Alazami syndrome (MIM#615071) is a rare developmental disorder caused by biallelic variants in the LARP7 gene. Hallmark features include short stature, global developmental delay, and distinctive ...facial features. To date, 23 patients from 11 families have been reported in the literature. Here we describe a 19-year-old man who, in association with the typical features of Alazami syndrome, was diagnosed at the age of 14 years with papillary thyroid carcinoma, harboring the somatic BRAF V600E mutation. Whole exome sequencing revealed two novel LARP7 variants in compound heterozygosity, whereas only common variants were detected in genes associated with familial nonmedullary thyroid cancer (MIM#188550). LARP7 acts as a tumor suppressor in breast and gastric cancer, and possibly, according to recent studies, in thyroid tumors. Since thyroid cancer is rare among children and adolescents, we hypothesize that the LARP7 variants identified in our patient are responsible for both Alazami syndrome and tumor susceptibility. We also provide an overview of the clinical findings in all Alazami syndrome patients reported to date and discuss the possible pathogenetic mechanism that may underlie this condition, including the role of LARP7 in tumor susceptibility.
Microcephaly primary hereditary (MCPH) is a congenital disease characterized by nonsyndromic reduction in brain size due to impaired neurogenesis, often associated with a variable degree of ...intellectual disability (ID). The genetic etiology of MCPH is heterogeneous and comprises more than 20 loci, nearly all following a recessive inheritance pattern. The first causative gene identified,
or
, encodes a centrosomal protein that modulates chromosome condensation and cell cycle progression. It is also involved in DNA damage response and telomere maintenance in the nucleus. Despite numerous studies on
function, MCPH1-affected individuals are rare and the available clinical reports are not sufficient to define the natural history of the disease. Here, we present a novel patient with congenital microcephaly, ID, language delay, short stature, and other minor features such as strabismus. magnetic resonance imaging revealed ventriculomegaly, simplified gyral pattern in the frontal lobes, and a neuronal migration defect. Genetic testing detected a homozygous deletion of exons 1-8 of
. We compare the patients' characteristics with a list of features from MCPH1 cases described in the literature, in an effort to provide additional clues for a comprehensive definition of disease presentation and evolution.
We aimed to report on previously unappreciated clinical features associated with
-related intellectual disability (ID) syndrome, a rare neurodevelopmental disorder characterized by global ...developmental delay, intellectual disability, and language delay, with or without autistic features.
We performed whole-exome sequencing (WES) to molecularly characterize an individual presenting with ID, epilepsy, autism spectrum disorder, behavioral problems, and facial dysmorphisms as major features.
WES allowed us to identify a previously unreported
splice site variant, c.1429-1G>T (NM_032682.6), in the
gene (OMIM
605515) as the causative event underlying the phenotype. Clinical reassessment of the patient and revision of the literature allowed us to refine the phenotype associated with
haploinsufficiency, including hyperkinetic movement disorder and flat angiomas as associated features. Interestingly, the patient also has an asymmetric face and choanal atresia and a novel
variant of the
gene.
We suggest that
-related ID syndrome may also predispose to the development of hyperkinetic movement disorders and flat angiomas. These features could therefore require specific management of this condition.
Basel-Vanagaite-Smirin-Yosef syndrome (BVSYS) is an extremely rare autosomal recessive genetic disorder caused by variants in the
MED25
gene. It is characterized by severe developmental delay and ...variable craniofacial, neurological, ocular, and cardiac anomalies. Since 2015, through whole exome sequencing, 20 patients have been described with common clinical features and biallelic variants in
MED25
, leading to a better definition of the phenotype associated with BVSYS. We report two young sisters, born to consanguineous parents, presenting with intellectual disability, neurological findings, and dysmorphic features typical of BVSYS, and also with bilateral perisylvian polymicrogyria. The younger sister died at the age of 1 year without autoptic examination. Whole exome sequencing detected a homozygous frameshift variant in the
MED25
gene: NM_030973.3:c.1778_1779delAG, p.(Gln593Argfs). This report further delineates the most common clinical features of BVSYS and points to polymicrogyria as a distinctive neuroradiological feature of this syndrome.
Split Hand-Foot Malformation (SHFM) is a congenital limb defect characterized by a median cleft of the hands and/or feet due to the absence/hypoplasia of the central rays. It may occur as part of a ...syndromic condition or as an isolated malformation. The most common of the six genetic loci identified for this condition is correlated to SHFM1 and maps in the 7q21q22 region. SHFM1 is characterized by autosomal dominant transmission, incomplete penetrance and variable expressivity. Associated features often include hearing loss, intellectual disability/developmental delay and craniofacial abnormalities. Disruption of the DLX5/DLX6 genes, mapping within the SHFM1 locus, is now known to be responsible for the phenotype. Through SNP array, we analyzed a patient affected by SHFM1 associated with deafness and an abnormality of the inner ear (incomplete partition type I); we identified a deletion in 7q21, not involving the DLX5/6 genes, but including exons 15 and 17 of DYNC1I1, known to act as exonic enhancers (eExons) of the DLX5/6 genes. We further demonstrated the role of DYNC1I1 eExons in regulating DLX5/6 expression by means of showing a reduced expression of the DLX5/6 genes through RT-PCR in a patient-derived lymphoblastoid cell line. Furthermore, our data and a review of published cases do not support the hypothesis that DLX5/6 are imprinted in humans. This work is an example of how the disruption of regulatory elements can be responsible for congenital malformations.
