Marfanoid Research Articles

Investigations of an individual with a Marfanoid habitus, mild intellectual disability, and severe social anxiety identifies PCDHGA5 as a candidate neurodevelopmental disorder gene.

Marfanoid habitus and intellectual disability (MHID) co-occur in multiple neurodevelopmental disorders (NDD). Among those, Lujan-Fryns, an X-linked genetic disorder associated with variants in MED12 was the first such syndrome identified. Accurate molecular diagnosis for these MHID syndromes remains a challenge due to significant clinical and genetic heterogeneity. We present a case report of a 20-year-old male patient with MHID and severe social anxiety. A comprehensive clinical evaluation, including morphotype assessment, cognitive, and psychometric and genetic testing, was conducted to provide a detailed understanding of the patient's complex clinical presentation. Psychometric assessments revealed severe social anxiety and various cognitive and emotional challenges. Despite some autism-like symptoms, the patient's clinical presentation was more aligned with mild intellectual disability. Exome sequencing was inconclusive but identified a heterozygous de novo missense variant in the PCDHGA5 gene. This gene is not known in human pathology yet, but we also report a second patient with a syndromic neurodevelopmental disorder and a rare de novo variant which leads us to propose this as a candidate gene. Our findings emphasize the importance of multidisciplinary approach in the diagnosis and management of MHID. This case report underscores the need for objective clinical evaluations and standardized tools to better understand the complex clinical profiles of patients with NDDs. The identification of novel PCDHGA5 gene variants adds this gene's candidacy to the genetic landscape of MHID-NDD, warranting further investigation to determine its potential contribution.

A Case report of multiple endocrine neoplasia type 2B

Introduction and importance: Multiple Endocrine Neoplasia Type 2 (MEN2) is a rare autosomal dominant neoplastic syndrome resulting from RET gene mutations, marked by medullary thyroid carcinoma (MTC) and increased risk of other endocrine tumors. MEN2 includes subtypes MEN2A, MEN2B, and familial MTC. Prophylactic thyroidectomy is recommended for MEN2A due to high MTC risk. Case presentation: A 38-year-old woman with a family history of thyroid cancer presented with headaches, sweating, and palpable breast mass. Exam revealed skin lesions. Lab abnormalities and imaging indicated a large adrenal mass and thyroid nodules. Inconclusive biopsies led to left adrenalectomy, confirming pheochromocytoma. Subsequent total thyroidectomy revealed MTC. Clinical discussion: This case represents rare MEN2B presentation, featuring MTC, pheochromocytoma, mucosal neuromas, and marfanoid habitus. Genetic testing for RET mutations is crucial with a positive family history. MEN2A individuals undergo prophylactic thyroidectomy due to high MTC risk. Although rare, pheochromocytoma can be an initial MEN2 manifestation, indicated by paroxysmal symptoms. Surgical resection is the treatment. Conclusions: The patient’s successful adrenalectomy followed by total thyroidectomy confirmed MTC. Thorough evaluation, including inconclusive initial findings, emphasizes imaging and biopsies. Early detection and appropriate management optimize MEN2 outcomes.

Novel UBE3B mutations: report of eight patients with Kaufman oculocerebrofacial syndrome with additional clinical findings from a highly consanguineous population.

Biallelic mutations in UBE3B cause Kaufman oculocerebrofacial syndrome (KOS; OMIM 244450) with a wide range of clinical manifestations. In this study, we employed genetic analyses including homozygosity mapping, candidate gene sequencing, whole exome sequencing, and confirmatory Sanger sequencing on eight patients from three unrelated consanguineous families. Our analysis yielded three different novel variants in UBE3B : a missense substitution [NM_130466.4: c.2975C>T; (p.Pro992Leu)] in the HECT domain in family 1, a 3-bp deletion within exon 14 [c.1692_1694delCTC; (p.Ser565del)] leading to removal of a serine residue in family 2, and a splice donor site variant in intron eight of UBE3B (c.630 + 1G>T) in family 3. Blepharophimosis, telecanthus, ptosis, intellectual disability and abnormal lipid profile were similar to those found in previously reported KOS patients. Longitudinal follow-up revealed rather marfanoid body habitus of the patients in family 1. This study reports eight patients from Saudi Arabia with novel deleterious variants in UBE3B and adds to the phenotypic spectrum of KOS.

