is characterized by thickening of the ventricular muscle without dilation and is often associated with dominant pathogenic variants in cardiac sarcomeric protein genes. Here, we report a family with two infants diagnosed with infantile-onset HCM and mitral valve dysplasia that led to death before one year of age. Using exome sequencing, we discovered that one of the affected children had a homozygous frameshift variant in Myosin light chain 2 (MYL2:NM_000432.3:c.431_432delCT: p.Pro144Argfs*57;MYL2-fs), which alters the last 20 amino acids of the protein and is predicted to impact the most C-terminal of the three EF-hand domains in MYL2. The parents are unaffected heterozygous carriers of the variant and the variant is absent in control cohorts from gnomAD. The absence of the phenotype in carriers and the infantile presentation of severe HCM is in contrast to HCM associated with dominant MYL2 variants. Immunohistochemical analysis of the ventricular muscle of the deceased patient with the MYL2-fs variant showed a marked reduction of MYL2 expression compared to an unaffected control. In vitro overexpression studies further indicate that the MYL2-fs variant is actively degraded. In contrast, an HCM-associated missense variant (MYL2:p.Gly162Arg) and three other MYL2 stop-gain variants (p.E22*, p.K62*, p.E97*) that result in loss of the EF domains are stably expressed but show impaired localization. The degradation of the MYL2-fs can be rescued by inhibiting the cell's proteasome function supporting a post-translational effect of the variant. In vivo rescue experiments with a Drosophila MYL2-homolog (Mlc2) knockdown model indicate that neither the MYL2-fs nor the MYL2:p.Gly162Arg variant supports normal cardiac function. The tools that we have generated provide a rapid screening platform for functional assessment of variants of unknown significance in MYL2. Our study supports an autosomal recessive model of inheritance for MYL2 loss-of-function variants in infantile HCM and highlights the variant-specific molecular differences found in MYL2-associated cardiomyopathy.

Prenatal sonographic diagnosis of Dandy-Walker malformation and type III lissencephaly: A novel association.

Dandy-Walker malformation (DWM) may occur as part of Mendelian disorders such as Walker-Warburg and Meckel-Gruber syndromes. We report a novel association with type III lissencephaly in a 22-week male fetus. Ultrasound showed fetal akinesia deformation sequence, single umbilical artery, microlissencephaly, hydranencephaly with cerebral lamination, DWM, and pontocerebellar hypoplasia. These abnormalities were confirmed by magnetic resonance imaging and autopsy, which also revealed pulmonary and adrenal hypoplasia, common mesentery and bilateral uretero-pyelo-calyceal dilatation. Neuropathological examination showed brain calcifications and diffuse neuronal degeneration. We conclude that DWM may be a feature of type III lissencephaly and that this association can be easily diagnosed by ultrasound.

Fetal mediastinal teratoma: Misinterpretation as congenital cystic lesions of the lung on prenatal ultrasound.

Congenital mediastinal teratoma can lead to development of hydrops fetalis and may be misinterpreted on ultrasound. In this case report, ultrasound revealed severe fetoplacental hydrops, moderate posthemorrhagic hydrocephalus, and multiple pulmonary cysts suggesting cystic adenomatoid malformation and displacement of the heart to the left side. Autopsy of the hydropic 24-weeks male fetus showed a large cystic-solid mediastinal mass that was consistent with nonmetastatic immature teratoma. It also demonstrated thymic, cardiac and pulmonary hypoplasia, and confirmed the germinal matrix-intraventricular hemorrhage. Accurate prenatal diagnosis of mediastinal teratoma may be achieved by a careful Doppler ultrasound assessment that also allows evaluating the fetal outcome.

Femoral-facial syndrome: Report of 2 fetal cases.

Femoral-facial syndrome (FFS) is a congenital disorder, characterized by facial dysmorphism and femoral hypoplasia. We describe the prenatal ultrasound and autopsy findings of FFS in 2 female fetuses born to diabetic mothers. Prenatal ultrasound showed micrognathia, low-set dysplastic ears and very short femora. Autopsy also demonstrated cleft palate, hypoplastic genitalia and visceral malformations including interventricular communication and posthemorrhagic hydrocephalus. Histologic study showed hyperplasia of the islets of Langerhans and femoral cartilage abnormalities. The growth plate displayed poor columnar organization of the growth plate with small zones of chondrocyte hypertrophy. Our case reports and the previously published cases of FFS allow discussing the variable expression of this challenging condition, its strong association with maternal diabetes mellitus and the main differential diagnoses.