Osteocraniostenosis (OCS, OMIM #602361) is a severe, usually lethal condition characterized by gracile bones with thin diaphyses, a cloverleaf-shaped skull and splenic hypo/aplasia. The condition is ...caused by heterozygous mutations in the
gene and is allelic to the non-lethal, dominant disorder Kenny-Caffey syndrome (KCS, OMIM #127000). Here we report two new cases of OCS, including one with a detailed pathological examination. We review the main diagnostic signs of OCS both before and after birth based on our observations and on the literature. We then review the current knowledge on the mutational spectrum of
associated with either OCS or KCS, including three novel variants, both from one of the OCS fetuses described here, and from further cases diagnosed at our centers. This report refines the previous knowledge on OCS and expands the mutational spectrum that results in either OCS or KCS.
The term "arthrogryposis" is used to indicate multiple congenital contractures affecting two or more areas of the body. Arthrogryposis is the consequence of an impairment of embryofetal neuromuscular ...function and development. The causes of arthrogryposis are multiple, and in newborns, it is difficult to predict the molecular defect as well as the clinical evolution just based on clinical findings. We studied a consecutive series of 13 participants who had amyoplasia, distal arthrogryposis (DA), or syndromic forms of arthrogryposis with normal intellectual development and other motor abilities. The underlying pathogenic variants were identified in 11 out of 13 participants. Correlating the genotype with the clinical features indicated that prenatal findings were specific for DA; this was helpful to identify familial cases, but features were non-specific for the involved gene. Perinatal clinical findings were similar among the participants, except for amyoplasia. Dilatation of the aortic root led to the diagnosis of Loeys-Dietz syndrome (LDS) in one case. The phenotype of DA type 5D (DA5D) and Escobar syndrome became more characteristic at later ages due to more pronounced pterygia. Follow-up indicated that DA type 1 (DA1)/DA type 2B (DA2B) spectrum and LDS had a more favorable course than the other forms. Hand clenching and talipes equinovarus/rocker bottom foot showed an improvement in all participants, and adducted thumb resolved in all forms except in amyoplasia. The combination of clinical evaluation with Next Generation Sequencing (NGS) analysis in the newborn may allow for an early diagnosis and, particularly in the DAs, suggests a favorable prognosis.
One of the recently described syndromes emerging from the massive study of cohorts of undiagnosed patients with autism spectrum disorders (ASD) and syndromic intellectual disability (ID) is ...White-Sutton syndrome (WHSUS) (MIM #616364), caused by variants in the
gene (MIM *614787), located on the long arm of chromosome 1 (1q21.3). So far, more than 50 individuals have been reported worldwide, although phenotypic features and natural history have not been exhaustively characterized yet. The phenotypic spectrum of the WHSUS is broad and includes moderate to severe ID, microcephaly, variable cerebral malformations, short stature, brachydactyly, visual abnormalities, sensorineural hearing loss, hypotonia, sleep difficulties, autistic features, self-injurious behaviour, feeding difficulties, gastroesophageal reflux, and other less frequent features. Here, we report the case of a girl with microcephaly, brain malformations, developmental delay (DD), peripheral polyneuropathy, and adducted thumb-a remarkable clinical feature in the first years of life-and heterozygous for a previously unreported, de novo splicing variant in
. This report contributes to strengthen and expand the knowledge of the clinical spectrum of WHSUS, pointing out the importance of less frequent clinical signs as diagnostic handles in suspecting this condition.
Variations in genes encoding for the enzymes responsible for synthesizing the linker region of proteoglycans may result in recessive conditions known as "linkeropathies". The two phenotypes related ...to mutations in genes
and
(encoding for galactosyltransferase I and II respectively) are similar, characterized by short stature, hypotonia, joint hypermobility, skeletal features and a suggestive face with prominent forehead, thin soft tissue and prominent eyes. The most outstanding feature of these disorders is the combination of severe connective tissue involvement, often manifesting in newborns and infants, and skeletal dysplasia that becomes apparent during childhood. Here, we intend to more accurately define some of the clinical features of
and
-related conditions and underline the extreme hypermobility of distal joints and the soft, doughy skin on the hands and feet as features that may be useful as the first clues for a correct diagnosis.
Lissencephaly describes a group of conditions characterized by the absence of normal cerebral convolutions and abnormalities of cortical development. To date, at least 20 genes have been identified ...as involved in the pathogenesis of this condition. Variants in
, encoding a protein involved in the regulation of neuronal migration, have been recently described as causative of lissencephaly with a posterior-prevalent involvement of the cerebral cortex and an autosomal dominant pattern of inheritance. Here, we describe a 3-year-old boy with slightly delayed psychomotor development and mild dysmorphic features, including bitemporal narrowing, protruding ears with up-lifted lobes and posterior plagiocephaly. Brain MRI at birth identified type 1 lissencephaly, prevalently in the temporo-occipito-parietal regions of both hemispheres with "double-cortex" (Dobyns' 1-2 degree) periventricular band alterations. Whole-exome sequencing revealed a previously unreported de novo pathogenic variant in the
gene (NM_001042475.3:c.232+1del). Only 20 patients have been reported as carriers of pathogenic
variants to date. They show lissencephaly with prevalent posterior involvement, variable cognitive deficits and epilepsy. The present case report indicates the clinical variability associated with
variants that are not invariantly associated with severe phenotypes and poor outcome, and underscores the importance of including this gene in diagnostic panels for lissencephaly.
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