Novel variant of FBN2 in a patient with congenital contractual arachnodactyly

Congenital contractual arachnodactyly (CCA) is a genetic connective tissue disorder that is characterized by arachnodactyly, kyphoscoliosis, marfanoid habitus, and crumpled ears. We report a case of a boy with suspected Marfan syndrome. Genetic analysis revealed c.3207_3217+9del in a heterozygote form of the fibrillin-2 (FBN2) gene. This patient was diagnosed with CCA based on his phenotype, and the pathogenicity of this variant was classified according to cDNA analysis and protein modeling.

Oral Manifestations of Multiple Endocrine Neoplasia 2B Syndrome: A Rare Case Report

Abstract Multiple endocrine neoplasia (MEN) 2B syndrome is a rare autosomal dominant hereditary condition of neuroendocrine origin characterized by pheochromocytoma, marfanoid habitus, and mucocutaneous neuromas. Multiple mucosal neuromas on the tongue, lips, cheeks, and inner eyelids are often appeared as the earliest signs in most of the undiagnosed cases. Early diagnoses, recognition of phenotype, adequate surgery, and appropriate genetic counseling are very much essential as patients often develop medullary thyroid carcinoma (MTC) and pheochromocytoma. This case report would highlight the oral manifestations of MEN 2B in a 22-year-old female patient with multiple mucosal neuromas and a previous history of thyroidectomy due to MTC.

Morphological and genetic aspects of Marfan Syndrome as demonstrated by a case of death during pregnancy with the discovery of two de novo missense mutations in the FBN1 gene

Marfan Syndrome (MFS) is an autosomal dominant disease caused in most cases by mutations in the FNB1 gene, which encodes for fibrillin 1. MFS does not alway shows typical phenotypic signs. Indeed, the occurrence of sudden death of unknown cause is increasingly seen in young adults without ante mortem preexisting pathology to explain the event. In many cases the diagnosis of Marfan Syndrome (MFS) is carried out post mortem, especially in cases where the disease’s external phenotype is absent. Here is reported a case of a young woman who died during a twin pregnancy investigated with medico-legal and forensic anthropological procedures. The autopsy showed the absence of a typical marfanoid habitus and the presence of a dissecting aneurysm of the aorta with histopathological degeneration of the aortic elastic fibers. The genetic investigation revealed two previously undetected de novo mutations of the FBN1 gene: c.T6181C: p.C2061R and c.G1415A: p.C472Y. This new mutations, together with a comprehensive analysis, demonstrates the existence of a causal relationship between these mutations and the dissecting aneurysm of the aorta. This also stresses the importance of a combined multidisciplinary approach to this condition which includes morphological and genetic studies.

Acute Type A Aortic Dissection Diagnosed by POCUS in a 29-year-old Man

Aortic dissection (AD) is a medical emergency with a poor prognosis if not recognized early and treated promptly. In this setting, clinical data may be equivocal, while electrocardiogram, laboratory tests, and chest radiography often show nonspecific findings. In contrast, cardiac point of care ultrasound (POCUS) has proven useful in the diagnosis and detection of complications of AD. We present the case of a 29-year-old man with marfanoid habitus presenting with chest pain and acute heart failure, in whom cardiac POCUS aided in the rapid diagnosis of type A AD and pulmonary edema. POCUS contributed to optimizing the medical treatment and allowed for early activation of the surgical team. 

SAT561 Pathogenic RET V804M Germline Variant Without Clinical Manifestations Of Multiple Endocrine Neoplasia Type 2 In An Elderly Male

