a case of mass phenotype

Dr Prasanth Sankar

Prof. E. Dhandapani’s UnitStanley Medical College

• Faiyaz• 22y male D.O.A:7-3-10 ;9.30 pm• Chennai•Admitted to toxiclogy ward with h/o• Alcohol intoxication• Hypoglycemia – CBG - 41mg %

•No clinically relevant past history•Smoker, Alcoholic - 2yrs•Shopkeeper/labourer

• Treated with Inj. Thiamine, Dextrose, IVF• Shifted to male medical ward at 8pm on 8-3-

10

O/EPatient conscious, oriented, cooperativeNo pallor, icterus, cyanosis, clubbing, No pedal edema, lymph nodesTobacco staining of tooth, caries tooth +Temp -98.6 fRR – 16/minPulse – 78/min regular, nl volume and characterBP – 120/80 mm hg

Anthropometry

•Height – 180 cm•Weight – 60 kg•BMI – 18.50•Head Circumference – 53 cm•Arm span – 192 cm•Arm span/Height ratio – 1.066•Upper Segment – 80 cm•Lower Segment – 100 cm•US/LS ratio – 0.80

• CBC, RFT, RUE, LFT – WNL• Ecg – NSR, WNL• X –Ray Chest• X–Ray Pelvis-wnl• USG abdomen - WNL

• Echo•Bicuspid aortic valve•No AS/AR•Aortic annulus – 26mm•Aortic Sinus – 45 mm•Ascending Aorta – 36mm•Distal Aorta normal•No evidence of CoA•MVP-AML; no MR•Normal LV fn-EF – 67 %

•Adv- •T. Atenolol 50 mg OD•Follow – up yearly

• Ophthalmology evaluation•Lids, cornea, conjunctiva – normal•Ant chamber – normal depth• Iris, Pupil – normal•Lens normally placed; clear•F/s –disc, macula, vessels - normal •Visual acuity – 6/60 b/l

• DIAGNOSISALCOHOL INTOXICATION/ HYPOGLYCEMIA/MARFAN SYNDROME

or is it something else ??

• AD- mutations in fbn1 gene on chromosome 15• Abnormalities in TGF β-signaling – new culprit• New group of Marfan – related connective-

tissue disorders - TGF β signalopathies• The diagnosis cannot be based on molecular

analysis alone because •molecular diagnosis is not generally available, •mutation detection is imperfect, and •not all FBN1 mutations are associated with MFS

Index case:• If the family/genetic history is not contributory, major criteria in ≥2 different organ systems and involvement of a third organ system.• If a mutation known to cause Marfan syndrome in others is detected, 1 major criterion in an organ system and involvement of a second organ system.

•Relative of an index case:•Presence of a major criterion in the family history, 1 major criterion in an organ system, and involvement of a second organ system.

•Major criteria:At least 4 of the following - a major criterion in the skeletal system.•Pectus carinatum•Pectus excavatum requiring surgery•Reduced US-LS ratio or arm span–to–height ratio >1.05•Wrist and thumb signs•Scoliosis of >20◦ or spondylolisthesis (displacement of vertebra, usually in lumbar spine)•Reduced extension at the elbows (<170◦)•Medial displacement of the medial malleolus causing pes planus•Protrusio acetabulae (protrusion of femoral head into the pelvis) of any degree (ascertained on radiographs)

• Minor criteria:• Pectus excavatum of moderate severity• Joint hypermobility• Highly arched palate with crowding of teeth• Facial appearance • dolichocephaly, • malar hypoplasia, • enophthalmos (deeply set eyes), • retrognathia (receding chin),• down-slanting palpebral fissures

• For involvement of the skeletal system, at least • 2 features contributing to major criteria,• 1 major criterion and 2 minor criteria must be present.

• Major criterion:•Ectopia lentis

• Minor criteria:•Abnormally flat cornea• Increased axial length of globe (myopia)•Hypoplastic iris or hypoplastic ciliary muscle causing decreased miosis

• For involvement of the ocular system, at least 2 of the minor criteria must be present.

• Major criteria:• Dilation of ascending aorta, with or without AR, and involving at least the sinuses of Valsalva• Dissection of the ascending aorta

• Minor criteria:•MVP with or without MR• Dilatation of the main PA, in the absence of valvular or peripheral PS or any other obvious cause, <age 40• Calcification of the mitral annulus <age 40• Dilatation or dissection of the descending thoracic or abdominal aorta <age 50

• For involvement of the cardiovascular system, only 1 of the minor criteria must be present.

