Isabella Mammi

Methimazole embryopathy: Delineation of the phenotype

We report on a further case of congenital anomalies in a child exposed to methimazole during the first trimester of pregnancy (from first to seventh gestational week), and define a specific malformation pattern related to prenatal methimazole exposure and consisting of choanal and esophageal atresia, scalp defects, minor facial anomalies and psychomotor delay.

Neurofibromatosis type 1 growth charts

Growth abnormalities such as macrocephaly and short stature have been described and are considered a consistent finding in neurofibromatosis type 1 (NF1), one of the most common autosomal dominant disorders in man. We present here a clinical study on the growth profile of a sample of NF1 patients collected through a population-based registry that covers three contiguous regions of North-East Italy (NEI-NF Registry). Auxometric traits of 528 NF1 patients have been measured with the aim of drawing growth charts for height, weight, and head circumference (OFC). Height velocity charts were based on a subset of 143 children who underwent multiple measurements. No differences in height were apparent between NF1 and normal subjects up to age 7 (girls) and 12 (boys) years; subsequently, the 50th centile of NF1 subjects tends to overlap with the 25th centile of normal subjects, and the 3rd centile is much lower in NF1 subjects than in normal subjects, mainly during adolescence. The negatively skewed distribution of height seems to indicate that height growth impairment affects only a proportion of NF1 subjects; height growth impairment does not seem related to disease severity. As for weight, our data suggest that slight overweight is a characteristic of adult NF1 subjects (mainly among males), independent of disease severity. Height growth velocity is normal during childhood for both sexes, whereas the pubertal spurt is slightly anticipated and reduced in NF1 boys but not in girls. Our data confirm previous observations that macrocrania affects most NF1 subjects; the shape of the head growth curve is similar in NF1 and normal girls, whereas NF1 boys present an OFC pubertal growth spurt much more pronounced and delayed than normal boys. The disproportion between OFC and height seems to be related to disease severity in boys but not in girls. Growth charts presented here can be useful in neurofibromatosis clinics for the identification of the effects of secondary growth disorders, for growth prognosis, and for the evaluation of the effects of a therapy such as GH therapy after radiotherapy for optic glioma.

NANS-mediated synthesis of sialic acid is required for brain and skeletal development

We identified biallelic mutations in NANS, the gene encoding the synthase for N-acetylneuraminic acid (NeuNAc; sialic acid), in nine individuals with infantile-onset severe developmental delay and skeletal dysplasia. Patient body fluids showed an elevation in N-acetyl-D-mannosamine levels, and patient-derived fibroblasts had reduced NANS activity and were unable to incorporate sialic acid precursors into sialylated glycoproteins. Knockdown of nansa in zebrafish embryos resulted in abnormal skeletal development, and exogenously added sialic acid partially rescued the skeletal phenotype. Thus, NANS-mediated synthesis of sialic acid is required for early brain development and skeletal growth. Normal sialylation of plasma proteins was observed in spite of NANS deficiency. Exploration of endogenous synthesis, nutritional absorption, and rescue pathways for sialic acid in different tissues and developmental phases is warranted to design therapeutic strategies to counteract NANS deficiency and to shed light on sialic acid metabolism and its implications for human nutrition.

Vertebral and spinal cavernous angiomas associated with familial cerebral cavernous malformation.

BACKGROUND Cerebral cavernous malformations are vascular malformations that affect the CNS and have been associated with cutaneous, retinal, and hepatic lesions. Until now, vertebral hemangiomas associated with CCM have been described only in one case. The coexistence of intracranial and spinal cavernous angiomas in familial CCM is extremely rare. In addition to previous studies, the occurrence of spinal, vertebral, and cutaneous cavernous angiomas is now described in different members of a large family with CCM. CASE DESCRIPTION Our study reports a previously described family (IFCAS-07) with 12 members affected by autosomal dominant cavernous angiomas: 11 had CCM either alone or associated with hepatic or retinal angiomas, and one had only hepatic angioma. In all 11 members affected by CCM, the mutation of CCM1 gene was detected. During the follow-up, 8 subjects underwent a spinal MRI: 2 because they were symptomatic (thoracic paresthesias, enuresis, back pain) and 6 as a screening examination. Spinal MRI showed in 5 subjects spinal cavernous angiomas either alone or associated with vertebral hemangiomas. CONCLUSIONS To our knowledge, this is the largest family reported with different subjects affected by CCM associated with multiple cavernous angiomas throughout (brain and spinal cord) and besides (retina, skin, liver, and vertebral column) the CNS. Comprehensive care of patients with familial CCM includes screening of all the tissues that can be affected and appropriate management by specialists. We emphasize the importance of spinal MRI in the diagnosis of spinal and vertebral cavernous angiomas in all patients affected by familial CCM.