Abstract Disclosure: R. Ghosh: None. G. Al-Naqeeb: None. P. Veeraraghavan: None. C. Craig: None. J. Klubo-Gwiezdzinska: None. S. Gubbi: None. Background: Germline pathogenic variants in the RET protooncogene give rise to multiple endocrine neoplasia (MEN) types 2A and 2B. MEN2A is mainly characterized by MTC (∼100%), pheochromocytoma (PHEO; 4% - 88%), and primary hyperparathyroidism (HPTH; 2% - 30%), while MEN2B predominantly manifests with MTC (100%), PHEO (50%), mucocutaneous neuromas, and marfanoid habitus. Both MEN2A and 2B follow an autosomal dominant mode of inheritance. While certain pathogenic RET variants (M918T, A883F, and C634X) have high penetrance and present with aggressive disease, other variants such as V804M are of low penetrance and manifest with clinically mild disease.Clinical case: A 75-year-old male was referred to our center for further evaluation of the finding of an abnormal RET gene that was identified on a peripheral blood whole-exome gene sequencing research panel performed at an outside center. The patient was noted to have a germline RET c.2410 G>A, p.V804M heterozygous pathogenic variant. The patient denied any history of lump in the neck, symptoms of hyper- or hypothyroidism, tremors, headaches, fatigue, facial flushing, palpitations, constipation, diarrhea, anxiety, depression, or history of fragility fractures. Medical history consisted of hypertension, nephrolithiasis, type 2 diabetes mellitus, obstructive sleep apnea, interstitial pulmonary fibrosis, and colonic diverticula and polyps. Family history was significant for leukemia, colon, and breast cancers, but none of the relatives had a history of MTC, PHEO, or MEN2, and his children, while healthy, had not undergone RET germline testing. Physical examination showed no evidence of hypothyroidism or hyperthyroidism. Neck examination showed no evidence of thyromegaly or cervical lymphadenopathy. Laboratory investigations were unremarkable [serum calcitonin: 7.9 pg/ml (NL: </=14.3), CEA 2.8 mcg/L (NL: 0.8-3.4), thyrotropin (TSH): 1.92 microIU/ml (NL: 0.35-4.94), free thyroxine: 0.9 ng/dl (NL: 0.7-1.5), plasma free normetanephrine: 0.31 nmol/L (NL: <0.9), plasma free metanephrines 0.24 nmol/L (NL: <0.5), parathyroid hormone: 28.2 pg/ml (NL: 15-65), and ionized calcium 1.23 mmol/l (NL: 1.09-1.30)]. Thyroid sonogram was normal. We recommended active annual surveillance with biochemical markers and imaging along with genetic testing of the RET gene in his children. Conclusion: The V804M RET variant has been often associated with MTC or MEN2A phenotypes [1]. However, the variable expression of this variant may lead to a mild clinical phenotype or even absence of MTC/MEN2A manifestations. Hence, active surveillance as opposed to radical surgery like prophylactic thyroidectomy would be more beneficial in patients with no clinical or biochemical evidence of disease. Reference: Pinna et al., 2007, V804M is the most frequent mutation and may be associated with FMTC/MEN-2A phenotype. Thyroid, 17(2), 101-104. Presentation Date: Saturday, June 17, 2023

FRI213 Multiple Endocrine Neoplasia Syndromes: A Rare Case With Variable Presentation

Abstract Disclosure: D.J. Gomez D' Aza: None. M. Kasap: None. T. Zahedi: None. F. Zhang: None. Introduction: Multiple endocrine neoplasia (MEN) syndromes are rare autosomal dominant inherited groups of disorders characterized by the presence of two or more primary endocrine glands tumors. MEN type 1 is usually associated with neoplastic lesions of the pituitary gland, the parathyroid gland, and the pancreas. MEN type 2 typically presents with overgrowth of parathyroid, adrenal glands (pheochromocytoma), and parathyroid hyperplasia (MEN 2A), Marfanoid body habitus, or mucosal neuromas (MEN 2B). It can also manifest with non-endocrine tumors including carcinoid tumors, adrenocortical tumors, meningiomas, facial angiofibromas, collagenomas, lipomas, and germline mutations (MEN type 4). It is extremely rare for MEN type 1 syndrome to have concomitant pheochromocytoma. Case Report: We present a case of a 69 yo female with multiple comorbidities who was hospitalized for heart failure exacerbation. CT scan showed incidental findings of a 4.1 cm right adrenal nodule, a 2.1 cm left anterior mediastinum nodule, and a 1.1 cm oval pituitary mass. She had multiple episodes of hypertension urgency during the last two years. After patient recovered to her base line, workup labs revealed elevated serum Catecholamine with Metanephrine 431.1 pg/mL, Normetanephrine 466.5 pg/mL, Norepinephrine 137 pg/mL, and high PTH 258 pg/mL. Further study was normal for pituitary function tests, aldosterone, renin, cortisol, thyroid, and renal function. PET scan showed mild hypermetabolic activity in bilateral adrenal glands without any abnormal hypermetabolic activity in the chest. Thyroid Ultrasound identified a 1 cm thyroid nodule. Phenoxybenzamine was started due to concern for pheochromocytoma. Patient was monitored closely since she declined surgical intervention. Discussion: MEN syndromes have variable clinical presentation with multiple hormone excess. This patient has imaging and laboratory findings highly suggestive of MEN syndrome with pituitary adenoma, pheochromocytoma, and hyperparathyroidism. Further work up and genetic testing would be helpful to identify the mutation of MEN type 1 or type 2. Clinicians should be aware of the variable presentation of MEN syndrome, and prompt treatment is warranted to prevent life-threatening conditions. Presentation: Friday, June 16, 2023

Classical homocystinuria presenting with transient basal ganglia pathology and dystonia.

