Cutis verticis gyrata associated with congenital heart disease.

Cutis verticis gyrata (CVG) is a very rare benign disorder characterised by convoluted folds and deep furrows of the scalp that mimic cerebral sulci and gyri. Associations with other pathologies as neuropsychiatric and/or ophthalmologic disorders, secondary cases to inflammatory or neoplastic processes, as well as cases associated to genetic disorders as Turner's syndrome have been reported, but there is no literature describing an association with a congenital structural heart defect and no other underlying condition. We report a case of primary CVG in a 3-week-old female infant associated with an echocardiographic diagnosis of cor triatriatum. Other systemic examination findings and investigations were unremarkable, and the patient has normal neurodevelopment at 1 year old. Aside from the neuropsychiatric and ophthalmologic pathologies commonly associated with primary non-essential CVG, it should be noted that isolated congenital cardiac lesions are also possible, so as to increase our index of suspicion in patients with the disorder.

Penetrating keratoplasty in brittle Cornea syndrome: Case series and review of the literature.

It concerns three siblings (two 28 year old twin boys and a 25 year old woman) who presented a previous history of rupture of eyeball in one eye and very poor vision in the other. At the first ophthalmoscopic and instrumental evaluation, three patients presented with bluish sclera and keratoglobus in the intact eye. A genetic analysis with whole exome sequencing was then performed on the three siblings, identifying a biallelic variant of the PRDM5 gene that led to the diagnosis of Brittle Cornea Syndrome (BCS), a rare autosomal recessive disorder characterized by corneal thinning and blue sclera. To preserve the only intact eye from possible breakage, the three siblings were trained in using protective measures (polycarbonate goggles etc.) to carry out close monitoring of symptoms and were asked to continue with follow-up visits for ocular and systemic diseases associated with BCS. Given the poor best corrected visual acuity achievable with glasses and contact lenses, penetrating keratoplasty was performed, achieving good visual acuity maintained in the 2-year follow-up in two of the three patients. Knowledge of this pathology and its clinical manifestations is essential for early diagnosis and correct management of this rare but very debilitating pathology. To our knowledge, this is the first case series of BCS reported in an Albanian population.

Clinical insights from an unusual Turner syndrome manifestation: Congenital cutis verticis gyrata.

Cutis verticis gyrata (CVG) is classified as primary or secondary according to the absence or presence of underlying soft tissue abnormalities. We report an infant with Turner syndrome (TS) who in addition presented with CVG on the scalp. The skin biopsy revealed a hamartoma-like lesion. We reviewed the clinical and histopathological findings of the 13 reported cases of congenital CVG in patients with TS, including ours. In 11 of them, CVG was localized on the skin of the scalp, mainly on the parietal region, and in two, on the forehead. Clinically, CVG had a flesh-colored aspect, with absent or sparse hair, and was not progressive. CVG was classified as primary in four patients who had skin biopsy and it was attributed to the intrauterine lymphedema of TS. However, histopathology in two of these patients identified dermal hamartoma as a secondary cause of CVG, and in three others, including ours, there were hamartomatous changes. Although further studies are required, previous findings support the proposal that some CVG may instead be dermal hamartomas. This report alerts clinicians to recognize CVG as a low-frequency manifestation of TS, but also to consider the possible co-occurrence of TS in all female infants with CVG.

A novel homozygous ZNF469 variant causing brittle cornea syndrome is associated with corneal ectasias in heterozygous carriers.

