New syndrome of congenital circumferential skin folds associated with multiple congenital anomalies.
ABSTRACT: Congenital circumferential skin folds can be found in individuals with no additional defects, as well as in patients with multiple congenital anomalies and developmental abnormalities. Current data point to etiological heterogeneity of syndromic cases. We describe a 7-month-old girl with a novel combination of symmetrical congenital circumferential skin folds, dysmorphic features, and multiple congenital abnormalities. Examination of the patient revealed symmetrical congenital circumferential skin folds and dysmorphic features, as well as multiple congenital anomalies including nasal pyriform aperture stenosis, ventricular septal defect, absent spleen, camptodactyly, and severe psychomotor retardation. Skin biopsy demonstrated subcutaneous fat extending into the superficial and deep reticular dermis. Sequencing of the CDON, SHH, ZIC2, SIX3, and TGIF genes (associated with holoprosencephaly) did not disclose pathogenic alterations. Extensive review of previously described cases of syndromic congenital circumferential skin folds did not reveal a similar combination of clinical and histopathological findings.
Project description:Intellectual disabilities are genetically heterogeneous and can be associated with congenital anomalies. Using whole-exome sequencing (WES), we identified five different de novo missense variants in the protein phosphatase-1 catalytic subunit beta (PPP1CB) gene in eight unrelated individuals who share an overlapping phenotype of dysmorphic features, macrocephaly, developmental delay or intellectual disability (ID), congenital heart disease, short stature, and skeletal and connective tissue abnormalities. Protein phosphatase-1 (PP1) is a serine/threonine-specific protein phosphatase involved in the dephosphorylation of a variety of proteins. The PPP1CB gene encodes a PP1 subunit that regulates the level of protein phosphorylation. All five altered amino acids we observed are highly conserved among the PP1 subunit family, and all are predicted to disrupt PP1 subunit binding and impair dephosphorylation. Our data suggest that our heterozygous de novo PPP1CB pathogenic variants are associated with syndromic intellectual disability.
Project description:BACKGROUND:Congenital symmetric circumferential skin creases (CSCSC) was initially described five decades ago. Exome sequencing has recently revealed the genetic etiology of CSCSC. Pathogenic variants in TUBB (OMIM# 191130) and MAPRE2 (OMIM# 605789) have been linked to CSCSC1 (OMIM# 156610) and CSCSC2 (OMIM# 616734), respectively, in an autosomal dominant manner. Four pathogenic variants in MAPRE2 have been previously reported to be associated with CSCSC2. METHODS:Whole-exome sequencing (WES) has been performed and an in-house pipeline was used to conduct a phenotype-driven data analysis. All candidate variants were confirmed by Sanger sequencing. RESULTS:Here we report a 2-year-old boy characterized by absent expressive speech, normal to mild over growth, facial dysmorphic features, remarkable circumferential skin creases on both forearms and ankles. WES disclosed a de novo missense MAPRE2 variant, c.518G>A (p.Arg173Gln), as the molecular cause of this complex phenotype. We described detailed clinical characterization of this patient and compared the available clinical data of individuals with MAPRE2 variants to demonstrate the phenotypic spectrum. CONCLUSION:Our study reports the first patient of Asian origin with CSCSC2 due to a pathogenic mutation of MAPRE2 and expands the clinical and genetic spectrum of CSCSC2.
Project description:Femoral-facial syndrome (FFS) is a very rare multiple congenital anomaly syndrome. The authors describe a case of FFS in a 2-day-old infant of a diabetic mother. The phenotypic features include bilateral symmetrical femoral involvement with completely aplastic right-sided femur, severely hypoplastic left femur and unusual facial dysmorphic features without other skeleton/spinal and genitourinary anomalies. Cases of FFS need to be carefully evaluated because of the similarity between FFS and caudal dysgenesis, a condition frequently related to maternal diabetes and with other syndromes characterised by femoral hypoplasia and associated anomalies, which can pose a diagnostic challenge.
Project description:Mutations in PIGN, resulting in multiple congenital anomalies-hypotonia-seizures syndrome, a glycosylphosphatidylinositol anchor deficiency, have been published in four families to date. We report four patients from three unrelated families with epilepsy and hypotonia in whom whole exome sequencing yielded compound heterozygous variants in PIGN. As with previous reports Patients 1 and 2 (full siblings) have severe global developmental delay, gastroesophageal reflux disease, and minor dysmorphic features, including high palate, bitemporal narrowing, depressed nasal bridge, and micrognathia; Patient 3 had early global developmental delay with later progressive spastic quadriparesis, intellectual disability, and intractable generalized epilepsy; Patient 4 had bilateral narrowing as well but differed by the presence of hypertelorism, markedly narrow palpebral fissures, and long philtrum, had small distal phalanges of fingers 2, 3, and 4, absent distal phalanx of finger 5 and similar toe anomalies, underdeveloped nails, unusual brain anomalies, and a more severe early clinical course. These patients expand the known clinical spectrum of the disease. The severity of the presentations in conjunction with the patients' mutations suggest a genotype-phenotype correlation in which congenital anomalies are only seen in patients with biallelic loss-of-function. In addition, PIGN mutations appear to be panethnic and may be an underappreciated cause of epilepsy.