Classical homocystinuria is caused by pathogenic variants in the CBS gene leading to a deficiency of the vitamin B6-dependent enzyme cystathionine beta synthase. The disease is typically associated with high blood homocysteine concentrations. Clinical features include developmental delay/intellectual disability, psychiatric problems, thromboembolism, lens dislocation, and marfanoid habitus. We report on a child with classical homocystinuria presenting with acute episodes of dystonia and symmetrical basal ganglia abnormalities mimicking a mitochondrial disease. After starting treatment with vitamin B6, homocysteine levels rapidly normalized and dystonic episodes did not re-occur. Moreover, brain-imaging findings almost completely disappeared. The case illustrates that homocystinuria should be considered as a treatable differential diagnosis of dystonia.

Meticulous and Early Understanding of Congenital Cranial Defects Can Save Lives.

Omitting the early closure of the cranial sutures in newly born children is not an uncommon practice. We describe the natural history of several unrelated children and adults from two unrelated families. These children were born with variable clinical manifestations: craniofacial asymmetry, ocular proptosis, floppiness, and progressive deceleration in cognitive development. None of these children underwent a cranial sutures assessment. False diagnoses of positional plagiocephaly, neonatal thyrotoxicosis, congenital muscular atrophy, and hydrocephalus were given to the parents. This sort of malpractice was the reason behind a sequence of devastating pathological events that occurred in the lifetime of these children and adults. This was a multigenerational study of two unrelated families. In total, we studied three children (aged 7-19 years) and three adults (aged 40-52 years) from two families. The children from the first family were referred to our departments because of pre-pubertal scoliosis, kyphoscoliosis, and early-onset osteoarthritis. Reading the clinical histories of these children signified apparent clinical misconceptions. For instance, craniofacial asymmetry was misinterpreted as positional plagiocephaly and treated by means of helmet molding therapy. Ocular proptosis was given the false diagnosis of neonatal thyrotoxicosis. Floppiness (hypotonia) was misdiagnosed as congenital muscular dystrophy. The index case from the second family showed progressive deceleration in his cognitive development, associated with signs of increased intracranial pressure. The only diagnosis was Dandy-Walker malformation. We documented every patient in accordance with the clinical and radiological phenotypic characterizations. The genotype characterization followed accordingly. All patients in family (I) manifested a phenotype consistent to a certain extent with the clinical phenotype of Shprintzen-Goldberg syndrome (SGS), though the intensity of spine deformities was greater than has been described in the literature. The second family showed a constellation of Marfanoid habitus, craniosynostosis, increased intracranial pressure, hydrocephalus, Dandy-Walker malformation, seizures, and intellectual disability. The overall clinical phenotype was consistent but not fully diagnostic of craniosynostosis-Dandy-Walker-malformation hydrocephalus syndrome. The early closure of the sutures was totally different from one patient to another, including the premature closure of the metopic, coronal, squamosal, and sagittal sutures. One patient from family (II) underwent the implementation of a shunt system at the age of 3 years, unfortunately passing over the pre-existing craniosynostosis. In addition to skeletal deformities, a history of seizures and severe intellectual disability was recorded. The proband underwent chromosomal karyotyping, the FISH test, and whole-exome sequencing. The purpose of this study was fivefold. Firstly, to gain a meticulous understanding in order to differentiate between positional plagiocephaly, hypotonia, and congenital exophthalmos and their connections to abnormal craniofacial contours was and still is our first and foremost concern. Secondly, we aimed to characterize craniosynostosis, seizures, intellectual disabilities, and hydrocephalus associated with Marfanoid habitus, which were clearly demonstrated in our patients. Thirdly, we aimed to address the imperative for interpretations of clinical and radiological phenotypes and relate these tools to etiological understanding, which is an essential basis for diagnosis in the majority of long-term pediatric admissions. Fourthly, we aimed to assess the impacts of the missed early closure by the pediatricians and pediatric neurologists, which added a heavy pathological burden on these patients and their families. Fifthly, we aimed to identify whether early and diligent recognition can assist in cranial vault remodeling via surgical intervention to halt premature cranial suture fusions and can possibly alter the devastating course and the complications of the synostosed sutures.