Epilepsy in Mowat-Wilson syndrome: delineation of the electroclinical phenotype.

Mowat–Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene and is characterized by distinctive facial features, epilepsy, moderate to severe intellectual disability, corpus callosum abnormalities and other congenital malformations. Epilepsy is considered a main manifestation of the syndrome, with a prevalence of about 70–75%. In order to delineate the electroclinical phenotype of epilepsy in MWS, we investigated epilepsy onset and evolution, including seizure types, EEG features, and response to anti‐epileptic therapies in 22 patients with genetically confirmed MWS. Onset of seizures occurred at a median age of 14.5 months (range: 1–108 months). The main seizure types were focal and atypical absence seizures. In all patients the first seizure was a focal seizure, often precipitated by fever. The semiology was variable, including hypomotor, versive, or focal clonic manifestations; frequency ranged from daily to sporadic. Focal seizures were more frequent during drowsiness and sleep. In 13 patients, atypical absence seizures appeared later in the course of the disease, usually after the age of 4 years. Epilepsy was usually quite difficult to treat: seizure freedom was achieved in nine out of the 20 treated patients. At epilepsy onset, the EEGs were normal or showed only mild slowing of background activity. During follow‐up, irregular, diffuse frontally dominant and occasionally asymmetric spike and waves discharges were seen in most patients. Sleep markedly activated these abnormalities, resulting in continuous or near‐to‐continuous spike and wave activity during slow wave sleep. Slowing of background activity and poverty of physiological sleep features were seen in most patients. Our data suggest that a distinct electroclinical phenotype, characterized by focal and atypical absence seizures, often preceded by febrile seizures, and age‐dependent EEG changes, can be recognized in most patients with MWS.

The role of MYH gene in genetic predisposition to colorectal cancer: Another piece of the puzzle

Biallelic germline mutations in the MYH gene cause MYH-Associated Polyposis but patients with a single mutation possibly have an increased colorectal cancer (CRC) risk. Using DNA from consecutive CRC patients we carried out a case-control study, with the aim to contribute data on the Italian population. Genotyping of four MYH mutations found two biallelic and two monoallelic carriers among 439 cases, and only one heterozygous individual among 247 age-matched controls. The frequencies of the mutant alleles were 0.68% (6/878) and 0.20% (1/494), respectively. These differences were not statistically significant. Results on the monoallelic carriers were combined with those from 11 studies on other populations, and the risk of developing a CRC was estimated with an OR=1.11 (95% CI=0.90; 1.36), yet not reaching a significant evidence of increased CRC risk.

Mutation producing alternative splicing of exon 26 in the COL1A2 gene causes type IV osteogenesis imperfecta with intrafamilial clinical variability.

We have characterized a familial form of osteogenesis imperfecta (OI). Following the identification by ultrasound of short limbs and multiple fractures in a fetus at 25 weeks of gestation, the family was referred with a provisional diagnosis of severe OI. We detected subtle clinical and radiological signs of OI in the father and in the paternal grandmother of the proposita, who had never received a diagnosis of OI. Linkage analysis indicated COL1A2 as the disease locus. Heteroduplex analysis of reverse transcription-polymerase chain reaction (RT-PCR) amplification products of pro alpha2(I) mRNA from an affected member and subsequent sequencing of the candidate region demonstrated the presence of normal transcripts and a minority of transcripts lacking exon 26 (54 bp) of COL1A2. Sequencing of PCR-amplified genomic DNA identified an A --> G transition in the moderately conserved +3 position of the IVS 26 donor splice site. The mutant pre-mRNA molecules were alternatively spliced, yielding both full-length and deleted transcripts that represented less than 30% of the total pro alpha2(I) mRNA. The biochemical data on type I collagen synthesized by dermal fibroblasts showed intracellular retention of the mutant protein; failure to detect the shortened alpha2(I) chains either in the medium or in the cell layer may be the consequence of their instability at physiological temperature. These observations justified the mild resulting phenotype.