Project description:X-linked intellectual disability (ID) type Nascimento (MIM #300860), also known as ubiquitin-conjugating enzyme E2 A (UBE2A) deficiency syndrome, is a congenital malformation syndrome characterized by moderate to severe ID, speech impairment, dysmorphic facial features, genital anomalies and skin abnormalities. Here, we report a Japanese patient with severe ID and congenital cataract. We identified a novel hemizygous mutation (c.76G>A, p.Gly26Arg) in UBE2A by whole-exome sequencing.
Project description:Aim. To identify dysmorphic features and cardiac, skeletal, and urogenital anomalies in patients with congenital hypothyroidism. Patients and Methods. Seventeen children with congenital primary hypothyroidism were recruited. Cause for congenital hypothyroidism was established using ultrasound of thyroid and (99m)Tc radionuclide thyroid scintigraphy. Malformations were identified by clinical examination, echocardiography, X-ray of lumbar spine, and ultrasonography of abdomen. Results. Ten (59%) patients (6 males and 4 females) had congenital malformations. Two had more than one congenital malformation (both spina bifida and ostium secundum atrial septal defect). Five (29%) had cardiac malformations, of whom three had only osteum secundum atrial septal defect (ASD), one had only patent ductus arteriosus (PDA), and one patient had both ASD and PDA. Seven patients (41%) had neural tube defects in the form of spina bifida occulta. Conclusion. Our study indicates the need for routine echocardiography in all patients with congenital hypothyroidism.
Project description:Cutis laxa is a heterogeneous group of diseases, with loose, wrinkled skin folds and hyperelasticity of the skin. There are overlapping of clinical features of the group of syndrome associated with cutis laxa, including congenital cutis laxa, wrinkly skin syndrome and gerodermia osteodysplastica. All these conditions present a challenge to the clinician. Thus, molecular diagnosis is the only way to resolve these phenotypically similar conditions. We hereby describe two Indian patients with wrinkled skin and mild craniofacial dysmorphic features who had molecular confirmation of autosomal recessive cutis laxa.
Project description:We identified a missense variant in PSMD12 gene, recently associated to an emerging syndromic form of NDD, in a patient with intellectual disability/speech delay, congenital anomalies and facial dysmorphisms. The variant described herein is useful to expand the molecular spectrum of heterozygous PSMD12 mutations and to provide insight into the molecular pathogenesis of this new condition since it is, to the best of our knowledge, the first missense substitution to date reported in medical literature. Finally, our patient is the one with the most detailed dysmorphic characterization and for this reason useful to start defining a typical facial gestalt that addresses the diagnosis.
Project description:Autosomal recessive congenital ichthyosis (ARCI) is a rare genetic disorder of the skin characterized by abnormal desquamation over the whole body. In this study we report four patients from three consanguineous Tunisian families with skin, eye, heart, and skeletal anomalies, who harbor a homozygous contiguous gene deletion syndrome on chromosome 15q26.3. Genome-wide SNP-genotyping revealed a homozygous region in all affected individuals, including the same microdeletion that partially affects two coding genes (ADAMTS17, CERS3) and abolishes a sequence for a long non-coding RNA (FLJ42289). Whereas mutations in ADAMTS17 have recently been identified in autosomal recessive Weill-Marchesani-like syndrome in humans and dogs presenting with ophthalmologic, cardiac, and skeletal abnormalities, no disease associations have been described for CERS3 (ceramide synthase 3) and FLJ42289 so far. However, analysis of additional patients with non-syndromic ARCI revealed a splice site mutation in CERS3 indicating that a defect in ceramide synthesis is causative for the present skin phenotype of our patients. Functional analysis of patient skin and in vitro differentiated keratinocytes demonstrated that mutations in CERS3 lead to a disturbed sphingolipid profile with reduced levels of epidermis-specific very long-chain ceramides that interferes with epidermal differentiation. Taken together, these data present a novel pathway involved in ARCI development and, moreover, provide the first evidence that CERS3 plays an essential role in human sphingolipid metabolism for the maintenance of epidermal lipid homeostasis.
Project description:Defects in the human glycosylphosphatidylinositol anchor biosynthetic pathway are associated with inherited glycosylphosphatidylinositol (GPI)-deficiencies characterized by a broad range of clinical phenotypes including multiple congenital anomalies, dysmorphic faces, developmental delay, hypotonia, and epilepsy. Biallelic variants in PIGN, encoding phosphatidylinositol-glycan biosynthesis class N have been recently associated with multiple congenital anomalies hypotonia seizure syndrome.Our patient is a 2 year old male with hypotonia, global developmental delay, and focal epilepsy. Trio whole-exome sequencing revealed heterozygous variants in PIGN, c.181G > T (p.Glu61*) and c.284G > A (p.Arg95Gln). Analysis of FLAER and anti-CD59 by flow-cytometry demonstrated a shift in this patient's granulocytes, confirming a glycosylphosphatidylinositol-biosynthesis defect, consistent with PIGN-related disease.To date, a total of 18 patients have been reported, all but 2 of whom have congenital anomalies and/or obvious dysmorphic features. Our patient has no significant dysmorphic features or multiple congenital anomalies, which is consistent with recent reports linking non-truncating variants with a milder phenotype, highlighting the importance of functional studies in interpreting sequence variants.