Congenital Large Cutaneous Hemangioma with Arteriovenous and Arterioarterial Malformations: A Novel Association.

BACKGROUND: Congenital cutaneous hemangioma is a benign vascular lesion that is a leading cause of severe hemodynamic compromise in a fetus when it is of significant size and especially in association with arteriovenous malformation. CASE REPORT: A large cutaneous hemangioma involving the right arm of a 32-week-old male fetus was complicated by fetal hypotrophy, hydrops fetalis and neonatal death. Axillary arteriovenous fistulas and bilateral arterial carotid-subclavian anastomosis were demonstrated at autopsy. Microscopically, the main tumor was a mixed capillary-cavernous hemangioma with vascular channels lined by CD31-positive and GLUT1/Ki-67-negative endothelial cells. CONCLUSION: Congenital hemangioma can be associated with vascular malformations, and that associations with other vascular malformations may increase the morbidity/mortality.

Hemochromatosis associated with cholelithiasis as a cause of hydrops fetalis and stillbirth: Prenatal diagnosis.

Prenatal diagnosis of neonatal hemochromatosis (NH) is usually raised in front of fetal hepatomegaly and heterogeneous liver architecture. We describe a novel sonographic feature that may be associated with NH. Ultrasound demonstrated reticulonodular liver and distended gallbladder with multiple gallstones in a hydropic fetus. These abnormalities were confirmed to be consistent with NH after correlation with autopsy findings. This case report highlights the value of cholelithiasis in clinical suspicion of NH and the importance to consider this sonographic feature when the liver has abnormal texture.

Fetal Cerebral Ventricular Dilatation: Etiopathogenic Study of 130 Observations.

BACKGROUND: Fetal cerebral ventricular dilatation (CVD) is a common abnormal prenatal finding that often predicts a poor prognosis. The etiology involves both genetic and nongenetic factors with diverse pathogenic mechanisms. We describe the neuropathological features of CVD in a large cohort of fetuses. The goals are to determine the physiopathological mechanisms and etiologies. METHODS: We retrospectively analyzed a series of 130 fetuses examined at the Necker University Hospital following termination of pregnancy between January 2000 and December 2014. Chiari II and Dandy-Walker malformations were excluded from our study population. Karyotype and/or array comparative genomic hybridization were performed in all cases. Targeted Sanger sequencing or next generation sequencing were carried out in 34 and 5 cases, respectively. RESULTS: We distinguished four groups of pathological entities: (1) midbrain/hindbrain patterning defects (54 cases, 42%), mainly related to aqueduct of Sylvius anomalies (atresia or stenosis); (2) cerebral cytoarchitectonic disorders (16 cases, 12%), essentially resulting from arachnoidal neuroglial ectopia; (3) hemorrhagic and perfusion failure (42 cases, 32%); and (4) nonspecific CVD (18 cases, 14%), without apparent obstruction, cortical malformation, or clastic injury. Although the pathogenic mechanisms of CVD were identified in 86% of cases, the causes, both acquired and genetic, were recognized in 21% of cases only. CONCLUSION: The neuropathological analysis is a powerful tool in the diagnosis of the fetal CVD pathogenic mechanisms and to identify homogeneous groups. The paucity of molecular diagnosis, notably in the major groups of midbrain/hindbrain patterning defects and hemorrhagic and perfusion failure, highlights the needs of future research to improve our current knowledge on CVD causes. Birth Defects Research 109:1586-1595, 2017. © 2017 Wiley Periodicals, Inc.

Triple negative breast cancer: A clinico-epidemiological and histopronostic study of 90 cases.