AIM: To describe a family segregating a novel truncating ZNF469 homozygous mutation causing brittle cornea syndrome type 1 in a male patient and associated with corneal ectasia in his two heterozygous young children. METHODS: A 49-year-old affected male and his 12- and 8-year-old, apparently healthy, siblings underwent phenotypic and genetic assessment. An Oculus Pentacam Scheimpflug topographer system was employed for keratometries and central corneal thickness measurements. Exome sequencing was performed in DNA from the index case with subsequent Sanger sequencing confirmation of the ZNF469 gene causal variant in his relatives. RESULTS: The index case had a history of bilateral keratoglobus, corneal perforations, bilateral hypoacusia, and skeletal anomalies. His two children exhibited topographic anomalies compatible with keratoconus suspects as well as mild skeletal anomalies. Genetic analysis identified a novel homozygous c.2340delC variant in the ZNF469 gene, which predicts a p.(Arg781Glufs*19) truncated protein. Sanger sequencing identified heterozygosity for the c.2340delC variant in DNA from both siblings. CONCLUSION: Our results expand the mutational spectrum associated with brittle cornea syndrome and provide the first demonstration of early corneal anomalies in subjects carrying monoallelic ZNF469 variants.

Brittle cornea syndrome: A tale of three brothers.

Brittle cornea syndrome (BCS) is a genetic connective tissue disorder with discernible ocular features such as blue scleral and thin cornea that predominantly presents in younger children. We herein describe cases of three siblings with BCS, two of whom presented to us with open globe injuries following trivial trauma. Clinical examination of the other eye in both showed diffusely thin corneas and blue sclera. A systemic evaluation revealed sensorineural hearing loss and hyperextensible joints. The third sibling was screened and found to have features concurrent with BCS. This report highlights the challenges faced in the management of ocular injuries and consecutive complications in these patients.

Oculocerebrocutaneous syndrome (Delleman Oorthuys syndrome) associated with congenital glaucoma: A case report.

INTRODUCTION: Oculocerebrocutaneous syndrome (Delleman Oorthuys syndrome) (OMIM 164180) is a rare syndrome affecting eyes, skin, and central nervous system, and it is usually associated with microphthalmia. CASE DESCRIPTION: A 4-day old baby boy was referred to our hospital for the evaluation of buphthalmos in the left eye. His clinical evaluation was remarkable for oculocerebrocutaneous syndrome with congenital glaucoma in the left eye and microphthalmos in the right eye. CONCLUSION: Our report represents the first case of oculocerebrocutaneous syndrome associated with unilateral congenital glaucoma so far in the literature.

A Novel Forkhead Box L2 Missense Mutation, c.1068G>C, in a Chinese Family With Blepharophimosis/Ptosis/ Epicanthus Inversus Syndrome.

ABSTRACT: The aim of the study was to report a novel forkhead box L2 (FOXL2) missense mutation in a Chinese blepharophimosis/ ptosis/epicanthus inversus syndrome family. Three generations of the Chinese family with blepharophimosis/ptosis/epicanthus inversus syndrome were enrolled in this study. Blood samples from patients of this family were collected and then analyzed by whole-exome sequencing. Confocal microscopy was performed to detect the subcellular location of FOXL2. Transactivation studies were performed and verified with real time polymerase chain reaction. A novel mutation (c.1068G>C) located in the downstream of deoxyribonucleic acid-binding forkhead domain was identified. Confocal photos showed the novel mutation did not disturb FOXL2 function, and the mutant protein could still transactivate steroidogenic acute regulatory protein, a key regulator of primary ovarian failure (POF). Our study revealed a novel missense mutation (c.1068G>C) and expanded the spectrum of FOXL2 gene mutations.

Rare neurological manifestations in a Saudi Arabian patient with Ehlers-Danlos syndrome and a novel homozygous variant in the TNXB gene.