A RARE TREATABLE CAUSE OF ADULT ONSET SPASTIC PARAPARESIS

pastic paraparesis refers to weakness and stiffness of both lower limbs caused by lesions affecting the Pyramidal tract. It could be due to genetic or acquired etiology. Genetic causes include leukodystophies, Heriditary Spastic Paraplegia (HSP), metabolic disorders etc,. Acquired causes include B12 and folate deficiency , infections like HTLV-1 virus, HIV, neurosyphilis , vascular malformations and so on. Here we encounter a rare treatable cause of spastic paraparesis. A 28 year old male born out of 3o Consanguinous parents with normal developmental history came with insidious onset slowly progressive spastic paraparesis for the past 4 years. Initially at onset he noticed difficulty in getting up from squatting position, which was associated with stiffness of lower limbs. Then he noticed there was slippage of slippers while walking and he was aware about it. Physical examination revealed marfanoid Habitus ,increased tone and exaggerated reflexes involving both lower limbs .Motor power was MRC Grade 4/5 in both lower limbs in both proximal and distal muscles. Ocular Examination revealed Ectopia Lentis. MRI Spine screening was normal. MRI Brain revealed symmetric T2/FLAIR hyperintensities involving periventricular and deep white matter of bilateral frontoparietal region. Possibilities of Primary demyelinating diseases and genetic/degenerative leukoencephalopathies were considered. CSF examination was normal and oligoclonal bands were absent. Clinical Exome sequence testing was done in suspicion of Adult onset leukodystrophy which showed Homozygous MTHFR gene mutation on exon4. Plasma Homocysteine levels were elevated ( 60 µmol/L).Patient was started on Oral Vitamin B12 1500mcg/day, Folic acid and pyridoxine supplementation. Patient showed symptomatic improvement and is under follow up. MTHFR deficiency in adults is a mimicker of leukodystrophies and other white matter disease. It is a potentially treatable disease. Before considering degenerative diseases like HSP, treatable diseases should be considered.

Difficult situation in treatment of medullary thyroid carcinoma in patient with multiple endocrine neoplasia type 2 B(MEN2B)

Abstract Introduction Multiple endocrine neoplasia type 2B (also known as ‘MEN2B’,‘Multiple endocrine neoplasia type 3′ or ‘Wagenmann–Froboese syndrome’) is a genetic disease characterized by the presence of medullary carcinoma of the thyroid, pheochromocytoma, mucosal neuromas, marfanoid features and multiple skeletal abnormalities such as kyphoscoliosis and pes cavus. Clinical Case A 16 years male presented with neck swelling and dysmorphic feature in the form of marfanoid habitus, including multiple tongue and oral mucosal swelling with mucosal neuromas on the anterior third of the tongue, the lips and the inner eyelid. Lips are thickened and bumpy. Visible neck swelling, palpable solid neck mass, high arm span to height ratio at >1.05, elongated fingers, pes cavus and positive wrist sign which is defined as when the distal phalanges of the thumb and fifth finger overlap on encircling the opposite wrist, were present. Ultrasound of the neck revealed a left solid irregular mass (57mmx33mm), that is hypoechoic, has coarse calcification, hypervascularity, that is mostly central, Multiple cervical lymph node(abnormal nodes include shape (round), absent hilum, intranodal necrosis, reticulation, calcification, peripheral vascularity),Investigation at beginning, Normal thyroid function test and biochemical and electrolyte were observed, Chest x ray was normal, FNAC done for thyroid nodule that showed multiple clumps of large hyperchromatic oval cells picture suggesting high suspicion of thyroid malignancy, thyroid biopsy advised, The patient was referred the FDEMC center for further evaluation and investigation prior to the surgery. During investigation at FDEMC center, thyroid function test normal, biochemistry normal, including PTH and electrolytes, Calcitonin was very high 465 pg/mL (0.2–27.7 pg/mL),GH under GTT was normal, IGF 1 182µg/L (150–350),Plasma metanephrine 40 pg/ml(<90pg/ml),and Plasma normetanephrine 27pg/ml(<196pg/ml) were normal. The patient referred to surgery, total thyroidectomy with radical neck dissection with multiple lymph node resection was performed. The biopsy revealed medullary thyroid carcinoma with cervical lymph node secondaries (bilateral multiple foci in both lobes). The patient kept on levothyroxine tab 100mcg.The follow up of the patient after one month by ultrasound and calcitonin level revealed residual thyroid tissue and two large cervical LN in the the ultrasound and a calcitonin level of 322 pg/mL Another surgical neck dissection to the metastatic LN <multiple LN 7×5cm, multiple suprasternal mass dissection 3×2.5cm,remnant of thyroid tissue 0.8cm,Follow up the patient after one month by ultrasound and calcitonin level still showed that there is residual pathological cervical LN, while the calcitonin level still high 412 pg/mL. PET scan done for him showed there is uptake in the head, neck and chest. The calcitonin was repeatedly was high.