PURPOSE: The aim of this study was to describe the clinico-epidemiological and histopronostic characteristics of triple negative breast cancer (TNBC) and to evaluate the therapeutic results in tunisian women. METHODS: We reported the results of a retrospective study including 90 patients treated for TNBC between Junuary 2008 and December 2009 in the Salah Azaiz Institute of Tunis. RESULTS: TNBCoccured in 14% of diagnosed breast cancers. The mean age at diagnosis was 53.67 years. Family history of breast cancer was reported in 10% of cases.The majority of tumors were classified as T2 (41%) and associated with invasive ductal carcinoma histological type (99%) and SBR grade-II (54%). Tumor lymph node metastases were detected in 44% of patients.Among operated patients, 46% of patients underwent conservative surgery and 54% radical surgery. Chemotherapy and postoperative radiotherapy were given in97% and 80%of patients, respectively. After a median follow-up of 33.51 months, 61% of patients remained free of disease, 12% hadloco-regional recurrence, 9% had disease progression during chemotherapy and 21% developed systemic disease. CONCLUSION: TNBC diagnosis is often made in the advanced stage and has a tendency to recur after treatment. The variable responseto chemotherapy is due to the molecular tumor heterogeneity. The development of targeted therapies is necessary to improve outcome of chemoresistant TNBC.

[Neu-Laxova syndrome: Three case reports and a review of the literature]. / Syndrome de Neu-Laxova : rapport de trois cas et revue de la littérature.

INTRODUCTION: The Neu-Laxova syndrome (NLS) is a rare autosomal recessive and early lethal disorder. It is characterized by severe intra-uterine growth retardation, abnormal facial features, ichthyotic skin lesions and severe central nervous system malformations, especially microlissencephaly. Others characteristic features associated with fetal hypokinesia sequence, including arthrogryposis, subcutaneous edema and pulmonary hypoplasia, are frequently reported in NLS. PATIENTS AND METHODS: The clinicopathological characteristics of NLS are described in three cases with striking prenatal diagnostic findings and detailed post-mortem examinations. A review of the literature is undertaken with a focus on molecular basis. RESULTS: We present three new patients with NLS: one stillbirth male and two female newborns, delivered at 29, 35 and 40 weeks of gestational age, respectively. Characteristic ultrasound findings included hydramnios, severe intra-uterine growth restriction, craniofacial and cental nervous system anomalies. The cytogenetic study, performed in one case, was normal. The post-mortem examination revealed characteristic abnormalities in all three cases, that allowed to make a prompt diagnosis of the NLS. Data from these patients suggest that the NLS represents a heterogeneous phenotype. This feature has been highlighted in the literature. CONCLUSION: The SNL is a lethal developmental disorder characterized by phenotypic heterogeneity with striking neurological defects. It is underpinned by genetic heterogeneity. It can be caused by mutations in all three genes involved in de novo L-serine biosynthesis: PHGDH, PSAT1 and PSPH. Hence, the NLS constitutes the most severe end of already known human disease, i.e. serine-deficiency disorder.

Light chain nephropathy.

Light chain deposition disease (LCDD) is characterized by the tissue deposition of monotypic immunoglobulin light chains of either kappa or lambda isotype. It is the archetypal systemic disease that is most frequently diagnosed on a kidney biopsy, although the deposits may involve several other organs. This brief review focuses on the clinicopathological features of LCDD-associated nephropathy with an emphasis on the diagnostic and therapeutic difficulties related to this elusive condition.

Light-chain deposition disease of the kidney: a case report.

A 41-year-old man was admitted for evaluation of nephrotic syndrome associated with microhematuria, hypertension, and moderate renal failure. In serum and urine samples, monoclonal IgG-lambda was detected. Bone marrow examination showed normal representation of all cell lines with normal range of plasma cells. Renal biopsy demonstrated diabetes-like nodular glomerulosclerosis. Immunofluorescence failed to demonstrate the presence of kappa or lambda light chains in the kidney. Electron microcopy showed granular electron-dense deposits along the glomerular basement membranes and in the mesangial nodules. The patient was diagnosed as having light-chain deposition disease (LCDD) without evidence of plasma cell dyscrasia. This report was designed to stress the significant challenges that remain in the diagnosis of LCDD-related glomerulopathy. The salient morphological features that help in making an accurate diagnosis are discussed.