CPC #5: A Case of Hidden Infirmities

1. CPC #5: A Case of Hidden Infirmities Bridging the Gap. Where Clinical and Basic Sciences Meet Louisa Balazs, MD, PhD Associate Professor of Pathology Brian Dockery, MD Fellow, Cardiovascular Diseases Karl T. Weber, MD Professor of Medicine

2. Saturday, July 3, 1954, and Nicole Struthers, resident in medicine, was aboard a train to Glasgow for her elective in pediatrics. Scotland’s countryside was awash with wild flowers. As she passed away time reading the Times she learned: recent municipal elections had led to a leftward swing in favor of Labour.

3. At the first race of the season, May 6, Oxford U. medical student Roger Bannister had run the mile in <4 min.

4. Nicole arrived at the Infirmary Sunday morning in what 10 years ago was announced as Derationing Day.

5. During free time she read children fairytales aboutplayful, yet mischievous elves (known in Scandinavia as huldre folk of elfame) who, while often alluring, had a hidden physical defect, such as a cow’s tail.

6. In clinic the next day, Nicole met Professor R. and several of his patients. W., age 7, caught Nicole by surprise. His facies resembled elves featured in yesterday’s stories; broad forehead, eyes set well apart, large ears, jowls with wide mouth and maloccluded teeth. Retarded growth and mental development.

7. Mother’s pregnancy and delivery had been uncomplicated and no consanguinity. In keeping with prevailing attitudes amongst Glaswegians during and since the war, mother had not breast fed W. Instead, she provided him the Ministry of Food’s vitamin D fortified National Dried Milk (NDM); while pregnant she consumed NDM and cod liver oil. Nicole wondered whether W. had a hidden infirmity.

8. R. noted that upon referral at age 5 months, a precordial systolic murmur of uncertain etiology had been detected; second heart sound physiologically split, each component of normal intensity, and no clicks. Hypercalcemia was corrected by cow’s milk. Nicole wondered whether vitamin D supplements during or after pregnancy were contributory to physical findings. Many children received NDM. Why would only a few, like W., have this problem?

9. R. had seen several youngsters with elfin facies in recent yearsand whose appearance was different from their siblings. B., a 6-year-old boy, was such an example. Mother’s pregnancy was unremarkable and she did not consume NDM.

10. B. received NDM and cod liver oil as an infant and at 4 months began to vomit after each feed, lost his appetite and became constipated. Failing to gain weight and mentally retarded he was referred to R.

11. Poor skin and muscle tone; normal blood pressure; systolic murmur in the aortic area. Hypercalcemia, hypercholesterolemia and renal failure; normal serum phosphorus and calcium excretion with reduced alkaline phosphatase.

12. Increased density of long bones on x-ray; normal parathyroid function. R. diagnosed infantile hypercalcemia. Was this another example of a hypersensitivity to vitamin D? Cow’s milk led to correction of hypercalcemia.

13. W. Age 7 • Provided NDM as an infant, mother consumed NDM and cod liver oil • Retarded growth and mental development • Facies resembled elves in fairytales • Broad forehead, eyes set well apart, large ears, wide mouth, maloccluded teeth • Precordial systolic murmur • Hypercalcemia

14. B. Age 6 • Uneventful pregnancy • Mother did not consume NDM • Received NDM and cod liver oil as an infant • Age 4: feeding difficulties, poor appetite, constipation • Failure to thrive, mentally retarded • Poor skin and muscle tone • Normal blood pressure, systolic murmur • Hypercalcemia, hypercholesterolemia, renal failure, normal phosphorus, normal calcium excretion, normal parathyroid function

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16. Distinguishing Features and Differential Diagnoses • Consumption of NDM / cod liver oil • Problems with calcium & vitamin D metabolism • Failure to thrive • Developmental delay / cognitive impairment • Short stature / growth retardation • Poor skin and muscle tone • Distinctive elfin facies • Feeding difficulties / constipation • Symptoms of hypercalcemia / hypervitaminosis D • Precordial systolic murmur • Congenital heart disorder • Endocrinopathies: hypercalcemia, hypercholesterolemia, renal failure hypercholesterolemia, normal parathyroid function

17. DiGeorge Syndrome • Palatal abnormalities • Immune deficiencies • Hypocalcemia • Feeding problems • Renal anomalies • Growth hormone deficiency • Seizure disorder • Skeletal abnormalities • Tetralogy of Fallot, interrupted aortic arch, ASD, VSD, truncus arteriosus in 75%

18. Down’s Syndrome • Short stature • Characteristic facies • Mental retardation • Thyroid disorders • AV septal defects, VSD, MVP, AI

19. Noonan Syndrome • Webbed neck • Pectus carinatum • Cryptorchidism • Coagulation defects • Lymphatic dysplasias • Mild mental retardation in 15% • Pulmonary valve stenosis, pulmonary artery stenosis, ASD

20. Smith-Magenis Syndrome • Cognitive impairment • Sleep disturbances • Self-injurious behaviors • Infantile feeding difficulties • Failure to thrive • Hypotonia, generalized lethargy