Abstract 11327: De Novo Heart Failure in a Young Adult: A Case of Severe Aortic Regurgitation Secondary to an Aortic Root Aneurysm in a Patient With Marfan's Syndrome

A 24-year-old male, with no past medical history, presented to the ER with a 15-day history of insidious abdominal pain and distention, associated with progressive dyspnea on exertion and bilateral lower extremity pitting edema. In the previous 48 hours before his hospital admission, patient began presenting orthopnea and paroxysmal nocturnal dyspnea.On presentation patient was normotensive and tachycardic, with low oxygen saturation on pulse oximetry. On auscultation a loud early diastolic decrescendo murmur was heard at the parasternal border, with and audible S3 gallop. Characteristic Marfanoid habitus was observed. Patient underwent TTE were there was a notable aortic root dilation, mainly at the level of the sinuses of Valsalva, which had a diameter of 85 mm and 62 mm at the sinotubular junction. Ascending and descending aorta had a normal diameter. An eccentric jet of severe aortic regurgitation was also noted, which collided with the anterior mitral valve leaflet causing an Austin Flint phenomenon. Left ventricular ejection fraction was estimated at 24%, severe dilation was noted on all chambers. There were no echocardiographic signs of aortic dissection. Patient underwent genetic testing and ophthalmic evaluation, confirming the diagnosis of Marfan’s syndrome. A contrast enhanced CT angiogram confirmed the presence of severe aortic root dilation without dissection. Patient underwent Bentall procedure and began treatment for HFrEF at discharge. Marfan Syndrome is an autosomal dominant connective tissue disorder, due to mutations mostly in the FBN1 gene. Most cardiovascular symptoms are related to dilation of the aortic root and subsequent aortic regurgitation due to aortic annulus dilation. In patients with Marfan’s syndrome, all aortic root aneurysms ≥5.0 mm should undergo surgical repair regardless of symptoms.

A rare combination of monogenic connective tissue diseases — Marfan and Stickler syndromes — in one patient

As DNA sequencing techniques have been used more widely in clinical practice, there have been reports of a combination of hereditary diseases in a single patient. Cases of combining diseases with similar clinical symptoms present a particular difficulty for diagnosis. We observe a child who has been identified to have a combination of autosomal dominant diseases associated with connective tissue involvement — Marfan and Stickler type 1 syndromes. Common symptoms of both diseases were as follows: marfanoid habitus, arachnodactyly, kyphoscoliosis, chest deformity, involvement in the process of joints (hypermobile syndrome) and eyes. Marfan syndrome was evidenced by dissociation of mass-growth parameters at birth, tallstature, “Gothic” palate, crowded teeth, aortic dilation at the level of Valsalva sinuses and its ascending part. Type 1 Stickler syndrome was indicated by high-grade myopia, degenerative vitreous changes requiring vitrectomy, flat face, mandibular micrognathia, latent cleft of the soft and hard palate, grade 1 bilateral conductive hearing loss, mild cognitive failure. The diagnosis of both diseases was confirmed by the detection of de novo heterozygous mutations in the FBN1 gene (c.5060_5061 delGCinvAA, p. Cys1687) and COL2A1 gene (c.4074+1G>A). Establishing a final diagnosis is of great importance for predicting the course of the disease and genetic counseling of the proband and their relatives. 