Pulmonary system

• Major criteria: none• Minor criteria:• Spontaneous pneumothorax• Apical blebs

• For involvement of pulmonary system, only 1 of the minor criteria must be present

Skin and integument

• Major criteria: none• Minor criteria:• Striae atrophicae (stretch marks) without marked weight gain, pregnancy, or repetitive stress• Recurrent or incisional herniae

• For involvement of skin and integument, only 1 of the minor criteria must be present

Dura

• Major criterion:• Lumbosacral dural ectasia (widening of the dural sac)

• Minor criteria: none

Family/genetic history

• Major criteria:• Having a parent, child, or sibling who meets these diagnostic criteria independently• Presence of a mutation in FBN1 that is known to cause MFS• Presence of a haplotype around FBN1, inherited by descent, associated with unequivocally diagnosed MFS in the family

• Minor criteria: none

• 1 major system criteria – CVS• 2 system involvement – skeletal & skin

• If not Marfan, then what??

•Loeys-Dietz syndrome type I •Aortic aneurysm, Craniofacial anomalies•Absence of long bone overgrowth or lens dislocation

•Loeys-Dietz syndrome type II •Reminiscent of vascular EDS.•Uterine rupture, peripartal bleedings, skin bleeds•Arterial aneurysm/dissections throughout arterial circulation.

•TGFβR1/2 mutations - mean age at death of 26.1 y. •Aortic dissections at smaller aortic dimensions (<40 mm)•High incidence of pregnancy-related complications.

•Beals Syndrome (CCA) – FBN2•Crumpled ears, Arachnodactyly, contractures, scoliosis

•Bicuspid Aortic Valve•Most common cardiac malformation •Aortic root dilation that often occurs above sinuses.

•Familial thoracic aortic aneurysm/dissection•Progressive; no or minor systemic involvement•FBN1/ TGFβR2 mutations identified

•Homocystinuria •Ectopia lentis, long bone overgrowth, mental retardation.•Thromboembolism and CAD without root dilatation.•Elevated homocystine in urine or plasma.

•Mitral valve prolapse, Aortic dilation, Skin, and Skeletal (MASS) phenotype •Many evaluated for Marfan syndrome who do not meet diagnostic criteria, have a varying constellation of •MITRAL VALVE PROLAPSE; MYOPIA; •AORTIC ROOT DILATION-MILD, NONPROGRESSIVE•SKELETAL AND •SKIN FEATURES.

•This phenotype may segregate as a dominant trait and remain stable over time.• In some instances, FBN1 mutations have been identified. 

• Familial Marfanlike (marfanoid) habitus• Familial Ectopia Lentis • Weill-Marchesani syndrome• Stickler syndrome • Shprintzen-Goldberg syndrome • Ehlers-Danlos Syndrome• Familial aortic dissection • Familial arachnodactyly• Familial mitral valve prolapse syndrome• XYY syndrome• …

•MASS phenotypeMASS phenotype

• Treatment of Mitral Valve Prolapse (MVP)• No major symptoms –Echocardiographic monitoring.• IE prophylaxis, Beta-blockers.• Severe symptoms- MVP/MR – surgery.

• Treatment of the Aortic Aneurysm• Ascending aorta - upper limits of normal.• Progression of aneurysm or dissection unusual• Yearly echocardiograpic monitoring

• Treatment of Skeletal Conditions• Scoliosis – surgery if curve is 40-50 degrees or greater• Annual spinal exams if there is a significant curvature or pain• Chest Wall Deformities – severe pectus excavatum – surgery

• Treatment of the Skin• Stretch marks require no medical treatment

Whatz new..•AT1 receptor Signaling contributes to pathogenesis•ARBs – • expression of TGFβ ligands and their receptors•Limit production of activators of TGFβ

•In murine models of Marfan syndrome ARBs •Prevent pathologic aortic root growth.•Normalize aortic wall architecture and thickness.• Improve non- cardiovascular manifestations such as pulmonary and skeletal muscle pathology

• Cardiac evaluation in all Marfanoid patients• Diagnosis of MFS is made only by Ghent

criteria• Progession of dilatation is rare in MASS

phenotype• Increased activation of and signaling by TGFβ.• Lifelong Beta-blockers • ARBs– future perspective.• Moderation in activity, lifestyle, Pregnancy• Elective repair if aortic root ≥ 5 cm in adults.• IE prophylaxis