We report a 38-year-old Saudi male with Ehlers-Danlos Syndrome (EDS). The patient presented with rare and unusual neurological manifestations, including but not limited to ophthalmoplegia and myopathic pattern on his electromyography. In addition to hand weakness, there was skin hyperextensibility, joint hyperflexibility, and frontal baldness. Next-generation sequencing was performed on target exon sequences, using whole exome sequencing and Burrows-Wheeler Aligner for alignment/base calling. Genome Analysis Toolkit and reference genome Homo sapiens (UCSC hg19) were used for sequence processing and analysis. Variant classification was done according to standard international recommendations. A novel homozygous variant, NM_019105.6: c.8488C>T p.(Gln2830*), was detected in the TNXB gene. This variant is not reported in the literature nor dbSNP or gnomAD databases. Additionally, this variant is predicted to create a premature stop codon and produce a truncated protein or nonsense-mediated mRNA decay. Hence, it is classified as a likely pathogenic variant. The same point variant was found in a heterozygous state in the patient's father and sister. Both presented with milder symptoms associated with Ehlers-Danlos syndromes and heritable connective tissue disorders. Therefore, the patient was diagnosed as a tenascin-X (TNX) deficient type of EDS known as classical-like Ehlers-Danlos syndrome. TNX deficient patients may present with clinical and electrophysiological manifestations that are unusual in EDS like frontal baldness, ophthalmoplegia, and myotonia, which mimic myotonic dystrophy type I. Clinicians should be aware of the potential overlap of symptoms among these two diseases to ensure correct diagnosis is made.

Corneal ectasia associated with posterior lamellar opacification.

BACKGROUND: Concomitant corneal ectasia and posterior lamellar corneal opacification is rare, and the genetic relationship between these two conditions is unclear. We report the genetic and clinical characterization of this phenotype in three unrelated individuals. MATERIALS AND METHODS: One previously reported affected individual and two unreported, unrelated, affected individuals were recruited for the study. Subjects and unaffected relatives underwent slit lamp examination, refraction, and multi-modal imaging. Saliva samples were obtained from two of the three affected individuals, from which DNA was extracted. Sanger sequencing was performed to identify mutations in genes associated with posterior amorphous corneal dystrophy (PACD), brittle cornea syndrome (BCS), and posterior polymorphous corneal dystrophy (PPCD), while copy number variation (CNV) analysis was used to identify CNV in the PACD locus. RESULTS: Affected individuals demonstrated bilateral corneal steepening, stromal thinning and lamellar posterior corneal opacification. Corneal topography and tomography revealed conical or globular corneal steepening and decreased thickness. Anterior segment optical coherence tomography demonstrated hyperreflectivity of the posterior stroma in each of the affected individuals. Genetic testing did not detect a heterozygous deletion involving the PACD locus on chromosome 12 or a pathogenic mutation in the genes associated with BCS or PPCD. CONCLUSIONS: Corneal ectasia may be associated with posterior lamellar stromal opacification that appears consistent with PACD. However, genetic testing for PACD as well as BCS and PPCD in affected individuals fails to reveal pathogenic deletions or mutations, indicating that other genetic factors are involved.

Inherited skin disorders presenting with poikiloderma.

Poikiloderma is a skin condition that combines atrophy, telangiectasia, and macular pigment changes (hypo- as well as hyperpigmentation). It is often mistaken for mottled pigmentation by general practitioners or nondermatology specialists. Poikiloderma can be a key presenting symptom of Rothmund-Thomson syndrome (RTS), dyskeratosis congenita (DC), hereditary sclerosing poikiloderma (HSP), hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP), xeroderma pigmentosum (XP), Bloom syndrome (BS), Kindler syndrome (KS), and Clericuzio-type poikiloderma with neutropenia (PN). In these conditions, poikiloderma starts early in life, usually before the second or third year. They may also be associated with photosensitivity and other significant multi-organ manifestation developed later in life. Poikiloderma could indicate the presence of a genetic disorder with potentially serious consequences. Poikiloderma almost always precedes more severe manifestations of these genodermatoses. Prompt diagnosis at the time of presentation could help to prevent complications and mitigate the course of the disease. This review discusses these to help the practicing clinician manage patients presenting with the symptom. To further facilitate early recognition, this paper also proposes a simple diagnostic algorithm.

A rare association of blepharophimosis-ptosis-epicanthus inversus case with congenital nasolacrimal duct obstruction.