Классическая гомоцистинурия: этиология, клинические проявления и методы лечения

Classic homocystinuria is a rare autosomal recessive disorder of methionine metabolism resulting from a deificiency of cystathionine beta-synthase that is involved in transsulfuration of homocysteine. The disorder is caused by mutations of CBS gene. Lack of enzyme is associated with accumulation of homocysteine that induce various toxicities, e.g. endothelial dysfunction and increased risk of thrombosis. Clinical manifestations of classic homocystinuria include ectopia lentis and/or severe myopia, skeletal abnormalities (marfanoid habitus, generalized osteoporosis and bone deformity), mental retardation, seizures, psychiatric and behavioral disorderts, venous and arterial thrombosis. Some patients with milder form of the disease can present only with thromboembolic events in adulthood. Diagnosis of classic homocystinuria should by established by biochemical (elevated plasma homocysteine and methionine and low cistathione) and genetic (homozygous and compound heterozygous mutations of CBS gene) tests. Low methionine diet, vitamin B6, folic acid and betaine anhydrous, a methylating agent, can be used to reduce homocysteine levels, to prevent progression of the homocystinuria and thromboembolic events.

A PEDIATRIC CASE OF TEK-RELATED MALFORMATIONS AND MARFANOID HABITUS: AN INCIDENTAL FINDING OR A FEATURE?

Vascular malformations encompass a wide range of complex vascular lesions. Due to the extreme variability of clinical presentation, classification and their related syndromes presents a challenge. Here we describe a case of a boy presenting with Marfanoid habitus, cutaneous vascular malformations, and severe acute anemia due to ileal venous malformations. Although a panel of genetic markers for the Marfan phenotype was negative, we identified a de novo mutation in the TEK gene in the patient. This case supports expansion of the phenotypic spectrum of TEK-related vascular malformations.

Young woman with Multiple Endocrine Neoplasia 2B (MEN 2B) Diagnosed by PET-CT-A Case Report

Multiple endocrine neoplasia, type 2B (MEN2B) is an autosomal dominant syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, multiple mucosal neuromas & intestinal ganglioneuromas. A young woman of 20 years presented with irregularity of both lips since childhood and a midline neck swelling which gradually increased in size within last 1 year. She had hypertension and history of three episodes of paroxysmal spells characterized by headache, palpitations and excessive sweating during past 5 months. On physical examination, patient was having tachycardia, high blood pressure level (140/100 mmHg), sweaty with no tremor or exophthalmos. She had bumpy lips, multiple mucosal neuromas in lip & buccal mucosae, a hard nodular goiter and no marfanoid habitus. Core biopsy from right thyroid lobe revealed medullary thyroid carcinoma. Calcitonin level were markedly elevated. 18F-FDG PET-CT scan showed heterogeneous mixed density soft tissue mass involving both lobes and isthmus of thyroid gland with intense FDG uptake and FDG avid enlarged right cervical lymph nodes. A well circumscribed complex mass was found in the left upper abdomen adjacent to pancreas. Left adrenal gland showed a heterogeneous mass with mild FDG uptake and according to PET-CT findings, patient was diagnosed as a case of MEN 2B. Bangladesh J. Nuclear Med. 24(1&2): 60-63, 2021

P178 TYPE–A AORTIC DISSECTION IN MARFANOID HABITUS

Abstract Aortic dissection (AD) is the tearing of the tunica intima of the aortic wall with creation of a false lumen. Type–A AD, in which the intimal flaps originates in the aortic tract proximal to the left subclavian artery, is a surgical emergency because – if left untreated – it has mortality rates as high as 1–2% every hour, from the onset of symptoms. Certain collagenopathies, such as Marfan Syndrome, are a predisposing condition for AD. We describe the case of a 25–year–old man with Marfanoid habitus who came to the Emergency Room of our facility, with acute pulmonary oedema. He had been complaining about thoraco–abdominal pain, bloody mucus and worsening dyspnoea since the week before. Upon cardiology consultation, a transthoracic echocardiogram showed an aneurysm of the aortic root (70 mm) and the ascending aorta (90 mm), with dissection flap extended beneath the aortic valvular plane, with torrential aortic valve insufficiency and eccentric jet, a left ventricle severely dilated and a severe systolic dysfunction (EF 25%). On urgent CT angiography the dissection flap was observed to extend cranially to the right common carotid artery and caudally to the renal arteries. The patient then underwent cardiac surgery to replace the aortic valve with a mechanical prosthesis and the ascending aorta as per the Bentall procedure and to replace the aortic arch with reimplantation and debranching of the supra–aortic trunks. Four months after discharge, the patient presented again due to sustained ventricular tachycardia (SVT) which was interrupted by electric cardioversion. On this occasion, an ICD implant was indicated as a secondary prevention measure. After one month, recurrence of SVT was observed, which was successfully treated by the implanted ICD, and therefore indication was given for an electrophysiologic study and subsequent transcatheter radiofrequency ablation of the ventricular arrhythmia. The case presented is of particular interest as it highlights the crucial role of a rapid echocardiographic assessment focussed on making a diagnosis and directing treatment, despite a misleading clinical picture due to duration and atypicality of symptoms. It should also be stressed that an overall assessment of the patient, based on habitus and age, plays a major role in establishing a suspected diagnosis and guiding the patient towards the most appropriate treatment.