21. William’s Syndrome • Described by William’s and Beuren in 1961 in infants with supravalvular aortic stenosis, mental retardation, and characteristic physical findings • Incidence is 1 per 20,000 births; vast majority are sporadic, autosomal dominant inheritance has been described • A submicroscopic deletion on chromosome band 7q11.23 that includes the elastin gene. • Hypercalcemia may be transient, occurs in about 15% • Etiology of hypercalcemia is uncertain but may involve an enhanced sensitivity to vitamin D • Vitamin D loading of rabbits results in calcification of aortic leaflets in offspring – suggesting a hypersensitivity phenomenon Williams, J.C. Circulation 24: 1311, 1961

22. William’s Syndrome Cardiovascular Findings: • 50-75% have progressive supravalvular aortic stenosis without post-stenotic dilation • Peripheral pulmonary artery stenosis tends to show no progression of right ventricular pressure with time • ECG: LVH or biventricular hypertrophy • Echo: dilated sinuses of Valsalva, normal size ascending aorta and arch normal in size • Catheterization: LVOT gradient of 100, 84, 68, and 38 in William’s original patients; large coronary arteries

23. Supravalvular Aortic Stenosis Parasternal long axis echoof the proximal ascending aorta shows the discrete narrowing (arrowhead at measured diameter #2) just above the sinotubular junction.

24. Supravalvular Aortic Stenosis

25. LV – Ao Pullback

26. Macroscopic pathological findings • Somatic developmental retardation • Poor tone of skin and skeletal muscle • Umbilical and bilateral inguinal hernia • Abnormal face: broad forehead, depressed nose

27. Facial abnormalities

28. Gross internal findings • Cardiomegaly with bilateral ventricular hypertrophy • “Washed leather”, hypoplastic aorta • Supravalvular aortic stenosis • Prominent intraparenchymal pulmonary arteries • Nephrosclerosis

29. Heart developmental malformation

30. Microscopic examination • Concentric fibroelastosis of aorta • Fibrous subintimal plaques • Mosaic appearance of intima • Disarray of elastic lamellae

31. Arterial fibroelastic dysplasia

32. Arterial fibroelastic dysplasia

33. Arterial fibroelastic dysplasia

34. Chromosomal abnormality

35. Chromosomal finding and final diagnosis • Hemizygosity of William’s syndrome locus of Chromosome 7, deletion of William’s syndrome gene • William’s syndrome

36. Theoretical background • Elastin synthesis is most active during the last trimester and early postnatal months • Elastin synthesis is repressed by D3, dependent on calcium and modulated by steroid hormones • Exact function of William’s syndrome locus not known

37. Functions of Vitamin D • Maintenance of normal plasma levels of calcium and phosphorus • Stimulates intestinal absorption of calcium and phosphorus • Collaborates with PTH in the mobilization of calcium from bone • Stimulates the PTH-dependent reabsorption of calcium in the distal renal tubules

38. William’s syndrome • Variable infantile hypercalcemia • Growth retardation • Poor skin tone and congenital hernias • Facial developmental malformations • Mental retardation • Supravalvular aortic stenosis and arterial fibroelastosis • Chromosome 7 abnormality [microdeletion or allelic loss]

39. Possible causative factors effecting patients with mental retardation, elfin face and supravalvular aortic stenosis • Maternal vitamin D intoxicosis (fetal hypercalcemia) • Deficient calcitonin secretion • Calcitonin gene-related products • Microdeletion of chromosome 7 Q11.23 (disruption of elastin gene) • Allelic loss of elastin gene

40. Possible causative factors leading to William’s syndrome • Combination of in utero vitamin D intoxication and disruption of elastin gene (ELN) by microdeletion or allelic loss

41. Infantile rickets had long been a serious health problem of the inner cities of Britain. Cod liver oil was used as a source of vitamin D as early as the 18th century; later, calciferol and irradiated milk were provided.

42. Heliopathy (sunlight) and natural sources of vitamin D were recommended for tenement residents in poor housing areas, such as Bridgeton in Glasgow, and upon which the design for new housing was based.

43. With heavy aerial bombardment of the British Isle in 1940 threatening to impede the distribution of milk to children, the government sought to prevent an outbreak of rickets by manufacturing powdered milk, cereals and cod liver oil fortified with calciferol.

44. In 1953 manufacturers were instructed to further raise vitamin D content of these products to minimize deterioration during storage. From all sources daily consumption could reach >4000 IU.

45. By 1953, infantile hypercalcemia was evident and often indistinguishable from children having supravalvular aortic stenosis, mental retardation and craniofacial malformation that would represent a syndrome described by Williams et al. several years later. In 1957, the ministry reduced vitamin D content of food products and these two entities largely disappeared.

46. The cause of this vascular malformation and craniofacial abnormalities remains unclear, but could be reproduced in offspring of pregnant rabbits given large doses of vitamin D. A link between vitamin D and in utero elastogenesis remains to be identified. Adult rabbits fed large doses of vitamin D acquire a destruction of aortic elastin and collagen and supravalvular aortic lesion that resembles that seen in affected children.