PURPOSE: The aim of reporting this case is to describe a rare combination of blepharophimosis-ptosis-epicanthus inversus syndrome with congenital nasolacrimal duct obstruction. A variety of lacrimal anomalies have been seen in blepharophimosis-ptosis-epicanthus inversus syndrome but the occurrence of nasolacrimal duct obstruction is rare. METHOD: The blepharophimosis-ptosis-epicanthus inversus syndrome is an autosomal dominant rare genetic defect with clinical manifestation of dysplasia of the eyelids, palpebral fissures, flat nasal bridge, and ptosis. A 20-month-old boy was referred with the complaints of watering and discharge from his right eyes since birth. On examination, the child had all the features of blepharophimosis-ptosis-epicanthus inversus syndrome with right congenital nasolacrimal duct obstruction in line with the published reports. RESULT: On endoscopic probing and irrigation, the probe could not be visualized into the inferior meatus. On dacryoendoscopy, the membranous part of the nasolacrimal duct was found to be completely obliterated with no light transmission into the nose indicating a malformed nasolacrimal duct. The child was managed by endoscopic dacryocystorhinostomy. We could find only one case report published so far on the combination of congenital nasolacrimal duct obstruction with blepharophimosis-ptosis-epicanthus inversus syndrome. This study adds one more case of blepharophimosis-ptosis-epicanthus inversus syndrome with congenital nasolacrimal duct obstruction and adjuvant use of dacryoendoscopy.

Clericuzio-type poikiloderma with neutropenia in a patient from India.

A 9-year-old boy presented for evaluation of variegated skin pigmentation. Palms and soles revealed honeycombed hyperpigmented hyperkeratosis. Irregular, firm, skin coloured nodules suggestive of cutaneous calcification were present on both elbows. Total leucocyte count and absolute neutrophil count were 3720/mm3 and 420/mm3 respectively. The neutropenia was not cyclical. Systematic analysis of the whole exome data revealed a homozygous mutation in USB1 gene; chr16:g.58043892TA>-[1/1]. A final diagnosis of poikiloderma with neutropenia- Clericuzio type (PNC) was made. Naegeli Franceschetti Jadassohn, dermatopathia pigmentosa reticularis, PNC and dyskeratosis congenita, all can present with overlapping cutaneous manifestations. Subtle clinical details like thickened nails, hyperextensible joints, calcinosis cutis, characteristic facies and a preceding erythematopapular rash strongly favor the diagnosis of PNC. The index case highlights two novel findings: obliterated dermatoglyphics and mucin deposition (features not described hitherto in PNC).

Dysfunction of dermal initial lymphatics of the arm and upper body quadrant causes congenital arm lymphedema.

OBJECTIVE: The objective of this study was to explore the pathologic process underlying primary lymphedema. METHODS: Twenty-seven patients with unilateral congenital arm lymphedema who visited our clinic from January 1, 2014, to May 30, 2019, were enrolled. The patients' clinical signs and the findings of indocyanine green (ICG) lymphography, skin tissue immunohistochemical staining, and whole exome sequencing of tissue and blood were evaluated. RESULTS: Among the 27 patients, 11 were diagnosed with stage II and 16 were diagnosed with stage III lymphedema. No lymphatic vessels were visualized in the affected arm in 25 of 27 (93%) patients who underwent ICG lymphography; likewise, no lymphatics were found in the territories of axillary lymph node drainage in the trunk, irrespective of any anomalies of the axillary lymph nodes. In only two (7%) patients, an unclear lymphatic trunk gradually appeared in the dorsum of the affected hand. The number of initial lymphatics was increased in the skin specimens of all nine patients in whom lymphatics were not demonstrated by ICG lymphography. Among 14 tested patients, we found compound heterozygote variants in the PIEZO1 gene in only one (7%) patient. Two missense variants, c.4072C>T; p.Arg1358Cys and c.5033C>T; p. Ala1678Val, were identified and found to have been inherited from the father and mother, respectively. No other pathogenic or likely pathogenic variants of currently known lymphedema-related genes were identified in the remaining 13 patients. No genetic difference was found between the lymphedematous and nonedematous healthy skin tissue of the same person. CONCLUSIONS: Segmental or regional dysfunction of the dermal initial lymphatics causes congenital arm lymphedema and may have implications for clinical treatment.