Familial cerebral, hepatic, and retinal cavernous angiomas: a new syndrome

New, non-invasive neuroradiological techniques [computed tomography (CT) and magnetic resonance (MR)] have led to reassessment of the incidence of cavernous angioma of the brain (CCA), which is sometimes multiple and associated with cavernomas in other organs. CCA is known to be familial, with dominant autosomal transmission. This paper concerns a family with multiple CCA, sometimes in association with liver angiomas, in ten members belonging to four different generations. These malformations can vary in clinical expression: no neurological symptoms have been detected in subjects from the first or second generations, but they were found in adult age in subjects from the third generation; two fourth-generation patients came under our observation at 2.5 years of age. Symptoms include partial epileptic fits, which sometimes become generalized later and which are generally controlled adequately by therapy. Patients also present paresthesia and occasional motor deficiencies corresponding to CCA bleeding episodes; these symptoms have always abated with medical treatment alone. None of the patients are mentally retarded or restricted in their daily lives. Neuroradiological investigations (CT, MR, angiography) reveal typical multiple brain lesions in all patients. Given the first-generation patients clinical history of symptomatic hepatomegaly and the postmortem finding of multiple liver and brain cavernomas, liver ultrasonography was performed on all members of the family. Liver angioma was detected in two subjects from the second and third generations. Retinal angioma was detected in one patient with quadrantanopsia. (a) This association of brain, liver and retinal angiomas had not been reported in the past; (b) the significant radiological findings contrast sharply with the relatively benign clinical picture; and (c) expression of the disease varies in consecutive generations, with an increasingly early onset. The authors emphasize the need for neuroradiological studies using CT and MR, liver ultrasonography, ophthalmologic evaluation, and genetic evaluation for CCA patients and their relations.

A spectrum of LMX1B mutations in Nail-Patella syndrome: New point mutations, deletion, and evidence of mosaicism in unaffected parents

Purpose: Nail-Patella syndrome (MIM 161200) is a rare autosomal dominant disorder characterized by hypoplastic or absent patellae, dystrophic nails, dysplasia of the elbows, and iliac horn. In 40% of cases, a glomerular defect is present and, less frequently, ocular damage is observed. Inter- and intrafamilial variable expressivity of the clinical phenotype is a common finding. Mutations in the human LMX1B gene have been demonstrated to be responsible for Nail-Patella syndrome in around 80% of cases.Methods: Standard polymerase chain reaction and sequencing methods were used for mutation and single nucleotide polymorphism identification and control of cloned sequences. Array-CGH (Agilent, 244A Kit) was used for detection of deletions. Standard cloning techniques and the Snapshot method were used for analysis of mosaicism.Results: In this study, we present the results of LMX1B screening of 20 Nail-Patella syndrome patients. The molecular defect was found in 17 patients. We report five novel mutations and a ∼2 Mb deletion in chromosome 9q encompassing the entire LMX1B gene in a patient with a complex phenotype. We present evidence of somatic mosaicism in unaffected parents in two cases, which, to our knowledge, are the first reported cases of inheritance of a mutated LMX1B allele in Nail-Patella syndrome patients from a mosaic parent.Conclusion: The study of the described case series provides some original observations in an “old” genetic disorder.

Family with branchial arch anomalies, hearing loss, ear and commissural lip pits, and rib anomalies. A new autosomal recessive condition : Branchio-oto-costal syndrome?

We report on a family in which 3 sibs were affected with conductive deafness, bilateral preauricular and commissural lip pits, monolateral branchial fistula, and rib anomalies. On the basis of parental consanguinity, lack of clinical variability and affected subjects of both sexes, this condition seems to be inherited as an autosomal recessive trait. We suggest that these findings comprise a new autosomal recessive entity of branchial, auricular and costal anomalies, for which we suggest the acronym BOC (branchio-oto-costal) syndrome.