EP267: De novo COL11A1 and COL9A2 variants corresponding to Stickler syndrome phenotype

Stickler Syndrome is a rare clinically and genetically heterozygous connective tissue disorder with variable clinical presentation including serious vision (eg, myopia, cataract, and retinal detachment), hearing loss (eg, sensorineural, mixed and/or conductive), craniofacial abnormalities (midface underdevelopment and cleft palate) and joint problems (eg, precocious arthritis, spondyloepiphyseal dysplasia). Stickler syndrome is associated with pathogenic variants in the COL2A1, COL11A1, COL11A2, COL9A1, COL9A2 and COL9A3 genes are present. This syndrome is mainly inherited as an autosomal dominant pathology. We are presenting the case of a 15-year-old female who was referred to genetics by cardiology due to hypoglycemia, tachycardia and to rule out Marfan syndrome due to Marfanoid habitus. Upon physical examination there was evidence of joint hyperlaxity and decreased muscle tone. She also presented mild thoracolumbar dextroscoliosis of 25 degrees in curvature documented by spine X-rays. A connective tissue disorder gene panel was requested. The results indicate that the patient is heterozygous for variants in three genes: COL11A1, COL9A2 and NEPRO. The COL11A1 gene is responsible for providing the blueprint to synthesize a component of type XI collagen, which is commonly located in cartilage. Type XI collagen can also be found in the inner ear, the vitreous and in the nucleus pulposus. A sequence variant c.4718C>T in the COL11A1 gene was identified in this patient. This change is expected to cause an amino acid substitution p.Ser1573Leu, which has not been reported in the literature. Pathogenic variants in COL11A1 have been associated with autosomal dominant Stickler syndrome type II, autosomal dominant Marshall syndrome, autosomal dominant deafness 37 as well as autosomal recessive fibrochondrogenesis 1. COL9A2 gene provides the blueprint for synthesizing a part of a large molecule called type IX collagen, which is more flexible than other types of collagen. A sequence variant designated as c.1553G>T was documented in this gene and is expected to result in an amino acid substitution designated as p.Arg518Leu. Pathogenic variants in COL9A2 have been linked with autosomal recessive Stickler syndrome type V and autosomal multiple epiphyseal dysplasia 2. This variant has not been reported in the literature. The NERPRO (Nucleolus and neural progenitor protein) gene could be involved in cortex development as part of the Notch signaling pathway and it may also be involved in preimplantation embryo development. A NEPRO gene sequence variant designated as c.871G>A was documented as well. This sequence variant is expected to result in an amino acid substitution p.Val291Met. This variant has not been reported in the literature. Fifteen years old female with genetic variants on COL11A1, COL9A2 and NEPRO genes. The patient presents scoliosis, myopia, and amblyopia, micrognathia, hyperlaxed joints and hypotonia. The COL11A1 and the COL9A2 genes has been associated with autosomal dominant and autosomal recessive Stickler syndrome phenotypes respectively. Stickler syndrome is a connective tissue disorder that can include ocular findings of myopia, cataract, and retinal detachment; hearing loss that is both conductive and sensorineural; midfacial underdevelopment and cleft palate (either alone or as part of the Robin sequence). The COL11A1 variant has not been reported in the medical literature associate to the disease however predictive algorithms suggest the possibility of a deleterious effect on the protein. The patient also has a genetic variant on the COL9A2 gene that has not been associate to the disease but haploinsufficiency mechanisms may also be playing a role in this patient phenotype.